BENZOHETEROCYCLIC COMPOUNDS

Technical Field

This invention relates to novel benzoheterocyclic compounds which have excellent vasopressin antagonistic activities and are useful as vasodilator, hypotensive agent, water diuretics, ρlate3 t aggregation inhibitor.

Disclosure of the Invention

The benzoheterocyclic compounds of this invention have the following formula:

wherein R ¹ is hydrogen atom, a halogen atom, a lower alkyl, an amino having optionally a lower alkyl substituent, or a lower alkoxy,

R"' is hydrogen atom, a halogen atom, a lower alkoxy, a phenyl(lower)alkoxy, hydroxy, a lower alkyl, an amino having optionally a lower alkyl substituent, a carbamoyl-substituted lower alkoxy, an amino-substituted lower alkoxy having optional¬ ly a lower alkyl substituent, or a benzoyloxy which has optionally a halogen substituent on the phenyl ring,

R ^J is or a group of

the formula: -

R is hydrogen atom, a benzoyl which has optionally a halogen substituent on the phenyl ring, or a lower alkyl,

[wherein R ¹ is a halogen atom; a lower alkyl which has optionally a substituent selected from a halogen atom and hydroxy; hydroxy; a lower alkoxy; a lower alkanoyloxy; a lower alkylthio; a lower alkanoyl; carboxy; a lower alkoxycarbonyl; cyano; nitro; an amino which has optionally a substituent selected from a lower alkyl and a lower alkanoyl; phenyl; a cycloalkyl; a lower alkanoyloxy- substituted lower alkoxy; a carboxy-substituted lower alkoxy; a halogen-substituted lower alkoxy; a carbamoyl- substituted lower alkoxy; a hydroxy-substituted lower alkoxy; a lower alkoxycarbonyl-substituted lower alkoxy; a phthalimido-substituted lower alkoxy; an aminocarbonyl-lower alkoxy having a lower alkyl substituent; or a group of the

R ⁶ formula: -O-A- ⁷ (A is a lower alkylene, and Rfi and R7 ⁷ are

the same or different and are each hydrogen atom, a lower alkyl having optionally a hydroxy substituent, a lower ~J alkanoyl, or benzoyl, or R and R' may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom wherein the hetero¬ cyclic group has optionally a substituent selected from piperidinyl and a lower alkyl); and m is an integer of 0 to 3] ^~ a phenyl-lower alkoxycarbonyl, a lower alkanoyl, a phenyl-

lower alkanoyl, a cycloalkyl-lower alkanoyl, a cycloalkyl- carbonyl, tricyclo[3.3.1.1]decanylcarbonyl, naphthyl- carbonyl, pyridylcarbonyl, furoyl, thenoyl, a phenoxy-lower alkanoyl which phenyl ring has optionally 1 to 3 substi ^¬ tuents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent, a phthalimido-substituted lower alkanoyl, a lower alkoxy- carbonyl-lower alkanoyl, a carboxy-lower alkanoyl, a naphthyloxy-lower alkanoyl, a halogen-substituted lower* alkanoyl, a group of the formula: -CO-( N-R ⁸ (wherein R° is hydrogen atom, a lower alkyl, a phenyl-lower alkoxycarbonyl, a carbamoyl-lower alkyl, an amino-lower alkanoyl having optionally a lower alkyl substituent, or a lower alkanoyl), an anilinocarbonyl which has optionally a lower alkyl substituent on the phenyl ring, phenoxycarbonyl, a phenylsulfonyl which has optionally a substituent selected from a halogen atom and a lower alkyl on the phenyl ring, quinolylsulfonyl, or a group of the formula:

-CO-B-(CO) -N _N (wherein B is a lower alkylene, n is an _R 10 integer of 0 or 1, and R and R are the same or different and are each hydrogen atom, a lower alkyl having optionally a hydroxy substituent, a cycloalkyl, a phenyl-lower alkyl, a lower alkanoyl, a lower alkenyl, a phenoxy-lower alkyl, a phenyl which has optionally 1 to 3 substituents selected from an amino-lower alkyl having optionally a lower alkanoyl substituent, a lower alkyl, a lower alkoxy and a halogen atom, a phthalimido-substituted lower alkyl, an amino-lower

alkyl having optionally a lower alkanoyl substituent, a lower alkynyl, cr an amino-lower alkyl having optionally a lower alkyl subsύituent, or R ⁹ and R may bind together with nitrogen atom to which they bond to form a 5- or 6- membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom wherein the hetero- cylic group has optionally a substituent selected from a lower alkyl, a lower alkoxycarboyl and piperidinyl), R ¹¹ is hydrogen atom or a lower alkyl, R ^XΛ is a cycloalkyl, or a phenyl which has optionally 1 to 3 substituents selected from a lower alkoxy, a lower alkyl and a halogen atom,

W is a group of the formula: -(CH ₂ ) _D - (p is an integ of 3 to 5), or a group of the formula: -CH=CH-(CH ₂ )„- (q is an integer of 1 to 3), the carbon atom of these groups: -(CH ₂ ) _p - and -CH=CH-(CH ₂ ) _q - being optionally replaced by oxygen atom, sulfur atom, sulfinyl, sulfonyl, or a group of

R ¹³ the formula: -N ¹ - (R13 ^J is hydrogen atom, a cycloalkyl, or a lower alkyl), and further said -(CH ₂ ) _p - and -CH=CH-(CH ₂ ) - groups having optionally 1 to 3 substituents selected from a lower alkyl having optionally a hydroxy substituent, a lower alkoxycarbonyl, carboxy, hydroxy, oxo, a lower alkanoyloxy having optionally a halogen substituent, an amino-lower alkyl naving optionally a substituent selected from a lower alkyl and a lower alkanoyl, a lower alkanoyloxy-substituted lower alkyl, a lower alkyl sulfonyloxy-lower alkyl, an

azido-lower alkyl, a group of the formula: 0, an aminocarbonyloxy having optionally a lower alkyl substituent, a lower alkoxy, a lower alkoxycarbonyl- substituted lower alkoxy, a carboxy-substituted lower alkoxy, an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent, an amino-lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a phthalimido-substituted lower alkoxy, hydroxyimino, a lower alkanoyloxy-imino, a lower alkylidene, a halogen atom, azido, sulfoxyimino, a group of the formula: R ⁸¹ -N-CH C00- (R ⁸¹ is hydrogen atom or a lower alkyl),

I hydrazino, pyrrolyl, an amino-lower alkanoyloxy having optionally a lower alkyl substituent, a group of the

formula: (A is as defined above, and R° and R _-_"_ are the same or different and are each hydrogen atom, a lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy- substituted lower alkyl, or a pyridyl-lower alkyl, or R ⁸² and R ⁸ may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen, oxygen or sulfur atom wherein the heterocyclic group has optionally a substituent selected from oxo, a lower alkyl, a lower alkanoyl, and carbamoyl), and a group of the formula:

-(CO) (wherein n is as defined above, and R ¹ and R ¹⁵

are the same or different and are each hydrogen atom, a lower alkyl, a lower alkenyl, a lower alkanoyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having optionally 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, benzoyl, a lower alkoxy¬ carbonyl, anilinocarbonyl, an aminocarbonyl having optionally a lower alkyl substituent, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent on the piperidinyl ring, a halogen-substituted lower alkanoyl, an imidazolyl-substituted lower alkanoyl, an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, an aminocarbonyl- lower alkyl having optionally a lower alkyl substituent, or a phenyl-lower alkoxycarbonyl, or R and R may bind together with nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen, wherein the heterocyclic group may o_ -ionally have a substi'uent selected from a lower alkyl, a phenyl-lower alkyl or a lower alkanoyl) .

The benzoheterocyclic compounds of the formula (1) an

their salts have excellent vasopressin antagonistic activities and vasodilating activity, hypotensive activity, activity for inhibiting saccharide release in liver, activity for inhibitin growth of mesangium cells, water diuretic activity, platelet agglutination inhibitory activity and are useful as vasodilator, hypotensive agent, water diuretics, platelet agglutination inhibitor and are used for the prophylaxis and treatment of hypertension, edema, ascites, heart failure, rena function disorder, vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, hypokaliemia, diabetic, circulation disorder, and the like.

Each group in the above formula (1) includes specifically the following groups.

The "lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert- butoxy, pentyloxy, hexyloxy, and the like.

The "lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and the like.

The "halogen atom" includes fluorine atom, chlorine atom, bromine atom and iodine atome.

The "amino having optionally a lower alkyl substi¬ tuent" includes an amino having optionally one or two substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, amino,

methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethyl amino, diethylamino, dipropylamino, dibutylamino, dipentyl- amino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propyl- amino, N-methyl-N-butylamino, N-methyl-N-hexylamino, and the like.

The "lower a-_κenyl" includes a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2- pentenyl, 2-hexenyl, and the like.

The "lower alkyl which has optionally a substituent selected from a halogen atom and hydroxy" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which may optionally have 1 to 3 substituents selected from a ^' halogen atom and hydroxy, for example, in addition to the above-mentioned lower alkyl groups, hydroxymethyl, 2- hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3- dihyroxypropyl, 4-hydroxybutyl, l,l-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1- hydroxyisopropyl, 2-methyl-3-hydroxypropyl, trifluoromethyl, trichloromethyl, chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, dibromomethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobu÷ l, 5- chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6- dichlorohexyl, and the like.

The "lower alkylene" includes a straight chain or

branched chain alkylene group having 1 to 6 carbon atoms, for example, methylene, ethylene, trimethylene, 2-methyltri- methylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, penta- methylene, hexamethylene, and the like.

The "lower alkanoyloxy" includes a straight chain or branched chain alkanoyloxy group having 1 to 6 carbon atoms, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, hexanoyl- oxy, and the like.

The "lower alkylthio" includes a straight chain or branched chain alkylthio group having 1 to 6 carbon atoms, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio, and the like.

The "lower alkanoyl" includes a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanolyl, and the like.

The "lower alkoxycarbonyl" includes a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy- carbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxy- carbonyl, and the like.

The "amino having optionally a substituent selected from a lower alkyl and a lower alkanoyl" includes an amino having optionally one or two substituents selected from a

straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, methyl- amino, ethylamino, propyla ino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-ethyl-N-propylamino, N- methyl-N-butylamino, N-methyl-N-hexylamino, N-methyl-N-acetyl- amino, N-acetylamino, N-formylamino, N-propionylamino, N- butyrylamino, N-isobutyrylamino, N-pentanoylamino, N-tert- butylcarbonylamino, N-hexanoylamino, N-ethyl-N-acetylamino, an the like.

The "cycloalkyl" includes a cycloalkyl having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclo- pentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The "lower alkanoyloxy-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group havin 1 to 6 carbon atoms which is substituted by a straight chain o branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethoxy, 2-propionyloxyethoxy, 1- butyryloxyethoxy, 3-acetyloxypropoxy, 4-acetyloxybutoxy, 4- isobutyryloxybutoxy, 5-pentanoyloxypentylox , 6-acetyloxy- hexyloxy, 6-tert-butylcarbonyloxyhexyloxy, 1,l-dimethyl-2- hexanoyloxyethoxy, 2-methyl-3-acetyloxypropoxy, and he like.

The "carbamoyl-substituted lower alkoxy" includes a carbamoyl-substituted alkoxy group wherein the alkoxy moiety i a straight chain or branched chain alkoxy group having 1 to 6

carbon atoms, for example, carbamoylmethoxy, 2-carbamoylethoxy 1-carbamoylethoxy, 3-carbamoylpropoxy, 4-carbamoylbutoxy, 5- carbamoylpentyloxy, 6-carbamoylhexyloxy, 1,l-dimethyl-2- carbamoylethoxy, 2-methyl-3-carbamoylpropoxy, and the like.

The "hydroxy-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and having 1 to 3 hydroxy substitutents, for example, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3- hydroxypropoxy, 2,3-dihydroxypropoxy, 4-hydroxybutoxy, 3,4- dihydroxybutoxy, l,l-dimethyl-2-hydroxyethoxy, 5-hydroxy- pentyloxy, 6-hydroxyhexyloxy, 2-metnyl-3-hydroxypropoxy, 2,3,4 trihydroxybutoxy, and the like.

The "lower alkoxycarbonyl-substituted lower alkoxy" includes an alkoxycarbonyl-substituted straight chain or branched chain alkoxy group having 1 to 6 carbon atoms wherein the alkoxycarbonyl moiety is a straight chain or branched chai alkoxycarbonyl group having 1 to 6 carbon atoms, for example, methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxy- carboxymethoxy, 3-ethoxycarbonylpropoxy, 4-ethoxycarbonyl- butoxy, 5-isopropoxycarbonylpentyloxy, 6-propoxycarbonyl- hexyloxy, 1,l-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-tert butoxycarbonylpropoxy, 2-pentyloxycarbonylethoxy, hexyloxy- carbonylmethoxy, and the like.

The "carboxy-substituted lower alkoxy" includes a carboxy-substituted alkoxy group wherein the alkoxy moiety is straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, carboxymethoxy, 2-carboxyethoxy, 1-

carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxy- pentyloxy, 6-carboxyhexyloxy, 1,l-dimethyl-2-carboxyethox , 2- methyl-3-carboxypropoxy, and the like.

The "phthalimido-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by phthalimido group, for example, phthalimidomethoxy, 2-phthalimidoethoxy, 1-phthal- imidoethoxy, 3-phthalimidopropoxy, 4-phthalimidobutoxy, 5- phthalimidopentyloxy, 6-phthalimidohexyloxy, l,l-dimethyl-2- phthalimidoethoxy, 2-methyl-3-phthalimidopropoxy, and the like.

The "5- or 6-membered saturated heterocyclic group wh is formed by binding the groups R ⁶ and R' together with the nitrogen atom to which they bond with or without being interve with nitrogen or oxygen atom" includes, for example, pyrrol- idinyl, piperidinyl, piperazinyl, morpholino, and the like.

The "heterocyclic group having a substituent selected from piperidinyl and a lower alkyl" includes a heterocyclic group having 1 to 3 substituents selected from piperidinyl and a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 4-methylpiperiazinyl, 3,4-dimethyl- piperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5- trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, 4-(1-piperidinyl)piperidinyl, 3-(l- piperidinyl)pyrrolidinyl, 3-(l-piperidinyl)-4-methyl- piperazinyl, 3-(l-piperidinyl)morpholino, and the like.

The "phenyl(lower)alkanoyl" includes a phenylalkanoyl wherein the alkanoyl moiety is a straight chain or branched

chain alkanoyl group having 2 to 6 carbon atoms, for example, phenylacetyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenyl- butyryl, 2, 2-dimethyl-3-phenylpropionyl, 5-phenylpentanoyl, 6- phenylhexanoyl, and the like.

The "cycloalkyl-lower alkanoyl" includes 3~Cg cycloalkyl-alkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, cyclohexylacetyl, 3-cyclopropylpropionyl, 2-cyclopentylpropionyl, 4-cyclohexylbutyryl, 2, 2-dimethyl-3- cycloheptylpropionyl, 5-cyclooctylpentan ^' oyl, 6-cyclohexyl- hexanoyl, and the like.

The "cycloalkylcarbonyl" includes a cycloalkylcarbony having 3 to 8 carbon atoms, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like.

The "amino having optionally a lower alkanoyl substituent" includes an amino having optionally a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, amino, formylamino, acetylamino, propionyla ino, butyrylamino, isobutyrylamino, pentanoylamino, tert-butylcarbonylamino, hexanoylamino, and the like.

The "phenoxy-lower alkanoyl which phenyl ring has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent" includes a phenoxyalkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms and the phenyl ring has optionally

to 3 substituents selected from a straight chain or branched chain alkyl having 1 to 6 carbon atoms, a straight chain or branched chain alkoxy having 1 to 6 carbon atoms and an amino having optionally a straight chain or branched chain alkanoyl having 1 to 6 carbon atoms, for example, phenoxyacetyl, 3- phenoxypropionyl, 2-phenoxypropionyl, 4-phenoxybutyryl, 2,2- dimethyl-3-phenoxypropionyl, 5-phenoxypentanoyl, 6-phenoxy- hexanoyl, (2-aminophenoxy)acetyl, 3-(4-aminophenoxy)propionyl , (2-methylphenoxy)acetyl, (4-methylphenoxy)acetyl, (3-methyl- phenoxy)acetyl, (3-methoxyphenoxy)acetyl, (3-acetylamino- phenoxy)acetyl, 4-(2-propionylaminophenoxy)butyryl, 2,2- dimethyl-3-(4-butyrylaminophenoxy)propionyl, 5-(2-pentanoyl- aminophenoxy)pentanoyl, 6-(4-hexanoylaminophenoxy)hexanoyl, 3- (2-ethylphenoxy)propionyl, 2-(4-propylphenoxy)propionyl, 4-(4-r butylphenoxy)butyryl, 5-(3-pentylphenoxy)pentanoyl, 6-(4-hexyl phenoxy)hexanoyl, (2,3-dimethylphenoxy)acetyl, (2,5-c. lethyl- phenoxy)acetyl, (3,4-d:τιethylphenoxy)acetyl, (3,4,5-trimethyl- phenoxy)acetyl, 3-(4—. ;noxyphenoxy)propionyl, 2-(2-propoxy- phenoxy)propionyl, 4-(3-butoxyphenoxy)butyryl, 5-(4-pentyloxy- phenoxy)pentanoyl, 6-(4-hexyloxyphenoxy)hexanoyl, (3,4- dimethoxyphenoxy)acetyl, (3,5-dimethoxyphenox )acetyl, (2,4- dimethoxyphenoxy)acetyl, (3,4,5-trimethoxyphenoxy)acetyl, (2- acetylamino-4-methylphenoxy)acetyl, (4-acetylamino-3-methoxy- phe ^τ )acetyl, and the like.

The "phthalimido-substituted lower alkanoyl" includes a straight chain or branched chain alkanoyl group havir - 2 to carbon atoms which is substituted by phthalimido group, for

example, 2-phthalimidoacetyl, 3-phthalimidopropionyl, 2-phthal i idopropionyl, 4-phthalimidobutyryl, 2,2-dimethyl-3-phthal- imidopropionyl, 5-phthalimidopentanoyl, 6-phthalimidohexanoyl, 3-methyl-4-phthalimidobutyryl, and the like.

The "lower alkoxycarbonyl-lower alkanoyl" includes an alkoxycarbonyl-alkanoyl group wherein the alkoxy moiety is a straight chain or branched chain alkoxy having 1 to 6 carbon atoms and the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, methoxycarbonylacetyl, 3-methoxycarbonylpropionyl, ethoxy- carbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonyl- butyryl, 3-propoxycarbonylpropionyl, 2-methoxycarbonyl- propionyl, 6-propoxycarbonylhexanoyl, 5-isopropoxycarbonyl- pentanoyl, 2,2-dimethyl-3-butoxycarbonylpropionyl, 2-methyl-3- tert-butoxycarbonylpropionyl, pentyloxycarbonylacetyl, hexyl- oxycarbonylacetyl, and the like.

The "carboxy-lower alkanoyl" includes a carboxy- alkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, carboxyacetyl, 3-carboxypropionyl, 2-carboxypropionyl, 4-carboxybutyryl, 2,2-dimethyl-3-carboxypropionyl, 5-carboxy- pentanoyl, 6-carboxyhexanoyl, and the like.

The "naphthyloxy-lower alkanoyl" includes a naphthyl- oxy-alkanoyl group wherein the alkanoyl moiety is a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms, for example, naphtyloxyacetyl, 3-naphtyloxypropionyl, 2- naphtyloxypropionyl, 4-naphthyloxybutyryl, 2,2-dimethyl-3-

naphthyloxypropionyl, 5-naphthyloxypentanoyl, 6-naphthyloxy- hexanoyl, and the like.

The "phenyl-lower alkoxycarbonyl" includes a phenyl- alkoxycarbonyl wherein the alkoxycarbonyl moiety is a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, benzyloxycarbonyl, 2-phenyl- ethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxy- carbonyl, 4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6 phenylhexyloxycarbonyl, 1,l-dimethyl-2-phenylethoxycarbo'nyl, 2 methyl-3-phenylpropoxycarbonyl, and the like.

The "lower alkyl having optionally a hydroxy substituent" includes a straight chain or branched chain alkyl having 1 to 6 carbon atoms and having optionally 1 to 3 hydrox substituents, for example, hydroxymethyl, 2-hydroxyethyl, 1- hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxy- butyl, 3,4-dihydroxybutyl, l,l-dimethyl-2-hydroxyethyl, 5- hydroxypentyl, 6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4 trihydroxybutyl, and the like.

The "phenyl-lower alkyl" includes a phenylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, benzyl, 2 phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5- phenylpentyl, 6-phenylhexyl, l,l-dimethyl-2-phenylethyl, 2- methyl-3-phenylpropyl, and the like.

The "phenoxy-lower alkyl" includes a phenoxyalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example,

phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 5-phenoxypentyl, 6-phenoxyhexyl, 1,1-dimethyl- 2-phenoxyethyl, 2-methyl-3-phenoxypropyl, and the like.

The "phenyl which has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and a halogen atom" includes a phenyl group which has optionally 1 to 3 substi¬ tuents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms and a halogen atom, for example, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 2,4-dimethoxyphenyl, 4- hexyloxyphenyl, 3, 4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, . 2, 6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxy- phenyl, 3,4 ,5-trimethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3- iodophenyl, 4-iodophenyl, 3,4-dichlorophenyl, 3,5-dichloro- phenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichloro- phenyl, 3,4-difluorophenyl, 3, 5-dibromophenyl, 3,4 ,5-trichloro- phenyl, 2-methoxy-3-chlorophenyl, 2-methylphenyl, 3-methyl- phenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4- ethylphenyl, 4-isopropylphenyl, 3-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl, 2,4- dimethylphenyl, 2, 5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5- trimethylphenyl, 3-chloro-4-methylphenyl, 3-methoxy-4-methyl-5

iodophenyl, 3,4-dimethoxy-5-bromophenyl, 3,5-diiodo-4- methoxyphenyl, and the like.

The "amino-lower alkyl having optionally a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1- dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminό- methyl, 1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropyl- aminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 6-hexyl- aminohexyl, dimethylaminomethyl, (N-ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, and the like.

The "5- or 6-membered saturated heterocyclic group which is formed by binding the groups R ⁹ and R together with the nitrogen atom to which they bond with or without being intervened with nitrogen or oxygen atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, r-orpholino, and the like.

The "heterocyclic group having a substituent selected from a lower alkyl, a lower alkoxycarbonyl and piperidinyl" includes a heterocyclic group having 1 to 3 substituents selected from a straight chain or branched chain alkyl c.cup having 1 to 6 carbon atoms, a straight chain or branched chain alkoxycarbonyl having 1 to 6 carbon atoms and piperidinyl, for example, in addition to the above-mentioned heterocyclic groups

having a substituent of a lower alkyl and piperidinyl, 4- methoxycarbonylpiperazinyl, 4-ethoxycarbonylpiperidinyl, 3- propoxycarbonylpyrrolidinyl, 2-pentyloxycarbonylmorpholino, 4- hexyloxycarbonylpiperidinyl, 4-ethoxycarbonyl-3-methyl- piperidinyl, 3-methyl-4-ethoxycarbonylpiperazinyl, and the like.

The "5- or 6-membered saturated heterocyclic group which is formed by binding the groups R and R ⁵ together wit the nitrogen atom to which they bond with or without being intervened with nitrogen or oxygen atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, and the like.

The "heterocyclic group having a lower alkyl substituent" includes a heterocyclic group having 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 4-methylpiperazinyl, 3, 4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propyl- _. pyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4-hexylpiperazinyl, and the like.

The heterocyclic ring in the formula (1) includes tetrahydroquinolyl, 2,3,4,5-tetrahydro-lH-benzazepinyl, 1, 2, 3,4,5,6-hexahydrobenzazocinyl, 1,2-dihydroquinolyl, 2,3- dihydro-lH-benzazepinyl, 1, 2,3,4-tetrahydrobenzazocinyl, and the like.

The heterocyclic ring in the formula (1) wherein the carbon atom in the group of the formula: -(CH ₉ ) - or -CH=CH-(CH ₂ )_- for W is replaced by oxygen atom, sulfur atom,

R ¹³ sulfmyl, sulfonyl, or a group of the formula: -N ¹ - (R13 i•s hydrogen atom or a lower alkyl) includes a heterocylic group wherein the carbon atom in the group of the formula: ~(CH ₂ )_- or -CH=CH-(CH ₂ ) - for W is replaced by oxygen atom, sulfur

R ¹³ atom, sulfinyl, sulfonyl, or a group of the formula: -N ¹ - (R13° is hydrogen atom or a straight chain or branched chain alkyl having 1 to 6 carbon atoms), for example, 3,4-dihydro-2H-l,4- benzoxazinyl, 1,2,3,5-tetrahydro-4,1-benzoxazepinyl, 1,2,3,4- tetrahydroquinoxalinyl, 1,2,3,4,5,6-hexahydro-l,5-benzo¬ diazocinyl, 5-methyl-l,2,3,4,5,6-hexahydro-l,5-benzodiazocinyl, 4-methyl-l,2,3,4-tetrahydroquinoxalinyl, 1,2,3,4-tetrahydro- 5,1-benzoxazepinyl, 3,4-dihydro-2H.-l,4-benzothiazinyl, 2,3,4,5 tetrahydro-1,5-benzothiazepinyl, 1,2,3,5-tet ahydro-4,1- benzothiazepinyl, 4-ethyl-l,2,3,4-tetrahydroquinoxalinyl, 4- propyl-1,2,3,4-tetrahydroquinoxalinyl, 4-butyl-l,2,3,4- tetrahydroquinoxalinyl, 4-pentyl-l,2,3,4-tetrahydro¬ quinoxalinyl, 4-hexyl-l,2,3,4-tetrahydroquinoxalinyl, 2,3,4,5- tetrahydro-lH-1,4-benzodiazepinyl, 4-methyl-2,3,4,5-tetrahydro 1H-1,4-benzodiazepinyl, 4-ethyl-2,3,4,5-tetrahydro-lH-1,4- benzodiazepinyl, 4-propyl-2,3,4,5-tetrahydro-lH-l,4-benzo¬ diazepinyl, 4-butyl-2,3,4,5-tetrahydro-lH-l,4-benzodiazepinyl, 4-pentyl-2,3,4,5-tetrahydro-lH-l,4-benzodiazepinyl, 4-hexyl- 2,3;4,5-tetrahydro-lH-l,4-benzodiazepinyl, 2,3,4,5-tetrahydro- 1H-1,5-benzodiazepinyl, 5-methyl-2,3,4,5-tetrahydro-lH-l ,5- benzodiazepinyl, 5-ethyl-2,3,4,5-tetrahydro-lH-l,5-benzo-

diazepinyl, 5-propyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepinyl, 5-butyl-2,3,4, 5-tetrahydro-lH-1,5-benzodiazepinyl, 5-pentyl- 2,3,4, 5-tetrahydro-lH-1, 5-benzodiazepinyl, 5-hexyl-2,3,4,5- tetrahydro-lH-1,5-benzodiazepinyl, 3,4-dihydro-l-oxo-2H-l,4- benzothiazepinyl, 3, -dihydro-l,l-dioxo-2H-l,4-benzo- thiazepinyl, l-oxo-2,3,4, 5-tetrahydro-1,5-benzothiazepinyl, 1,l-dioxo-2,3,4, 5-tetrahydro-1,5-benzothiazepinyl, 4-oxo- l,2,3,5-tetrahydro-4,l- enzothiazepinyl, ,4-dioxo-l,2, 3, 5- tetrahydro-4 ,1-benzothiazepinyl, and the like.

The "halogen-substituted lower alkoxy" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which has 1 to 3 substituents of a halogen atom, for example, trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2- trichloroethoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4,4,4- trichlorobutoxy, 4-fluorobutoxy, 5-chloropentyloxy, 3-chloro-2- methylpropoxy, 6-bromohexyloxy, 5,6-dichlorohexyloxy, and the like.

The "halogen-substituted lower alkanoyl" includes a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms which has 1 to 3 substituents of a halogen atom, for example, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, 2- chloroacetyl, 2-bromoacetyl, 2-fluoroacetyl, 2-iodoacetyl, 2,2- difluoroacetyl, 2,2-dibromoacetyl, 3,3,3-t ifluoropropionyl, 3,3,3-trichloropropionyl, 3-chloropropionyl, 2,3-dichloro- propionyl, 4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-

chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl, 5,6-dibromohexanoyl, and the like.

The "aminocarbonyl-lower alkoxy having a lower alkyl substituent" includes a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by an aminocarbonyl group having 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methylaminocarbonylmethoxy, 1-ethylaminocarbonyl- ethoxy, 2-propylaminocarbonylethoxy, 3-isopropylaminocarbonyl- propoxy, 4-butylaminocarbonylbutoxy, 5-pentylaminocarbonyl- pentyloxy, 6-hexylaminocarbonylhexyloxy, dimethylaminocarbonyl- methoxy, 3-diethylaminocarbonylpropoxy, diethylaminocarbonyl- methoxy, (N-ethyl-N-propylamino)carbonylmethoxy, 2-(N-methyl-N- hexylamino)carbonylethoxy, and the like.

The "carbamoyl-lower alkyl" includes a carbamoyl- substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, carbamoylmethyl, 2-carbamoylethyl, 1-carbamoyl- ethyl, 3-carbamoylpropyl, 4-carbamoylbutyl, 5-carbamoylpentyl, 6-carbamoylhexyl, l,l-dimethyl-2-carbamoylethyl, 2-methyl-3- carbamoylpropyl, and the like.

The "amino-lower alkanoyl having optionally a lower alkyl substituent" includes a straight chain or branched chain alkanoyl having 2 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, 2-aminoacetyl, 3-aminopropionyl, 2-aminopropionyl,

4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 2,2- dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, 2-methyl- aminoacetyl, 2-ethylaminopropionyl, 3-propylaminopropionyl, 3- isopropylaminopropionyl, 4-butylaminobutyryl, 5-pentylamino- pentanoyl, 6-hexylaminohexanoyl, 2-dimethylaminoacetyl, 2- diethylaminoacetyl, 2-(N-ethyl-N-propylamino)acetyl, 3-(N- methyl-N-hexylamino)propionyl, and the like.

The "amino-lower alkyl having optionally a lower alkanoyl substituent" includes a straight chain or branched chain alkyl having 1 to 6 carbon atoms which is substituted by an amino group having optionally a substituent of a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3- aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1- dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, acetylamino- methyl, 1-acetylaminoethyl, 2-propionylaminoethyl, 3- isopropionylaminopropyl, 4-butyrylaminobutyl, 5-pentanoylamino- pentyl, 6-hexanoylaminohexyl, formylaminomethyl, and the like.

The "anilinocarbonyl having optionally a lower alkyl substituent on the phenyl ring" includes an anilinocarbonyl group having optionally 1 to 3 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms on the phenyl ring, for example, anilinocarbonyl, 2-methylanilino- carbonyl, 3-methylanilinocarbonyl, 4-methylanilinocarbonyl, 2- ethylanilinocarbonyl, 3-ethylanilinocarbonyl, 4-εthylanilinc- carbonyl, 4-isopropylanilinocarbonyl, 3-butylanilinocarbonyl, 4-pentylanilinocarbonyl, 4-hexylanilinocarbonyl, 3, 4-dimethyl-

anilinocarbonyl, 3,4-diethylanilinocarbonyl, 2,4-dimethyl- anilinocarbonyl, 2,5-dimethylanilinocarbonyl, 2,6-dimethyl- anilinocarbonyl, 3, ,5-trimethylanilinocarbonyl, and the like.

The "phenylsulfonyl which has optionally a substituent selected from a halogen and a lower alkyl on the phenyl ring" includes a phenylsulfonyl group which has optionally 1 to 3 substitutents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a halogen atom, for example, phenylsulfonyl, 2-chlorophenylsulfonyl, 3-chloro- phenylsulfonyl, 4-chlorophenylsulfonyl, 2-fluorophenylsulfonyl, 3-fluorophenylsulfonyl, 4-fluorophenylsulfonyl, 2-bromophenyl- sulfonyl, 3-bromophenylsulfonyl, 4-bromophenylsulfonyl, 2-iodo- phenylsulfonyl, 3-iodophenylsulfonyl, 4-iodophenylsulfonyl, 3,4-dichlorophenylsulfonyl, 3,5-dichlorophenylsulfonyl, 2,6-di- chlorophenylsulfonyl, 2,3-dichlorophenylsulfonyl, 2,4-dichloro- phenylsulfonyl, 3,4-difluorophenylsulfonyl, 3,5-dibromophenyl- sulfonyl, 3,4,5-trichlorophenylsulfonyl, 2-ethyl-3-chloro- phenylsulfonyl, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl, 4-methylphenylsulfonyl, 2-ethylphenylsulfonyl, 3-ethylphenyl- sulfonyl, 4-ethylphenylsulfonyl, 4-isopropylphenylsulfonyl, 3- butylphenylsulfonyl, 4-pentylphenylsulfonyl, 4-hexylphenyl- sulfonyl, 3,4-dimethylphenylsulfonyl, 3,4-diethylphenyl- sulfonyl, 2,4-dimethylphenylsulfonyl, 2,5-dimethylphenyl- sulfonyl, 2,6-dimethylphenylsulfonyl, 3,4,6-trimethylphenyl- sulfonyl, 3,4,5-trimethylphenylsulfonyl, 3-chloro-4-methyl- phenylsulfonyl, 4-methyl-5-iodophenylsulfonyl, 3,4-dimethyl- 5-bromophenylsulfonyl, 3,5-diiodo-4-methylphenylsulfonyl,

and the like.

The "phthalimido-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by phthalimido group, for example, phthalimidomethyl, 2-phthalimidoethyl, 1-phthal- imidoethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5- phthalimidopentyl, 6-phthalimidohexyl, 1,l-dimethyl-2- phthalimidoethyl, 2-methyl-3-phthalimidopropyl, and the like.

The "lower alkynyl" includes a straight chain or. branched chain alkynyl having 2 to 6 carbon atoms, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1- methyl-2-propynyl, 2-pentynyl, 2-hexynyl, and the like.

The "benzoyl which has optionally a halogen substituent on the phenyl ring" includes a benzoyl group which has optionally 1 to 3 substituents of a halogen atom on the phenyl ring, for example, benzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2-fluorobenzoyl, 3-fluoro¬ benzoyl, 4-fluorobenzoyl, 2-bromobenzoyl, 3-bromobenzoyl, 4- bromobenzoyl, 2-iodobenzoyl, 3-iodobenzoyl, 4-iodobenzoyl, 3,4-dichlorobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichloro- benzoyl, 2,3-dichlorobenzoyl, 2,4-dichlorobenzoyl, 3,4- difluorobenzoyl, 3,5-dibromobenzoyl, 3,4, 5-trichlorobenzoyl, and the like.

The "phenyl-lower alkoxy" includes a phenylalkoxy group wherein the alkoxy moiety is ^' a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for

example, benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3- phenylpropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenyl- hexyloxy, l,l-dimethyl-2-phenylethoxy, 2-methyl-3-phenyl- propoxy, and the like.

The "amino-lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl" include a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethoxy, 2-aminoethoxy, 1-aminoethoxy, 3-aminopropox , 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1- dimethyl-2-aminoethoxy, 2-methyl-3-aminopropoxy, acetyl- aminomethoxy, 1-acetylaminoethoxy, 2-propionylaminoethoxy, 3-isopropionylaminopropoxy, 4-butyrylaminobutoxy, 5- pentanoylaminopentyloxy, 6-hexanoylaminohexyloxy, formyl- aminomethoxy, methylaminomethoxy , 1-ethylaminoethoxy, 2- propyla inoethox , 3-isopropylaminopropoxy, 4-butylamino- bύtoxy, 5-pentylaminopentylox , 6-hexylaminohexyloxy, dimethylaminomethoxy, (N-ethyl-N-propylamino)methoxy, 2-(N- methyl-N-hexylamino)ethoxy, and the like.

The "benzoyloxy which has optionally a halogen substituent on the phenyl ring" includes a benzoyloxy group which has optionally 1 to 3 substituents of a halogen atom on the phenyl ring, for example, benzoyloxy, 2-chloro-

benzoyloxy, 3-chlorobenzoyloxy, 4-chlorobenzoyloxy, 2- fluorobenzoyloxy, 3-fluorobenzoyloxy, 4-fluorobenzoyloxy, 2- bromobenzoyloxy, 3-bromobenzoyloxy, 4-bromobenzoylox , 2- iodobenzoyloxy, 3-iodobenzoyloxy, 4-iodobenzoyloxy, 3,4- dichlorobenzoyloxy, 3, 5-dichlorobenzoyloxy, 2, 6-dichloro- benzoyloxy, 2,3-dichlorobenzoyloxy, 2,4-dichlorobenzoyloxy, 3,4-difluorobenzoyloxy, 3,5-dibromobenzoyloxy, 3,4,5- trichlorobenzoyloxy, and the like.

The "lower alkanoyloxy-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkanoyloxy group having 2 to 6 carbon atoms, for example, acetyloxymethyl, 2-propion- yloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl, 4-acetyl- oxybutyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl, 6- acetyloxyhexyl, 6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl- 2-hexanoyloxyethyl, 2-methyl-3-acetyloxypropyl, and the like.

The "lower alkylsulfonyloxy-lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by a straight chain or branched chain alkylsulfonyloxy group having 1 to 6 carbon atoms, for example, methylsulfonyloxymethyl, 1-ethyl- sulfonyloxyethyl, 2-propylsulfonyloxyethyl, 3-isopropyl- sulfonyloxypropyl, 4-fcαιtylsulfonyloxybutyl, 5-pentylsulfoyl- oxypentyl, 6-hexylsulfonyloxyhexyl, 1,l-dimethyl-2-methyl- sulfoyloxyethyl, 2-methyl-3-ethylsulfonyloxypropyl, and the

like .

The "azido-lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an azido group, for example, azidomethyl, 1-azidoethyl, 2-azidoethyl, 3-azidopropyl, 4- azidobutyl, 5-azidopentyl, 6-azidohexyl, l,l-dimethyl-2- azidoethyl, 2-methyl-3-azidopropyl, and the like.

The "lower alkanoyloxyimino" includes a straight chain or branched chain alkanoyloxyimino group having 1 to 6 carbon atoms, for example, formyloxyimino, acetyloxyimino, ^' propionyloxyimino, butyryloxyimino, isobutyryloxyimino, pentanoyloxyimino, tert-butylcarbonyloxyimino, hexanoyl- oxyimino, and the like.

The "lower alkylidene" includes a straight chain or branched chain alkylidene group having 1 to 6 carbon atoms, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene, and the like.

The "oxiranyl-substituted lower alkyl" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by oxiranyl group, for example, oxiranylmethyl, 1-oxiranylethyl, 2-oxiranylethyl, 3-oxiranylpropyl, 4-oxiranylbutyl, 5-oxiranylpentyl, 6- oxiranylhexyl, l,l-dimethyl-2-oxiranylethyl, 2-methyl-3- oxiranylpropyl, and the like.

The "lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having

optionally a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and having 1 to 2 substituents selected from a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, hydroxy and an amino having optionally a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methoxymethyl, 1-ethoxyethyl, 2- propoxyethyl, 3-isopropoxypropyl, 4-butoxybutyl, 5-pentyl- oxypentyl, 6-hexyloxyhexyl, 1,l-dimethyl-2-methoxyethyl, 2- methyl-3-ethoxypropyl, 3-methoxy-2-hydroxypropyl, hydroxy- ^' methyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 3,4-dihydroxybutyl, 1,1- dimethyl-2-hydroxyethyl, 5,6-dihydroxyhexyl, 5-hydroxy- pentyl, 6-hydroxyhexyl, 6-(N-ethyl-N-methylamino)-5-methoxy- hexyl, 2-methyl-3-hydroxypropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6- aminohexyl, 1,l-dimethyl-2-aminoethyl, 2-methyl-3-amino- propyl, methylaminomethyl, ethylaminometh , propylamino- methyl, isopropylaminomethyl, butylaminomethyl, tert- butylaminomethyl, pentylaminomethyl, hexylaminomethyl, dimethylaminomethyl, diethylaminomethyl, dipropylamino- methyl, dibutylaminomethyl, dipentylaminomethyl, dihexyl- aminomethyl, N-methyl-N-ethylaminomethyl, N-methyl-N- propylaminomethyl, N-methyl-N-butylaminomethyl, N-methyl-N- hexylaminouiethyl, 1-methylaminoethyl, 2-ethylaminoethyl, 3- propylaminopropyl, 4-butylaminobutyl, 1,l-dimethyl-2-pentyl- aminoethyl, 5-hexylaminopentyl, 6-dimethylaminohexyl, 4-

dimethylaminobutyl, 2-diethylaminoethyl, l-(N-methyl-N- hexylamino)ethyl, 3-dihexylaminopropyl, 6-diethylaminohexyl, 4-dibutylaminobutyl, 2-(N-methyl-N-pentylamino)ethyl, 2- hydroxy-3-diethylaminopropyl, 3-hydroxy-4-methylaminobutyl, 5-hydroxy-6-diethylaminohexyl, 4-hydroxy-5-dimethylamino- pentyl, 4-hydroxy-5-methylaminopentyl, 4-hydroxy-5-diethyl- aminopentyl, 5-hydroxy-6-ethylaminohexyl, 5-hydroxy-6- isopropylaminohexyl, 5-hydroxy-6-aminohexyl, and the like.

The "aminocarbonyloxy having optionally a lower alkyl substituent" includes an aminocarbonyloxy group having optional 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminocarbonyloxy methylaminocarbonyloxy, ethylaminocarbonylox , propylamino- carbonyloxy, isopropylaminocarbonyloxy, butylaminocarbonyloxy, tert-butylaminocarbonyloxy, pentylaminocarbonyloxy, hexylamino- carbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, dipropylaminocarbonyloxy, dibutylaminocarbonyloxy, dipentylamin carbonyloxy, dihexylaminocarbonyloxy, N-methyl-N-ethylamino- carbonyloxy, N-ethyl-N-propylaminocarbonyloxy, N-methyl-N-butyl aminocarbonyloxy, N-methyl-N-hexylaminocarbonyloxy, and the lik

The "lower alkanoyloxy having optionally a halogen substituent" includes a straight chain or branched chain alkanoyloxy group having 1 to 6 carbon atoms which has optional 1 to 3 substituents .. a halogen atom, for example, in addition to the above lower alkanoyl group, 2,2,2-trifluoroacetyloxy, 2,2,2-trichloroacetyloxy, 2-chloroacetyloxy, 2-bromoacetyloxy, fluoroacetyloxy, 2-iodoacetyloxy, 2,2-difluoroacetyloxy, 2,2-

dibromoacetyloxy, 3,3,3-trifluoropropionyloxy, 3, 3,3-trichloro- propionyloxy, 3-chloropropionyloxy, 2,3-dichloropropionyloxy, 4,4, 4-trichlorobutyryloxy, 4-fluorobutyryloxy, 5-chloropentanoyl oxy, 3-chloro-2-methylpropionyloxy, 6-bromohexanoyloxy, 5,6- dibromohexanoyloxy, and the like.

The "amino-lower alkyl having optionally a substituent selected from a lower alkyl and a lower alkanoyl" include a straight chain or branched chain alkyl group having 1 to 6 carbo atoms which is substituted by an amino group having optionally 1 to 2 substituents selected from a straight chain or branched chain alkyl group having 1 to 6 carbon atoms and a straight chai or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, l,l-dimethyl-2-amino- ethyl, 2-methyl-3-aminopropyl, acetylaminomethyl, 1-acetylamino- ethyl, 2-propionylaminoethyl, 3-isopropionylaminopropyl, 4- butyrylaminobutyl, 5-pentanoylaminopentyl, 6-hexanoylaminohexyl, formylaminomethyl, methylaminomethyl, 1-ethylaminoethyl, 2- propylaminoethyl, 3-isopropylaminopropyl, 4-butylaminobutyl, 5- pentylaminopentyl, 6-hexylaminohexyl, dimethylaminomethyl, (N- ethyl-N-propylamino)methyl, 2-(N-methyl-N-hexylamino)ethyl, and the like.

The "amino-lower alkanoyloxy having optionally a lower alkyl substituent" includes a straight chain or branched chain alkanoyloxy having 2 to 6 carbon atoms which is substituted by a amino group having optionally 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms,

for example, 2-aminoacetyloxy, 3-aminopropionyloxy, 2-amino- propionyloxy, 4-aminobutyryloxy, 5-aminopentanoyloxy, 6-amino- hexanoyloxy, 2,2-dimethyl-3-aminopropionyloxy, 2-methyl-3-amino propionyloxy, 2-methylaminoacetyloxy, 2-ethylaminopropionyloxy, 3-proρylaminopropionyloxy, 3-ιsopropylammopropιonyloxy , 4-buty aminobutyryloxy, 5-pentylaminopentanoyloxy, 6-hexylaminohexanoy oxy, 2-dimethylaminoacetyloxy, 2-diethylaminoacetyloxy, 2-(N- ethyl-N-propylamino)acetyloxy, 3-( -meth l-N-hexylamino)- propionyloxy, and the like.

The "pyridyl-lower alkyl" include a pyridylalkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, (4-pyridyl) methyl, l-(3-pyridyl)ethyl, 2-(2-pyridyl)ethyl, 3-(2-pyridyl)- propyl, 4-(3-pyridyl)butyl, 5-(4-pyridyl)pentyl, 6-(2-pyridyl)- hexyl, l,l-dimethyl-2-(3-pyridyl)ethyl, 2-methyl-3-(4-pyridyl)- propyl, and the like.

The "5- or 6-membered saturated heterocyclic group whi is formed by binding the groups R° and R ^OJ together with the nitrogen atom to which they bond with or without being interven with nitrogen, oxygen or sulfur atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thio- morpholino, and the like.

The above heterocyclic group which has a substituent selected from oxo, a lower alkyl, a lower alkanoyl and carbamoy includes the above heterocyclic groups which have 1 to 3 substituents selected from oxo, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain

branched chain alkanoyl group having 1 to 6 carbon atoms, and carbamoyl group, for example, 4-methylpiperazinyl, 3,4-dimethyl piperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5- trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 4 hexylpiperazinyl, 2-methylthiomorpholino, 4-acetylpiperazinyl, propionylmorpholino, 3-butyrylthiomorpholino, 3-pentanoyl- pyrrolidinyl, 4-hexanoylpiperidinyl, 3-methyl-4-acetylpiperazin yl, 2-carbamoylpyrrolidinyl, 4-carbamoylpiperazinyl, 3-carbamoy thiomorpholino, 2-carbamoylmorpholino, 3-carbamoylpiperidinyl, oxo-thiomorpholino, 1,1-dioxothiomorpholino, and the like.*

The "lower alkylsulfonyl" includes a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentyl- sulfonyl, hexylsulfonyl, and the like.

The "aminocarbonyl having optionally a lower alkyl substituent" includes an aminocarbonyl group having optionally to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, tert-butylamino- carbonyl, pentylaminocarbonyl, hexylaminocarbonyl, dimethylamin carbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutyl- aminocarbonyl, dipentylaminocarbonyl, dihexylaminocarbonyl, N- methyl-N-ethylaminocarbonyl, N-ethyl-N-propylaminocarbcnyl, N- methyl-N-butylaminocarbonyl, N-methyl-N-hexylaminocarbonyl, and the like.

The "cyano-substituted lower alkyl" includes a straigh chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by cyano group, for example, cyanomethyl, cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyano- pentyl, 6-cyanohexyl, l,l-dimethyl-2-caynoethyl, 2-methyl-3- cyanopropyl, and the like.

The "lower alkoxycarbonyl-substituted lower alkyl" includes an alkoxycarbonyl-substituted straight chain or branch chain alkyl group having 1 to 6 carbon atoms wherein the alkoxy carbonyl moiety is a straight chain or branched chain alkoxy¬ carbonyl group having 1 to 6 carbon atoms, for example, methoxy carbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarboxymethyl, 3 ethoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxy- carbonylpentyl ^" , 6-propoxycarbonylhexyl, l,l-dimethyl-2-butoxy- carbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentylox carbonylethyl, hexyloxycarbonylmethyl, and the like.

The "carboxy-substituted lower alkyl" includes a carboxy-substituted alkyl group wherein the alkyl moiety is a straight chain or branched chain alkyl group having 1 to 6 carb atoms, for example, carboxymethyl, 2-carboxyethyl, 1-carboxy- ethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6- carboxyhexyl, l,l-dimethyl-2-carboxyethyl, 2-methyl-3-carboxy- propyl, and the like.

The "tetrahydropyranyloxy-substituted lower alkyl" includes a tetrahydropyranyloxy-substituted straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, (2-tetrahydropyranyloxy)methyl, 2-(3-tetrahydropyranyl

oxy)ethyl, l-(4-tetrahydropyranyloxy)ethyl, 3-(2-tetrahydro- pyranyloxy)propyl, 4-(3-tetrahydropyranyloxy)butyl, 5-(4-tetra- hydropyranyloxy)pentyl, 6-(2-tetrahydropyranyloxy)hexyl, 1,1- dimethyl-2-(3-tetrahydropyranyloxy)ethyl, 2-methyl-3-(4-tetra- hydropyranyloxy)propyl, and the like.

The "piperidinyl having optionally a phenyl-lower alky substituent" includes a piperidinyl which has optionally a substituent of a phenylalkyl group wherein the alkyl moiety is straight chain or branched chain alkyl group having 1 to 6 carb atoms, for example, piperidinyl, l-benzyl-4-piperidinyl, l-(2- phenylethyl)-3-piperidinyl, l-(l-phenylethyl)-2-piperidinyl, 1- (3-phenylpropyl)-4-piperidinyl, l-(4-phenylbutyl)-4-piperidinyl 1-(5-phenylpentyl)-4-piperidinyl, 1-(6-phenylhexyl)-4- piperidinyl, l-(l,l-dimethyl-2-phenylethyl)-3-piperidinyl, l-(2 methyl-3-phenylpropyl)-2-piperidinyl, and the like.

The "imidazolyl-substituted lower alkanoyl" includes a imidazolyl-substituted alkanoyl group wherein the alkanoyl moie is a straight chain or branched chain alkanoyl group having 2 t 6 carbon atoms, for example, (l-imidazolyl)acetyl, 3-(2-imidazo yl)propionyl, 2-(4-imidazolyl)propionyl, 4-(l-imidazolyl)butyry 2, 2-dimethyl-3-(2-imidazolyl)propionyl, 5-(4-imidazolyl)- pentanoyl, 6-(l-imidazolyl)hexanoyl, and the like.

The "amino-lower alkanoyl having optionally a substi¬ tuent selected from a lower alkyl and a lower alkoxycarbonyl" includes a straight chain or branched chain alkanoyl having 2 t 6 carbon atoms which is substituted by an amino group having optionally 1 to 2 substituents selected from a straight chain o

branched chain _^ -kyl group naving 1 to 6 carbon atoms and a straight chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, for example, 2-aminoacetyl, 3-amino- propionyl, 2-aminopropionyl, 4-aminobutyryl, 5-amino- pentanoyl, 6-aminohexanoyl, 2,2-dimethyl-3-aminopropionyl, 2-methyl-3-aminopropionyl, 2-methylaminoacetyl, 2-ethyl- aminopropionyl, 3-propylaminopropionyl, 3-isopropylamino- propionyl, 4-butylaminobutyryl, 5-pentylaminopentanoyl, 6- hexylaminohexanoyl, 2-dimethylaminoacetyl, 2-diethylamino- acetyl, 2-(N-ethyl-N-propylamino)acetyl, 3-(N-methyl-N- hexylamino)propionyl, 2-methoxycarbonylaminoacetyl, 2- ethoxycarbonylaminoacetyl, 3-propoxycarbonylaminopropionyl, 4-butoxycarbonylaminobutyryl, 2-tert-butoxycarbonylamino- acetyl, 5-pentyloxycarbonylaminopentanoyl, 6-hexyloxy- carbonylaminohexanoyl, 2-(N-methyl-N-tert-butoxycarbonyl- amino)acetyl, and the like.

The "aminocarbonyl-lower alkyl having a lower alkyl substituent" includes a straight chain or branched chain alkyl group having 1 to 6 carbon atoms which is substituted by an aminocarbonyl group having 1 to 2 substituents of a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methylaminocarbonylmethyl, 1-ethyl- aminocarbonylethyl, 2-propylaminocarbonylethyl, 3-isopropyl- aminocarbonylpropyl, 4-butylaminocarbonylbutyl, 5-pentylamino- carbonylpentyl, 6-hexylaminocarbonylhexyl, dimethylamino- carbonylmethyl, 3-diethylaminocarbonylpropyl, diethylamino- carbonylmethyl, (N-ethyl-N-propylamino)carbonylmethyl, 2-(N-

methyl-N-hexylamino)carbonylethyl, and the like.

The "amino-substituted lower alkoxy having optionally a lower alkyl substituent" includes an amino- substituted straight chain or branched chain alkoxy having 1 to 6 carbon atoms which has optionally 1 to 2 substituents of a straight chain or branched chain alkyl having 1 to 6 carbon atoms, such as aminomethoxy, 2-aminoethoxy, 1-amino- ethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6- aminohexyloxy, l,l-dimethyl-2-aminoethoxy, 2-methyl-3-amino- propoxy, methylaminomethoxy, 1-ethylaminoethoxy, 2-propyl- ^' aminoethoxy, 3-isopropylaminopropoxy, 4-butylaminobutoxy, 5- pentyla inopentyloxy, 6-hexylaminohexyloxy, dimethylamino- methoxy, (N-ethyl-N-propylamino)methoxy, 2-(N-methyl-N- hexylamino)ethoxy, and the like.

The compounds of the present invention can be prepared by various processes, for example, by the processes shown in the following reaction schemes. [Reaction Scheme-1]

(1) wherein R _ , R , R3, and W are the same as defined above.

The process of Reaction Scheme-1 is carried out by

reacting a benzoheterocyclic compound of the formula (2) and a carboxylic acid compound of the formula (3) by a conventional amido bond forming reaction. The amido bond forming reaction can be carried out under the conditions for the conventional amido bond forming reaction, for example,

(a) a mixed acid anhydride process, i.e. a process of reacting the carboxylic acid compound (3) with an alkyl- halocarboxylic acid to form a mixed acid anhydride and reacting the resultant with the amine compound (2),

(b) an activated ester process, i.e. a process of converting the carboxylic acid compound (3) into an activated ester, such as p-nitrophenyl ester, N-hydroxy¬ succinimide ester, 1-hydroxybenzotriazole ester, etc., and reacting the resultant with the amine compound (2),

(c) a carbodiimide process, i.e. a process of condensing the carboxylic acid compound (3) and the amine compound (2) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, etc.,

(d) other processes, i.e. a process of converting the carboxylic acid compound (3) into a carboxylic anhydride by treatment with a dehydrating agent such as acetic anhydride, and reacting the resultant with the amine compound (2); a process of reacting an ester of the carboxylic acid compound (3) with a lower alcohol and the amine compound (?) at a high temperature under high pressure; a process of reacting an acid halide compound of the carboxylic acid compound (3), i.e. a carboxylic acid

halide, with the amine compound (2), and the like.

The mixed acid anhydride used in the above mixed acid anhydride process (a) is obtained by the known Schotten-Baumann reaction, and the reaction product is used without isolation from the reaction mixture for the reaction with the amine compound (2) to give the desired compound of the formula (1). The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. The basic compound is any conventional compounds used for the Schotten-Baumann reaction and includes, for example, organic basic compounds such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diaza- bicyclo[4.3.0]nonene-5 (DBN), l,8-diazabicyclo[5.4.0]- undecene-7 (DBU), 1,4-diazabicyclo[ 2.2.2]octane (DABCO), etc., and inorganic basic compounds such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is usually carried out at a temperature of from about -20°C to about 100°C, preferably from about 0°C to about 50°C, for about 5 minutes to about 10 hours, preferably about 5 minutes to about 2 hours.

The reaction of the thus obtained mixed acid anhydride with the amine compound (2) is usually carried out at a temperature of from about -20°C to about 150°C, preferably about 10°C to about 50°C, for about 5 minutes to about 10 hours, preferably about 5 minutes to about 5 hours. The mixed acid anhydride process is usually carried

out in n appropriate solvent. The solvent is any conventional solvents which are usually used in the mixed acid anhydride process and includes, for example, halogenated hydrocarbons (e.g. chloroform, dichloromethane dichloroethane, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahycrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl- sulfoxide, hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The alkylhalocarboxylic acid used in the mixed acid anhydride process includes, for example, methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. In said process, the carboxylic acid compound (3), the alkylhalocarboxylic acid anr' the amine (2) are usually used in each equimolar amount, but preferably, the alkylhalocarboxylic acid and the carboxylic acid compound (3) are used each in an amount of about 1 to 1.5 mole to 1 mole of the amine (2).

Among the above other processes (d), in case of the process of reacting the carboxylic acid halide with the amine compound (2), the reaction is usually carried out in the presence of a basic compound in an appropriate solvent. The basic compound is any conventional compounds and includes, in addition to the basic compounds used for the above-mentioned Schotten-Baumann reaction, sodium hydroxide,

potassium hydroxide, sodium hydride, potassium hydride, etc. The solvent includes, in addition to the solvents used for the above-mentioned mixed acid anhydride process, alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-l- butanol, ethylcellosolve, methylcellosolve, etc.), aceto- nitrile, pyridine, acetone, water, and the like. The amount of the amine compound (2) and the carboxylic acid halide is not critical, but the carboxylic acid halide is usually used at least in equimolar amount, preferably about 1 to 5 moles to 1 mole of the amine compound (2). The reaction is usually carried out at a temperature of from about -20°C to about 180°C, preferably from about 0°C to about 150°C, for about 5 minutes to about 30 hours.

The amido bond forming reaction in the above Reaction Scheme-1 may also be carried out by reacting the carboxylic acid compound (3) and the amine (2) in the presence of a condensation agent, i.e. phosphoric compounds such as triphenylphosphine, diphenylphosphinyl chloride, phenyl-N-phenylphosphoramide chloridate, diethyl chloro- phosphate, diethyl phosphorocyanidate, diphenylphosphoric azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc. The reaction is usually carried out in the presence of the solvent and basic compound as used in the above reaction of the carboxylic acid halide and the amine (2) at a tempera¬ ture of from about -20 ^C C to about 150°C, preferably about 0°C to about 100°C, for about 5 minutes to about 30 hours. The condensation agent and the carboxylic acid compound (3)

are used at least in equimolar amount, preferably about 1 to 2 moles, to 1 mole of the amine (2). [Reaction Scheme-2]

(2b) (lb) wherein R ¹ , R ² , R ⁴ and W are as defined above, R ^5a is the same as R ⁵ as defined above except excluding an anilino¬ carbonyl having optionally a lower alkyl substituent on the phenyl ring, a phenylsulfonyl having optionally a substituent selected from a halogen atom and a lower alkyl on the phenyl ring and quinolylsulfonyl.

The reaction of the compound (2b) and the compound (4) is carried out in the same manner as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

(5) (lc) wherein R ¹ , R ² , R ¹¹ , R ¹² and W are as defined above.

The reaction of the compound (5) and the compound (6) is carried out under the same conditions as used in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. [Reaction Scheme-4]

(7) (Id) wherein R ¹ , R ² , R and W are as defined above, and R ^4a is a lower alkyl, R and R are each hydrogen atom or a lower alkyl, and X is a halogen atom.

The reaction of the compound (7) and the compound (8) is usually carried out in an inert solvent in the

presence or absence of a basic compound. The inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, tert-butanol, etc.), acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, etc., or a mixture of these solvents. The basic compound includes, for example, carbonates (e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium amide, metal alcoholates (e.g. sodium methoxide, sodium ethoxide, etc.), and organic basic compounds (e.g. pyridine, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo- [4.3.0]nonene-(5) (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), etc.). The amount of the compound (7) and the compound (8) is not critical, but the compound (8) is usually used at least in equivalent amount, preferably l to 10 moles, to 1 mole of the compound (7). The reaction is usually carried out at a temperature of from about 0°C to about 200°C, preferably from about 0°C to about 170°C, for about 30 minutes to about 30 hours. In the reaction, an alkali metal halide (e.g.

sodium iodide, potassium iodide, etc.) may be added to the reaction system.

The reaction of the compound (7) and the compound (9) is carried out in an appropriate solvent or without solvent in the presence of a reducing agent. The solvent includes, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic acid, ethers (e.g. dioxane, diethyl ether, diglyme, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), or a mixture of these solvents. The reducing agent includes, for example, formic acid, fatty acid alkali metal salts (e.g. sodium formate, etc.), hydrogenating reducing agents (e.g. sodium boro hydride, sodium cyanoboro hydride, lithium aluminum hydride, etc.), catalystic reducing agents (e.g. palladium black, palladium- carbon, platinum oxide, platinum black, Raney nickel, etc. ) .

When formic acid is used as the reducing agent, the reaction is usually carried out at a temperature of from room temperature to about 200°C, peferably about 50°C to about 150°C, for about 1 to 10 hours. The formic acid is usually used in a large excess amount to the compound (7).

When a hydrogenating reducing agent is used, the reaction is usually carried out at a temperature of about -30°C to about 100°C, preferably about 0 ^D C to about 70°C, for about 30 minutes to about 12 hours. The reducing agent is usually used in an amount of 1 to 20 moles, preferably 1

to 6 moles, to 1 mole of the compound (7). When lithium aluminum hydride is used as the reducing agent, it is preferable to use a solvent selected from ethers (e.g. diethyl ether, dioxane, tetrahydrofuran, diglyme, etc.) and aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.).

When a catalytic reducing agent is used, the reaction is usually carried out under atmospheric pressure to about 20 atm. , preferably atmospheric pressure to about 10 atm. under hydrogen atmosphere or in the presence of a ^• hydrogen donor (e.g. formic acid, ammonium formate, cyclo-' hexene, hydrazine hydrate, etc.) at a temperature of about -30°C to about 100°C, preferably about 0°C to about 60°C, for about 1 to 12 hours. The catalytic reducing agent is usually used in an amount of about 0.1 to 40 % by weight, preferably about 1 to 20 % by weight, of the amount of the compound (7). The compound (9) is usually used at least in equivalent amount, preferably equivalent to a large excess amount, to the compound (7). [Reaction Scheme-5A]

(10) de)

wherein R ¹ , R ² , R ¹² , R ¹⁷ , R ¹⁸ , X and W are as defined above, and R ^lla is a lower alkyl. [Reaction Scheme-5B]

(12) (If) wherein R ¹ , R ² , R ¹¹ , X and W are as defined above, and R ^{1 a} is a cycloalkyl.

The reaction of the compound (10) and the compound (11) in the Reaction Scheme-5A and the reaction of the compound (12) and the compound (13) in the Reaction Scheme- SB are carried out in the same manner as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

Besides, the reaction of the compound (10) and the compound (9) in the Reaction Scheme-5A is carried out in the same manner as in the reaction of the compound (7) and the compound (9) in the above Reaction Scheme-4.

(lg) (lh) wherein R ¹ , R ² , R ⁴ , R ¹⁶ , R ^δ _ R ⁷ , X, W, and A are as defined above, J is 0 or an integer of 1 to 3, i ¹ and s." are each an integer of 1 to 3, provided that s, + £' and i + s." are each an integer not more than 3.

(ig) (ii) wherein R ¹ , R ² , R ⁴ , R ¹⁶ , X, W, A, x,, £' , and ϊ." are as defined above, and R ⁹ is a lower alkanoyloxy, R ° is a lower alkanoyloxy-, hydroxy or phthalimido, R ²¹ is the same

1 q *jn as as R and R , and M is an alkali metal (e.g. potassium, sodium, etc. ) .

The reaction of the compound (lg) and the compound (14) in the Reaction Scheme-6A and the reaction of the compound (lg) and the compound (15) or (16) in the Reaction Scheme-6B can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system.

dj) (Ik) wherein R ^x , R , R , R , W, a, a' s," and A are as defined above.

The reaction of converting the compound (lj) into the compound (Ik) can be carried out by reacting the compound (lj) with hydrazine in an appropriate solvent or by hydrolyzing the compound (lj). The solvent used in the reaction with hydrazine includes water and further the same solvent as used in the reaction of the compound (2b) and the compound (4) in the above Reaction Scheme-2. The reaction is usually carried out at a temperature of from room temperature to about 120°C, preferably about 0°C to about 100°C, for about 0.5 to 5 hours. Hydrazine is usually used in an amount of at least 1 mole, preferably about 1 to 5 moles, to 1 mole of the compound (lj).

The hydrolysis can be carried out in an appropriate solvent or without solvent in the presence of an acid or a basic compound. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) and organic ^' acids (e.g. formic acid, acetic acid, aromatic sulfonic acids, etc.). The basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. The reaction is usually carried out at a temperature of from room temperature to about 200°C, preferably from room temperature to about 150°C for about 10 minutes to 25 hours.

[Reaction Scheme-8]

(It) dm) wherein R ¹ , R ² , R ⁴ , W, R ¹⁶ , a, a ¹ , a", X, and A are as defined above, and R is a lower alkanoyl.

The reaction of the compound (la) and the compound (17) is carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system.

The reaction of converting the compound (lm) into the compound (la) can be carried out under the same condition as in the hydrolysis of the compound (lj) in the Reaction Scheme-7.

(In) (lo) wherein R ¹ , R ² , R ⁴ , W, R ¹⁶ , a, a', a", and X are as defined

** ^* ) ~> above, and R ^J is a lower alkyl, a lower alkanoyloxy- substituted lower alkyl, a halogen-substituted lower alkyl, a carboxy-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a phthalimido- substituted lower alkyl, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a group of the

R ⁵ formula: -A- / (A, Rfi ^D and R7' are as defined above). R ⁷

The reaction of the compound (In) and the compound

(18) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be

added to the reaction system [Reaction Scheme-10]

wherein R ¹ , R ² , R ⁴ , W, R ¹⁶ , R ¹⁷ , R ¹⁸ , a, X, and A are as defined above, and R is hydrogen atom, a lower alkyl

having optionally a hydroxy substituent, a lower alkanoyl, or benzoyl, R ^7a is a lower alkyl having optionally a hydroxy substituent, and R ⁷ ° is a lower alkanoyl or benzoyl.

The reaction of the compound (lp) and the compound

(19) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.

The reaction of the compound (lp) and the compound

(20) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the Reaction Scheme-1.

Besides, the compound (lr) can also be obtained by reacting the compound (lp) with a compound of the formula: (R ^7t) ) ₂ 0 (R ^7t) is as defined above). The reaction can be carried out in an appropriate solvent or without solvent in the presence or absence, peferably presence, of a basic compound. The solvent includes, for example, the above- mentioned aromatic hydrocarbons, lower alcohols (e.g. methanol, ethanol, propanol, etc.), dimethylformamide, dimethylsulfoxide, and further halogenated hydrocarbons (e.g. chloroform, methylene chloride, etc.), acetone, pyridine, etc. The basic compound includes, for example, tertiary amines (e.g. triethylamine, pyridine, etc.), sodium hydroxide, potassium hydroxide, sodium hydride, and the like. The above reaction can also be carried out in a solvent such as acetic acid or benzoic acid in the presence of a mineral acid (e.g. sulfuric acid, etc.). The acid

anhydride is usually used in an equimolar amount or more, preferably 1 to 10 moles, to 1 mole of the starting compound, and the reaction is usually carried out at a temperature of about 0°C to about 200°C, preferably from about 0°C to about 150°C, for about 0.5 to 15 hours.

[Reaction Scheme-11]

wherein R ¹ , R ² , R ⁴ , R ⁹ , R ¹⁰ , W, and B are as defined above. The reaction of the compound (Is) and the compound (21) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

[ Reaction Scheme-12 ]

( lu ) ( lv ) wherein R ¹ , R ² , R ⁴ , W, R ⁹ , R ¹⁰ , X, and B are as defined above.

The reaction of the compound (lu) and the compound (21) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. In the reaction, an alkali metal halide (e.g. sodium iodide, potassium iodide, etc.) may be added to the reaction system.

(lx) wherein R , R , R , W, and B are as defined above, and R ²⁴ is a lower alkyl.

The reaction of the compound (2b) and the compound

(22) can be carried out in an appropriate inert solvent.

The inert solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers

(e.g. tetrahydrofuran, dioxane, diethylene glycol dimethyl

ether, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol, butanol, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), acetic acid, ethyl acetate, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, and the like. The amount of the compound (2b) and the compound (22) is not critical, but the compound (22) is usually used in an amount of at least one mole, preferably 1 to 2 moles, to 1 mole of the compound (2b). The reaction is usually carried out at a temperature of from about 0°C to about 150°C, preferably from about 0°C to about 100°C, for about 30 minutes to about 10 hours.

The esterification of the compound (lw) is usually carried out by reacting the starting compound with an alcohol (e.g. methanol, ethanol, isopropanol, etc.) in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.) and a halogenating agent (e.g. thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc.) at a temperature of 0°c to 150°C, preferably 50°C to 100°C, for about 1 to 10 hours.

The hydrolysis of the compound (lx) can be carried out under the same conditions as in the hydrolysis of the compound (lj) in the Reaction Scheme-7.

[Reac ^t ion Scheme-14]

wherein R ¹ , R ² , R , W, B, M, and X are as defined above, and R ⁵ is a phenyl which has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent, or naphthyl,

*) C I

-nd R" is a phenoxy which has optionally 1 to 3 substituents selected from a lower alkyl, a lower alkoxy and an amino having optionally a lower alkanoyl substituent, naphthyloxy or phthalimido.

The reaction of the compound (lu) and the compound (23) or (23a) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

9 c ⁱ The compound (ly) wherein R" is phthalimido can uc uOil v ci tcu lii LU uc υual uuiiu { iγ ici ciu is amino under the same conditions as in the reaction of converting the compound (lj) into the compound (Ik) in the above

wherein R , R and R are as defined above, and R ^D is oxo, R ²⁷ is hydroxy, and W ¹ is the same as W, provided that the substituents on the group -(CH ₂ ) _p - or -CH=CH-(CH ₂ ) - are 0 to 2, and R^ "? r°\ and R "? Q are the same or different and are each hydrogen atom, a lower alkenyl, a cycloalkyl, an oxiranyl- substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl- lower alkyl, a pyridyl-lower alkyl, a cyano-substituted

lower alkyl, a lower alkoxycarbonyl-substituted _^ ower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl which has optionally a phenyl-lower alkyl substituent, an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, or a lower alkyl, or R ²⁸ and R ²⁹ may bind together with the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom, which heterocyclic ring may optionally have a substituent selected from a lower alkyl, a phenyl-lower alkyl, or a lower alkanoyl.

The conversion of the compound (1A) into the compound (IB) is carried out by reduction thereof. The reducing reaction is preferably carried out by using a hydrogenating reducing agent (e.g. lithium aluminum hydride, sodium boro hydride, diborane, etc.). The reducing agent is usually used in an amount of at least one mole, preferably 1 to 15 moles, to 1 mole of the starting compound. The reducing reaction is usually carried out in an appropriate solvent, for example, water, alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diir -nropyl ether, diglyme, etc.), or a mixture of these solvents, at a temperature of from about -60°C to about 150°C, peferably about -30°C to about 100°C, for about 10 minutes to 15 hours. When lithium aluminum

hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as tetrahydro¬ furan, diethyl ether, diisopropyl ether, diglyme, etc.

The reaction of converting the compound (1A) into the compound (1C) is usually carried out in an appropriate solvent or without solvent in the presence or absence of a dehydrating agent. The solvent includes, for example, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), aprotic polar solents (e.g. dimethylformamide, dimethyl- acetamide, N-methylpyrrolidone, etc.), or a mixture of these solvents. The dehydrating agent includes, for example, conventional drying agent used for dehydrating solvents (e.g. molecular sieves, etc.), mineral acids (e.g. hydrochloric acid, sulfuric acid, borone trifluoride, etc.), organic acids (e.g. p-toluenesulfonic acid, etc.), and the like. The reaction is usually carried out at a temperature of from room temperature to about 250°C, preferably from about 50°C to about 200°C, for about 1 to 48 hours. The amount of the compound (24) is not critical, but it is usually used at least in an equivalent amount, preferably equimolar to largely excess to the amount of the compound (1A). The dehydrating agent is preferably used in a largely excess amount in case of the drying agent and in a catalytic amount in case of the acid.

The subsequent reducing react_....n can be carried out by various methods, for example by catalytically hydrogenating the compound in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, iso¬ propanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the starting compound. The reaction is usually carried out at a temperature of from about -20°C to about 100°C, peferably about 0°C to about 70°C, under a hydrogen atmospheric pressure of 1 to 10 atm. for about 0.5 to 20 hours.

Although the reducting reaction can be carried out under the above conditions, it is preferably carried out by using a hydrogenating reducing agent. The hydrogenating reducing agent includes, for example, lithium aluminum hydride, sodium borohydride, diborane, etc., and it is usually used in an amount of at least one mole, preferably 1 to 10 moles, to 1 mole of the compound (1A). The reaction is usually carried out in an appropriate solvent, such as

water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.), dimethylformamide, or a mixture of these solvents, at a temperature of about -60°C to about 50°C, preferably about -30°C to room temperature, for about 10 minutes to about 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc.

The compound (1C) wherein at least one of R and ^'

»

R-" is hydrogen atom can be converted into the compound (1C) n o oq wherein at least one of R ° and R ' is a lower alkyl by reacting the compound (1C) with the compound (8) or the compound (9) under the same conditions as in the reaction of the compound (7) and the compound (8) or (9) in the above Reaction Scheme-4.

[Reaction Scheme-16]

I

(1F) (IG)

(i) Halogenation ψ (ii) MN ₃ (26)

NHCOOR 31

(1J)

wherein R ¹ , R ² , R ³ , R ¹⁴ , R ¹⁵ , W ¹ , and M are as defined above, and R ³¹ is a phenyl-lower alkyl, and R is a lower alkoxycarbonyl.

The reaction of converting the compound (ID) into the compound (IE) can be carried out under the same conditions as in the reaction of converting the compound (1A) into the compound (IB) in the above Reaction Scheme- 15.

The reaction of converting the compound (ID) into the compound (IF) can be carried out under the same conditions as in the hydrolysis reaction of the compound (lj) in the above Reaction Scheme-7.

The reaction of the compound (IF) and the compound (25) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The halogenation of the compound (IF) can be carried out under a conventional condition for halogenation of a carboxylic acid. The reaction of the thus-obtained carboxylic acid halide of the compound (IF) with the compound (26) is carried out in an appropriate solvent in the presence or absence of a basic compound. The solvent includes, for example, halogenated hydrocarbons (e.g. methylene chloride, chloroform, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters (e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents

(e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethyl- phosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, propanol, butanol, 3-methoxy-l-butanol, ethyl cellosolve, methyl cellosolve, etc.), pyridine, acetone, acetonitrile, water, or a mixture of these solvents. The basic compound includes, for example, organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N- methylmorpholine, DBN, DBU, DABCO, etc., inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, silver carbonate, alcoholates (e.g. sodium methylate, sodium ethylate, etc.), and the like. The compound (26) is usually used in an amount of at least 1 mole, preferably 1 to 1.5 mole, to 1 mole of the carboxylic acid halide of the compound (IF). The reaction is usually carried out at a temperature of from -30°C to about 180°C, preferably from about 0°C to about 150°C, for about 5 minutes to 30 hours.

The reaction of the compound _(1H) and the compound (27) is carried out in an appropriate solvent or without solvent at a temperature of from about 0°C to about 200°C, preferably from room temperature to about 150°C. The solvent includes the same solvents as used in the above reaction of the carboxylic acid halide of the compound (IF) and the compound (26). The compound (27) is preferably used in an amount largely excess to the the compound (1H). The reaction is usually completed in a reaction time of about 1

to 5 hours.

The reaction of converting the compound (II) into the compound (1J) can be carried out by reducing the compound. The reducing reaction is usually carried out by catalytically hydrogenating the compound in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cycl-ohexane, etc.), ethers (e.g. dioxane, tetra¬ hydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, etc.), acetic acid, or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the starting compound. The reaction is usually carried out at a temperature of from about -20°C to about 100°C, peferably about 0°C to about 80°C, under a hydrogen atmospheric pressure of 1 to 10 atm. for about 0.5 to 20 hours.

[Reaction Scheme-17]

(IM) wherein R ¹ , R ² , R ³ , W', a, R ¹⁷ , R ¹⁸ , and X are as defined above, and R ^14a is hydrogen atom, a lower alkyl, a lower alkanoyl, a lower alkenyl, a cycloalkyl, an oxiranyl- substituted lower alkyl, a lower alkyl having 1 to 2 substi¬ tuents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl,

benzoyl, a lower alkoxycarbonyl, anilinocarbonyl, an amino¬ carbonyl having optionally a lower alkyl substituent, a cyano-substituted lower alkyl, a lower alkoxycarbonyl- substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydro- pyranyloxy-substituted lower alkyl, a lower alkanoyloxy- substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent, a halogen-substituted lower alkanoyl, an imiazolyl-substituted lower alkanoyl, an amino- lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, an aminocarbonyl- lower alkyl having optionally a lower alkyl substituent, or a phenyl-lower alkoxycarbonyl, R ^15a is a lower alkyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, a cyano-substituted lower alkyl, a lower alkoxycarbonyl-substituted lower alkyl, a carbamoyl- substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyloxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent, an amino¬ carbonyl-lower alkyl having optionally a lower alkyl substituent, or a lower alkenyl, and R is a lower alkanoyl, a phenyl-lower alkoxycarbonyl, benzoyl, a lower alkoxycarbonyl, a halogen-substituted lower alkanoyl, an

imidazolyl-substituted lower alkanoyl, or an amino-lov r alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl.

The reaction of the compound (IK) and the compound

(28) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.

The reaction of the compound (IK) and the compound

(29) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. The compound (IM) can also be obtained by reacting the compound (IK) with a compound of the formula (R ^15b ) ₂ 0 (wherein R ^15t> is as defined above). The reaction can be carried out under the same conditions as in the reaction of the compound (lp) and the compound of the formula: (R ^7b ) ₂ 0 as described hereinbefore.

The compound (IM) wherein R ¹⁵ is formyl can also be prepared by reacting the compound (IK) with a formate of the formula: HCOOR ⁸² (R ⁸² is a lower alkyl). The reaction is usually carried out in the solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4 or without solvent, at a temperature of about 0°C to about 200°C, preferably about 0°C to about 170°C, for about 30 minutes to about 30 hours. The formate is preferably used in a largely excess amount to the compound (IK) .

( IN ) ( 10)

(IP) (IP') wherein R ¹ , R ² , R ⁴ , R ¹⁶ , W, a, a ¹ and a" are as defined above, and R ³² is a lower alkoxycarbonyl-substituted lower alkoxy, R ³³ is a carbamoyl-substituted lower alkoxy, R ³⁴ is

a carboxy-substituted lower alkoxy, R is an amino having optionally a lower alkyl substituent, and R ⁵ is an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent.

The conversion of the compound (IN) into the compound (10) can be carried out by reacting the compound with aqueous ammonia in an appropriate solvent in an autoclave. The solvent includes the same solvents as used in the reaction of the carboxylic acid halide and the ami-ne (2) in the above Reaction Scheme-1. The aqueous ammonia is used in a largely excess amount to the compound (IN). The reaction proceeds advantageously by adding an ammonium halide (e.g. ammonium chloride, etc.) to the reaction system. The reaction is usually carried out at a temperature of from room temperature to about 200°C, preferably from room temperature to about 150°C, for about 1 to 10 hours.

The reaction of converting the compound (IN) into the compound (IP) can be carried out under the same conditions as in the hydrolysis of the compound (lj) in the above Reaction Scheme-7.

The reaction of the compound (IP) and the compound (30) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

( N0 ₂ ) ₁ , ( NH ₂ ) _J . „

(IQ) (IR) wherein R ¹ , R ² , R ⁴ , R ¹⁶ , W, a, a' and a" are as defined above.

The reducing reaction in the above reaction scheme is usually carried out, for example, (i) with a reducing catalyst in an appropriate solvent or (ii) with a reducing agent such as a mixture of a metal or metal salt with an acid, or a mixture of a metal or metal salt with an alkali metal hydroxide, a sulfide or an ammonium salt in an appropriate inert solvent.

In case of using a reducing catalyst, the solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane. cyclohexane, etc.), ethers (e.g. dioxane, tetra¬ hydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.),

aprotic polar solvents (e.g. N,N-dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to 1 part by weight to 1 part by weight of the starting compound. The reaction is usually carried out at a temperature of from about -20°C to about 150°C, peferably about 0°C to about 100°C, under a hydrogen pressure of 1 to 10 atm. for about 0.5 to 10 hours. In the reaction, an acid such as hydrochloric acid may optionally added to the reaction system.

In case of the above method (ii), the reducting agent includes a mixture of iron, zinc, tin or stannous chloride and a mineral acid (e.g. hydrochloric acid, sulfuric acid, etc.), or a mixture of iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide, etc.), a sulfide (e.g. ammonium sulfide, etc.), aqueous ammonia, or an ammonium salt (e.g. ammonium chloride, etc.). The inert solvent includes, for example water, acetic acid, methanol, ethanol, dioxane, and the like. The reducing reaction conditions are determined depending on the kinds of the reducting agent, but in case of using a reducing agent comprising stannous chloride and hydrochloric acid, for example, it is preferably carried out at a temperature of about 0°C to room temperature for about 0.5 to 10 hours. The reducing agent is usually used in an

amount of at least one mole, preferably 1 to 5 moles, to 1 mole of the starting compound. [Reaction Scheme-20]

)

IU) wherein R ¹ , R ² , R ⁴ , R ¹⁶ , R ¹⁷ , R ¹⁸ , a, a', a" and W are as

defined above, and R is a lower alkyl, R ³⁷ is a lower alkanoyl, and R ³⁵ is hydrogen atom, a lower alkyl or a lower alkanoyl.

The reaction of the compound (IS) and the compound

(31) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.

The reaction of the compound (IS) and the compound

(32) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. Besides, the compound (IU) can also be obtained by reacting the compound (IS) with a compound of the formula: (R ^J 37') ₂ 0 (R ^J 37 is as defined above). The reaction is carried out under the same conditions as in the aDove reaction of the compound (lp) and a compound of the formula: (R ^7b ) ₂ 0. o

The compound (1) wherein R° is a phenyl-lower alkoxycarbonyl can be converted into the compound (1) wherein R ⁸ is hydrogen atom in the same manner as in the reaction of converting the compound (II) into the compound (1J) in the above Reaction Scheme-16.

Other derivatives of the starting compound (2) can be prepared, for example, by the process _ shown in the following reaction scheme.

[ Reaction Scheme-21 ]

R'

(2a) wherein R ¹ , R ² , and W are as defined above.

The reaction of the compound (2) and the compound (33) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of converting the compound (34) into the compound (2a) can be carried out under the same conditions as in the reducing reaction in the above Reaction Scheme-19.

The starting compound (5) can be prepared, for example, by the process of the following reaction scheme.

[Reaction Scheme-22]

(5) wherein R , R , and W are as defined above, and R ³⁸ is a lower alkyl..

The reaction of the compound (2) and the compound (35) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of converting the compound (36) into the compound (5) can be carrit out under the same conditions as in the hydrolysis reaction in the above Reaction Scheme-7.

[Reaction Scheme-23]

(1W) (IX) wherein R ¹ , R ^Λ , R , R ^xo , a, a', a", X, and W are as defined above, and R ³⁹ is a lower alkanoyl.

The reaction of the compound (1W) and the compound (37) can be carried out under the same conditions as in the reaction of the compound (In) and the compound (18) in the above Reaction Scheme-9.

The hydrolysis reaction of the compound (IX) can be carried out under the same conditions as in the hydrolysis of the compound (lj) in the above Reaction Scheme-7.

(1Y) (IZ) wherein R ¹ , R ² , R ⁴ , R ¹⁶ , a, a', a", and W are as defined above, R is a lower alkanoyl, and R is a hydroxy- substituted lower alkyl.

The reaction of converting the compound (1Y) into the compound (IZ) can be carried out under the same conditions as in the reaction of converting the compound (1A) into the compound (IB) in the above Reaction Scheme- 15.

..

( laa ) ( lbb ) wherein R ¹ , R ² , R ⁴ , R ¹⁶ , a, a', a", and W are as defined above, R is a lower alkoxycarbonyl and R ⁴³ is carboxyl.

The reaction of converting the compound (laa) into the compound (lbb) can be carried out under the same conditions as in the hydrolysis of the compound (lj) in the above Reaction Scheme-7.

The esterification reaction of the compound (lbb) can be carried out under the same conditions as in the esterification of the compound (lw) in the above Reaction Scheme-13.

(2b)

0 dec) wherein R ¹ , R ² , R , and W are as defined above, and R ^4δ is a phenyl having optionally a lower alkyl substituent.

The reaction of the compound (2b) and the compound (38) is usually carried out in an appropriate solvent or without solvent in the presence or absence, preferably in the absence, of a basic compound. The solvent and basic compound are the same as those used in the reaction of the carboxylic acid halide and the amine (2) in the above Reaction Scheme-1.

The compound (38) is usually used in an amount of about 1 to 5 moles, preferably about 1 to 3 moles, to 1 mole of the compound (2b). The reaction is usually carried out at a temperature of from about 0°C to about 200°C, prefer¬ ably from room temperature to about 150°C, for about 5 iϊiinute__ uo about 30 hours. In the reaction, a boron compound (e.g. boron trifluoride etherate, etc.) may be added to the reaction system.

[Reaction Scheme-27]

(ldd) wherein R , R , R , W, and X are as defined above, and R ⁷ is a phenylsulfonyl which has optionally a substituent selected from a halogen atom and a lower alkyl on the phenyl ring, or quinolylsulfonyl.

The reaction of the compound (2b) and the compound (39) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

[Reaction Scheme-28]

(iff) wherein R ¹ , R ² , R ⁴ , W, R ¹⁷ , R ¹⁸ , and X are as defined above,

,48 is a phenyl-lower alkoxycarbonyl, a lower alkanoyl, an amino-lower alkanoyl having optionally a lower alkyl substituent, and R is a lower alkyl or a carbamoyl-lower alkyl.

The reaction of the compound (lee) and the compound (40) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the

above Reaction Scheme-1.

The reaction of the compound (lee) and the compound (41) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4, provided that in the reaction product (Iff) produced by the reaction of the compound (lee) and the compound (9), the group R 4Q is a lower alkyl.

[Reaction Scheme-29]

(7) (lhh) wherein R ¹ , R , R , and W are as defined above, and R^° is a benzoyl having optionally a halogen substituent on the phenyl ring.

The reaction of the compound (7) and the compound (42) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

[Reaction Scheme-30]

(1A) (Iii) wherein R ¹ , W ¹ , R ²⁶ , R ² , and R ³ are as defined above, R ¹⁰³ is hydroxy or sulfoxy, and R ⁵ is hydroxyimino or sulfoxy- imino.

The reaction of the compound (1A) and the compound (43) is usually carried out in an appropriate inert solvent in the presence or absence of a basic compound. The basic compound includes, for example, inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and organic basic compounds such as piperidine, pyridine, triethylamine, l,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo- [5.4.0]undecene-7 (DBU) , 1,4-diazabicyclo[2.2.2Joctane (DABCO), etc. The inert solvent includes, for example, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, ethylene glycol monomethyl ether, etc.). aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, dichloro¬ ethane, chloroform, carbon tetrachloride, etc.), pyridine,

dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc., or a mixture of these solvents. The compound (43) is usually used at least in equivalent amount, preferably 1 to 5 moles, to 1 mole of the compound (1A). The reaction is usually carried out at a temperature of from room temperature to about 200°C, preferably from about 50°C to 150°C, for about 1 to 10 hours. [Reaction Scheme-31]

(IB) djj)

MN ₃ (44)

(laa ) (lkk) wherein R ¹ , W ¹ , R ^Δ ' , R , M, and R° are as defined above, and R ⁵² is a halogen atom.

The halogenation of the compound (IB) is usually carried out in an appropriate solvent or without solvent by

reacting the compound (IB) with a halogenating agent.

The halogenating agent includes mineral acids (e.g. hydrochloric acid, hydrobromic acid, etc.), N,N-diethyl- 1,2,2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, or a combination of a phenyl-lower alkyl halide (e.g. p-toluenesulfonyl chloride, etc.) and a basic compound. The basic compound includes the same compounds as used in the reaction of the compound (1A) and the compound (43) in the above Reaction Scheme-30. The solvent includes, for example, ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbon tetrachloride, etc.), and the like. The amount of the halogenating agent may vary depending on the kinds of the halogenating agents, and in case of a combination of a phenyl-lower alkyl halide (e.g. p-toluenesulfonyl chloride, etc.) and a basic compound, it is used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (IB), and in case of other halogenating agents, it is used at least in an equimolar amount, usually in a largely excess amount, to the compound (IB). The reaction is usually carried out at a temperature of from room temperature to about 150°C, preferably from room temperature to about 80°C, for about 1 to 80 hours.

The reaction of the compounu (ljj) and the compound (44) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the

above Reaction Scheme-4.

The reducing reaction of the compound (lkk) can be carried out under the same conditions as in the reducing reaction using a reducing catalyst for converting the compound (1A) into the compound (IC) in the above Reaction Scheme-15.

[Reaction Scheme-32A]

dPP ⁾ dqq) wherein R ¹ , W' , R ² , R ³ , R ²⁷ , X, and A are as defined above, R ⁵ is a lower alkanoyloxy having optionally a halogen substituent R^ is a lower alkoxy, an amino-lower alkanoyloxy having optionally a lower alkyl substituent, or a group of the formul

(A, R ⁸² and R ⁸³ are as defined above), R ⁵⁵ is a lower alkoxycarbonyl-substituted lower alkoxy, R is a carboxy-substituted lower alkoxy, R is an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent, R ^54a is a lower alkyl, an amino-lower alkanoyl having optionally a

82

/ R lower alkyl substituent, or a group of the formula: -A-CON _R 83

, _{Λ R} 82 and R are as defined above), R is a lower alkoxy¬ carbonyl-substituted lower alkyl, R ⁵⁸ and R ⁵⁹ are the same or different and are each hydrogen atom or a lower alkyl, and R ^a is a lower alkanoyl having optionally a halogen substituent. [Reaction Scheme-32B]

IB) (iqq' ) wherein R ¹ , W' , R ² , R ³ , X, R ²⁷ , and A are as defined above, and R ⁶¹ and R° are the same or different and are each hydrogen atom, a lower alkyl or a lower alkanoyl.

The reaction of the compound (IB) and the compound (45) or the compound (46) in the Reaction Scheme-32A can be carried out under the same conditions as in the reaction of the compound (In) and the compound (18) in the above Reaction Scheme-9.

The reaction of the compound (IB) and the compound

(47) and the reaction of the compound (IB) and the compound

(48) can be carried out under the same conditions as in the reaction of the compound (In) and the compound (18) in the above Reaction Scheme-9.

The reaction of converting the compound (loo) into the compound (Ipp) can be carried out under the same conditions as in the hydrolysis reaction of the compound (lj) in the above Reaction Scheme-7.

The reaction of the compound (loo) and the compound

(49) and the reaction of the compound (Ipp) and the compound (49) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of the compound (IB) and the compound (49a) in the Reaction Scheme-32B can be carried out under the same conditions as in the reaction of the compound (In) and the compound (18) in the above Reaction Scheme-9.

[Reaction Scheme-33]

(ltt) (luu) wherein R ¹ , W , R ² , R ³ , R ²⁷ , R ⁶¹ , R ⁶² , M, and X are as defined above, R is a halogen-substituted lower alkyl, R ⁶⁴ is a phthalimido-substituted lower alkyl, R ⁶³ is an amino-

lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl, or a phthalimido- substituted lower alkoxy, and R is an amino-substituted lower alkyl.

The reaction of the compound (IB) and the compound

(50) and the reaction of the compound (IB) and the compound (52) can be carried out under the same conditions as in the reaction of the compound (In) and the compound (18) in the above Reaction Scheme-9.

The reaction of the compound (lrr) and the compound

(51) or the compound (23a) can be carried out under the same conditions as in the reaction of the compound (lg) and the compound (14) in the above Reaction Scheme-6.

The reaction of converting the compound (ltt) into the compound (luu) can be carried out under the same conditions as in the reaction of converting the compound (lj) into the compound (Ik) in the above Reaction Scheme- 7.

[Reaction Scheme-34]

(lxx) wherein R ¹ , R ² , R ³ , R ⁶¹ , W', A, R ¹⁷ , R ¹⁸ , and X are as defined above, R° ^2a is a lower alkyl, and R ^62b i _s a lower alkanoyl.

The reaction of the compound (lvv) and the compound

(53) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.

The reaction of the compound (lvv) and the compound

(54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the

above Reaction Scheme-1.

The reaction of the compound (lvv) and the compound (55) can be carried out under the same conditions as in the reaction of the compound (lp) and the compound of the formula: (R ^b ) ₂ 0 in the above Reaction Scheme-10. [Reaction Scheme-35]

dyy) (lzz) wherein R ¹ , R ² , R , and W' are as defined above, R ⁵⁸ ' and cq i

R ³³ are the same or different and are each hydrogen atom, a lower alkyl, or a lower alkanoyl.

The reaction of converting the compound (lyy) into the compound (lzz) is usually carried out by reducing the compound (lyy) .

The reducting reaction is preferably carried out by using a hydrogenating reducing agent. The hydrogenating reducing agent includes, for example, lithium aluminum hydride, sodium boro hydride, diborane, etc. The reducing agent is usually used in an amount of at least one mr e, preferably 1 to 15 moles, to 1 mole of the starting compound. The reducing reaction is usually carried out in an appropriate solvent, such as water, lower alcohols (e.g.

methanol, ethanol, isopropanol, etc.), ethers (e.g. tetra¬ hydrofuran, diethyl ether, diisopropyl ether, diglyme, etc.), or a mixture of these soslvents, at a temperature of about -60°C to about 150°C, preferably about -30°C to 100°C, for about 10 minutes to about 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc. [Reaction Scheme-36]

(IBB) wherein R ¹ , W', R", R ^J , R ^Uώα , R ^OΛU , X, R ^x ' , R ^o , and A are as defined above, R ^58a is hydrogen atom, a lower alkyl or a lower alkanoyl.

The reaction of the compound (1AA) and the compound

(53) or the compound (9) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) or the compound (9) in the above Reaction Scheme-4.

The reaction of the compound (1AA) and the compound

(54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of the compound (1AA) and the compound

(55) can be carried out under the same conditions as in the reaction of the compound (lp) and the compound of the formula: (R ^7b ) ₂ 0 in the above Reaction Scheme-10.

The compound (IBB) wherein R ^62b is formyl can also be prepared by reacting the compound (1AA) with a formate of the formula: HC00R° under the same conditions as in the reaction of the compound (IK) and the compound of the formula: HCOOR as described hereinbefore.

The compounds of the formula (1) wherein W is sulfur atom or sulfinyl, or R ⁸² and R ⁸³ bind together with the nitrogen atom to which they bond to form thiomorpholino or 1-oxo-thiomorpholino can be converted into the corres¬ ponding compounds of the formula (1) wherein W is sulfinyl or sulfonyl, or R ⁸² and R bind together with the nitrogen atom to which they bond to form l-oxo-thiomor' iOlino or 1,1- dioxo-thiomorpholino, respectively, by oxidation the. -of. The oxidation reaction is carried out in an

appropriate solvent in the presence of an oxidizing agent. The solvent includes, for example, water, organic acids (e.g. formic acid, acetic acid, trifluoroacetic acid, etc.), alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chloroform, dichloromethane, etc.), or a mixture of these solvents. The oxidizing agent includes, for example, peracids (e.g. performic acid, peracetic acid, trifluoro-peracetic acid, perbenzoic acid, m-chloro- perbenzoic acid, o-carboxy-perbenzoic acid, etc.), hydrogen peroxide, sodium metaperiodate, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate, etc.), permanganic acid, permanganates (e.g. potassium permanganate, sodium permanganate, etc.), lead salts (e.g. lead tetraacetate, etc.), and the like. The oxidizing agent is usually used in an amount of at least 1 mole, preferably

1 to 2 moles, to 1 mole of the starting compound. Besides, in cases of the oxidation of converting the sulfur atom into sulfonyl group, the oxidizing agent is usually used at least

2 moles, preferably 2 to 4 moles, to 1 mole of the starting compound. The above reaction is usually carried out at a temperature of about -10°C to about 40°C, preferably from about -10°C to room temperature, for about 1 to 100 hours.

The compound (1) wherein R ^xo or R is a lower alkoxy can be converted into the correspond compound (1) wherein R or R is hydroxy by heating the compound in a mixture of an acid (e.g. hydrobromic acid, hydrochloric acid, etc.) and a solvent (e.g. water, methanol, ethanol,

isopropyl alcohol, etc.) at 30 to 150°C, preferably at 50 to 120°C.

-i c o

Besides, the compound (1) wherein R ^XD or R is hydroxy can also be prepared by hydrolysis of the above compound (1) wherein R ¹⁶ or R is a lower alkoxy. The hydrolysis can be carried out in an appropriate solvent in the presence of an acid. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), ethers (e.g. dioxane, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride, etc.), polar solvents (e.g. acetonitrile, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, hydrobromic acid, etc.), Lewis acids (e.g. boron trifluoride, aluminum chloride, boron tri- bromide, etc.), iodides (e.g. sodium iodide, potassium iodide, etc.), or a mixture of the above Lewis acid and iodide. The reaction is usually carried out at a tempera¬ ture of from room temperature to about 150°C, preferably from room temperature to about 100C, for about 0.5 to 30 hours.

[Reaction Scheme-37]

(Iii') (IDD; wherein R ¹ , R ² , R ³ , R ^{6 b} , and W' are as defined above, R ^51a is hydroxyimino, and R°° is a lower alkanoyloxyimino.

The reaction of the compound (Iii ¹ ) and the compound (54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of the compound (Iii ¹ ) and the compound (55) can be carried out under the same conditions as in the reaction of the compound (lp) and the compound of the formula: (R ^7b ) ₂ 0 in the above Reaction Scheme-10.

[Reaction Scheme-38A]

(1A) (1EE)

(IGG) (IFF)

Reaction Scheme-38B^

(IE)

R ⁷⁰ X 56)

R ^J ₂ OR 70

(UJ) (1HH)

[Reaction Scheme-38C]

(III)

[Reaction Scheme-38D]

(IKK)

[Reaction Scheme-38E]

(1EE)

(1LL) (1MM) wherein . RR ¹ , R ² , R R ³³ ,, Ww' ¹ , R R ²²⁶⁶ ,, R R ¹¹⁴⁴ ,, R R ¹¹⁵⁵ ,, R R ^6622bb ,, X X aa;nd M are as defined above, R ' is methylidene, R ⁵ is a group of the

\ formula: _^ Ω, and R ,°6'9 i *s a group of th

^

(R ¹⁴ and R ¹⁵ are as defined above), or amino having optionally a substituent selected from a lower alkyl and a lower alkanoyl, R 7fl is a lower alkylsulfonyl, and W" is the same as the above W, provided that the number of the substituent in the groups -(CH ₂ ) - and -CH=CH-(CH ₂ )_- is 0 or 1.

The reaction of converting the compound (1A) into the compound (1EE) is carried out in an appropriate solvent in the presence of a Wittig reagent and a basic compound. The Wittig reagent includes, for example, a phosphoric compound of the formula:

[ (R ⁷¹ ) ₃ P ⁺ -CH ₂ -R ⁷ ]X ^" (A) wherein R ⁷ is phenyl, R is hydrogen atom or a lower alkyl, and X is a halogen atom. The basic compound includes inorganic bases (e.g. metallic sodium, metallic potassium, sodium hydride, sodium amide, sodium hydroxide, potassium- hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.), metal alcoholates (e.g. sodium methylate, sodium ethylate, potassium t-butoxide, etc.), alkyl or aryl lithiums or lithium amides (e.g. methyl lithium, n- butyl lithium, phenyl lithium, lithium diisopropylamide, etc.), organic bases (e.g. pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline, etc.). The solvent includes any solvent which does not affect on the reaction, for example, ethers (e.g. diethyl ether, dioxane, tetra¬ hydrofuran, monoglyme, diglyme, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydro¬ carbons (e.g. n-hexane, heptane, cyclohexane, etc.), amines (e.g. pyridine, N,N-dimethylaniline, etc.), aprotic polar solvents (e.g. N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, isopropanol, etc.), and the like. The reaction is usually carried out at a temperature of about -80°C to about 150°C, preferably about -80°C to about 120°C,

for about 0.5 to 15 hours.

The reaction of converting the compound (1EE) into the compound (ILL) can be carried out under the same conditions as in the catalytically hydrogenation reaction for converting the compound (1A) into the compound (IC) in the above Reaction Scheme-15.

The reaction of converting the compound (1EE) into the compound (IFF) is carried out under the same conditions as in the reaction of converting the compound (1) wherein W is sulfur atom or sulfinyl into the corresponding compound (1) wherein W is sulfinyl or sulfonyl respectively as described herebefore.

The reaction of the compound (IFF) and the compound (25) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

The reaction of converting the compound (1EE) into the compound (IE) can be carried out by firstly subjecting it to hydroboration reaction and then to oxidation.

The hydroboration reaction is carried out in a solvent such as ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.) in the presence of a hydroborating agent at a temperature of from about 0°C to about 50°C, preferaly about 0°C to room temperature, for about 1 to 10 hours. Th° hydroborating agent includes b..on hydride compounds, for example, BH ₃ .tetrahydrofuran, BH ₃ .S(CH ₃ ) ₂ , BH ₂ C1, (CH ₃ ) ₂ CHC(CH ₃ ) ₂ BH ₂ , (CH ₃ ) ₂ CHCH(CH ₃ )BH, (Q-) ₂ -BH, (|< YJ ₂ BH,

, BHC1 ₂ , and the like.

The subsequent oxidation is carried out in water in the presence of an oxidizing agent. The oxidizing agent includes, for example, alkaline hydrogen peroxides (e.g. hydrogen peroxide - sodium hydroxide, etc.), and air oxidation is also used. The reaction is usually carried out at a temperature of from room temperature to about 150°C, preferably from room temperature to about 100°C, for 0.5 to 7 hours.

The hydroborating agent and the oxidizing agent are each used in an amount of at least 1 mole, preferably 1 to 2 mole, to 1 mole of the compound (1EE).

The reaction of the compound (IE) and the compound

(54) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1.

The reaction of the compound (IE) and the compound

(55) can be carried out under the same conditions as in the reaction of the compound (lp) and the compound of the formula: (R ^7b ) ₂ 0 in the above Reaction Scheme-10.

The reaction of the compound (IE) and the compound

(56) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

The reaction of the compound (1HH) and the compound (44) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

The reducing reaction of the compound (1JJ) can be carried out under the same conditions as in the catalytic hydrogenation reaction for converting the compound (1A) into the compound (IC) in the above Reaction Scheme-15.

The reaction of converting the compound (1EE) into the compound (1MM) can be carried out by reacting with an oxidizing agent in an appropriate solvent in the presence of a co-oxidizing agent.

The solvent used for the reaction with an oxidizing agent includes, for example, pyridine, ethers (e.g. dioxane, tetrahydrofuran, diethyl ether, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydro¬ carbons (e.g. dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), esters (e.g. ethyl acetate, etc.), water, alcohols (e.g. methanol, ethanol, isopropanol, t-butanole, etc.), or a mixture of these solvents. The co- oxidizing agent includes, for example, organic amine N- oxides (e g. pyridine N-oxide, N-ethyldiisopropylamine N- oxide, N-methylmorpholine N-oxide, trimethylamine N-oxide, triethylamine N-oxide, etc.). The oxidizing agent includes, for example, osmium tetraoxide, and the like. The oxidizing agent is usually used in an amount of at least 1 mole, preferably 1 to 5 moles, to 1 mole of the starting compound. The reaction is usually carried out at a temperature of from -20°C to 150°C, preferably from room temperature to 100°C, for about 1 to 10 hours.

( INN ' ) 1 9 3 97 wherein R , R , R , R ' , W ¹ , M , and X are as def ined above ,

R 7'3 is an aminocarbonyl having optionally a lower alkyl substituent, R ⁷ is an aminocarbonyloxy having optionally a lower alkyl substituent, R 7'4 ' is a lower alkyl.

The reaction of the compound (1A) and the compound (57) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

The reaction of the compound (1A) and the compound (59) is carried out in an appropriate solvent in the presence of an acid. The solvent includes the same solvent

as used in the reaction of the ^' compound (7) and the compound (8) in the above Reaction Scheme-4. The acid includes, for example, mineral acids (e.g. hydrochloride acid, sulfuric acid, etc.), sulfonic acids (e.g. methanesulfonic acid, p- toluenesulfonic acid, etc.), alkanoic acids (e.g. trifluoroacetic acid, etc.), and the like. The compound (59) is used in an amount of at least 1 mole, preferably 1 to 5 moles, to 1 mole of the compound (1A). The reaction is usually carried out at a temperature of from room temperature to about 150°C, preferably from room temperature to about 100°C, for about 1 to 7 hours.

The reaction of the compound (1A) and the compound (58) can be carried out under the same conditions as in the reaction of the compound (2b) and the compound (38) in the above Reaction Scheme-26. [Reaction Scheme-40]

wherein R ¹ , R ² , R , X, and q are as defined above, and R ⁷⁵ ,

R 76 and R ⁷⁷ are each a lower alkyl, and the carbon atom in the formula: -(CH ₂ ) - may be substituted by oxygen atom.

sulfur atom, sulfinyl, sulfonyl, or a group of the formula:

R ¹³ -N ¹ - (R13 ^J is as defined above), and further the group: -(CH ₂ ) - may optionally have 1 to 3 substituents selected from a lower alkyl having optionally a hydroxy substituent, a lower alkoxy¬ carbonyl, carboxyl, hydroxy, oxo, a lower alkanoyloxy having optionally a halogen substituent, an amino-lower alkyl having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a lower alkanoyloxy-substituted lower alkyl, a lower alkylsulfonyloxy-lower alkyl, an azido-lower alkyl, a- group of the formula: D, an aminocarbonyloxy having optional¬ ly a lower alkyl substituent, a lower alkoxy, a lower alkoxy¬ carbonyl-substituted lower alkoxy, a carboxy-substituted lower alkoxy, an aminocarbonyl-lower alkoxy having optionally a lower alkyl substituent, an amino-lower alkoxy having optionally a substituent selected from a lower alkyl and a lower alkanoyl, a phthalimido-substituted lower alkoxy, hydroxyimino, a lower alkanoyloxyimino, a lower alkylidene, a halogen atom, azido, sulfoxyimino, a group of the formula: R -N-CH COO- (R ⁸¹ is

hydrogen atom or a lower alkyl), hydrazino, pyrrolyl, an amino- lower alkanoyloxy having optionally a lower alkyl substituent,

a group of the formula: (A is as defined above, and R ⁸² and R ⁸³ are the same or different and are each hydrogen atom, a lower alkyl, a carbamoyl-substituted lower alkyl, a hydroxy-substituted lower alkyl, or a pyridyl-lower alkyl, or R ⁸² and R may bind together with nitrogen atom to which they

bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen, oxygen or sulfur atom wherein the heterocyclic group has optionally a substituent selected from oxo, a lower alkyl, a lower alkanoyl,

and carbamoyl), and a group of the formula: -(C0) _n ~N ⁴ (n is

_R 15 as defined above, and R and R ⁵ are the same or different and are each hydrogen atom, a lower alkyl, a lower alkenyl, a lower alkanoyl, a cycloalkyl, an oxiranyl-substituted lower alkyl, a lower alkyl having 1 to 2 substituents selected from a lower alkoxy, hydroxy and an amino having optionally a lower alkyl substituent, a phenyl-lower alkyl, a pyridyl-lower alkyl, a lower alkylsulfonyl, benzoyl, a lower alkoxycarbonyl, anilino¬ carbonyl, an aminocarbonyl having optionally a lower alkyl substituent, a cyano-substituted lower alkyl, a lower alkoxy¬ carbonyl-substituted lower alkyl, a carbamoyl-substituted lower alkyl, a carboxy-substituted lower alkyl, a tetrahydropyranyl- oxy-substituted lower alkyl, a lower alkanoyloxy-substituted lower alkyl, a piperidinyl having optionally a phenyl-lower alkyl substituent on the piperidinyl ring, a halogen-substi¬ tuted lower alkanoyl, an imidazolyl-substituted lower alkanoyl, an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, an aminocarbonyl-lower lkyl having optionally a lower alkyl substituent, or a p ^h enyl-lower alkoxycarbonyl, or R ¹⁴ and R may bind together ^r , -.h the nitrogen atom to which they bond to form a 5- or 6-membered saturated heterocyclic group with or without being intervened with nitrogen or oxygen atom, which

heterocyclic group may optionally have a substituent selected from a lower alkyl, a phenyl-lower alkyl and a lower alkanoyl.

The reaction of the compound (100) and the compound (60) is carried out in an appropriate solvent in an autoclave. The solvent includes any solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme- 4. The reaction is usually carried out at a temperature of from room temperature to about 200°C, preferably from room temperature to about 150°C, for about 1 to 7 hours.

The subsequent deamination reaction is carried out in an appropriate solvent in the presence of a basic compound.

The solvent includes the same solvent as used in the above reaction of the compound (100) and the compound (60). The basic compound includes any basic compound as used in the reaction of converting the compound (1A) into the compound

(1EE) in the above Reaction Scheme-38. The reaction is usually carried out at a temperature of from room temperature to about

150°C, preferably from room temperature to about 100°C, for about 1 to 10 hours.

[Reaction Scheme-41]

(1QQ) (1RR) wherein R ¹ , R ² , R , R , M, and W' are as defined above, R ⁷⁸ is

— lib —

an oxiranyl-substituted lower alkyl, R 7'9 is a lower _lkoxy, o an amino having optionally a lower alkyl substituent, and R

is a lower alkyl having 2 substituents selected from hydroxy, lower alkoxy, and an amino having optionally a lower alkyl substituent.

The reaction of the compound (1QQ) and the compound

(61) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the abov Reaction Scheme-4.

The reaction of the compound (1QQ) and the compound

(62) can be carried out by firstly reacting them in trifluoro acetic acid at a temperature of about 0°C to about 100°C, preferably about 0°C to about 50°C, for about 1 to 7 hours, followed by hydrolysis of the resultant.

The hydrolysis is carried out in an appropriate solvent or without solvent in the presence of an acid or a basic compound. The solvent includes, for example, water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, etc.), and the like. Th basic compound includes, for example, metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide

etc.). The reaction is usually carried out at a temperature of from room temperature to about 200°C, preferably from room temperature to about 150°C, for about 0.5 to 25 hours. [Reaction Scheme-42]

Reduction

(ISS) (lu ) wherein R , R ² , R ³ , and W ¹ are as defined above, and R ^{81 ls} hydroxyimino or a lower alkanoyloxyimino.

The reaction of converting the compound (ISS) into the compound (la ) is carried out by catalytically hydrogenating the compound (ISS) in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g. dimethylformamide, etc.), or a mixture of these solvents. The catalyst includes, for example, palladium, palladium black, palladium-carbon, platinum, platinum oxide, copper chromate, Raney nickel, and the like. The catalyst is usually used in an amount of 0.02 to

1 part by weight to 1 part by weight of the compound (ISS).

The reaction is usually carried out at a temperature of from

about -20°C to about 100°C, peferably about 0°C to about 70°C, under a hydrogen atmospheric pressure of 1 to 10 atm. for abou 0.5 to 20 hours.

Alternatively, the reducing reaction can also be carried out by using a hydrogenating reducing agent. The hydrogenating reducing agent includes, for example, lithium aluminum hydride, sodium boro hydride, diborane, etc. The reducing agent is usually used in an amount of at least one mole, preferably 1 to 10 moles, to 1 mole of the compound (ISS). The reaction is usually carried out in an appropriate solvent, such as water, lower alcohols (e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, etc.), acetic acid, and the like, at a temperature of about 0°C to about 200°C, preferably about 0°C to 170°C, for about 10 minutes to about 10 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran, diglyme, etc. [Reaction Scheme-43]

{ —- ) (1TT) wherein R ¹ , R ² , R ³ , W' , a, R ^14a are as defined above, and R ⁸³ is phenyl or a lower alkyl.

The reaction of the compound (IK) and the compound (63) can be carried out under the same conditions as in the reaction of the compound (2b) and the compound (38) in the above Reaction Scheme-26. [Reaction Scheme-44]

(IK) (1UU) wherein R ¹ , R ² , R ³ , W ¹ , a, R ^{1 a} are as defined above.

The reaction of the compound (IK) and the glyco- nitrile (64) can be carried out in an appropriate solvent. The solvent includes the same solvent as used in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4. The reaction is usually carried out at a temperature of from about 0°C to about 150°C, preferably about 0°C to about 100°C, for about 1 to 10 hours. The glyconitrile (64) is used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (IK) .

[Reaction Sc .?-45]

(1XX) wherein R ¹ , R ² , R ³ , W' , a, R ^{1 a} are as defined above, R ,8*"4 is lower alkoxycarbonyl-substituted lower alkyl, R" is an amino having optionally a lower alkyl substituent, R°° is an aminocarbonyl-lower alkyl having optionally a lower alkyl substituent, and R ⁸⁷ is a carboxy-substituted lower alkyl.

The reaction of the compound (1W) and the compound

(65) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above

Reaction Scheme-1. The hydrolysis reaction of the compound (l. ^" V) can be carried out under the same conditions as in the hydrolysis reaction of the compound (IQQ) and the compound (62) in the above Reaction Scheme-41.

[Reaction Scheme-46]

(laaa) wherein R ¹ , R ² , R ³ , W ¹ , a, X, and R ^14a are as defined above, R ⁸⁸ is a tetrahydropyranyloxy-substituted lower alkyl, R ⁸⁹ is a lower alkanoyloxy-substituted lower alkyl, R ⁹⁰ is a hydroxy- substituted lower alkyl, and R ⁹¹ is a lower alkanoyl.

The reaction of the compound (1YY) and the compound (66) can be carried out in a solvent such as acetic acid at a temperature of about 0°C to about 200°C, preferably about 0°C to about 150°C, for about 0.5 to 15 hours.

The hydrolysis reaction of the compound (1YY) can be carried out under the same conditions as in the hydrolysis reaction of the compound (IQQ) and the compound (62) in the above Reaction Scheme-41, wherein a pyridinium salt (e.g. pyridinium p-toluenesulfonate, etc.) may be used as the acid.

[Reaction Scheme-47]

(1A) (lbbb) wherein R ¹ , R ² , R ³ , W', and R ²⁶ are as defined above.

The reaction of converting the compound (1A) into the compound (lbbb) can be carried out under the same conditions a in the reaction of converting the compound (1A) into the compound (IC) in the above Reaction Scheme-15. [Reaction Scheme-48]

(laa) (lccc) wherein R , R , R and W' are as defined above, R ⁹² and R ⁹³ ar each a lower alkoxy.

The reaction of the compound (la ) and the compound (68) is carried out in an appropriate solvent in the presence of an acid. The solvent includes, for example, water, alcohol (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, etc.), fatty

acids (e.g. acetic acid, formic acid, etc.), or a mixture of these solvents. The acid includes, for example, mineral acids (e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g. formic acid, acetic .acid, aromatic sulfonic acids, etc.). The reaction is usually carried out at a temperature of from room temperature to about 200°C, preferably from room temperature to about 150°C, for about 0.5 to 5 hours. The compound (68) is usually used in an amount of at least 1 mole, preferably 1 to 2 moles, to 1 mole of the compound (laa ) . [Reaction Scheme-49]

(lddd) (leee) wherein R ¹ , R , R , W' , and R ^14a are as defined above, R ⁹⁴ is a halogen-substituted lower alkanoyl, R ⁹⁵ is an imidazolyl- substituted lower alkanoyl or an amino-lower alkanoyl having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl, and R ⁹⁶ is imidazolyl, or an amino having optionally a substituent selected from a lower alkyl and a lower alkoxycarbonyl.

The reaction of the compound (lddd) and the compound (69) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above

Reaction Scheme-4. [Reaction Scheme-50]

(ifff) (iggg) wherein R , R ² , R , and W' are as defined above, R ⁹⁷ is a lowe no alkanoyloxy having a halogen substituent, R'° is an amino having optionally a lower alkyl substituent, and R ⁹⁹ is an amino-lower alkanoyloxy having optionally a lower alkyl substituent.

The reaction of the compound (lfff) and the compound (70) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) i:, the above Reaction Scheme-4.

(lhhh) (liϋ) wherein R ¹ , R ² , R ³ , W ¹ , R ⁸² , and R ⁸³ are as defined above, R 10 is a carboxy-substituted lower alkoxy, and R ¹⁰¹ is a

group of the formula: (A, R ⁸² and R ⁸³ are as defined above) .

The reaction of the compound (lhhh) and the compound (71) can be carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the above Reaction Scheme-1. [Reaction Scheme-52]

djjj ⁾ ( lkkk ) wherein R ¹ , R ² , R ³ , W", X, and R ⁸² are as defined above, and R ¹⁰² is hydrogen atom or a lower alkyl, provided that in the compound (ljjj), the groups of the formulae: -NH-R ¹⁰² and -OH are substituted at the positions adjacent each other.

The reaction of the compound (ljjj) and the compound (-72) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction Scheme-4.

(1A) (laaa ) wherein R ¹ , R ² , R ³ , W ¹ , R and X are as defined above, and R ¹⁰⁴ is a lower alkyl.

The reaction of the compound (1A) and the compound ( 7.* ) can be carried out in an appropriate solvent. The solven includes, for example, ethers (diethyl ether, dioxane, tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), saturated hydrocarbons (e.g. pentane, hexane, heptane, cyclohexane, etc.), or a mixture of these solvents. The reaction is usually carried out at a temperatur of from about -70°C to about 50°C, preferably from about -30°C to room temperature, for about 1 to 6 hours. The compound (73 is used in an amount of at least 1 mole, preferably 1 to 5 moles, to 1 mole of the compound (1A). [Reaction Scheme-54]

(lmmm) (lnnn)

wherein R ¹ , R ² , R ³ , W ¹ , R ⁵⁸ , R , and A are as defined above and R ¹⁰⁵ is a lower alkylsulfonyloxy.

The reaction of the compound (lmmm) and the compound (74) can be carried out under the same conditions as in the reaction of the compound (7) and the compound (8) in the above Reaction'Scheme-4.

Among the active compounds (1) of this invention, the compounds having an acidic group can easily be converted into salts by treating with a pharmaceutically acceptable basic compound. The basic compound includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, etc., alkali metal carbonates or hydrogen carbonates such as sodium carbonate, sodium hydrogen carbonate, etc., alkali metal alcoholates such as sodium methylate, potassium ethylate, etc. Besides, among the active compounds (1) of this invention, the compounds having a basic group can easily be converted into acid additio salts thereof by treating with a pharmaceutically acceptable acid. The acid includes, for example, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, etc., and organic acids such as acetic acid, p-toluene- sulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, etc. These salts are useful as an active ingredient as like as the compounds (1) in the free form.

In addition, the compounds (1) of this invention include stereoisomers and optical isomers, and these isomers are also useful as the active ingredient in this invention.

The compounds of this invention thus obtained can easily be isolated and purified by conventional isolation methods. The isolation methods are, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromtography, preparative thin layer chromatography, extraction with a solvent, and the like.

The compounds and their salts of this invention are useful as a vasopressin antagonist and are used in the form of a conventional pharmaceutical preparation. The preparation is prepared by using conventional dilutents or carriers such as fillers, thickening agents, binders, wetting agents, disinte¬ grators, surfactants, lubricants, and the like. The pharma¬ ceutical preparations may be selected from various forms in accordance with the desired utilities, and the representative forms are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like. In order to for in tablets, there are used carriers such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, urea, starches calcium carbonate, kaolin, crystalline cellulose, silicic acid etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxy- methyl cellulose, s, lac, merhyl cellulose, potassium phosphate, polyviny.. rroiidone, etc.), disintegrators (e.g. dry starch, sodium arginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic

monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin, cacao butter, hydro¬ genated oils, etc.), absorption promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. purified talc, stearates, boric acid powder, polyethylene glycol, etc.), and the like. Moreover, the tablets may also be in the form of a conventional coated tablet, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film coating tablets, or double or multiple layer tablets. In the preparation of pills, the carriers include vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar, etc.), and the like. In the preparation of suppositories, the carriers include, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi- synthetic glycerideε, and the like. Capsules can be prepared by charging a mixture of the compound of this invention with the above carriers into hard gelatin capsules or soft capsules in a usual manner. In the preparation of injections, the solutions, emulsions or suspendions are sterilized and are preferably made isotonic with the blood. In the preparation o these solutions, emulsions and suspensions, there are used conventional diluents, such as water, ethyl alcohol, macrogol

(propylene glycol), ethoxylated isostearyl alcohol, polyoxyl- ated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the pharmaceutical preparations may also be incorporated with sodium chloride, glucose, or glycerin in an amount sufficient to make them isotonic, and may also be incorporated with conventional solubilizers, buffers, anesthetizing agents. Besides, the pharmaceutical preparations may optionally be incorporated wit coloring agents, preservatives, perfumes, flavors, sweeting agents, and other medicaments, if required.

The amount of the active compound of this invention (active ingredient) to be incorporated into the anti-vaso- pressin preparations is not specified but may be selected from a broad range, but usually, it is preferably in the range of 1 to 70 % by weight, more preferably 5 to 50 % by weight.

The anti-vasopressin preparation of this invention may be administered in any method, and suitable method for administration may be determined in accordance with various forms of preparation, ages, sexes and other conditions of the patients, the degree of severity of diseases, and the like. For instance, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. The injections are intraveneously administered alone or together with a conventional auxiliary liquid (e.g. glucose, amino acid solutions), and further are optionally administ¬ ered alone in intramuscular, intracutaneous, subcutaneous, or intraperitoneal route, if required. Suppositories are

administered in intrarectal route.

The dosage of the anti-vasopressin agent of this invention may be selected in accordance with the usage, ages, sexes and other conditions of the patients, the degree of severity of the diseases, and the like, but is usually in the range of about 0.6 to 50 mg of the active compound of this invention per 1 kg of body weight of the patient per day. The active compound is preferably contained in an amount of 10 to 1000 mg per the dosage unit.

Brief Description of Drawing

Fig. 1 to Fig. 4 show a chart of NMR (CDC1 ₃ ) of the compounds in Examples 978 and 979.

Best Mode for Carrying Out the Invention

The present invention is illustrated by the following Preparations of anti-vasopressin agent, Reference Examples of processes for preparing the starting compounds to be used for preparing the active compounds, Examples of processes for preparing the active compounds, and Experiments of the activities of the active compounds of this invention.

Preparation 1

Film coated tablets are prepared from the following components.

Components Amount

4-Methyiamino-l-[4-(3,5-dichlorobenzoyl- amino)benzoyl]-l,2,3,4-tetrahydroquinoline 150 g

Avicel (tradename of microcrystalline cellulose, manufactured by Asahi Chemical Industry Co., Ltd., Japan) 40 g

Corn starch 30 g

Magnesium stearate 2 g

Hydroxypropyl methylcellulose 10 g

Polyethylene glycol-6000 3 g

Castor oil 40 g

Ethanol 40 g

The active component of this invention, Avicel, corn starch and magnesium stearate are mixed and kneaded and the mixture is tabletted using a conventional pounder (R 10 mm) for sugar coating. The tablets thus obtained are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil and ethanol to give film coated tablets.

Preparation 2

Tablets are prepared from the following components.

Components Amount l-[4-(N-Butylanilinoacetylamino)benzoyl]- 2,3,4,5-tetrahydroy-lH-benzazepine 150 g

Citric acid 1.0 g

Lactose 33.5 g

Dicalcium phosphate 70.0 g

Pullonic F-68 30.0 g

Sodium laurylsulfate 5.0 g

Folyvinylpyrrolidone _<■_0 g

Polyethylene glycol (Carbowax 1500) 4.5 g

Polyethylene glycol (Carbowax 6000) 45.0 g

Corn starch 30.0 g

Dry sodium stearate 3.0 g

Dry magnesium stearate 3.0 g

Ethanol q.s.

The active compound of this invention, citric acid, lactose, dicalcium phosphate, Pullonic F-68 and sodium laurylstearate are mixed. The mixture is screened with No. 60 screen and is granulated with an alcohol solution containing polyvinylpyrrolidone, carbowax 1500 and 6000. If required, an alcohol is added thereto so that the powder mixture is made a paste-like mass. Corn starch is added to the mixture and the mixture is continuously mixed to form uniform particles. The resulting particles are passed through No. 10 screen and entered into a tray and then dried in an oven at 100°C for 12 to 14 hours. The dried particles are screened with No. 16 screen and thereto are added dry sodium laurylsulfate and dry magnesium stearate, and the mixture is tabletted to form the desired shape.

The core tablets thus prepared are vanished and dusted with talc in order to guard from wetting. Undercoating is applied to the core tablets. In order to administer the tablets orally, the core tablets are vanished several times. In order to give round shape and smooth surface to the tablets, further undercoating and coating with lubricant are applied thereto. The tablets are further coated with a coloring coating material until the desired

colored tablets are obtained. After drying, the coated tablets are polished to obtain the desired tablets having uniform gloss.

Preparation 3

An injection preparation is prepared from the following components.

Components Amount

4-Methyl-l-[4-(2,3-dimethylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro- 5 g

1H-1,4-benzodiazepine

Polyethylene glycol (molecular weight: -4000) 0.3 g.

Sodium chloride 0.9 g

Polyoxyethylene sorbitan monooleate 0.4 g

Sodium metabisulfite 0.1 g

Methyl-paraben 0.18 g

Propyl-paraben 0.02 g

Distilled water for injection 10.0 ml

The above parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water of half.volume of the above with stirring at 80°C. The solution thus obtained is cooled to 40°C, and the active compound of this invention and further polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved in the above solution. To the solution is added distilled water for injection to adjust to the desired volume, and the solution i terilized by filtering with an appropriate filter pa^er to give an injection preparation.

Reference Example 1

To a solution of 1,2,3,4-tetrahydroquinoline (28.7 g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g), and thereto is added p-nitrobenzoyl chloride (40 g) under ice-cooling and the mixture is stirred at room temperature overnight. To the reaction mixture is added a suitable amount of water. The precipitated crystal is collected by filtration and dried to give l-(4-nitro- benzoyl)-l, 2,3,4-tetrahydroquinoline (40.8 g) as white powder, m.p. 86 - 88°C.

Reference Example 2

To a solution of 10 % Pd-C (5 g) in ethanol (500 ml) is added l-(4-nitrobenzoyl)-l,2,3,4-tetrahydroquinoline (53.4 g) and the mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After the reduction, 10 % Pd-C is removed by filtration, and the filtrate is concentrated under reduced pressure to give l-(4-aminobenzoyl)-l,2,3,4-tetrahydro- quinoline (46.7 g) as yellow powder, m.p. 185 - 188°C.

Reference Example 3

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1. l-(3-Nitrobenzoyl)-l, 2, 3,4-tetrahydroquinoline, white powder, m.p. 134 - 136°C l-(2-Nitrobenzoyl)-l, 2, 3,4-tetrahydroquinoline,

yellow powder, m.p. 152 - 154°C

3-Methyl-l-(4-nitrobenzoyl)-1,2,3,4-tetrahydro¬ quinoline, yellow powder, m.p. 109 - 110°C

4-Methyl-l-(4-nitrobenzoyl)-1,2,3,4-tetrahydro- quinoline, yellow powder, m.p. 134 - 136°C

2-Methyl-l-(4-nitrobenzoyl)-1,2,3,4-tetrahydro- quinoline, yellow powder, m.p. 143 - 145°C

1-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, yellow powder, m.p. 143 - 145°C

1-(3-Methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro- ^' lH- benzazepine, white powder, m.p. 100 - 102°C

1-(3-Me*-hoxy-4-nitrobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, yellow powder, m.p. 146 - 148°C

1-(4-Nitrobenzoyl)-l,2,3,4,5,6-hexahydrobenz- azocine, white powder, m.p. 83 - 85°C

1-(4-Nitrobenzoyl)-3,4-dihydro-2H-l,4-benzoxazine, yellow powder, m.p. 167 - 169°C

1-(4-Nitrobenzoyl)-1,2,3,5-tetrahydro-4,1- benzoxazepine, yellow powder, m.p. 196 - 198°C l-(4-Nitrobenzoyl)-4-methyl-l,2,3,4-tetrahydro- quinoxaline, brown powder H-NMR (CDC1 ₃ ) δ : 3.03 (3H, s), 3.54 (2H, t, J=5.7 Hz), 4.06 (2H, t, J=5.7 Hz), 6.2-6.5 (2H, m), 6.70 (IH, d, J=8.2 Hz), 6.9-7.1 (IH, m) , 7.54 (2H, d, J=8.8 Hz), 8.13 (2H, d, J = 8.8 Hz)

1-{4-Nitrobenzoyl)-5-methyl-2,3,4,5-tetrahydro- H-

1,5-benzodiazepine, yellow oil H-NMR (CDCI3) δ : 1.7-2.0 (IH, m) , 2.0-2.3 (IH, m), 2.8-3.0 (IH, m) , 2.98 (3H, s), 3.0-3.2 (IH, m) , 3.4-3.6 (IH, m), 4.6-4.8 (IH, m) , 6.5-6.7 (2H, m) , 6.94 (IH, d, J=8.1 Hz), 7.1-7.2 (IH, m) , 7.33 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.9 Hz)

1- ( 4-Nitrobenzoyl ) -4-methyl-2 ,3,4, 5-tet rahydro-lH- 1,4-benzodiazepine, brown oil

^X H-NMR (CDCI3) δ : 2.44 (3H, s), 3.0-3.3 (3H, ^' m), 3.77 (IH, d, J=13.7 Hz), 4.06 (IH, d, J=13.6 Hz), 4.9-5.1 (IH, m), 6.59 (IH, d, J=7.7 Hz), 6.97 (IH, t, J=7.6 Hz), 7.15 (IH, t, J=7.4 Hz), 7.2-7.5 (3H, m) , 8.03 (2H, d, J=8.8 Hz) l-(3-Methoxy-4-nitrobenzoyl)-4-methyl-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine, yellow powder, m.p. 146 - 148°C

1-(4-Nitrobenzoyl)-4-n-propyl-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine, yellow powder, m.p. 131 - 133°C

1-(4-Nitrobenzoyl)-5-chloro-l,2,3,4-tetrahydro- quinoline, white powder, m.p. 134 - 136°C

1-(4-Nitrobenzoyl)-6-methoxy-l,2,3,4-tetrahydro- quinoline, yellow powder, m.p. 149 - 151°C l-(4-Nitrobenzoyl)-6-methyl-l,2,3,4-tetrahydro¬ quinoline, yellow powder, m.p. 109 - 110°C

1-(4-Nitrobenzoyl)-7-methoxy-l,2,3,4-tεtrahydro- quinoline, yellow powder, m.p. 139 - 141°C

1-(4-Nitrobenzoyl)-3-(4-methyl-l-piperazinyl)- 1,2,3,4-tetrahydroquinoline, yellow amorphous H-NMR (CDC1 ₃ ) δ : 2.29 (3H, ε), 2.35-3.20 (11H, m) , 3.86-4.15 (2H, m) , 6.48-6.63 (IH, m) , 6.89 (IH, t, J=7.4 Hz), 7.05 (IH, t, J=7.4 Hz), 7.22 (IH, d, J=7.4 Hz), 7.52 (2H, d, J=8.8 Hz), 8.11 (2H, d, J=8.8 Hz)

1-(4-Nitrobenzoyl)-3-(1-pyrrolidinyl)-1,2,3,4- tetrahydroquinoline, yellow amorphous H-NMR (CDCI3) δ : 1.70-1.95 (4H, m) , 2.52-3.30 (7H, m) , 3.80-4.22 (2H, m) , 6.52 (IH, brs), 6.88 (IH, t, J=7.6 Hz), 6.96-7.11 (IH, m) , 7.20 (2H, d, J=7.6 Hz), 7.54 (2H, d, J=8.8 Hz), 8.12 (2H, d, J=8.8 Hz)

1-(4-Nitrobenzoyl)-4-oxo-l,2,3,4-tetrahydro- quinoline, yellow powder, m.p. 189 - 190°C

1-(4-Nitrobenzoyl)-3-hydroxymethyl-l,2,3,4-tetra- hydroquinoline, yellow powder, m.p. 97 - 100°C

1-(4-Nitrobenzoyl)-3-ethoxycarbony1-1,2,3,4-tetra- hydroquinoline, pale yellow powder, m.p. 162 - 163°C

1-(4-Nitrobenzoyl)-4-dimethylamino-l,2,3,4-tetra- hydroquinoline, light brown oil

^X H-NMR (CDCI3) δ : 1.80-2.02 (IH, m) , 2.20-2.50 (7H, m), 3.47 (IH, t, J=4.9 Hz), 3.70-3.88 (IH, m) , 4.06- 4.25 (IH, m), 6.46 (IH, d, J=7.5 Hz), 6.89 (IH, t, J=7.5 Hz), 7.05 (IH, t, J=7.5 Hz), 7.34 (IH, d, J=7.5 Hz), 7.50 (2H, d, J=7.0 Hz), 8.10 (2H, d, J=7.0 Hz)

Reference Example 4

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.

1-(3-Aminobenzoyl)-1,2,3,4-tetrahydroquinoline, white powder, m.p. 128 - 130°C

1-(2-Aminobenzoyl)-1,2,3,4-tetrahydroquinoline, yellow powder H-NMR (CDC1 ₃ ) δ : 2.01 (2H, quint, J=6.6 Hz), 2.81 (2H, t, J=6.6 Hz), 3.86 (2H, t, J=6.4 Hz), 4.6-4.8 (2H, m) , 6.43 (IH, t, J=7 Hz), 6.66 (IH, d, J=8 Hz), 6.79 (IH, dd, J=1.4 Hz, J=7.6 Hz), 6.8-7.2 (5H, m)

3-Methyl-l-(4-aminobenzoyl)-1,2,3,4-tetrahydro¬ quinoline, yellow powder, m.p. 197 - 200°C

4-Methyl-l-(4-aminobenzoyl)-1,2,3,4-tetrahydro¬ quinoline, yellow powder, m.p. 197 - 199°C

2-Methyl-l-(4-aminobenzoyl)-1,2,3,4-tetrahydro¬ quinoline, yellow powder, m.p. 204 - 206°C

4-Aminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine yellow powder, m.p. 172 - 174°C 1- 3-Methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine white powder, m.p. 156 - 158°C 1- 3-Methoxy-4-aminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine white powder, m.p. 165 - 167°C 1- 4-Aminobenzoyl)-1, 2,3,4,5,6-hexahydrobenz- azocine, white powder, m.p. 177 - 179°C

4-Aminobenzoyl)-3,4-dihydro-2H-l,4-benzoxazine,

white powder, m.p. 192 - 194°

1-(4-Aminobenzoyl)-1,2,3,5-tetrahydro-4,1-benz- oxazepine, yellow powder, m.p. 196 - 198°C

1-(4-Aminobenzoyl)-4-methyl-l,2,3,4-tetrahydro- quinoxaline, yellow powder, m.p. 210 - 212°C

1-(4-Aminobenzoyl)-5-methyl-2,3,4,5-tetrahydro-lH- 1,5-benzodiazepine, white powder, m.p. 159 - 161°C

1-(4-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-lH- 1,4-benzodiazepine, brown powder, m.p. 169 - 171°C

1-(3-Methoxy-4-aminobenzoyl)-4-methyl-2,3,4,5- tetrahydro-lH-l,4-benzodiazepine, yellow oil H-NMR (CDC1 ₃ ) δ : 2.41 (3H, s), 2.9-3.2 (3H, m) , 3.61 (3H, s), 3.6-4.2 (4H, m) , 4.8-5.2 (IH, m) , 6.38 (IH, d, J=8.1 Hz), 6.6-6.8 (3H, m) , 6.9-7.2 (2H, m) , 7.2-7.4 (IH, m)

1-(4-Aminobenzoyl)-4-n-propyl-2,3,4,5-tetrahydro- lH-l,4-benzazepine, brown powder, m.p. 151 - 153°C

1-(4-Aminobenzoyl)-5-chloro-l,2,3,4-tetrahydro¬ quinoline, white powder, m.p. 174 - 175°C

1-(4-Aminobenzoyl)-6-methoxy-l,2,3,4-tetrahydro¬ quinoline, pale yellow powder, m.p. 159 - 160°C

1-(4-Aminobenzoyl)-6-methyl-l,2,3,4-tetrahydro¬ quinoline, white powder, m.p. 145 - 146°C

1-(4-Aminobenzoyl)-7-methoxy-l,2,3,4-tetrahydro¬ quinoline, pale yellow powder, m.p. 150 - 1 ^{^} C

1-(4-Aminobenzoyl)-3-{4-methyl-l-p. εrazinyl)- 1,2,3,4-tetrahydroquinoline, light beige powder, m.p. 157 -

159°C

1-(4-Aminobenzoyl)-3-(1-pyrrolidinyl)-1,2,3, 4- tetrahydroquinoline, pale yellow powder, m.p. 173 - 174.5°C l-( 4-Aminobenzoyl)-2,3-dihydro-4(lH)-quinolinone, pale yellow powder, m.p. 178 - 180°C

1-(4-Aminobenzoyl)-3-hydroxymethyl-l,2,3,4-tetra- hyd.roquinoline, white powder, m.p. 179 - 181°C l-( 4-Aminobenzoyl)-3-ethoxycarbonyl-l, 2,3,4-tetra¬ hydroquinoline, pale yellow amorphous

^X H-NMR (CDC1 ₃ ) δ : 1.21 (3H, t, J=7.1 Hz), 3.00- 3.24 (3H, m), 3.70-4.30 (6H, m) , 6.48 (2H, d, J=8.5 Hz), 6.69 (IH, d, J=7.9 Hz), 6.77-7.30 (5H, m) l-( 4-Aminobenzoyl )-4-dime thy land no-1, 2,3, 4-tetra¬ hydroquinoline, brown oil

^X H-NMR (CDC1 ₃ ) δ : 1.83-2.05 (IH, m) , 2.13-2.30 (IH, m), 2.34 (6H, m) , 3.55-3.83 (2H, m) , 3.89 (IH, brs), 3.97-4.18 (IH, m) , 6.47 (2H, d, J=7.0 Hz), 6.68 (IH, d, J=7.9 Hz), 6.85-7.05 (2H, m) , 7.20 (2H, d, J=7.0 Hz), 7.37 (IH, d, J=7.4 Hz)

Reference Example 5

To terephthalic acid monomethyl ester (15 g) is added thionyl chloride (100 ml) and the mixture is refluxed for 2 hours. The thionyl chloride is distilled off under reduced pressure to give terephthalic acid chloride monomethyl ester. Separately, to a solution of 1,2, 3,4- tetrahydroquinoline (14.4 g) in dichloromethane (200 ml) is

added triethylamine (16.9 g) and further thereto is added slowly terephthalic acid chloride monomethyl ester obtained above under ice-cooling. Then, the mixture is stirred at room temperature for 1 hour. After completion of the reaction, water is added to the reaction mixture. The mixture is extracted with dichloromethane and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane) to give l-(4-methoxycarbonylbenzoyl)-l,2,3,4-tetrahydro¬ quinoline (22.7 g) as white powder, m.p. 72 - 74°C.

Reference Example 6

To a solution of l-(4-methoxycarbonylbenzoyl)- 1,2,3,4-tetrahydroquinoline (22.7 g) in methanol (300 ml) is added 5 % aqueous sodium hydroxide solution (150 ml) and the mixture is refluxed for 2 hours. Methanol is distilled off under reduced pressure and the resulting residue is acidified with diluted hydrochloric acid, extracted with diethyl ether, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting crystal is collected by filtration to give l-(4- carboxybenzoyl)-1,2,3,4-tetrahydroquinoline (13.2 g) as white powder, m.p. 181 - 183°C.

Reference Example 7

Using the suitable starting materials, the

following compounds are obtained in the same manner as in Reference Example 1.

5-Dimethylamino-l-( 4-nitrobenzoyl)-2, 3,4,5- tetrahydro-lH-benzazepine, pale yellow powder, m.p. 139 - 142°C

5-Dimethylamino-l-(3-methoxy-4-nitrobenzoyl)- 2,3,4 ,5-tetrahydro-lH-benzazepine, white powder, m.p. 139 - 141°C

4-(N-Methyl-N-ethylamino)-l-(4-nitrobenzoyl)- 1, 2,3,4-tetrahydroquinoline, pale yellow oil

^X H-NMR (CDC1 ₃ ) δ : 1.11 (3H, t, J=7.1 Hz), 1.90- 2.25 (2H, m), 2.30 (3H, s), 2.57 (2H, q, J=7.1 Hz), 3.55- 3.85 (2H, m), 4.00-4.21 (IH, m) , 6.35-6.60 (IH, m) , 6.80- 6.98 (IH, t, J=7.9 Hz), 7.00-7.15 (IH, m) , 7.33-7.60 (3H, m) , 8.10 (2H, d, J=8.8 Hz)

4-Dimethylamino-l-(3-methoxy-4-nitrobenzoyl)- 1,2,3,4-tetrahydroquinoline, brown oil H-NMR (CDC1 ₃ ) δ : 1.80-2.05 (IH, m) , 2.33 (6H, s), 2.30-2.50 (IH, m) , 3.40-3.52 (IH, m) , 3.78 (3H, s), 3.70- 3.88 (IH, m), 4.04-4.24 (IH, m) , 6.52 (IH, d, J=8.2 Hz), 6.85-7.13 (4H, m) , 7.28-7.38 (IH, m) , 7.71 (IH, d, J=8.2 Hz)

1-(4-Nitrobenzoyl)-4-ethyl-2,3,4, 5-tetrahydro-lH- 1, 4-benzodiazepine, yellow oil H-NMR (CDC1 ₃ ) δ : 1.16 (3H, t, J=7.1 Hz), 2.5-2.7 (2H, m), 3.0-3.3 (3H, m) , 3.98 (2H, q, J=14 Hz), 4.8-5.0 (IH, m), 6.59 (IH, d, J=7.7 Hz), 6.96 (IH, t, J=7.7 Hz),

7.14 (IH, t, J=7.4 Hz), 7.2-7.4 (3H, m) , 8.02 (2H, d, J=8.8 Hz)

1-(4-Nitrobenzoyl)-4-isopropyl-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine, yellow powder, m.p. 222 - 223°C

1-(4-Nitrobenzoyl)-4-cyclohexyl-2,3,4,5-tetrahydro- lH-l,4-benzodiazepine, brown oil

^X H-NMR (CDC1 ₃ ) δ : 1.0-1.5 (5H, m) , 1.5-2.1 (5H, m), 2.4-2.7 (IH, m) , 2.9-3.3 (3H, m) , 3.94 (2H, s), 179-5.1 (IH, m), 6.57 (IH, d, J=7.7 Hz), 6.8-7.0 (IH, m) , 7.0-7.2 (IH, m), 7.2-7.4 (3H, m) , 8.01 (2H, d, J=8.8 Hz)

1- ( 4-Nitrobenzoyl ) -5-methyl-l ,2,3,4,5, 6-hexahydro- 1, 5-benzodiazocine, yellow oil

^X H-NMR (CDCI3) δ : 1.5-2.1 (2H, m) , 2.40 (3H, s), 2.3-2.6 (IH, m), 2.8-3.2 (2H, m) , 3.50 (IH, d, J=13.4 Hz), 3.84 (IH, d, J=13.4 Hz), 4.8-5.0 ( IH., m) , 7.0-7.3 (4H, m) , 7.41 (2H, d, J=8.9 Hz), 8.00 (2H, d, J=8.9 Hz)

1-(4-Nitrobenzoyl)-1,2,3,4-tetrahydro-5,1- benzoxazepine, white powder, m.p. 144.5 - 145.5°C

1-(2-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-lH- 1,4-benzodiazepine, yellow powder, m.p. 177 - 180°C

1-(3-Nitrobenzoyl)-4-methyl-2,3,4,5-tetrahydro-lH- 1,4-benzodiazepine, yellow powder, m.p. 145 - 146°C

6-Fluoro-l-(4-nitrobenzoyl)-1,2,3,4-tetrahydro¬ quinoline, yellow needles, m.p. 145 - 146°C

Reference Example 8

Using the suitable starting materials, the

following compounds are obtained in the same manner as in Reference Example 2.

5-Dimethylamino-l-( -aminobenzoyl)-2,3,4,5-te ra- hydro-lH-benzazepine, white powder, m.p. 120 - 122°C

5-Dimethylamino-l-( 3-methoxy-4-amino)-2,3,4, 5- tetrahydro-lH-benzazepine, white powder, m.p. 121 - 123°C

4-(N-Methy-N-ethylamino)-1-(4-aminobenzoyl)- 1,2, 3,4-tetrahydroquinoline, orange amorphous

^X H-NMR (CDC1 ₃ ) δ : 1.11 (3H, t, J=7.1 Hz), 1.90- 2.20 (2H, m), 2.28 (3H, s), 2.26 (2H, q, J=7.1 Hz), 3.60- 4.25 (5H, m), 6.48 (2H, d, J=8.5 Hz), 6.69 (IH, d, J=7.9 Hz), 6.80-7.05 (2H, m) , 7.24 (2H, d, J=8.5 Hz), 7.46 (IH, d, J=6.2 Hz)

4-Dimethylamino-l-(3-methoxy-4-aminobenzoyl)- 1,2,3,4-tetrahydroquinoline, pale yellow amorphous

^X H-NMR (CDCI3) δ : 1.83-2.04 (IH, m) , 2.15-2.32 (IH, m), 2.33 (6H, s), 3.50-3.82 (2H, m) , 3.64 (3H, s), 3.95-4.18 (3H, m) , 6.50 (IH, d, J=7.9 Hz), 6.65 (IH, dd, J=7.9 Hz, 1.1 Hz), 6.78-7.03 (4H, m) , 7.34 (IH, dd, J=7.5 Hz, 1.5 Hz)

1-( 4-Aminobenzoyl)-4-ethyl-2,3,4, 5-tetrahydro-lH- 1,4-benzodiazepine, white powder, m.p. 186 - 188°C l-(4-Aminobenzoyl)-4-isopropy1-2,3,4, 5-tetrahydro- 1H-1,4-benzodiazepine, white powder, m.p. 191 - 192°C

1-(4-Aminobenzoyl)-4-cyclohexyl-2,3,4,5-tetrahydro- 1H-1,4-benzodiazepine, white powder, m.p. 149.5 - 150.5°C

1-(4-Aminobenzoyl)-5-methyl-l,2,3,4,5,6-hexahydro- 1,5-benzodiazocine, yellow powder, m.p. 143 - 145°C

1-(4-Aminobenzoyl)-1,2,3,4-tetrahydro-5,1- benzoxazepine, yellow powder, m.p. 163.5 - 164.5°C

1-(2-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-lH- 1,4-benzodiazepine, yellow powder, m.p. 144 - 146°C

1-(3-Aminobenzoyl)-4-methyl-2,3,4,5-tetrahydro-lH- 1,4-benzodiazepine, white powder, mp. 153 - 155°C

6-Fluoro-l-(4-aminobenzoyl)-1,2,3,4-tetrahydro¬ quinoline, white powder, m.p. 160.5 - 161.5°C

Reference Example 9

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1. l-(2-Chloro-4-nitrobenzoyl)-4-methyl-2,3,4,5- tetrahydro-lH-1, -benzodiazepine H-NMR (CDC1 ₃ ) δ : 2.40 (3H, s), 2.96-3.33 (3H, m) , 3.60-3.79 (IH, m) , 3.96-4.23 (IH, m) , 4.70-4.91 (IH, m) , 6.80-7.43 (5H, m) , 7.80-7.99 (IH, m) , 8.08-8.21 (IH, m) l-(3-Methyl-4-nitrobenzoyl)-4-methyl~2,3,4,5- tetrahydro-lH-1,4-benzodiazepine

^X H-NMR (CDC1 ₃ ) δ : 2.43 (3H, s), 2.48 (3H, s), 2.92-3.28 (3H, m) , 3.91 (2H, AB-q, J=13.9 Hz, 45.5 Hz), 4.77-5.01 (IH, 1), 6.54-6.70 (IH, m) , 6.88-7.37 (5H, m) , 7.62-7.78 (IH, m)

5-Dimethylamino-l-(2-chloro-4-nitrobenzoyl)-

2,3,4,5-tetrahydro-lH-benzazepine

^X H-NMR (CDC1 ₃ ) δ : 1.23-2.57 (10H, m) , 2.68-5.15 (3H, m), 6.79-7.45 (4H, m) , 7.49-8.39 <3H, m)

5-Oxo-l-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, white powder (ethyl acetate/n-hexane), m.p. 147

- 148°C

5-Hydroxy-l-(4-nitrobenzoyl)-2,3, 4,5-tetrahydro-lH- benzazepine, white powder (ethyl acetate/n-hexane), m.p. 148

- 150°C

5-Methoxy-l-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, colorless amorphous H-NMR (CDCI3) δ : 1.47-2.48 (4H, m) , 2.70-3.10 (IH, m), 3.26-3.64 (3H, m) , 4.29-5.12 (2H, m) , 6.60 (IH, d, J=7.7 Hz), 6.88-7.67 (5H, m) , 7.92-8.12 (2H, m)

5-Ethoxycarbonylmethoxy-l- ( 4-nitrobenzoyl ) -2 , 3 , 4 , 5- tetrahydro-lH-benzazepine, white powder, m.p. 107 - 108°C (recrystallized from ethyl acetate/n-hexane)

5-( 4-Bromobutoxy )-!-( 4-nitrobenzoyl ) -2, 3,4,5- tetrahydro-lH-benzazepine, colorless oil H-NMR (CDCI3) δ : 1.49-2.55 (8H, m) , 2.72-3.07 (IH, m), 3.24-3.77 (4H, m) , 4.40-5.15 (2H, m) , 6.53-6.66 (IH, m), 6.91-7.06 (IH, m) , 7.07-7.80 (4H, m) , 7.94-8.13 (2H, m)

5-( 4-Dimethylaminobutoxy)-l-(4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lK-benzazcpine, colorless oil

^X H-NMR (CDCI3) δ : 1.51-1.88 (6H, m) , 2.23-2.61

(4H, m), 2.27 (3H, s), 2.35 (3H, s), 2.74-3.14 (IH, m) , 3.55-3.77 (2H, m) , 4.48-5.11 (2H, m) , 6.54-6.66 (IH, m) , 6.91-7.04 (IH, m), 7.06-7.80 (4H, m) , 7.93-8.11 (2H, m)

5-[4-(Phthalimid-l-yl)propoxy-l-(4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, colorless amorphous

^X H-NMR (CDC1 ₃ ) δ : 1.48-2.56 (6H, m) , 2.71-3.05 (IH, m), 3.40-4.05 (4H, m) , 4.47-5.11 (2H, m) , 6.50-6.64 (IH, m) , 6.84-7.03 (IH, m) , 7.03-7.20 (IH, m) , .7.20-7.57 (2H, m), 7.57-7.93 (5H, ) , 7.97-8.20 (2H, m)

5-Chloro-l-{4-nitrobenzoyl)-2,3,4, 5-tetrahydro-lH- benzazepine, light brown powder H-NMR (CDC1 ₃ ) δ : 1.75-3.3 (4H, m) , 4.6-6.25 (3H, m), 6.45-6.7 (IH, m) , 6.8-7.5 (4H, m) , 7.55-7.7 (IH, m) , 7.9-8.1 (2H, m)

5-Oxo-l-(2-chloro-4-nitorobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, pale yellow amorphous H-NMR (CDC1 ₃ ) δ : 1.95-2.45 (2H, m) , 2.94 (IH, t, J=6 Hz), 3.05-5.3 (2H, m) , 6.96-7.1 (IH, m) , 7.12-7.5 (3H, m), 7.75-7.85 (IH, m) , 7.95-8.1 (IH, m) , 8.14 (IH, s)

4-Dimethylaminomethyl-l- ( 4-nitrobenzoyl ) -l , 2 , 3 , 4- tetrahydroquinoline , white powder , m.p. 117 - 119°C

3-Dimethylamino-l- ( 4-nitrobenzoyl ) -2 , 3 , 4 , 5- tetrahydro-lH-benzazepine , yellow oil H-NMR ( CDC1 ₃ ) δ : 1. 5-1.7 ( IH, m) , 2.1-2 . 4 ( IH, m), 2.42 (6H, s), 2.6-2.7 (IH, ) , 2.8-3.0 (3H, rc, , 5.1-5.3 (IH, m), 6.62 (IH, d, J=7.8 Hz), 6.95 (IH, t, J=7.7 Hz),

7 . 14 ( IH, t , J=7 . 5 Hz ) , 7 . 2-7 . 4 ( 3H, m) , 8 . 00 ( 2H , d , J=8 . 9 Hz )

3-Dimethylamino-l-(3-methoxy-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, yellow oil H-NMR (CDC1 ₃ ) δ : 1.5-1.7 (IH, m) , 2.0-2.3 (IH, m), 2.41 (6H, s), 2.5-2.8 (IH, m) , 2.8-3.0 (3H, m), 3.75 (3H, s), 5.1-5.3 (IH, m) , 6.6-6.8 (2H, m) , 6.9-7.3 (4H, m) , 7.59 (IH, d, J=8.3 Hz)

4-(4-Nitrobenzoyl)-3,4-dihydro-2H-l,4-benzo- thiazine, yellow powder, m.p. 180 - 182°C

5-(4-Nitrobenzoyl)-2,3,4,5-tetrahydro-1,5- benzothiazepine, yellow powder, m.p. 162 - 163°C

Reference Example 10

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.

1-(2-Chloro-4-aminobenzoyl)-4-methyl-2,3,4,5- tetrahydro-lH-1,4-benzodiazepine, white powder (recrystallized from methanol/diethyl ether), m.p. 194.5 - 195.5°C

1-(3-Methyl-4-aminobenzoyl)-4-methyl-2,3,4,5- tetrahydro-lH-1,4-benzodiazepine H-NMR (CDCI3) δ : 2.01 (3H, s), 2.41 (3H, s), 2.82-3.21 (3H, m) , 3.50-4.21 (4H, m) , 4.78-5.14 (IH, m) , 6.24-6.40 (IH, m) , 6.59-6.82 (211, m) , 6.90-7.18 (3H, m) , 7.19-7.34 (IH, m)

5-Dimethylamino-l-(2-chloro-4-aminobenzoyl)- 2,3,4,5-te rahydro-lH-benzazepine, white powder

(recrystallized from dichloromethane/diethyl ether), m.p. 162 - 164°C

5-Dimethylamino-l-(2-methoxy-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine (recrystallized from methanol/diethyl ether) H-NMR (CDC1 ₃ ) δ : 1.23-2.80 (11H, m) , 2.90-3.38 (IH, m), 3.50-5.19 (6H, m) , 5.87-6.41 (2H, m) , 6.65-7.56 (5H, m)

5-Methoxy-l-(4-aminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, white powder (recrystallized from ethyl acetate/n-hexane), m.p. 154 - 155°C

5-Ethoxycarbonylmethoxy-l-(4-aminobenzoyl)-2,3,4,5- tetrahydro-lH-benzazepine, white powder (recrystallized from ethyl acetate/n-hexane), m.p. 231 - 232°C

5-(4-Dimethylaminobutoxy)-1-(4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, colorless oil H-NMR (CDCI3) δ : 1.47-1.83 (6H, m) , 1.83-2.54 (4H, m), 2.29 (6H, s), 2.61-3.00 (IH, m), 3.36-3.76 (2H, m) , 4.35-5.20 (2H, m) , 6.27-6.48 (2H, m) , 6.57-6.76 (IH, m) , 6.90-7.61 (5H, m)

5-[4-(Phthalimid-l-yl)propoxy]-l-(4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, colorless amorphous

^X H-NMR (CDC1 ₃ ) δ : 1.30-2.47 (6H, ) * 2.57-3.01 (IH, m), 3.30-4.06 (4H, ) , 4.34-5.20 (2H, m) , 6.30-6.53

(2H, m) _r 6.57-6.78 (IH, m) , 6.87-7.57 (5H, m) , 7.62-7.76 (2H, m) , 7.76-7.97 (2H, m)

5-Chloro-l-(4-aminobenzoyl)-2, 3,4,5-tetrahydro-lH- benzazepine, pale yellow amorphous

^X H-NMR (CDC1 ₃ ) δ : 1.35-4.3 (7H, m) , 4.55-6.7 (2H, m), 6.3-6.55 (2H, m) , 6.6-6.8 (IH, m) , 6.85-7.45 (5H, m)

5-Oxo-l-(4-aminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, pale yellow amorphous H-NMR (CDCI3) δ : 1.95-2.35 (2H, m) , 2.89 (2H, t, J=6.3 Hz), 3.0-5.3 (4H, m) , 6.35-6.47 (2H, m) , 6.72-6.83 (IH, m), 7.0-7.15 (2H, m) , 7.18-7.32 (2H, m) , 7.81-7.93 (IH, m)

5-Oxo-l-(2-chloro-4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, white powder H-NMR (CDCI3) δ : 1.85-2.3 (2H, m) , 2.87 (2H, t, J=6.2 Hz), 3.1-4.75 (4H, m) , 6.15-7.5 (6H, m) , 7.65-7.9 (IH, m)

4-Dimethylaminomethyl-l-(4-aminobenzoyl)-1,2,3,4- tetrahydroquinoline, white powder, m.p. 123 - 125°C

3-Dimethylamino-l-(4-aminobenzoyl)-2,3,4,5- tetrahydro-lH-benzazepine, white powder, m.p. 175 - 177°C

3-Dimethylamino-l-(3-methoxy-4-aminobenzoyl)- 2, 3, 4, 5-tetrahydro-lH-benzazepine, yellow oil H-NMR (CDCI3) δ : 1.5-1.7 (IH, m) , 2.1-2.3 (IH, m), 2.3-2.6 (III, m) , 2.40 (6H, s), 2.7-3.0 (3H, ) , 3.60 (3H, s), 3.8-4.0 (2H, br ) , 5.2-5.4 (IH, m) , 6.37 (IH, d,

J=8 . 2 Hz ) , 6 . 5-6 . 8 ( 3H , m) , 6 . 9-7 . 4 ( 3H, m)

4-(4-Aminobenzoyl)-3,4-dihydro-2H-l,4-benzo- thiazine, yellow powder, m.p. 207 - 210°C

5-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-l,5- benzothiazepine, yellow powder, m.p. 193 - 195°C

Reference Example 11

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 1.

5-Carbamoyloxy-l-(4-nitrobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, white powder, m.p. 243 - 244°C (recrystallized from ethyl acetate/diisopropyl ether)

5-Methylaminocarbonyloxy-l-(4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 207 - 208°C (recrystallized from ethyl acetate/n-hexane)

5-Dimethylaminocarbonyloxy-l-(4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 155 - 156°C (recrystallized from ethyl acetate/diisopropyl ether/n-hexane)

5-Methylidenyl-l-(4-nitrobenzoyl)-2 ,3,4,5- tetrahydro-lH-benzazepine, colorless prisms, m.p. 133.5 - 134°C (recrystallized from ethyl acetate/diisopropyl ether)

5-Oxo-6-methyl-l-(2-chloro-4-nitrobenzoyl)-2,3,4,5- tetrahydro-lH-benzazepine, colorless prisms, m.p. 90 - 92°C (recrystallized from ethanol) l-(4-Nitrobenzoyl)-1,2, 3, 5-tetrahydro-4,1-

benzothiazepine, yellow powder, m.p. 185 - 187°C (recrystallized from dichloromethane/diethyl ether)

5-Dimethylamino-l-( 2-dimethylamino-4-nitrobenzoyl) ^■ 2,3,4,5-tetrahydro-lH-benzazepine, yellow powder, m.p. 123 - 125°C (recrystallized from diethyl ether/dichloromethane)

5-Oxo-l-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-lH-l,4- benzodiazepine, white powder, m.p. 201.5 - 202.5°C (recrystallized from diethyl ether/dichloromethane)

5-Oxo-4-methy1-1-(4-nitrobenzoyl)-2,3,4,5- tetrahydro-lH-1,4-benzodiazepine, white powder, m.p. 136 - 138°C (recrystallized from diethyl ether/dichloromethane)

5-Dimethylamino-l-( 3-methyl-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, yellow oil

^X H-NMR (CDCI3) δ : 1.16-3.18 (11H, m) , 2.18 (3H, s), 3.40-5.15 (2H, m) , 6.50-7.68 (6H, m) , 7.70-7.84 (IH, m)

5-Dimethylamino-l-( 2-methyl-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, colorless amorphous

^X H-NMR (CDCI3) δ : 1.19-2.86 (11H, m) , 2.20 (3H, s), 2.94-3.24 (IH, ) , 3.36-5.18 (IH, m) , 6.49-8.20 (7H, m)

5-Dimethylamino-l-( 2-fluoro-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, yellow oil H-NMR (CDCI3) δ : 1.21-2.66 (10H, m) , 2.66-5.11 (3H, m), 6.63-8.25 (7H, m)

5-Dimethylamino-l-(3-fluoro-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-bεnzazεpine, white powder, m.p. 152 - 152.5°C (recrystallized from chloroform/diethyl ether)

Reference Example 12

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.

5-Carbamoyloxy-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, white powder, m.p. 215 - 216°C (recrystallized from ethyl acetate/n-hexane)

5-Methylaminocarbonyloxy-l-(4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 192 - 195°C (recrystallized from ethyl acetate/n-hexane)

5-Dimethylaminocarbonyloxy-l-(4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 228 - 230°C (recrystallized from ethyl acetate/diisopropyl ether)

5-Methyl-l-(4-aminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine, white powder, m.p. 155 - 156°C (recrystallized from ethyl acetate/n-hexane)

5-Oxo-6-methyl-l-(2-chloro-4-aminobenzoyl)-2,3,4,5- tetrahydro-lH-benzazepine, white powder, m.p. 193 - 195°C (recrystallized from ethanol)

1-(4-Aminobenzoyl)-1,2 ,3,5-tetrahydro-4,1-benzo- thiazepine, white powder, m.p. 179 - 180°C (recrystallized from dichloromethane/diethyl ether)

5-Dimethylamino-l-(2-dimethylamino-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 163 - I65°C (recrysLallized from diethyl ether/dichloromethane)

5-Oxo-l-(4-aminobenzoyl)-2,3,4,5-tetrahydro-lH-

benzazepine, yellow powder, m.p. 195 - 197°C (recrystallized from diethyl ether/dichloromethane)

5-Oxo-4-methyl-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-l,4-benzazepine, yellow powder, m.p. 190 - 192°C (recrystallized from diethyl ether/dichloromethane)

5-Dimethylamino-l-{2-ethoxy-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. Ill - 114°C (recrystallized from diethyl ether)

5-Dimethylamino-l-(3-methy1-4-amiήobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, yellow oil

^X H-NMR (CDC1 ₃ ) δ : 0.66-2.56 (14H, ) , 2.93-5.22 (4H, m) , 6.23-7.80 (7H, m)

5-Dimethylamino-l-(2-methyl-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 154 - 156°C (recrystallized from methanol/diethyl ether)

5-Dimethylamino-l-(2-fluoro-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 161 - 163°C (recrystallized from dichloromethane/diethyl ether)

5-Dimethylamino-l-(3-fluoro-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 156 - 157°C (recrystallized from methanol/diethyl ether)

5-Oxo-l-(2-methoxy-4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, colorless prisms, m.p. 160 - 160.5°C (recrystallized from methanol/diethyl ether)

Example 1

To a solution of 1,2,3,4-tetrahydroquinoline (28.7

g) in acetone (400 ml) and water (200 ml) is added potassium carbonate (38.8 g) and further thereto is added 4-benzoyl- aminobenzoyl chloride (56 g) under ice-cooling. The mixture is stirred at room temperature overnight. Water is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography and recrystallized from methanol to give 1-[4-(benzoylamino)benzoyl]-l,2,3,4-tetrahydroquinoline (57 g) as white powder, m.p. 202.5 - 203.5°C.

Using the suitable starting materials, the compounds as shown in the following Table 1 are obtained in the same manner as in Example 1.

Table 1

Example 2 Structure

Crystalline form: Light yellow powder Recrystallization solvent: Methanol Melting Point: 198.5 - 199.5°C Form: Free

Example 3 Structure

0

R- 4-NHC Cl

<_>

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 200.5 - 201.5 ^β C Form: Free

Example 4 Structure

R 3 . 4 A .-NHC- Λ ^■ Br

\=/

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 206 - 207°C Form: Free

Example 5 Structure

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 216 - 217°C Form: Free

Example 6 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 202 - 203°C Form: Free

Example 7 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 212 - 213°C Form: Free

Example 8 Structure

R ³ : 4-NHC- / -CH ₂ CH ₂ CH ₃

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 167.5 - 168.5°C Form: Free

Example 9 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 205 - 206°C Form: Freε

Examplε 10 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: >300°C NMR analysis: 1) Form: Free

Example 11 Structure

0

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 176 - 177°C Form: Free

Example 12 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 219 - 220°C Form: Free

Example 13 Structure

O R ³ : 4-NHC-v' -0(CH ₂ ) ₃ CH ₃

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 193 - 194°C Form: Free

Example 14 Structure

4-NHC ^■ O- OCOCH-

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 232 - 233°C Form: Free

Example 15 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 209 - 210°C Form: Free

Example 16 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 184.5 - 185.5°C Form: Free

Example 17 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 224.5 - 225.5°C Form: Free

Example 18 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 220.5 - 221.5°C Form: Free

Example 19 Structure

R- 4-NHC COCH .

^■ © ^■

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 231 - 232°C Form: Free

Example 20 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: >300°C NMR analysis: 2) Form: Free

Example 21 Structure

R ³ : 4-NHC-V -CO )C<--H«-

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 208 - 209°C Form: Free

Example 22 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234.5 - 235.5°C Form: Free

Example 23 Structure

0

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 263.5 - 264.5°C Form: Free

Example 24 Structure

. ³ : 4-NHC-V 7-NH.

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 237 - 238°C Form: Free

Example 25 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234 - 235°C Form: Free

Example 26 Structure

0

4-NHC // W

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 236.5 - 237.5°C Form: Free

Example 27 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 206.5 - 207.5°C Form: Free

Example 28 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 210 - 211°C

Form: Free

Example 29 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 210.5 - 211.5°C

Form: Free

Example 30 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178 - 179°C Form: Free

Example 31 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 192 - 193°C Form: Free

Example 32 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 217 - 218°C Form: Free

Example 33 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 143 - 144°C Form: Free

Example 34 Structure

0

Crystalline form: White powder

Recrystallization solvent: Methanol Melting Point: 170.5 - 171.5°C Form: Free

Example 35 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 169.5 - 170.5°C

Form: Free

Example 36 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 174.5 - 175.5°C Form: Free

Example 37 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 148.5 - 149.5°C Form: Free

Example 38 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165 - 166°C Form: Free

Example 39 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 243 - 244°C Form: Free

Example 40 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 199 - 200°C Form: Free

Example 41 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 232.5 - 233.5°C Form: Free

Example 42 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178.5 - 179.5°C Form: Free

Example 43 Structure

0

R

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 205.5 - 206.5°C Form: Free

Example 44 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234 - 235°C Form: Free

Example 45 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 225 - 226°C Form: Free

Example 46 Structure

0 CH

4-NHC ^■ O

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 224 - 225°C Form: Free

Example 47 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 236 - 237°C Form: Free

Example 48 Structure

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 175.5 - 176.5°C Form: Free

Example 49 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 231 - 232°C Form: Free

Example 50 Structure

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 204 - 205°C Form: Free

Example 51 Structure

0 OCH-

R- 4-NHC ^■ OCH,

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 190 - 191°C Form: Free

Example 52 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 156 - 157°C Form: Free

Example 53 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 200 - 201°C Form: Free

Example 54 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 206 - 207°C Form: Free

Example 55 Structure

Crystalline form: Colorless amorphous

NMR analysis: 3)

Form: Free

Example 56 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 215.5 - 216.5°C Form: Free

Example 57 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 189 - 190°C Form: Free

Example 58 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203.5 - 204.5°C Form: Free

Example 59 Structure

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 254.5 - 255.5°C Form: Free

Example 60 Structure

Crystalline form: Brown powder Recrystallization solvent: Methanol Melting Point: 182.5 - 183.5°C Form: Free

Example 61 Structure

Crystalline form: Colorless amorphous

NMR analysis: 4)

Form: Free

Example 62 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 263 - 264°C Form: Free

Example 63 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 217 - 218°C

Form: Free

Example 64

Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol Melting Point: 183 - 184°C Form: Free

Example 65 Structure

Crystalline form: Yellow powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 207.5 - 208.5°C

Form: Free

Example 66

Structure

Crystalline form: Yellow powder

Recrystallization solvent: Dichloromethane/ethanol Melting Point: 251 - 252°C Form: Free

Example 67 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 208.5 - 209.5°C

Form: Free

Example 68

Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol Melting Point: 231 - 232°C Form: Free

Example 69 Structure

R ³ : 4-NHCCH ₃ Crystalline form: Colorless amorphous NMR analysis: 5) Form: Free

Example 70 Structure

R ^J : 4-NHC(CH ₂ ) ₂ CH ₃ Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 134 - 135°C Form: Free

Example 71 Structure

R ^J : 4-NHC(CH ₂ ) ₄ CH ₃ Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 115 - 116°C Form: Free

Example 72 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 178.5 - 179.5°C

Form: Free

Example 73 Structure

R ^J : 4-NHCCH(CH ₃ ) ₂ Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 182.5 - 183.5°C Form: Free

Example 74 Structure

0

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 164 - 165°C

Form: Free

Example 75 Structure

0

Crystalline form: Colorless amorphous NMR analysis: 6) Form: Free

Example 76 Structure

Crystalline form: Yellow amorphous NMR analysis: 7) Form: Free

Example 77 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 155 - 156°C Form: Free

Example 78 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 182.5 - 183.5°C Form: Free

Example 79 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 164.5 - 165.5°C Form: Free

Example 80 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165 - 167°C Form: Free

Example 81 Structure

0

Crystalline form: White powder Recrystallization solvent: Mεthanol Melting Point: 124 - 125°C Form: Free

Example 82 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 140.5 - 141.5°C Form.: Free

Example 83 Structure

Crystalline form: Colorless amorphous NMR analysis: 8) Form: Free

Example 84 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 211 - 212°C Form: Free

Example 85 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 178 - 179°C Form: Free

Example 86 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 212.5 - 213.5°C Form: Free

Example 87 Structure

0

II

R- ³ : 4-NHICC

Crystalline form -: White powder Recrystallization solvent: Methanol Melting Point: 193 - 194°C Form: Free

Example 88 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203 - 204°C Form: Free

Example 89 Structure

0

R ³ : 3-NHC <

Crystalline form: Colorless amorphous NMR analysis: 9) Form: Free

Example 90 Structure

R- 3-NHC OCH-

Crystalline form: Colorless amorphous NMR analysis: 10) Form: Free

_ r

- 202

Example 91 Structure

0

Crystalline form: Colorless amorphous NMR analysis: 11) Form: Free

Example 92 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 156.5 - 157.5°C Form: Free

Example 93 Structure

Crystalline form: Colorless amorphous NMR analysis: 12) Form: Free

Example 94 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203.5 - 204.5°C Form: Free

- -

Example 95 Structure

Crystalline form: Colorless amorphous NMR analysis: 13) Form: Free

Example 96 Structure

0

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 126 - 127°C Form: Free

Example 97 Structure

0

R ^J : 2-NHC -©- OCH-

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 158.5 - 159.5°C Form: Free

Example 98 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 129 - 130°C Form: Free

- 206 -

Example 99 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 131.5 - 132.5°C Form: Free

Example 100 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 140 - 141°C Form: Free

Example 101 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 138.5 - 139.5°C Form: Free

Example 102 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 128 - 129°C Form: Free

208 -

Example 103 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 160 - 161°C Form: Free

Example 104 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 175 - 176°C Form: Free

Example 105 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 197 - 198°C Form: Free

Example 106 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 204 - 205°C Form: Free

Example 107 Structure

0

R~ :

Crystalline form: White powder

Recrystallization solvent: Methanol Melting Point: 174 - 175°C Form: Free

Example 108 Structure

Crystalline form: Yellow powder Recrystallization solvent: Methanol Melting Point: 202 - 203°C Form: Free

Example 109 Structure

R- 4-NHC OCH,

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 203 - 204°C Form: Free

Example 110 Structure

0

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 170.5 - 171.5°C

Form: Free

- -

Example 111 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 149 - 150°C Form: Free

Example 112 Structure

0

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 185 - 186°C

Form: Free

Example 113 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 225 - 226°C

Form: Free

Example 114

Structu

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 234 - 235°C Form: Free

Example 115 Struct

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 149.5 - 150.5°C Form: Free

Example 116 Struct

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol Melting Point: 197 - 198°C Form: Free

Example 117 Structure

0

R- 4-NHC \

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 204 - 205°C Form: Free

Example 118 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 224.5 - 225.5°C Form: Free

Example 119 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 189.5 - 190.5°C

Form: Free

Example 120

Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 221.5 - 222.5°C Form: Free

Example 121 Structure

Crystallinε form: Colorless needles Recrystallization solvent: Methanol Melting Point: 154 - 155°C Form: Free

Example 122 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165 - 166°C Form: Free

Example 123 Structure

0

Crystalline form: Colorless needles Recrystallization solvent: Methanol Melting Point: 141 - 142°C Form: Free

Example 124 Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 165.5 - 166.5°C Form: Free

Example 125 Structure

Crystalline form: Colorless needles Recrystallization solvent: Methanol Melting Point: 164 - 165°C Form: Free

Example 126 Structure

0

Crystalline form: White powder

Recrystallization solvent: Methanol

Melting Point: 203.5 - 204.5°C

Form: Free

Example 127 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 236.5 - 237.5°C

Form: Free

Example 128

Structure

0

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 206.5 - 207.5°C Form: Free

Example 129 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 271 - 272°C Form: Free

Example 130 Structure

0

Crystalline form: White powder Recrystallization solvent: Mεthanol Melting Point: 246 - 247°C Form: Free

Example 131 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 210 - 211°C

Form: Free

Example 132

Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 230.5 - 231.5°C Form: Free

Example 133 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 203 - 204°C

Form: Free

Example 134

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 170 - 171°C Form: Free

- 224

Example 135 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 225.5 - 226.5°C

Form: Freε

Example 136

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 210.5 - 211.5°C Form: Free

Example 137 Structure

l 3 ^J :

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 183 - 184°C

Form: Free

Example 138

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 191.5 - 192.5°C Form: Free

- 226

Example 139 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 203.5 - 204.5°C

Form: Free

Example 140

Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 215.5 - 216.5°C Form: Free

Example 141 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 211.5 - 212.5°C Form: Free Example 142 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 280.5 - 281.5°C Form: Free

Example 143 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 235.5 - 236.5°C Form: Free

Crystalline form: White powder

Recrystallization solvent: Ethanol/dichloromethane

Melting Point: 249.5 - 250.5°C

Form: Free

Example 145 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 217 - 218°C

Form: Free

Example 146

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 201.5 - 203°C Form: Free

Example 147 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 221 - 222°C

Form: Free

Example 148

Structure

t ³ : 4-NHC- t? -CH,

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 193 - 194°C Form: Free

Example 149 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 176 - 177°C

Form: Freε

Example 150

Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 188 - 189.5°C Form: Free

Example 151 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 227 - 228°C

Form: Free

Example 152

Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 186 - 187°C Form: Free

Example 153 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 135 - 136°C

Form: Free

Example 154

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 173 - 174°C Form: Free

- -

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 174.5 - 175.5°C Form: Free

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 156 - 157°C

Form: Free

Example 157 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 153 - 154°C Form: Free Example 158 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 169 - 170°C Form: Free

Example 159 Structure

Crystalline form: Whitε powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 185 - 186°C

Form: Free

Example 160

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 213 - 214°C Form: Free

Example 161 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 240 - 241°C

Form: Free

Example 162

Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 225 - 226°C

« Form: Free

Example 163 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 209.5 - 210.5°C

Form: Free

Example 164

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 198 - 199°C Form: Free

Example 165 Structure

0

R ^J : 4-NHC OCH-

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 214.5 - 215.5°C

Form: Free

Example 166

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 196.5 - 197.5°C Form: Free

Example 167 Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 194 - 195°C

Form: Free

Example 168

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 191 - 192°C Form: Free

Example 169 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/ethanol

Melting Point: 227 - 228°C

Form: Free

Example 170

Structure

0

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 182 - 183°C

Form: Free

Example 171 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 222 - 223°C

Form: Free

Example 172

Structure

0

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 204 - 205°C

Form: Free

Example 173 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 194 - 195°C

Form: Free

Example 174

Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 213 - 214°C Form: Free

Example 175 Structure

R ^J : 4-NH °C--VT V-OCH3

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 201 - 202°C

Form: Free

Example 176

Structure

Crystalline form: Colorless needles

Recrystallization solvent: Dichloromethanε/diethyl ether

Melting Point: 173 - 174°C

Form: Free

Example 177 Structure

0

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether Melting Point: 150.5 - 151.5°C Form: Free Example 178 Structure

0

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 207.5 - 208.5°C

Form: Free

Example 179 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 256.5 - 257.5°C

Form: Free

Example 180

Structure

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 199.5 - 200.5°C Form: Free

Examplε 181 Structure

Crystalline form: White powdεr

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 211 - 212°C

Form: Free

Example 182

Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 189.5 - 190.5°C Form: Free

Example 183 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 176.5 - 177.5°C

Form: Free

Example 184

Structure

0

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 202 - 203°C Form: Free

Example 185 Structure

Crystalline form: White powdεr

Rεcrystallization solvεnt: Ethanol/diεthyl εther

Melting Point: 219 - 220°C

Form: Freε

Examplε 186

Structurε

Crystallinε form: Whitε powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 272 - 273°C Form: Free

Example 187 Struct

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 146 - 147°C Form: Free

Example 188 Struct

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 229.5 - 230.5°C Form: Free

Example 189 Struct

R- 4-NHC -©- CH,

Crystalline form: Yellow powder Recrystallization solvent: Ethanol/diethyl ether Melting Point: 119.5 - 120.5°C Form: Free

Example 190 Struct

Crystallinε form: Yεllow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 189 - 190°C Form: Free

Example 191 Struct

0

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 207 - 208°C Form: Free

Example 192 Struct

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 196.5 - 197.5°C Form: Free

Example 193 Struct

Crystallinε form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 182 - 183°C

Form: Free

Example 194

Struct

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 172 - 173°C Form: Free

Example 195 Structu

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 197.5 - 198.5°C Form: Free

Example 196 Struct

Crystalline form: Yellow powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 227 - 228°C Form: Free

Example 197 Struct

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 216.5 - 217.5°C Form: Free

Example 198 Struct

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 207 - 208°C Form: Free

Example 199 Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl εther Melting Point: 236 - 237°C Form: Free

Example 200 Struct

R- 4-NHC CH, _>

Crystallinε form: Whitε powder

Recrystallization solvent: Ethanol/diεthyl εther Melting Point: 199.5 - 200.5°C Form: Frεε

Examplε 201 Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 171.5 - 172.5°C Form: Free

Example 202 Structu

0

Crystalline form: White powder

Rεcrystallization solvεnt: Ethanol/diethyl ether Melting Point: 222.5 - 223.5°C Form: Free

Example 203 Struct

0

Crystalline form: White powder

Recrystallization solvεnt: Ethanol/diεthyl εther Melting Point: 209.5 - 210.5°C Form: Freε Examplε 204 Struct

Crystallinε form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 14) Form: Hydrochloride

Example 205 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 15) Form: Hydrochloride

Example 206 Structu

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 16) Form: Hydrochloride

Examplε 207 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol/watεr NMR analysis: 17) Form: Hydrochloridε

Examplε 208 Structu

_3. Δ 4--NHC- /T _CH3

Crystalline form: Whitε powdεr Rεcrystallization solvεnt: Ethanol/watεr NMR analysis: 18) Form: Hydrochloride

Example 209 Struct

4-NHC ^■ CH,

Crystalline form: Yellow powder Recrystallization solvent: Ethanol/water NMR analysis: 19) Form: Hydrochloride

Example 210 Struct

0

Crystalline form: Whitε powdεr Rεcrystallization solvent: Ethanol/water NMR analysis: 20) Form: Hydrochloride

Example 211 Struct

0 i - - Δ 4--NHC- // W OCH ₃

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 159.5 - 160.5°C Form: Free

Example 212 Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 189.5 - 190.5°C Form: Free.

Example 213 Struct

0

Crystalline form: Whitε powder

Recrystallization solvent: Ethanol/diεthyl ether

Melting Point: 170.5 - 171.5°C

Form: Free

Example 214

Structu

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 165 - 166°C Form: Frεe

Examplε 215 Structu

0

_3. Δ 4--NHC- <^ -Cl

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 173.5 - 174.5°C Form: Free

Example 216 Struct

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diεthyl εther Melting Point: 182 - 183°C Form: Free

Examplε 217 Structu

Crystalline form: White powder

Recrystallization solvent: Ethanol/diεthyl ether

Melting Point: 225.5 - 226.5°C

Form : Frεε

Example 219

Struct

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 21) Form: Hydrochloride

Examplε 220 Structu

Crystallinε form: Whitε powdεrr

Recrystallization solvent: Ethanol/diethyl ethεr Melting Point: 147.5 - 148.5°C Form: Free

Example 221 Struct

0

Crystalline form: White powder

Recrystallization solvent: Ethanol/diεthyl εthεr Melting Point: 136 - 137°C Form: Free

Example 222 Structu

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 191.5 - 192.5°C Form: Free Example 223 Struct

Crystalline form: White powdεr

Rεcrystallization solvent: Ethanol/diethyl ethεr

Mεlting Point: 145 - 146°C

Form: Frεε

Example 224 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 22) Form: Hydrochloride

Example 225 Struct

Crystalline form: Whitε powdεr Rεcrystallization solvεnt: Ethanol/watεr NMR analysis: 23) Form: Hydrochloridε

Example 226 Structure (CH 2 ) ^J 2CH,

0

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 24) Form: Hydrochloride

Example 227 Struct

0

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 25) Form: Hydrochloride

Example 228 Struct

0

Crystalline form: White powder Recrystallization solvent: Ethanol/water NMR analysis: 26) Form: Hydrochloride

Example 229 Structure

0

Crystalline form: White powder Rεcrystallization solvεnt: Ethanol/watεr NMR analysis: 27) Form: Hydrochloride

Example 230 Structu

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 206 - 207°C Form: Free Example 231 Structu

Crystalline form: White powder Recrystallization solvent: Chloroform/methanol Mεlting Point: 211 - 213°C Form: Free

Examplε 232 Struct

Crystalline form: White powder Recrystallization solvent: Chloroform/methanol Melting Point: 228.5 - 229.5°C Form: Frεε

Examplε 233 Struct

Crystalline form: White powdεr Rεcrystallization solvεnt: Chloroform/mεthanol Mεlting Point: 237 - 238°C Form: Free

Example 234 Structure

Crystalline form: White powder

Recrystallization solvent: Chloroform/methanol

Melting Point: 226 - 228°C

Form: Freε

Examplε 235

Struct

Crystalline form: White powder Recrystallization solvent: Chloroform/methanol Melting Point: 220 - 222°C Form: Free

Example 236 Structure

Crystalline form: Colorless amorphous NMR analysis: 28) Form: Freε

Examplε 237 Struct

Crystalline form: Whitε powdεr Recrystallization solvent: Ethanol Melting Point: 162 - 165°C Form: Free

Example 238 Struct

Crystalline form: Light brown amorphous

NMR analysis: 29)

Form: Freε

Example 239 Struct

0

Crystalline form: Light brown amorphous NMR analysis: 30) Form: Free

Example 240 Struct

Crystalline form: White powder Rεcrystallization solvεnt: Ethanol Melting Point: 215 - 217°C Form: Free

Example 241 Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol

Melting Point: 221 - 223°C

Form: Free

Example 242 Struct

Crystalline form: Colorless amorphous NMR analysis: 31) Form: Free

Example 243 Structu

Crystalline form: White powder Recrystallization solvent: Ethanol Malting Point: 207 - 210°C Form: Frεe

Example 244 Struct

Crystalline form: Colorless amorphous NMR analysis: 32) Form: Free

NHCOCH,

Crystallinε form: Colorlεss amorphous NMR analysis: 33) Form: Frεε

Examplε 246 Struct

Crystallinε form: Colorlεss amorphous

NMR analysis: 34) Form: Free

Example 247 Struct

Crystallinε form: Colorlεss amorphous NMR analysis: 35) Form: Free

Example 248 Struct

Crystalline form: Light yellow powder Recrystallization solvent: Ethanol Malting Point: 186 - 187°C Form: Free

Example 249 Structure

Crystalline form: Colorlεss needles Recrystallization solvent: Ethanol Melting Point: 190 - 191°C Form: Free

Example 250 Structure

Crystalline form: Light yellow scales

Recrystallization solvent: Ethanol/water

Melting Point: 230 - 231°C

Form: Freε

Examplε 251

Structure

0

R ³ : 4-NHC ^■ O

Crystalline form: Light yεllow nεεdlεs Recrystallization solvent: Ethanol Melting Point: 227 - 228°C Form: Free

Examplε 252 Structure

R- : 4-NHCCH ₂ CH ₂ C00H Crystalline form: Colorless needlεs Recrystallization solvent: Ethyl acetate Melting Point: 192°C Form: Free Example 253 Structurε

0 R 3 ³ : 4-NHC*CH ₂ CH ₂ CH ₂ COOH

Crystalline form: White powdεr

Recrystallization solvent: Ethyl acetate

Malting Point: 186.5 - 189°C

Form: Free

Example 254 Structure

R ³ : 4-NHC(CH ₂ ) ₂ CN(C ₂ H ₅ ) ₂ Crystalline form: Light yellow scalεs Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 165 - 167°C Form: Free Example 255 Structure

0 0

, II II R ³ : 4-NHC(CH ₂ ) ₂ CNH(CH ₂ ) ₃ CH ₃

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate

Melting Point: 169 - 170°C

Form: Free

Example 256 Structurε

0 0

Crystallinε form: Colorless scales

Recrystallization solvent: n-Hexane/ethyl acetate

Melting Point: 174 - 177°C

Form: Frεε

Example 257

Structure

0 0

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε

Mεlting Point: 114 - 118°C

Form: Free

Example 258 Structure

O

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate

Melting Point: 170 - 172°C

Form: Free

Example 259

Structure

0 0 R ³ : 4-NHC(CH ₂ ) ₂ CN C0 ₂ C ₂ H ₅

Crystalline form: White powder

Recrystallization solvent: n-Hexanε/εthyl acetate Melting Point: 179 - 181°C Form: Free

Example 260 Structure

0 0 R 3 ³ : 4-NHC' (CH ₂ ) ₂ C'NH ₂

Crystalline form: White powder

Recrystallization solvεnt: Ethyl acεtatε

Melting Point: 118 - 121°C

Form: Free

0 0 - II II R ³ : 4-NHC(CH ₂ ) ₃ CN(C ₂ H ₅ ) ₂

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε

Melting Point: 144 - 148°C

Form: Freε

Example 262 Structure

R ³ : 4-NHC(CH ₂ ) ₃ CNH(CH ₂ ) ₃ CH ₃ Crystalline form: Colorless scales Recrystallization solvent: Ethyl acetate Melting Point: 156 - 157°C Form: Free Example 263 Structure

0

Crystalline form: White powder Recrystallization solvent: Ethyl acεtatε Melting Point: 204 - 206°C Form: Free

Example 264 Structure

0

R 3 ³ : 4-NHC " CH ₂ Cl

Crystalline form: Light yellow powder

Recrystallization solvent: n-Hexane/ethyl acetatε

Melting Point: 165 - 167°C

Form: Freε

Example 265

Structure

R- 4-NHCCH ₂ CH ₂ Cl

Crystalline form: Light yellow amorphous NMR analysis: 36) Form: Free

Examplε 266 Structurε

R ³ : 4-NHC(CH ₂ ) ₃ C1 Crystalline form: White powder

Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 122 - 124°C Form: Free Examplε 267 Structurε

0

₃ ii

R~ : 4-NHCCH ₂ C0 ₂ C ₂ H ₅ Crystallinε form: Light yεllow powdεr Rεcrystallization solvεnt: n-Hexane/εthyl acetate Mεlting Point: 116 - 117°C Form: Frεε

Example 268 Structure

0

₃ I R ³ : 4-NHC(CH ₂ ) ₂ C0 ₂ C ₂ H ₅

Crystalline form: White powder

Recrystallization solvent: n-Hexane/ethyl acetate

Melting Point: 121 - 123°C

Form: Free

Example 269

Structure

0 Br

Crystallinε form: Colorlεss nεedles

Recrystallization solvent: Ethyl acetate

Melting Point: 186 - 187°C

Form: Frεε

Example 270 Structure

0

R ³ : 4-NHCCH ₂ NH _. Crystalline form: White powder

Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 139 - 142°C Form: Freε Example 271 Structure

0

Crystalline form: Light yellow amorphous NMR analysis: 37) Form: Free

Example 272 Structure

R~ : 4-NHCCH ₂ NHCH(CH ₃ ) ₂ Crystalline form: White powder Recrystallization solvent: Ethyl acetatε Mεlting Point: 149.5 - 152.5°C Form: Frεε Examplε 273 Structure

0 R 3 ³ : 4-NHC"CH ₂ NHC(CH ₃ ) ₃

Crystalline form: Colorless neεdlεs

Recrystallization solvent: Ethanol

Melting Point: 150 - 152.5°C

Form: Free

Example 274 Structure

R- ³ : 4-NHCCH ₂ NH(CH ₂ ) ₂ OH Crystalline form: White powder Recrystallization solvεnt: Ethyl acetate Melting Point: 150°C Form: Free Example 275 Structure

0 R 3 ^J : 4-NHC"CH ₂ N(C ₂ H ₅ ) ₂

Crystalline form: Colorless neεdlεs

Recrystallization solvent: n-Hexanε/εthyl acetate

Melting Point: 101 - 104°C

Form: Freε

Crystalline form: White powder

Rεcrystallization solvεnt: n-Hεxanε/εthyl acεtate

Melting Point: 120 - 122°C

Form: Free

Example 277

Structure

Crystalline form: Light yellow amorphous NMR analysis: 38) Form: Freε

Example 278 Structure

Crystalline form: Colorless needles Recrystallization solvεnt: Ethanol Malting Point: 183 - 186°C Form: Frεε

Examplε 279 Structurε

R ³ : 4-NHCCH ₂ -N

Crystallinε form: Light brown powdεr Rεcrystallization solvεnt: n-Hεxanε/εthyl acεtatε Melting Point: 139 - 142°C Form: Free

Example 280 Structure

R- 4-NHCCH ₂ -N 0

Crystalline form: Light yellow powder Recrystallization solvent: Ethanol Melting Point: 162 - 165°C Form: Free

Example 281 Structure

0

Crystalline form: Light yellow scales Recrystallization solvent: Ethyl acetatε Mεlting Point: 224 - 227°C Form: Free

Example 282 Structure

R ^J : 4-NHCCH- C0 ₂ C ₂ H ₅

Crystalline form: Light yellow amorphous

NMR analysis: 39)

Form: Frεε

Examplε 283

Structure

0

II

Crystalline form: Light yellow powder Recrystallization solvent: Ethanol/water Melting Point: 162 - 164°C Form: Free

Example 284 Structure

R- 4-NHCCH ₂ NH ₂

Crystalline form: Light yellow powder Recrystallization solvent: Ethanol Melting Point: 238 - 241°C (decomposεd) Form: Hydrochloride

Example 285 Structurε

0 0

R°: 4-NHCCH ₂ NHCCH ₃ Crystalline form: Light yellow amorphous NMR analysis: 40) Form: Free

Example 286 Structure

Crystallinε form: Colorlεss amorphous NMR analysis: 41) Form: Free

Example 287 Structure

Crystalline form: Colorless nεεdles Recrystallization solvent: n-Hεxanε/εthyl acetate Melting Point: 168 - 169°C Form: Free

Example 288 Structure

0

R~ : 4-NHCCH ₂ NH /Y

Crystalline form: Light brown powder Recrystallization solvent: Ethanol Melting Point: 189 - 191°C Form: Freε

Example 289 Structure

0 R ³ : Crystalline form: White powder

Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 200 - 202°C Form: Freε

Example 290 Structure

R ³ :

Crystalline form: Colorless scales

Recrystallization solvent: n-Hexanε/εthyl acεtate

Melting Point: 143 - 146°C

Form: Freε

Example 291

Structure

0

Crystalline form: White powder

Recrystallization solvεnt: n-Hexane/εthyl acεtatε Mεlting Point: 117 - 117.5°C Form: Frεε

Examplε 292 Structure

0

R ³ :

Crystalline form: Light brown powdεr

Rεcrystallization solvεnt: Diεthyl εthεr/εthyl acεtatε Melting Point: 225 - 226°C Form: Free

Examplε 293 Structurε

R- 4-NHCCH ₂ NH-

Crystalline form: White powder Recrystallization solvεnt: n-Hexane/ethanol Melting Point: 175 - 176.5°C Form: Frεe

Example 294 Structure

R ³ : 4-NHCCH ₂ NH- ^' Vci

Crystalline form: Whitε powdεr

Rεcrystallization solvent: Ethyl acetatε

Melting Point: 234 - 236°C

Form : Free

Example 295

Structurε

0

Crystallinε form: Colorlεss scales Recrystallization solvent: Ethyl acetate Melting Point: 172 - 174°C Form: Free

Example 296 Structure

0

R ³ :

Crystalline form: White powder

Rεcrystallization solvεnt: Ethyl acεtatε

Melting Point: 154 - 155°C

Form: Free

Example 297

Structure

0

R~ : 4-NHCCH ₂ NH o- OCH,

Crystalline form: Light yellow nεεdlεs Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 181.5 - 183.5°C Form: Freε

Example 298 Structure

R ³ : 4-NHCCH ₂ NH-/' /-CH- CH,

Crystalline form: White powder

Recrystallization solvent: n-Hexane/ethyl acetate

Melting Point: 173 - 175°C

Form: Freε

Examplε 299

Structure

CH,

R- ³ : 4-NHCCH ₂ N _>

Crystalline form: White powder

Recrystallization solvεnt: n-Hεxanε/εthyl acetate Melting Point: 137 - 138°C Form: Free

Examplε 300 Structurε

Crystallinε form: Light yellow amorphous

NMR analysis: 42)

Form: Free

Example 301

Structurε

Crystallinε form: Colorless neεdles

Recrystallization solvent: Diεthyl ether/ethyl acεtate Melting Point: 129 - 130°C Form: Freε

Example 302 Structure

Crystalline form: Colorless neεdles

Recrystallization solvent: n-Hεxane/ethyl acetate

Melting Point: 181 - 183°C

Form: Frεε

Example 303

Structure

Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 248 - 249°C Form: Free

Example 304 Structure

Crystalline form: Light yellow amorphous .

NMR analysis: 43)

Form: Free

Example 305

Structure

0

R ³ : 4-NHCCH ₂ CH ₂ \

Crystalline form: Light yellow neεdles Rεcrystallization solvent: Ethanol Melting Point: 94 - 96°C Form: Free

Example 306 Structure

0

R ³ : 4-NHCCH ₂ CH ₂ 0

Crystalline form: Light brown powder

Recrystallization solvent: Ethyl acetate

Melting Point: 159 - 161°C

Form: Free

Example 307

Structure

R ³ : 4-NHCCH ₂ CH ₂ NH

Crystallinε form: Whitε p -owder Recrystallization solvent: Ethyl acetate Melting Point: 180 - 183°C Form: Free

Example 308 Structure

Crystalline form: Light brown powder Recrystallization solvent: Ethanol Melting Point: 177 - 180°C Form: Free

Example 309 Structure

0

R ³ : 4-NHC(CH ₂ ) ₃

Crystalline form: Whit oe powder Recrystallization solvent: Ethyl acεtate Melting Point: 91 - 93°C Form: Free

Example 310 Structure

0

4-NHCCH ₂ 0 f

Crystalline form: Light brown scales Recrystallization solvent: Ethanol Melting Point: 155 - 156.5°C Form: Freε

Examplε 311 Structurε

Crystalline form: Colorless scales Rεcrystallization solvεnt: Ethyl acetate Melting Point: 172.5 - 175°C Form: Free

Crystallinε form: Whitε powdεr Rεcrystallization solvεnt: Ethanol Mεlting Point: 148 - 150.5°C Form: Frεe

Example 313 Structure

0 R ^J : 4-NHCCH->0-< ^X >-CH

Crystalline form: White powder Recrystallization solvent: Ethyl acetatε Melting Point: 172 - 173°C Form: Free

Example 314 Structure

R ^J :

Crystalline form: Colorless scales

Recrystallization solvent: n-Hexane/εthyl acεtatε

Melting Point: 133 - 135°C

Form: Free

Example 315

Structure

0

Crystalline form: White powder Rεcrystallization solvεnt: Ethyl acεtatε Mεlting Point: 217 - 219°C Form: Frεε

Example 316 Structure

0

Crystalline form: Colorless needles

Recrystallization solvent: Ethyl acetate

Melting Point: 226 - 227.5°C

Form: Frεe

Example 317

Structure

Crystalline form: Colorlεss amorphous NMR analysis: 44) Form: Frεε

Example 318 Structure

0

Crystalline form: White powder

Recrystallization solvent: Dichloromethane

Melting Point: 234 - 235°C

Form: Free

Example 319

Structure

Crystalline form: Colorless prisms Recrystallization solvent: Methanol Melting Point: 218 - 218.5°C Form: Freε

Example 320 Structure

R ^3J ::

Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Malting Point: 202.5 - 206°C Form: Frεε

Example 321 Structure

Crystallinε form: White powder

Recrystallization solvent: Ethanol Melting Point: 174 - 176°C Form: Freε

Example 322 Structure

Crystalline form: Colorlεss prisms Recrystallization solvent: Ethanol Melting Point: 216 - 218°C Form: Free

Example 323 Structure

Crystalline form: White powder Melting Point: >300°C NMR analysis: 45) Form: Freε

Example 324 Structure

Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 250.5 - 251°C Form: Freε

Examplε 325 Structurε

0 Cl

R~ : 4-NHC :-/0 ^λ >--Cl

Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 223 - 225°C Form: Free

Example 326 Structure

Crystalline form: Colorless prismsr Recrystallization solvent: Methanol Melting Point: 213 - 214°C Form: Free

Example 327 Structure

Crystallinε form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 246 - 247°C Form: Free

Example 328 Structure

Crystalline form: Colorless prisms Recrystallization solvent: Methanol Melting Point: 248 - 251°C Form: Free

Example 329 Structure

Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Mεlting Point: 268.5 - 270.5°C Form: Free

Example 330 Structure

0

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diethyl ether

Melting Point: 174 - 176°C

Form: Hydrochloride

Example 331

Structure

Crystalline form: White powder Recrystallization solvent: Ethanol Mεlting Point: 130 - 134°C Form: Free

Examplε 332 Structurε

0

Crystallinε form: Whitε powder

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 214 - 217°C

Form: Hydrochloride

Examplε 333

Structure

0

Crystalline form: Whitε powdεr

Rεcrystallization solvεnt: Methanol/diethyl ether Melting Point: 218 - 220°C Form: Hydrochloride

Example 334 Structure

0

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε

Mεlting Point: 222 - 225°C

Form: Free

Example 335

Structure

0

₆ NHCOCH ₃ Crystalline form: Colorless neεdlεs Recrystallization solvent: Methanol/diεthyl εther Melting Point: 171 - 172°C Form: Free

Examplε 336 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether

Melting Point: 235.5 - 236°C

Form: Dihydrochloride

Examplε 337

Structurε

Crystalline form: White powdεr

Rεcrystallization solvεnt: Methanol/diethyl ether Melting Point: 241 - 243°C Form: Free

Example 338 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether

Melting Point: 187 - 191°C

Form: Free

Example 339

Structure

0

/ CH, R 3 ³ : 4-NHC"-/f Vθ(CH ₂ )gN ^/

CH-

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 240 - 244°C Form: Hydrochloride

Example 340 Structure

Crystalline form: Colorless prisms

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 181 - 182°C

Form: Free

Example 341

Structure

Crystalline form: Colorless prisms Rεcrystallization solvεnt: Methanol/diethyl ether Melting Point: 188 - 190°C Form: Dihydrochloride

Example 342 Structure

Crystalline form: White powder

Recrystallization solvent: Isopropyl alcohol

Melting Point: 218 - 218.5°C

Form: Hydrochloride

Example 343

Structure

0

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl εthεr Mεlting Point: 243 - 245.5°C Form: Free

Example 344 Structure

0

Crystallinε form: White powder

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 130 - 133°C

Form: Freε

Examplε 345

Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 155 - 158°C Form: Free

Example 346 Structure

Crystalline form: White powder

Rεcrystallization solvεnt: Mεthanol/diεthyl εthεr

Melting Point: 208 - 210°C

Form: Hydrochloride

Examplε 347

Structure

Crystalline form: Colorless prisms Recrystallization solvent: Methanol/diethyl ether Melting Point: 154 - 155°C Form: Hydrochloride

Examplε 348 Structure

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diεthyl εthεr Melting Point: 142 - 143°C Form: Free

Crystalline form: White powdεr

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 120 - 125°C Form: Hydrochloride

Examplε 350 Structurε

Crystalline form: White powder

Rεcrystallization solvent: Methanol/diethyl ether

Melting Point: 91 - 95°C

Form: Hydrochloride

Example 351

Structurε

Crystallinε form: Whitε powdεr

Recrystallization solvent: Methanol/diethyl ether Melting Point: 145 - 146.5°C Form: Free

Example 352 Structure

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diethyl ether

Melting Point: 105 - 105.5°C

Form: Freε

Examplε 353

Structurε

Crystallinε form: Whitε powdεr

Recrystallization solvent: Mεthanol/diεthyl εther Melting Point: 151 - 155°C Form: Dihydrochloride

Example 354 Structure

Crystalline form: White powder

Recrystallization solvεnt: Mεthanol/diεthyl ether

Melting Point: 135.5 - 137.5°C

Form: Freε

Example 355

Structure

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 178 - 178.5°C Form: Free

Example 356 Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane

Melting Point: 266.5 - 268°C

Form: Free

Example 357

Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl εther Melting Point: 123 - 124°C Form: Free

Example 358 Structure

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε

Melting Point: 212 - 213.5°C

Form: Free

Example 359

Structure

0 0(CH ₂ ) ₃ C0 ₂ C ₂ H ₅

R ³ : 4-NHC

^■ & ^'

Crystalline form: Colorless scales Recrystallization solvent: Ethyl acεtate Melting Point: 160.5 - 162°C Form: Free

Example 360 Structure

Crystalline form: Colorless neεdles Recrystallization solvent: Ethanol Melting Point: 103 - 105°C Form: Free

Example 361 Structure

₆ OCOCH ₃

Crystalline form: White powdεr Rεcrystallization solvεnt: Ethanol Malting Point: 145 - 146°C Form: Free

Example 362 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 247 - 250°C

Form: Free

Example 363

Structure

Crystalline form: Whitε powdεr

Recrystallization solvent: Methanol/diethyl ether Melting Point: 198 - 199°C Form: Free

Example 364 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ethεr Mεlting Point: 181.5 - 182.5°C Form: Frεe

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 170 - 170.5°C Form: Frεε

Example 366 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 156 - 158°C

Form: Hydrochloride

Example 367

Structure

Crystallinε form: Whitε powdεr Rεcrystallization solvεnt: Diethyl ethεr Mεlting Point: 168.5 - 170.5°C Form: Free

Example 368 Structure

0

R ³ : 4-NHC-< NH

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diεthyl ether

Melting Point: 177 - 181.5°C

Form: Hydrochloride

Examplε 369

Structurε

0 0

R 3~ : 4-NHC"-→A N-C ⁱⁱ CH ₃

Crystalline form: White powdεr

Rεcrystallization solvεnt: Mεthanol/diεthyl εther Melting Point: 211 - 213°C Form: Free

Examplε 370 Structurε

Crystalline form: White powder NMR analysis: 46) Form: Freε

Examplε 371 Structurε

0

Crystalline form: White powder

Recrystallization solvent: Methanol/ethyl acetatε Mεlting Point: 166 - 167°C Form: Frεe

Example 372 Structure

0

gBr Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 127 - 131°C Form: Freε Examplε 373 Structure

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 170 - 171°C Form: Free

Example 374 Structure

0 CH,

R- .- OCH ₃

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 125 - 126°C Form: Free

Example 375 Structu

Crystalline form: Light yellow amorphous NMR analysis: 47) Form: Hydrochloride

Examplε 376 Structu

Crystalline form: Colorless amorphous NMR analysis: 48) Form: Hydrochloridε

1) H-NMR (CDCI3) δ : 1.92 (IH, t, J=6.2 Hz), 1.98 (IH, t, J=6.4 Hz), 2.8 (2H, t, J=6. Hz), 3.76 (2H, t, J=6.2 Hz), 6.75 (IH, d, J=7.6 Hz), 6.86 (2H, d, J=8.6 Hz), 6.8-7.1 (2H, m) , 7.20 (IH, d, J=7 Hz), 7.30 (2H, d, J=8.6 Hz), 7.72 (2H, d, J=8.6 Hz), 7.84 (2H, d, J=8.6 Hz), 10.13 (IH, s)

2) ^X H-NMR (DMSO-dg) δ : 2.05 (2H, quint, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz), 3.86 (2H, t, J=6.4 Hz), 6.85 (IH, d, J=7.6 Hz), 6.9-7.2 (2H, ) , 7.30 (IH, d, J=7.2 Hz), 7.44 (2H, d, J=8.5 Hz), 7.85 (2H, d, J=8.5 Hz), 8.1-8.2 (4H, m) , 10.65 (IH, s), 13.2- 13.4 (IH, br)

3) ^X H-NMR {CDCI3) δ : 1.9-2.1 (2H, m) , 2.84 (2H, t, J=6.5 Hz), 3.82 (6H, s), 3.90 (2H, t, J=6.6 Hz), 6.5-7.2 (7H, m), 7.35 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.7 Hz), 8.05 (IH, s)

4) H-NMR (CDCI3) δ : 1.9-2.1 (2H, m) , 2.37 (6H, s), 2.84 (2H, t, J=6.6 Hz), 3.90 (2H, t, J=6.6 Hz), 6.71 (IH, d, J=7.9 Hz), 6.8-7.2 (4H, m) , 7.35 (2H, d, J=8.6 Hz), 7.44 (2H, s), 7.56 (2H, d, J=8.6 Hz), 8.00 (IH, s)

5) H-NMR (CDCI3) δ : 1.9-2.2 (2H, m) , 2.12 (3H, s), 2.84 (2H, t, J=6.6 Hz), 3.89 (2H, t, J=6.5 Hz), 6.71 (IH, d, J=7.8 Hz), 6.87 (IH, t, J=7 Hz), 6.99 (IH, t _f 3=1 _* 3 Hz), 7.15 (IH, d, J=6.5 Hz), 7.28 (2H, d, J=8.6 Hz), 7.41 (2H, d, J=8.6 Hz), 8.03

(IH, S)

6) ^X H-NMR (CDC1 ₃ ) δ : 0.8-1.3 (6H, m) , 1.6-2.3 (9H, ), 2.83 (2H, t, J=6.6 Hz), 3.89 (2H, t, J=6.5 Hz), 6.72 (IH, d, J=7.9 Hz), 6.8-7.1 (2H, m) , 7.15 (IH, d, J=7.4 Hz), 7.28 (2H, d, J=8.3 Hz), 7.44 (2H, d, J=8.4 Hz), 7.9-8.1 (IH, m)

7) H-NMR (CDC1 ₃ ) δ : 2.02 (2H, quint, J=6.5 Hz),

2.81 (2H, t, J=6.6 Hz), 3.69 (2H, s) , 3.87 (2H, t, J=6.6 Hz), 6.66 (IH, d, J=8.2 Hz), 6.8-7.0 (2H, m) , 7.13 (IH, d, J=7.3 Hz), 7.2-7.4 (9H, m) , 7.59 (IH, s)

8) ^X H-NMR (CDCI3) δ : 1.7-2.1 (17H, m) , 2.83 (2H, t, J=6.7 Hz), 3.90 (2H, t, J=6.6 Hz), 6.68 (IH, d, J=8.1 Hz), 6.8-7.1 (2H, m) , 7.14 (IH, d, J=7 Hz), 7.32 (2H, d, J=8.7 Hz), 7.39 (IH, s), 7.46 (2H, d, J=8.7 Hz)

9) ^X H-NMR (CDCI3) δ : 1.99 (2H, quint, J=6.5 Hz),

2.82 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=6.5 Hz), 6.8-7.1 (4H, m), 7.1-7.3 (2H, m) , 7.4-7.6 (3H, m) , 7.67 (IH, s), 7.8-8.0 (3H, m) , 8.42 (IH, s)

10) ^X H-NMR (CDCI3) δ : 2.00 (2H, quint, J=6.5 Hz),

2.83 (2H, t, J=6.6 Hz), 3.85 (2H, t, J=6.6 Hz), 3.86 (3H, s), 6.8-7.1 (6H, m) , 7.1-7.3 (2H, m) , 7.64 (IH, s), 7.8-8.0 (3H, m) , 8.22 (IH, s)

11) H-NMR (CDCI3) δ : 1,98 (2H, quint, J=6.5 Hz), 2.82 (2H, t, J=6.5 Hz), 3.81 (2H, t, J=6.5 Hz),

3.84 (3H, s), 6.8-7.5 (10H, m) , 7.68 (IH, s), 7.95 (IH, d, J=8.2 Hz), 8.52 (IH, s)

12) ^X H-NMR (CDC1 ₃ ) δ : 1.7-1.9 (2H, m) , 2.70 (2H, t, J=6.6 Hz), 3.70 (2H, t, J=6.4 Hz), 6.8-7.3 (6H, m) , 7.4-7.7 (2H, m), 7.8-7.9 (5H, m) , 8.04 (IH, d, J=8 Hz), 8.33 (IH, s), 8.90 (IH, s)

13) H-NMR (CDC1 ₃ ) δ : 1.7-2.1 (17H, m) , 2.84 (2H, t, J=6.5 Hz), 3.89 (2H, t, J=6.4 Hz), 6.8-7.2 (6H, m) , 7.42 (IH, s), 7.56 (IH, s), 7.81 (IH, d, J=8.1 Hz)

14) ^X H-NMR (DMSO-dg) δ : 1.0-1.5 (5H, m) , 1.5-2.0 (5H, m), 2.2-3.8 (8H, m) , 4.2-5.2 (3H, m) , 6.77 (IH, d, J=7.2 Hz), 7.1-7.4 (4H, m) , 7.47 (2H, d, J=8.6 Hz), 7.58 (IH, d, J=6.2 Hz), 10.06 (IH, s), 10.9-12.1 (IH, br)

15) ^X H-NMR (DMSO-dg) δ : 2.5-3.8 (6H, m) , 4.2-5.2 (3H, m) , 6.81 (IH, d, J=6.8 Hz), 7.1-7.3 (4H, m) , 7.5- 7.7 (3H, m), 7.8-8.0 (IH, m) , 7.97 (2H, d, J=l.8 Hz), 10.66 (IH, s), 11.1-12.3 (IH, br)

16) ^X H-NMR (DMSO-dg) δ : 2.20 (3H, s), 2.27 (3H, s), 2.5-3.8 (6H, m), 4.3-5.3 (3H, m) , 6.82 (IH, d, J=7.2 Hz), 7.1-7.4 (7H, m) , 7.5-7.8 (3H, m) , 10.43 (IH, s), 11.0-12.2 (IH, br)

17) H-NMR (DMCO-dg) δ : 2.34 (3H, s), 2.5-3.7 (6H, m) , 4.3-5.2 (3H, m), 6.82 (IH, d, J=6.8 Hz), 7.2-7.7 (11H, m), 10,41 (IH, s), 10.8-12.3 (IH, br)

18) ^X H-NMR (DMSO-dg) δ : 2.38 (3H, s), 2.5-3.8 (6H, m) ,

4.3-5.3 (3H, m), 6.81 (IH, d, J=7.0 Hz), 7.1-7.5

(6H, m) , 7.5-7.8 (5H, m) , 10.35 (IH, s), 10.9-12.2

(IH, br)

19) ^X H-NMR (DMSO-dg) δ : 2.37 (3H, s), 2.5-3.7 (6H, ) , 4.3-5.2 (3H, m), 6.81 (IH, d, J=7.2 Hz), 7.2-7.4 (6H, m), 7.5-7.7 (3H, m) , 7.84 (2H, d, J=8.0 Hz),

10.31 (IH, s), 10.9-12.2 (IH, br)

20) H-NMR (DMSO-dg) δ : 2.5-3.8 (6H, m) , 4.3-5.2 (3H, m), 6.82 (IH, d, J=7.4 Hz), 7.2-7.3 (4H, m) , 7.5- 7.8 (5H, m), 7.75 (IH, d, J=1.8 Hz), 10.70 (IH, s), 10.8-12.2 (IH, br)

21) H-NMR (DMSO-dg) δ : 2.5-3.8 (9H, m) , 4.3-4.7 (IH, m), 4.7-5.1 (2H, m) , 6.8-7.1 (3H, m) , 7.1-7.4 (2H, m) , 7.5-7.7 (2H, m) , 7.8-8.0 (3H, ) , 9.79 (IH, s), 10.8-12.2 (IH, br)

22) H-NMR (DMSO-dg) δ : 0.8-1.2 (3H, m) , 1.7-2.2 (2H, m), 2.5-3.8 (5H, m) , 4.3-5.2 (3H, m) , 6.80 (IH, d, J=7.2 Hz), 7.1-7.3 (4H, m) , 7.6-7.7 (3H, m) , 7.85 (IH, s), 7.96 (2H, d, J=1.8 Hz), 10.62 (IH, s), 10.8-12.0 (IH, br)

23) H-NMR (DMSO-dg) δ : 0.8-1.1 (3H, m) , 1.7-2.1 (2H, m) , 2.37 (3H, s), 2.7-3.8 (5H, m) , 4.4-5.2 (3H, m) , 6.81 (IH, d, J=7.6 Hz), 7.2-7.4 (6H, m) , 7.6-7.7 (3H, m), 7.84 (2H, d, J=8.2 Hz), 10.29 (IH, s), 10.5-11.8 (IH, br)

24) H-NMR (DMSO-dg) δ : 0.8-1.2 (3H, m) , 1.7-2.1 (2H,

m), 2.38 (3H, s), 2.6-3.8 (5H, m) , 4.3-5.2 (3H, m) , 6.81 (IH, d, J=7.0 Hz), 7.2-7.5 (6H, m) , 7.6-7.8 (5H, m), 10.33 (IH, s), 10.5-11.7 (IH, br)

25) ^X H-NMR (DMSO-dg) δ : 0.8-1.2 (3H, m) , 1.7-2.1 (2H, m), 2.6-3.8 (5H, m) , 3.8-5.2 (3H, m) , 6.82 (IH, d, J=7.2 Hz), 7.1-7.5 (8H, m) , 7.5-7.7 (3H, m) , 10.42 (IH, s), 10.7-12.0 (IH, br)

26) ^X H-NMR (DMSO-dg) δ : 0.8-2.0 (15H, m) , 2.2-2.5 (IH, m), 2.6-3.7 (5H, m) , 4.3-5.2 (3H, m) , 6.76 (IH, d, J=7.0 Hz), 7.1-7.4 (4H, m) , 7.46 (2H, d, J=8.6 Hz), 7.61 (IH, d, J=6.4 Hz), 10.03 (IH, s), 10.5-11.8 (IH, br)

27) ^X H-NMR (DMSO-dg) δ : 0.8-1.1 (3H, m) , 1.7-2.0 (2H, m), 2.20 (3H, s), 2.29 (3H, s), 2.6-3.7 (5H, m) , 4.3-5.2 (3H, m), 6.82 (IH, d, J=7.0 Hz), 7.2-7.4 (7H, m), 7.5-7.7 (3H, m) , 10.41 (IH, s), 10.6-12.0 (IH, br)

28) H-NMR (CDC1 ₃ ) δ : 1.21 (3H, t, J=7.1 Hz), 3.00- 3.25 (3H, m), 4.00-4.30 (4H, m) , 6.63 (IH, d, J=7.8 Hz), 6.86 (IH, t, J=7.3 Hz), 7.00 (IH, t, J=6.3 Hz), 7.10-7.31 (3H, ) , 7.40-7.57 (3H, m) , 7.77 (2H, d, J=1.9 Hz), 8.76 (IH, brs)

29) H-NMR (CDC1 ₃ ) δ : 2.29 (3H, s), 2.32 (3H, s), 2.34 (3H, s), 2.50-3.15 (11H, m) , 3.79 (IH, dd, J=13.2 Hz, 7.3 Hz), 4.05 (IH, dd, J=13,2 Hz, 5.7 Hz), 6.62 (IH, d, J=7.7 Hz), 6.82-7.48 (8H, m) , 7.53 (2H, d,

J=8.4 Hz), 8.05 (IH, brs)

30) ^X H-NMR (CDC1 ₃ ) δ : 1.65-2.01 (4H, m) , 2.31 (3H, s), 2.35 (3H, s), 2.55-3.02 (6H, m) , 3.09 (IH, dd,

J=15 Hz, 5 Hz), 3.70 (IH, dd, J=12.5 Hz , 8.0 Hz ) ,

4.22 (IH, dd, J=12.5 Hz, 5 Hz), 6.67 (IH, d, J=7.8 Hz), 6.80-7.32 (7H, m) , 7.37 (2H, d, J=8.6 Hz), 7.53 (IH, d, J=8.3 Hz), 7.66 (IH, brs)

31) H-NMR (CDCI3) δ : 2.80 (IH, dd, J=16.1 Hz, 5.3 Hz), 3.16 (IH, dd, J=15.8 Hz, 5.3 Hz), 3.75-4.50 (3H, m) , 4.87-5.10 (3H, m) , 6.80-7.60 (14H, ) , 7.74 (2H, d, J=1.9 Hz), 8.47 (IH, brs)

32) H-NMR (CDCI3) δ : 2.35 (6H, s), 2.72-3.10 (3H, m), 3.65-3.78 (IH, m) , 4.06-4.18. (IH, m) , 6.60-7.62 (9H, m), 7.74 (2H, d, J=1.8 Hz), 8.52 (IH, brs)

33) H-NMR (CDCI3) δ : 1.87 (3H, s), 2.68 (IH, dd, J=5.6 Hz, 16 Hz), 3.14 (IH, dd, J=5.6 Hz, 16 Hz), 3.70-3.95 (2H, m) , 4.32-4.50 (IH, m) , 6.29 (IH, d, J=7.6 Hz), 6.90-7.80 (11H, m) , 9.16 (IH, brs)

34) ^X H-NMR (CDCI3) δ : 1.62 (IH, brs), 1.90-2.25 (2H, m), 2.55 (3H, s), 3.78 (IH, t, J=5.1 Hz), 3.95 (2H, t, J=6.7 Hz), 6.69 (IH, t, J=7.9 Hz), 6.90-7.13 (2H, m), 7.23-7.40 (3H, m) , 7.42-7.56 (3H, m) , 7.77 (2H, d, J=1.9 Hz), 8.53 (IH, brs)

35) H-NMR (CDCI3) δ : 1.80-2.02 (IH, m) , 2.20-2.35 (IH, m), 2.31 (6H, s), 3.52 (IH, t, J=5.4 Hz), 3.68-3.83 (IH, m) , 3.95-4.15 (IH, m) , 6.59 (IH, d,

J=7.8 Hz), 6.81-7.10 (2H, m) , 7.16-7.50 (6H, m) , 7.80 (2H, d, J=1.8 Hz), 9.13 (IH, brs)

36) H-NMR (CDC1 ₃ ) δ : 1.35-1.60 (IH, m) , 1.65-2.20 (3H, m), 2.65-3.20 (5H, m) , 3.81 (2H, d, J=6.5 Hz), 4.90-5.10 (IH, m), 6.60 (IH, d, J=8.0 Hz), 6.90 (IH, t, J=8.0 Hz), 7.00-7.50 (6H, m)

37) H-NMR (CDCI3) δ : 1.30-2.25 (4H, m) , 2.55-3.20 (3H, m) , 3.35 (2H, s), 3.80 (2H, s), 4.90-5.10 (IH, m), 6.62 (IH, d, J=8.0 Hz), 6.85-7.45 (12H, m) , 9.27 (IH, brs)

38) ^X H-NMR (CDCI3) δ : 1.35-2.25 (4H, m) , 2.33 (3H, s), 2.60-3.20 (3H, m) , 3.12 (2H, s), 3.61 (2H, s), 5.00 (IH, brs), 6.50-7.60 (13H, m) , 9.14 (IH, brs)

39) ^X H-NMR (CDCI3) δ : 1.27 (3H, t, J=7.1 Hz), 1.25- 2.50 (12H, m), 2.70-3.10 (4H, m) , 3.05 (2H, s), 4.15 (2H, q, J=7.0 Hz), 4.90-5.10 (IH, m) , 6.63 (IH, d, J=7.5 Hz), 6.91 (IH, t, J=7.5 Hz), 7.00- 7.50 (6H, m) , 9.14 (IH, brs)

40) ^X H-NMR (CDCI3) δ : 1.30-1.65 (IH, m) , 1.80-2.25 (5H, m), 2.70-3.20 (3H, m) , 4.01 (2H, d, J=5.0 Hz), 4.90-5.10 (IH, m), 6.61 (IH, d, J=7.7 Hz), 6.89 (IH, t, J=7.0 Hz), 7.00-7.45 (6H, m) , 9.05 (IH, brs)

41) H-NMR (CDCI3) δ : 1.18 (6H, s), 1.30-2.20 (4H, m) , 2.60-3.20 (3H, m) , 3.30 (2H, s), 3.73 (2H, s), 4.90-5.10 (IH, m), 6.61 (IH, d, J=7.3 Hz), 6.70-

7.45 (12H, m), 9.50 (IH, brs)

42) H-NMR (CDC1 ₃ ) δ : 1.19 (3H, t, J=7.0 Hz), 1.30-

1.70 (IH, m), 1.75-2.20 (3H, m) , 2.65-3.15 (3H, m) ,

3.46 (2H, q, J=7.0 Hz), 3.88 (2H, s), 4.90-5.10

(IH, m), 6.55-7.45 (13H, m) , 8.36 (IH, brs)

43) H-NMR (CDCI3) δ : 1.08 (3H, t, J=7.2 Hz), 1.05- 2.25 (14H, m), 2.25-3.25 (10H, m) , 4.90-5.10 (IH, m), 6.64 (IH, d, J=7.6 Hz), 6.90 (IH, t, J=7.2 Hz), 6.94-7.50 (6H, m) , 11.50 (IH, brs)

44) H-NMR (CDCI3) δ : 1.06 (3H, t, J=7.5 Hz), 1.30- 2.20 (6H, m), 2.60-3.20 (3H, m) , 3.65 (IH, m) , 3.95 (IH, brs), 4.90-5.10 (IH, m) , 6.50-6.75 (3H, m) , 6.75-7.05 (2H, m) , .7.05-7.55 (8H, m) , 8.67 (IH, brs)

45) H-NMR (DMSO-dg) δ : 1.28-1.57 (IH, m) , 1.69-2.20 (3H, m) , 2.59-3.15 (3H, m) , 4.74-4.98 (IH, m) , 6.62-6.80 (IH, m) , 6.86-7.37 (5H, m) , 7.50-7.70 (2H, m), 8.95-9.02 (IH, m) , 9.03-9.15 (2H, m) , 10.85 (IH, s)

46) H-NMR (CDCI3) δ : 1.40-1.66 (5H, m) , 1.72-2.20 (7H, m), 2.63-3.18 (3H, m) , 3.42 (2H, t, J=6.7 Hz), 4.00 (2H, t, J=6.3 Hz), 4.91-5.13 (IH, m) , 6.58-

6.72 (IH, m), 6.82-7.00 (3H, m) , 7.02-7.30 (4H, m) ,

7.36-7.51 (2H, m) , 7.70-7.88 (2H, m) , 7.91 (IH, s)

47) ^X H-NMR (DMSO-dg) δ : 2.05-2.95 (8H, m) , 3.43-3.70 (IH, m), 4.08-4.30 (IH, m) , 4.72-5.00 (IH, m) ,

6.70-8.08 (11H, m) , 10.8 (IH, s), 11.1 (IH, brs) 48) ^X H-NMR (DMSO-dg) δ : 2.10-3.00 (8H, m) , 3.47-3.70

(IH, m), 4.07-4.33 (IH, m) , 4.75-4.98 (IH, m) ,

6.78-6.91 (IH, m) , 7.05-7.22 (2H, m) , 7.30-7.97

(9H, m), 10.75 (IH, s), 10.94 (IH, brs)

Example 377

To a solution of l-[ 4-(4-formylbenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinoline (0.3 g) in methanol (10 ml) is added gradually sodium borohydride (59 mg) under icε- cooling and the mixture is stirred at room temperaturε for 2 hours. Water is added to the mixture and the solvent is distilled off under reduced pressure. The resulting residuε is εxtractεd with dichloromεthanε, washed with water, and dried over magnesium sulfate. The solvent is distilled off under reducεd prεssurε and the resulting residuε is purifiεd by silica gεl column chromatography (εluεnt; dichloromεthane : methanol = 50 : 1), and recrystallized from methanol to give l-[ -( 4-hydroxymethylbenzoylamino)benzoyl]-l,2,3, 4- tetrahydroquinoline (165 mg) as white powdεr, m.p. 224.5 - 225.5°C.

Using the suitable starting materials, the compound of the above Examplε 37 is obtained in the samε mannεr as in Examplε 377.

Examplε 378

To a solution of l-[ -{4-methoxycarbonvlbεnzovl-

amino)benzoyl]-l,2,3,4-tetrahydroquinolinε (0.5 g) in -methanol (20 ml) is added 5 % aqueous sodium hydroxide solution (10 ml) and the mixture is stirred at room temperature overnight. Methanol is distilled off undεr reduced pressure and the resulting rεsidue is acidified with diluted aquεous hydrochloric acid solution. Thε prεcipitated crystal is collected by filtration to give 1- [4-(4-carboxybenzoylamino)benzoyl]-1,2,3,4-tetrahydro¬ quinoline (0.4 g) as white powder, m.p. >300°C. H-NMR (DMSO-dg) δ : 2.05 (2H, quint, J=6.4 Hz), 2.91 (2H, t, J=6.4 Hz), 3.86 (2H, t, J=6.4 Hz), 6.85 (IH, d, J=7.6 Hz), 6.9-7.2 (2H, m) , 7.30 (IH, d, J=7.2 Hz), 7.44 (2H, d, J=8.5 Hz), 7.85 (2H, d, J=8.5 Hz), 8.1-8.2 (4H, m) , 10.65 (IH, s), 13.2-13.4 (IH, br)

Using the suitable starting materials, the compounds of the above Examples 39, 241, 252, 253 and 362 are obtained in the same mannεr as in Example 378.

Example 379

To a solution of l-[4-(3-acetyloxybenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinolinε (1.5 g) in mεthanol (20 ml) is added 5 % aqueous sodium hydroxide solution (10 ml) and the mixture is stirrεd at room temperature overnight. Methanol is distilled off under rεducεd pressure and the resulting residuε is acidifiεd with diluted aqueous hydrochloric acid solution. Thε precipitated crystal is collected by filtration and recrystallizεd from mεthanol to

give 1-[4-(3-hydroxybenzoylamino)benzoyl]-!, 2,3,4- tetrahydroquinoline (1.22 g) as white powder, m.p. 217 - 218°C.

Using the suitable starting materials, the compounds of the above Examples 10, 343, 356, 364 and 365 are obtained in the same manner as in Example 379.

Example 380

To a solution of l-[ 4-(3-hydroxybenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinoline (0.4 g) in acetone (5 ml) are added potassium carbonate (0.22 g) and ethyl iodide (0.34 g), and the mixture is refluxεd for 5 hours. Then, acetonε is distilled off under rεducεd pressure and watεr is addεd to the residue. The precipitated crystal is collected by filtration, and recrystallized from methanol to givε 1- [ 4-( 3-ethoxybenzoylamino)benzoyl]-1,2,3,4-tetrahydro¬ quinoline (0.36 g) as white powder, m.p. 170.5 - 171.5°C.

Using the suitable starting materials, the compounds of the above Examples 11, 12, 13, 14, 33, 35, 48, 50 - 55, 90 - 92, 97 - 100, 109 - 111, 120 - 122, 136 - 138, 165 - 167, 175 - 177, 192 - 194, 211, 212, 214, 321, 322, 330 - 333, 335, 336, 339 - 342, 344 - 355, 357 - 366 and 370 - 374 are obtainεd in thε same mannεr as in Examplε 380.

Example 381

Ethanol (50 ml) is added to 10 % Pd-C (0.1 g) and thereto is added-l-[4-(3-nitrobenzoylamino)benzoyl]-l, 2,3,4- tetrahydroquinoline (0.73 g). The mixture is subjected to

catalytic reduction at ordinary tempεraturε undεr atmospheric pressure of hydrogen. After completion of the rεduction, 10 % Pd-C is rεmovεd by filtration and thε filtratε is concεntrated under reduced pressure. Thε residue is extractεd with dichloromethane and the extract is dried over magnεsium sulfatε. Thε solvεnt is distillεd off undεr rεducεd prεssure and recrystallized from methanol to give 1-[4-(3-aminobenzoylamino)bεnzoyl]-1,2,3,4-tεtrahydro- quinolinε (0.54 g) as white powder, m.p. 205.5 - 206.5°C.

Using thε suitable starting materials, thε compounds of the above Examples 24, 334 and 338 arε obtainεd in the same manner as in Example 381.

Example 382

To a solution of l-(4-aminobenzoyl)-l,2,3,4-tetra- hydroquinoline (0.5 g) in dichloromεthanε (20 ml) is added triethylamine (0.3 g), and therεto is addεd benzoyl chloride (0.28 g) under ice-cooling. The mixture is stirred at room temperaturε for 1 hour. To thε rεaction mixturε is added water and extracted with dichloromethanε. Thε extract is dried over magnesium sulfatε and the solvent is distilled off under reducεd prεssurε. The resulting rεsidue is purified by silica gel column chromatography (eluent; dichloromethane : methanol = 50 : 1) and recrystallizεd from mεthanol to givε l-[4-(benzoylamino)benzoyl]-l,2,3,4- tetrahydroquinoline (245 mg) as white powder, m.p. 202.5 - 203.5°C.

Using the suitable starting materials, the compounds of the above Examples 2 - 119, 131 - 373, 375 and 376 are obtained in the same manner as in Example 382.

Example 383

Thionyl chloride (10 ml) is added to l-(4-carboxy- benzoyl)-l,2,3,4-tetrahydroquinoline (0.5 g) and the mixture is refluxεd for 1 hour. Thionyl chloridε is distillεd off undεr rεducεd prεssure to give 4-[l-(1,2,3,4-tetrahydro- quinolyl)carbonyl]bεnzoyl chloridε. Sεparately, to a solution of m-anisidine (0.27 g) in dichloromεthane (20 ml) is added triethylamine (0.34 g), and thereto is added gradually the abovε obtainεd 4-[1-(1,2,3,4-tetrahydro- quinolyl)carbonyl]benzoyl chloride under ice-cooling and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is extracted with dichloromethane. The extract is dried ovεr magnεsium sulfate. The solvent is distilled off under reducεd pressure and the resulting residue is purified by silica gel column chromatography (εluent; dichloromethane : methanol = 50 : 1), and recrystallized from methanol to give l-[4-(3- methoxyanilinocarbonyl)bεnzoyl]-l,2,3,4-tεtrahydroquinolin e (203 mg) as colorless needles, m.p. 154 - 155°C.

Using the suitable starting materials, the compounds of the above Examples 120, 122 - 130 and 374 are obtainεd in the same manner as in Example 383,

Example 384

To 4-oxo-l-[4-( 3 ,5-dichlorobenzoylamino)benzoyl]- 1,2,3,4-tetrahydroquinoline (0.7 g) are added tetrahyrdo- furan (10 ml) and methanol (10 ml). To the mixture is added sodium borohydride (0.1 g) in portions and thε mixture is stirred at room tεmpεraturε for 1 hour. Watεr is addεd to the reaction mixture and the mixture is extracted with dichloromethanε. The solvent is concεntratεd and the resulting residuε is purifiεd by silica gεl column chromatography (εluent; dichloromethanε ^■ * ^■ dichloromethane : methanol = 20 : 1), and recrystallizεd from εthanol to give 4-hydroxy-l-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4- tetrahydroquinolinε (0.4 g) as whitε powder, m.p. 215 - 217°C.

Example 385

To 3-ethoxycarbonyl-l-[4-(3,5-dichlorobenzoyl- amino)bεnzoyl]-l,2,3,4-tetrahydroquinoline (0.6 g) are added an aqueous solution of sodium hydroxide (0.1 g) in water (1 ml) and ethanol (5 ml). The mixture is stirred at room temperaturε for 15 minutes, and acidified with diluted hydrochloric acid, extracted with dichloromethanε. The solvent is distilled off and thε rεsulting residue is purified by silica gel column chromatography (eluent; dichloromethane •* dichloromethanε : methanol = 50 : 1), and recrystallizεd from ethanol to give 3-carboxy-l-[4-(3,5- dichlorobεnzoylamino)benzoyl ]-l, 2,3,4-tetrahydroquinoline (0.4 g) as white powder, m.p. 221 - 223°C.

Example 386

To 3-carboxy-l-[ 4-(3,5-dichlorobenzoylamino)- benzoyl]-l,2,3, -tetrahydroquinoline (3.7 g) are added tetrahydrofuran (50 ml) and thionyl chloride (5 ml). The mixture is reacted at 60°C for 1 hour. The reaction mixture is concentratεd and to the residue is added acetonε (20 ml). To the mixture is added dropwise a solution of sodium azide (1.0 g) in water (5 ml) under ice-cooling. The reaction mixture is stirred at the same temperature for 30 minutes and extracted with dichloromethane, dried over magnesium sulfate. The solvent is concentrated and to the resulting residue are added anhydrous toluene (30 ml) and benzyl alcohol (1.7 g). Thε mixturε is rεfluxεd for 1 hour. The reaction mixture is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane ^■ + dichloromethanε : mεthanol = 50 : 1) to give 3-benzyloxycarbonylamino-l-[ - (3,5-dichlorobεnzoylamino)bεnzoyl)-l,2,3,4- tetrahydroquinolinε (3.7 g) as colorlεss amorphous. H-NMR (CDCI3) δ : 2.80 (IH, dd, J=16.1 Hz, 5.3 Hz), 3.16 (IH, dd, J=15.8 Hz, 5.3 Hz), 3.75-4.50 (3H, m) , 4.87-5.10 (3H, m) , 6.80-7.60 (14H, m) , 7.74 (2H, d, J=l.9 Hz), 8.47 (IH, brs)

Example 387

To 3-benzyloxycarbonylamino-l-[4-( 3,5-dichloro- benzoylamino)benzoyl ]-l,2,3,4-tetrahydroquinoline (3.3 g)

are added acetic acid (40 ml) and 10 % Pd-C (0.4 g) and the reaction mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressurε of hydrogen. One hour thereafter, the catalyst is removed by filtration and the filtratε is concεntratεd. The resulting residue is purifiεd by silica gεl column chromatography (eluent; dichloromethane : methanol = 20 : 1), and recrystallized from ethanol to give 3-amino-l-[4-(3,5- dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.6 g) as white powder, m.p. 207 - 210°C.

Example 388

To 3-amino-l-[4-(3,5-dichlorobenzoylamino)benzoyl]- 1,2,3,4-tetrahydroquinoline (0.5 g) are added mεthanol (10 ml), 37 % formalinε (0.8 ml) and sodium cyanoborohydride (0.16 g). To the mixture is added acεtic acid (0.5 ml) under ice-cooling and the mixture is stirrεd at room temperaturε for 1 hour. Water is added to the reaction mixturε and thε mixturε is basifiεd with potassium carbonatε and εxtractεd with dichloromεthanε. Thε solvent is concentrated and thε rεsulting residue is purifiεd by silica gel column chromatography (eluent; dichloromethane -»• dichloromεthanε : mεthanol = 20 : 1) to givε 3-dimethyl- amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4- tetrahydroquinoline (0.3 g) as colorless amorphous. H-NMR (CDC1 ₃ ) δ : 2.35 (6H, s), 2.72-3.10 (3H, m) , 3.65-3.78 (IH, m) , 4.06-4.18 (IH, m) , 6.60-7.62 (9H, m) ,

7.74 (2H, d, J=1.8 Hz), 8.52 (IH, brs)

Using the suitable starting materials, the compounds of the above Examples 246, 247, 375 and 376 are obtained in the same manner as in Example 388.

Example 389

To 3-amino-l-[4-(3, 5-dichlorobenzoylamino)benzoyl]- 1, 2, 3,4-tetrahydroquinoline (0.44 g) are added dichloro¬ methane (5 ml) and acetic anhydride (0.12 g) and the mixture is stirred for 1 hour. The reaction mixture is concentrated and the rεsulting rεsidue is purified by silica gεl column chromatography (εluεnt; dichloromethane ^■ * ^■ dichloromethanε : mεthanol = 50 : 1) to give 3-acetylamino-l-[4-(3,5-dichloro- benzoylamino)benzoyl]-l,2,3,4-tεtrahydroquinolinε (0.3 g) as colorless amorphous. H-NMR (CDC1 ₃ ) δ : 1.87 (3H, s), 2.68 (IH, dd, J=5.6 Hz, 16 Hz), 3.14 (IH, dd, J=5.6 Hz, 16 Hz), 3.70-3.95 (2H, m) , 4.32-4.50 (IH, m) , 6.29 (IH, d, J=7.6 Hz), 6.90- 7.80 (11H, m), 9.16 (IH, brs)

Using the suitable starting materials, the compound of the above Example 242 is obtained in the same manner as in Example 389.

Example 390

To 4-oxo-l-[ 4-(3,5-dichlorobenzoylamino)bεnzoyl ]- 1,2,3,4-tetrahydroquinoline (0.5 g) are added 40 % solution of methylamine in mεthanol (5 ml), molecular sieves 4A (1 g) and dimεthylformamide (6 ml), and the mixture is refluxed

for 4 hours. After cooling, the reaction mixture is filtered and to the filtrate is added sodium borohydridε (80 mg), and thε mixturε is stirred at room tempεrature for 1 hour. The reaction mixturε is concentrated and water is added to the resulting residue, and extracted with ethyl acεtatε. The solvent is concεntratεd and thε resulting residue is purified by silica gel column chromatography (εluent; dichloromethane : methanol = 20 : 1) to give 4- methylamino-1-[4-(3,5-dichlorobenzoylamino)bεnzoyl]-1,2,3,4 - tetrahydroquinolinε (0.2 g) as colorlεss amorphous. H-NMR (CDC1 ₃ ) δ : 1.62 (IH, brs), 1.90-2.25 (2H, m), 2.55 (3H, s), 3.78 (IH, t, J=5.1 Hz), 3.95 (2H, t, J=6.7 Hz), 6.99 (IH, d, J=7.9 Hz)*, 6.90-7.13 (2H, m)

Using thε suitable starting materials, the compounds of the above Examples 238, 239, 244, 247, 375 and 376 arε obtainεd in the same manner as in Example 390.

Example 391

To 3-carboxy-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinoline (0.7 g) are added dimethylformamidε (7 ml), diεthyl cyanophosphatε (0.3 ml) and dimεthylaminε hydrochloridε (0.15 g). Furthεr thεreto is added triethylamine (0.8 ml) and the mixturε is stirred at room tempεrature for 1 hour. Water is addεd to thε reaction mixture and extractεd with ethyl acetatε. Thε solvεnt is concentrated and to thε resulting rεsiduε is addεd diethyl ether. The precipitated crystal is collectεd by filtration

to give 3-dimethylamido-l-[4-(3, 5-dichlorobenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinoline (0.5 g) as light yellow powder, m.p. 186 - 187°C.

Example 392

To a solution of l-(4-aminobenzoyl)-2,3,4,5- tetrahydro-lH-benzazepine (3.0 g) in dichloromethane (50 ml) is added succinic anhydride (1.4 g) and the mixture is stirred at room temperature for 4.5 hours. The reaction mixturε is evaporated under reducεd prεssurε in ordεr to rεmovε the solvent thεrεfrom, and thε rεsulting crystal is rεcrystallized from ethyl acetatε to givε l-[4-(3-carboxy- propionylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (3.61 g) as colorless neεdlεs, m.p. 192°C.

Using the suitable starting materials, the compound of the above Example 253 is obtainεd in the same manner as in Example 392.

Example 393

1-[4-(3-Carboxypropionylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazεpine (0.5 g) is dissolved in dimethyl- formamidε (1 ml) and thereto is added dropwise diεthyl cyanophosphate (0.25 g) under ice-cooling. The mixture is stirred at room tempεraturε for 30 minutεs and then cooled again with ice. Therεto are added dropwise a solution of diethylamine (0.11 g) in dimethylformamide (1 ml) and triethylamine (0.34 g). The mixture is stirred at room temperature for 16 hours. The solvent is distillεd off

under reduced pressure and water is added to the resulting residue. The mixture is extracted with dichloromethanε. The organic layer is washed successivεly with dilutεd hydrochloric acid, water, saturated sodium hydrogen carbonate solution, watεr and saturatεd saline solution, and dried ovεr magnεsium sulfate. The solvent is distilled off under reduced pressure and the resulting residuε is purified by silica gel column chromatography (eluεnt; εthyl acεtate), and recrystallized from n-hexanε/εthyl acεtate to give l-[4- (3-diethylaminocarbonylpropionylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazepinε (0.42 g) as colorlεss scales, m.p. 165 - 167°C.

Using the suitablε starting matεrials, thε compounds of thε abovε Examplεs 255 - 263 arε obtained in the same manner as in Examplε 393.

Exampla 394

To a solution of l-[4-(2-chloroacetylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpine (2.06 g) in dimethylformamide (5 ml) are added sodium iodide (0.90 g), potassium carbonate (1.1 g) and cyclohexylaminε (0.89 g), and thε mixturε is stirred at room temperature for 2 hours. Dimethylformamide is distilled off under reducεd pressure and water is added to the resulting residuε. The mixture is extracted with dichloromethane. The organic layer is washed successivεly with watεr and saturated saline solution, and driεd over magnesium sulfate. Thε solvεnt is

distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetatε), and rεcrystallizεd from n-hεxanε/- ethyl acetate to give l-[4-( 2-cyclohexylaminoacetylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε (2.03 g) as white powder, m.p. 139 - 142°C.

Using the suitable starting materials, the compounds of the above Examples 271 - 309 and 317 arε obtainεd in thε same manner as in Example 394.

Example 395 o-Cresol (0.36 g) is dissolved in dimethylsulfoxide (4 ml) containing sodium hydroxide powder (0.18 g) and therεto is addεd l-[4-(2-chloroacεtylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazepine (1.03 g). The mixture is stirred at 90°C for 7.5 hours. The reaction mixture is poured into ice-water (300 ml) and the precipitated crystal is collected by filtration, washed with water, and purified by silica gel column chromatography (eluent; n-hexane : ethyl acetate = 2 : 1), and recrystallizεd from ethyl acetate to give l-{4-[2- (2-methylphenoxy)acetylamino]benzoyl}-2,3,4,5-tetrahydro-lH- benzazεpinε (546 mg) as colorless scales, m.p. 172.5 - 175°C.

Using thε suitablε starting matεrials, thε compounds of thε above Examples 310 and 312 - 316 are obtained in the same manner as in Example 395.

Example 396

A mixture of l-{4-[2-( 6-bromohexyloxyJbenzoyl-

amino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-benzazepine (2.00 g), sodium acetate (0.36 g), sodium iodide (0.55 g) and acetic acid (20 ml) is rεfluxed for 1 day. The solvent is distilled off and the resulting residue is extracted with ethyl acetate. The organic layer is washed successively with 2N aqueous sodium hydroxidε solution and saturatεd saline solution, and dried over magnεsium sulfatε. Thε solvent is concentrated and the resulting residue is purified by silica gel column chromatography (εluεnt; chloroform : mεthanol = 500 : 1), and rεcrystallizεd from εthanol to givε l-{4-[2-(6-acetyloxyhexyloxy)bεnzoylamino]- benzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpine (1.07 g) as white powder, m.p. 145 - 146°C.

Using the suitable starting materials, the compound of thε abovε Examplε 360 is obtainεd in thε samε mannεr as in Example 396.

Example 397

A mixture of l-{4-[2-(6-bromohexyloxy)benzoyl- amino]benzoyl}-2,3,4,5-tetrahydro-lH-benzazepinε (0.70 g), diethylamine (0.16 ml), triethylaminε (0.21 ml) and acetonitrile (20 ml) is refluxed overnight. The solvent is distilled off and the resulting residue is dissolved in chloroform, washed successively with water and saturated saline solution, and dried over magnεsium sulfatε. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluεnt;

chloroform : methanol = 200 : 1 →- 50 : 1) and convertεd into the hydrochloride thereof in methanol. The product is recrystallized from methanol/diethyl ethεr to givε l-{4-[2- (6-diethylaminohexyloxy)benzoylamino]bεnzoyl}-2,3,4,5- tetrahydro-lH-bεnzazεpinε hydrochloridε (0.42 g) as white powder, m.p. 91 - 95°C.

Using the suitable starting materials, the compounds of the above Examples 330, 332, 333, 335, 336, 339, 341, 342, 344 - 349, 352 - 355, 357 and 366 are obtained in the same manner as in Example 397.

Example 398

A mixture of l-{4-[2-( 6-bromohexyloxy)benzoyl- amino]benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine (4.00 g), potassium phthalimide (2.02 g) and dimethylformamide (100 ml) is stirred at 100°C for 5 hours. The reaction mixture is filtered and the filtrate is distilled off. The resulting rεsiduε is εxtracted with ethyl acetatε and thε organic layer is washed successively with water and saturated saline solution, and driεd ovεr magnesium sulfate. The solvent is distilled off and the resulting residuε is purifiεd by silica gel column chromatography (eluent; dichloromethane), and recrystallized from methanol/diεthyl εthεr to give l-{4-[2-(6-phthalimido- hexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-lH- benzazepine (4.06 g) as white powder, m.p. 145 - 146.5°C.

Using the suitablε starting matεrials, thε

compounds of the above Examples 331, 340, 364 and 365 are obtained in the same mannεr as in Example 398.

Example 399

A mixture of l-{4-[2-[6-phthalimidohexyloxy)- benzoylamino]bεnzoyl}-2,3,4, 5-tetrahydro-lH-benzazepine (3.75 g), hydrazine hydrate (0.44 ml) and ethanol (30 ml) is refluxεd for 3.5 hours. The precipitatεd crystal is collεcted by filtration, dried and purified by silica gel column chromatography (eluent; chloroform : methanol : aqueous ammonia = 100 : 10 : 1), and recrystallized from methanol/diεthyl εthεr to givε l-{4-[2-(6-aminohεxyloxy)- bεnzoylamino]bεnzoyl}-2,3,4, 5-tεtrahydro-lH-benzazepine (2.52 g) as white powder, m.p. 135.5 - 137.5°C.

Using the suitable starting materials, the compounds of the above Examplεs 284, 344 and 345 are obtained in the same manner as in Example 399.

Example 400

A mixture of l-{4-[ 2-(6-aminohexyloxyJbenzoyl- amino]benzoyl}-2,3,4,5-tetrahydro-lH-bεnzazεpine (0.70 g) , acetic anhydride (20 ml) and two drops of cone, sulfuric acid is stirrεd at room temperature for 3 hours. To the reaction mixture is added aqueous 2N aquεous sodium hydroxidε solution undεr ice-cooling and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distillεd off

and the resulting residue is purified by silica gel column chromatography (eluεnt; chloroform : methanol = 200 : 1), and recrystallizεd from mεthanol/diεthyl εther to givε l-{4- [2-(6-acetylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5- tetrahydro-lH-bεnzazεpine (0.60 g) as colorless needles, m.p. 171 - 172°C.

Example 401

A mixture of l-{4-[2-(6-aminohexyloxy)bεnzoyl- amino]benzoyl}-2,3,4, 5-tetrahydro-lH-benzazεpine (0.70 g), benzoyl chloride (0.20 ml), triethylamine and dichloro¬ methane (20 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residuε is rεcrystallizεd from εthanol to give l-{4-[2-(6- bεnzoylaminohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tεtra- hydro-lH-benzazepine (0.71 g) as white powdεr, m.p. 178 - 178.5°C.

Using thε suitablε starting materials, the compounds of the above Examples 348 and 357 are obtainεd in thε same manner as in Examplεs 400 and 401.

Example 402

A mixture of l-[ 4-( 2-ethoxycarbonylmethoxybenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine (1.00 g), aquεouε ammonia (100 ml), ammonium chloride (0=3 g) and methanol (150 ml) is heatεd at 100°C for 4 hours in a sealed

tube. The solvent is distilled off and the resulting residue is extracted with chloroform, washed successivεly with water and saturated saline solution, and dried over magnesium sulfate. The solvent is concentratεd and thε resulting residuε is purifiεd by silica gel column chromatography (eluεnt; chloroform : methanol = 50 : 1), and recrystallized from methanol/diεthyl εther to givε l-[4-(2- carbamoylmethoxybenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine (0.43 g) as white powder, m.p. 198 - 199°C.

Example 403

A mixture of l-[4-(2-chloro-4-aminobenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.55 g), acεtic anhydride (15 ml), acetic acid (5 ml) and a drop of sulfuric acid is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated saline solution and dried over magnεsium sulfatε. The solvent is concentrated and the reεulting rεsiduε is rεcrystallized from methanol/diεthyl εthεr to givε l-[4-(2-chloro-4- acetylaminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine (0.28 g) as white powder, m.p. 214 - 243°C.

Using the suitable starting materials, the compound of the above Examplε 44 is obtainεd in thε same manner as in Example 403.

Example 404

A mixture of l-[4-(l-benzyloxycarbonyl-4- piperidinylcarbonylamino)benzoyl ]-2,3,4,5-tetrahydro-lH- bεnzazepine (8.00 g), 10 % Pd-C (0.8 g) and ethanol (250 ml) is subjected to catalytic hydrogenation at 50°C under 4 atm. of hydrogen prεssurε for 6 hours. The catalyst is removed by filtration and the filtrate is evaporated under reduced pressure. The resulting rεsidue is extracted with ethyl acetate and washed successively with water and saturated saline solution, and driεd over magnesium sulfate. The solvent is distillεd off and thε rεεulting residue is purified by silica gel column chromatography (eluεnt; chloroform : methanol : ammonium hydroxide = 50 : 10 : 1) to give l-{4-[4-(4-pipεridinyl)benzoylamino)benzoyl]-2,3,4,5- tεtrahydro-lH-bεnzazepine (4.80 g), and a part (0.5 g) thereof is converted .into the hydrochloride thereof in methanol. The hydrochloride is recrystallized from methanol/diεthyl εthεr to give l-{4-[4-(4-piperidinyl)- bεnzoylamino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-benzazepine hydrochloride (0.42 g) as white powder, m.p. 177 - 181.5°C.

Example 405

Using the suitable starting materials, the following compound is obtained in the same manner as in the above Examples 1, 382 and 388. l-[4-(4-Dimethylaminobenzoylamino)benzoyl]-l,2,3,4- tetrahydroquinolinε, colorlεss amorphous

H-NMR (DMSO-dg) δ : 1.90-2.00 (2H, m) , 2.82 (2H, t, J=6.5 Hz), 2.98 (6H, ε), 3.77 (2H, t, J=6.5 Hz), 6.70- 7.30 (6H, m), 7.32 (2H, d, J=8.6 Hz), 7.73 (2H, d, J=8.6 Hz), 8.00-8.20 (IH, m) , 8.39 (IH, d, J=2.2 Hz), 10.37 (IH, s)

Uεing thε suitablε starting materials, the following compounds are obtained in the same mannεr as in Examplε 1.

Table 2

Example 406

Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol

Melting Point: 216 - 218°C

Form: Freε

Examplε 407 Struct

Crystallinε form: Whitε powdεr Rεcryεtallization εolvεnt: Ethanol Mεlting Point: 181 - 183°C Form: Frεε

Examplε 408 Struct

Cryεtallinε form: White powder Rεcrystallization solvent: Ethanol Melting Point: 207 - 208°C Form: Free

Example 409 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 213 - 214°C Form: Freε

Example 410 Structure N(CH ₃ ) ₂

Crystalline form: Whitε powder Rεcrystallization solvεnt: Ethanol Melting Point: 136 - 138°C Form: Free

Examplε 411 Struct

Cryεtalline form: White powder Rεcryεtallization εolvεnt: Ethanol Malting Point: 130 - 132°C Form: Frεε

Examplε 412 Struct

Crystalline form: White powder Rεcrystallization solvεnt: Ethanol Mεlting Point: 143 - 145°C Form: Free

Example 413 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 171 - 173°C Form: Freε

Example 414 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 162 - 164°C Form: Free

Example 415 Struct

Crystallinε form: Colorlεss amorphous NMR analysis: 49) Form: Frεε

Examplε 416 Struct

Crystallinε form: Colorleεε amorphouε

NMR analysis: 50) Form: Freε

Example 417 Struct

Cryεtalline form: Colorlεss amorphous NMR analysis: 51) Form: Free

Example 418 Structu

Cryεtallinε form: Colorleεε neεdlεs Recrystallization solvent: Ethyl acεtatε/n-hεxane Melting Point: 228.5 - 230°C Form: Free

Example 419 Structure

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε

Melting Point: 205.5 - 206.5°C

Form: Free

Example 420

Structurε _v

Cryεtalline form: White powder

Recryεtallization solvεnt: Ethyl acεtatε/n-hεxanε Mεlting Point: 210 - 212°C Form: Free

Example 421 Structu

0 CH,

R- 4-NHC ^■ O

Crystalline form: White powder Recryεtallization εolvent: Ethanol Melting Point: 166 - 167°C Form: Free

Example 422 Struct

Cryεtalline form: White powder Recryεtallization εolvent: Ethanol Melting Point: 191.5 - 192.5°C Form: Freε

Example 423 Struct

Crystalline form: White powdεr Rεcrystallization solvεnt: Ethanol Malting Point: 209 - 210°C Form: Free

Crystalline form: Colorless amorphous NMR analysis: 52) Form: Free

Example 425 Struct

Crystalline form: White powder Recrystallization solvεnt: Ethanol Malting Point: 148 - 149°C Form: Free

Example 426

Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 157 - 158°C Form: Free

Example 427

Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 194.5 - 195.5°C Form: Freε

Example 1428

Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 179.5 - 180.5°C Form: Frεε

Cryεtalline form: White powder Recryεtallization εolvent: Ethanol Melting Point: 190 - 191°C Form: Free

Exampl Struct

0 CH - B.-.

4-NHC ^■ σ

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 159 - 160°C Form: Free

Example 431 Struct

Crystalline form: Colorlesε amorphouε NMR analysis: 53) Form: Hydrochloride

Example 432 Struct

Crystalline form: White powdεr Rεcrystallization solvεnt: Ethanol Malting Point: 155 - 156°C Form: Free

Crystallinε form:Colorlεss amorphous NMR analysiε: 54) Form: Frεε

Examplε 434 Struct

Crystallinε form: Colorless amorphous NMR analysis: 55) Form: Freε

Crystallinε form: Whitε powdεr Rεcrystallization solvεnt: Ethanol Melting Point: 175 - 177°C Form: Free

Example 436 Structurε CH,

/

Crystallinε form: Colorlεsε amorphouε . NMR analysis: 56) Form: Frεe

Example 437 Structu

Cryεtalline form: Colorleεε amorphouε NMR analysis: 57) Form: Freε

Examplε 438 Structure

0 CH ₃

R°: 4-NHC ^■ O

Crystalline form: White powdεr

Rεcrystallization solvent: Dichloromethane/diethyl ether

Melting Point: 219 - 220°C

Form: Frεε

Example 439 Structure

Crystalline form: White powder

Recrystallization εolvent: Dichloromethane/diεthyl ether

Melting Point: 215 - 218°C

Form: Free

Example 440 Structu

Crystalline form: White powder Recrystallization solvεnt: Ethanol Malting Point: 128.5 - 129.5°C Form: Frεε

Example 441 Structure

Crystalline form: Colorless amorphous NMR analysis: 58) Form: Free

0 CH-

2-NHC ^■ O

Crystalline form: White pov/der Recrystallization solvent: Ethanol Melting Point: 153 - 154°C Form: Freε

Examplε 443 Structu

0

Crystallinε form: Whitε powdεr Recrystallization εolvent: Ethanol Malting Point: 150 - 153°C Form: Frεε

Examplε 444 Struct

Cryatalline form: White powder Recrystallization solvent: Ethanol Melting Point: 139 - 141°C Form: Freε

Example 445 Struct

Crystalline form: Colorless amorphous NMR analysis: 59) Form: Free

Example 446 Struct

0

Crystalline form: Colorless amorphous NMR analysis: 60) Form: Free

Example 447 Structu

Crystalline form: Colorless amorphous NMR analysis: 61) Form: Free

Example 448 Struct

Crystalline form: Colorless amorphous NMR analysis: 62) Form: Free

Example 449 Structure

0

Crystalline form: Colorlesε amorphous NMR analyεiε: 63) Form: Free

Example 450 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 172.5 - 173.5°C Form: Freε

Example 451 Structure

Crystalline form: Colorlesε priεmε

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 122.5 - 123°C

Form: Free

Example 452

Structure

Crystallinε form: Whitε powdεr

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 198 - 199.5°C Form: Free

Crystalline form: White powder

Recryεtallization solvent: Methanol/diεthyl ether

Melting Point: 118 - 119.5°C

Form: Hydrochloride

Example 454

Structure

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 163 - 165°C Form: Dihydrochloride

Examplε 455 Structurε

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 246 - 248°C

Form: Hydrochloride

Example 456

Structure

Crystalline form: White powder Recrystallization solvent: Chloroform/εthanol Melting Point: 204 - 205°C Form: Free

Example 457 Structure

Crystalline form: Colorless prismε Recryεtallization εolvent: Methanol/diethyl ethεr Mεlting Point: 127 - 128°C Form: Hydrochloridε

Crystallinε form: Whitε powdεr

Rεcrystallization solvεnt: Mεthanol/diεthyl εther Melting Point: 220 - 221°C Form: Frεe

Examplε 459 Structure

Crystalline form: Colorleεs needles Recrystallization solvent: Ethanol Melting Point: 190 - 192°C Form: Freε

Examplε 460 Structure

Crystalline form: White powdεr

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 189 - 191°C Form: Hydrochloridε

Example 461 Structure

Crystalline form: Colorlesε needles Recrystallization solvent: Ethanol Melting Point: 173 - 174°C Form: Free

Crystallinε form: White powder

Recrystallization εolvent: Dichloromethane/ethanol Melting Point: 129 - 130°C Form: Free

Examplε 463 Structure

Crystallinε form: Whitε powdεr

Recrystallization solvent: Methanol/diεthyl ether

Melting Point: 130 - 133°C

Form: Hydrochloride

Example 464

Structure

Crystalline form: Light yellow powder Recrystallization solvent: Methanol/diεthyl εther Melting Point: 170.5 - 172°C Form: Hydrochloride

Example 465 Structure

Crystalline form: White powder

Recrystallization solvεnt: Mεthanol/diεthyl ether

Melting Point: 126 - 131°C

Form: Hydrochloride

Example 466

Structure

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 182 - 185°C Form: Dihydrochloride

Example 467 Structure

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diεthyl εthεr

Mεlting Point: 116 - 121°C

Form: Hydrochloridε

Examplε 468

Structurε

Crystallinε form: Colorlεss prismε Recryεtallization εolvent: Mεthanol/diεthyl εther Melting Point: 178 - 182.5°C Form: Free

Example 469 Structure

Crystalline form: Colorlesε particles

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 185 - 187°C

Form: Free

Example 470

Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 215 - 217°C Form: Free

Example 471 Structure

Crystallinε form: White powder

Recrystallization solvεnt: Mεthanol/diεthyl εther

Melting Point: 176 - 178°C

Form: Free

Example 472

Structure

Crystalline form: Light yellow powder Recrystallization solvent: Methanol/n-hexane Melting Point: 194.5 - 197°C Form: Freε

Example 473 Structure

Cryεtalline form: White powder

Recryεtallization εolvent: Methanol/diεthyl ether

Melting Point: 161.5 - 165.5°C

Form: Hydrochloride

Example 474

Structure

Cryεtalline form: White powder Recrystallization solvent: Ethyl acetatε Mεlting Point: 152 - 153°C Form: Frεe

Example 475 Structure

0

_/ C ₂ H ₅

R ³ : 4-NHCCH ₂ N

Crystallinε form: Colorlεεε nεedles Recrystallization solvent: n-Hexanε/ethyl acetate Melting Point: 147 - 148°C Form: Free Example 476 Structure

Crystalline form: Light yellow powder Recrystallization εolvent: Ethyl acetate Melting Point: 215 - 217°C Form: Free

Example 477 Structure

0

Cryεtalline form: Colorleεε amorphouε NMR analyεiε: 64) Form: Free

Example 478 Structure

Crystalline form: White powder Recrystallization solvent: Ethyl acetate Melting Point: 180 - 181°C Form: Free

Example 479 Structure

Y w V ^CH3

Crystalline form: Colorlesε amorphouε NMR analyεiε: 65) Form: Free

Example 480 Structure

Crystalline form: Colorlεsε amorphous NMR analysis : 66 ) Form : Frεε

Example 481 Structure

Cryεtalline form: Colorless amorphous NMR analysiε: 67) Form: Frεε

Example 482 Structure

Cryεtalline form: Colorless scales Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 165 - 167°C Form: Free

Example 483 Structure

Crystallinε form: Colorlεsε amorphouε NMR analysis: 68) Form: Frεε

Examplε 484 Structurε

Crystallinε form: Colorlεsε amorphouε NMR analysis: 69) Form: Free

Example 485

Structure

0

Crystalline form: Colorlesε amorphouε NMR analyεiε: 70) Form: Free

Example 486 Structure

0

R~ :

Crystalline form: Colorless amorphous NMR analysis: 71) Form: Free

Example 487 Structure

0 0

R ^J : 4 Λ_-.-Nκι-HπCnnC-Hu ₂ - _)m NH_-m<V --CH-_ ₂ N"H~C _m ^CH~ ₃

Crystalline form: Colorless amorphous NMR analysis: 72) Form: Freε

Example 488 Structure

0

0

II _/ (CH ₂ ) ₃ NHCCH ₃

R ^J : 4-NHCCH,N /-—v

Crystalline form: Colorlεss amorphous NMR analysis: 73) Form: Free

Example 489 Structure

Crystalline form: Light yellow amorphous

NMR analysiε: 74)

Form: Freε

Example 490

Structure

Crystalline form: White powder Recrystallization solvent: Ethyl acetatε Mεlting Point: 182 - 182.5°C Form: Frεε

Example 491 Structure

R ³ : 4-NHCNH-/ y

Crystallinε form: Whitε powdεr

Recrystallization solvent: Ethyl acetate

Melting Point: 244 - 245°C

Form: Free

Example 492

Structure

0

R°: 4-NHCNH /7 CH,

Crystalline form: White pov/der Recrystallization solvεnt: Ethyl acetate Melting Point: 220 - 221.5 ^β C Form: Freε

Example 493 Structure

0

Crystalline form: Light yellow amorphous

NMR analysis: 75)

Form: Free

Example 494

Structure

II _/ C ₂ H ₅ R ³ : 4-NHCCH,N _π —-v

Crystalline form: Light yellow amorphous NMR analyεiε: 76) Form: Frεε

Examplε 495 Structurε

0

Crystallinε form: Colorless needles Recrystallization εolvent: Methanol/diεthyl εthεr Mεlting Point: 171 - 172°C Form: Frεε Examplε 496 Structure

Crystalline form: Whitε powdεr Rεcrystallization solvεnt: Ethanol Melting Point: 178 - 178.5°C Form: Free

Example 497 Structure

Example 498 Structure

Example 499 Structure

0

R ^J : 4-NHC oo)(CH ₂ ) ₂ NHCH ₃

Example 500 Structure

Example 501 Structure

0

Example 502 Structure

Example 503 Structure

Example 504 Structure

0

Crystalline form: Light yellow scales Recrystallization solvent: Ethanol/water Melting Point: 129 - 131°C Form: Frεε

Example 505 Structurε

R ³ : 4-NHCO ^Λ

Cryεtalline form: White pov/der Recryεtallization solvent: Ethyl acetatε Melting Point: 199 - 201°C Form: Free

Example 506 Struct

0 CH,

4-NHC ^■ O

Crystalline form: Colorless amorphous NMR analysis: 77) Form: Frεe

Example 507 Structu

Crystalline form: White powder

Recrystallization solvent: n-Hexanε/ethyl acetate Melting Point: 187.5 - 189°C Form: Free

Example 508 Structu

Crystallinε form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 161 - 164°C Form: Free

Example 509 Structure 0

Crystalline form: Colorless prismε Recryεtallization εolvεnt: Ethanol Malting Point: 242 - 243°C Form: Frεε

Examplε 510 Structurε

R ³ : 4-NHCOCH ₂ Cl Cryεtallinε form: Whitε powder

Recrystallization solvent: Dichloroethanε/diεthyl εther Melting Point: 186 - 188°C Form: Freε

Example 511 Structure

0

Crystalline form: Colorlesε amorphous NMR analysis: 78) Form: Freε

) ₂ C1

Crystalline form: Colorless amorphous NMR analysis: 79) Form: Free

49) H-NMR(CDC1 ₃ ) δ ; 1.11 (3H, t, J=7.1 Hz), 1.90-2.25 (2H, m), 2.29 (3H, s), 2.55 (2H, q, J=7.1 Hz), 3.62-3.90 (2H, m) , 4.00-4.20 (IH, m) , 6.63 (IH, d, J=7.9 Hz), 6.85-7.10 (2H, m) , 7.25-7.80 (9H, m) , 8.25 (IH, brε)

50) H-NMR(CDC1 ₃ ) δ ; 1.10 (3H, t, J=7.1 Hz), 1.90-2.20 (2H, m), 2.28 (3H, ε), 3.60-3.90 (2H, m) , 3.95-4.20 (IH, m), 6.62 (IH, d, J=7.9 Hz), 6.80-7.10 (2H, m) , 7.20 (2H, d, J=8.6 Hz), 7.31-7.55 (4H, m) , 7.80 (2H, d, J=1.9 Hz), 9.05 (IH, brε)

51) ^X H-NMR(CDC1 ₃ ) δ ; 1.80-2.05 (IH, m) , 2.15-2.50 (IH, m), 2.34 (6H, ε), 2.51 (3H, s), 3.48-3.62 (IH, m) , 3.72 (3H, s), 3.70-3.85 (IH, m) , 4.00-4.22 (IH, m) , 6.64 (IH, d, J=7.8 Hz), 6.84-7.58 (9H, m) , 8.16 (IH, brs), 8.40 (IH, d, J=8.7 Hz)

52) ^X H-NMR(CDC1 ₃ ) δ ; 1.16 (3H, t, J=7.1 Hz), 2.40-2.70 (2H, m), 2.90-3.30 (3H, m) , 3.80-4.20 (2H, m) , 4.80-5.00 (IH, m), 6.60-6.80 (IH, m) , 7.00-7.70 (10H, ) , 8.24 (IH, s)

53) H-NMR( DMSO-dg) δ ; 1.0-2.5 (10H, m) , 2.34 (3H, s), 3.30-3.80 (4H, m) , 4.50-5.30 (3H, m) , 6.70-7.00 (IH, m), 7.10-7.80 (11H, m) , 10.43 (IH, s), 10.5- 12.0 (IH, br)

54) H-NMR(CDC1 ₃ ) δ ; 1.10-2.10 (10H, m) , 2.40-2.70 (IH, m) , 2.80-3.20 (3H, m) , 3.92 (2H, s), 4.90-5.20 (IH, m), 6.50-6.70 (IH, m) , 6.80-7.60 (8H, m) , 7.75

(2H, s), 8.73 (IH, s)

55) ^X H-NMR(CDC1 ₃ ) δ ; 1.10-2.20 (10H, m) , 2.40-2.70 (IH, m), 2.90-3.30 (3H, m) , 3.93 (2H, s), 4.90-5.20 (IH, m), 6.62 (IH, d, J=7.6 Hz), 6.90-7.70 (10H, m), 8.29 (IH, s)

56) ^X H-NMR(CDC1 ₃ ) δ ; 1.50-2.10 (2H, m) , 2.38 (6H, ε), 2.30-2.70 (IH, m), 2.70-3.00 (2H, m) , 3.45 (IH, d, J=13 Hz), 3.81 (IH, d, J=14 Hz), 4.70-5.00 (IH, m) , 7.0-7.50 (12H, m), 8.23 (IH, ε)

57) H-NMR(CDC1 ₃ ) δ ; 1.50-2.10 (2H, m) , 2.42 (3H, ε), 2.40-2.70 (IH, m), 2.80-3.00 (2H, m) , 3.52 (IH, d, J=13 Hz), 3.85 (IH, d, J=13 Hz), 4.70-5.00 (IH, m) , 7.00-7.70 (12H, m) , 8.54 (IH, s)

58) H-NMR(CDC1 ₃ ) δ ; 2.43 (3H, s), 2.47 (3H, s), 3.00- 3.30 (3H, m), 3.76 (IH, d, J=14 Hz), 4.06 (IH, d, J=14 Hz), 4.90-5.20 (IH, m) , 6.50-6.80 (3H, m) , 6.90-7.50 (6H, m) , 7.70-8.00 (2H, m) , 8.48 (IH, d, J=8 Hz), 10.58 (IH, s)

59) H-NMR(CDC1 ₃ ) δ ; 2.41 (3H, s), 2.44 (3H, s), 2.90- 3.20 (3H, m), 3.74 (IH, d, J=13 Hz), 4.07 (IH, d, J=14 Hz), 4.80-5.00 (IH, m) , 6.67 (IH, d, J=7 Hz), 6.76 (IH, d, J=7 Hz), 7.00-7.50 (8H, m) , 7.55 (IH, s), 7.70-7.90 (2H, )

60) H-NMR(CDC1 ₃ ) δ ; 2.41 (3H, S), 2.80-3.20 (3H, m) , 3.73 (IH, d, J=13 Hz), 4.03 (IH, d, J=14 Hz), 6.66 (2H, d, J=7.6 Hz), 6.90-8.00 (10H, m) , 8.57 (IH, s)

61) ^X H-NMR(CDC1 ₃ ) δ ; 2.40 (3H, s), 2.90-3.20 (3H, m) , 3.73 (IH, d, J=13 Hz), 4.07 (IH, d, J=13 Hz), 4.70- 5.00 (IH, m) , 6.60-6.80 (2H, m) , 6.90-8.00 (10H, m), 8.54 (IH, s)

62) H-NMR(CDC1 ₃ ) δ ; 2.41 (3H, s), 2.90-3.20 (3H, m) , 3.75 (IH, d, J=14 Hz), 4.08 (IH, d, J=14 Hz), 4.80- 5.00 (IH, m), 6.67 (IH, d, J=7.6 Hz), 6.82 (IH, d, J=7.6 Hz), 6.90-7.90 (10H, m) , 8.08 (IH, s)

63) ^X H-NMR(CDC1 ₃ ) δ ; 1.23 (3H, t, J=7 Hz), 1.40-1.70 (IH, m), 1.90-2.20 (3H, m) , 2.70-3.30 (3H, m) , 3.40-3.60 (5H, m) , 3.91 (2H, s), 5.00-5.20 (IH, m) , 6.60-7.40 (11H, m) , 8.12 (IH, d, J=8 Hz), 8.99 (IH, s)

64) ^X H-NMR(CDC1 ₃ ) δ ; 1.35-1.70 (IH, m) , 1.80-2.20 (3H, m), 2.25-2.35 (IH, m) , 2.65-3.20 (3H, m) , 4.01 (2H, s), 4.05-4.17 (2H, m) , 4.90-5.10 (IH, m) , 6.61 (IH, d, J=7.5 Hz), 6.75-7.50 (12H, m) , 8.44 (IH, brs)

65) H-NMR(CDC1 ₃ ) δ ; 1.13 (3H, t, J=7.0 Hz), 1.30-1.65 (4H, m), 1.80-2.20 (3H, m) , 2.28 (3H, s), 2.65-3.40 (5H, m), 4.90-5.10 (IH, ) , 6.63 (IH, d, J=7.8 Hz), 6.75-7.00 (3H, m) , 7.00-7.45 (8H, m) , 8.85 (IH, brs)

66) ^X H-NMR(CDC1 ₃ ) δ ; 0.88 (3H, t, J=7.4 Hz), 1.16 (3H, t, J=7.0 Hz), 1.35-2.20 (6H, m) , 2.27 (3H, s), 2.60-3.20 (3H, m) , 3.20-3.45 (2H, m) , 3.85-4.10 (IH, m), 4.90-5.10 (IH, m) , 6.63 (IH, d, J=7.4 Hz),

6.77 (2H, d, J=8.5 Hz), 6.92 (IH, t, J=8.0 Hz), 7.00-7.45 (8H, m) , 8.85 (IH, brs)

67) H-NMR(CDC1 ₃ ) δ ; 1.17 (3H, t, J=7.0 Hz), 1.35-1.65 (4H, m), 2.60-3.45 (5H, m) , 4.20 (2H, q, J=7.0 Hz), 4.90-5.10 (IH, m), 6.63 (IH, d, J=7.6 Hz), 6.80- 7.45 (12H, m), 8.66 (IH, brs)

68) H-NMR(CDC1 ₃ ) δ ; 0.96 (6H, d, J=6.6 Hz), 1.35-1.65 (IH, m), 1.80-2.25 (4H, m) , 2.65-3.15 (3H, m) , 3.19 (2H, d, J=7.3 Hz), 3.99 (2H, s), 4.90-5.10 (IH, m) , 6.60 (IH, d, J=7.8 Hz), 6.75-7.05 (4H, m) , 7.05- 7.40 (8H, m) , 8.15 (IH, brs)

69) ^X H-NMR(CDC1 ₃ ) δ ; 1.19 (3H, t, J=7.0 Hz), 1.35-1.65 (IH, m), 1.80-2.25 ^" (3H, m) , 2.70-3.20 (3H, m) , 3.44 (2H, q, J=7.0 Hz), 3.77 (3H, s), 3.87 (2H, s), 4.90-5.10 (IH, m), 6.25-6.50 (3H, m) , 6.67 (IH, d, J=7.5 Hz), 6.85-7.45 (8H, m) , 8.29 (IH, brs)

70) ^X H-NMR(CDC1 ₃ ) δ ; 1.05 (3H, t, J=7.1 Hz), 1.35-1.65 (IH, m), 1.85-2.25 (3H, m) , 2.65-3.30 (5H, m) , 3.74 (2H, s), 4.95-5.15 (IH, m) , 6.63 (IH, d, J=7.5 Hz), 6.80-7.55 (11H, m), 9.51 (IH, brs)

71) H-NMR(CDC1 ₃ ) δ ; 1.30-1.65 (IH, m) , 1.80-2.30 (3H, m) , 2.65-3.15 (3H, m) , 3.75 (2H, s), 3.74 (2H, s), 4.95-5.10 (IH, m), 6.45-6.70 (3H, m) , 6.88 (IH, t, J=6.8 Hz), 7.00-7.45 (8H, m) , 8.74 (IH, brs)

72) H-NMR(CDC1 ₃ ) δ ; 1.30-1.70 (IH, m) , 1.75-2.25 (6H, m), 2.65-3.15 (3H, m) , 3.78 (2H, d, J=5.4 Hz), 4.28

(2H, d, J=5.5 Hz), 4.53 (IH, brε), 4.90-5.10 (IH, m), 5.89 (IH, brs), 6.50-6.70 (3H, m) , 6.89 (IH, t, J=7.5 Hz), 7.00-7.40 (8H, m) , 8.61 (IH, brs)

73) ^X H-NMR(CDC1 ₃ ) δ ; 1.35-1.65 (IH, m) , 1.70-2.20 (8H, m), 2.65-3.20 (3H, m) , 3.25-3.55 (4H, m) , 3.88 (2H, s), 4.90-5.10 (IH, m), 5.79 (IH, brε), 6.55-7.40 (13H, m), 8.37 (IH, brε)

74) H-NMR(CDC1 ₃ ) δ ; 1.35-2.00 (8H, m) , 2.65-3.20 (3H, m), 3.30-3.35 (2H, m) , 3.60-3.85 (2H, m) , 3.90 (2H, ε), 4.95-5.15 (IH, m) , 6.55-7.00 (5H, m) , 7.00-7.40 (8H, m), 7.65-7.90 (4H, ) , 8.22 (IH, brε)

75) ^X H-NMR(CDC1 ₃ ) δ ; 1.16 (3H, t, J=7.0 Hz), 2.39 (3H, ε), 2.80-3.20 (3H, m) , 3.44 (2H, q, J=7.0 Hz), 3.65-4.20 (4H, m) , 4.80-5.05 (IH, m) , 6.50-7.45 (13H, m), 8.50 (IH, brε)

76) H-NMR(CDC1 ₃ ) δ ; 1.23 (3H, t, J=7.0 Hz), 2.41 (3H, s), 2.75-3.20 (3H, m) , 3.40-3.60 (5H, m) , 3.65-3.90 (IH, m), 3.92 (2H, s), 3.90-4.20 (IH, m) , 4.85-5.10 (IH, m), 6.65-7.45 (11H, m) , 8.13 (IH, d, J=8.4

Hz), 9.01 (IH, brε)

77) ^X H-NMR(CDC1 ₃ ) δ ; 1.80-1.95 (IH, m) , 2.20-2.70 (10H, m) , 3.50-3.60 (IH, ) , 3.63-3.80 (IH, m) , 4.00-4.15 (IH, m), 6.60 (IH, d, J=7.6 Hz), 6.92 (IH, t, J=7.6 Hz), 7.02 (IH, t, J=6.3 Hz), 7.20- 7.65 (9K, m) , 7.87 (IH, brε)

78) H-NMR(CDC1 ₃ ) δ ; 1.40-1.62 (IH, m) , 1.84-2.22 (3H,

m), 2.65-3.19 (3H, m) , 3.97 (2H, t, J=4.9 Hz), 4.43 (2H, t, J=4.9 Hz), 4.95-5.18 (IH, m) , 6.60-6.77 (IH, m), 6.85-7.02 (2H, m) , 7.02-7.30 (5H, m) , 7.40-7.68 (3H, m) , 8.20-8.32 (IH, m) , 9.62-9.81 (IH, m) 79) ^X H-NMR(CDC1 ₃ ) δ ; 1.38-1.65 (IH, m) , 1.84-2.21 (3H, m), 2.64-3.15 (3H, m) , 3.81 (2H, t, J=5.7 Hz), 4.25 (2H, t, J=5.7 Hz), 4.90-5.13 (IH, m) , 6.58-6.71 (IH, m), 6.82-7.00 (IH, m) , 7.00-7.52 (10H, m) , 8.11 (IH, brs) Examplε 513

To a solution of l-(4-aminobenzoyl)-2,3,4,5-tεtra- hydro-lH-bεnzazεpinε (1.06 g) in dichloromεthane (80 ml) is added o-methylphεnyl isocyanatε (0.66 g) undεr icε- cooling. The mixture is stirred at room temperature for 4 hours. After completion of the reaction, the solvent is concentratεd undεr rεducεd prεssure and the resulting residue is purified by silica gel column chromatography (eluent; n-hexanε : εthyl acεtatε = 1 : 1), and rεcrystallizεd from ethyl acetate to give l-[4-(2-methyl- anilinocarbonylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazεpinε (0.97 g) as whitε powder, m.p. 182 - 182.5°C.

Using the suitable starting materials, the compounds of the above Examples 491 - 492 are obtained in the same manner as in Example 513. Example 514

A mixture of l-(4-aminobenzoyl)-2,3,4,5-tetrahydro- lH-benzazepinε (0.50 g), phεnylsulfonyl chloride (0.29 ml), triethylamine (0.32 ml) and dichloromethane (30 ml) iε εtirred at room temperature overnight. The rεaction mixturε iε washεd succεεεivεly with watεr and εaturated εaline εolution, and dried over magnεεium εulfate. The εolvεnt is distilled off and the resulting residuε is purifiεd by silica gεl column chromatography (εluεnt; chloroform), and recrystallized from methanol/diεthyl ether to give l-(4- phenylsulfonylaminobenzoyl)-2,3,4,5-tetrahydro-lH- benzazepine (0.27 g) as colorlεss prismε, m.p. 178 - 182.5°C.

Uεing thε εuitablε εtarting matεrialε, thε compounds of thε above Examples 469 - 471, 498, 502 and 503 are obtained in the same manner aε in Example 514.

Example 515

To a solution of l-[4-(4-piperidinylcarbonylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpine (0.70 g) in dimethylformamide (20 ml) is added 60 % sodium hydridε disperεion in mineral oil (82 mg) and thε mixturε iε εtirred at room temperature for 30 minutes. Thereto is added mεthyl iodidε (0.14 ml) and thε mixture is stirred ar room temperaturε ovεrnight. Thε εolvεnt iε diεtillεd off and the resulting residuε is εxtractεd with chloroform, and washεd successivεly with water and εaturated saline solution, and dried over magnesium sulfate. The solvent is distilled off

and the resulting residuε is purifiεd by silica gεl column chromatography (εluεnt; chloroform : mεthanol = 10 : 1), and recrystallized from methanol/n-hexanε to givε l-{4-[N-(l- methyl-4-pipεridinylcarbony1)-N-methylamino]benzoyl}- 2,3,4,5-tetrahydro-lH-benzazepinε (0.03 g) as light yellow powder, m.p. 194.5 - 197°C.

Using the suitable εtarting materialε, the compounds of the above Examples 497 and 501 are obtained in the same manner as in Example 515.

Example 516

6-Fluoro-l-(4-aminobenzoyl)-1,2,3,4-tetrahydro¬ quinoline (0.15 g) is disεolved in dichloromethane (10 ml) and thereto iε added triethylamine (0.31 ml). To the mixture iε added dropwiεe a εolution of 3, 5-dichlorobenzoyl chloride (0.14 g) in dichloromεthanε (2.0 ml) under ice- cooling, and the mixture is stirred for 30 minutes under ice-cooling, and further, at room tempεrature for 1 hour. To the mixture arε addεd triethylamine (0.31 ml) and 3,5- dichlorobεnzoyl chloridε (0.14 ml). The mixture is stirred at room tempεraturε for 4 hours. Thε rεaction mixture iε waεhed with water, and dried over magneεium εulfate. The εolvent is distillεd off and thε rεεulting reεidue iε purified by silica gel column chromatography (eluεnt; εthyl acεtatε : n-hεxanε = 1 : 5 - 1 : 4 ) , and rεcrystallizεd from εthyl acetate/n-hεxane to give 6-fluoro-l-[4-(3,5- dichlorobenzoylamino)benzoyl]-l,2,3,4-tetrahydroquinoline

(0.12 g) and 6-fluoro-l-{4-[bis-(3,5-dichlorobεnzoyl)amino]- benzoyl}-1,2,3,4-tetrahydroquinoline.

The formεr: White powder, m.p. 205.5 - 206.5°C

The latter: White powder, m.p. 210.5 - 212°C

Example 517

Using the suitable starting materials, the compounds of the abovε Examplεs 450 and 504 arε obtained in the same manner as in Example 378.

Example 518

Using the εuitable starting matεrials, thε compoundε of thε abovε Examplεε 450 - 467, 495, 496, 499, 500, 511 and 512 arε obtainεd in thε εame manner aε in Example 380.

Example 519

Using thε suitable starting materials, the compounds of thε abovε Examplεs 449, 474 - 489, 493 and 494 are obtained in the εamε mannεr aε in Examplε 394.

Exampla 520

Using thε suitablε atarting matεrialε, thε compounds of thε abovε Examplεs 453, 455, 457, 459, 460, 463 - 467, 495, 496 and 499 are obtained in the same manner as in Example 397.

Example 521

Using the suitablε starting matεrials, the compound of the above Example 461 is obtained in the same manner as

in Example 396.

Example 522

Using the suitable starting materials, the compound of the above Example 456 is obtained in the same manner as in Example 398

Example 523

Using the suitable starting materials, the compound of the above Example 459 is obtained in the same manner as in Example 399.

Example 524

Using the suitable starting materials, the compounds of the abovε Examples 495 and 496 are obtained in the same manner aε in Examplεs 400 and 401.

Exampla 525

Using the suitable starting materials, the compound of the above Example 458 is obtained in the same manner as in Example 402.

Using the suitable starting materials, the compounds of the following Table 3 are obtained in the same manner as in Examples 1 and 382.

Table 3

Example 527 Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ethεr Melting Point: 225 - 226°C Form: Freε

Examplε 528 Structu

Crystallinε form: Whitε powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 142.5 - 145°C Form: Freε

Example 529 Structu

0 Cl

R ³ : 4-NHC-< )-C1

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diεthyl ether Melting Point: 213 - 215°C Form: Frεε

Example 530 Struct

Crystalline form: White powdεr

Recrystallization εolvent: Methanol/diethyl ether Melting Point: 167 - 167.5°C Form: Free

Example 531 Struct

Crystalline form: Colorlεss scaleε Recrystallization solvent: Methanol/diεthyl εther Mεlting Point: 217 - 221°C Form: Frεε

Examplε 532 Structure

Crystalline form: White powder

Recrystallization solvεnt: Mεthanol/diεthyl ether Melting Point: 182 - 184°C Form: Free

Example 533 Structu

0 Cl

R- 4-NHC ^■ O

Crystalline form: White powder

Rεcrystallization solvεnt: Mεthanol/diεthyl ether Melting Point: 209 - 210°C Form: Free

Example 534 Struct

Crystalline form: White powder

Rεcrystallization solvεnt: Mεthanol/diεthyl εther Mεlting Point: 148 - 149°C Form: Frεε

Examplε 535 Struct

Crystalline form: White powder

Rεcrystallization solvent : Methanol/diεthyl εther Melting Point : 202 - 203 °C Form: Free

CH-

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 218 - 219°C Form: Freε

Example 537 Structu

0 CH,

,3. 4-NHC ^■ O

Crystalline form: White powder Recrystallization solvent: Methanol/n-hεxanε Melting Point: 159 - 160°C Form: Free

Examplε 538 Structu

Crystalline form: White powdεr Recrystallization solvent: Methanol/n-hεxanε Mεlting Point: 201 - 202°C Form: Free

Examplε 539 Struct

Crystalline form: White powder Recrystallization solvent: Methanol/n-hεxanε Mεlting Point: 205 - 207°C Form: Free

Example 540 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 201.5 - 202.5°C Form: Freε

Example 541 Structu

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 226 - 228°C Form: Free

Examplε 542 Structu

0 Cl

4-NHC ^■ O

Crystalline form: White powdεr

Rεcryatallization εolvent: Methanol/diεthyl εthεr Mεlting Point: 218 - 221°C Form: Free

Example 543 Struct

Cryεtallinε form: Whitε powdεr

Rεcryεtallization solvent: Methanol/diεthyl εthεr Mεlting Point: 156 - 157°C Form: Free

Example 544 Struct

0

Crystalline form: White powder NMR analysis: 80) Form: Freε

Example 545 Struct

Crystalline form: Colorless amorphous NMR analysiε: 81) Form: Free

Example 546 Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 82) Form: Free

Example 547 Struct

Cryεtalline form: Light yellow amorphouε NMR analysis: 83) Form: Freε

Example 548 Structure

Crystallinε form: Colorlεsε amorphouε NMR analyεis: 84) Form: Free

Example 549 Struct

Crystalline form: Colorless amorphous NMR analysis: 85) Form: Free

Examplε 550 Struct

Crystallinε form: Whitε powdεr

Recrystallization solvent: n-Hεxanε/εthyl acεtatε Mεlting Point: 135 - 136°C Form: Free

Example 551 Struct

Crystallinε form: Colorlεss prismε Rεcrystallization solvεnt: n-Hεxanε/εthyl acεtatε Melting Point: 122 - 123°C Form: Free

Example 552 Structure N(CH ₃ ) ₂

Crystalline form: Colorless prisms Recrystallization solvent: n-Hexane/ethyl acetate Melting Point: 118 - 119°C Form: Freε

Examplε 553 Struct

0 CH,

4-NHC ^■ O

Crystalline form: Colorlesε priεmε Rεcryεtallization εolvεnt: n-Hexane/εthyl acεtatε Mεlting Point: 145 - 147°C Form: Free

Example 554 Structure

Crystalline form: Light yellow needleε Recryεtallization εolvent: n-Hexanε/εthyl acεtatε Mεlting Point: 169.5 - 170.5°C Form: Free

Examplε 555 Struct

Crystallinε form: Colorlεss prismε Rεcryεtallization εolvεnt: n-Hexane/εthyl acεtate Melting Point: 194 - 195°C Form: Free

Examplε 556 Structu

Crystalline form: Colorless needles

Recrystallization solvent: n-Hexanε/εthyl acεtate

Melting Point: 202 - 204°C

Form: Freε

Example 557

Structu

Crystalline form: Colorless prismε Recryεtallization solvent: Ethanol Melting Point: 242 - 243°C Form: Free

Example 558 Struct

Crystalline form: Light yellow powder NMR analysiε: 86) Form: Free

Example 559 Structure 0

0 Cl

R~ 4-NHC ^■ O

Crystalline form: Light yellow powder NMR analysiε: 87) Form: Frεe

Example 560 Structu

Cryεtallinε form: Colorlεεε needlεε Rεcryεtallization εolvent: Ethanol Melting Point: 237 - 238°C Form: Freε

Example 561 Struct

Cryεtallinε form: Colorlεss prisms Recrystallization solvent: Dioxane Melting Point: 258 - 259°C Form: Freε

Example 562 Struct

0 Cl

Cryεtallinε form: Colorlεss prismε Rεcryεtallization εolvent: Ethanol Melting Point: 182.5 - 183.5°C Form: Free

Example 563 Struct

Crystalline form: Colorlesε priεmε Recrystallization solvent: Ethanol Mεlting Point: 209 - 211°C Form: Free

Example 564 Struct

Crystalline form: Colorlesε priεmε Rεcrystallization εolvεnt: Dioxanε Mεlting Point: 210 - 211°C Form: Frεe

Example 565 Struct

Cryεtalline form: Colorleεs needleε Recryεtallization solvεnt: Ethyl acεtatε/n-hεxane Melting Point: 176 - 178°C Form: Frεe

Example 566 Struct

Crystalline form: Light yellow amorphous NMR analysiε: 88) Form: Free

Example 567 Structure N-OH

Cryεtalline form: White powder Recryεtallization εolvent: Dioxane/water Melting Point: 272 - 273°C Form: Free

Example 568 Structu

Crystallinε form: Colorlεss prismε Rεcryεtallization solvεnt: Dioxanε Mεlting Point: 253 - 254°C Form: Free

Example 569 Struct

Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 248.5 - 249.5°C Form: Free

Example 570 Struct

Crystalline form: Colorlesε needleε Recryεtallization εolvent: Ethanol Melting Point: 266.5 - 267.5°C Form: Free

Example 571 Struct

Crystalline form: Colorless neεdles Recrystallization solvent: Ethanol Melting Point: 252 - 253°C Form: Free

Example 572 Structure

Crystallinε form: Light yεllow powdεr NMR analysiε: 89) Form: Free

Example 573 Struct

Crystalline form: Light brown powder NMR analysis: 90) Form: Free

Example 574 Struct

Crystalline form: White powder Recrystallization solvent: Diethyl ether Melting Point: 198.5 - 199.5°C Form: Free

Example 575 Struct

0 CH,

R ³ : 4-NHC ^■ O

Crystallinε form: Colorlesε needleε Recryεtallization solvent: Ethanol Melting Point: 297 - 299°C Form: Free

Examplε 576 Struct

Crystallinε form: Colorlesε amorphous NMR analysis: 91) Form: Free

Example 577 Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol/petroleum ether Melting Point: 202 - 203°C Form: Free

Example 578 Struct

Crystalline form: Colorless amorphous NMR analysis: 92) Form: Free

Example 579

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 232 - 233°C Form: Free

Example 580 Structure

Crystalline form: Colorlesε amorphous NMR analysis: 93) Form: Free

Example 581 Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hexane Melting Point: 256.5 - 257°C Form: Free

Crystallinε form: White powder

Recrystallization solvent : Ethyl acetate/n-hεxane

Melting Point : 193 - 194 °C

Form: Free

Example 583

Struct

Crystalline form: White powdεr

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 227 - 230°C Form: Free

Example 584 Structu

Crystallinε form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε Mεlting Point: 199.5 - 202°C Form: Frεε

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxane Mεlting Point: 219 - 220°C Form: Free

Example 586 Struct

Crystalline form: White powder

Recrystallization solvεnt: Ethyl acetate/n-hεxane Melting Point: 190 - 191.5°C Form: Free

Example 587 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 184 - 185°C Form: Free

Example 588 Structu

Crystallinε form: White powder

Recryεtallization solvent: Ethyl acetate/n-hexane Melting Point: 223 - 224°C Form: Free

Example 589 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 178 - 181°C Form: Freε

Example 590 Struc

Crystalline form: Colorless needles Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 168 - 168.5°C Form: Free

Example 591 Struct

Crystalline form: Colorlesε amorphous NMR analysis: 94) Form: Free

Example 592 Structure

Crystalline form: Colorless amorphous NMR analysiε: 95) Form: Free

Example 593 Structurε OCH ₂ CONH ₂

Cryεtallinε form: Whitε powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε Mεlting Point: 196 - 197°C Form: Frεε

Example 594 Struct

Crystalline form: Colorless amorphous NMR analysis: 96) Form: Free

Example 595 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol/water Melting Point: 188 - 189°C Form: Free

Example 596 Structure OCH ₂ COOH

Crystalline form: Colorless amorphous NMR analysiε: 97) Form: Free

Example 597 Struct

Crystalline form: Colorless amorphous NMR analysis: 98) Form: Free

Example 598 Struct

Crystalline form: Colorlesε prisms Recrystallization solvent: Ethyl acetatε/n-hεxanε Melting Point: 203 - 204°C Form: Free

Example 599 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 196 - 197°C Form: Free

Cryεtalline form: Colorleεs amorphous NMR analyεis: 99) Form: Freε

Example 601 Struct

0 CH,

4-NHC ^■ O

Crystalline form: Colorlesε amorphouε NMR analysis: 100) Form: Frεε

Examplε 602 Struct

Crystallinε form: Colorlεsε amorphous NMR analysiε: 101) Form: Free

Example 603 Struct

Cryεtalline form: Colorlεεε amorphous NMR analysis: 102) Form: Free

Examplε 604

Struct

Crystalline form: Colorless amorphous NMR analysiε: 103) Form: Free

Examplε 605 Struct

Crystalline form: Colorleεε amorphous NMR analysis: 104) Form: Free

Example 606 Structu

Crystalline form: Colorlesε amorphouε NMR analyεis: 105) Form: Freε

Example 607 Struct

Crystalline form: Colorlesε neεdleε Recryεtallization solvent: Ethanol Melting Point: 169 - 171°C Form: Free

Example 608 Struct

Crystalline form: Colorlesε neεdlεε Rεcrystallization εolvεnt: Ethanol/diεthyl εther Mεlting Point: 178 - 181°C Form: Free

Example 609 Struct

0 CH,

R-O 4-NHC ^■ O

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 187 - 188°C Form: Freε

Example 610 Struct

Cryεtallinε form: White powder Recryεtallization solvent: Ethanol Melting Point: 181 - 183°C Form: Free

Example 611 Struct

0 Cl

R ^J : 4-NHC-f - _c C1

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 124 - 127°C Form: Free

Example 612 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 179 - 181°C Form: Free

Example 613 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 148 - 150°C Form: Free

Example 614 Struct

Crystalline form: Colorless amorphous NMR analysiε: 106) Form: Freε

Example 615 Struct

Crystalline form: Whitε powder Recrystallization solvent: Ethanol Melting Point: 219 - 220°C Form: Free

Example 616 Struct

Cryεtalline form: White powder Recrystallization solvent: Ethanol Melting Point: 226 - 228°C Form: Free

Example 617 Structu

Crystalline form: Colorless amorphous NMR analysis: 107) Form: Free

Example 618 Struct

Cryεtalline form: Colorleεs amorphous NMR analysiε: 108) Form: Free

Example 619 Structu

Crystalline form: Colorless amorphous NMR analysis: 109) Form: Free

Example 620 Structure

Crystalline form: Colorless amorphous NMR analysiε: 110) Form: Free

Example 621 Structure

Crystalline form: Colorless amorphous NMR analysis: 111) Form: Free

Example 622 Structure

Crystalline form: Colorless amorphous NMR analysis: 112) Form: Free

Example 623 Structure

0 CH,

4-NHC ^■ O

Crystalline form: Colorless amorphous NMR analysis: 113) Form: Free

Example 624 Structure

Crystalline form: Colorless amorphous NMR analysis: 114) Form: Free

Example 625 Structure

Crystalline form: Colorless amorphous NMR analysis: 115) Form: Free

Example 626 Structure

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 183 - 184°C

Form: Free

Example 627 Structurε

0 CH,

R~ : 4-NHC ^■ O

Cryεtallinε form: Whitε powder

Recrystallization solvent: Diεthyl ether/dichloromethane

Melting Point: 219 - 220°C

Form: Free

Example 628 Structurε

Crystalline form: White powder

Rεcrystallization solvent: Diethyl ethεr/dichloromethane

Melting Point: 240 - 241°C

Form: Freε

Example 629

Structure

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 205 - 206°C

Form: Free

Example 630 Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 238 - 239°C

Form: Free

Example 631 Struct

0 CH,

4-NHC ^■ O

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 233 - 234°C

Form: Free

Example 632 Structure

0 Cl

R 3 . 4-NHC ^• ■--rf -iCl

Crystalline form: Colorless amorphous NMR analysis: 116) Form: Free

Example 633 Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 259.5 - 260.5°C

Form: Free

80) H-NMR(CDC1 ₃ ) δ ; 1.24-5.26 (18H, m) , 6.39-7.59 (13H, m)

81) H-NMR(CDC1 ₃ ) δ ; 1.70-2.10 (m, 2H) , 2.15-2.60 (m, 12H), 3.56 (t, J=5.8 Hz, IH) , 3.65-3.95 (m, 4H) 4.05-4.25 (m, IH) , 6.64 (d, J=7.7 Hz, IH) , 6.85- 7.50 (m, 9H), 8.11 (brε, IH) , 8.42 (d, J=8.8 Hz, IH)

82) H-NMR(CDC1 ₃ ) δ ; 2.00-2.90 (m, 3H) , 2.49 (ε, 3H) , 3.70-3.90 (m, IH) , 4.00-4.20 (m, IH) , 4.80-5.00 (m, IH), 6.89 (d, J=6.3 Hz, IH) , 6.95-7.65 (m, 11H) , 7.70 (brε, IH)

83) ^X H-NMR(CDC1 ₃ ) δ ; 1.95-2.90 (m, 2H) , 2.48 (s, 3H) , 2.55 (s, 3H), 3.77 (t, J=5.1 Hz, IH), 3.92 (t, J=6.7 Hz, 2H), 6.72 (d, J=8.0 Hz, IH) , 6.90-7.15 (m, 2H), 7.15-7.70 ( , 9H) , 7.81 (brε, IH)

84) H-NMR(CDC1 ₃ ) δ ; 2.11 (s, 3H) , 2.20-2.40 ( , 2H) , 2.50 (ε, 3H), 3.80-4.10 (m, IH) , 4.12-4.25 (m, IH) , 6.03 (t, J=4.3 Hz, IH), 6.80-7.65 (m, 12H) , 7.80 (brε, IH)

85) H-NMR(CDC1 ₃ ) δ ; 1.80-2.40 (m, 5H) , 2.45 (s, 3H) , 2.81 (ε, 3H), 3.55-3.82 (m, IH) , 4.15-4.40 (m, IH), 5.90-6.10 (m, IH) , 6.80-7.80 (m, 12H) , 8.67 (brs, IH)

86) H-NMR(CDC1 ₃ ) δ ; 1.95-2.35 (2H, m) , 2.75-3.0 (2H, m), 3.0-5.4 (2H, m) , 6.55-7.95 (11H, m) , 8.09 (IH, s)

87) H-NMR( DMSO-dg) δ ; 1.85-2.2 (2H, m) , 2.7-2.95 (2H, m), 3.5-5.0 (2H, m) , 6.8-7.8 (12H, m) , 10.60 (IH, s)

88) ^X H-NMR(CDC1 ₃ ) δ ; 0.8-1.1 (3H, m) , 1.2-2.35 (6H, m), 2.35-5.25 (6H, m) , 6.63 (IH, d, J=7.7 Hz), 6.8- 7.6 (9H, m), 7.67 (IH, d, J=8.2 Hz), 7.9-8.15 (IH, m)

89) H-NMR(CDC1 ₃ ) δ ; 1.7-2.9 (7H, m) , 4.5-6.5 (3H, ) , 6.55-6.75 (IH, ) , 6.85-7.6 (12H, m)

90) H-NMR(CDC1 ₃ ) δ ; 1.65-3.1 (7H, m) , 4.7-6.6 (3H, m) , 6.6-6.8 (IH, m) , 6.85-7.65 (12H, m)

91) H-NMR(CDC1 ₃ ) δ ; 1.8-2.4 (2H, m) , 2.86 (2H, t, J=6 Hz), 3.1-5.15 (2H, m) , 6.85-7.5 (8H, m) , 7.5-7.85 (3H, m), 8.19 (IH, s)

92) H-NMR(CDC1 ₃ ) δ ; 1.46-2.28 (4H, m) , 2.37 (3H, ε), 2.58-2.90 (IH, m) , 4.57-5.10 (2H, m) , 6.59 (IH, d, J=7.6 Hz), 6.91-7.52 (11H, m) , 7.62 (IH, d, J=7.6 Hz), 8.10-8.40 (IH, m)

93) ^X H-NMR(CDC1 ₃ ) δ ; 1.45-1.91 (2H, m) , 1.91-2.65 (2H, m), 2.65-2.90 (IH, m) , 4.63-5.22 (2H, m) , 6.63 (IH, d, J=7.4 Hz), 7.34-8.03 (11H, m) , 10.16-10.44 (IH, m)

94) H-NMR(CDC1 ₃ ) δ ; 1.08-1.47 (3H, m) , 1.50-1.97 (2H, m), 1.97-2.48 (2H, m) , 2.65-3.02 (IH, m) , 4.00-4.43 (4H, m) , 4,52-5.15 (2H, m) , 6.50-6.79 (IH, m) , 6.90-7.70 (10H, m) , 8.26-8.60 (IH, m)

95) H-NMR(CDC1 ₃ ) δ ; 1.56-2.67 (4H, m) , 2.46 (3H, s), 2.67-3.03 (IH, ) , 3.82-4.32 (2H, m) , 4.45-5.15 (2H, m), 5.43-5.83 (IH, m) , 6.20-6.45 (IH, m) , 6.50-6.86 (2H, m) , 6.86-7.70 (10H, m) , 7.76-8.10 (IH, m)

96) H-NMR(CDC1 ₃ ) δ ; 1.52-1.90 (2H, m) , 1.90-2.54 (2H, m) , 2.67-3.05 (IH, m) , 3.74-4.32 (2H, m) , 4.38-5.17 (2H, m), 5.52-5.98 (IH, brs), 6.20-6.48 (IH, brε), 6.55-6.84 (IH, m) , 6.89-7.55 (9H, m) , 7.55-7.77 (IH, m), 8.15-8.86 (IH, brε)

97) ^X H-NMR( DMSO-dg) δ ; 1.26-2.49 (4H, m) , 2.57-2.93 (IH, m), 4.07-4.43 (2H, m) , 4.44-4.98 (2H, m) , 6.62-6.87 (IH, m) , 6.92-7.80 (11H, m) , 10.57 (IH, s), 12.74 (IH, s)

98) H-NMR(CDC1 ₃ ) δ ; 1.52-1.89 (2H, m) , 1.89-2.56 (2H, m), 2.65-3.02 (IH, m) , 3.90-4.40 (2H, m) , 4.40-5.07 (2H, m) , 6.58-6.78 (IH, m) , 6.90-7.70 (10H, ) , 8.57-8.81 (IH, brε)

99) H-NMR(CDC1 ₃ ) δ ; 1.49-1.89 (2H, m) , 1.89-2.60 (2H, m), 2.63-3.23 (7H, m) , 4.04-4.49 (2H, m) , 4.52-5.21 (2H, m) , 6.52-6.80 (IH, m) , 6.89-7.84 (10H, ) , 8.08-8.52 (IH, m)

100) H-NMR(CDC1 ₃ ) δ ; 1.41-1.86 (6H, m) , 1.86-2.53 (4H, m), 2.25 (3H, ε), 2.29 (3H, s), 2.43 (3H, s) , 2.60- 2.97 (IH, m) , 3,36-3.77 (2H, m) , 4.40-5.10 (2H, m) , 6.54-6.72 (IH, m) , 6.88-7.67 (11H, m) , 8.27-8.58

(IH, m)

101) ^X H-NMR(CDC1 ₃ ) δ ; 1.44-1.85 (6H, m) , 1.85-2.61 (4H, m), 2.32 (3H, s), 2.35 (3H, ε), 2.61-3.00 (IH, m) , 3.33-3.76 (2H, m) , 4.40-5.20 (2H, m) , 6.57-6.75 (IH, m), 6.90 - 7.70 (11H, m) , 8.50-8.93 (IH, m)

102) H-NMR(CDC1 ₃ ) δ ; 1.49-2.04 (6H, m) , 2.10-3.02 (5H, m) , 2.47 (6H, s), 3.40-3.88 (2H, ) , 4.30-5.17 (2H, m), 6.59-6.78 (IH, m) , 6.93-7.76 (10H, m) , 8.75- 9.40 (IH, m)

103) H-NMR(CDC1 ₃ ) δ ; 1.47-2.47 (6H, m) , 2.44 (3H, s), 2.62-3.03 (IH, m) , 3.47-4.03 (4H, m) , 4.48-5.17 (2H, ), 6.51-6.74 (IH, m) , 6.87-7.62 (11H, m) , 7.62-7.77 (2H, m) , 7.77-8.03 (3H, m)

104) H-NMR(CDC1 ₃ ) δ ; 1.42-2.32 (6H, m) , 2.44 (3H, s), 2.57-2.97 (IH, m) , 3.12-3.83 (4H, m) , 4.39-5.13 (2H, m) , 6.50-6.71 (IH, m) , 6.90-7.73 (12H, m)

105) ^X H-NMR(CDC1 ₃ ) δ ; 1.50-2.63 (9H, m) , 2.47 (3H, s), 2.66-3.07 (IH, m) , 3.10-3.88 (4H, m) , 4.40-5.17 (2H, m), 5.87-6.23 (IH, brs), 6.60-6.79 (IH, m) , 6.94-7.60 (11H, m) , 7.67 (IH, s)

106) ^X H-NMR(CDC1 ₃ ) δ ; 1.20-2.53 (13H, m) , 2.63-2.82, 3.00-3.13, 3.50-3.67, 4.05-4.23 (total 3H, m) , 6.55 - 8.00 (13H, m)

107) H-NMR(CDC1 ₃ ) δ ; 1.41 (9H, s), 1.20-2.55 (10H, m) , 3.42-4.20 (5.8H, m) , 5,00-5,20 (0.2H, m) , 6.60-7.67 (10H, m), 7.99 (IH, brs), 8.26 (IH, d, J=8.4 Hz)

108) ^X H-NMR(CDC1 ₃ ) δ ; 1.2-3.0 (10H, m) , 3.0-5.2 (6H, m), 6.5-7.7 (8H, m) , 8.22 (IH, d, J=8.4 Hz), 8.36 (IH, S)

109) ^X H-NMR(CDC1 ₃ ) δ ; 1.2-3.0 (10H, ) , 3.0-5.2(6H, m) , 6.3-7.7 (10H, m)

110) ^X H-NMR(CDC1 ₃ ) δ ; 1.5-1.7 (IH, m) , 2.2-2.7 (2H, m) , 2.40 (6H, s), 2.7-3.0 (3H, m) , 5.1-5.3 (IH, m) , 6.67 (IH, d, J=7.7 Hz), 6.9-7.5 (10H, m) , 7.69 (IH, d, J=6 Hz), 8.06 (IH, s)

111) H-NMR(CDC1 ₃ ) δ ; 1.4-1.7 (IH, m) , 2.1-2.7 (2H, m) ,

2.40 (6H, s), 2.44 (3H, s), 2.7-3.0 (3H, m) , 5.1- 5.3 (IH, m), 6.68 (IH, d, J=7.8 Hz), 6.9-7.5 (11H, m), 7.66 (IH, s)

112) ^X H-NMR(CDC1 ₃ ) δ ; 1.5-1.8 (IH, m) , 2.1-2.7 (2H, m) , 2.38 (6H, s), 2.7-3.0 (3H, m) , 5.1-5.3 (IH, m) , 6.66 (IH, d, J=7.7 Hz), 6.9-7.0 (9H, m) , 7.57 (IH, d, J=8.3 Hz), 8.42 (IH, s)

113) H-NMR(CDC1 ₃ ) δ ; 1.5-1.8 (IH, m) , 2.1-2.7 (2H, m) ,

2.41 (6H, s), 2.48 (3H, s), 2.7-3.0 (3H, m) , 3.68 (3H, s), 5.2-5.4 (IH, m) , 6.6-6.8 (2H, m) , 6.9-7.5 (8H, m), 8.09 (IH, s), 8.26 (IH, d, J=8.1 Hz)

114) H-NMR(CDC1 ₃ ) δ ; 1.5-1.7 (IH, m) , 2.1-2.3 (IH, m) , 2.41 (6H, s), 2.4-2.6 (IH, m) , 2.8-3.0 (3H, m) , 3.71 (3H, s), 5.2-5.4 (IH, m) , 6.6-6.8 (2H, m) , 6.9-7.5 (7H, m), 7.7-7.8 (IH, m) , 8.27 (IH, d, J=8.4 Hz), 8.57 (IH, s)

115) H-NMR(CDC1 ₃ ) δ ; 1.5-1.7 (IH, m) , 2.1-2.7 (2H, m) , 2.41 (6H, s), 2.7-3.0 (3H, m) , 3.71 (3H, s), 5.2- 5.4 (IH, m), 6.6-7.6 (8H, m) , 7.70 (IH, d, J=8.3 Hz), 8.24 (IH, d, J=8.5 Hz), 8.59 (IH, s)

116) H-NMR(CDC1 ₃ ) δ ; 1.8-2.3 (3H, m) , 2.7-2.9 (2H, m) , 3.5-3.7 (IH, m), 6.8-8.0 (10H, m) , 8.7-9.1 (IH, br) Example 634

To a mixture of 5-oxo-l-[4-(3,5-dichlorobenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (4 g) and pyridine (50 ml) iε addεd hydroxylaminε hydrochloridε (1.84 g) and thε mixturε iε rεfluxed for 2.5 hourε. The reaction εolution is concentratεd and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallizεd from dioxanε/water to give 5- hydroxyimino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine (2 g) as white powder, m.p. 272 - 273°C.

Example 635

5-Chloro-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazepine (0.8 g) is dissolved in dimethylformamide and thereto is added sodium azide (0.18 g) at room temperature. The mixture is stirred at room temperature overnight, and further reacted with heating at 50°C for 5 hours. Water is added to the reaction mixture and the precipitated crystal is collected by filtration to give 5-azido-l-[4-(2-methylbεnzoylamino)bεnzoyl]-2,3,4,5-

tetrahydro-lH-benzazepinε (0.68 g) as light brown powder.

^X H-NMR(CDC1 ₃ ) δ ; 1.65-3.1 (8H, m) , 4.7-6.6 (3H, m), 6.6-6.8 (IH, m) , 6.85-7.65 (12H, m)

Example 636

5-Azido-l-[ -(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine (0.63 g) is dissolved in ethanol and thereto is added 10 % Pd-C (0.1 g). The mixture is subjected to catalytic hydrogenation at room temperature under 1 atm. of hydrogen. Pd-C is removed by filtration and the filtrate is εvaporatεd. Thε rεsulting reεidue is purifiεd by silica gel column chromatography (eluεnt; dichloromethane : methanol = 50 : 1), and recrystallized from diethyl ethεr to give 5-amino-l-[4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.34 g) as whitε powdεr, m.p. 198.5 - 199.5°C.

Examplε 637

To 5-hydroxy-1-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε (0.58 g) arε added acetic anhydride (8.0 ml) and pyridine (2.0 ml). The mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the precipitated crystal is collected by filtration, and recrystallized from ethyl acetate/n-hexane to give 5-acetyloxy-l-[4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.56 g) as white powder, m.p. 193 - 194°C.

Example 638

5-Ethoxycarbonylmεthoxy-l-[4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (1.00 g) is disεolved in methanol (35 ml) and thereto are added aqueous ammonia (20 ml) and ammonium chloride (0.50 g). The mixture is heatεd at 100°C for 3.5 hours in a εealed tube. After cooling, the rεaction εolution iε concentrated under reduced pressurε and acidifiεd with hydrochloric acid, and εxtracted with dichloromεthanε. The extract is dried over magnesium sulfate and the solvent is distilled off. The rεsulting residue is purified by silica gel column chromatography (eluent; dichloromethane : methanol = 15 : 1) to give 5- carbamoylmethoxy-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine (0.68 g) as colorless amorphous. H-NMR(CDC1 ₃ ) δ ; 1.56-2.67 (4H, m) , 2.46 (3H, s), 2.67-3.03 (IH, m) , 3.82-4.32 (2H, m) , 4.45-5.15 (2H, m) , 5.43-5.83 (IH, m) , 6.20-6.45 (IH, m) , 6.50-6.86 (2H, m) , 6.86-7.70 (10H, m) , 7.76-8.10 (IH, m)

Using the suitable starting materials, the compounds of the above Examples 593 and 594 are obtained in the same manner as in Example 638.

Exampla 639

5-Ethoxycarbonylmεthoxy-1-[4-(2,4-dichlorobenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.94 g) is dissolved in ethanol (100 ml) and thereto is added 5N aqueous εodium hydroxide εolution (0.50 ml). The mixture is

stirred at room temperature for 2 hours. The reaction solution is concentratεd under reduced pressure and to the resulting residue iε added dilutεd hydrochloric acid and than εxtractεd with dichloromεthanε. Thε extract is dried over magnesium sulfate and the solvent is distilled off. The resulting residuε iε waεhed with n-hexane and collected by filtration to give 5-carboxymεthoxy-l-[4-(2,4-dichloro- bεnzoyla ino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.79 g) as colorlεss amorphous. H-NMR(CDC1 ₃ ) δ ; 1.52-1.89 (2H, m) , 1.89-2.56 (2H, m), 2.65-3.02 (IH, m) , 3.90-4.40 (2H, m) , 4.40-5.07 (2H, m) , 6.58-6.78 (IH, m) , 6.90-7.70 (10H, m), 8.57-8.81 (IH, brs)

Using thε suitablε starting materials, the compounds of the above Examples 595 and 596 are obtained in the same manner as in Example 639.

Example 640

5-Carboxymεthoxy-1-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.55 g) is dissolved in dimethylformamide (20 ml) and thereto are added dimethylaminε hydrochloridε (0.20 g) and diethyl chloro- phoεphatε (0.33 g). To thε mixture iε added triethylamine (1.0 ml) under icε-cooling, and thε mixture is stirred under ice-cooling for 30 minutes, and at room temperature for more 2 hours. Water is added to the reaction solution and the precipitated crystal is collected by filtration and recrystallized from ethyl acetate/n-hexane to give 5-

dimethylaminocarbonylmethoxy-1- [ 4- ( 2-methylbenzoylamino ) - benzoyl ] -2 , 3 , 4 , 5-tεtrahydro-lH-bεnzazεpinε ( 0. 50 g ) as colorless prisms , m. p . 203 - 204°C .

Using the suitable starting mater ials , the compounds of the above Examples 599 and 600 are obtained in the same manner as in Example 640 .

Example 641

5-[3-(Phthalimid-1-yl)propoxy]-1-[4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (1.26 g) is disεolved in εthanol (100 ml) and thereto is added hydrazine hydrate (1.0 ml). The mixture is refluxed with stirring for 1 hour. The reaction solution is evaporated under rεducεd prεssurε and to thε resulting residuε is added dichloromethanε. Thε insolublε matεrials are removed by filtration. The filtrate is purified by silica gel column chromatography (eluεnt; dichloromεthane : methanol : aqueous ammonia = 70 : 10 : 1) to give 5-(3- aminopropoxy)-1-[4-(2-methylbεnzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-bεnzazεpine (0.70 g) as colorless amorphous. H-NMR(CDC1 ₃ ) δ ; 1.42-2.32 (6H, m) , 2.44 (3H, s), 2.57-2.97 (IH, m) , 3.12-3.83 (4H, m) , 4.39-5.13 (2H, m) , 6.50-6.71 (IH, m) , 6.90-7.73 (12H, m)

Example 642

A solution of 5-dimethylamino-l- [ 3-mεthoxy-4- ( 2- methylbenzoylami no ) benzoyl ] -2 , 3 , 4 , 5-tetrahydro-lH-

benzazepine (0.50 g) in dichloromethanε (30 ml) is added dropwise to a solution of IM boron tribromide in dichloro¬ mεthane (5.46 ml) at -45°C. After completion of the dropping, the mixture is εtirrεd for 1 day whilε thε tεmperature of the reaction mixture is gradually raised to room temperature. To the reaction solution is added water and the mixture is neutralizεd with εodium hydrogen carbonate, and extracted with dichloromethane. The extract iε washed with saturated saline solution and dried over magnesium sulfate. The solvent iε distilled off and the resulting residue is purified by εilica gel column chromatography (eluεnt; chloroform : methanol = 500 : 1), and recrystallized from methanol/diethyl ether to give 5- dimethylamino-1-[3-hydroxy-4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepinε (0.33 g) as white powder, m.p. 201.5 - 202.5°C.

Using the suitable starting matεrials, the compounds of the above Examples 10, 32, 343, 356, 535, 555 and 556 are obtained in the same manner as in Example 642.

Example 643

To a solution of 4-[4-(2-methylbenzoylamino)- benzoyl]-3,4-dihydro-2H-l,4-benzazepine (0.5 g) in dichloro¬ methane (10 ml) is added m-chloroperbenzoic acid (0.58 g) under ice-cooling, and the mixturε is stirred at room temperature for 6 hours. The abovε reaction solution is poured into an aqueous solution of sodium carbonate (0.6 g) in water (10 ml) and the mixture is extracted with dichloro-

methane. The extract is washed with water, and dried over magnesium sulfate. The solvent is distilled off undεr rεducεd presεure and the reεulting residue is purified by silica gel column chromatography (eluent; dichloromethane : methanol = 100 : 1), and recrystallized from diethyl ether/dichloromethane to give 4-[4-(2-mεthylbεnzoylamino)- bεnzoyl]-3,4-dihydro-2H-l,4-benzothiazine-l,l-dioxide (0.49 g) as white powder, m.p. 219 - 220°C.

Using the suitable starting materials, the compound of the above Example 630 is obtained in the same manner as in Example 643.

Example 644

To a suspension of 4-[4-(2-methylbenzoylamino)- benzoyl]-3,4-dihydro-2H-l,4-benzothiazine (0.5 g) in methanol (15 ml) is added an aqueous solution of sodium metaperiodate (0.28 g) in water (2.5 ml) and the mixture is stirred at room tempεrature for 72 hours. Water is added to the reaction solution and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced prεssurε. The resulting residue is purified by silica gel column chromatography (eluεnt; dichloromεthane : mεthanol = 100 : 1), and recrystallized from dichloromethanε/diεthyl ether to give 4- [4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-l,4- bεnzothiazin-1-oxide (0.34 g) as whitε powdεr, m.p. 240 - 241°C.

Using the suitable starting materials, the compound of the above Example 631 is obtained in the same manner as in Example 644.

Example 645

5-Hydroxy-l-[4-( 2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine (3.57 g) iε dissolved in dichloromethanε (30 ml) and pyridinε (1.1 ml), and thεreto is added dropwise methanεsulfonyl chloridε (0.9 ml) in small portions at 0°C. Than, the mixture is stirred at room temperature for 3 days. The solvεnt is distillεd off and thε resulting residuε is poured into ice-watεr. Thε precipitated crystal is collectεd by filtration, washed with water, and dried to givε 5-chloro-l-[4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε (3.10 g) as light yellow powder. H-NMR(CDC1 ₃ ) δ ; 1.7-2.9 (8H, m) , 4.5-6.5 (3H, ) , 6.55-6.75 (IH, m) , 6.85-7.6 (12H, m)

Examplε 646

5-Hydroxy-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε (2.69 g) is dissolvεd in dimethylformamide (30 ml) and thereto are added 60 % sodium hydride dispersion in mineral oil (0.44 g) and εthyl bromoacetate (1.00 ml) under ice-cooling, and the mixture is stirred at room temperature for 4 hours. The reaction solution is poured into an aqueous ammonium chloride solution under ice-cooling, and εxtractεd with εthyl

acεtatε. Thε extract is dried over magnεsium sulfatε and thε solvεnt iε distilled off. The resulting rεsidue is purified by silica gel column chromatography (eluεnt; ethyl acetate : n-hexane = 1 : 2), and recrystallizεd from ethyl acetate/n-hexane to give 5-ethoxycarbonylmethoxy-l-[4-( 2- methylbenzoylamino)benzoyl-2,3,4,5-tetrahydro-lH-benzazepine (2.10 g) as white powder, m.p. 178 - 181°C.

Using the suitable starting materials, the compounds of the above Examples 585 - 588 and 590 - 606 are obtainεd in thε samε mannεr as in Examplε 646.

Example 647

Using the suitable starting materialε, thε compoundε of thε above Examples 546 and 578 - 581 are obtained in the same manner as in Example 384.

Example 648

Using the suitablε starting materials, the compounds of thε above Examples 537 - 545, 547, 549 - 556, 561 - 564, 566, 568 - 571, 577, 601 - 603 and 607 - 625 are obtained in the same manner as in Example 388.

Example 649

Using the suitable starting materials, the compounds of the above Examples 549, 568 - 571, 575 and 606 are obtainεd in thε same manner as in Example 389.

Example 650

Using the suitable starting materials, the compounds of the above Examples 537 - 545, 547, 549 - 556,

561 - 566, 568 - 571, 575, 577, 607, 608 and 613 - 625 are obtained in the same manner as in Example 390.

Example 651

Using the suitablε starting matεrials, thε compounds of thε abovε Examples 601 - 603, 605 and 606 are obtained in the samε manner as in Example 397.

Example 652

Using the suitable εtarting matεrials, thε compound of thε above Example 604 is obtained in the same manner as in Example 398.

Example 653

Using thε suitablε starting matεrials, the following compound iε obtained in thε εame manner as in Examples 1, 382, 388 and 390.

5-Methylamino-l-[2-chloro-4-(2-methylbenzoyl¬ amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine, white powder, m.p. 184.5 - 185.5°C (recrystallized from ethanol)

Using the suitable starting matεrials, the compounds of the following Table 4 arε obtained in the same manner as in Examples 1 and 382.

Table 4

Example 654 Structu

Crystalline form: White powder Recrystallization solvent: Methanol/n-hexane Melting Point: 193.5 - 196°C Form: Free

Example 655 Struct

Crystalline form: White powder Recrystallization εolvent: Methanol/n-hexane Melting Point: 195 - 198°C Form: Free

Example 656 Struct

Crystalline form: White powder Recrystallization solvent: Methanol Melting Point: 230.5 - 231.5°C Form: Free

Example 657 Structu

Crystalline form: Whitε powdεr

Rεcrystallization εolvent: Methanol/diεthyl ether Melting Point: 223 - 224.5°C Form: Free

Example 658 Struct

Cryεtallinε form: White powder

Recryεtallization solvent: Methanol/diεthyl ether Melting Point: 173 - 174°C Form: Freε

Example 659 Struct

Cryεtalline form: White powder

Recryεtallization εolvent: Methanol/diεthyl εther Melting Point: 174 - 175°C Form: Free

Example 660 Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 198 - 200°C Form: Free

Example 661 Structure

Cryεtalline form: White powdεr Recryεtallization εolvent: Methanol/n-hexane Melting Point: 149 - 150.5°C Form: Free

Example 662 Structure N(CH ₃ ) ₂

Crystalline form: White powdεr

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 183 - 185°C Form: Free

Example 663 Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 203 - 207°C Form: Free

Example 664 Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 221 - 222°C Form: Free

Example 665 Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 189 - 191°C Form: Free

Example 666 Structu

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 215.5 - 217°C Form: Free

Example 667 Structu

0 Cl

R ^J : 4-NHC :--<OV>~cC1

Crystalline form: White powder Recrystallization solvent: Methanol/n-hεxanε Mεlting Point: 192 - 194°C Form: Free

Example 668 Structure

Crystalline form: Whitε powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 195 - 196°C Form: Freε

Example 669 Struct

Crystalline form: White powder

Recrystallization solvεnt: Mεthanol/diethyl εthεr Mεlting Point: 202 - 204.5°C Form: Free

Examplε 670 Structu

Crystallinε form: White powder

Recrystallization solvent: Methanol/diεthyl εther Melting Point: 183 - 187°C Form: Free

Examplε 671 Struct

Crystalline form: White powdεr

Recrystallization solvent: Mεthanol/diethyl εthεr Mεlting Point: 120 - 122°C Form: Frεε

Examplε 672 Struct

Crystalline form: White powdεr

Recrystallization solvent: Chloroform/diethyl ether

Melting Point: 208 - 210°C

Form: Freε

Example 673 Structure 0

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether

Melting Point: 182 - 183°C

Form: Freε

Examplε 674

Struct

Cryεtalline form: White powder

Recrystallization solvent: Mεthanol/diethyl ether Melting Point: 257 - 259°C Form: Frεε

Example 675

Structu

0

Crystalline form: Whitε powdεr

Rεcrystallization solvεnt: Dichloromεthane/diethyl ether

Melting Point: 134 - 135°C

Form: Free

R ³ : 4-NHCOCH ₂ -/ X

Crystalline form: White powdεr

Recrystallization solvent: Methanol/diethyl ether Melting Point: 167 - 169°C Form: Freε

Example 677

Struct

Crystalline form: Light brown prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 170 - 172°C Form: Freε

Example 678 Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 181.5 - 182.5°C Form: Free

Example 679 Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 176.5 - 177°C Form: Freε

Example 680 Struct

0 Cl

R- 4-NHC ^■ O

Crystalline form: Yellow amorphous NMR analysiε: 117) Form: Free

Example 681 Structu

Crystalline form: Yellow amorphouε NMR analysis: 118) Form: Free

Example 682

Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 236 - 239°C Form: Free

Example 683

Struct

Crystalline form: White powder

Recrystallization εolvent : Ethyl acetatε/n-hεxane

Melting Point : 153 - 154°C

Form: Free

Examplε 684

Struct

0 Cl

Crystalline form: White powder Rεcrystallization solvent: Ethyl acetate Melting Point: 128 - 130°C Form: Frεε

Examplε 685

Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether Melting Point: 231 - 234°C Form: Free

Exampl Struct

Crystalline form: Whitε pov/dεr Recrystallization solvent: Ethyl acetate Melting Point: 246 - 248°C Form: Free

Example 687

Struct

Crystallinε form: Whitε powder

Recrystallization solvent : Ethanol/water

Melting Point : 248 - 248 . 5 °C

Form: Freε

Example 688

Structure

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diεthyl ether

Melting Point: 204 - 205°C

Form: Free

Example 689 Struct

Crystalline form: White powder

Recrystallization solvent: Dichloromethanε/diethyl ethεr

Mεlting Point: >300°C

NMR analysis: 119)

Form: Free

Example 690

Structure

Crystalline form: Whitε powdεr

Rεcrystallization solvεnt: Dichloromεthanε/diεthyl εthεr

Mεlting Point: 292 - 294°C

Form: Free

Example 691 Struct

Crystalline form: Colorlesε amorphouε NMR analysis: 120) Form: Free

Crystalline form: Colorlesε amorphouε NMR analysis: 121) Form: Freε

Example 693 Struct

Crystalline form: Colorlesε amorphous . NMR analysiε: 122) Form: Free

Example 694

Struct

Crystalline form: Colorless amorphous NMR analysis: 123) Form: Free

Example 695

Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Mεlting Point: 198.5 - 199°C Form: Free

Example 696 Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 168 - 170°C

Form: Free

Example 697

Structu

Cryεtalline form: White powder

Recrystallization εolvent: Diethyl ether/dichloromethane

Melting Point: 175 - 176°C

Form: Free

Example 698

0 CH-

R- 4-NHC ^■ O

Cryεtalline form: White powder

Recrystallization solvent: Diethyl ethεr/dichloromεthanε

Mεlting Point: 177 - 178°C

Form: Frεε

Example 699 Structure OH

Crystalline form: White powdεr

Rεcrystallization solvεnt: Diεthyl εthεr/dichloromεthanε

Mεlting Point: 222 - 223.5°C

Form: Frεε

Examplε 700

Struct

Crystallinε form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 243 - 244°C

Form: Free

Example 701 Structu

Crystallinε form: Whitε powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 180 - 181°C

Form: Free

Example 702 Struct

Crystalline form: Colorlesε amorphous NMR analysis: 124) Form: Free

Example 703 Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ethεr/dichloromethane Melting Point: 231 - 233°C Form: Free

Example 704 Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 196 - 198°C

Form: Free

Example 705 Struct

0

Crystalline form: Colorlεss amorphous NMR analysis: 125) Form: Free

Example 706 Structure OH

Crystalline form: Yellow amorphous NMR analysis: 126) Form: Freε

Examplε 707 Struct

R ³ : 4-NHCCH ₂ Cl Crystallinε form: Yεllow powdεr

Recrystallization solvent: Diethyl ethεr/dichloromethane Melting Point: 146 - 147°C Form: Free

Examplε 708 Struct

Crystalline form: Colorless amorphous NMR analysis: 127) Form: Freε

Example 709 Structure

Crystalline form: Whitε powdεr

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 220 - 221°C

Form: Free

Example 710 Structure 0

0 Cl

R ^J : 4-NHC ^■ O

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 170 - 172°C

Form: Free

Example 711 Struct

Crystalline form: Colorless amorphous NMR analysis: 128) Form: Freε

Example 712 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 224 - 225°C Form: Frεε

Example 713 Struct

Crystalline form: Whitε powdεr Recrystallization solvent: Ethanol Melting Point: 193 - 196°C Form: Freε

Example 714 Structure

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 212 - 214°C Form: Freε

Example 715 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 211 - 213°C Form: Freε

Examplε 716 Struct

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 213 - 215°C Form: Free

Examplε 717 Structu

Crystallinε form: White powder Recrystallization solvent: Ethanol Melting Point: 199 - 201°C Form: Free

Example 718 Struct

Crystalline form: Whitε powdεr Recrystallization solvent: Ethanol Melting Point: 238 - 240°C Form: Freε

Crystalline form: White powder Recrystallization solvent: Ethanol Melting Point: 188 - 189°C Form: Free

Example 720 Struct

0 CH,

R- 4-NHC ^■ O

Crystalline form: Colorless prisms Recrystallization solvent: Dioxane/water Melting Point: 135.5 - 137°C Form: Freε

Examplε 721

Structure

Crystalline form: White powder

Recrystallization solvent: Iεopropyl alcohol/ petroleum ether

Melting Point: 192 - 193°C

Form: Free

Example 722

Struct

Cryεtalline form: Colorleaε needles Rεcrystallization solvεnt: Ethyl acεtatε Melting Point: 239 - 240°C Form: Free

Example 723

Struct

Crystallinε form: Colorlεss amorphous NMR analysis: 129) Form: Free

Example 724

Struct

Crystalline form: Colorless amorphous NMR analysis: 130) Form: Free

Example 725 Struct

Crystallinε form: Colorlεss needlεs

Rεcryεtallization solvεnt: Ethanol/petroleum ether

Melting Point: 193 - 194°C

Form: Free

Example 726

Structu

Crystalline form: Light yellow prisms Recrystallization solvent: Ethanol Melting Point: 245.5 - 247°C Form: Free

Example 727 Struct

Crystalline form: Colorless prisms

Recrystallization solvent: Ethanol/petrolεum ether

Melting Point: 142 - 144°C

Form: Free

Example 728

Struct

Crystalline form: Light yellow prisms Recrystallization solvent: Ethanol Melting Point: 214 - 217°C Form: Free

Example 729 Structurε

Crystalline form: Colorlesε needles Recrystallization solvent: Ethanol Melting Point: 205 - 207°C Form: Freε

Example 730 Struct

Crystalline form: Colorlesε neεdlεs Recrystallization solvent: Ethanol/diethyl ether Melting Point: 201 - 203°C Form: Freε

Example 731

Struct

Crystallinε form: Colorlεsε nεedleε

Recrystallization solvent: Ethanol/diεthyl εther

Melting Point: 180 - 182°C

Form: Free

Example 732

Structure

Crystalline form: Light yellow scales Recrystallization solvent: Ethanol/diεthyl ether Melting Point: 178 - 180°C Form: Freε

Example 733

Struct

0 Cl

Crystalline form: Colorless needles Recryεtallization εolvent: Methanol/diethyl ethεr Mεlting Point: 208 - 213°C Form: Frεε

Examplε 734

0 CH-

R- 4-NHC ^■ O

Crystalline form: Whitε powdεr

Rεcrystallization solvεnt: Ethanol/diεthyl εthεr Mεlting Point: 175 - 177°C Form: Frεε

Example 735 Struct

Crystallinε form: White powder NMR analysiε: 131) Form: Free

Example 736 Structu

Crystalline form: Whitε powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 277 - 279°C Form: Free

Example 737 Struct

Crystalline form: Colorlεsε amorphouε NMR analyaiε: 132) Form: Frεe

Example 738 Struct

Cryεtalline form: Colorleεε amorphous NMR analysis: 133) Form: Free

Example 739 Struct

0 Cl

>3~ . 4-NHC"- J

\_=/

Crystalline form: Colorless amorphous NMR analysis: 134) Form: Free

Example 740 Struct

0 Cl

R- 4-NHC ^■ O

Crystalline form: Colorlesε amorphouε NMR analysis: 135) Form: Free

Example 741 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 213 - 214°C Form: Freε

Examplε 742 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 216 - 217°C Form: Freε

Example 743 Struct

Crystalline form: White powder

Re-crystallization solvent: Ethyl acetate/n-hexane Melting Point: 165 - 167°C Form: Free

Example 744 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 202 - 206°C Form: Free

Examplε 745 Structu

Crystalline form: White powder

Recrystallization solvεnt: Ethyl acεtatε/n-hεxanε

Melting Point: 220 - 221.5 ^β C

Form: Freε

Example 746

Struct

0 CH-

R- 4-NHC ^■ O

Crystalline form: Colorlesε neεdlεs Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 186 - 186.5°C Form: Free

Example 747 Structu

Crystalline form: Colorlesε amorphouε NMR analyεiε: 136) Form: Free

Example 748 Structu

0 CH,

4-NHC ^■ O

Cryεtalline form: White powder

Recryεtallization εolvent: Ethyl acetate/n-hexane Melting Point: 136 - 140°C Form: Free

Example 749 Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 151 - 153°C Form: Free

Example 750 Structu

Crystalline form: Colorlesε needleε Recryεtallization εolvent: Ethyl acetate/n-hexanε Melting Point: 155 - 156°C Form: Freε

Examplε 751 Structu

Crystalline form: White powder

Rεcrystallization εolvent: Ethyl acetate/n-hεxanε Mεlting Point: 189 - 190°C Form: Frεε

Examplε 752 Structu

0 CH,

R- 4-NHC ^■ O

Crystalline form: White powdεr

Rεcrystallization solvεnt: Ethyl acεtate/n-hexane Melting Point: 188 - 190°C Form: Free

Example 753 Structu

Crystalline form: Colorless needlεs Rεcrystallization solvent: Ethanol Melting Point: 233 - 235°C Form: Freε

Example 754

Struct

0 CH,

R ^J : 4-NHC ^■ O

Crystallinε form: Colorlεss amorphous NMR analysiε: 137) Form: Frεε

Examplε 755

CH ₂ NHCH ₃

Structure

Crystalline form: White powder

Recrystallization solvent: Ethyl acεtatε/n-hεxane Mεlting Point: 176 - 179°C Form: Free

Example 756 Struct

Crystalline form: Colorlesε nεεdlεε Recryεtallization solvent: Methanol/diethyl ether Melting Point: 183 - 185°C Form: Free

117) ^X H-NMR(CDC1 ₃ ) δ ; 1.3-2.3 (4H, m) , 3.1-3.4 (3H, m) , 3.8-4.6 (2H, m), 5.0-5.3 (2H, m) , 5.8-6.1 (IH, m) , 6.8-8.5 (11H, m)

118) ^X H-NMR(CDC1 ₃ ) δ ; 1.6-2.2 (4H, ) , 2.46, 2.53 (3H, each s), 3.1-3.5 (3H, m) , 3.8-4.6 (2H, m) , 5.0-5.3 (2H, m), 5.8-6.1 (IH, m) , 6.8-8.0 (11H, m)

119) H-NMR( DMSO-dg) δ ; 2.33 (3H, s), 3.36 (2H, m) , 3.89 (IH, m), 4.41 (IH, m) , 5.07 (IH, m) , 5.40 (IH, d, J=14.8 Hz), 6.85 (IH, d, J=7.2 Hz), 7.15-7.65 (11H, m) , 10.35 (IH, s)

120) H-NMR(CDC1 ₃ ) δ ; 1.25-5.05 (22H, m) , 6.65-7.65 (11H, m), 7.75-8.25 (IH, m)

121) H-NMR(CDC1 ₃ ) δ ; 1.15-5.05 (19H, m) , 6.75-7.85 (11H, m), 7.85-8.25 (IH, m)

122) H-NMR(CDC1 ₃ ) δ ; 1.25-2.85 (8H, m) , 2.95 - 4.95 (2H, m), 6.75-7.85 (10H, ) , 9.25-9.75 (IH, m)

123) ^X H-NMR(CDC1 ₃ ) δ ; 0.20-0.70 (4H, m) , 0.95-2.35 (6H, m), 2.65-5.00 (2H, m) , 6.75-7.90 (10H, m) , 8.65- 9.25 (IH, m)

124) H-NMR(CDC1 ₃ ) δ ; 1.20-3.15 (11H, m) , 3.45-3.70 (IH, m), 4.05-5.20 (IH, m) , 6.60-7.65 (10H, m) , 8.15-8.45 (2H, m)

125) H-NMR(CDC1 ₃ ) δ ; 1.19 (3H, t, J=7 Hz), 1.25-3.25 (8H, m), 3.46 (2H, q, J=7 Hz), 3.40-4.10 (3H, m) , 4.45-5,10 (IH, m), 6,65-7-75 (12H, m), 8.30-8.60 (IH, m)

126) H-NMR(CDC1 ₃ ) δ ; 1.10-1.30 (3H, m) , 1.50-2.35 (4H, m) , 2.65-3.05 (2H, m) , 3.35-3.60 (2H, m) , 3,80-4.05 (2H, m), 4.65-5.15 (2H, m) , 6.55-7.85 (12H, m) , 8.35-8.65 (IH, m)

127) H-NMR(CDC1 ₃ ) δ ; 1.20 (3H, t, J=7 Hz), 1.10-3.15 (11H, m), 3.45-3.65 (3H, m) , 3.88 (2H, s), 3.95- 5.15 (IH, m), 6.55-7.65 (13H, m) , 8.37 (IH, ε)

128) ^X H-NMR(CDC1 ₃ ) δ ; 2.45 (3H, s), 3.40 (3H, ε), 4.01 (2H, m), 4.38 (2H, m) , 7.20-7.77 (13H, )

129) H-NMR(CDC1 ₃ ) δ ; 1.35-4.55 (22H, m) , 6.3-7.8 (13H, m)

130) ^X H-NMR(CDC1 ₃ ) δ ; 1.10 (6H, t, J=7 Hz), 1.35-5.1 (23H, m), 6.55-7.8 (13H, m)

131) ^X H-NMR(CDC1 ₃ ) δ ; 1.94-3.21 (3H, m) , 3.30-4.82 (3H, m), 6.57 (IH, d, J=7.5 Hz), 6.86-8.10 (11H, m) , 8.72 (IH, brε)

132) H-NMR( DMSO-dg) δ ; 1.57-1.85 (2H, m) , 1.85-2.28 (2H, ), 2.33 (3H, s), 2.64-2.86 (IH, m) , 4.53-5.07 (IH, m), 5.79-5.94 (IH, m) , 6.47-7.68 (2H, br), 6.64-6.77 (IH, m) , 6.96-7.62 (12H, m)

133) H-NMR(CDC1 ₃ ) δ ; 1.61-1.97 (2H, m) , 2.00-2.54 (2H, m), 2.47 (3H, s), 2.60-3.23 (7H, m) , 4.76-5.22 (IH, m), 5.94-6.19 (IH, m) , 6.61-6.74 (IH, m) , 6.91-7.62

(12H, m)

134) H-NMR(CDC1 ₃ ) δ ; 1.68-1.97 (2H, m) , 2.03-2.53 (2H, m), 2.61-3.24 (7H, m) , 4.76-5.22 (IH, m) , 5.97-6.17

(IH, m), 6.59-6.74 (IH, m) , 6.92-7.13 (IH, m) , 7.13-7.58 (9H, m) , 7.66-7.85 (IH, m) , 7.85-8.00 (IH, m)

135) H-NMR(CDC1 ₃ ) δ ; 1.57-1.93 (2H, m) , 1.93-2.54 (2H, m), 2.54-2.72 (IH, m), 2.79-3.09 (3H, m) , 3.90-4.32 (2H, m), 4.49-5.18 (2H, m), 6.31-6.93 (2H, m) , 6.96-7.63 (10H, m) , 7.63-7.89 (IH, m) , 7.89-8.16 (IH, )

136) ^X H-NMR(CDC1 ₃ ) δ ; 1.44-1.95 (2H, m) , 1.95-2.28 (2H, m), 2.40-2.67 (3H, m) , 2.73-3.38 (3H, m) , 3.40-3.97 (IH, m), 4.50-5.20 (IH, m) , 6.67-8.11 (11H, m)

137) H-NMR(CDC1 ₃ ) δ ; 1.50-2.10 (3H, m) , 2.10-2.28 (IH, m), 2.36 (3H, s), 2.48 (3H, ε), 2.68-2.97 (IH, m) , 3.26-3.47 (IH, m) , 4.16 (IH, d, J=13.8 Hz), 4.25 (IH, d, J=13.8 Hz), 5.95 (IH, brε), 6.60-6.76 (IH, m) , 6.97-7.52 (8H, m) , 7.52-7.73 (2H, m) , 7.73-7.97 (2H, m)

Examplε 757

A mixture of 5-dimethylamino-l-[4-(2-chlorobenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine (10 g), mεthyl iodide (1.7 ml) and chloroform (10 ml) is heated with stirring at 100°C for 3 hours in an autoclave. After completion of the reaction, the solvent is distilled off under reduced pressurε and the resulting residue is ^r dissolved in methanol. The mixture is treated with IRA-400

(trade mark; Organo Co., Ltd., OH- type). Methanol is

distilled off and the resulting residuε is suεpεndεd in t- butyl alcohol (90 ml), and thεrεto iε added potaεsium t- butoxide (2.3 g). The mixture is refluxed for 5 hours. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in dichloromethane. The mixture is washed succesεivεly with water and saturated saline solution and dried over magnεsium sulfatε. The solvent is distilled off and to the resulting residue is addεd dichloromεthane/diethyl ether. Thε prεcipitated crude crystal is recrystallized from ethanol to give l-[4-(2- chlorobεnzoyla ino)benzoyl]-2,3-dihydro-lH-benzazepine (5.15 g) as colorless nεεdlεs, m.p. 205 - 207°C.

Example 758

1-[4-(2-Chlorobenzoylamino)benzoyl]-2,3-dihydro-lH- benzazepine (4.7 g) iε diεsolved in dichloromethanε (50 ml) and thereto iε added 80 % m-chloroperbεnzoic acid (3 g). Thε mixturε iε εtirrεd at room tεmpεrature overnight. The dichloromethanε layεr iε washεd succεsεively with εaturated aqueous sodium hydrogen carbonatε solution and saturated εaline εolution, and thε solvent is distilled off under reduced pressure. The resulting residue is purified by εilica gel column chromatography (eluent; dichloromethanε : methanol = 50 : 1) to give 4,5-epoxy-l-[4-(2-chlorobεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (4.26 g) aε white Tio er,

^X H-NMR(CDC1 ₃ ) δ ; 1.94-3.21 (3H, m) , 3.30-4.82 (3H,

m), 6.57 (IH, d, J=7.5 Hz), 6.86-8.10 (11H, m) , 8.72 (IH, brs)

Example 759

A mixture of 4,5-epoxy-l-[4-(2-chlorobenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.5 g), dimethylamine hydrochloridε (2.6 g), triethylamine (4.5 g) and methanol (15 ml) is refluxed for 19 hours. After completion of the rεaction, thε solvεnt iε distillεd off and the resulting residue is disεolved in dichloromεthanε. Thε mixturε is washed succesεively with water and saturated saline solution. The solvent is distilled off and the resulting residuε is purified by silica gel column chromatography (eluent; dichloromethanε : methanol = 50 : 1), and recrystallized from ethanol/diethyl ether to give trans-5-dimethylamino-4-hydroxy-l-[4-(2-chlorobenzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine (0.38 g) aε colorleεε neεdles, m.p. 180 - 182°C.

Using the suitable starting materials, the compounds of the above Examples 733 and 734 are obtained in the same manner aε in Example 759.

Example 760

Methyltriphenylphosphonium bromide (4.30 g) is suspended in tetrahydrofuran (100 ml) and thereto is added potasεium t-butoxide (1.58 g) under ice-cooling. The mixturε is stirred at -5°C for 1 hour and thereto is added 5-oxo-l-[4-(2-methylbenzoylamino)bεnzoyl]-2,3,4,5-

tetrahydro-lH-benzazepine (1.60 g) and the mixture is stirred at room temperaturε for 1 hour. Thε rεaction solution is pourεd into icε-watεr (200 ml) and εxtracted with ethyl acetate. The extract is washed with saturated saline solution and dried ovεr magnesium sulfate. The solvent iε distilled off and thε rεsulting rεsidue is purified by silica gεl column chromatography (εluεnt; ethyl acetate : n-hexane = 1 : 2), and recrystallized from ethyl acetate/n-hexanε to givε 5-methylidene-l-[4-(2-methyl- bεnzoylamino)benzoyl]-2,3,4,5-tetrahydrd-lH-bεnzazepine (1.34 g) as white powder, m.p. 216 - 217°C.

Using the suitablε starting matεrials, thε compound of thε abovε Examplε 743 is. obtainεd in thε samε manner as in Example 760.

Example 761

5-Methylidεne-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazεpinε (2.84 g) is εuspended in tetrahydrofuran (50 ml) and thereto iε added 1 M solution of boran-tetrahydrofuran complex in tetrahydrofuran (43 ml). The mixture is stirred at room tempεrature for 6 hours. After completion of the reaction, the reaction solution is cooled with ice, and therεto is addεd water (70 ml). After tεrmination of thε εvolution of hydrogen gas, to the rεaction solution are added 25 % aqueous sodium hydroxide solution (7,0 ml), and subεequently 31 % aquεouε hydrogen peroxidε solution (4.7 ml), and thε mixturε is heated with

stirring at 50°C for 1 hour. After cooling, to the reaction solution is added saturated saline solution and the tetrahydrofuran layer is collectεd, washεd with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residuε iε recryεtallized from εthyl acεtatε/n-hεxanε to givε 5- hydroxymεthyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazεpine (1.96 g) aε white powder, m.p. 202 - 206°C.

Uεing the suitable starting materials, thε compound of the above Example 745 is obtained in the same manner aε in Example 761.

Example 762

5-Methylidεnε-l-[ 2-chloro-4-(2-mεthylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine (0.81 g) is disεolvεd in dichloromεthanε (30 ml) and thεrεto is added m- chloroperbenzoic acid (0.57 g). Thε mixture iε stirred at room tempεraturε for 15 hours. After completion of the reaction, the reaction solution is washed successively with aqueous sodium hydrogensulfite solution, aqueous sodium hydrogen carbonate solution and εaturated εaline εolution, and dried over magneεium sulfatε. Thε solvεnt is distilled off and the rεsulting rεsiduε is purified with silica gel column chromatography (eluent; ethyl acetate : n-hexane = 2 : 3) to give 5,5-epoxy-l-[2-chloro-4-(2-methylbεnzoylamino)- benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine (0.70 g) as

colorless amorphous. H-NMR(CDC1 ₃ ) δ ; 1.44-1.95 (2H, m) , 1.95-2.28 (2H, m), 2.40-2.67 (3H, m) , 2.73-3.38 (3H, m) , 3.40-3.97 (IH, m) , 4.50-5.20 (IH, m) , 6.67-8.11 (11H, m)

Uεing the εuitable εtarting materialε, the compound of thε abovε Examplε 746 iε obtainεd in thε samε mannεr as in Examplε 762.

Examplε 763

To 5-methylidene-l-[4-(2-mεthylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε (0.60 g) arε added succeεεively t-butyl alcohol (6.0 ml), water (1.2 ml), pyridine (0.3 ml), oεmium tεtroxidε (1.2 mg) and trimεthyl- aminε N-oxidε dihydratε (0.22 g), and thε mixture iε refluxεd with εtirring for 2.5 hourε. After cooling, to the reaction solution is added 20 % aqueous sodium hydrogen- sulfitε solution (10 ml), and thε mixturε is stirrεd at room temperature for 1.5 hour. The reaction solution is εxtracted with a mixturε of εthyl acεtate/tetrahydrofuran (1:1). The extract is washed succesεivεly with diluted hydrochloric acid and εaturated εaline solution, and dried over magnεsium εulfatε. Thε εolvεnt iε diεtillεd off and the resulting residuε is rεcrystallizεd from εthyl acetate/ n-hexane to give 5-hydroxymethyl-5-hydroxy-l-[4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine (0.55 g) as white powder, m.p, 136 - 140°C.

Using the εuitable εtarting materials, the compound

of the above Example 749 iε obtained in the εame manner aε in Example 763.

Example 764

To 5-hydroxymethyl-l-[4-(2-methylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine (0.40 g) arε addεd acεtic anhydridε (4.0 ml) and pyridinε (0.5 ml), and the mixture iε εtirrεd at room tεmpεraturε for 5 hours. Aftεr complεtion of the reaction, the reaction solution is poured into ice-water and extractεd with εthyl acεtatε. Thε extract is washed successivεly with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and thε rεsulting rεsidue is recrystallizεd from ethyl acetate/n-hexane to give 5-acetyloxymethyl-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine (0.43 g) as colorless needles, m.p. 155 - 156°C.

Example 765

5-Hydroxymethyl-l-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε (0.70 g) is dissolved in a mixture (30 ml) of dichloromethane/ acetonitrile (1:1) and therεto arε addεd mεthanesulfonyl chloride (0.8 ml) and pyridine (1.0 ml), and the mixture is refluxed with stirring for 2 hourε. After cooling, thε rεaction εolution iε εvaporatεd undεr reduced preεεurε and to the resulting residue is added water and then extracted with ethyl acetate. The extract is washed succeεεivεly with

— —

diluted hydrochloric acid and εaturated εaline εolution, and dried over magneεium εulfate. The solvent is distilled off and the resulting residuε is rεcrystallized from ethyl acetate/n-hexane to give 5-methaneεulfonyloxymεthyl-l-[4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine (0.72 g) aε white powder, m.p. 189 - 190°C.

Example 766

5-Methanεsulfonyloxymεthyl-1-[4-(2-mεthylbεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (0.49 g) is disεolved in a mixture (25 ml) of acetonitrile/dimethyl- formamidε (4:1) and thεrεto is addεd sodium azidε (0.11 g). Thε mixture is refluxed with stirring for 3.5 hours. After cooling, the reaction solution is poured into ice- water (40 ml), extracted with ethyl acetate, washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gεl column chromatography (εluent; ethyl acetate : n-hexanε = 1 : 2), and recrystallized from ethyl acεtatε/n-hεxanε to give 5- azidomethyl-l-[4-(2-methylbenzoylamino)benzoly]-2,3,4,5- tetrahydro-lH-benzazepine (0.29 g) as white powder, m.p. 188 - 189°C.

Example 767

5-Azidomethyl-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3, ,5-tetrahydro-lH-benzazepine (0,27 g) is suspended in ethanol (50 ml) and the mixturε is subjεctεd to catalytic

~> hydrogenation at room temperaturε undεr 3 kg/cm" for 6 hours by using 10 % Pd-C (27 mg). The catalyst is removed by filtration with celite and the filtrate is distilled off and the resulting reεidue is recrystallizεd from εthanol to give

5-aminomethyl-l-[4-(2-m thylbεnzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazεpinε (0.12 g) as colorlεsε nεεdlεs, m.p. 233 - 235°C.

Example 768

To 5,5-epoxy-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazεpinε (0.30 g) is addεd 30 % solution of mεthylaminε in mεthanol (30 ml), and thε mixturε is rεfluxεd for 14 hours. Aftεr compeltion of the reaction, the reaction solution is evaporatεd under reduced pressurε and thε rεsulting residue is purified by silica gel column chromatography (eluent; ethyl acεtate : n-hexane = 1 : 1 - _* dichloromethane : methanol : aqueous ammonia = 60 : 10 : 1) to give 5-hydroxymethyl-5-methylamino-l-[4-(2-methylbenzoyl- amino]benzoyl]-2,3,4,5-tεtrahydro-lH-benzazepine (A; 35.3 mg) and 5-methylaminomethyl-5-hydroxy-l-[4-( 2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (B; 109 mg) . (A); Colorless amorphous H-NMR(CDC1 ₃ ) δ ; 1.50-2.10 (3H, m) , 2.10-2.28 (IH, m), 2.36 (3H, s), 2.48 (3H, s), 2.68-2.97 (IH, m) , 3.26-3.47 (IK, ), 4.16 (IH, d, J=13,8 Hz), 4,25 (IH, d, J=13.8 Hz), 5.95 (IH, brs), 6.60-6.76 (IH, m) , 6.97-7.52 (8H, m) , 7.52-

7.73 (2H, m), 7.73-7.97 (2H, m)

(B); White powder (recrystallizεd from εthyl acεtate/ n-hexane) m.p. 176 - 179°C

Example 769

5-Mεthylamino-l-[4-(2-mεthylbεnzoylamino)bεnzoyl]- 2,3,4,5-tεtrahydro-lH-bεnzazepine (1 g) is disεolvεd in dimεthylformamidε (10 ml) and thεrεto arε added potaεεium carbonate (0.5 g) and ethyl iodide (0.45 g). The mixturε is stirrεd at room tεmpεrature overnight. After completion of the reaction, the reaction solution is poured into ice-water and the precipitated crystal is collected by filtration, and purified by silica gel column chromatography (eluent; dichloromethane : methanol = 90 : 1), and recrystallized from diisopropyl alcohol/petrolεum ether to give 5-(N- mεthyl-N-εthylamino)-1-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine (50 mg) as whitε powder, m. p. 192 - 193°C.

Using the suitable starting materials, the compounds of the above Examples 244, 246 - 248, 330, 339, 342, 346, 350, 366, 375, 376, 406 - 418, 453, 455, 457, 460, 464, 467, 506, 507, 537 - 545, 547, 549 - 556, 561 - 566, 568 - 571, 577, 601 - 603, 607 - 625, 654 - 672, 675, 677 - 681, 691 - 695, 697, 698, 701 - 705, 707, 708, 712, 713, 715, 716, 719, 720 and 722 - 725 are obtained in the same manner as in Example 769.

Example 770

To a suεpenεion of 5-methylamino-l-[4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (3 g) in methanol (30 ml) are added potassium carbonate (1.5 g) and epichlorohydrine (5.7 ml), and the mixture is refluxed for 3 hours. The solvent is distilled off and to thε rεsulting rεsiduε is added water and extracted three times with dichloromethane. The extract is washed with saturatεd salinε solution and driεd over magnesium sulfatε. Thε rεsulting residue iε purified by εilica gel column chromatography (eluεnt; dichloromεthanε : mεthanol = 80 : 1) to givε 5-(N-mεthyl-N-oxiranylmεthylamino)-l-[4-( 2-mεthyl- bεnzoylamino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (C; 1.92 g) and 5-[N-mεthyl-N-(2-hydroxy-3-mεthoxypropyl)amino]- 1-[4-(2-mεthylbεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine (D; 0.38 g).

(C); Colorless neεdles (rεcrystallization from εthyl acεtatε) m.p. 239 - 240°C (D); Colorlεsε amorphouε H-NMR(CDC1 ₃ ) δ ; 1.35-4.55 (22H, m) , 6.3-7.8 (13H, m)

Example 771

5-[N-Methy1-N-oxiranylmethylamino)-l-[4-(2-methyl¬ benzoylamino)benzoyl1-2,3,4,5-tetrahydro-lH-benzazepine (0.5 g) iε diεsolved in methanol (10 ml) and therεto is added

diethylaminε (0.13 ml). Thε mixturε is refluxed for 3 hours. After completion of the reaction, the solvent is distilled off and the rεsulting residue is purified by silica gεl column chromatography (εluent; dichloromethane : methanol = 30 : 1 - dichloromethane : methanol : aqueous ammonia = 9 : 1 : 0.1 ) to give 5-[N-methyl-N-(2-hydroxy-3- diεthylaminopropy1)amino]-1-[4-(2-mεthylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε (0.38 g) as colorlesε amorphous.

^X H-NMR(CDC1 ₃ ) δ ; 1.10 (6H, t, J=7 Hz), 1.35-5.1 (23H, m), 6.55-7.8 (13H, m)

Example 772

A solution of 5-hydroxyimino-l-[4-(2-chlorobenzoyl- amino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpine (1.06 g) in acetic anhydride (10 ml) and pyridine (10 ml) is stirred at room temperaturε ovεrnight. Aftεr completion of the reaction, the reaction solution is concentratεd. To the resulting residue is added water and the mixture is extracted with dichloromethanε. The extract is washed with saturated εaline εolution and dried over magneεium εulfatε. The εolvent is distilled off and the resulting residue iε purified by silica gel column chromatography (eluent; dichloromethane : methanol = 80 : 1), and recrystallized from ethanol/pεtrolεum εther to give 5- acεtyloxyimino-1-[4-{2-chlorobenzoylamino)benzoyl]-2,3.4,5- tetrahydro-lH-benzazepinε (0.75 g) as colorless prisms, m.p.

142 - 144°C.

Example 773

Using the suitable starting materials, thε compounds of the above Examples 671 and 672 are obtained in the same manner as in Example 380.

Example 774

Using the suitable starting materials, the compounds of the above Examples 674, 699, 700, 706, 718 and 730 are obtained in the same manner as in Example 384.

Example 775

Using the suitable starting materials, the compounds of the above Examples 654 - 672, 675, 677 - 687, 691 - 695, 697, 698, 701 - 705, 707, 708, 712, 713, 715, 716 and 719 - 725 are obtained in thε samε mannεr as in Example 390.

Example 776

Using the suitable starting materials, the compoundε of the above Exa pleε 654 - 672, 675, 677 - 679, 691 - 693, 698, 701 - 705, 707, 708, 712, 713, 715, 716 and 719 - 725 arε obtainεd in thε same manner as in Example 388.

Example 777

Using the εuitable εtarting materials, the compounds of the abovε Examplεs 705, 706 and 708 arε obtained in the same manner as in Example 394.

Example 778

Using the suitable starting materials, thε compound

of thε above Example 671 is obtained in the same manner as in Example 397.

Example 779

Using the suitable starting materials, the compound of the abovε Example 672 is obtained in the same manner as in Examplε 402.

Example 780

Using the suitable starting materials, the compound of the above Example 726 is obtained in the same manner as in Examplε 634.

Examplε 781

Using the suitable starting materials, thε compound of thε abovε Examplε 740 is. obtainεd in thε same manner as in Exampleε 638 and 640.

Example 782

Uεing the suitable starting materials, the compound of the above Examplε 689 is obtainεd in the same manner as in Example 643.

Example 783

Using the suitablε εtarting matεrialε, thε compound of thε abovε Examplε 690 iε obtainεd in thε εamε mannεr aε in Examplε 644.

Example 784

Uεing the suitablε starting materialε, the following compound iε obtainεd in thε εamε manner aε in Exampleε 1, 382, 388 and 390.

5-Dimethylamino-l-[4-( 2-methylbenzoylamino)- benzoyl]-2,3,4, 5-tetrahydro-lH-benzazεpinε hydrochloridε, colorlεss needleε (recrystallizεd from εthanol/watεr), m.p. 233 - 237°C

Rεfεrence Examplε 13

Using thε suitablε starting matεrials, thε following compounds arε obtained in thε same manner as in Reference Example 1.

5-( 2-Chloroacetyloxy)-1-(4-nitrobenzoyl)-2,3,4,5- tetrahydro-lH-bεnzazεpinε, white powder, m.p. 156 - 159°C (recrystallized from ethyl acetate/n-hexane)

5-(2-Dimethylaminoacetyloxy)-1-(4-nitrobenzoyl)- 2,3 ,4,5-tetrahydro-lH-benzazεpinε, whitε powdεr, m.p. 108 - 109°C ( rεcrystallized from ethyl acetate/n-hexane)

5-Oxo-7-chloro-l-( 4-nitrobenzoyl)- ,3,4,5-tetra- hydro-lH-bεnzazεpinε, whitε powder, m.p. 157.5 - 159.5°C (recrystallized from diethyl ether/dichloromεthane)

5-Oxo-8-chloro-l-(4-nitrobenzoyl)-2,3,4,5-tεtra- hydro-lH-benzazepine, white powder, m.p. 151.5 - 153.5°C (recrystallizεd from diethyl ethεr/dichloromεthanε)

Reference Example 14

Using the suitable starting materials, the following compounds are obtained in the same manner as in Reference Example 2.

5-(2-Dimethylaminoacetyloxy)-1-(4-aminobenzovl)- 2,3,4 , 5-tεtrahydro-lH-benzazepine, colorless amorphous

^X H-NMR (CDCI3) δ ; 1.63-1.98 (2H, m) , 1.98-2.25 (IH, m), 2.27 (3H, s), 2.43 (3H, ε), 2.65-3.23 (2H, m) , 3.38 (2H, s), 3.67 (2H, brs), 4.77-5.28 (IH, m) , 6.04-6.31 (IH, m), 6.31-6.56 (2H, m) , 6.58-6.86 (IH, m) , 6.86-7.46 (5H, m)

5-Oxo-7-chloro-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-bεnzazepine, whitε powdεr, m.p. 193 - 193.5°C (rεcrystallizεd from diethyl ethεr/dichloromεthane)

5-Oxo-8-chloro-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepinε, white powder, m.p. 171 - 174°C (rεcrystallizεd from diεthyl ethεr/dichloromεthane)

Rεfεrεncε Examplε 15

Using thε suitablε starting matεrials, thε following compounds are obtained in the εame manner as in Referεncε Examplε 1.

5-Dimεthylaminocarbonylmethoxy-1-(4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazεpinε, whitε powder, m.p. 129 - 131°C (recrystallized from ethyl acetate/n-hexanε)

6-Oxo-l-(4-nitrobεnzoyl)-1,2,3,4,5,6-hexahydro- bεnzazocinε, yεllow nεεdles

^X H-NMR (CDCI3) δ ; 1.65-2.3 (4H, m) , 2.5-5.2 (4H, m), 6.7-6.9 (IH, m) , 7.27-7.5 (4H, m) , 7.90-8.15 (3H, m)

6-Chlor0-5-oxo-l-(4-nitrobεnzoyl)-2,3,4,5- tεtrahydro-lH-bεnzazεpinε, white powder, m.p. 198 - 202°C

(recrystallizεd from dichloromεthanε/diεthyl εther) Referencε Exampla 16

Using thε suitablε εtarting matεrialε, thε

following compounds are obtained in the same manner as in Reference Example 2.

5-Dimethylaminocarbonylmεthoxy-l-(4-aminobεnzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, colorless amorphous H-NMR (CDCI3) δ ; 1.52-2.10 (3H, m) , 2.10-3.20 (2H, m) , 2.97 (3H, s), 3.05 (3H, ε), 4.03-4.48 (2H, m) , 4.50-5.35 (2H, m) , 6.26-6.57 (2H, m) , 6.57-6.88 (IH, m) , 6.88-7.76 (5H, m)

6-Oxo-l-( 4-aminobenzoyl)-1, 2,3,4, 5,6-hexahydro- benzazocine, light yellow amorphouε H-NMR (CDCI3) δ ; 1.7-2.2 (4H, m) , 2.5-5.2 (6H, m), 6.42 (2H, d, J=8.7 Hz), 6.75-6.9 (IH, m) , 7.05-7.4 (4H, m) , 7.95-8.1 (IH, m)

6-Chlor0-5-oxo-l-(4-aminobenzoyl)-2,3,4,5-tεtra- hydro-lH-benzazepine, white powder, m.p. 166 - 169°C ( recryεtallized from dichloromethanε/diethyl ether)

9-Chloro-5-oxo-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, yellow powder, m.p. 192.5 - 195°C (recryεtallized from dichloromethanε/diethyl ether)

Referεnce Example 17

5-Dimethylamino-l-(2-methyl-4-nitrobεnzoyl)- 2,3,4,5-tetrahydro-lH-bεnzazepine (86.0 g) iε dissolved in ethanol (800 ml), and therεto is addεd platinum oxide (10 g). The mixture is subjectεd to hydrogεnation at ordinary tempεraturε under atmosphεric prεssure of hydrogen for 4 hours. The catalyst is removed by filtration, and the

solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluεnt; dichloromethane : methanol = 200 : 1 - 100 : 1), and further purified by silica gel thin layer chromatography (dεveloper; chloroform : methanol = 10 : 1), and recrystallized from methanol/ diethyl ether to give 5-dimethylamino-l-(2-methyl-4-amino- benzoyl)-2,3,4,5-tetrahydro-lH-bεnzazεpinε (G) (Rf: 0.52, 27.4 g) and 5-dimethylamino-l-(2-methyl-4-amino-b*_-nzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine (H) (Rf: 0.48, 12.3 g). (G) : White powder

M.p. 154 - 156°C

[α] ²² = 0° (c=1.0, chloroform)

^X H-NMR (CDC1 ₃ ) δ ; 1.10-1.50 (IH, m) , 1.50-2.00 (IH, m), 2.00-2.35 (11H, m) , 2.90-5.18 (5H, m) , 6.00-6.76 (3H, m) , 6.81-7.64 (4H, m) (H) : White powder

M.p. 169.5 - 170°C

[α] ²² = 0° (c=1.5, chloroform)

^X H-NMR (CDC1 ₃ ) δ ; 1.11 - 2.90 (13H, m) , 2.91-5.23 (5H, m), 6.15-6.53 (IH, m) , 6.57-7.62 (6H, m)

Using the suitable starting materials, the compounds of the following Table 5 are obtained in thε same manner as in above Examples 1 and 382.

Table 5

Example 785 Struct

Crystalline form: Colorless needles Recrystallization solvent: Ethanol Melting Point: 174 - 175°C Form: Free

Example 786 Struct

Crystalline form: Colorlesε priεms

Recrystallization solvent: Ethanol/diethyl ether

Melting Point: 176 - 178°C

Form: Free

Exampl

Struct

0 Cl

R°: 4-NHC ^■ O

Crystalline form: Colorlesε priεmε

Recrystallization solvent: Ethyl acetatε/pεtrolεum ether

Melting Point: 154.5 - 155°C

Form: Free

Example 788

Structure

Crystalline form: Colorless amorphous NMR analysis: 138) Form: Frεe

Example 789 Structu

Cryεtalline form: Colorleεs scales Recrystallization solvent: Ethanol Melting Point: 197 - 198°C Form: Freε

Examplε 790 Structu

Crystalline form: Colorless needles Recrystallization solvent: Ethanol Mεlting Point: 248 - 249°C Form: Frεε

Examplε 791 Struct

Crystallinε form: Colorlεss nεεdlεs Rεcrystallization solvεnt: Ethanol/n-hεxanε Mεlting Point: 162 - 163°C Form: Frεε

Examplε 792 Structure NHCHO

Crystalline form: Colorless prisms

Recrystallization solvent: Ethanol/petrolεum εther Melting Point: 235 - 236.5°C Form: Free

Exampl Struct

0 Cl

R- 4-NHC ^■ O

Crystalline form: Colorless amorphous NMR analysiε: 139) Form: Free

Example 794

0

Structu

Crystalline form: Colorlesε prisms Recrystallization solvent: Dioxanε Melting Point: 269 - 271°C Form: Free

Example 795 Struct

Crystalline form: Colorleεε priεmε Recryεtallization solvent: Dimethylformamidε Mεlting Point: 286 - 287°C . Form: Frεε

Example 796 Structu

Cryεtalline form: Colorless needles Recrystallization solvent: Acetonitrile Melting Point: 227 - 228°C Form: Free

Example 797

OH

Struct

Crystalline form: Colorless amorphous NMR analyεiε: 140) Form: Free

Examplε 798 Struct

Crystallinε form: Colorlεsε priεmε

Recryεtallization εolvent: Ethyl acetatε/pεtrolεum ether

Melting Point: 167 - 168°C

Form: Free

Examplε 799 Struct

Cryεtalline form: Colorleεε amorphouε NMR analyεiε: 141)

Example 800 Struct

Crystalline form: Colorless neεdles Recrystallization solvent: Diethyl ether Melting Point: 164 - 171°C Form: K^

Example Structu

Crystallinε form: Colorlεεε amorphouε NMR analyεiε: 142) Form: Free

Example 802 Struct

Crystalline form: Colorless amorphous NMR analysis: 143) Form: Free

Example 803 Struct

Crystallinε form: Colorless amorphous NMR analysis: 144) Form: Freε

Example 804

_/ CH ₃ Structure NHCH

Crystalline form: Colorless amorphous NMR analysis: 145) Form: Freε

Examplε 805 Struct

Crystallinε form: Colorlesε neεdleε Recrystallization solvent: Ethanol Melting Point: 207 - 208°C Form: Freε

Example 806 Structure <

Crystalline form: White powder

Recryεtallization εolvεnt: Dichloromεthanε/diεthyl ether

Melting Point: 187 - 189°C

Form: Freε

Examplε 807 Struct

Crystalline form: Colorlesε priεms Recrystallization solvent: Ethanol/petrolεum ether Melting Point: 217 - 218°C Form: Free

Example 808 St ructure NHCH ₂ CH ₂ CH ₃

Crystalline form: Colorlesε neεdleε Recryεtallization εolvent: Ethyl acεtate Melting Point: 170 - 171°C Form: Freε

Examplε 809 Structurε N~OH

Crystalline form: Colorlesε priεms Recrystallization solvent: Ethanol Melting Point: 239.5 - 241°C Form: Free

Examplε 810 Struct

Crystalline form: Colorless needles Recrystallization εolvent: Ethanol Mεlting Point: 190 - 191°C Form: Frεε

Examplε 811 Struct

0 CH ₃

4-NHC ^■ O

Cryεtallinε form: Colorlεεε priεmε Recryεtallization εolvent: Diεthyl εther Melting Point: 163 - 163.5°C Form: Freε

Example 812

Struct

Crystalline form: Colorlesε prisms Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 208 - 210°C Form: Freε

Examplε 813 Struct

Crystalline form: White powder NMR analysis: 146) Form: Freε

Examplε 814 Struct

Crystalline form: Colorlesε amorphouε NMR analysis: 147) Form: Free

Example 815 Struct

Crystalline form: Colorlεsε nεεdlεs Rεcrystallization solvεnt: Ethanol/n-hεxanε Mεlting Point: 250 - 252°C Form: Frεe

Example 816 Structu

Crystalline form: Colorleεs priεms Rεcrystallization solvεnt: Ethyl acetate Melting Point: 214 - 216°C Form: Free

Example 817 Struct

Crystalline form: Colorless prisms Recryεtallization εolvεnt: Ethanol/n-hexane Melting Point: 243 - 245°C Form: Freε

Examplε 818 Structu

Crystalline form: Colorlεss prismε Rεcryεtallization εolvent: Diethyl εthεr Melting Point: 159 - 162°C Form: Free

Examplε 819 Struct

Crystallinε form: Colorlεss amorphous NMR analyεiε: 148) Form: Frεe

Example 820 Struct

Cryεtalline form: Colorleεε priεmε Recryεtallization solvεnt: Ethyl acetate Melting Point: 287 - 289°C Form: Freε

Exampl Struct

Crystalline form: Colorlεss prisms Rεcrystallization solvent: Diethyl ether Melting Point: 170 - 171°C Form: Free

Example 822 Struct

Cryεtalline form: White powder

Recryεtallization εolvent: Ethyl acetatε/n-hexane Melting Point: 204 - 205°C Form: Freε

Examplε 823

Cryεtalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxane Melting Point: 273 - 273.5°C Form: Freε

Example 824 Struct

Crystalline form: Colorless amorphous NMR analysiε: 149) Form: Frεε

Examplε 825 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acatete/n-hεxanε Mεlting Point: 240 - 241°C Form: Frεε

Example 826 Structu

Crystalline form: White powder

Recrystallization εolvent: Acetonitrilε/εthanol Melting Point: 231 - 232°C Form: Freε

Examplε 827 Struct

0 Cl

4-NHC ^■ O

Crystallinε form: White powder

Recrystallization solvent: Acetonitrile/εthanol Melting Point: 222 - 224°C Form: Free

Example 828 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε Melting Point: 235 - 237°C Form: Freε

Example 829 Struct

Crystalline form: Colorless amorphous NMR analysiε: 150) Form: Freε

Example 830 Struct

Crystalline form: Colorless amorphous NMR analysis: 151) Form: Frεε

Examplε 831 Struct

Crystallinε form: Colorlεss amorphous NMR analyεiε: 152) Form: Frεε

Example 832 Struct

Crystalline form: Colorless amorphous NMR analyεis: 153) Form: Free

Example 834 Structu

Crystalline form: White powdεr

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 247 - 248°C Form: Freε

Example 835

Struct

Crystalline form: Colorless amorphous NMR analysiε: 154) Form: Free

Example 836 Struct

Crystalline form: Colorless amorphous NMR analysiε: 155) Form: Free

Example 837 Struct

Crystalline form: Colorless amorphous NMR analysis: 156) Form: Free

Example 838 Structu

Crystalline form: Colorleεε amorphous NMR analysiε: 157) Form: Free

Examplε 839 Struct

Crystalline form: White powdεr

Recrystallization solvent: Ethyl acetatε/n-hexane

Mεlting Point: 234 - 235°C

Form: Free

Examplε 840

Struct

Crystallinε form: Whitε powdεr

Rεcrystallization solvent: Ethyl acetatε/n-hεxanε Mεlting Point: 234 - 235°C Form: Frεε

Example 841 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε

Mεlting Point: 226 - 228°C

Form: Frεε

Examplε 842

Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hεxane Melting Point: 230 - 231°C Form: Freε

Examplε 843 Ξtructurε

Crystallinε form: White powder

Recrystallization solvent: Ethyl acεtatε/n-hεxanε

Mεlting Point: 186 - 188°C

Form: Free

Example 844

Struct

Crystalline form: Colorlesε priεmε Rεcryεtallization εolvεnt: Chloroform/methanol Melting Point: 286 - 290°C Form: Free

Examplε 845

^CH 3 ^CH 3 Structurε

Crystalline form: Colorlesε neεdlεε Rεcryεtallization εolvεnt: Ethanol Melting Point: 186 - 188.5°C Form: Freε

Example 846 Struct

0 CH-

Rθ 4-NHC ^■

Crystalline form: Colorless prisms Recrystallization solvent: Ethanol Melting Point: 220 - 222°C Form: Freε

Example 847 Struct

Crystalline form: White powder NMR analysis: 158) Form: Free

Example 848 Struct

R ³ : 4-NHCOCH ₂ CONH ₂ Crystallinε form: Colorlεεε prisms

Recrystallization solvent: Dichloromethane/diethyl ethεr Melting Point: 189 - 192°C Form: Free

Example 849 Structu

Crystalline form: Colorless amorphous NMR analysis: 159) Form: Free

Example 850 Struct

0 Cl

4-NHC -D

Crystalline form: White powder

Recrystallization solvent: Dichloromethanε/diεthyl ether

Melting Point: 207 - 209°C (decomposed)

Form: Free

Examplε 851 Struct

Cryεtalline form: Whitε powdεr NMR analyεis: 160) Form: K®

Exampl Struct

Crystallinε form: Whitε powdεr

Recrystallization solvent: Dichloromεthanε/diεthyl ether

Melting Point: 193 - 194°C

Form: Free

Example 853 Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 185.5 - 186°C

Form: Freε

Example 854

Struct

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromεthanε

Mεlting Point: 223.5 - 226°C (dεcomposεd)

Form: Frεe

Example 855 Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 161) Form: Free

Example 856

0

Crystalline form: White powder

Recrystallization solvent: Diethyl ethεr/dichloromεthanε Mεlting Point: 225.5 - 227°C Form: Free

Crystalline form: White powder

Recrystallization solvent: Diethyl ethεr/dichloromethane

Mεlting Point: 212 - 214°C

Form: Free

Exampl Struct

Crystallinε form: White powder

Recrystallization solvent: Diethyl ethεr/dichloromεthanε

Mεlting Point: 230.5 - 233°C

Form: Frεε

Example 859 Struct

Crystalline form: White powdεr

Rεcryεtallization εolvεnt: Diεthyl ether/dichloromethane Mεlting Point: 212.5 - 215°C (dεcompoεed) Form: Free

Example 860 Struct

Crystallinε form: Whitε powdεr

Rεcrystallization solvεnt: Diεthyl εthεr/dichloromεthanε

Mεlting Point: 192 - 194.5°C

Form: Frεε

Example 861 Structure

Crystalline form: White powder

Recrystallization solvεnt: Diεthyl εthεr/dichloromεthane Melting Point: 175 - 177°C Form: Freε Examplε 862 Structure 0

Crystalline form: White powder

Recrystallization solvent: Diethyl εthεr/dichloromethane

Melting Point: 208.5 - 209.5°C

Form: Freε

Examplε 863 Struct

Crystalline form: White powder

Recryεtallization solvent: Diethyl ethεr/dichloromεthanε

Mεlting Point: 191 - 193.5°C

Form: Free

0 Cl

4-NHC ^■ O

Crystalline form: Whitε powdεr

Recrystallization solvent: Diethyl ethεr/dichloromεthanε

Mεlting Point: 204 - 205.5°C

Form: Free

Example 865

Structu

O

R- 4-NHC / \

Crystalline form: Light yellow prisms Recryεtallization εolvent: Ethanol Melting Point: 221 - 223°C Form: Free

Example 866

Struct

Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acetatε Melting Point: 171 - 173°C Form: Free

- -

Examplε 867

Struct

0

Crystallinε form: Colorlεsε priεmε Rεcrystallization solvent: Ethyl acetatε Melting Point: 185 - 187°C Form: Free

Example 868

Struct

Crystalline form: Colorlεsε priεms Rεcrystallization εolvεnt: Ethanol Melting Point: 190 - 192°C Form: Free

Example 869

Structu

Cryεtalline form: Colorleεε priεmε Rεcryεtallization solvent: Ethanol Melting Point: 175- 177°C Form: Freε

Examplε 870

Struct

Crystallinε form: Colorlεss powdεr Recrystallization solvent: Ethyl acetatε/n-hεxanε Mεlting Point: 148 - 151°C Form: Frεε

Examplε 871

Struct

Crystallinε form: Colorlεsε priεmε Recryεtallization εolvent: Ethanol Mεlting Point: 200 - 202°C Form: Free

Example 872

Struct

0

Cryεtalline form: Colorlεεs prismε Recryεtallization εolvent: Ethanol Melting Point: 200 - 202°C Form: Free

Examplε 873

Struct

Crystalline form: Light yellow powder Recrystallization solvent: Acetone Melting Point: 235 - 238°C Form: Free

Example 874

Struct

Crystalline form: Light yεllow powdεr Recrystallization solvent: Acεtonε Melting Point: 198 - 201°C Form: Free

Example 875

Structu

Crystalline form: Light yellow neεdles Rεcrystallization solvεnt: Chloroform/ethyl acetate Melting Point: 232 - 237°C Form: Free

Example 876

Struct

0 NH-

4-NHC ^■ O

Crystalline form: Colorlεss prismε

Rεcryεtallization εolvεnt: Chloroform/εthyl acεtate Mεlting Point: 224 - 227°C Form: Frεe

Example 877

Struct

Crystalline form: Colorless prisms Recrystallization εolvent: Ethanol Melting Point: 211 - 214°C Form: Freε

Example 878

Struct

0

Crystalline form: Colorlesε powder

Recrystallization solvent: Dichloromεthanε/n-hεxanε Mεlting Point: 238 - 243°C Form: Free

Example 879

Struct

Crystalline form : Colorless amorphous NMR analysiε : 162 ) Form: Freε

Examplε 880

Struct

Cryεtallinε form: Colorlεss amorphous NMR analysiε: 163) Form: Frεε

Examplε 881

Struct

R 3 ³ : 4-NHC"- iTX)-N ^/CH 3

Λ=/ _C H ₃

Crystalline form: Colorlesε priεms

Recrystallization solvent: Dichloromethane/diethyl ethεr

Mεlting Point: 198 - 202°C

Form: Frεε

Examplε 882

Struct

Crystallinε form: Colorlesε priεms

Recrystallization solvent: Chloroform/ethyl acεtatε Melting Point: 226 - 229°C Form: Free

Example 883 Struct

Cryεtallinε form: White powder

Recryεtallization εolvent: Methanol/diεthyl εthεr

Melting Point: 139 - 140°C

Form: Free

Example 884

Structure

Cryεtalline form: Whitε powdεr

Recrystallization solvent: Methanol/diethyl ether Melting Point: 149 - 152°C Form: Freε

Example 885 Struct

0

Cryεtalline form: White powder

Recryεtallization εolvent: Mεthanol/diεthyl εther Mεlting Point: 180.5 - 182°C Form: Frεε Examplε 886 Struct

0

Crystalline form: White powder

Rεcrystallization εolvεnt: Chloroform/diεthyl εther Mεlting Point: 211 - 214°C Form: Free

Examplε 887 Struct

0

Crystalline form: White powder

Recrystallization solvent: Chloroform/diεthyl εthεr

Mεlting Point: 171 - 174.5°C

Form: Free

Example 888

Struct

Crystalline form: White powdεr

Rεcrystallization solvεnt: Mεthanol/diεthyl εthεr Melting Point: 203 - 205°C Form: Free

Examplε 889

Struct

Crystallinε form: Whitε powdεr Recrystallization solvent: Ethanol Melting Point: 202 - 202.5 Form: Free

Example 890

Structu

0 CH-

R 3~ : 4-NHC "- ⁷⁷ ^

Crystalline form: White powder

Recrystallization solvent: Mεthanol/diεthyl εthεr Mεlting Point: 130 - 133°C Form: Free

Example 891

Struct

Crystalline form: White powder Recrystallization solvent: Methanol/n-hεxanε Mεlting Point: 104.5 - 106°C Form: Free

Example 892

Struct

Crystalline form: White powder

Recrystallization εolvent: Methanol/diεthyl εthεr Mεlting Point: 197 - 198°C Form: Free

Example 893

Struct

0

Crystalline form: White powder

Recrystallization solvent: Dichloromethanε/ethyl acεtatε Mεlting Point: 191 - 192°C Form: Free

Example 894 Structure NHCHO

Crystalline form: Colorless columnar Recrystallization εolvent: Ethanol/petrolεum εthεr Melting Point: 211 - 213°C

Pnrm • Priap

Example 895 Structu

0

Crystalline form: Colorless amorphous NMR analysiε: 164) Form: Free

Examplε 896

Struct

0

₃ ii

R ³ : 4-NHCCH ₂ C0 ₂ C ₂ H ₅ Crystallinε form: Colorlεss amorphous NMR analysiε: 165) Form: Frεe

Example 897

Struct

Crystalline form: Colorless amorphous NMR analysiε: 166) Form: Free

Example 898

Struct

0

Crystalline form: Colorless prisms Rεcrystallization solvεnt: Ethanol Mεlting Point: 224 - 228°C Form: Frεε

138) H-NMR (CDC1 ₃ ) δ ; 1.3-2.95 (19H, ) , 3.05-3.3 (IH, m) , 3.85-4.1 (2H, m) , 4.3-4.6 (IH, m) , 6.64 (IH, d, J=7.8 Hz), 6.9-7.8 (12H, m)

139) ^X H-NMR (CDCI3) δ ; 1.1-2.3 (13H, m) , 2.65-3.2 (IH, m), 4.55-5.6 (3H, m) , 6.55-6.7 (IH, m) , 6.9-7.6 (12H, m)

140) ^X H-NMR (CDCI3) δ ; 1.3-4.15 (19H, m) , 4.3-5.0 (IH, m), 6.65 (IH, d, J=7.7 Hz), 6.9-8.05 (12H, m)

141) ^X H-NMR (CDCI3) δ ; 1.4-3.0 (9H, m) , 3.05-3.6 (3H, ra), 3.9-4.1 (IH, m) , 4.35-4.55 (IH, m) , 4.9-5.65 (IH, m), 6.67 (IH, d, J=7.4 Hz), 6.85-7.6 (12H, m) , 7.6-7.85 (2H, m)

142) H-NMR (CDCI3) δ ; 1.3-2.85 (21H, m) , 3.2-4.0 (4H, m), 4.3-4.4 (IH, m) , 4.45-5.2 (2H, m) , 6.61 (IH, d, J=7.6 Hz), 6.9-7.65 (12H, m)

143) H-NMR (CDCI3) δ ; 1.3-3.45 (17H, m) , 3.8-5.7 (5H, m), 6.5-7.65 (13H, m)

144) H-NMR (CDCI3) δ ; 1.25-3.1 (14H, m) , 3.3-4.0 (4H, m), 4.15-4.4 (IH, m) , 4.45-5.2 (IH, m) , 6.64 (IH, d, J=7.4 Hz), 6.9-7.7 (12H, m)

145) H-NMR (CDCI3) δ ; 0.9-3.25 (16H, m) , 3.9-5.9 (2H, m), 6.65 (IH, d, J=7.4 Hz), 6.85-7.5 (11H, m) , 7.9- 8.3 (IH, m)

146) ^X H-NMR (DMSO-dg) δ ; 1.3-2.15 (4H, m) , 2.32 (3H,

___. \ -1 o_o nc / ^* ιtι m \ A ^• -) A i TCI np__-r T— I *O O _I C A

Hz), 4.35-4.55 (IH, m) , 4.9-5.25 (IH, m) , 6.68 (IH,

d, J=7.6 Hz), 6.9-7.45 (9H, m) , 7.52 (2H, d, J=8.6 Hz), 8.9-9.05 (IH, m) , 10.31 (IH, s)

147) H-NMR (CDC1 ₃ ) δ ; 1.5-2.35 (4H, m) , 2.45 (3H, s), 2.6-2.85 (IH, m), 3.32 (3H, s), 4.19 (2H, AB-q, J=12.2 Hz, 15.6 Hz), 5.0-5.2 (IH, m) , 5.82 (IH, d, J=10.3 Hz), 6.69 (IH, d, J=7.8 Hz), 6.75-7.95 (12H, m)

148) H-NMR (CDC1 ₃ ) δ ; 1.2-3.3 (17H, m) , 3.45 (2H, AB- q, J=14.7, 22.9 Hz), 3.9-4.35 (2H, m) , 6.60 (2H, d, J=7.7 Hz), 6.8-8.0 (11H, m) , 8.39 (IH, s)

149) H-NMR (CDC1 ₃ ) δ ; 1.45-3.40 (8H, m) , 2.23 (3H, ε), 2.33 (3H, ε), 2.46 (3H, ε), 4.44-5.23 (IH, m) , 6.54-6.78 (IH, m) , 6.84-7.94 (12H, m)

150) H-NMR (CDC1 ₃ ) δ ; 1.50-1.92 (3H, m) , 1.92-2.05 (IH, m), 2.47 (3H, ε), 2.55-3.06 (5H, m) , 3.43-5.76 (8H, m), 6.63-6.82 (IH, m) , 6.97-8.08 (12H, m)

151) H-NMR (CDC1 ₃ ) δ ; 1.43-2.65 (4H, m) , 2.48 (3H, ε), 2.69-3.25 (5H, m) , 3.90-5.40 (8H, m) , 6.64-6.94 (IH, m), 6.94-7.77 (12H, m)

152) H-NMR (CDC1 ₃ ) δ ; 1.50-1.90 (3H, m) , 1.90-2.20 (IH, m), 2.20-2.64 (4H, m) , 2.32 (3H, ε), 2.47 (3H, ε), 2.64-3.27 (IH, m) , 3.36-3.83 (4H, m) , 3.93-4.52 (2H, m), 4.52-5.27 (2H, m) , 6.57-6.82 (IH, m) , 6.93-7.87 (12H, m)

153) H-NMR (CDCI3) δ ; 1.52-1.93 (2H, m) , 1.93-2.23 (4H, m), 2.23-2.57 (IH, m) , 2.45 (3H, ε), 2.72-3.02 (IH, m), 3.02-3.77 (8H, m) , 3.93-4.50 (2H, m) ,

4.50-5.20 (2H, m), 6.60-6.80 (IH, m) , 6.94-7.64 (11H, m), 8.16 (IH, brs)

154) H-NMR (CDC1 ₃ ) δ ; 1.48-2.60 (8H, m) , 2.46 (3H, s), 2.65-3.01 (IH, m), 3.20-3.74 (2H, m) , 3.80-5.14 (4H, m), 5.30-5.84 (IH, m), 6.51-8.14 (13H, m)

155) ^X H-NMR (CDC1 ₃ ) δ ; 1.54-1.91 (2H, m) , 1.91-2.20 (IH, m), 2.22-2.64 (IH, m) , 2.44 (3H, s), 2.70-3.13 (IH, m) , 3.60-4.40 (4H, m) , 4.50-5.20 (2H, m) , 6.07-8.00 (13H, m) , 9.93 (IH, s)

156) ^X H-NMR (CDC1 ₃ ) δ; 1.56-1.92 (2H, m) , 1.92-2.19 (IH, m), 2.19-2.60 (IH, m) , 2.46 (3H, s), 2.66-3.26 (4H, m), 3.33-3.95 (4H, m) . 4.00-5.20 (4H, m) , 6.58-6.82 (IH, m) , 6.93-8.21 (12H, m)

157) H-NMR (CDC1 ₃ ) δ ; 1.57-2.17 (3H, m) , 2.21-2.68 (IH, m), 2.47 (3H, ε), 2.73-3.04 (IH, m) , 3.91-4.42 (4H, m), 4.50-5.17 (2H, m) , 6.61-6.99 (2H, m) , 6.99-8.10 (14H, m) , 8.21-8.71 (2H, m)

158) H-NMR (CDC1 ₃ ) δ ; 1.31 (3H, d, J=6.7 Hz), 1.53- 1.90 (IH, m), 2.29-2.58 (IH, m) , 2.47 (3H, ε), 2.94-3.63 (2H, m) , 4.57-5.05 (IH, m) , 6.68-6.82 (IH, m), 7.10-7.59 (10H, m) , 7.72 (IH, s), 7.78- 7.96 (IH, m)

159) H-NMR (CDC1 ₃ ) δ ; 1.20-2.60 (17H, m) , 2.65-5.10 (3H, m), 6.85-3.85 (12H, m)

160) ^X H-NMR (DMSO-dg) δ ; 1.40-1.75 (IH, m) , 1.90-2.15 (IH, m), 2.33 (3H, s), 2.50-2.80 (2H, m) , 3.10-3.50

(IH, m), 4.40-4.65 (IH, m) , 6.85-7.60 (10H, m) , 7.85 (IH, ε), 10.44 (IH, ε)

161) ^X H-NMR (CDC1 ₃ ) δ ; 1.30-2.70 (11H, m) , 3.00-5.20 (3H, m), 6.58 (IH, d, J=8 Hz), 6.90-7.05 (IH, m) , 7.10-7.70 (10H, m)

162) H-NMR (CDC1 ₃ ) δ ; 1.25-2.90 (4H, m) , 2.44 (6H, ε), 2.79-3.57 (2H, m) , 2.79 (6H, s), 4.10-5.25 (IH, m) , 6.60-6.80 (IH, m), 6.94-7.60 (10H, m) , 8.23 (IH, d, J=6.2 Hz) , 12.41 (IH, m)

163) H-NMR (CDC1 ₃ ) δ ; 1.25-3.00 (4H, m) , 2.42 (6H, s), 2.99 (6H, s), 3.40-3.65 (2H, m) , 4.01-5.15 (IH, m) , 6.58-7.59 (12H, m) , 7.94 (IH, brε)

164) ^X H-NMR (DMSO-dg) δ ; 1.40-2.18 (4H, m) , 2.34 (3H, s), 2.47 (3H, s), 2.54-3.50 (4H, m) , 4.30-5.08 (IH, m), 6.56-6.82 (IH, m) , 6.87-7.48 (10H, m) , 7.48- 7.75 (2H, m), 10.35 (IH, s)

165) H-NMR (CDC1 ₃ ) δ ; 1.08-5.20 [20H, m, 1.30 (3H, t, J=7.2 Hz), 3.41 (2H, ε), 4.22 (2H, q, J=7.2 Hz)], 6.49-7.73 (8H, m) , 9.25-9.58 (IH, m)

166) ^X H-NMR (CDC1 ₃ ) δ ; 1.17-2.80 (4H, m) , 2.05 (3H, ε), 2.42 (6H, s), 3.02-3.53 (2H, m) , 4.06-5.15 (IH, m) , 6.55-7.80 (12H, m) , 8.53-8.74 (2H, m)

Examplε 899

To a solution of 5-acetyloxyimino-l-[4-( 2-chloro- benzoylamino) benzoyl ]-2, 3,4, -tetrahydro-lH-benzazepine (0.48 g) in acetic acid (20 ml) is added platinum oxidε

(0.05 g) and the mixture is subjectεd to catalytic rεduction undεr hydrogen atmosphere. After completion of thε rεaction, the catalyst is removed by filtration, and the filtrate is concentrated. The reεulting rεεiduε iε purifiεd by εilica gεl column chromatography (εluεnt; dichloromεthane : methanol = 20 : 1 + 10 :1) , and recrystallizεd from εthanol/diethyl ether to give 5-amino-l-[4-(2-chlorobenzoyl- amino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε (0.19 g) as colorless prisms, m.p. 176 - 178°C.

Example 900

To a solution of 5-methylamino-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε (0.6 g) in dichloromethane (10 ml) is added triethylamine (0.24 ml). Subsequently, thereto is added methanesulfonyl chloridε (0.14 ml) undεr ice-cooling, and then, the mixture is warmed to room tempεraturε and stirrεd ovεrnight. Watεr is addεd to thε rεaction solution, extracted three timeε with dichloromethane. The extract iε washed with saturated saline εolution, and dried ovεr magneεium εulfate. The εolvent is distilled off and the resulting residuε is purifiεd by silica gel column chromatography (eluεnt; dichloromethane : mεthanol = 20 : 1), and rεcrystallizεd from ethanol to give 5-(N-methyl-N-mεthanesulfonylamino)-l- [4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazεpine (0.48 g) as colorless scales, m.p. 197 - 198°C.

Example 901

To a solution of 5-methylamino-l-[4-(2-mεthyl- bεnzoylamino)bεnzoyl]-2,3,4, 5-tεtrahydro-lH-bεnzazεpinε (0.6 g) in dichloromethane is added triethylamine (0.24 ml). Subsequently, thereto is added benzoyl chloride (0.2 ml) under ice-cooling, and the tεmpεraturε thεreof is raised to room temperature, and the mixture is stirred overnight. Water is added to the reaction solution and extractεd thrεe times with dichloromethane. The extract is waεhed with saturated saline solution and dried over magnesium εulfatε. Thε solvεnt is distillεd off and thε resulting residue is purified by silica gel column chromatography (εluεnt; dichloromεthanε : methanol = 20 : 1), and recrystallizεd from εthanol to givε 5-(N-mεthyl-N-benzoyl- amino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazepine (0.64 g) as colorless needles, m.p. 248 - 249°C.

Example 902

A mixture of 5-amino-l-[4-( 2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε (0.6 g) and ethyl formate (10 ml) is refluxεd for 4 hours. Thε rεaction solution is concεntrated and the resulting rεsiduε iε rεcryεtallized from ethanol/petroleum ethεr to givε 5- formylamino-l-[4-(2-mεthylbεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazepinε (0.38 g) aε colorless columnar crystal, m.p. 211 - 213°C.

Using the suitable starting materials, the compounds of above Examples 825 and 894 are obtained in the same manner as in above Example 902.

Example 903

To a solution of 5-amino-l-[4-(2-chlorobenzoyl- amino)bεnzoyl]-2, 3,4, 5-tetrahydro-lH-benzazεpinε (0.6 g) in dichloromεthanε (10 ml) is addεd triethylamine (0.22 ml). Subsequεntly, thεrεto iε addεd di-tεrt-butyl dicarbonate (0.34 g) at room temperature and the mixture iε εtirred for 2 hours. Then, therεto is addεd additional di-tεrt-butyl dicarbonate (0.1 g) and the mixture is stirrεd for 1 hour. Thε rεaction mixture is concentratεd and thε rεsulting reεidue iε purified by silica gεl column chromatography (εluent; n-hexane : ethyl aceate = 1 : 1) to givε 5-t- butoxycarbonylamino-1-[4-(2-chlorobεnzoylamino)bεnzoyl]- 2,3,4,5-tεtrahydro-lH-bεnzazεpinε (0.66 g) as colorlεss amorphous. H-NMR (CDC1 ₃ ) δ ; 1.1-2.3 (13H, m) , 2.65-3.2 (IH, m) , 4.55-5.6 (3H, m) , 6.55-6.7 (IH, m) , 6.9-7.6 (12H, m)

Using thε suitable starting materials, the compound of above Example 791 is obtained in the samε manner as in above Example 903.

Examplε 904

To a solution of 5-amino-l-[4-(2-methylbenzoyl¬ amino)benzoyl]-2,3,-4,-5-tetrahydro-lH-bεnzazεpine (0.6 g) in dichloromethane (10 ml) is added phεnyl isocyanatε (0.2 g)

under ice-cooling. The mixture is stirred at the same temperature for 30 minutes, and the temperature therεof is raisεd to room tεmperature and thεn thε mixture iε stirred overnight. The reaction solution is distilled off and the resulting residue is recrystallized from dioxane to give 5- anilinocarbonylamino-1-[4-(2-methylbenzoylamino)benzoyl]- 2,3 , 4,5-tetrahydro-lH-benzazepine (0.65 g) as colorless prisms, m.p. 269 - 271°C.

Using the suitable starting materials, the compound of above Example 795 is obtained in the samε mannεr aε in abovε Examplε 904.

Example 905

To a solution of 5-methylamino-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH-bεnzazεpine (0.6 g) in methanol (10 ml) is added glycolonitrilε (50 %, 0.19 ml) and thε mixturε is stirred at room tempεrature for 20 minutεs, and thεn rεfluxεd for 30 minutεs. Thεrεto is addεd additional glycolonitrile (0.5 ml) and the mixture is refluxed for 5.5 hours. The reaction solution is concentratεd and to the resulting residue is added ethyl acetate. The precipitatεd crystal is collεctεd by filtration, and rεcrystallizεd from acεtonitrilε to givε 5- (N-methyl-N-cyanomethylamino)-1-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4, 5-tetrahydro-lH-benzazεpine (0.32 g) aε colorlεεε neεdles, m.p. 227 - 228°C.

Example 906

To 5-(N-mεthyl-N-oxiranylmεthylamino)-l-[4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε (0.62 g) is addεd trifluoroacεtic acid (1.22 ml) under ice-cooling and thε mixturε is stirrεd for 4 hours. Thε rεaction solution is neutralized with aqueous sodium carbonate solution, and extractεd thrεε times with dichloromethanε. Thε extract is washed with εaturatεd εaline εolution and dried over magneεium sulfatε. The solvent is distilled off and the resulting residue is disεolved in methanol (10 ml). Thereto is addεd 40 % aquεous sodium hydroxidε solution (10 ml) and watεr (10 ml), and thε mixturε is stirrεd at room tεmpεraturε overnight. Methanol is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane : methanol = 30 : 1) to givε 5-[N-methyl-N- (2,3-dihydroxypropyl)amino)-1-[4-(2-mεthylbenzoylamino)- benzoyl]-2,3,4,5-tεtrahydro-lH-benzazepinε (0.23 g) as colorlεss amorphous.

^X H-NMR (CDC1 ₃ ) δ ; 1.3-4.15 (19H, m) , 4.3-5.0 (IH, m), 6.65 (IH, d, J=7.7 Hz), 6.9-8.05 (12H, m)

Examplε 907

A mixture of 5-methylamino-l-[4-(2-mεthylbenzoyl- amino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazepine (1.64 g), acetonitrile (20 ml), potassium carbonate (0.6 g) and ethyl bromoacetate (0,44 ml) is refluxed for 3 hours. The reaction solution is concentrated and water is added to the

resulting residue, and the mixture is extractεd three times with dichloromethane. The extract is washed with saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane : methanol = 30 : 1), and recrystallized from ethyl acetatε/pεtrolεum ether to give 5-(N-mεthyl-N- ethoxycarbonylmethylamino)-l-[4-(2-methy1benzoylamino)- benzoyl]-2,3,4, 5-tetrahydro-lH-benzazepine (0.82 g) as colorleεε priεms, m.p. 167 - 168°C.

Uεing the suitable starting materials, the compounds of above Examples 785, 787, 799, 800, 802 - 806, 808, 811, 819, 824, 826, 827, 845, 848, 849, 850, 852, 855 - 858, 860, 861, 863 - 882, 885 - 893 and 895 - 898 arε obtainεd in thε samε mannεr as in abovε Examplε 907.

Examplε 908

5-(N-Mεthyl-N-ethoxycarbonyImethylamino)-1-[ 4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazεpine (0.6 g) iε diεεolved in εaturated solution of ammonia in methanol (20 ml), and the mixture is hεated at 100°C for 8 hours in a sealed tube. The reaction solution is concentrated and the resulting residuε iε purified by εilica gel column chromatography (eluεnt; dichloromethane : methanol = 30 : 1) to give 5-(N-methyl-N-carbamoylrnethyl- amino)-l-[4-( 2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-bεnzazεpinε (0.4 g) aε colorlεεε amorphouε.

^X H-NMR (CDCI3) δ ; 1.4-3.0 (9H, m) , 3.05-3.6 (3H, m), 3.9-4.1 (IH, m), 4.35-4.55 (IH, m) , 4.9-5.65 (IH, m) , 6.67 (IH, d, J=7.4 Hz), 6.85-7.6 (12H, m) , 7.6-7.85 (2H, m)

Example 909

To a solution of 5-(N-mεthyl-N-εthoxycarbonyl- methylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazεpinε (0.6 g) in dioxanε (10 ml) is addεd aqueous solution (1 ml) of εodium hydroxide (0.07 g) and the mixturε iε εtirrεd at room tεmpεraturε for 2 days. Thε reaction solution is concentratεd and to thε rεsulting rεsidue is addεd watεr. Thε inεolublε matεrialε arε rεmovεd by filtration. Thε filtratε iε neutralized with 10 % hydrochloric acid and extracted three timεε with dichloro¬ mεthanε. Thε εxtract iε washεd with saturated saline solution and driεd over magnesium sulfate. The solvent iε diεtilled off and to thε rεεulting rεεidue iε added a εolution of potaεεium ethylhexanoatε (0.2 g) in dichloromethane (20 ml). The εolvent iε distilled off, and diεthyl εther is addεd to the resulting rεsiduε. Thε prεcipitated crystal is collectεd by filtration, and rεcrystallizεd from diethyl ether to give potassium 2-[N- mεthyl-N-{l-[4-(2-mεthylbεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-bεnzazεpin-5-yl}amino]acεtatε (0.6 g) as colorless neεdlεs, m.p. 164 - 171°C.

Exampla 910

To a solution of 5-mεthylamino-l-[4-(2-mεthyl-

benzoylamino)benzoyl]-2,3, , 5-tetrahydro-lH-benzazepine (1.5 g) in dimεthyformamide (20 ml) are added potassium carbonate (0.6 g), potasεium iodide (0.72 g) and 2-(3-bromopropyloxy)- 3,4,5,6-tetrahydro-2H-pyrane (0.97 g) and thε mixturε is stirrεd at room temperaturε overnight. The reaction solution is concentrated and to the resulting residue iε added water. The mixture is extracted threε timεs with dichloromεthane. Thε extract is washed with saturatεd salinε εolution, and driεd ovεr magnεεium εulfatε. The εolvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane →- dichloromethanε : methanol = 50 : 1) to give 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2- yloxy)propyl ]amino}-l-[4-(2-mεthylbεnzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazεpinε (1.3 g) as colorlεss amorphous. H-NMR (CDC1 ₃ ) ; 1.3-2.85 (21H, m) , 3.2-4.0 (4H, m), 4.3-4.4 (IH, m) , 4.45-5.2 (2H, m) , 6.61 (IH, d, J=7.6 Hz), 6.9-7.65 (12H, m)

Exampla 911

To 5-{N-mεthyl-N-[3-(3,4,5,6-tεtrahydro-2H-pyran-2- yloxy)propyl]amino}-l-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε (0.4 g) is added a mixture of acetyl chloridε (0.5 ml) and acεtic acid (5 ml) at room temperature, and thε mixture is stirred overnight. The reaction solution is concentrated and the resulting residue

is purified by silica gel column chromatography (eluent; dichloromethanε : mεthanol = 30 : 1), and furthεr purifiεd again by silica gεl column chromatography (εluεnt; n-hεxanε

: εthyl acεtatε = 1 : 2) to givε 5-[N-mεthyl-N-(3- acεtyloxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]- 2,3,4,5-tεtrahydro-lH-bεnzazεpinε (0.06 g) as colorlεss amorphous. H-NMR (CDC1 ₃ ) δ ; 1.3-3.45 (17H, m) , 3.8-5.7 (5H, m) , 6.5-7.65 (13H, m)

Examplε 912

To a solution of 5-{N-mεthyl-N-[3-(3,4,5,6- tεtrahydro-2H-pyran-2-yloxy)propyl]amino}-l-[4-(2-mεthyl- bεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpine (0.55 g) in ethanol (10 ml) is added pyridinium p- toluenesulfonate (0.03 g) and the mixture is heated at 60°C overnight. After the mixturε iε rεfluxεd for morε 2 hourε, watεr and pyridinium p-toluεnεsulfonatε (0.03 g) are added thereto. The mixture iε refluxed for 4 hours. The reaction solution iε concεntratεd and to thε rεsulting rεsiduε is added dichloromethanε. The mixture is basified with aqueouε εodium hydrogεn carbonatε solution and εxtractεd thrεε timεs with dichloromεthanε. The extract is washed with saturatεd salinε εolution and driεd over magnesium sulfatε. Thε εolvεnt iε distillεd off and thε rεsulting rεsiduε iε purified by silica gel column chromatography (eluεnt; dichloromethane : methanol = 30 : 1) to give 5-[N-methyl-N-

( 3-hydroxypropyl)amino]-l-[ 4-( 2-mεthylbεnzoylamino)bεnzoyl]- 2, 3,4,5-tεtrahydro-lH-bεnzazεpinε (0.26 g) as colorless amorphous. H-NMR (CDC1 ₃ ) δ ; 1.25-3.1 (14H, m) , 3.3-4.0 (4H, m), 4.15-4.4 (IH, m) , 4.45-5.2 (IH, m) , 6.64 (IH, d, J=7.4 Hz) , 6.9-7.7 (12H, m)

Example 913

To a solution of 5-amino-l-[4-(2-methylbεnzoyl- amino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepine (0.6 g) in acetic acid (10 ml) is added dropwise 2,5-dimethoxytetra- hydrofuran (0.19 ml), and thε mixture is refluxεd for 1 hour. The reaction solution is concentratεd and thε resulting reεidue iε purified by εilica gel column chromatography (eluent; dichloromethane : methanol = 50 : 1), and recryεtallizεd from εthyl acεtatε/n-hεxanε to give 5-(1-pyrrolyl)-1-[4-(2-methylbεnzoylamino)benzoyl]-2,3,4,5- tεtrahydro-lH-bεnzazεpinε (0.31 g) as colorlεsε priεmε, m.p. 208 - 210°C.

Examplε 914

To a solution of 5-amino-l-[4-(2-methylbenzoyl- amino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepinε (2.5 g) in dichloromεthanε (30 ml) is addεd triεthylamine (0.96 ml) and furthεr thereto is added dropwise chloroacetyl chloride (0.55 ml) under ice-cooling. The mixture is stirred for 5 minutes. Thε reaction solution iε concentrated and to the resulting residue is added water. Thε prεcipitatεd crystal

is collected by filtration, washed with v/ater, and dried to give 5-(2-chloroacetylamino)-l-[4-(2-mεthylbεnzoylamino)- benzoyl]-2,3,4, 5-tetrahydro-lH-benzazεpine (1.4 g) as white powder .

^X H-NMR (DMSO-dg) δ ; 1.3-2.15 (4H, m) , 2.32 (3H, s), 2.8-3.05 (IH, m), 4.24 (2H, AB-q, J=12.8, 15.4 Hz), 4.35-4.55 (IH, m) , 4.9-5.25 (IH, m) , 6.68 (IH, d, J=7.6 Hz), 6.9-7.45 (9H, m) , 7.52 (2H, d, J=8.6 Hz), 8.9-9.05 (IH, m) , 10.31 (IH, s)

Using thε suitablε starting matεrials, thε compound of above Example 814 is obtainεd in thε same manner as in above Examplε 914.

Example 915

A mixed solution of 5-(2-chloroacεtylamino)-l-[4- ( 2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazεpine (0.6 g), imidazole (0.1 g) and potasεium carbonate (0.19 g) in acetonitrilε (30 ml) iε rεfluxεd for 8 hourε. Thε rεaction εolution iε concεntrated and the reεulting rεεidue is washed with watεr and εεparatεd by dεcantation. Thε rεmaindεr iε purifiεd by silica gel column chromatography (eluent; dichloromethane : mεthanol = 20 : 1 -■ 15 : 1), and recrystallized from εthanol/n-hexane to give 5- [ 2-(1-imidazolyl)acetylamino]-1-[4-(2-mεthylbenzoylamino)- benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε (0.15 g) aε colorleεs needles, m_p, 250 - 252°C.

Uεing the εuitablε εtarting matεrials, thε compound

of above Example 818 is obtained in the same manner as in above Example 915.

Example 916

To a solution of 5-( 2-chloroacεtylamino)-l-[4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε (0.6 g) in dimεthylformamidε (20 ml) are added dimethylaminε hydrochloridε (0.21 g) and potassium carbonate (0.54 g), and the mixture is stirred at room temperature for 2 days. The reaction solution is concεntratεd and watεr is addεd to thε rεεulting reεidue. The precipitated cryεtal is collected by filtration, and recrystallizεd from ethyl acetate to give 5-( 2-dimethylaminoacεtylamino)-l-[4-(2- methylbεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε (0.24 g) as colorlεsε priεms, m.p. 214 - 216°C.

Uεing thε εuitablε εtarting matεrials, the compounds of above Examples 816, 817, 820, 821, 826 and 827 arε obtainεd in thε εamε mannεr as abovε Example 916.

Example 917

A mixture of 5-methylamino-l-[4-(2-methylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine (0.6 g), N,N-dimethyl-2-chloroacεtamidε (0.19 g) and potassium carbonatε (0.22 g) is refluxed for 24 hours. The reaction solution is concentrated and water is addεd to thε rεsulting residue. The mixture is extracted three times with dichloromethanε. Thε εxtract is washεd with saturated

saline εolution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residuε iε purified by εilica gel column chromatography (εluεnt; dichloromεthanε : mεthanol = 30 : 1) to give 5-[N-methyl-N- (dimethylaminocarbonylmethy1)amino]-1-[4-(2-mεthylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε (0.05 g) as colorlεsε amorphous. H-NMR (CDC1 ₃ ) δ ; 1.2-3.3 (17H, m) , 3.45 (2H, AB- q, J=14.7, 22.9 Hz), 3.9-4.35 (2H, m) , 6.60 (IH, d, J=7.7 Hz), 5.8-8.0 (11H, m) , 8.39 (IH, s)

Examplε 918

To a solution of t-butoxycarbonylglycinε (0.84 g) in dimethylformamide (20 ml) are addεd diεthyl cyano¬ phosphatε (0.73 ml) and 5-amino-l-[4-(2-methylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine (1.74 g), and further therεto is addεd triεthylaminε (1.8 ml) undεr ice- cooling. The mixture is stirred for 30 minutes, and then εtirred at room tempεraturε ovεrnight. Thε rεaction εolution is concεntratεd and watεr is addεd to the resulting residue. The precipitatεd cryεtal iε collεctεd by filtration, waεhed with water, and recryεtallized from ethyl acetate to give 5-(2-aminoacεtylamino)-l-[4-(2-mεthyl- bεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine (E) (0.16 g). Separately, the filtrate is concεntratεd and purifiεd by silica gel column chromatography (eluent; dichloromethane : methanol = 50 : 1), and recrystallizεd

from diethyl ether to give 5-[ 2-(t-butoxycarbonylamino)- acεtylamino]-l-[4-(2-methylbεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazepine (F) (0.19 g).

(E): Colorless prisms, m.p. 287 - 289°C

(F): Colorless prisms, m.p. 170 - 171°C Example 919

5-Oxo-l-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-benzazepinε (0.50 g) is suspεndεd in tεtrahydrofuran (20 ml), and thereto iε added dropwiεe a 3.0 M εolution of methyl magneεium bromide in diethyl εther (1.5 ml) at room tempεraturε. The mixture is stirred at room temperaturε for 1 hour. Thε rεaction solution is pourεd into icε-watεr (20 ml), and -εxtracted with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off. The reεulting rεεiduε iε purified by silica gel column chromatography (εluεnt; εthyl acεtatε : n- hexane = 2 : 3 •* 1 : 1), and recrystallizεd from εthyl acεtatε/n-hεxane to givε 5-mεthyl-5-hydroxy-l-[ 4-(2-methyl- benzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH-bεnzazepine (0.23 g) as white powder, m.p. 204 - 205°C. Example 920

To a solution of 5-carboxymethoxy-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine (1.50 g) in dimethylformamide (60 ml) are added successively thiomorpholine (0.56 ml), diethyl cyanophosphate (0.89 g) and triethylamine (1.37 ml) with stirring under ice-

cooling. The mixture is stirred for 30 minutes under ice- cooling, and at room tεmpεrature for 20 minutes. Watεr (60 ml) is addεd to thε rεaction solution, and εxtractεd with dichloromεthanε. The extract is dried over magneεium sulfatε, and the solvent is distillεd off. The resulting residuε iε purified by εilica gel column chromatography (eluent; ethyl acetate : n-hexane = 5 : 2 -* ^■ 3 : 1), and rεcryεtallizεd from εthyl acetate/n-hexane to give 5- (thiomorpholinocarbonylmethoxy)-l-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine (1.60 g) as white powder, m.p. 235 - 237°C.

Using the suitable starting materials, the compoundε of above Exampleε 829 - 838 arε obtained in the same mannεr aε in above Example 920.

Example 921

To a εolution of 5-(thiomorpholinocarbonylmεthoxy)- 1-[4-(2-mεthylbεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-l H- bεnzazεpinε (0.40 g) in dichloromεthane (40 ml) is added 80 % m-chloroperbεnzoic acid (175 mg) with stirring at -8°C, and thε mixturε iε stirrεd at -8°C for 1 hour. To thε rεaction solution iε addεd 20 % aquεous sodium hydrogεnsulfitε solution (40 ml) and thε mixture is stirred at room tempεraturε for 30 minutεs. Thε dichloromεthanε layεr is collεctεd, waεhed with εaturated εaline solution αuu ui icu u vc l iiiα^u - dm o uitα c . x iic suiVcπ i. l o QxSlx xc - off and thε rεεulting rεεiduε iε purifiεd by εilica gεl

column chromatography (eluent; dichloromethane : methanol = 20 : 1) to give 5-[ (1-oxothiomorpholino)carbonylmεthoxy]-l- [4-(2-m thy1benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine (0.32 g) as colorleεε amorphouε.

^X H-NMR (CDC1 ₃ ) δ ; 1.50-1.92 (3H, m) , 1.92-2.05 (IH, m), 2.47 (3H, ε), 2.55-3.06 (5H, m) , 3.43-5.76 (8H, m) , 6.63-6.82 (IH, m) , 6.97-8.08 (12H, m)

Example 922

To a solution of 5-(thiomorpholinocarbonylmεthoxy)- l-[4-(2-mεthylbεnzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH- bεnzazεpinε (0.40 g) in dichloromεthanε (40 ml) is added 80 % m-chloroperbenzoic acid (0.35 g), and the mixture is stirred at room temperature for 1 hour. The reaction solution is washed εuccessivεly with an aquεouε εodium hydrogεnεulfitε εolution and εaturatεd salinε εolution, and driεd over magneεium sulfate. The solvent is distilled off to give 5-[ (1,l-dioxothiomorpholino)carbonylmethoxy]-l-[4- (2-methylbεnzoylamino)bεnzoyl]-2,3,4, 5-tetrahydro-lH- bεnzazεpinε (0.41 g) as colorlεsε amorphous.

^X H-NMR (CDCI3) δ ; 1.43-2.65 (4H, m) , 2,48 (3H, s), 2.69-3.25 (5H, m) , 3.90-5.40 (8H, m) , 6.64-6.94 (IH, m) , 6.94-7.77 (12H, m)

Exampla 923

To a solution of 5-oxo-l-[4-(2-hydroxybenzoylamino)- benzoyl]-2,-3,4,5-tetrahydro-lH-benzazepine (400 mg) in acetone (20 ml) are added potassium carbonate (210 mg), potassium

iodide (250 mg) and 2-chloroacetamide (120 mg), and the mixture is refluxεd for 2 hours. Thε insolublε matεrials arε rεmovεd by filtration, and thε filtratε is distilled off. Dichloromethane is added to thε rεsulting rεsiduε, and thε mixture is washed with saturatεd salinε solution, and driεd ovεr magnεεium εulfate. The εolvent is distilled off and the resulting residue is recrystallizεd from ethyl acetate/n-hexanε to givε 5-oxo-l-[4-(2-carbamoylmethoxy- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε ( 36 mg) as whitε powdεr, m.p. 226 - 228°C.

Using the suitable starting materials, thε compound of abovε Examplε 842 is obtainεd in thε samε mannεr as above Example 923.

Exampla 924

A mixturε of 5-methylamino-4-hydroxy-l-[4-(2- chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepinε (0.13 g), εthyl α-bromoacetatε (58 mg), diisopropylεthylaminε (49 mg) and acεtonitrilε (5 ml) is refluxed for 10 hourε. Acetonitrile is distilled off under reduced presεurε, and thε rεεulting rεsiduε is disεolvεd in dichloromεthanε, waεhed with water, driεd over magneεium εulfatε, and diεtillεd off undεr rεducεd pressure. The resulting residuε iε purifiεd by εilica gεl column chromatography (εluεnt; dichloromεthane : methanol = 50 : 1), and recryεtallized from chloroform/methanol to give 7- [4-(2-chlorobenzoylamino)benzoyl]-1-methyl-l,2,3,4a,5,6,7,11 b-

octahydro-3-oxo[l]benzazepino[ 4, 5-b] [1,4 ]oxazine (80 mg) as colorless prisms, m.p. 286 - 290°C.

Example 925

To a solution of 5-oxo-l-[2-chloro-4-(2-methyl- benzoylamino)benzoyl]-2,3,4, 5-tεtrahydro-lH-benzazepine (1 g) in methanol (20 ml) and dichloromethane (20 ml) is added hydroxylamine-O-sulfonic acid (0.28 g) with stirring at room tεmperature, and thε mixture is stirred at the same temperature for 1 hour. Subsequεntly, to thε rεaction solution is added with stirring an aqueous solution of patassium carbonate (0.34 g) in water (1 ml) at room temperature, and the mixture is stirred at the same temperature for 2 hours. The precipitated cryεtal iε removεd by filtration, and thε filtratε iε concεntrated undεr reduced preεsurε. Thε rεsulting rεsiduε is purified by silica gel column chromatography to give potassium {l-[2- chloro-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro- lH-benzazεpin-5-yl}imino-0-εulfonatε (0.4 g) as whitε powdεr . H-NMR (DMSO-dg) δ ; 1.40-1.75 (IH, m) , 1.90-2.15 (IH, m), 2.33 (3H, s), 2.50-2.80 (2H, m) , 3.10-3.50 (IH, m) , 4.40-4.65 (IH, m) , 6.85-7.60 (10H, m) , 7.85 (IH, s), 10.44 (IH, ε)

Example 926

U<-_ ^ " α t *"> P e ii ϊ l- a hl a c f a r t ^* i n n ma l- p r i a l ς f hp compounds of above Examples 841 - 843, 868 - 870, 888 and

889 arε obtained in the same manner as in above Example 380.

Example 927

Using the εuitable εtarting materials, the compounds of above Examples 876 - 878 are obtained in the same manner as in above Example 381.

Example 928

Using the εuitablε εtarting materials, the compounds of abovε Examplεs 840, 842 and 846 arε obtained in the same manner as in above Example 384.

Example 929

Using the suitablε starting matεrials, the compounds of above Examples 788 - 790, 796 - 804, 805, 808, 811, 814, 818, 819, 824, 826., 827, 837, 845, 848, 850, 852, 855, 856 - 858, 860, 861, 863 - 882, 885,.886, 888 - 893 and 895 - 898 are obtainεd in thε samε manner aε in above Example 388.

Exampla 930

Uεing thε εuitablε εtarting materialε, the compound of above Example 848 is obtained in the same mannεr as in abovε Examplε 393.

Exampla 931

Using thε suitablε starting materials, the compounds of above Examples 841 and 842 are obtained in the samε mannεr as in abovε ^" Examplε 402.

Example 932

Using the εuitablε εtarting materialε, the

compoundε of abovε Exampleε 882 and 897 are obtained in the same manner as in above Example 403.

Example 933

Using the suitable starting materials, the compound of above Example 809 is obtained in the same manner as in above Example 634.

Examplε 934

Using thε suitablε starting matεrials, thε compounds of abovε Examples 828 - 838 are obtainεd in the same manner as in above Example 640.

Example 935

Using the suitable starting materials, the compound of above Example 810 is obtained in the same manner as in above Example 772.

Example 936

Using the suitable starting materials, the compound of above Example 788 is obtained in thε same manner as in abovε Examplε 771.

Examplε 937

Uεing thε εuitablε εtarting materials, the compounds of above Examplεs 785, 787, 788 - 790, 796 - 805, 806, 807, 808, 811, 814, 818, 819, 845, 848, 849, 850, 852, 855, 856 - 858, 860, 861, 863 - 882, 885, 886, 888 - 893 and 896 - 898 arε obtainεd in thε samε mannεr as in abovε Examplε 390.

Example 938

To 5-methanεsulfonyloxymethyl-1-[4-(2-methyl- bεnzoylamino)bεnozyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpin� � (0.50 g) iε addεd a 30 % εolution of mεthylaminε in methanol (50 ml), and the mixture iε hεatεd at 100°C for 3 hours in a sealed tube. After cooling, the rεaction solution is εvaporated under reducεd prεεsurε, and thε reεulting residue is purified by εilica gεl column chromatography (εluent; dichloromεthanε : methanol : aqueouε ammonia = 100 : 10 : 1) to give 5-mεthylaminomεthyl-l-[4-(2-methylbenzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepine (0.07 g) . H-NMR (DMSO-dg) δ ; 1.40-2.18 (4H, m) , 2.34 (3H, s), 2.47 (3H, s), 2.54-3.50 (4H, m) , 4.30-5.08 (IH, m) , 6.56-6.82 (IH, m) , 6.87-7.48 (10H, m) , 7.48-7.75 (2H, m) , 10.35 (IH, s)

Using the suitable starting materials, the compounds of above Examplεs 823 - 825 are obtained in the εame manner as in above Example 938.

Using thε above suitable starting materials, the compounds of the following Table 6 are obtained in the same manner as in Examples 1 and 382.

Table 6

Example 939

Crystalline form: White powder Recrystallization solvent: Ethanol Mεlting Point: 208 - 211°C Form: Frεe

Examplε 940 Struct

0

R ³ : 4-NHCCH ₂ - ^

Cryεtalline form: White powder

Rεcryεtallization εolvent: Methanol/diεthyl εther

Melting Point: 171.5 - 172.5°C

Form: Freε

Example 941

Struct

0

Crystalline form: White powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 151 - 154°C Form: Free

Example 942 Structu

) ₃ NHCOCH ₃

Crystalline form: Colorlesε amorphouε NMR analysiε: 167) Form: Free

Example 943

Structu

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl εthεr Melting Point: 180 - 183°C Form: Freε

Examplε 944 Struct

Crystallinε form: Whitε powdεr

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 109 - 110°C Form: Free

Example 945

Struct

Crystallinε form: Colorleεs oil NMR analysiε: 168) Form: Freε

Example 946 Structu

Cryεtalline form: Colorless oil NMR analysis: 169) Form: Freε

Examplε 947

Struct

Crystallinε form: Whitε powder

Recrystallization solvent: Methanol/diethyl ether Melting Point: 177 - 178.5°C Form: Frεε

Example 948 Struct

Cryεtalline form: Colorless amorphous NMR analysiε: 170) Form: Free

Example 949

Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 162 - 165°C Form: Free

Example 950 Structure

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl εthεr

Mεlting Point: 212 - 215°C

Form: Frεε

Example 951

Structu

RO 4-NHCCH,NH / V CH-

Crystalline form: Colorless oil NMR analysiε: 171) Form: Free

Examplε 952 Struct

Crystalline form: White powdεr

Recrystallization solvent: Methanol/diεthyl εther

Melting Point: 112 - 114°C

Form: Free

Example 953

Structure

Crystalline form: Colorlesε oil NMR analyεiε: 172) Form: Free

Examplε 954 Struct

0 R ³ : 4-NHC-/ NHCOCH ₃

Crystalline form: Colorlεsε amorphouε NMR analyεiε: 173) Form: Free

Example 955

Struct

Crystallinε form: Light yεllow amorphous NMR analysis: 174) Form: Frεe

Examplε 956 Struct

R ³ : 4-NHC- VcOOH

Crystalline form: White powder Rεcrystallization solvεnt: Diεthyl εther Melting Point: 189 - 193°C Form: Free Example 957

Struct

Crystalline form: Colorlεsε amorphous NMR analysiε: 175) Form: Free

Example 958 Structu

0

Crystalline form: Colorlesε priεmε Recrystallization solvent: Ethanol Melting Point: 234 - 238°C Form: Free

Example 959

Structure Cl 0

0

Crystalline form: White powder

Recrystallization solvent: Diethyl ether/dichloromethanε

Mεlting Point: 183 - 184.5°C

Form: Frεε

Crystallinε form: Brown oil NMR analysis: 176) Form: Free

Example 961

Struct

Crystallinε form: Colorlεsε amorphous NMR analysiε: 177) Form: Free

Example 962 Struct

0

R~ : 4-NHCCH ₂ N

Cryεtalline form: Colorlεεε amorphouε NMR analyεis: 178) Form: Free

Example 963

Struct

Crystalline form: White powder

Rεcrystallization solvεnt: Dichloromεthane/diethyl ether Melting Point: 202.5 - 204.5°C Form: Free

Example 964 Structu

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diεthyl εther

Melting Point: 199.5 - 201°C

Form: Freε

Examplε 965

Structurε Cl 0

Crystalline form: White powder

Recrystallization εolvent: Dichloromethanε/diethyl ethεr

Mεlting Point: 196.5 - 197°C

Form: Free

Example 966 Struct

0

Crystalline form: White powder

Recrystallization εolvent: Dichloromethane/diethyl ether

Melting Point: 204 - 205°C

Form: Freε

Example 967

Struct

0

Cryεtalline form: White powder

Recryεtallization εolvent: Dichloromethanε/diεthyl εthεr

Melting Point: 175 - 177°C

Form: Free

Examplε 968 Structurε

0

Crystallinε form: Pink amorphous NMR analysiε: 179) Form: Free

Example 969

Struct

Cryεtalline form: White powder

Recryεtallization solvent: Dichloromεthanε/diεthyl ether Melting Point: 186 - 189°C Form: Free

Example 970 Structu

Crystalline form: Colorlεsε prisms Recrystallization solvent: Ethyl acetate/n-hεxanε Melting Point: 211 - 212°C Form: Free Example 971

Structure

Crystalline form: Colorless amorphous NMR analysis: 180) Form: Freε

Example 972 Struct

Crystalline form: Colorleεε needles Recrystallization solvent: Ethanol Melting Point: 206 - 207°C Form: Free

Example 973

Struct

0

Crystalline form: Colorlesε amorphous NMR analysis: 181) Form: Free

Examplε 974 Structu

0

Crystallinε form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε Mεlting Point: 152 - 154°C Form: Frεε

Examplε 975

Struct

Crystalline form: Colorlesε amorphous NMR analysis: 182) Form: Freε

Example 976 Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε

Mεlting Point: 204 - 206°C

Form: Free

Example 977

Struct

Crystalline form: Colorlesε needlεε Recryεtallization εolvent: Ethyl acetatε/n-hεxanε Melting Point: 162 - 163°C Form: Free

167) H-NMR (CDC1 ₃ ) δ ; 1.14-2.83 (13H, m) , 2.43 (3H, s), 2.95-5.19 (4H, m) , 4.12 (2H, t, J=6.2 Hz), 6.27-6.83 (2H, m) , 6.83-7.36 (6H, m) , 7.36-7.67 (4H, ), 7.93-8.11 (IH, ) , 9.77 (IH, brs)

168) ^X H-NMR (CDC1 ₃ ) δ ; 1.11-2.98 (11H, m) , 2.80 (3H, s), 3.69 (2H, ε), 2.98-5.24 (2H, m) , 6.50-7.71 (12H, m), 9.37 (IH, brε)

169) H-NMR (CDC1 ₃ ) δ ; 1.10-2.80 (14H, m) , 2.99 (3H, s), 3.39-5.20 (2H, m) , 4.00 (2H, s), 6.49-7.67 (12H, m), 8.51 (IH, brs)

170) H-NMR (CDC1 ₃ ) δ ; 1.10-1.98 (3H, m) , 1.98-2.82 (10H, m), 2.82-3.20 (2H, m) , 3.34-5.15 (2H, m) , 6.48-7.68 (15H, m), .7.86 (IH, brs)

171) ^X H-NMR (CDC1 ₃ ) δ ; 1.10-2.84 (10H, m) , 2.40 (3H, s), 2.90-5.20 (2H, m) , 3.79 (2H, d, J=2.7 Hz), 4.33 (IH, br), 6.30-7.68 (12H, m) , 8.67 (IH, brs)

172) H-NMR (CDC1 ₃ ) δ ; 1.10-2.85 (14H, m) , 2.72 (3H, ε), 2.98-5.20 (2H, m) , 3.62 (2H, ε), 6.50-7.75 (12H, m), 9.18 (IH, brs)

173) H-NMR (DMSO-dg) δ ; 1.28-2.62 (4H, m) , 2.07 (3H, s), 2.34 (6H, s), 3.04-3.57 (2H, m) , 3.99-4.86 (IH, m), 6.62-7.88 (12H, m) , 10.12-10.20 (2H, m)

174) ^X H-NMR (CDC1 ₃ ) δ ; 1.39 (3H, t, J=7.1 Hz), 1.64- 2.68 (4H, m), 2.42 (6H, ε), 3.04-3.58 (2H, m) , 3.98-5.01 (IH, m), 4.38 (2H, q, J=7,l Hz), 6.57- 8.57 (13H, m)

175) H-NMR (DMSO-dg) _ ; 1.67-5.02 (7H, m), 3.35 (6H, s), 6.75-8.17 (12H, m) , 8.46 (IH, s), 10.54 (IH, ε)

176) H-NMR (CDC1 ₃ ) δ ; 1.21 (3H, t, J=7.1 Hz), 1.95- 2.30 (2H, m), 2.88 (2H, t, J=6.2 Hz), 3.40-3.65 (2H, m), 3.70-4.50 (2H, m) , 3.91 (2H, ε), 6.66 (IH, d, J=8.5 Hz), 6.70-7.00 (3H, m) , 7.10-7.50 (7H, m) , 7.81 (IH, d, J=2.5 Hz), 8.44 (IH, ε)

177) H-NMR CDC1 ₃ ) δ ; 1.21 (3H, t, J=7 Hz), 1.30-5.20 (11H, m , 3.48 (2H, q, J=7 Hz), 3.90 (2H, s), 6.53 (IH, d, J=8.3 Hz), 6.65-7.00 (4H, m) , 7.00-7.40 (6H, m) 7.51 (IH, d, J=2.5 Hz), 8.40 (IH, s)

178) H-NMR CDC1 ₃ ) δ ; 1.21 (3H, t, J=7 Hz), 1.20-5.20 (15H, m , 3.90 (2H, s), 6.48 (IH, d, J=8.3 Hz),

6.50-7.70 (11H, m) , 8.39 (IH, ε)

179) H-NMR (CDC1 ₃ ) δ ; 1.60-2.20 (IH, m) , 2.10-2.35

(IH, m), 2.45 (3H, ε), 2.70-2.95 (2H, m) , 3.25-3.45

(IH, m), 4.60-4.85 (IH, m) , 7.10-7.80 (12H, m)

180) CDC1 ₃ ) δ ; 1.65-2.15 (4H, m) , 2.46 (3H, s), 2.6-5.15 (4H, m), 6.75-6.95 (IH, m) , 7.15-7.55

(10H, m , 7.61 (IH, s), 7.95-8.1 (IH, m)

181) ^X H-NMR CDC1 ₃ ) δ ; 1.60-2.15 (3H, m) , 2.15-2.90 (2H, m) 2.90-3.22 (6H, m) , 4.00-4.50 (2H, m) , 4.13 (2H, s) 4.58-5.22 (2H, m) , 6.53-6.80 (IH, m) , 6.90-7.90 (7H, m) , 8.48 (IH, ε)

1821 H-NMR (CDCl ) δ ; 1.48-2.20 (3H, m) , 2.20-2.85

(2H, m), 2.85-3.27 (6H, m) , 4.05-4.47 (2H, m) ,

4.47-5.22 (2H, m) , 6.50-6.76 (IH, m) , 6.76-6.91

(IH, m), 6.91-7.69 (9H, m) , 7.69-8.13 (IH, m) , 9.28

(IH, s), 11.87 (IH, brs)

Example 978

5-Dimethylamino-l-(2-methyl-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazεpine (H) (1.00 g) is dissolved in dichloromethane (30 ml), and therεto is addεd triethyl¬ amine (0.48 ml) under ice-cooling, and furthεr addεd dropwisε 2-mεthylbenzoyl chloride (0.44 ml). The mixture is εtirred at room tempεraturε for 1 hour. Thε reaction εolution iε washed with water, and dried over magnesium sulfatε. Thε solvεnt is distillεd off, and thε resulting residue is crystallized by adding thereto εthyl acεtate. The prεcipitated crystal is recrystallizεd from dichloro- methane/εthyl acεtatε to give 5-dimethylamino-l-[2-methyl-4- (2-methylbεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine (0.92 g) as whitε powdεr, m.p. 191 - 192°C. HPLC rεtention time: 7.5 minutes

Column; Wakosil II δC-^g (trade mark; Wako Pure Chemical Co., Ltd.)

Solvent; acetonitrilε : 50 mN aquεouε Na ₂ S0 ₄ aolution : acetic acid = 27 : 73 : 1

Rate; 1.0 ml/min. [ct] ²² = 0° (c=1.0, chloroform)

^X H-NMR (CDC1 ₃ ) δ ; 1.15-3.25 (17H, m) , 3.35-5.14

(2H, m) , 6.62-8.05 (12H, m)

Charts of H-NMR (CDC1 ₃ ) of the starting compound (H) and the compound obtained in Exmaple 978 are shown in Fig. 1 and Fig. 2, reεpεctively.

Example 979

Uεing 5-dimethylamino-l-(2-mεthyl-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-bεnzazεpinε (G) (1.00 g), 5-dimεthyl- amino-1-[2-mεthyl-4-(2-mεthylbenzoylamino)benzoyl]-2,3,4,5 - tetrahydro-lH-benzazepine (0.48 g) is obtainεd in thε same manner as in Example 978 excεpt that mεthanol/diethyl εthεr is usεd inεtead of ethyl acetate aε recrystallization εolvεnt, aε white powder, m.p. 183 - 185°C. HPLC retention time : 8.1 minuteε

(the conditionε of HPLC are εamε aε thoεε in Examplε 978) [α] ²² = 0° (c=1.3, chloroform)

H-NMR (CDC1 ₃ ) δ ; 1.10-3.20 (17H, m) , 3.35-5.15 (2H, m), 6.50-6.80 (IH, m) , 6.86-7.62 (10H, m) , 7.65-8.09 (IH, m)

Chartε of ^X H-NMR (CDC1 ₃ ) of thε εtarting compound (G) and the compound obtained in Exmaplε 979 arε εhown in Fig. 3 and Fig. 4, reεpectivεly.

Referεncε Exampla 18

Using thε suitablε starting matεrials, thε following compounds arε obtainεd in thε εamε mannεr aε in Rεfεrence Examplε 1.

7-Methoxy-5-oxo-l-(4-nitrobεnzoyl)-2,3,4, 5-tεtra- hydro-lH-benzazepine, colorlesε neεdlεs, m.p. 178 - 178.5°C (recrystallized from ethyl acetate/n-hεxanε)

7-Methoxy-5-oxo-l-(2-chloro-4-nitrobenzoyl)- 2,3, 4,5-tetrahydro-lH-benzazεpinε, whitε powdεr, m.p. 150 - 151°C (recrystallized from ethyl acetate/n-hexane)

7-Methoxy-5-oxo-l-(3-methoxy-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazεpinε, white powder, m.p. 116 - 118°C (recrystallizεd from εthyl acεtatε/n-hεxanε)

7-Chloro-5-oxo-l-(3-mεthoxy-4-nitrobenzoyl)- 2,3,4,5-tetrahydro-lH-bεnzazεpinε, yεllow powdεr, m.p. 156 - 158°C (recrystallized from diethyl ether/dichloromethane)

Referεnce Example 19

Using the suitable starting materials, thε following compounds are obtained in the same manner as in Refεrεncε Example 2.

7-Methoxy-5-oxo-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-bεnzazεpinε, whitε powdεr, m.p. 172.5 - 173.5°C (recryεtallized from ethyl acetate/n-hexanε)

7-Mεthoxy-5-oxo-l-( 2-chloro-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-bεnzazεpine, white powder, m.p. 153 - 155°C (rεcryεtallizεd from ethyl acetate/n-hexanε)

7-Mεthoxy-5-oxo-l-( 3-mεthoxy-4-aminobεnzoyl)- 2,3,4,5-tεtrahydro-lH-bεnzazεpinε, colorlεss nεεdlεs, m.p. 170 - 171°C (rεcrystallized from ethyl acetate/n-hexane)

7-Chloro-5-oxo-l-(3-methoxy-4-aminobenzoyl)-

2,3,4,5-tεtrahydro-lH-bεnzazεpinε, yεllow oil

^X H-NMR (CDC1 ₃ ) δ ; 2.05-2.30 (2H, m) , 2.85-3.00 (2H, m) , 3.70 (3H, s), 3.85-4.30 (4H, m) , 6.42 (IH, d, J=8.1 Hz), 6.64 (IH, dd, J=1.7 Hz, 8.1 Hz), 6.72 (IH, d, J=8.5 Hz), 6.80 (IH, d, J=1.8 Hz), 7.19 (IH, dd, J=2.6 Hz, 8.5 Hz) , 7.81 (IH, d, J=2.5 Hz)

Using the suitable starting materials, the compounds of the following Table 7 are obtained in the same manner as in above Examples 1 and 382.

Table 7

Example 980

Struct

0

Rθ 4

Crystalline form: Colorless amorphouε NMR analyεiε: 183) Form: Free

Examplε 981

Struct

Crystallinε form: Colorlεss amorphous NMR analysis: 184) Form: Frεε

Example 982

Struct

Crystalline form: Colorlesε amorphouε NMR analysis: 185) Form: Freε

Example 983

Struct

Cryεtallinε form: Colorlεεε amorphouε NMR analysis: 186) Form: Free

Example 984

Structu

^{0 CH} 3

R 3: 4-NHC"-C'HNH- J ⁷ T ⁷

Crystalline form: Colorlεss amorphous NMR analysiε: 187) Form: Frεε

Example 985 ructure

Crystalline form: Colorlesε amorphous NMR analysiε: 188) Form: Freε

Examplε 986

Cryεtallinε form: Colorlεss amorphous NMR analysiε: 189) Form: Frεε

Example 987 ture

Crystalline form: White powder

Recrystallization solvent: Ethanol/watεr

Melting Point: 267 - 268°C

Form: Free

Example 988

Struct

Crystalline form: White powder Recryεtallization solvent: Ethanol/water Melting Point: 264 - 266°C Form: Frεε

Examplε 989

Struct

Cryεtalline form: White powder

Recrystallization solvent: Dichloromεthane/diethyl ether Melting Point: 218 - 220°C Form: Free Example 990 Structure

Cryεtalline form: Yellow oil NMR analyεiε: 190) Form: Free

Example 991 Structure

Crystalline form: Yellow oil NMR analysis: 191) Form: Free

Example 992 Struct

Crystalline form: Yεllow powdεr

Rεcrystallization solvent: Dichloromethanε/diethyl ether

Melting Point: 174 - 177°C

Form: Free

Example 993

Crystalline form: Yεllow amorphouε NMR analyεiε: 192) Form: Frεε

Example 994 Struct

Cryεtalline form: Colorlεss amorphous NMR analysiε: 193) Form: Frεε

Example 995 Struct

Crystalline form: Whitε powder

Recrystallization solvent: Diethyl ether/dichloromethanε Mεlting Point: 163 - 165°C Form: Free Example 996

Crystallinε form: Colorlεsε amorphous NMR analysiε: 194) Form: Free

Example 997 Struct

Crystalline form: Colorlesε amorphouε NMR analysis: 195) Form: Free

183) H-NMR (CDC1 ₃ ) δ ; 1.10-2.83 (11H, m) , 2.96-5.21 (2H, m), 4.55 (2H, s), 6.48-7.72 (13H, m) , 8.30 (IH, brs)

184) ^X H-NMR (CDC1 ₃ ) δ ; 1.10-2.85 (11H, m) , 1.58 (3H, d, J=6.8 Hz), 2.23 (3H, s), 2.95-5.19 (4H, m) , 6.38- 7.70 (12H, m), 8.69 (IH, brε)

185) ^X H-NMR (CDC1 ₃ ) δ ; 1.10-2.85 (14H, m) , 2.26 (3H, ε), 2.96-5.19 (4H, m) , 6.36-7.68 (12H, m) , 8.72 (IH, brs)

186) H-NMR (CDC1 ₃ ) δ ; 1.09-2.72 (11H, m) , 1.53 (3H, d, J=6.9 Hz), 2.24 (3H, S), 2.93-5.21 (4H, m) , 6.30- 7.78 (12H, m), 8.76 (IH, brε)

187) ^X H-NMR (CDCI3) δ ; 1.10-2.82 (14H, m) , 2.96-5.20 (4H, m), 6.38-7.70 (12H, m) , 8.54 (IH, brε)

188) H-NMR (CDCI3) δ ; 1.64-2.28 (2H, m) , 2.41 (3H, ε), 2.60-2.90 (2H, m) , 2.90-3.70 (IH, m) , 3.76 (3H, s), 4.10-5.10 (IH, m), 6.60-7.70 (10H, m) , 8.51 (IH, s)

189) ^X H-NMR (CDCI3) δ ; 1.64-2.43 (2H, m) , 2.67-2.97 (2H, m), 3.00-3.70 (IH, m) , 3.77 (3H, s), 4.20-5.10 (IH, m), 6.60-7.75 (10H, m) , 8.51 (IH, s)

190) ^X H-NMR (CDCI3) δ ; 2.00-2.35 (2H, m) , 2.49 (3H, ε), 2.89 (2H, t, J=6.2 Hz), 3.72 (3H, ε), 3.40-4.80 (2H, m), 6.74 (2H, d, J=8.5 Hz), 6.80-7.00 (2H, m) , 7.25-7.60 (5H, m) , 7.80 (IH, d, J=2.6 Hz), 8.16 (IH, ε), 8.37 (IH, d, J=8.6 Hz)

191) ^X H-NMR (CDC1 ₃ ) δ ; 1.90-2.40 (2H, m) , 2.90 (2H, t, J=6.2 Hz), 3.75 (3H, s), 3.40-4.80 (2H, m) , 6.74

(IH, d, J=8.5 Hz), 6.80-7.00 (2H, m) , 7.10-7.50 (4H, m), 7.73 (IH, dd, J=2.3 Hz, 6 Hz), 7.80 (IH, d, J=2.5 Hz), 8.38 (IH, d, J=8.8 Hz), 8.65 (IH, s)

192) H-NMR (CDC1 ₃ ) δ ; 1.10-2.10 (13H, m) , 2.90-5.20 (6H, m), 6.56 (IH, d, J=8.4 Hz), 6.69 (IH, d, J=7 Hz), 6.85-7.70 (7H, m) , 8.15 (IH, s), 8.31 (IH, d, J=8.4 Hz)

193) H-NMR (CDCI3) δ ; 0.30-0.65 (4H, m) , 1.20-2.50 (7H, m) , 2.50 (3H, s), 3.10-5.20 (2H, m) , 3.75 (3H, ε), 6.60 (IH, d, J=8.3 Hz), 6.70-7.60 (8H, m) , 8.14 (IH, ε), 8.20-8.40 (IH, m)

194) H-NMR (CDCI3) δ ; 0.80-2.50 (10H, m) , 2.90-4.10 (6H, m), 6.50-7.80 (9H, m) , 8.32 (IH, d, J=8 Hz), 8.62 (IH, s)

195) ^X H-NMR (CDCI3) δ ; 0.30-0.65 (4H, m) , 0.70-2.40 (6H, m), 2.60-5.20 (6H, m) , 6.50-7.80 (9H, m) , 8.30 (IH, d, J=8 Hz), 8.62 (IH, ε)

Refεrence Example 20

Using the suitablε starting matεrials, thε following compounds arε obtainεd in thε samε mannεr as in

Reference Example 1.

7-Methy1-5-oxo-l-(4-nitrobenzoyl)-2,3,4,5-tεtra- hydro-lH-benzazεpine, white nεεdles H-NMR (CDCI3) δ ; 2.20 (2H, brs), 2.32 (3H, s),

2.88 (2H, t, J=6.3 Hz), 3.40-4.79 (2H, m) , 6.57 (IH, d, J=8.0 Hz), 7.04 (IH, d, J=7.7 Hz), 7.36 (2H, d, J=8.6 Hz), 7.62 (IH, d, J=1.7 Hz), 8.04 (2H, d, J=8.7 Hz)

7-Dimethylamino-5-oxo-l-(4-nitrobεnzoyl)-2,3,4,5- tetrahydro-lH-benzazepinε, red brown prismε (recrystallized from dichloromethane/diethyl ethεr) H-NMR (CDC1 ₃ ) δ ; 1.75-2.47 (2H, m) , 2.60-3.62, 4.51-4.92 (total 4H, m) , 2.93 (6H, s), 6.46 (IH, dd, J=2.2 Hz, 7.0 Hz), 6.52 (IH, d, J=7.0 Hz), 7.33 (2H, d, J=7.0 Hz), 8.00 (2H, d, J=7.0 Hz)

7-Bromo-5-oxo-l-( -nitrobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepinε, whitε powder (recryεtallizεd from dichloromεthane/diethyl ether.), m.p. 177 - 182°C

7-Chloro-5-oxo-l-(2-methyl-4-nitrobenzoyl)-2,3,4,5- tetrahydro-lH-benzazεpine, white powder (recryεtallized from dichloromethanε/diethyl ether)

^X H-NMR (CDC1 ₃ ) δ ;1.78-2.37 (2H, m) , 2.48 (3H, ε), 2.88 (2H, t, J=6.1 Hz), 3.30-5.12 (2H, m), 6.47-6.82 (IH, m), 6.82-7.09 (IH, m) , 7.09-7.27 (IH, m) , 7.48-8.35 (3H, m)

6-Oxo-l-(2-chloro-4-nitrobenzoyl)-l,2,3,4,5,6- hexahydrobenzazocine, yellow amorphous

^X H-NMR (CDC1 ₃ ) δ ; 1.7-2.1 (4H, m) , 2.85-4.7 (4H, m), 7.12 (IH, d, J=8.4 Hz), 7.17-7.51 (4H, m) , 7.89 (IH, dd, J=7.8 Hz, 2.1 Hz), 8.11 (IH, d, J=2.2 Hz)

8-Chloro-6-oxo-l-( 2-chloro-4-nitrobenzoyl)-

1,2,3,4,5, 6-hexahydrobenzazocine, yellow amorphous H-NMR (CDC1 ₃ ) δ ; 1.7-2.15 (4H, m), 2.85-4.8 (4H, m), 7.14 (IH, d, J=8.5 Hz), 7.16 (IH, d, J=8.4 Hz), 7.34 (IH, dd, J=8.3 Hz, 2.5 Hz), 7.85 (IH, d, J=2.5 Hz), 7.94 (IH, dd, J=8.4 Hz, 2.2 Hz), 8.13 (IH, d, J=2.1 Hz)

8-Methyl-6-oxo-l-(2-chloro-4-nitrobεnzoyl)- 1,2,3,4,5,6-hεxahydrobεnzazocinε, yεllow amorphous H-NMR (CDCI3) δ ; 1.65-2.2 (4H, m) , 2.33 (3H, s), 2.7-5.0 (4H, m), 7.0-7.25 (3H, m) , 7.67 (IH, d, J=2.0 Hz), 7.89 (IH, dd, J=8.4 Hz, 2.2 Hz), 8.10 (IH, d, J=2.1 Hz)

8-Mεthoxy-6-oxo-l-(2-chloro-4-nitrobεnzoyl)- 1,2,3,4,5,6-hexahydrobenzazocinε, light yεllow amorphous

^X H-NMR (CDCI3) δ ; 1.6-2.05 (4H, m) , 2.8-5.2 (4H, m), 3.78 (3H, s), 6.88 (IH, dd, J=8.6 Hz, 3.1 Hz), 7.11 (IH, d, J=8.4 Hz), 7.12 (IH, d, J=8.6 Hz), 7.38 (IH, d, J=3.0 Hz), 7.90 (IH, dd, J=8.4 Hz, 2.2 Hz), 8.11 (IH, d, J=2.2 Hz)

7-Chloro-5-oxo-l-( 2-chloro-4-nitrobεnzoyl)-2,3,4,5- tetrahydro-lH-benzazεpine, yellow powder (recryεtallized from diethyl ether/dichloromethanε), m.p. 125 - 126.5°C

Rεfεrεncε Exampla 21

Uεing thε εuitablε εtarting matεrials, thε following compounds arε obtainεd in thε samε mannεr as in Referεncε Example 2.

7-Methyl-5-oxo-l-(4-aminobenzoyl)-2,3,4, 5-tεtra- hvdro—IH—benzazepine, yellow powder H-NMR (CDCI3) δ ; 2.13 (2H, brs), 2.32 (3H, s),

2.86 (2H, t, J=6.2 Hz), 2.89-5.29 (2H, m) , 3.86 (2H, brε), 6.41 (2H, m), 6.65 (IH, d, J=8.1 Hz), 7.06 (3H, m) , 7.65 (IH, d, J=1.7 Hz)

7-Dimethylamino-5-oxo-l-(4-aminobεnzoyl)-2,3,4,5- tetrahydro-lH-benzazεpinε, yellow needlεε (recryεtallized from dichloromethane/diethyl ether) H-NMR (CDC1 ₃ ) δ ; 1.78-2.49 (2H, m) , 2.64-3.78, 4.07-5.02 (total 4H, m) , 2.93 (6H, m) , 3.96 (2H, m) , 6.38 (2H, d, J=8.7 Hz), 6.55 (IH, dd, J=2.7, 8.7 Hz), 6.62 (IH, d, J=8.7 Hz), 6.96-7.18 (3H, m)

7-Bromo-5-oxo-l-(4-aminobenzoyl)-2,3,4,5-tetra- hydro-lH-benzazepine, white powder (recrystallized from methanol/diethyl ether)

^X H-NMR (CDC1 ₃ ) δ ; 1.98-2.37 (2H, m) , 2.88 (2H, t, J=6.3 Hz), 3.52-4.55 (4H, m) , 6.28-6.57 (2H, m) , 6.57-6.76 (IH, m), 6.92-7.20 (2H, m) , 7.28-7.42 (IH, m) , 7.90-8.09 (IH, m)

7-Chloro-5-oxo-l- ( 2-methyl-4-aminobenzoyl )-2 ,3,4,5- tetrahydro-lH-bεnzazεpinε, whitε powdεr (recryεtallized from dichloromethanε/diεthyl εther), m.p. 190 - 191°C

6-Oxo-l- ( 2-chloro-4-aminobenzoyl ) -1 , 2 , 3 , 4 , 5 , 6- hexahydrobenzazocine, light yellow amorphous H-NMR (CDC1 ₃ ) δ ; 1.3-2.25 (4H, m) , 2.8-4.4 (6H, m), 6.1-6.9 (3H, m), 6.95-7.75 (3H, m) , 7.8-8.3 (IH, m)

8-Chloro-6-oxo-l-(2-chloro-4-aminobenzoyl)- 1,2,3,4,5,6-hεxahydrobεnzazocinε, light yellow amorphouε

H-NMR (CDCI3) δ ; 1.59-2.2 (4H, m) , 2.6-4.4 (6H, m), 6.1-6.9 (3H, m) , 6.95-7.5 (2H, m) , 7.8-8.05 (IH, m)

7-Chloro-5-oxo-l-(2-chloro-4-aminobenzoyl)-2,3,4,5- tetrahydro-lH-benzazεpinε, yεllow powdεr (rεcrystallized from diethyl ethεr/dichloromεthane), m.p. 188 - 191.5°C

Uεing the εuitablε εtarting matεrialε, thε compoundε of thε following Tablε 8 arε obtained in the same mannεr as in above Examples 1 and 382.

Table 8

Example 998 Struct

Crystalline form: White powder NMR analysis: 196) Form: Freε

Example 999 Structu

Cryεtalline form: White powder NMR analysis: 197) Form: Free

Example 1000 Struct

Crystalline form: White powder

Recrystallization solvεnt: Dichloromethane/diεthyl ether Melting Point: 200 - 205°C Form: Frεe

Examplε 1001

Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 198) Form: Free

Example 1002

Structure

Cryεtallinε form: Whitε powdεr

Rεcrystallization solvεnt: Dichloromethane/diethyl ether Melting Point: 234 - 238°C Form: Frεε

Example 1003

Struct

Crystalline form: White powder

Recrystallization εolvent: Ethyl acetate/n-hεxanε

Mεlting Point: 174 - 178°C

Form: Frεe

Example 1004

Struct

Cryεtalline form: Light yellow amorphouε NMR analyεiε: 199) Form: Free

Examplε 1005 Struct

Crystallinε form: Light yellow amorphous

NMR analysis: 200)

Form: Free

Example 1006

Struct

Crystallinε form: Light yεllow amorphous NMR analysiε: 201) Form: Frεe

Example 1007 Struct

Crystalline form: Light yellow amorphous NMR analysiε: 202) Form: Frεε

Example 1008 Structu

Crystalline form: Light yellow amorphous MNR analysis: 203) Form: Free

Example 1009 Struct

Crystalline form: Light yellow amorphous NMR analysiε: 204) Form: Free

Example 1010

Structure

Crystallinε form: Colorlεss amorphoua NMR analyεiε: 205) Form: Free

Example 1011

Struct

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε

Melting Point: 153 - 155°C

Form: Freε

Examplε 1012

Struct

Crystalline form: White powder

Recrystallization εolvent: Ethyl acetate/n-hexanε Mεlting Point: 142 - 143°C Form: Frεε

Example 1013

Structu

Crystallinε form: Whitε powdεr

Rεcrystallization solvεnt: Ethyl acεtatε/n-hεxanε Mεlting Point: 176 - 178°C Form: Frεε

Examplε 1014

Struct

Crystallinε form: White powder

Recrystallization solvεnt: Ethyl acεtatε/n-hεxane Mεlting Point: 186 - 188°C Form: Frεε

Example 1015

Structu

Crystalline form: Colorless amorphous NMR analysiε: 206) Form: Free

Example 1016

Struct

Cryεtallinε form: Colorlεss amorphous NMR analysiε: 207) Form: Frεε

Example 1017 Structure

Crystalline form: White powder

Recrystallization solvent: Ethyl acetate/n-hexane Melting Point: 191 - 191.5 ^β C Form: Free

Example 1018

Struct

Crystalline form: White powder

Recrystallization εolvent: Ethyl acetatε/n-hεxanε Melting Point: 210 - 212°C Form: Freε

Examplε 1019

Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acetatε/n-hεxanε Melting Point: 196 - 198°C Form: Freε

Exampl Struct

Crystallinε form: Colorlεsε amorphouε NMR analysis: 208) Form: Frεε

Examplε 1021

Crystallinε form: Colorlεsε amorphouε NMR analysis: 209) Form: Frεε

Examplε 1022

Structu

Crystalline form: Colorlesε amorphouε NMR analyεis: 210) Form: Free

Example 1023

Crystallinε form: Colorlεss amorphous NMR analysis: 211) Form: Free

Example 1024

Structu

Crystalline form: Colorless amorphous NMR analysis: 212) Form: Free

Examplε 1025 Struct

Crystallinε form: Colorlεss amorphous NMR analysis : 213 ) Form: Frεe

Examplε 1026

Struct

Crystallinε form: Colorlεsε amorphouε NMR analysis: 214) Form: Frεε

Example 1027 Structure Cl O

Crystalline form: Colorless prismε Recryεtallization εolvent: Ethanol Melting Point: 207 - 208°C Form: Freε

Example 1028 Struct

Crystalline form: White powder Recryεtallization εolvent: Ethanol Melting Point: 201 - 202°C Form: Freε

Examplε 1029 Struct

Crystallinε form: Whitε powdεr Rεcrystallization solvεnt: Ethanol Mεlting Point: 193 - 194°C Form: Free

Ex St

Cl

R~ : 4-NHCO ^■ O

Crystalline form: White powdεr Rεcrystallization solvent: Ethanol Melting Point: 205 - 208°C Form: Free

Example 1031

Struct

Cl

Rθ 4-NHCO

Crystalline form: White powder Recrystallization εolvent: Ethanol Melting Point: 214 - 216°C Form: Free

Example 1032

Crystalline form: Yellow needles Recrystallization solvent: Ethanol Melting Point: 223 - 226°C Form: Freε

Examplε 1033

Crystalline form: Colorlesε neεdlεε Recrystallization solvent: Ethanol/diethyl εthεr Mεlting Point: 203 - 206°C Form: Frεε

Examplε 1034

Crystalline form: Colorless neεdlεs

Recrystallization solvent: Ethanol/diethyl ethεr/n-hexane Melting Point: 168 - 171°C Form: Free

Example 1035 Struct

Crystalline form: White powder

Recrystallization solvent: Methanol/diεthyl εthεr Mεlting Point: 206 - 208°C Form: Frεε

Examplε 1036

Struct

Crystallinε form: White powder

Recrystallization solvent: Methanol/diεthyl εther Mεlting Point: 229 - 232°C Form: Frεε

Example 1037

Struct

Crystalline form: White powder

Rεcrystallization solvεnt: Mεthanol/diεthyl ether

Melting Point: 220 - 222°C

Form: Freε

Example 1038

Struct

Crystallinε form: Whitε powder

Recrystallization εolvent: Mεthanol/diεthyl εthεr Melting Point: 232 - 233.5°C Form: Freε

Example 1039 Structu

Crystalline form: Colorlεss amorphous NMR analysis: 215) Form: Free

Example 1040

Struct

Crystalline form: Colorless amorphous NMR analysiε: 216) Form: Freε

Example 1041

Structu

CH,

RO 4-NHCOCHBr

Crystallinε form: Whitε powdεr

Recrystallization solvent: Methanol/diεthyl εthεr Mεlting Point: 147 - 151°C Form: Frεε

Examplε 1042

Structu

CH ₃ Cl

R ³ : 4-NHCOCHNH- X

Cryεtalline form: Whitε powdεr Rεcrystallization solvεnt: Mεthanol/n-hεxane Mεlting Point: 127 - 129°C Form: Free

Examplε 1043

Structurε

Crystallinε form: Whitε powdεr

Recrystallization solvent: Methanol/n-hεxane

Melting Point: 109 - 112°C

Form: Free

Example 1044

Structu

Crystalline form: Whitε powdεr

Recrystallization solvent: Mεthanol/diεthyl εthεr Mεlting Point: 198 - 200°C Form: Frεe

- -

Example 1045 Structure Br 0

Crystallinε form: White powder

Recrystallization εolvεnt: Mεthanol/diεthyl εthεr Mεlting Point: 210 - 211°C Form: Free

Example 1046 Structu

Crystalline form: Colorlesε amorphouε NMR analyεis: 217) Form: Frεε

Example 1047

Structu

Crystalline form: Colorless amorphous NMR analysis: 218) Form: Freε

Examplε 1048 Structure

Crystalline form: Colorless amorphous NMR analysis: 219) Form: Free

Example 1049

Crystalline form: Colorlesε nεεdlεε Rεcryεtallization εolvent: Ethanol Melting Point: 243 - 243.5°C Form: Free

Example 1050

Struct

Cryεtallinε form: Colorlεεs prisms Rεcryεtallization solvεnt: Ethanol/pεtrolεum εthεr Mεlting Point: 207 - 209°C Form: Free

Example 1051

Structu

Cryεtalline form: Colorlεεs nεεdlεs

Rεcrystallization solvεnt: Ethanol/petroleum ethεr

Mεlting Point: 239 - 241°C

Form: Free

Example 1052

Structure ,,

Crystalline form: Colorlesε amorphous NMR analysis: 220) Form: Free

Examplε 1053 Structu

Crystallinε form: Colorlεsε amorphouε NMR analyεis: 221) Form: Free

Example 1054

Crystalline form: Light yellow amorphous NMR analyεiε: 222) Form: Free

Example 1055

Struct

Crystalline form: Light yellow amorphous

NMR analysis: 223)

Form: Free

Example 1056

Struct

Crystallinε form: White powder

Recrystallization solvent: Diethyl ether/dichloromethane

Melting Point: 169.5 - 173°C

Form: Free

Example 1057 Structurε Cl 0

Crystallinε form: Colorlεsε amorphouε NMR analysis: 224) Form: Frεe

Example 1058 Struct

Crystalline form: Colorlεss amorphous NMR analysis: 225)

Example 1059

Structu

Crystalline form: Colorlesε amorphous NMR analysiε: 226) Form: Freε

Examplε 1060

Struct

Crystalline form: Colorless amorphous NMR analysis: 227) Form: Freε

Example 1061

Struct

Crystalline form: Colorless amorphous NMR analysis: 228) Form: Free

Example 1062

Structu

Crystalline form: Colorlesε amorphouε NMR analysis: 229) Form: Free

Example 1063

Structure

Crystalline form: Colorlesε amorphous NMR analysis: 230) Form: Free

Example 1064

Structu

Crystalline form: Colorless amorphous NMR analysis: 231) Form: Free

Crystalline form: Colorless amorphous NMR analysis: 232) Form: Free

Example 1066

Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 233) Form: Free

Example 1067 Struct

Crystalline form: Colorleεε amorphous NMR analysis: 234) Form: Freε

Examplε 1068 Structu

Crystalline form: Colorless amorphous NMR analysis: 235) Form: Free

Example 1069

Struct

Crystalline form: Colorlesε amorphous NMR analysis: 236) Form: Free

Example Struct

Crystalline form: Colorlesε amorphous NMR analysis: 237) Form: Free

196) ^X H-NMR (CDC1 ₃ ) δ ; 2.14 (2H, brε), 2.33 (3H, s), 2.46 (3H, s), 2.85 (2H, t, J=6.1 Hz), 4.83 (2H, brs), 6.64 (IH, d, J=8.1 Hz), 7.07 (IH, d, J=8.0 Hz), 7.21-7.48 (8H, m) , 7.65 (IH, m) , 7.74 (IH, brs)

197) H-NMR (CDC1 ₃ ) δ ; 2.12 (2H, brs), 2.33 (3H, s), 2.85 (2H, t, J=6.2 Hz), 2.88-5.28 (2H, m) , 6.63 (IH, d, J=8.1 Hz), 7.06 (IH, dd, J=1.7 Hz, 8.1 Hz), 7.19-7.69 (9H, m) , 8.26 (IH, brs)

198) H-NMR (CDCI3) δ ; 0.49 (4H, m) , 1.25-5.13 (9H, m) , 2.33 (3H, s), 2.45 (3H, ε), 6.53 (IH, m) , 6.79 (IH, m), 7.07-7.42 (9H, m) , 7.73 (IH, m)

199) ^X H-NMR (CDCI3) δ ; 2.04 (2H, brs), 2.29 (3H, s), 2.82 (2H, t, J=5.9 Hz), 2.85-5.29 (2H, m) , 6.82- 7.69 (10H, m), 8.31 (IH, brs)

200) H-NMR (CDCI3) δ ; 2.05 (2H, brs), 2.29 (3H, s), 2.44 (3H, s), 2.79 (2H, t, J=5.5 Hz), 2.82-5.28 (2H, m) , 6.82-8.12 (11H, m)

201) ^X H-NMR (CDCI3) δ ; 1.40-4.85 (11H, m) , 2.51 (3H, s), 6.78-7.63 (10H, m) , 8.64 (IH, brs)

202) ^X H-NMR (CDCI3) δ ; 1.40-4.85 (11H, m) , 2.45 (3H, s), 2.50 (3H, s), 6.78-7.55 (10H, m) , 8.10 (IH, brs)

203) H-NMR (CDCI3) δ ; 0.49 (4H, m) , 1.25-4.85 (9H, m) ,

2.28 (3H, s), 6.77-7.62 (10H, m) , 8.64 (IH, brs)

204) ^X H-NMR (CDCI3) δ ; 0.48 (4H, m) , 1.26-4.85 (9H, m) ,

2.29 (3H, s), 2.44 (3H, s), 6.78-7.58 (10H, m) , 8.18 (IH, brs)

205) ^X H-NMR (CDC1 ₃ ) δ ; 1.14 (6H, d, J=6.3 Hz), 1.52- 2.20 (7H, m), 2.20-2.60 (IH, m) , 2.64-3.66 (10H, m), 4.00-4.50 (4H, m) , 4.50-5.23 (2H, m) , 6.57-7.90 (11H, m), 8.10-8.30 (IH, m) , 9.97 (IH, s)

206) ^X H-NMR (CDCI3) δ ; 1.24-2.08 (4H, m) , 2.08-2.26 (3H, m), 2.26-3.16 (4H, m) , 3.47-4.03 (4H, m) , 4.18-4.92 (IH, m) , 6.40-7.94 (10H, m) , 8.45-9.03 (IH, m)

207) ^X H-NMR (CDCI3) δ ; 1.26-2.10 (4H, m) , 2.10-2.28 (3H, m), 2.28-3.20 (IH, m) , 3.43-4.06 (4H, m) , 4.20-4.93 (IH, m) , 6.40-8.00 (10H, m) , 8.78-9.30 (IH, m)

208) H-NMR (CDCI3) δ ; 1.10-1.98 (4H, m) , 1.98-3.10 (7H, m), 3.30-3.90 (4H, m) , 3.90-5.10 (IH, m) , 6.45-8.25 (12H, m)

209) ^X H-NMR (CDCI3) δ ; 1.06-1.94 (4H, m) , 1.94-3.19 (10H, m), 3.19-3.90 (4H, m) , 3.90-5.10 (IH, m) , 6.44-8.60 (11H, m)

210) ^X H-NMR (CDCI3) δ ; 1.06-1.97 (4H, m) , 1.97-3.20 (7H, m), 3.20-3.92 (4H, m) , 3.92-5.10 (IH, m) , 6.44-8.55 (11H, m)

211) H-NMR (CDCI3) δ ; 1.07-1.98 (4H, m) , 1.98-3.10 (10H, m), 3.37-5.20 (8H, m) , • 6.44-6.86 (3H, m) , 6.97-7.60 (6H, m) , 8.13 (IH, s), 8.19-8.38 (IH, m)

212) ^X H-NMR (CDCI3) δ ; 1.08-1.99 (4H, m) , 1.99-3.13 (7H, m) , 3.33-5.14 (8H, m) , 6.40-6.90 (3H, m) ,

6.95-7.56 (5H, m) , 7.63-7.87 (IH, m) , 8.17-8.37 (IH, m), 8.60 (IH, s)

213) H-NMR (CDC1 ₃ ) δ ; 0.30-0.64 (4H, m) , 0.70-3.42 (9H, m), 3.42-5.10 (5H, m) , 6.40-8.70 (11H, m)

214) ^X H-NMR (CDCI3) δ ; 0.30-0.76 (4H, m) , 0.80-3.43 (6H, m) , 3.50-5.00 (5H, m) , 6.40-9.04 (11H, m)

215) H-NMR (CDC1 ₃ ) δ ; 1.25-3.25 (14H, m) , 3.55-5.06 (2H, m), 6.43-7.00 (2H, m) , 7.00-7.71 (8H, m) , 7.91-8.45 (IH, m)

216) H-NMR (CDC1 ₃ ) δ ; 1.11-3.20 (17H, m) , 3.28-5.12 (2H, m), 6.41-7.01 (2H, m) , 7.02-7.63 (8H, m) , 7.76-8.21 (IH, m)

217) H-NMR (CDC1 ₃ ) δ ; 1.92-2.29 (2H, m) , 2.36 (3H, ε), 2.45 (3H, ε), 2.84 (2H, t, J=6.3 Hz), 3.32-4.64 (2H, m), 6.40-8.10 (11H, m)

218) H-NMR (CDC1 ₃ ) δ ; 1.92-2.25 (2H, m) , 2.34 (3H, s), 2.83 (2H, t, J=6.3 Hz), 3.21-4.52 (2H, m) , 6.39- 7.97 (10H, m), 8.43 (IH, brs)

219) H-NMR (CDC1 ₃ ) δ ; 1.7-2.15 (4H, m) , 2.5-5.2 (4H, m), 6.75-6.9 (IH, m), 7.27-7.6 (9H, m) , 7.65-7.85 (IH, m), 7.9-8.15 (2H, m)

220) H-NMR (CDC1 ₃ ) δ ; 1.65-2.1 (4H, m) , 2.44 (3H, ε),

A 2.8-4.5 (4H, m), 6.75-8.0 (12H, m) f

221) H-NMR (CDC1 ₃ ) δ ; 1.65-2.3 (4H, m) , 2.7-4.8 (4H, m) ,- 6.75-8.4 (12H, m)

222) ^X H-NMR (CDC1 ₃ ) δ ; 1.45-2.15 (4H, m) , 2.45-2.55

(3H, m) 2.85-4.6 (4H, m) , 6.8-8.25 (11H, m)

223) ^X H-NMR CDC1 ₃ ) δ ; 1.5-2.2 (4H, m) , 2.8-4.7 (4H, m) , 6.8 8.4 (11H, m)

224) H-NMR CDC1 ₃ ) δ ; 1.75-2.25 (2H, m) , 2.30-2.70

(3H, m) 2.70-2.95 (2H, m) , 3.20-5.10 (2H, m) ,

6.70-8. 0 (11H, m)

225) ^X H-NMR CDC1 ₃ ) δ ; 1.20-2.60 (8H, m) , 2.60-5.10

(3H, m) 6.80-7.90 (10H, m) , 8.20-8.60 (IH, m)

226) H-NMR CDC1 ₃ ) δ ; 1.20-2.60 (10H, m) , 2.60-5.10

(3H, m) 6.80-8.15 (11H, m)

227) ^X H-NMR CDC1 ₃ ) δ ; 0.30-0.70 (4H, m) , 1.20-2.45

(6H, m) 2.60-5.10 (3H, m), 6.80-7.95 (10H, m) ,

8.15-8. 0 (IH, m)

228) H-NMR CDC1 ₃ ) δ ; 1.20-2.40 (5H, m) , 2.60-5.35

(7H, m) 5.80-6.15 (IH, m), 6.75-7.95 (10H, m) ,

8.20-8. 0 (IH, m)

229) H-NMR CDC1 ₃ ) δ ; 1.20-2.55 (7H, m) , 2.60-5.35

(7H, m) 5.85-6.05 (IH, m) , 6.70-7.10 (2H, m) ,

7.10-7. 0 (8H, m), 8.15-8.60 (IH, m)

230) H-NMR CDC1 ₃ ) δ ; 1.00-1.20 (6H, m) , 1.00-2.40

(5H, m) 2.60-5.10 (4H, m), 6.80-8.00 (10H, m) ,

8.15-8. 5 (IH, m)

231) H-NMR CDC1 ₃ ) δ ; 0.80-2.50 (13H, m) , 2.60-5.10

(4H, m) 6.70-8.85 (10H, m) , 8.25-8.60 (IH, m)

232) H-NMR CDC1 ₃ ) δ ; 1.30-2.60 (11H, m) , 2.60-5.10

(3H, m) 6.80-8.15 (11H, m)

233) H-NMR (CDCI3) δ ; 1.10-2.50 (13H, m) , 2.50-5.10 (3H, m), 6.75-8.40 (11H, m)

234) H-NMR (CDC1 ₃ ) δ ; 0.30-0.65 (4H, m), 1.20-2.30 (6H, m), 2.35-2.55 (3H, m) , 2.60-5.10 (3H, m) , 6.75-8.35 (11H, m)

235) ^X H-NMR (CDC1 ₃ ) δ ; 1.20-2.60 (8H, m) , 2.60-5.40 (7H, m), 5.80-6.15 (IH, m) , 6.80-8.20 (11H, m)

236) H-NMR (CDC1 ₃ ) δ ; 1.25-2.60 (10H, m) , 2.60-5.40 (7H, m), 5.75-6.10 (IH, m) , 6.75-7.10 (2H, m) , 7.10-8.40 (9H, m)

237) H-NMR (CDC1 ₃ ) δ ; 0.95-1.20 (6H, m) , 0.95-2.25 (5H, m), 2.40-2.60 (3H, m) , 2.60-5.10 (4H, m) , 6.75-7.05 (2H, m) , 7.10-8.30 (9H, m) Refεrεnce Example 22

Using the suitablε starting matεrials, thε following compoundε arε obtained in the samε mannεr as in Rεference Examplε 1.

8-Chlor0-6-oxo-l-(4-nitrobεnzoyl)-l,2,3,4,5,6- hexahydrobenzazocinε, yεllow prisms H-NMR (DMSO-dg) δ ; 1.3-2.2 (4H, m) , 2.6-5.0 (4H, m), 7.05-8.5 (7H, m)

5-Oxo-7-methyl-l-( 2-chloro-4-nitrobenzoyl)-2,3, 4,5- tetrahydro-lH-benzazepinε, light yεllow amorphous H-NMR (CDC1 ₃ ) δ ; 1.71-2.32 (2H, m) , 2.29 (3H, s), 2.86 (2H, t, J=6.3 Hz), 3.10-5.30 (2H, m) , 6.84-8.38 (6H, m)

5-Oxo-7-mεthyl-l-(3-mεthoxy-4-nitrobεnzoyl)-

2,3,4,5-tetrahydro-lH-bεnzazεpinε, light yellow amorphous ^X H-NMR (CDCI3) δ ; 2.17 (2H, brs), 2.34 (3H, s),

2.84 (2H, t, J=6.0 Hz), 3.10-5.29 (2H, m) , 3.77 (3H, ε), 6.67 (IH, d, J=7.9 Hz), 6.85 (2H, m) , 7.10 (IH, d, J=8.0

Hz) , 7.57-7.65 (2H, m)

5-Oxo-7-dimethylamino-l-(2-chloro-4-nitrobεnzoyl)- 2,3,4,5-tetrahydro-lH-benzazεpinε, yεllow powder H-NMR (CDCI3) δ ; 1.66-2.38 (2H, m) , 2.65-2.88 (2H, m), 2.92 (6H, ε), 3.08-3.64, 4.58-5.01 (total 2H, m) , 6.49 (IH, dd, J=3.1, 8.7 Hz), 6.82 (IH, d, J=8.7 Hz), 6.90 (IH, d, J=3.1 Hz), 7.02-7.37 (IH, m) , 7.94 (IH, dd, J=l.9, 8.4 Hz), 8.08 (IH, d, J=1.9 Hz)

Referεncε Exampla 23

Uaing thε εuitablε starting matεrials, thε following compounds are obtained in thε εamε mannεr aε in Rεfεrεncε Examplε 2.

8-Chlor0-6-oxo-l-(4-aminobεnzoyl)-1,2,3,4,5,6- hexahydrobεnzazocine, light yellow amorphouε H-NMR (CDC1 ₃ ) δ ; 1.7-2.2 (4H, m) , 2.3-4.8 (6H, m), 6.4-6.6 (2H, m) , 6.74 (IH, d, J=8.5 Hz), 7.1-7.4 (3H, m) , 7.99 (IH, d, J=2.6 Hz)

8-Methyl-6-oxo- ( 2-chloro-4-aminobεnzoyl ) - 1,2,3,4,5,6-hεxahydrobεnzazocinε, colorlεεs amorphous H-NMR (CDC1,) δ ; 1.4-2.1 (4H, m), 2.15-2.6 (3H, m), 2.7-4.4 (6H, m) , 6.15-6.35 (IH, m) , 6.51 (IH, s), 6.6-

6.85 (IH, m), 6.9-7.25 (2H, m) , 7.72 (IH, ε)

8-Methoxy-6-oxo-(2-chloro-4-aminobenzoyl)- 1,2,3,4,5,6-hεxahydrobεnzazocinε, light yεllow amorphous H-NMR (CDCI3) δ ; 1.4-2.2 (4H, m) , 2.7-5.0 (9H, m), 6.25 (IH, dd, J=8.3 Hz, 2.2 Hz), 6.51 (IH, d, J=2.2 Hz); 6.66 (IH, d, J=8.3 Hz), 6.88 (IH, dd, J=8.6 Hz, 3.0 Hz), 7.23 (IH, d, J=8.6 Hz), 7.43 (IH, d, J=3.0 Hz)

5-Oxo-7-chloro-l-( 2-mεthoxy-4-aminobεnzoyl)- 2,3,4,5-tεtrahydro-lH-bεnzazepine, colorless particles (recrystallizεd from mεthanol/diεthyl εthεr), m.p. 206 - 208°C

5-OXO-7-mεthy1-1-(2-chloro-4-aminobεnzoyl)-2,3,4,5- tetrahydro-lH-benzazεpinε, light yεllow amorphouε H-NMR (CDCI3) δ ; 2.09 (2H, brs), 2.29 (3H, s), 3.10-5.00 (2H, m) , 3.78 (2H, brs), 6.34-7.54 (6H, m)

5-Oxo-7-mεthyl-l-(3-methoxy-4-aminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine, light yellow amorphous

^X H-NMR (CDCI3) δ ; 2.12 (2H, brs), 2.32 (3H, s), 2.85 (2H, t, J=5.9 Hz), 3.30-5.00 (2H, m) , 3.65 (3H, s), 3.98 (2H, brs), 6.40 (IH, d, J=8.1 Hz), 6.64-6.76 (3H, m) , 7.06 (IH, dd, J=1.6, 8.1 Hz), 7.63 (IH, d, J=2.0 Hz)

5-Oxo-7-dimethylamino-l-( 2-chloro-4-aminobenzoyl)- 2,3,4,5-tεtrahydro-lH-bεnzazepine, yεllow amorphous

^X H-NMR (CDCI3) δ ; 1.60-2.32 (2H, m) , 2.67-5.13 (4H, m) , 2.92 (6H, s), 3.75 (2H, s), 6.31 (IH, dd, J=2.1, 8.3 Hz), 6.46 (IH, d, J=2.1 Hz), 6.48 (IH, dd, J=3.1, 8.7 Hz), 6.66-6.89 (2H, m) , 6.95 (IH, d, J=3.1 Hz)

Using thε stuitablε starting materials, the compounds of thε following Table 9 are obtained in the samε mannεr as in above Examples 1 and 382.

Table 9

Examplε 1071 Struct

Crystalline form: Colorless prismε Rεcryεtallization εolvεnt: Ethanol Melting Point: 227 - 230°C Form: Free

Examplε 1072 Structu

Crystalline form: Colorlesε needles

Recrystallization solvent: Ethanol/pεtrolεum εther

Melting Point: 216 - 218°C

Form: Freε

Example 1073

Struct

Crystalline form: Colorless prisms Recrystallization solvent: Ethyl acεtatε/n-hexane Melting Point: 227 - 228°C Form: Free

Example 1074 Struct

Crystalline form: White powder NMR analyεiε: 238) Form: Freε

Example 1075 Struct

Crystalline form: Whitε powdεr NMR analysiε: 239) Form: Frεε

Examplε 1076 Structurε

Crystalline form: Light yellow amorphous

NMR analysis: 240)

Form: Freε

Examplε 1077

Struct

Crystalline form: Light yellow amorphous NMR analyεis: 241) Form: Freε

Example 1078 Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 242) Form: Free

Examplε 1079 Structu

Crystallinε form: Colorless amorphous NMR analysis: 243) Form: Free

Example 1080 Structure

CH,

R ³ : 4-NHCO 00

Crystalline form: Light yellow powder Recrystallization solvent: Ethyl acetate/diethyl ether Melting Point: 179 - 181°C Form: Free

Example 1081 Structu

Crystalline form: White powder

Recrystallization solvent: Ethyl acεtate/diethyl ether

Melting Point: 213 - 216°C

Form: Free

Examplε 1082 Structurε

Crystalline form: Light yellow powder

Recrystallization εolvent: Ethyl acεtatε/diεthyl ether Melting Point: 185 - 187°C Form: Free

Examplε 1083 Structu

Crystallinε form: Colorlesε priεmε Recryεtallization solvent: Ethanol Mεlting Point: 249 - 251°C Form: Frεε

Example 1084 Struct

Cryεtalline form: Colorleas needlεs Rεcrystallization solvεnt: Ethanol Mεlting Point: 239 - 241°C Form: Frεε

Example 1085 Structu

Cryεtalline form: White powder

Recryεtallization εolvent: Ethyl acεtatε/diεthyl εther

Melting Point: 208 - 210°C

Form: Free

Exampl Struct

Crystalline form: White powder Recrystallization εolvent: Mεthanol/n-hexane Mεlting Point: 178 - 180.5°C Form: Frεε

Examplε 1087 Struct

Crystallinε form: Colorlesε amorphouε NMR analyεis: 244) Form: Free

Examplε 1088

Structurε

Crystallinε form: Colorlεsε amorphous NMR analysis: 245) Form: Free

Example 1089 Structure

Cryεtalline form: White powder

Recryεtallization solvent: Methanol/diethyl ether NMR analysis: 246) Form: Freε

Examplε -1090

Structure

Crystalline form: Colorlesε amorphouε NMR analyεiε: 247) Form: Freε

Examplε 1091 Struct

Crystallinε form: Colorlεsε amorphouε NMR analyεiε: 248) Form: Frεε

Examplε 1092

Struct

Crystalline form: Colorless amorphous NMR analysis: 249) Form: Free

Example 1093

Structu

Crystalline form: White powder

Rεcrystallization solvεnt: Mεthanol/diεthyl εthεr Mεlting Point: 205 - 206°C Form: Frεe

Crystallinε form: Colorlεss amorphous NMR analysis: 250) Form: Free

Example 1095 Struct

Crystalline form: White powder Rεcrystallization solvεnt: Mεthanol/n-hexane Melting Point: 172.5 - 174°C Form: Free

Example 1096

Struct

Crystalline form: White powdεr

Rεcrystallization solvεnt: Methanol/diethyl ether Melting Point: 215 - 216.5°C Form: Freε

Crystallinε form: White powder

Recrystallization solvεnt: Mεthanol/diethyl εther Melting Point: 133 - 136°C Form: Free

Example 1098

Structu

Crystalline form: Colorless amorphous NMR analyεis: 251) Form: Free

Example 1099 Structu

Crystalline form: White powdεr Rεcrystallization solvεnt: Mεthanol/n-hεxanε Mεlting Point: 179 - 180°C Form: Free

Example 1100 Structu

Crystalline form: White powder

Recryεtallization εolvent: Methanol/n-hεxanε

Melting Point: 167.5 - 169.5°C

Form: Free

Example 1101

Struct

Cryεtalline form: White powdεr

Recryεtallization εolvent: Methanol/diεthyl ether Melting Point: 176 - 178°C Form: Freε

Examplε 1102 Structurε

Crystallinε form: Colorlεsε amorphous NMR analysis: 252) Form: Free

Example 1103 Struct

Crystalline form: White powder

Rεcrystallization εolvεnt: Mεthanol/diεthyl ether Mεlting Point: 185 - 188°C Form: Frεε

Examplε 1104 Struct

Crystalline form: White powder

Recrystallization εolvent: Methanol/diεthyl εthεr Mεlting Point: 180 - 181.5°C Form: Free

Example 1105

Struct

Cryεtalline form: White powder

Recrystallization solvent: Methanol/diεthyl ether Melting Point: 181 - 184°C Form: Free

Examplε 1106

Crystalline form: White powder

Recrystallization εolvεnt: Methanol/diethyl εthεr

Mεlting Point: 186.5 - 187°C

Form: Free

Example 1107

Struct

Cryεtalline form: White powdεr

Recrystallization solvent: Methanol/diethyl ether Melting Point: 183 - 184°C Form: Free

Example 1108 Struct

Crystalline form: White powder

Recrystallization εolvent: Methanol/diethyl ether

Melting Point: 151 - 153°C

Form: Freε

Examplε 1109

Structurε

Crystallinε form: Colorlesε amorphouε NMR analysis: 253) Form: Free

Example 1110 Struct

Crystalline form: Colorless amorphous NMR analysis: 254) Form: Free

Example 1111 Struct

Crystalline form: White needles Recrystallization solvent: Ethanol/n-hexane Melting Point: 191 - 195°C Form: Free

Examplε 1112

Structu

Crystallinε form: Whitε powdεr

Rεcrystallization solvεnt: Diεthyl ether/n-hεxanε Mεlting Point: 227 - 230°C Form: Frεε Example 1113

Structu

Crystalline form: Colorlesε amorphouε

NMR analyεiε: 289)

Form: Freε

Examplε 1114

Struct

Crystallinε form: Light yεllow amorphous NMR analysiε: 255)

Examplε 1115 Structurε

Crystallinε form: White powder

Rεcrystallization solvεnt: Diεthyl εthεr/n-hεxanε Melting Point: 172 - 174°C Form: Freε

Example 1116

Struct

Crystalline form: Colorlesε amorphous NMR analysis: 305) Form: Free

Example 1117 Structu

Crystalline form: Colorlesε amorphouε NMR analyεiε: 290) Form: Free

Example 1118

Struct

Crystallinε form: Colorlesε amorphous NMR analysis: 291) Form: Free

Example 1119

Struct

Crystalline form: Colorless amorphous NMR analysiε: 264) Form: Free

Example 1120

Struct

Crystalline form: Colorleεs amorphouε NMR analysis: 265) Form: Freε

Examplε 1121 Structu

Crystalline form: Colorlesε amorphouε NMR analyεis: 266) Form: Free

Examplε 1122 Struct

Crystalline form: Colorless amorphous NMR analysis: 267) Form: Free

Example 1123

Struct

Crystalline form: Colorlesε amorphouε NMR analyεis: 268) Form: Free

Example 1124

Struct

Cryεtalline form: Colorleεs amorphous NMR analysis: 269) Form: Free

Example 1125

Struct

Crystalline form: Colorless amorphous NMR analysiε: 270) Form: Free

Example 1126

Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 271) Form: Free

Example 1127 Struct

Cryεtalline form: Colorleεε amorphouε NMR analysis: 272) Form: Free

Example 1128 Struct

Crystalline form: Colorless amorphous NMR analysis: 273) Form: Free

Example 1129 Structu

Crystallinε form: Colorlesε amorphous NMR analysis: 274) Form: Free

Example 1130 Structu

Crystalline form: Colorless amorphous NMR analysis: 275) Form: Free

Example 1131

Struct

Crystalline form: Colorless amorphous NMR analysiε: 276) Form: Free

Examplε 1132

Struct

Crystalline form: Colorless amorphous NMR analysis: 277) Form: Free

Example 1133

Crystallinε form: Colorlεss amorphous NMR analysiε: 278) Form: Frεε

Example 1134

Struct

Crystalline form: Colorless amorphous NMR analysis: 279) Form: Free

Example 1135 Structu

NMR analysiε: 280) Form: Free

Example 1136 Struct

NMR analysis: 281) Form: Freε

Example 1137 Struct

NMR analysis: 282) Form: Free

Examplε 1138 Struct

NMR analysiε: 283) Form: Freε

Examplε 1139

Structure

NMR analysis: 306) Form: Free

Examplε 1140

St

Crystallinε form: Colorlεεε amorphous NMR analysiε: 284) Form: Frεε

Example 1141

Structu

Crystallinε form: Colorlεsε amorphouε NMR analyεis: 285) Form: Frεε

Examplε 1142

Struct

Crystallinε form: Colorlεss amorphous NMR analysiε: 286) Form: Free

Example 1143

Struct

Cryεtalline form: Colorlεεε amorphouε

NMR analysis: 287)

Form: Free

Examplε 1144

Crystallinε form: Whitε powdεr

Rεcrystallization solvεnt: Dichloromεthanε/diεthyl εthεr

Melting Point: 203 - 207°C

Form: Free

Example 1145 Struct

Cryεtalline form: White powder

Recryεtallization εolvent: Dichloromethanε/diethyl ethεr

Melting Point: 199 - 203°C

Form: Free

Examplε 1146

Structu

Crystalline form: Whitε powdεr

Rεcrystallization solvεnt: Dichloromεthane/diethyl ethεr

Mεlting Point: 210 - 212°C

Form: Frεe

Example 1147

Struct

Crystallinε form: Whitε powdεr

Recryεtallization εolvent: Dichloromethane/diethyl ether

Melting Point: 211 - 214°C

Form: Free

Example 1148

Cryεtalline form: White powder

Recrystallization solvεnt: Dichloromεthane/diethyl ether Melting Point: 186 - 189°C Form: Free

Example 1149 Struct

Crystalline form: Colorlesε amorphouε NMR analyεiε: 288) Form: Frεε

Example 1150

Structu

Cryεtallinε form: Colorlεss amorphous NMR analysis: 292) Form: Frεε

Examplε 1151

Structurε

Crystallinε form: Colorlesε amorphouε NMR analyεiε: 293) Form: Freε

Example 1152 Struct

Crystalline form: White powder

Recrystallization solvent: Dichloromethane/diεthyl ether Melting Point: 144 - 145°C Form: Freε Examplε 1153 Struct

Crystallinε form: Whitε powdεr

Recrystallization solvent: Dichloromethanε/diεthyl εther Melting Point: 149 - 150°C Form: Freε

Example 1154

Struct

Cryεtallinε form: Colorlεεε amorphouε NMR analyεiε: 294) Form: Frεε

Examplε 1155

Struct

Crystallinε form: Colorlesε amorphous NMR analysiε: 295) Form: Free

Example 1156

Struct

Crystalline form: Colorless amorphous NMR analysiε: 301) Form: Freε

Example 1157

Structure

Crystalline form: Colorless amorphous NMR analysiε: 302) Form: Free

Example 1158

Cryεtalline form: Colorleεε amorphouε NMR analyεiε: 303) Form: Free

Example 1159

Structu

Cryεtalline form: Colorleεε amorphouε NMR analyεiε: 304) Form: Free

Crystallinε form: Whitε powdεr

Recrystallization solvent: Ethyl acetate/diisopropyl ether

Melting Point: 191 - 193°C

Form: Freε

Examplε 1161 Struct

Crystallinε form: Whitε powdεr

Recrystallization solvent: Ethyl acetate/diiεopropyl ether

Melting Point: 221 - 223°C

Form: Free

Crystalline form: White powder

Rεcrystallization solvεnt: Ethyl acetate/n-hεxanε

Melting Point: 159 - 161°C

Form: Free

Example 1163

Crystalline form: White powder

Recrystallization εolvent: Ethyl acεtatε/n-hεxanε Mεlting Point: 174 - 175°C Form: Free

Example 1164 Struct

Crystalline form: Colorleεε amorphous NMR analysis: 256) Form: Freε

Examplε 1165

Crystalline form: Colorless amorphous NMR analysis: 257) Form: Freε

Examplε 1166

Crystalline form: Colorlesε amorphouε NMR analysis: 258) Form: Free

Example 1167

Crystalline form: Colorless amorphous NMR analysis: 259) Form: Free

Examplε 1168

Struct

Cryεtallinε form: Colorlεss amorphous NMR analysis: 260) Form: Free

Example 1169

Crystallinε form: Colorlεsε amorphous NMR analyεiε: 261) Form: Frεε

Examplε 1170

Struct

Crystalline form: Colorless amorphous NMR analysiε: 296) Form: Free

Example 1171

Structu

Crystalline form: Whitε powdεr

Recrystallization solvent: Ethanol/diethyl εthεr/n-hεxane

Mεlting Point: 159 - 162°C

Form: Frεε

Examplε 1172

Struct

Crystalline form: Colorleεε nεεdlεs

Rεcrystallization solvεnt: Ethanol/diεthyl ether/n-hεxanε

Mεlting Point: 221 - 224°C

Form: Frεε

Examplε 1173

Structu

Crystalline form: Colorlesε priεmε Rεcrystallization εolvεnt: Ethanol/diethyl ether Melting Point: 199 - 202°C Form: Free

Example 1174

Struct

Crystallinε form: Colorlεεε priεmε Recrystallization solvent: Ethanol/diεthyl ether Melting Point: 215 - 218°C Form: Free Example 1175

Struct

Crystalline form: Colorless neεdlεs

Rεcryεtallization solvεnt: Ethanol/diethyl ether/n-hexane Melting Point: 167 - 170°C Form: Free

Example 1176

Struct

Crystalline form: White powder

Recrystallization solvent: Ethanol/diethyl ether/n-hexane

Melting Point: 191 - 193°C

Form: Free

Example 1177

Struct

Crystalline form: Light yellow amorphous NMR analysis: 262) Form: Free

Examplε 1178

Structu

Crystallinε form: Light yεllow amorphous NMR analysis: 263) Form: Frεε

Examplε 1179

Struct

Crystallinε form: Colorlεsε amorphouε NMR analyεiε: 297) Form: Frεε

Example 1180

Struct

Crystalline form: Colorlesε amorphouε NMR analysis: 298) Form: Free

Example 1181 Struct

Crystallinε form: Colorlεεε amorphous NMR analysiε: 299) Form: Free

Examplε 1182 Structu

Crystallinε form: Colorlεεε amorphouε NMR analysis: 300) Form: Free

Examplε 1183

Structu

Crystalline form: Colorless amorphous NMR analysiε: 307) Form: Frεε

Examplε 1184

Struct

Crystalline form: Colorless amorphous NMR analysis: 308) Form: Freε

Example 1185 Structu

Crystalline form: Colorless amorphous NMR analysis: 309) Form: Frεε

Example 1186 Structure

Crystalline form: Colorless amorphous NMR analysiε: 310) Form: Frεε

Examplε 1187

Struct

Crystalline form: Colorless amorphous NMR analysiε: 311) Form: Free

Example 1188

Structure

Crystalline form: Colorless amorphous NMR analysiε: 312) Form: Free

238) H-NMR (DMSO-dg) δ ; 1.4-2.1 (4H, m) , 2.34 (3H, s), 2.8-5.4 (4H, m), 7.09 (IH, d, J=8.4 Hz), 7.15-7.7 (9H, m), 7.76 (IH, d, J=2.6 Hz), 10.41 (IH, s)

239) H-NMR (DMSO-dg) δ ; 1.5-2.2 (4H, m) , 2.8-5.2 (4H,- m), 7.09 (IH, d, J=8.4 Hz), 7.2-7.7 (9H, m) , 7.76 (IH, d, J=2.6 Hz), 10.63 (IH, s)

240) H-NMR (CDC1 ₃ ) δ ; 1.65-2.2 (4H, m) , 2.25-2.65 (6H, m), 2.75-4.6 (4H, m) , 6.8-8.15 (11H, m)

241) H-NMR (CDCI3) δ ; 1.4-2.25 (4H, m) , 2.25-2.55 (3H, m), 2.7-4.8 (4H, m) , 6.8-8.3 (11H, m)

242) ^X H-NMR (CDCI3) δ ; 1.4-2.1 (4H, m) , 2.35-2.6 (3H, m), 2.8-5.2 (7H, m) , 6.8-8.05 (11H, m)

243) ^X H-NMR (CDCI3) δ ; 1.4-2.15 (4H, m) , 2.4-5.2 (7H, m), 6.8-7.85 (10H, m) , 7.9-8.3 (IH, m)

244) ^X H-NMR (CDCI3) δ ; 1.20-2.38 (11H, m) , 2.98-5.10 (3H, m), 6.45-7.04 (2H, m) , 7.05-7.86 (8H, m) , 8.00-8.50 (IH, m)

245) H-NMR (CDCI3) δ ; 1.05-2.78 (14H, m) , 2.78-5.18 (2H, m), 6.36-7.03 (2H, m) , 7.06-7.90 (8H, m) , 7.98-8.39 (IH, m)

246) H-NMR (CDCI3) δ ; 1.75-2.54 (2H, m) , 2.60-4.03 (4H, m), 3.37 (3H, brε), 5.17 (2H, s), 6.60-6.83

(3H, m) , 6.90-7.07 (IH, m) , 7.07-7.20 (IH, m) ,

7.22-7.50 (6H, m) , 7.73-7.84 (IH, m)

247) ^X H-NMR (CDCI3) δ ; 1.60-2.40 (2H, m) , 2.45 (3H, s), 2.65-3.06 (2H, m) , 3.06-5.28 (2H, m) , 3.35 (3H,

brs), 6.59-7.60 (9H, m) , 7.67-7.88 (IH, m) , 8.12 (IH, brs)

248) H-NMR (CDCI3) δ ; 1.60-2.52 (2H, m) , 2.64-5.32 (4H, m), 3.37 (3H, brs), 6.60-7.98 (10H, m) , 8.50 - (IH, brs)

249) H-NMR (CDCI3) δ ; 1.18-3.15 (12H, m) , 3.40-4.38 (5H, m), 6.58-7.75 (10H, m) , 8.30-8.71 (IH, m)

250) H-NMR (CDCI3) δ ; 0.26-0.71 (4H, m) , 1.15-3.29 (lOH, m), 3.40-4.95 (5H, m) , 6.60-7.85 (10H, m) , 8.18-8.68 (IH, m)

251) H-NMR (CDCI3) δ ; 0.25-0.72 (4H, m) , 1.16-2.35 (6H, m), 2.35-3.30 (4H, m) , 3.43-4.98 (2H, m) , 6.57-7.94 (10H, m) , 8.22-8.89 (IH, m)

252) H-NMR (CDCl- _j ) δ ; 0.69-2.90 (9H, m) , 2.90-5.10 (5H, m), 6.40-7.85 (10H, m) , 8.25-8.54 (IH, m)

253) ^X H-NMR (CDC1 ₃ ) δ ; 2.17 (2H, brs), 2.34 (3H, s), 2.49 (3H, s), 2.87 (2H, t, J=6.0 Hz), 3.10-5.00 (2H, m) , 3.70 (3H, s), 6.67 (IH, d, J=8.0 Hz), 6.85-6.88 (2H, m) , 7.09 (IH, dd, J=l .5 , 8.0 Hz), 7.21-7.50 (4H, m) , 7.64 (IH, d, J=l .9 Hz), 8.11 (IH, m), 8.33 (IH, d, J=8.8 Hz)

254) H-NMR (CDC1 ₃ ) δ ; 1.42-5.06 (13H, m) , 6.51 (IH, d, J=7.8 Hz), 6.76 (IH, m) , 7.01-7.63 (10H, m) , 8.53 (IH, m)

255) ^X H-NMR (CDC1 ₃ ) δ ; 1.26-4.93 (16H, m) , 6.69-7.73 (10H, m) , 8.62-8.84 (IH, m)

256) H-NMR (CDCI3) δ ; 1.45-1.90 (2H, m) , 1.90-2.33 (2H, m), 2.33-3.25 (4H, m) , 3.60-3.93 (3H, m) , 4.45-5.15 (2H, m) , 6.40-8.25 (11H, m)

257) H-NMR (CDC1 ₃ ) δ ; 1.49-1.97 (2H, m) , 1.97-3.10 (3H, m), 3.58-3.98 (3H, m) , 4.60-5.26 (2H, m) , 6.44-8.36 (11H, m)

258) ^X H-NMR (CDC1 ₃ ) δ ; 1.82-2.13 (IH, m) , 2.13-2.43 (IH, m), 2.50 (3H, s), 2.57 (3H, s), 3.69-4.06 (3H, m), 3.78 (3H, ε), 6.45-6.80 (2H, m) , 6.85-7.00 (IH, m), 7.18-7.80 (9H, m)

259) H-NMR (CDC1 ₃ ) δ ; 1.72-2.05 (IH, m) , 2.11-2.40 (IH, m), 2.51 (3H, ε), 2.57 (3H, s), 3.40-4.20 (3H, m), 3.77 (3H, s), 6.35-6.64 (IH, m) , 6.79-6.96 (IH, m), 7.15-8.13 (9H, m)

260) H-NMR (CDC1 ₃ ) δ ; 1.71-2.05 (IH, m) , 2.07-2.32 (IH, m) , 2.33 (6H, s), 2.47 (3H, s), 3.50-3.80 (2H, m), 3.76 (3H, ε), 3.95-4.17 (IH, m) , 6.40-6.70 (2H, m), 6.90-7.03 (IH, m) , 7.14-7.77 (8H, m) , 7.90-8.14 (IH, m)

261) H-NMR (CDC1 ₃ ) δ ; 1.76-2.70 (2H, m) , 2.30 (6H, ε), 2.47 (3H, ε), 3.23-4.40 (3H, m) , 3.73 (3H, ε), 6.30-6.65 (2H, m) , 6.65-8.76 (9H, m)

262) H-NMR (CDC1 ₃ ) δ ; 1.68-2.35 (2H, m) , 2.36-5.11 [13H, m, 2.45 (3H, ε), 2.92 (6H, ε)], 6.56 (IH, dd, J=3.1, 8,7 Hz), 6.78-7.06 (2H, m) , 6.82 (IH, d, J=8.7 Hz), 7.11-7.68 (6H, m) , 7.97 (IH, brε)

263) H-NMR (CDCI3) δ ; 1.69-2.30 (2H, m) , 2.59-5.10 [10H, m, 2.92 (6H, ε)], 6.56 (IH, dd, J=3.1, 8.8 Hz), 6.72-7.90 (9H, m) , 8.42 (IH, brε)

264) ^X H-NMR (CDCI3) δ ; 1.49 (IH, brε), 1.82-2.01 (IH, . m), 2.03-2.26 (IH, m) , 2.46 (3H, s), 2.54 (3H, s), 3.67-3.76 (IH, m) , 3.86 (2H, t, J=6.8 Hz), 6.67 (IH, d, J=8.6 Hz), 6.93 (IH, dd, J=8.6, 2.5 Hz), 7.13-7.43 (9H, m) , 8.15 (IH, brs)

265) H-NMR (CDC1 ₃ ) δ ; 1.58 (IH, brs), 1.86-2.03 (IH, m) , 2.08-2.30 (IH, m) , 2.56 (3H, s), 3.69-3.78 (IH, m), 3.91 (2H, t, J=6.5 Hz), 6.69 (IH, d, J=8.7 Hz), 6.94 (IH, dd, J=8.6, 2.5 Hz), 7.33-7.47 (6H, m) , 7.54-7.63 (2H, m) , 7.67-7.77 (IH, m) , 8.16 (IH, brs)

266) H-NMR (CDC1 ₃ ) δ ; 1.50 (IH, brε), 1.76-2.23 (2H, m) , 2.42 (3H, ε), 2.47 (3H, ε), 3.55-3.94 (3H, m) , 6.28-7.78 (10H, m) , 8.91 (IH, brε)

267) H-NMR (CDC1 ₃ ) δ ; 1.46 (IH, brs), 1.82-2.28 (2H, m), 2.50 (3H, s), 3.52-4.08 (3H, m) , 6.34-7.75 (10H, m), 8.61 (IH, brs)

268) ^X H-NMR (CDC1 ₃ ) δ ; 1.80-2.31 (2H, m) , 2.32 (3H, s), 2.48 (3H, s), 3.51-3.82 (2H, m) , 3.95-4.15 (IH, m) , 6.59 (IH, d, J=8.6 Hz), 6.90 (IH, dd, J=8.6, 2.5 Hz), 7.16-7.61 (9H, m) , 7.88 (IH, brs)

269) H-NMR (CDC1,) δ ; 1.86-2.04 (IH, m) , 2.13-2.31 (IH, m), 2.33 (3H, s), 3.53-3.62 (IH, m) , 3.76 (IH,

dt, J=12.8, 6.4 Hz), 6.60 (IH, d, J=8.7 Hz), 6.91 (IH, dd, J=8.7, 2.5 Hz), 7.33-7.52 (6H, m) , 7.54- 7.66 (2H, m), 7.73-7.82 (IH, m) , 8.07 (IH, brs)

270) ^X H-NMR (CDC1 ₃ ) δ ; 1.65-2.27 (2H, m) , 2.28 (6H, s), 2.48 (3H, s), 3.37-4.07 (3H, m) , 6.33-7.91 (10H, m), 8.20 (IH, brε)

271) H-NMR (CDC1 ₃ ) δ ; 1.71-2.26 (2H, m) , 2.28 (6H, s), 3.36-4.10 (3H, m) , 6.35-7.95 (10H, m) , 8.59 (IH, brε)

272) H-NMR (CDC1 ₃ ) δ ; 2.02-2.23 (2H, m) , 2.28 (3H, s), 2.47 (3H, ε), 2.56 (3H, s), 3.73-4.07 (3H, m) , 4.68 (IH, brs), 6.61 (IH, d, J=8.1 Hz), 6.72-6.83 (IH, m), 7.17-7.63 (11H, m) , 8.03 (IH, brs)

273) H-NMR (CDC1 ₃ ) δ ; 1.61 (IH, brs), 1.87-2.25 (2H, m) , 2.29 (3H, s), 2.56 (3H, s), 3.67-3.78 (IH, m) , 3.91 (2H, t, J=6.9 Hz), 6.52-6.79 (2H, m) , 7.09- 7.15 (IH, m) , 7.30-7.90 (8H, m) , 8.23 (IH, brs)

274) H-NMR (CDC1 ₃ ) δ ; 1.58 (IH, brs), 1.82-2.23 (2H, m), 2.27 (3H, s), 2.48 (3H, s), 2.50 (3H, ε), 3.47- 4.05 (3H, m), 6.23-6.83 (2H, m) , 7.00-7.50 (7H, m) , 7.53-7.74 (IH, m) , 8.28 (IH, brε)

275) H-NMR (CDC1 ₃ ) δ ; 1.60 (IH, brs), 1.82-2.35 (5H, m), 2.49 (3H, s), 3.41-4.08 (3H, m) , 6.30-6.80 (IH, m) , 6.98-7.68 (8H, m) , 7.31-7.82 (IH, m) , 8.77 (IH, brε)

276) H-NMR (CDC1 ₃ ) δ ; 1.76-2.03 (2H, m) , 2.27 (3H, s),

2.32 (6H, ε), 2.47 (3H, s), 3.48-3.58 (IH, m) , 3.66 (IH, dt, J=12.7, 6.1 Hz), 3.97-4.14 (IH, m) , 6.48 (IH, d, J=8.2 Hz), 6.65-6.77 (IH, m) , 7.14-7.59 (9H, ), 7.96 (IH, brs)

277) H-NMR (CDC1 ₃ ) δ ; 1.75-2.04 (2H, m) , 2.27 (3H, s),

2.33 (6H, s), 3.48-3.58 (IH, m) , 3.67 (IH, dt , J=12.7, 6.1 Hz), 3.98-4.16 (IH, m) , 6.48 (IH, d, J=8.2 Hz), 6.72 (IH, dd, J=8.2, 1.9 Hz), 7.16 (IH, d, J=1.9 Hz), 7.27-7.91 (8H, m) , 8.31 (IH, brs)

278) H-NMR (CDC1 ₃ ) δ ; 1.72-2.05 (2H, m) , 2.28 (9H, s), 2.47 (3H, s), 3.16-4.34 (3H, m) , 6.38-7.79 (10H, m) , 8.37 (IH, brs)

279) ^X H-NMR (CDC1 ₃ ) δ ; 1.65-2.07 (2H, m) , 2.28 (9H, s), 3.26-4.38 (3H, m) , 6.34-8.06 (10H, m) , 8.53 (IH, brε)

280) Two sterεoisomerε: Both colorleεs amorphous Isomer A:

[α] ²² = 0° (chloroform, c=1.0)

H-NMR (CDC1 ₃ ) δ ; 1.04 (3H, d, J=6.9 Hz), 1.59 (IH, brε), 2.25-2.45 (IH, m) , 2.49 (3H, s), 2.52 (3H, s), 3.53-3.69 (2H, m) , 3.91 (IH, abq, J=7.2, 12.9 Hz), 6.60 (IH, d, J=8.6 Hz), 6.93 (IH, dd, J=8.6, 2.5 Hz), 7.18-7.60 (9H, m) , 7.76 (IH, brε) Iεomer B: [α] ²² = 0° (chloroform, c=1.0)

H-NMR (CDCI3) δ ; 1.06 (3H, d, J=6.9 Hz), 1.60 (IH, brε), 2.21-2.43 (IH, m) , 2.47 (3H, s), 2.52 (3H, s), 3.51-3.66 (2H, m) , 3.93 (IH, abq, J=7.5, 12.9 Hz), 6.60-6.68 (IH, m) , 6.95 (IH, dt, J=7.5,. 1.8 Hz), 7.03 (IH, dt, J=7.4, 1.4 Hz), 7.17-7.55 (8H, m), 7.81 (IH, brs)

281) Two stεreoiεomerε: Both colorlεεε amorphouε Isomεr A:

[α] ²² = 0° (chloroform, c=1.0)

H-NMR (CDC1 ₃ ) δ ; 1.04 (3H, d, J=6.9 Hz), 1.55 (IH, brs), 2.23-2.46 (IH, m) , 2.53 (3H, s), 3.53- 3.67 (2H, m), 3.91 (IH, abq, J=7.1, 12.9 Hz), 6.61 (IH, d, J=8.6 Hz), 6.93 (IH, dd, J=8.6, 2.5 Hz), 7.28-7.52 (6H, m) , 7.54-7.65 (2H, m) , 7.70-7.79 (IH, m) , 8.16 (IH, brs) Isomεr B: [α] ²² = 0° (chloroform, c=1.0)

^X H-NMR (CDC1 ₃ ) δ ; 1.06 (3H, d, J=6.9 Hz), 1.61 (IH, brs), 2.21-2.42 (IH, m) , 2.51 (3H, s), 3.48- 3.67 (2H, m), 3.90 (IH, abq, J=7.4, 12.9 Hz), 6.59- 6.67 (IH, m), 6.94 (IH, dt, J=7.5, 1.9 Hz), 7.03 (IH, dt, J=7.4, 1.4 Hz), 7.23-7.75 (8H, m) , 8.41 (IH, brε)

282) Two εtεreoiεomerε: Both colorlεss amorphous Isomer A:

[α] ²² = 0° (chloroform, c=1.0)

H-NMR (CDCI3) δ ; 0.99 (3H, d, J=6.5 Hz), 1.37

(IH, brs), 2.16-2.40 (IH, m) , 2.46 (3H, s), 2.48

(3H, s), 3.38-3.96 (3H, m) , 6.30-7.28 (10H, m) ,

8.26 (IH, brε)

Iεomer B:

[α] ²² = 0° (chloroform, c=1.0)

H-NMR (CDCI3) δ ; 1.03 (3H, d,J=6.7 Hz), 1.44 (IH, brs), 2.17-2.40 (IH, m) , 2.45 (3H, s), 2.47 (3H, s), 3.40-3.98 (3H, m) , 6.47-7.73 (10H, m) , 8.23 (IH, brs)

283) Two sterεoiεomεrε: Both colorlεεs amorphous Isomεr A:

[α] ²² = 0° (chloroform, c=l.0)

H-NMR (CDCI3) δ ; 1.00 (3H, d, J=6.6 Hz), 1.40 (IH, brs), 2.18-2.42 (IH, m) , 2.47 (3H, s), 3.36- 4.02 (3H, m), 6.32-7.78 (10H, m) , 8.55 (IH, brs) Isomεr B: [α] ²² = 0° (chloroform, c=1.0)

^X H-NMR (CDCI3) δ ; 1.03 (3H, d, J=6.5 Hz), 1.39 (IH, brs), 2.14-2.39 (IH, m) , 2.45 (3H, s). 3.34- 3.98 (3H, m), 6.53-7.98 (10H, m) , 8.78 (IH, brε)

284) H-NMR (CDCI3) δ ; 1.05-1.25 (3H, ) , 1.25-2.80 (10H, m), 3.00-5.10 (3H, m) , 6.75-8.40 (11H, m)

285) ^X H-NMR (CDCI3) δ ; 1.00-2.80 (12H, m) , 3.00-5.10 (3H, m), 6.70-7.80 (10H, m) , 8.30-8.80 (IH, m)

286) ^X H-NMR (CDCI3) 6 ; 0.95-2.80 (15H, m) , 2.80-5.15 (3H, m), 6.70-7.05 (2H, m) , 7.10-7.80 (10H, m) , 7.95-8.45 (IH, m)

287) H-NMR (CDCI3) δ ; 0.80-2.60 (16H, m) , 2.60-5.05 (4H, m), 6.70-7.70 (10H, m) , 7.85-8.40 (IH, m)

288) ^X H-NMR (CDC1 ₃ ) δ ; 1.30-2.60 (8H, m) , 2.60-5.10 (3H, m), 6.60-7.95 (10H, m) , 8.25-8.70 (IH, m)

289) H-NMR (CDCI3) δ ; 1.27-4.91 (19H, m) , 6.68-7.73 (10H, m), 8.40-8.71 (IH, m)

290) H-NMR (CDCI3) δ ; 1.81-2.54 (6H, m) , 2.15 (3H, ε), 2.41 (3H, ε), 2.46 (3H, ε), 3.61-3.71 (3H, m) , 6.91-7.43 (10H, m) , 8.60 (IH, ε)

291) ^X H-NMR (CDC1 ₃ ) δ ; 1.86-2.50 (3H, m) , 2.28 (9H, ε), 2.49 (3H, s), 6.60-7.47 (10H, m) , 7.75 (IH, m)

292) H-NMR (CDC1 ₃ ) δ ; 1.15-2.55 (13H, m) , 2.55-5.10 (3H, m), 6.60-8.40 (11H, m)

293) ^X H-NMR (CDC1 ₃ ) δ ; 1.15-2.45 (10H, m) , 2.55-5.10 (3H, m), 6.60-7.80 (10H, m) , 8.30-8.70 (IH, m)

294) ^X H-NMR (CDC1 ₃ ) δ ; 1.10-2.60 (4H, m) , 2.41 (6H, s), 2.49 (3H, s), 3.76 (3H, ε), 2.60-5.20 (3H, m) , 6.50-6.80 (3H, ) , 6.90-7.60 (6H, m) , 8.13 (IH, s), 8.30 (IH, d, J=8.5 Hz)

295) ^X H-NMR (CDC1,) δ ; 1.15-2.50 (4H, m) , 2.41 (6H, s), 2.60-5.20 (3H, m) , 3.77 (3H, s), 6.50-7.50 (8H, m) ,

7.65-7.80 (IH, m) , 8.31 (IH, d, J=8.4 Hz), 8.61 (IH, s)

296) H-NMR (CDCI3) δ ; 1.55-3.13 (12H, m) , 2.44 (3H, s), 4.60-5.14 (2H, m) , 6.28 (IH, dd, J=2.5, 8.5 Hz), 6.48 (IH, d, J=8.5 Hz), 6.99 (IH, d, J=2.5 Hz), 7.07-7.58 (8H, m) , 7.80 (IH, brs)

297) H-NMR (CDCI3) δ ; 1.01-2.88, 3.22-4.41, 4.90-5.28 [total 18H, 1.17 (3H, t, J=7.2 Hz), 2.40 (3H, s), 3.77 (3H, ε)], 6.55 (IH, d, J=8.1 Hz), 6.60-7.98 (8H, m), 8.23-8.75 (2H, m)

298) ^X H-NMR (CDCI3) δ ; 1.00-3.04, 3.24-4.45. 4.91-5.27 [total 21H, m, 1.17 (3H, t, J=7.0 Hz), 2.39 (3H, ε), 2.50 (3H, s), 3.75 (3H, s)], 8.56 (IH, d, J=8.3 Hz), 6.69 (IH, d, J=8.3 Hz), 6.82-7.75 (7H, m) , 8.05-8.49 (2H, m)

299) H-NMR (CDCI3) δ ; 1.21-4.62, 4.90-5.43 (total 15H, m), 5.70-6.11 (IH, m), 6.35-7.90 (9H, m) , 8.07-8.92 (2H, m)

300) H-NMR (CDCI3) δ ; 1.20-4.68, 5.01-5.3 [total 18H, m, 2.50 (3H, ε)], 5.72-6.14 (IH, m) , 6.49-7.69 (9H, m), 8.01-8.58 (2H, m)

301) H-NMR (CDCI3) δ ; 1.25-2.80 (14H, m) , 3.00-5.10 (6H, m) , 6.40-8.00 (11H, m)

302) H-NMR (CDCI3) δ ; 1.30-2.90 (11H, m) , 3.00-5.10 (6H, m), 6.40-7.80 (10H, m) , 8.00-8,35 (IH, m)

303) ^X H-NMR (CDCI3) δ ; 1.10-2.80 (16H, m) , 2.85-5.15

(6H, m) , 6.40-7.80 (11H, m)

304) ^X H-NMR (CDC1 ₃ ) δ ; 1.10-2.80 (13H, m) , 2.90-5.10 (6H, m), 6.40-7.85 (10H, m) , 7.90-8.20 (IH, m)

305) ^X H-NMR (CDC1 ₃ ) δ ; 1.27-5.28 (19H, m) , 3.75 (3H, ^■ ε), 6.51 (IH, d, J=7.9 Hz), 6.69-6.81 (2H, m) , 7.05-7.49 (6H, m) , 8.14 (IH, m) , 8.27 (IH, d, J=8.4 Hz)

306) Two εtεreoiεomerε: Both colorlεss amorphous Isomar A:

[α] ²² = 0° (chloroform, c=l.0)

^X H-NMR (CDC1 ₃ ) δ ; 0.78-1.02 (3H, m) , 2.23-2.52

(IH, m), 2.39 (6H, ε), 2.48 (3H, ε), 3.17-4.30 (3H, m), 6.85-7.84 (10H, m) , 8.17 (IH, brs)

Isomεr B:

[α] ²² = 0° (chloroform, c=1.0)

^X H-NMR (CDCI3) δ ; 0.73-1.00 (3H, m) , 2.17-2.52

(IH, m), 2.39 (6H, s), 2.49 (3H, ε), 3.15-4.33 (3H, m), 6.36-7.55 (8H, m) , 7.58-7.83 (2H, m) , 8.19 (IH, brε)

307) H-NMR (CDCI3) δ ; 1.25-4.44, 4.98-5.41 [total 17H, m, 2.40 (3H, ε), 3.76 (3H, ε)], 5.72-6.13 (IH, m) , 6.5601H, d, J=8.4 Hz), 6.69 (IH, d, J=7.9 Hz), 6.77-7.93 (7H, m) , 8.32 (IH, d, J=8.3 Hz), 8.49-

8.95 (IH, m)

308) H-NMR (CDCI3) δ ; 1.23-5.42 (20H, m) , 5.78-6.09

(IH, m) , 6.56 (IH, d, J=8.3 Hz), 6.61-7.82 (8H, m) , 8.14 (IH, s), 8.30 (IH, d, J=8 Hz)

309) H-NMR (CDC1 ₃ ) δ ; 1.20-2.70 (11H, m) , 2.80-4.90 (9H, m), 6.40-7.70 (10H, m) , 8.30-8.70 (IH, m)

310) H-NMR (CDCI3) δ ; 1.20-2.80 (8H, m) , 2.85-5.05 (9H, m), 6.40-7.80 (10H, m) , 8.10-8.50 (IH, m)

311) H-NMR (CDCI3) δ ; 1.20-2.75 (13H, m) , 2.80-5.10 (9H, m) , 6.40-8.00 (11H, m)

312) ^X H-NMR (CDCI3) δ ; 1.20-2.80 (10H, m) , 2.90-5.10 (9H, m), 6.40-7.80 (10H, m) , 8.00-8.40 (IH, m) Example 1189

By using di-p-toluoyl-L-tartaric acid monohydride or di-p-toluoyl-D-tartaric acid monohydridε, thε compound obtainεd in abovε Examplε 408 iε optically reaovled to give the following compoundε.

(+)-5-Dimethylamino-l-[4-(2-methylbenzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepine hydrochloride White amorphous

[α] ²⁵ = +234° (methanol, c=0.2)

Purity; more than 99 % eε, dεtεrmined by HPLC using an optical acitive column HPLC conditions; Mobile phase; n-hexanε : εthanol : diεthylaminε

= 950 : 50 : 1 Flow ratε; 1.0 ml/min.

Column; CHIRALCEL OD, 25 cm x 0.46 cm

(manufactured by Daicel Chemical Ind. Ltd.)

Concentration of εample; 0.1 % in methanol

Retention time; 34 minuteε

^X H-NMR (DMSO-dg) δ ; 0.85-1.20, 1.56-4.06, 4.94- 5.21 (total 13H, ) , 2.36 (3H, ε), 6.79 (IH, d, J=7.6 Hz), 7.12-7.60 (8H, m) , 7.62 (2H, d, J=8.4 Hz), 8.00 (IH, d, J=7.6 Hz), 10.43 (IH, s), 11.80 (IH, brs)

(-)-5-Dimεthylamino-l-[4-(2-mεthylbεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpine hydrochloride White amorphouε

[α] ²⁵ = -23.1° (methanol, c=0.2)

Purity; more than 99 % eε, dεtεrminεd by HPLC uεing an optical activε column, and thε conditions are the same as above excεpt that thε rεtεntion timε is 40 minutεs.

^X H-NMR (DMSO-dg) δ ; 0.83-1.19, 1.55-4.06, 4.94- 5.20 (total 13H, m) , 2.36 (3H, ε), 6.80 (IH, d, J=7.8 Hz), 7.12-7.60 (8H, m) , 7.63 (2H, d, J=8.5 Hz), 8.00 (IH, d, J=7.8 Hz), 10.44 (IH, ε), 11.74 (IH, brε)

Pharmacological Teat Experiment 1 : V- _j _ recεptor binding assay

Using rat livεr plasma mεmbranε preparations prepared according to Ichihara's method [cf: Akira Ichihara*, J. Bio. Chem., 258, 9283 (1983)], the plasma membrane (50000dpm, 2xl0 ^-10 M) of [ ³ H]-Arg-vasopreεεin and a test compound (60 yg, 10 ^~8 -10 ^~4 M) are incubated at 37°C for 10 minutes in 100 mM Tris-HCl buffer (pH: 8.0, 250 μl) containing 5 mM MgCl , 1 mM EDTA and 0.1 % BSA. After incubation, the mixture is filtered three times using the glasε filter (GF/F) εo as to separata the mεmbranε preparation combined with vasopresεin and then waεhed with the buffer (5 ml). This glass filter is taken out and mixed with liquid scintillation cocktail. The amount of [ H]- vasoprεssin combinεd with the membranε iε mεaεurεd by liquid scintillation counter and the rate of the inhibitory effεct of thε tεst compound is estimated according to the following equation.

^C l ^{" B} l Rate of thε inhibitory εffεct (%) = 100 - X 100

C ₀ - B _±

C 1 : Thε amount of [ ^J 3H]-vasoprεεεin combined with the membrane in the presεncε of thε tεst compound (in prescribed amount).

C : The amount of [ ³ H]-vasopressin combined with the membrane in the absence of the test compound.

B : Thε amount of [ ³ H]-vasoprεεεin combinεd with the membranε in thε prεsεnce of the εxcεsε amount of vasoprεεεin (10 M) .

The reεultε arε expreaεed aε IC^ _Q values, which is thε concεntration of ^' thε test compound required to achievε the inhibitory effect in the rate of 50 %.

The rεsultε arε shown in thε following Tablε 5. Test compound

1. 1-(4-Benzoylaminobenzoyl)-1,2,3 ,4-tetrahydro- quinolinε

2. 1-[4-(3-Chlorobεnzoylamino)bεnzoyl]-1,2,3,4- tetrahydroquinoline

3. 1-[4-(3-Mεthoxybεnzoylamino)benzoyl]-1,2,3,4- tεtrahydroquinolinε

4. 1-[4-(3-Cyanobεnzoylamino)bεnzoyl]-1,2,3,4- tetrahydroquinoline

5. l-[4-(3-Aminobenzoylamino)benzoyl]-l,2,3,4- tεtrahydroquinolinε

6. l-[4-(2,3-Dimεthylbεnzoylamino)bεnzoyl]-l,2,3,4- tetrahydroquinoline

7. l-[4-(2-Methylbenzoylamino)benzoyl]-l,2,3,4- tεtrahydroquinolinε

8. l-[4-(2-Trifluoromεthylbεnzoylamino)benzoyl]- 1,2,3,4-tetrahydroquinoline

9. l-[4-(2-Nitrobεnzoylamino)benzoyl]-!,2,3,4- tetrahydroquinoline

10. l-[4-(3,5-Dichlorobenzoylamino)bεnzoyl]- 1,2,3,4-tetrahydroquinoline

11. l-[4-(3,3-Dimethylbutyrylamino)benzoyl]- 1,2,3,4-tetrahydroquinoline

12. 1-[4-(2-Cyclohεxylacεtylamino)benzoyl]-1,2,3,4- tetrahydroquinoline

13. l-[4-(2-Phenylacεtylamino)bεnzoyl]-l,2,3,4- tεtrahydroquinolinε

14. l-(4-Cyclohεxylcarbonylaminobεnzoyl)-l,2,3,4- tetrahydroquinoline

15. 1-(4-Cycloheρtylcarbonylaminobεnzoyl)-1,2,3,4- tetrahydroquinoline

16. 1-(4-Cyclooctylcarbonylaminobεnzoyl)-1,2, 3,4- tetrahydroquinoline

17. l-(4-Tricyclo[3.3.1.1jdεcanylcarbonylamino- benzoyl)-l,2,3,4-tetrahydroquinolinε

18. 1-[4-(α-Naphthylcarbonylamino)benzoyl]-1,2,3,4- tεtrahydroquinolinε

19. 1-[4-(3-Thεnoyl)bεnzoyl]-1,2 ,3,4-tεtrahydro- quinoline

20. 1-[2-(β-Naph hylcarbonylamino)benzoyl]-1,2,3,4- tetrahydroquinoline

21. 1-[4-(4-Mεthoxyanilinocarbonyl)bεnzoyl]- 1,2,3,4-tεtrahydroquinoline

22. 1-[4-(2-Mεthylanilinocarbonyl)benzoyl]-1, 2, 3,4- tetrahydroquinoline

23. l-[4-(3-Chloroanilinocarbonyl)bεnzoyl]-l,2,3,4- tεtrahydroquinolinε

24. 1-[4-(3,5-Dichloroanilinocarbonyl)bεnzoyl]- 1,2,3,4-tεtrahydroquinolinε

25. l-(4-Cyclohεxylaminocarbonylbεnzoyl)-l,2,3,4- tetrahydroquinoline

26. 1-(4-Cyclohexylcarbonylaminobεnzoyl)-2, 3,4,5- tetrahydro-lH-bεnzazεpine

27. 1-(4-Benzoylaminobεnzoyl)-2,3,4,5-tetrahydro- lH-bεnzazεpinε

28. 1-[4-(2-Mεthylbεnzoylamino)benzoyl]-2,3,4,5- tεtrahydro-lH-bεnzazεpinε

29. 1-[4-(3-Mεthoxybεnzoylamino)bεnzoyl]-2,3,4,5- tεtrahydro-lH-bεnzazεpinε

30. l-[4-(3-Chlorobεnzoylamino)bεnzoyl3-2,3,4,5- tetrahydro-lH-benzazepine

31. l-[4-( 3-Cyanobεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazepine

32. l-[4-(3,5-Dichlorobεnzoylamino)bεnzoyl]- 2,3,4,5-tεtrahydro-lH-benzazepine

33. 1-[4-(2,3-Dimethylbεnzoylamino)bεnzoyl]- 2,3,4,5-tetrahydro-lH-benzazepinε

34. 1-(4-Cyclohexylcarbonylaminobenzoyl)- 1,2,3,4,5,6-hεxahydrobεnzazocine

35. l-(4-Benzoylaminobenzoyl)-l,2,3,4,5,6- hexahydrobenzazocine

36. l-[4-( 2-Methy lbenzoylamino) benzoyl ]- 1,2,3,4,5, 6-hexahydrobεnzazocine

37. l-[ 4-( 3 -Methoxy benzoylamino) benzoyl ]- 1,2,3,4,5, 6-hεxahydrobenzazocine

38. l-[4-(2,3-Dimεthylbεnzoylamino)benzoyl]- 1,2,3,4,5, 6-hexahydrobenzazocine

39. l-[4-( 3,5-Dichlorobεnzoylamino)bεnzoyl]- 1,2,3,4,5, 6-hεxahydrobenzazocine

40. 1- ( -Cyclohexylcarbonylaminobenzoyl ) -1 , 2 , 3 , 5- tntrahydro-4,l-bεnzoxazepine

41. l-[4-(3-Mεthylbεnzoylamino)bεnzoyl]-l,2,3,5- tεtrahydro-4,1-benzoxazepinε

42. 1-[4-(2,3-Dimεthylbεnzoylamino)benzoyl]- 1,2,3,5-tetrahydro-4,1-benzoxazepinε

43. l-[4-(3,5-Dichlorobεnzoylamino)benzoyl]- 1,2,3,5-tetrahydro-4,1-benzoxazepine

44. 3-Methyl-l-( 4-cyclohexylcarbonylaminobenzoyl)- 1,2,3,4-tetrahydroquinoline

45. 3-Methyl-l-(4-benzoylaminobenzoyl)-1,2,3,4- tetrahydroquinoline

46. 3-Mεthyl-l-[4-(2-mεthylbenzoylamino)benzoyl]- 1,2,3,4-tetrahydroquinolinε

47. 3-Mεthyl-l-[ 4-(3-mεthoxybεnzoylamino)bεnzoyl]- 1,2,3,4-tεtrahydroquinolinε

48. 3-Methyl-l-[4-(2,3-dimethylbεnzoylamino)- benzoyl]-1 , 2,3,4-tetrahydroquinoline

49. 3-Mεthyl-l-[4-(3,5-dichlorobεnzoylamino)- benzoyl]-l,2,3,4-tεtrahydroquinolinε

50. 4-Mεthyl-l-(4-cyclohεxylcarbonylaminobεnzoyl)- 1,2,3,4-tetrahydroquinoxaline

51. 4-Meth 1-1-[4-(2-methylbenzoylamino)benzoyl]- 1,2,3,4-tetrahydroquinoxaline

52. 4-Methyl-l-[4-(2,3-dimεthylbεnzoylamino)- bεnzoyl]-l,2,3,4-tεtrahydroquinoxalinε

53. 4-Methyl-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-1,2,3,4-tetrahydroquinoxalinε

54. 2-Mεthy1-1-[4-(3,5-dichlorobεnzoylamino)- bεnzoyl]-1,2,3,4-tεtrahydroquinolinε

55. 4-Methyl-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-1,2,3,4-tεtrahydroquinolinε

56. 1-[4-(2-Bromobεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazεpine

57. l-[4-(3-Nitrobenzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazepine

58. 1-[4-(3-Trifluoromethylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε

59. 1-[4-(3-Ethoxybεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazεpinε

60. 1-[4-(3,5-Dimethoxybenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazεpinε

61. 1-[4-(2-Chloro-4-ni robenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazepine

62. l-[4-(2,4-Dichlorobenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

63. 1-[4-(2-Chloro-6-fluorobenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

64. 1-[4-(2,6-Dimεthylbεnzoylamino)bεnzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

65. l-[4-(2-Chloro-4-aminobenzoylamino)bεnzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

66. l-[4-(2-Chloro-4-acetylaminobεnzoylamino)- benzoyl]-2,3, ,5-tetrahydro-lH-bεnzazεpine

67. l-[4-(3-Aminobenzoylamino)benzoyl]-2,3,4, 5- tetrahydro-lH-bεnzazεpine

68. l-{4-[2-(4-Isopropylaminobutoxy)benzoylamino]- bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpinε hydrochloridε

69. 1-[4-(3-Hydroxybεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazepinε

70. l-{4-[2-(4-Aminobutoxy)bεnzoylamino]benzoyl}- 2,3,4,5-tetrahydro-lH-bεnzazεpine

71. l-{4-[ 2-(2-Diethylaminoεthoxy)bεnzoylamino]- bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpinε hydrochloride

72. l-{4-[2-(4-Acεtylaminobutoxy)benzoylamino]- benzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

73. l-{4-[2-(6-Phthalimidohεxyloxy)bεnzoylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-benzazepinε

74. l-{4-[2-(6-Morpholinohexyloxy)benzoylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine

75. l-{4-[2-(6-[4-Methyl-l-piperazinyl]hεxyloxy)- bεnzoylamino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-benzazepinε- dihydrochloridε

76. 1-(3-Mεthoxy-4-cyclohεxylcarbonylaminobεnzoyl)-- 2,3,4,5-tetrahydro-lH-benzazεpinε

77. 1-(3-methoxy-4-benzoylamino)bεnzoyl]-2,3,4,5- tεtrahydro-lH-bεnzazεpinε

78. 1-[3-M thy1-4-(2-mεthylbεnzoylaminoJbεnzoy]- 2,3,4,5-tetrahydro-lH-benzazεpine

79. 4-Methyl-l-(4-cyclohexylcarbonylaminobenzoyl)- 2,3,4,5-tetrahydro-lH-l,4-bεnzodiazεpinε hydrochloridε

80. 4-Methyl-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine hydrochloridε

81. 4-Mεthyl-l-[4-(2,3-dimεthylbεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-l,4-benzodiazepinε hydrochloride

82. 4-Methyl-l-[4-(2-mεthylbεnzoylamino)bεnzoyl]- 2,3,4,5-tetrahydro-lH-l,4-benzodiazεpine hydrochloride

83. 4-Methyl-l-[4-(3-methoxybεnzoylamino)bεnzoyl]- 2,3,4,5-tεtrahydro-lH-l,4-benzodiazepinε

84. 4-Mεthyl-l-[4-(3-chlorobεnzoylamino)bεnzoyl]- 2,3,4,5-tεtrahydro-lH-l,4-bεnzodiazεpinε

85. 4-Mεthy1-1-[4-(2,3,5-trichlorobεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine

86. 4-Propyl-l-[4-(2,3-dimethylbεnzoylamino)-

benzoyl]-2,3,4,5-tetrahydro-lH-1,4-benzodiazepine hydrochloride

87. 5-Methyl-l-(4-benzoylaminobenzoyl)-2,3,4,5- tetrahydro-lH-l,5-benzodiazepine

88. 5-Methyl-l-( 4-cyclohεxylcarbonylaminobεnzoyl) -2,3,4,5-tεtrahydro-lH-l,5-benzodiazepine

89. 5-Methyl-l-[ 4-( 3,5-dichlorobenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-l,5-bεnzodiazepine

90. 5-Mεthyl-l-[ 4-(2-mεthylbεnzoylamino)bεnzoyl] -2,3,4,5-tεtrahydro-lH-l, 5-benzodiazepinε

91. 5-Methyl-l-[4-(2,3-dimethylbεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-l,5-bεnzodiazepine

92. 4-Methyl-l-[3-methoxy-4-(3,5-dichlorobenzoyl¬ amino)benzoyl]-2,3,4,5-tetrahydro-lH-l,4-bεnzodiazεpine

93. 3-(1-Pyrrolidinyl)-l-[4-(2,3-dimethylbεnzoyl- amino)benzoyl]-l,2,3,4-tεtrahydroquinoline

94. 6-Methyl-l-[4-(3,5-dichlorobenzoylamino)- bεnzoyl]-l,2,3,4-tεtrahydroquinolinε

95. 6-Methoxy-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-1,2,3,4-tetrahydroquinoline

96. 3-Hydroxymethyl-l-[4-(3,5-dichlorobenzoyl¬ amino)bεnzoyl]-1,2,3,4-tetrahydroquinolinε

97. 4-Mεthylamino-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinolinε

98. 3-Amino-l-[4-( 3,5-dichlorobenzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinolinε

99. 3-Acetylamino-l-[4-(3,5-dichlorobεnzoylamino)- benzoyl]-l,2,3,4-tetrahydroquinoline

100. 4-Dimethylamino-l-[4-(3,5-dichlorobεnzoyl- amino)benzoyl]-l,2,3,4-tetrahydroquinoline

101. 1-[4-(2-t-Butylaminoacetylamino)bεnzoyl]- 2,3,4,5-tetrahydroquinoline-lH-bεnzazεpinε

102. l-{4-[2-(N-Cyclohεxyl-N-εthyl)acetylamino]- bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

103. 1-{4-[2-(1-Pipεridinyl)acεtylamino]bεnzoyl}- 2,3,4,5-tetrahydro-lH-benzazεpinε

104. 1-[4-(2-Phenoxyacetylamino)benzoyl]-2,3,4,5- tetrahydro-lH-bεnzazεpine

105. 1-[4-(2-Phthalimidoacetylamino)bεnzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε

106. 1-{4-[2-(1,l-Dimεthyl-2-phεnoxyεthyl)amino- acεtylamino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazepine

107. l-{4-[2-(3-Mεthylphεnoxy)acεtylamino]benzoyl}- 2,3,4,5-tetrahydro-lH-bεnzazεpinε

108. l-{4-[2-(3-Mεthoxyanilino)acεtylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-bεnzazεpinε

109. l-{4-[2-(β-Naphthyloxy)acεtyamino]benzoyl}- 2,3,4,5-tetrahydro-lH-bεnzazεpinε

110. l-{4-[2-(4-Mεthylanilino)acεtylamino]bεnzoyl}- 2,3,4,5-tεtrahydro-lH-bεnzazεpinε

111. l-{4-[2-(3-Methoxyphenoxy)acetylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-benzazepinε

112. 1-[4-(4-Pyridylcarbonylaminobenzoyl]-2,3,4,5- tetrahydro-lH-benzazεpine

113. l-{4-[2-(2,4-Dimεthylanilino)acetylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine

114. l-{4-[2-(N-Ethylanilino)acetylamino]benzoyl}- 2,3,4,5-tetrahydro-lH-benzazεpinε

115. l-{4-[2-(N-Allylanilino)acetylamino]bεnzoyl}- 2,3,4,5-tεtrahydro-lH-bεnzazεpinε

116. l-{4-[2-(2-Chloroanilino)acetylamino]benzoyl}- 2,3,4, 5-tetrahydro-lH-benzazepine

117. l-{4-[2-(4-Acetyloxybutoxy)bεnzoylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-benzazεpinε

118. 1-[4-(2-Carboxymεthoxybεnzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpine

119. l-[4-(2-Carbamoylmethoxybεnzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε

120. l-{4-[ 2-(4-Hydroxybutoxy)benzoylamino]- benzoyl}-2,3,4,5-tetrahydro-lH-benzazepinε

121. l-[4-( 2-Ethoxycarbonylmethoxybenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

122. 6-Fluoro-l-[4-(3,5-dichlorobenzoylamino)- benzoyl]-1,2,3,4-tetrahydroquinoline

123. 6-Fluoro-l-{4-[di-(3,5-dichlorobenzoyl)aminoJ- benzoyl}-l,2,3,4-tetrahydroquinoline

124. 1-[4-(2-Diethylaminocarbonylmethoxybenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

125. l-{4-[2-(2-[ (N-(2-hydroxyεthyl)-N-mεthyl- amino]ethoxy)benzoylamino]benzoyl}-2,3,4,5-tεtrahydro-lH- bεnzoazεpinε hydrochloridε

126. l-[4-(2-Mεthylanilinocarbonylamino)bεnzoyl]- - 2,3,4,5-tetrahydro-lH-benzazεpinε

127. l-[4-(2-Chlorophεnylsulfonylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

128. l-{4-[2-(4-Aminomethylanilino)acεtylamino]- bεnzoyl}-2,3,4,5-tetrahydro-lH-benzazεpine

129. l-{4-[2-(N-Phenyl-N-(3-acεtylaminopropyl)- amino)acεtylamino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzaz� �pinε

130. l-{4-[2-(N-Phεnyl-N-propargylamino)acεtyl- amino]benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine

131. 4-(N-Methyl-N-ethylamino)-l-[4-(3,5-dichloro- bεnzoylamino)bεnzoyl]-1,2,3,4-tεtrahydroquinoline

132. 5-Dimethylami.no-l-[4-(2,4-dichlorobenzoyl- amino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine

133. 4-Dimεthylamino-l-[3-mεthoxy-4-(2-methyl¬ benzoylamino)benzoyl]-1,2,3,4-tεtrahydroquinolinε

134. 5-Dimεthylamino-l-[3-mεthoxy-4-(2-chloro¬ benzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

135. 1-[4-(2,3-Dimεthylbεnzoylamino)bεnzoyl]-4- ethyl-2,3,4,5-tetrahydro-lH-l,4-bεnzodiazεpinε

136. l-[4-(3,5-Dichlorobεnzoylamino)bεnzoyl]-4- isopropyl-2,3,4,5-tεtrahydro-lH-1,4-bεnzodiazεpinε

137. l-[4-(2-M thylbεnzoylamino)bεnzoyl]-5-mεthyl-

1,2,3,4,5,6-hexahydro-l,5-benzodiazocine

138. 1-[4-(2-Methylbenzoylamino)benzoyl]-1,2,3,4- tεtrahydro-5,1-benzoxazepine

139. 5-Oxo-l-[4-(3,5-dichlorobenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

140. 4-Methyl-l-[2-chloro-4-(3,5-dichlorobenzoyl¬ amino)benzoyl]-2,3, ,5-tetrahydro-lH-l,4-benzodiazepine

141. 5-Methylamino-l-[4-(3,5-dichlorobenzoyl¬ amino)benzoyl]-2,3,4, 5-tetrahydro-lH-benzazepinε

142. 5-(N-Acetyl-N-methylamino)-l-[4-(3,5-dichloro- bεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpin� �

143.5-Hydroxy-l-[4-(2-mεthylbεnzoylamino)bεnzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε

144. 4-Dimεthylamino-l-[3-methoxy-4-(2,3-dimethyl- benzoylamino)benzoyl]-l,2,3,4-tetrahydroquinoline

145. 4-Dimethylaminomεthyl-l-[4-(2-mεthylbenzoyl- amino)benzoyl]-l,2,3,4-tetrahydroquinoline

146. 4-Dimethylaminomethyl-l-[ 4-(3,5-dichloro¬ benzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline

147. 5-Methoxy-l-[4-(2-mεthylbεnzoylamino)bεnzoy1]- 2,3,4,5-tεtrahydro-lH-bεnzazεpine

148. 4-Methyl-l-[3-πtethyl-4-(2,4-dichlorobεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-1,4-benzodiazερinε

149. 5-Mεthoxy-l-[4-(2,4-dichlorobεnzoylamino)- benzoyl]-2,3,-4,5-tetrahydro-lH-benzazepine

150. 4-Dimethylamino-l-[4-( 2-chlorobεnzoylamino)-

bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpine

151. 4-Acetyloxy-l-[4-( 2-methylbenzoylamino)- benzoyl]-1,2,3,4-tetrahydroquinolinε

152. 5-Hydroxyimino-l-[4-(3,5-dichlorobεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

153. 5-Acεtyloxy-l-[4-(2-chlorobenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε

154. 5-Ethoxycarbonylmεthoxy-l-[4-(2,4-dichloro- bεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpin� �

155. 4-Allylamino-l-[4-(3,5-dichlorobεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine

156. 5-Dimethylamino-l-[3-methoxy-4-(2,3,5- trichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine

157. 4-[4-(2-Methylbεnzoylamino)benzoyl]-3,4- dihydro-2H-l,4-benzothiazine

158. 5-Dimethylamino-l-[2-chloro-4-(2-mεthyl- bεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpin� �

159. 5-Dimεthylamino-l-[4-(2-mεthylanilino- carbonyl)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

160. 5-Ethoxycarbonylmethoxy-l-[4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

161. 5-(4-dimεthylaminobutoxy)-l-[4-(2-mεthyl- bεnzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH-benzazεpine

162. 5-Carboxymεthoxy-l-[ -(2-chlorobεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

163. 5-Dimethylaminocarbonylmethoxy-l-[4-(2- mεthylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepinε

164. 5-Carbamoylmethoxy-l-[4-(2-chlorobenzoyl¬ amino)bεnzoy1]-2,3,4,5-tetrahydro-lH-benzazepine

165. 5-Dimεthylamino-l-[3-εthoxy-4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

166. 5-[4-(2-Methylbenzoylamino)bεnzoyl]-2,3,4,5- tεtrahydro-1,5-bεnzothiazεpinε

167. 5-Amino-l-[4-(2-mεthylbenzoylamino)benzoyl]- 2,3,4,5-tεtrahydro-lH-bεnzazεpinε

168. 5-Dimethylamino-l-[3-hydroxy-4-[2-methyl- bεnzoylamino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

169. 5-n-Propylamino-l-[4-(2,4-dichlorobenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

170. 5-Dimethylamino-l-[3-benzyloxy-4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

171. 5-[4-(2-Methylbenzoylamino)benzoyl]-2,3,4,5- tεtrahydro-1,5-bεnzothiazεpin-l-oxide

172. 5-[3-(Phthalimid-l-yl)-propoxy]-l-[4-(2- mεthylbεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-lH- bεnzazεpinε

173. 5-(3-Aminopropoxy)-1-[4-(2-mεthylbεnzoyl- amino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepine

174. 5-{3-Acεtylaminopropoxy)-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpine

175. 5-Dimethylamino-l-[2-chloro-4-(2-t-butyl- benzoylamino)benzoyl]-2,3, ,5-tetrahydro-lH-benzazepinε

176. 5-Mεthylamino-l-[2-chloro-4-(2-chlorobεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine

177. 5-Dimethylamino-l-[2-mεthoxy-4-(2-chloro- benzoylamino)bεnzoyl]-2,3,4, 5-tεtrahydro-lH-bεnzazepine

178. 5-Hydroxy-l-[ 4-(3,5-dichlorobenzoylamino)- bεnzoyl]-2,3, ,5-tεtrahydro-lH-bεnzazεpinε

179. 5-Dimεthylamino-l-[4-(2-methylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

180. 5-Dimεthylamino-l-[4-(2-chlorobεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

181. 5-Mεthylamino-l-[4-(2-chlorobεnzoylamino)- bεnzoyl]-2,3,4,5-tεtr hydro-lH-bεnzazεpinε

182. 5-Mεthylamino-l-[2-chloro-4-(2-mεthylbenzoyl- amino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε

183. 5-Dimεthylamino-l-[2-mεthoxy-4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

184. 5-Dimεthylamino-l-[2-chloro-4-(2-chloro- bεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpine

185. 5-Methylamino-l-[2-chloro-4-(2-mεthylbεnzoyl- amino)benzoyl-2,3,4,5-tetrahydro-lH-benzazepine

186. 5-Cyclopropylamino-l-[2-chloro-4-(2,4- dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazepine

187. 5-Dimεthylaminocarbonyloxy-l-[4-( 2-mεthyl-

benzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH-benzazepine

188. 5-Dimethylamino-l-[4-(2-trifluoromεthyl- bεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε

189. 5-Dimethylamino-l-[3-(2-chlorobenzoyloxy)-4- (2-chlorobenzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH- benzazεpinε

190. 5-(N-Methyl-N-Allylamino)-l-[2-chloro-4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε

191. 5-Carbamoyloxy-l-[4-(2-methylbenzoylamino)- bεnzoy1]-2,3,4 ,5-tεtrahydro-lH-bεnzazepine

192. 1-[4-(2-Methylbenzoylamino)benzoyl]-1,2,3,5- tetrahydro-4,1-bεnzothiazεpinε

193. 4-Oxo-l-[4-(2-methylbεnzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-bεnzazεpinε

194. 1-[4-(2-Mεthylbεnzoylamino)bεnzoyl]-1,2,3,5- tεtrahydro-4,1-benzothiazepine-l,1-dioxidε

195. 5-Mεthylaminocarbonylmethoxy-l-[4-(2-chloro¬ benzoylamino)benzoyl]-2,3,4, 5-tεtrahydro-lH-bεnzazεpinε

196. 5-Mεthylaminocarbonyloxy-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahyro-lH-benzazepinε

197. 5-Dimethylamino-l-[2-dimethylamino-4-(2- methylbenzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH- benzazεpine

198. 5-Methylamino-l-[ 2-chloro-4-(2-trifluoro- mεthylbεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-

bεnzazεpinε

199. 5-Cycloropropylamino-l-[2-chloro-4-(2- methylbenzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH- benzazεpine

200. 5-Cyclopropylamino-l-[2-chloro-4-(2-chloro¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

201. 5-Allylamino-l-[2-chloro-4-(2-methylbenzoyl¬ amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

202. 5-(l-Piperidinyl)-l-[4-(2-chlorobεnzoylamino)* benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

203. 5-(4-Bεnzyl-l-pipεrazinyl)-l-[4-(2-chloro- bεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

204. 5-(l-Pyrrolidinyl)-l-[4-(2-chlorobεnzoyl- amino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

205. 5-(4-Acεtyl-l-pipεrazinyl)-l-[4-(2-chloro- bεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

206. 5-(4-Methyl-l-pipεrazinyl)-1-[4-(2-chloro- bεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

207. 1-[4-(2-Chlorobenzoylamino)benzoyl]-2,3- dihydro-lH-benzazεpinε

208. 5-Mεthyl-l-[4-(2-mεthylbεnzoylamino)bεnzoy1]- 2,3,4,5-tetrahydro-lH-benzazεpinε

209. 5-Methylidenε-l-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

210. 5-Hydroxy-l-[2-chloro-4-{2-mεthylbenzoyl- amino)bεnzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine

211. 5-(l-Morpholino)-l-[4-(2-chlorobenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine

212. 5-Dimεthylamino-l-[4-(2-fluorobεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε

213. 5-Dimethylamino-l-[4-(2,4-difluorobenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

214. 4-Hydroxy-l-[4-(2-mεthylbεnzoylamino)bεnzoyl]- 2,3,4,5-tεtrahydro-lH-bεnzazepine

215. 5-Hydroxymethyl-l-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

216. 5-Dimethylamino-4-hydroxy-l-[4-(2-chloro¬ benzoylamino)bεnzoyl]-2,3,4, 5-tetrahydro-lH-bεnzazepine

217. l-[4-(2-Mεthylbεnzoylamino)bεnzoy1]-1,2- dihydroquinolinε

218. 5-Dimεthylamino-l-[2-mεthyl-4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε (thε compound of Examplε 979)

219. 5-Dimεthylamino-l-[2-mεthyl-4-(2-chloro- bεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpin� �

220. 5-Dimethylamino-l-[2-methyl-4-(2,4-dichloro- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine

221. 5-Methylamino-l-{2-chloro-4-[2-(N-εthyl- anilino)acεtylamino]bεnzoy1}-2,3,4,5-tεtrahydro-lH- bεnzazεpinε

222. 5-Hydroxy-l-{2-chloro-4-[2-(N-ethylanilino)- acetylamino]benzoyl}-2,3,4,5-tetrahydro-lH-benzazepine

223. 5-Dimethylamino-l-[2-fluoro-4-(2-chloro-

benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

224. 5-Methylamino-4-hydroxy-l-[2-chloro-4-(2- chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine • hydrochloride

225. 5-Hydroxymethyl-5-hydroxy-l-[2-chloro-4-(2- methylbεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε

226. 5-Dimethylamino-l-[2-fluoro-4-(2-mεthyl- bεnzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH-benzazepine

227. 5-Dimethylamino-l-[3-mεthyl-4-(2,4-dichloro- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

228. 5-(N-Mεthyl-N-εthylamino)-1-[4-(2-methyl- bεnzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH-bεnzazεpine

229. 5-Ethylamino-l-[4-(2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazεpinε

230. 5-Dimεthylamino-l-[4-(3,5-difluorobεnzoyl- amino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpine

231. 5-Acεtyloxymethyl-l-[4-( 2-mεthylbεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

232. 5-Dimεthylamino-l-[3-fluoro-4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

233. 4,4-Dimεthoxy-l-[4-(2-mεthylbεnzoylamino)- bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

234. 5-Acetyloxyimino-l-[4-(2-chlorobenzoylamino)- benzoyl]-2,3, ,5-tetrahydro-lH-bεnzazepine

235. 5-Methylεulfonyloxymεthyl-l-[4-(2-mεthyl-

bεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

236. 5,5-Epoxy-l-[4-(2-methylbenzoylamino)benzoyl] ^• 2,3,4,5-tetrahydro-lH-benzazεpinε

237. 5-Hydroxymεthyl-5-hydroxy-l-[4-(2-mεthyl- bεnzoylamino)bεnzoy1]-2,3,4, 5-tεtrahydro-lH-benzazepine

238. 5-Hydroxy-l-[2-mεthoxy-4-(2-mεthylbenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine

239. 5-Dimethylamino-l-[4-(2-carbamoylmethoxy- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazερine

240. 5-Hydroxy-6-methyl-l-[2-chloro-4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

241. 5-(2-Dimethylaminoethyl)amino-l-[2-chloro-4- (2-mεthylbεnzoylamino)bεnzoy1]-2,3,4, 5-tεtrahydro-lH- bεnzazεpinε

242. 5-Hydroxymεthyl-5-mεthylamino-l-[4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

243. 5-Methylaminomεthyl-5-hydroxy-l-[4-(2-mεthyl- bεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

244. 5-Aminomethyl-l-[4-(2-methylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

245. 5-[N-Methyl-N-(3-methoxy-2-hydroxypropyl)- amino]-1-[4-(2-methylbεnzoylamino)benzoyl]-2,3,4,5-tetra¬ hydro-lH-benzazεpine

246. 5-[N-Methyl-N-(3-diεthylamino-2-hydroxy- propyl)amino]-!-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-lH-bεnzazepine

247. 5-Dimethylamino-l-[3-methoxy-4-( 2-mεthyl- benzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazepine

248. 5-Dimεthylamino-l-[3-mεthoxy-4-(2,4-dichloro- benzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpine

249. 5-Dimethylamino-l-[4-(2-mεthylbεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepinε • hydrochloride

250. 5-Azidomethyl-l-[4-(2-methylbεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

251. 7-[4-(2-Chlorobenzoylamino)benzoyl]-1-methyl- 1,2,3,4a,5,6,7,llb-octahydro-3-oxo[1]bεnzazεpino[4,5-b]- [l,4]oxazinε

252. 5-Bεnzylamino-l-[4-(2-chlorobεnzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

253. 5-Amino-l-[4-(2-chlorobenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazεpinε

254. 5-Dimεthylamino-4-mεthyl-l-[4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazεpine

255. 5-Acetylaminomethyl-l-[4-(2-methylbεnzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

256. 5-Hydroxy-4-mεthyl-l-[4-(2-methylbenzoyl¬ amino)benzoyl]-2,3, ,5-tetrahydro-lH-bεnzazεpine

257. 5-[2-(2-Pyridyl)ethylamino]-l-[4-(2-chloro¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpine

258. 5-{N-Methyl-N-methanesulfonylamino)-l-[4-( 2- mεthylbεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-

benzazepine

259. 5-(N-Methyl-N-benozylamino)-l-[4-(2-methyl- benzoylamino)benzoyl]—2,3,4,5-tetrahydro-lH-bεnzazεpine

260. 5-Ethoxycarbonylamino-l-[4-(2-methylbenzoyl- • amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

261. 5-Methyl-5-hydroxy-l-[4-(2-methylbenzoyl¬ amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

262. 5-(N-Mεthyl-N-εthoxycarbonylmεthylamino)-l-[4- (2-mεthylbεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε

263. 5-Cyclopentylamino-l-[2-chloro-4-(2-methyl¬ benzoylamino)bεnzoyl ]-2,3,4,5-tetrahydro-lH-bεnzazepine

264. 5-[N-Methyl-N-(2,3-dihydroxypropyl)amino]-1- [4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazεpinε

265. 5-( -Mεthyl-N-cyanomεthylamino)-1-[4-(2- methylbεnzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- bεnzazepine

266. 5-( -Mεthyl-N-carbamoylmethylamino)-1-[4-(2- methyIbεnzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH- benzazεpine

267. 5-{N-Methyl-N-[3-(3,4,5,6-tεtrahydro-2H-pyran- 2-yloxy)propyl]amino}-l-[4-(2-mεthylbenzoylamino)benzoyl]- 2,3,4,5-tetrahydro-lH-benzazepine

268. 5-Dimethylaminomethyl-l-[4-( 2-methylbenzoyl¬ amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

269. 5-Formylaminomethyl-l-[4-(2-methylbεnzoyl- amino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

270. 5-[ -Methyl-N-(3-acetyloxypropyl)amino]-1-[ 4- (2-mεthylbεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH- benzazepinε

271. 5-[ -Methyl-N-(3-hydroxypropyl)amino]-1-[4-(2- mεthylbεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzaz epin

272. Potassium {l-[2-chloro-4-(2-mεthylbεnzoyl- amino)benzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpin-5-yl}imin o- o-εulfonate

273. 5-Dimεthylamino-l-(4-benzoylaminobenzoyl)- 2,3,4,5-tetrahydro-lH-benzazepine

274. 5-(l-Bεnzyl-4-pipεridinyl)amino-l-[4-(2- mεthylbεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH- benzazepinε

275. 5-(2-Dimethylaminoacetyloxy)-1-[4-(2-methyl- bεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpin� �

276. 5-Dimεthylamino-l-[4-(3-mεthoxybεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpine

277. 5-[ (4-Mεthyl-l-pipεrazinyl)carbonylmεthoxy]-l- [4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH- benzazepinε

278. 5-Morpholinocarbonylmεthoxy-l-[4-(2-methyl¬ benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

279. 5-Thiomorpholinocarbonylmethoxy-l-[4-( 2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-

benzazepine

280. 5-Anilinocarbonylamino-l-[4-(2-methyIbenzoy1- amino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

281. 5-(l-Oxothiomorpholino)carbonylmεthoxy-l-[4- • (2-m thylbεnzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH- benzazepine

282. 5-Hydrazino-l-[4-( 2-methylbenzoylamino)- benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

283. 5-Methylaminocarbonylamino-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

284. 5-[ (2-α-Carbamoyl-l-pyrrolidinyl)carbonyl- mεthoxy]-l-[4-( 2-mεthylbεnzoylamino)bεnzoy1]-2,3,4,5- tεtrahydro-lH-benzazepinε

285.- 5-(Carbamoylmεthylaminocarbonylmεthoxy)-1-[4- (2-mεthylbεnzoylamino)bεnzoyl]-2,3,4,5-tεtrahydro-lH- bεnzazepine

286. 5-(1,1-Dioxothiomorpholino)carbonylmεthoxy-1- [4-(2-methylbenzoylamino)bεnzoyl]-2,3,4, 5-tεtrahydro-lH- bεnzazεpinε

287. 7-Chloro-5-mεthylamino-l-[4-(2-methylbenzoyl¬ amino)bεnzoy1]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

288. 5-[ (4-Acεtyl-l-pipεrazinyl)carbonylmethoxy]-l- [4-(2-methylbεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH- benzazepine

289. 5-Dimεthylamino-l-[4-(3-nitrobenzoylamino)- bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazεpine

290. 5-[ (4-Pyridyl)mεthylaminocarbonylmethoxy]-l- [4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine

291. 5-[2-(Methylamino)acetylamino]-l-[4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH- bεnzazepine

292. 5-Dimεthylamino-l-[4-(3-aminobεnzoylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

293. 5-{[N-Mεthyl-N-(2-hydroxyεthyl)amino]carbonyl- mεthoxy}-l-[4-(2-mεthylbεnzoylamino)bεnzoyl]-2,3,4,5-tet ra¬ hydro-lH-benzazεpinε

294. 5-Dimethylamino-l-[3-(2-diethylaminoεthoxy)-4- (2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine

295. 5-[N-Methyl-N-(dimεthylaminocarbonylmεthyl)- amino]-1-[4-(2-mεthylbεnzoylamino)bεnzoyl]-2,3,4,5- tetrahydro-lH-benzazεpinε

296. Potaεsium 2-[N-mεthyl-N-{l-[4-(2-mεthyl- bεnzoylamino)bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazεpin-5- yl}aminε]acεtatε

297. 5-{N-Mεthyl-N-[2-(1-imidazolyl)acεtyl]amino}- 1-[4-(2-mεthylbenzoylamino)benzoyl]-2,3, ,5-tetrahydro-lH- benzazepine

298. 5-Dimethylamino-l-[4-(2-dimεthylaminobεnzoyl- amino)benzoyl]-2,3,4, 5-tetrahydro-lH-benzazεpinε

299. 5-[ (2-Aminoacεtyl)amino]-l-[4-(2-mεthyl-

benzoylamino)benzoyl]-2,3,4, 5-tetrahydro-lH-benzazepine

300. 5-Dimethylamino-l-[4-(3-acetylaminobenzoyl- amino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepinε

301. 5-(2-t-Butoxycarbonylaminoacetylamino)-l-[4- ^■ (2-methylbenzoylamino)benzoyl]-2,3,4,5-tεtrahydro-lH- bεnzazεpinε

302. 5-Mεthylamino-7-chloro-l-[4-(2-chlorobenzoyl¬ amino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazεpinε

303. 5-Dimεthylamino-7-chloro-l-[4-(2-mεthyl- benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

304. 5-Dimethylamino-7-chloro-l-[4-(2-chloro- bεnzoylamino)bεnzoy1]-2,3,4, 5-tetrahydro-lH-benzazepine

305. 5-Dimethylamino-l-[4-(phεnylacεtylamino)- bεnzoyl]-2,3,4, 5-tεtrahydro-lH-bεnzazεpinε

306. 5-Dimεthylamino-l-[4-(3-phεnylpropionylamino)- bεnzoyl]-2,3,4,5-tetrahydro-lH-benzazεpine

307. 5-Methylamino-7-chloro-l-{4-[ (N-εthylanilino)- acεtylamino]bεnzoyl}-2,3,4,5-tetrahydro-lH-benzazεpinε

308. 5-Dimethylamino-7-chloro-l-{4-[ (N-ethyl- anilino)acetylamino]benzoyl}-2,3,4,5-tεtrahydro-lH- benzazepinε

309. 5-Dimethylamino-l-[4-(2-bromobenzoylamino)- ^: - benzoyl]-2,3,4,5-tetrahydro-lH-benzazepine

310. 5-Cyclopropylamino-7-chloro-l-[4-(2-methyl¬ benzoylamino)benzoyl]-2, 3,4 ,5-tetrahydro-lH-benzazepine

311. 5-Cyclopropylamino-7-chloro-l-[4-(2-chloro-

benzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-bεnzazepine

312. 5-hydroxy-l-{4-[2-(4-isopropylaminobutoxy)- benzoylamino]benzoyl}-2,3,4,5-tetrahydro-lH-bεnzazεpinε

313. 5-Dimethylaminocarbonylmethoxy-l-{4-[ (N-ethy-1- anilino)acetylamino]benzoyl}-2,3,4,5-tεtrahydro-lH- benzazεpine

314. 5-(N-Methyl-N-ethylamino)-l-[2-chloro-4-(2- chlorobεnzoylamino)bεnzoy1]-2,3,4,5-tεtrahydro-lH- bεnzazepine

315. 5-Dimεthylamino-l-{4-[ (2-chloroanilino)acεtyl- amino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

316. 5-Dimεthylamino-l-{4-[ (2-mεthylanilino)acetyl- amino]bεnzoyl}-2,3,4,5-tεtrahydro-lH-bεnzazεpinε

317. 5-Dimethylamino-l-{4-[ (N-methyl-2-mεthyl- anilino)acεtylamino]bεnzoyl}-2,3,4,5-tεtrahydro-lH- bεnzazεpinε

318. 5-Mεthylamino-9-chloro-l-[4-(2-mεthylbenzoyl- amino)bεnzoyl]-2,3,4,5-tεtrahydro-lH-bεnzazepine

319. 5-Dimethylamino-l-[4-(phεnoxyacεtylamino)- bεnzoyl]-2,3,4,5-tεtrahydro-lH-benzazepinε

320. 6-M thylamino-l-[4-(2-methylbenzoylamino)- benzoyl]-l,2,3,4,5,6-hexahydrobenzazocine

321. 5-Methylamino-7-chloro-l-[3-methoxy-4-(2- chlorobεnzoylamino)bεnzoy1]-2,3,4,5-tetrahydro-lH- benzazepine

322. 5-Cyclopropylamino-7-chloro-l-[3-methoxy-4-(2-

chlorobenzoylamino)benzoyl ]-2,3,4,5-tetrahydro-lH- benzazepine

323. 5-Methylamino-7-chloro-l-[3-mεthoxy-4-( 2- methyIbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH- benzazepine

Table 10

Pharmacological Tεst Experiment 2 : V ₂ recεptor binding assay

Using rat kidnεy plasma mεmbranε prεparationε prεpared according to 0. Hechter'ε mεthod [cf: J. Bio. Chεm., 253, 3211 (1978)], thε plaεma mεmbrane (lOOOOOdpm, 4x10 ° M) of [ ³ H]-Arg-vasopresεin and a tεst compound (0.6 mg, 10 ^_10 - 10~ ⁵ M) are incubated at 4°C for 3 houra in 100 mM Tris-HCl buffer (pH: 8.0, 250 μl) containing 5 mM MgCl ₂ , 1 mM EDTA and 0.1 % BSA. Aftεr incubation, thε mixturε is filtεrεd using thε glass filtεr (GF/F) so as to εεparatε thε mεmbranε prεparation combinεd with vaεoprεεεin and then waεhed twice with thε buffεr (5 ml). Thiε glass filter is taken out and mixed with liquid scintillation cocktail. The

~> amount of [°H]-vaεopressin combined with the membranε iε mεaεurεd by liquid εcintillation countεr and thε rate of the inhibitory effect of the teεt compound iε εεtimatεd according to thε following aquation.

Ratε of thε inhibitory εffεct (%) = 100 - X 100

C ₀ - B _±

C 1 : Thε amount of [3H]-vasopresεin combinεd with thε mεmbranε in thε preεencε of the teεt compound (in preεcribεd amount).

Λ O

C : Thε amount of [ H]-vasopreεsin combined with the membranε in thε absεnce of the teεt compound,

1 ~>

B ^x : The amount of [ H]-vaεoprεεεin combinεd

with the membranε in thε presencε of the excεsε amount of vasoprεεεin (10~ ⁶ M) . Thε reεultε are expreεεεd aε IC^ _Q valuεs, which is the concentration of the test compound required to achieve ^■ the inhibitory effect in the rate of 50 %.

The resultε are εhown in the following Table 6.

Table 11

Expεriment 3: Anti-antidiuretic activity (εffεct on εndogenouε ADH)

A teεt compound or εolvent (dimethylformamidε) iε administεrεd into a caudal vεin of untrεatεd, unrestrained SD rats (male, weight: 300 - 350 g) and the amount of urine, which is spontaneouεly excretεd for a pεriod of 2 hours thεrεaftεr, is collεctεd and mεasurεd by using a mεtabolic gauge. During thiε meaεurεment, the rats are allowed to take water and feed freely.

The amount of urine of control rats (solvent- trεatεd group) is rεgardεd as 100 %, and thε resultε arε εxprεεεed as ED ₃ value, which is the dose of the teεt compound to bε rεquirεd to εxcrεtε thε urinε by thrεε timεε than that of thε control ratε. Thε rεεultε are εhown in the following Table 7.

Table 12

Teεt compound No. ED ₃ (mg/kg)

6 10 33 1.9

178 4.2

249 0.4 * ⁾

*): Phyεicological εaline solution was usεd as a solvent instead of dimethylformamide.