One object of this invention is to provide the new and useful guanidine derivatives and salts thereof which possess a strong inhibitory activity on Na+/H+ exchange in cells.

Another object of this invention is to provide processes for preparation of the guanidine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceutical composition comprising said guanidine derivatives or a pharmaceutically acceptable salt thereof.

Still further object of this invention is to provide a use of said guanidine derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of cardiovascular diseases, cerebrovascular diseases, renal diseases, arteriosclerosis, shock and the like in human being and animals.

BACKGROUND ART Some guanidine derivatives having pharmaceutical activities such as inhibitory activity on Na+/H+ exchange in cells have been known as described in WO 94/26709.

DISCLOSURE OF INVENTION The object guanidine derivatives of the present invention are novel and can be represented by the following general formula (I)

wherein R1 is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, protected amino, aryl or a heterocyclic group; R2 is hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amino, protected amino, aryl or a heterocyclic group; X is -CH2-, -5-, -SO2-, -O- or -NH-; Y is bond or -(CH2)n-, in which n is 1, 2 or 3 Z is bond or -(CH2)m-, , in which m is 1 or 2; and The object compound (I) of the present invention can be prepared by the following process.

Process (1) NH2 R1 O HN=C=NH2 NH 41 0 / or its or its reactive y½½.cN=c½NH2 derivative at the R2 imino group, or a salt thereof (11) (I) or its reactive derivative or a salt thereof at the carboxy group, or a salt thereof wherein R1, R2, X, Y, Z and are each as defined above.

The starting compound (II) can be prepared by the following processes or Preparations mentioned below, or similar manners thereto.

Process (A) (IV) or a salt thereof (VI) or a salt thereof X | cyclization

(VII) or a salt thereof reduction (VIII) or a salt thereof dehydration (IIa) or a salt thereof

hydrogenation (IIb) or a salt thereof wherein R1, R2, X, Y and Z are each as defined above, is is lower alkyl, is is lower alkyl, and L is a leaving group.

Salts of the object guanidine derivatives (I) are pharmaceutically acceptable, conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N -dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, isethionate, methane- sulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine,

aspartic acid, glutamic acid, etc.).

In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.

The term "lower" is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.

Suitable "lower alkyl" may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, preferably one having 1 to 4 carbon atom(s).

Suitable "lower alkylene" is straight or branched one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methylmethylene, dimethylmethylene, ethylmethylene, diethylmethylene, methylethylene, dimethylethylene, ethylethylene, diethylethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene, ethylene, trimethylene or dimethylmethylene.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like, in which the preferred one may be C1-Ct alkoxy.

Suitable "halogen" may include fluorine, bromine, chlorine and iodine.

Suitable "aryl" may include phenyl, naphthyl and the like.

Suitable "protected amino" may include an acylamino or an amino group substituted by a conventional protecting group such as ar(lower)alkyl (e.g., benzyl, trityl, etc.)

or the like.

Suitable "acyl" moiety in the term "acylamino" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows Carboxy; Carbamoyl; Thiocarbamoyl; Sulfamoyl; Aliphatic acyl such as lower or higher alkanoyl 'e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanovl, nonadecanoyl, icosanoyl, etc.); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxcarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkylsulfinyl (e.g., methylsulfinyl, ethylsulflnyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); lower or higher alkoxysulfinyl (e.g., methoxysulfinyl, ethoxysulfinyl, etc.); mono(or di or tri)halo(lower)alkylsulfonyl [e.g. fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, chloromethylsulfonyl, dichloromethylsulfonyl, trichloromethylsuifonyl, 1 or 2-fluoroethylsulfonyl, 1 or 2-chloroethylsulfonyl, etc.); mono(or di or tri)halo(lower)alkylsulfinyl [e.g.

fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, chloromethylsulfinyl, dichloromethylsulfinyl, trichloromethylsulfinyl, 1 or 2-fluoroethylsulfinyl, 1 or 2-chloroethylsulfinyl, etc.); or the like; Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryioyl, phenylpentenoyl, phenvlhexenoyl, etc.), naphthyl (lower) alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; ar(lower)alkoxycarbonyl [e.g., phenyl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.); aryloxy(lower) alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.); arylglyoxylol (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like; Heterocyclic acyl such as heterocycliccarbonyl; heterocyclic(lower) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl, heterocyclichexanoyl, etc.); heterocyclic (lower) alkenoyl (e.g., heterocycliopropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or

the like.

Suitable "heterocyclic" and "heterocyclic" moiety in the terms ttheterocycliccarbonyl", "heterocyclic(lower)- alkanoyl", heterocyclic (lower) alkenoyl", 1,heterocyclicglyoxyloyl", etc. may include saturated or unsaturated, monocclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.

And, especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3- triazolyl, etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,

oxazolidinyl, morpholinyl, sydnonyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocvclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.; unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.; and the like.

The acyl moiety as stated above may have one to ten,

same or different, suitable substituent(s) such as lower alkyl as exemplified above; lower alkoxy as exemplified above; lower alkylthio wherein lower alkyl moiety is as exemplified above; lower alkylamino wherein lower alkyl moiety is as exemplified above; halogen; amino; protected amino as exemplified above; hydroxy; cyano; nitro; carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)alkyl wherein lower alkyl moiety is as exemplified above; carbamoyloxy; hydroxy(lower)alkyl wherein lower alkyl moiety is as exemplified above; diamino(lower)alkylidene (e.g., diaminomethylene, etc.); di (lower) alkylamino wherein lower alkyl moietv is as exemplified above; di(lower)alkylamino(lower)alkyl wherein lower alkyl moiety is as exemplified above, or the like.

Suitable "leaving group" may include acid residue and the like, and suitable examples of "acid residue" may be halogen (e.g., fluorine, chlorine, bromine, iodine), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] or the like.

The process for preparing the object compound of the present invention is explained in detail in the following.

Process (1) The compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the carboxy group, or a salt thereof with the compound (III) or its reactive derivative at the imino group, or a salt thereof.

Suitable reactive derivative at the imino group of the compound (III) may include a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl)acetamide,

mono(trimethylsilyl)acetamide [e.g. N-(trimethylsilyl)- acetamide], bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.

Suitable reactive derivative at the carboxy group of the compound (II) may include a conventional one such as an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.

Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.j; a symmetrical acid anhydride; an activated amide with imidazole, 1-hydroxy-1H-benzotriazole, 4-substituted iidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. cyanomethyl ester, methyl ester, ethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3) 2N=CH-]ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenvl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, benzothiazolyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)- pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,

1-hydroxy-lH-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.

The reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form or its salt form, the reaction is preferably carried out In the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; <BR> <BR> <BR> <BR> N-cyclohexyl-N' -morpholinoethylcarbodiimide; <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> N-cycloheXyl-N'-(4-diethvlaminocyclohexyl)carboxiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; <BR> <BR> <BR> <BR> N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> N,N'-carbonyl-bis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cvclohexylimine; ethoxyacetylene; 1-alkoxv-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1- (p-chlorobenzenesulfonyloxy) -6- chloro-1H-benzotriazole; a combination of N-lower alkylhalopyridium halide (e.g., 1-methyl-2- chloropyridinium iodide, etc.) and tri(lower)alkylamine (e.g. triethylamine, etc.); so-called Vilsmeier reagent

prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine (e.g. triethylamine, etc.), pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, alkali metal lower alkoxide (e.g. sodium methoxide, etc.) or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process (A)-O The compound (VI) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V).

This reaction can be carried out in the manner disclosed in Preparation 13 or 15 or similar manners thereto.

Process (A)-O The compound (VII) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to cyclization reaction.

This reaction can be carried out in the manner disclosed in Preparation 1 or similar manners thereto. rocess (A)-O The compound (VIII) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof to reduction reaction.

This reaction can be carried out in the manner disclosed in Preparation 3 or similar manners thereto.

Process (A)- The compound (IIa) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to dehydration reaction.

This reaction can be carried out in the manner disclosed in Preparation 5 or similar manner thereto.

Process The compound (IIb) or a salt thereof can be prepared by subjecting the compound (IIa) or a salt thereof to hydrogenation reaction.

This reaction can be carried out in the manner disclosed in Preparation 7 or similar manners thereto.

It is to be noted that the object compound (I) may include one or more stereoisomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope o this invention.

Regarding the object compound (I), it is to be understood that they include tautomeric isomers.

That is, a group of the formula can be also alternatively represented by its tautomeric formula

That is, both of the said groups are in the state of equilibrium and such tautomerism can be represented by the following equilibrium.

And it is obvious to any person skilled in the arts that both of the tautomeric isomers are easily convertible reciprocally and are included within the same category of the compound rer se.

Accordingly, the both of the tautomeric forms of the object compound (I) are clearly included within the scope of the present invention.

In the present specification, the object compound including the group of such tautomeric isomers is represented by using one of the expressions therefor, that is the formula only for the convenient sake.

It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.

It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope

of the present invention.

Suitable salts of the object and starting compounds and their reactive derivatives in Process (1) can be referred to the ones as exemplified for the compound (I).

The new guanidine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess a strong inhibitory activity on Na+/H+ exchange In cells and therefore are useful as an inhibitor on Nay/+ exchange in cells.

Accordingly, the new guanidine derivatives (I) and a pharmaceutically acceptable salt thereof can be used for the expectorant and for the treatment and/or prevention of cardiovascular diseases [e.g. hypertension, angina pectoris, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, arrhythmia after PTCA (percutaneous transluminal coronary angioplasty), thrombolysis or CABG (coronary artery bypass graft), etc.), restenosis after PTCA or PTA (percutaneous transluminal angioplasty), etc.], cerebrovascular diseases [e.g. ischemic stroke, hemorrhagic stroke, edema, etc.], renal diseases [e.g. diabetic nephropathy, ischemic acute renal failure, etc.], arteriosclerosis, shock [e.g. hemorrhagic shock, endotoxin shock, etc.], hyperlipidemia and the like, and can also be used as an agent for ischemic reperfusion injury, myocardial protection, organ protection In organ transplantation, in non-cardiac and cardiac surgery, and the like.

In order to show the utilities of the guanidine derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the guanidine

derivatives (I) are illustrated in the following.

[1] Test Compound (a) [6,7-Dihydro-5H-benzocycloheptene-8- carbonyl]guanidine methanesulfonate [2] Inhibitory activity on Na+/H+ exchange in cells [i] Test Method Procedure was carried out according to a similar manner to the method described in Snzymology 173, 777 (1989).

Cell preparation : One male SD strain rat weighing 250-300 g was sacrificed with the blow on the head. Then, the thymus was removed into ice-cold NaCl medium (140 mM sodium chloride, 1 m potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose and 20 mM N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid (HEPES)---pH 7.3), cut in small fragments, and transferred to glass homogenizer. The cells were dissociated by gentle strokes, and the resulting suspension was filtrated through six layers of surgical gauze and the filtrate was centrifuged at 4"C at 1000 g for 5 minutes. The pellet was resuspended in RPMI 1640 medium (pH 7.3) at room temperature to adjust final cell concentration (1 x 107 cells/ml).

Assay : This method detects the swelling that accompanies activation of Na+/H+ exchanger in cells incubated with sodium propionate. Propionic acid rapidly penetrates through the membrane. Intracellular dissociation brings about cytoplasmic acidification and consequently

activation of Na+/H+ exchanger, which exchange extracellular Na+ for cytoplasmic H+. The uptake of osmotically obliged water was manifested as cell swelling.

Cell sizing and counting were performed electrically with the Coulter Counter-Channelyzer (AT-II). 0.1 ml Thymocytes solution were suspended in 20 ml sodium- propionate medium (140 mM sodium propionate, 1 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 0 mM glucose, 20 mN N-2-hydroxyethylpiperazine- N'-2-ethanesulfonic acid (HEPES)---pH 6.8) including test compound solved in dimethyl sulfoxide (final concentration of dimethyl sulfoxide was 0.1). During 4 minutes, increase of cell volume induced b Na+/H+ exchanger was kept near, and the time course of swelling was observed each minute after the addition of thymocytes. Rate of Swelling (a volume/min.) was measured by using 3-5 concentrations of test compound. Then, apparent Ki value of test compound was calculated by using Line weaver-Burk plot.

[3] Test Result Test Compound Ki (M) (a) <1.0 x 10-7 The object compound (I) or its pharmaceutically acceptable salts can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as oral dosage form (e.g., capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, suspension, emulsion, etc.), injectIon dosage form, suppository, ointment, or the like.

The pharmaceutical composition of this invention can

contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose such as excipient (e.g., sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (e.g., cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g., starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropylstarch, sodium glycolestarch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g., magnesium stearate, talc, sodium laurylsulfate, etc.), flavoring agent (e.g., citric acid, menthol, glycine, orange powders, etc.), preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (e.g., citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g., methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g., water, etc.), base wax (e.g., cacao butter, polyethyleneglycol, white petrolatum, etc.).

The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions o the patient or the administering method.

Preferred embodiments of the object compound (I) are as follows.

R1 is hydrogen, halogen (more preferably fluorine, chlorine or iodine), lower alkyl (more preferably C1-C4 alkyl, most preferably methyl or isopropyl), lower alkoxy (more preferably

C1-C4 alkoxy, most preferably methoxy), nitro, amino, protected amino (more preferably lower alkoxycarbonylamino, lower alkanoylamino, lower alkylsulfonylamino, ureido, N'-(lower)- alkylureido, thioureido or N'-(lower)- alkylthioureido, most preferably methoxycarbonylamino, acetylamino, methanesulfonylamino, N' -ethylureido or N'-ethylthioureido), aryl (more preferably C6-C10 aryl, most preferably phenyl) or a heterocyclic group (more preferably unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s) or saturated 3 to 8-membered (more preferably 5 or 6-membered) heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), most preferably pyrrolyl, pyrrolidinyl or morpholinyl); R2 is hydrogen, halogen (more preferably fluorine, chlorine or iodine), lower alkyl (more preferably C1-C4 alkyl, most preferably methyl or isopropyl), lower alkoxy (more preferably C1-C4 alkoxy, most preferably methoxy), nitro, amino, protected amino (more preferably lower alkoxycarbonylamino, lower alkanoylamino, lower alkylsulfonylamino, ureido, N'- (lower) alkylureido, thioureido or N'-(lower)alkylthioureido, most preferably methoxycarbonylamino, acetylamino, methanesulfonylamino, N'-ethylureido or N'-ethylthioureido), aryl (more preferably C6-C10 aryl, most preferably phenyl) or

a heterocyclic group (more preferably unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 3 to 8- membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s) or saturated 3 to 8-membered (more preferably 5 or 6-membered) heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), most preferably pyrrolyl, pyrrolidinyl or morpholinyl); X is -CH2-, -S-, -S02- or -O-; Y is bond or Z is bond or .CH2-; and The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail. The solvents indicated between parentheses after the melting point represent the crystallization solvents.

Preparation 1 To a solution of ethyl 5-fluoro-2-(3- ethoxycarbonylpropoxy)benzoate (2.66 g) in N,N- dimethylformamide (27 mi) containing ethanol (0.026 ml) was added sodium hydride (0.78 g, 60% dispersion in mineral oil) in portions at 0°C under nitrogen atmosphere.

The reaction mixture was stirred for 1.5 hours at ambient temperature, poured into a cold solution of acetic acid (1.35 ml) in water (150 ml), and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with silica

gel column chromatography using a mixture of hexane and ethyl acetate to give colorless solid of ethyl 7-fluoro- 2,3,4,5-letrahydro-5-oxo-l-benzoxepin-4-carboxylate (2.12 g). mp : 50-51°C IR (Nujol) : 1615, 1560 cm-1 NMR (CDCl3, #) : 1.21 and 1.35 (total 3H, each t, J=7.1Hz), 2.35-2.75 (2H, m), 4.0-4.5 (5H, m), 6.9-7.2 (2H, m), 7.45-7.65 (1H, m) CI-MS (m/z) : 253 (M++1) Preparation 2 The following compounds were obtained according to a similar manner to that o Preparation (1) Ethyl 2,3,4,5-tetrahydro-5-oxo-9-phenyl-1-benzoxepin- 4-carboxylate IR (Film) : 1730, 1674, 1630, 1605, 1585 cm 1 NMR (CDCl3, #) : 1.21 (3H, t, J=7.3Hz), 2.4-2.7 (2H, m), 3.95-4.5 (5H, m), 7.1-7.55 (H, m), 7.75-7.9 (1H, m) CI-MS (m/z) : 311 (M++1) (2) Ethyl 2,3,4,5-tetrahydro-5-oxo-7-methyl-1-benzoxepin- 4-carboxylate IR (Film) : 1730, 1675, 1610 cm - NMR (CDCl3, #) : 1.12 and 1.35 (total 3H, each t, J=7.1Hz), 2.32 and 2.34 (total 3H, each s), 2.4- 2.7 (2H, m), 3.95-4.5 (4H, m), 6.94 (1H, dd, J=6.8, 8.2Hz), 7.1-7.3 (1H, m), 7.55-7.75 (1H, m) CI-MS (m/z) : 249 (M++1) (3) Ethyl 2,3,4,5-tetrahydro-5-oxo-9-methyl-1-benzoxepin- 4-carboxylate

IR (Film) : 1735, 1675 cm NMR (CDCl3, #) : 1.15-1.4 (3H, m), 2.28 (3H, s), 2.4-2.7 (2H, m), 4.0-4.55 (5H, m), 6.95-7.1 (1H, m), 7.2-7.35 (1H, m), 7.6-7.7 (1H, m) CI-MS (m/z) : 249 (M++1) (4) Ethyl 2,3,4,5-tetrahydro-5-oxo-9-iodo-1-benzoxepin-4- carboxylate IR (Film) : 1730, 1675, 1580 cm 1 NMR (CDCl3, 5) : 1.22 (3H, t, J=7.1Hz), 2.45-2.75 (2H, m), 4.0-4.45 (4H, m), 4.45-4.65 (1H, m), 6.89 (1H, dd, J=7.8, 7.8Hz), 7.77 (1H, dd, J=1.7, 7.8Hz), 7.95 (1H, dd, J=1.7, 7.8Hz) CI-MS (m/z) : 361 (M++1) (5) Ethyl 2,3,4,5-tetrahydro-5-oxo-9-isopropyl-1- benzoxepin-4-carboxylate IR (Film) : 1735, 1680 cm NMR (CDCl3, 5) : 1.1.-1.3 (9H, m), 2.3-2.7 (2H, m), 3.25-3.5 (1H, m), 4.0-4.55 (5H, m), 7.0-7.15 (1H, m), 7.3-7.45 (1H, m), 7.55-7.7 (1H, m) CI-MS (m/z) : 277 (M++1) (6) Ethyl 2,3,4,5-tetrahydro-5-oxo-9-pyrrolidino-1- benzoxepin-4-carboxylate IR (Film) : 1730, 1670 cm-1 NMR (CDCl3, #) : 1.22 and 1.35 (total 3H, each t, J=7.lHz), 1.85-2.1 (4H, m), 2.35-2.7 (2H, m), 3.25-3.5 (4H, m), 3.95-4.55 (5H, m), 6.7-7.3 (3H, m) CI-MS (m/z) : 304 (M++1) (7) Ethyl 2,3,4,5-tetrahydro-9-methoxy-5-oxo-1- benzoxepin-4-carboxylate IR (KBr) : 1749, 1678 cm-1

NMR (CDC13, #) : 2 2.4-2.6 (2H, m), 3.82 (3r" s), 3.90 (3H, s), 4.0-4.15 (2H, m), 7.0-7.15 (2H, m), 7.30-7.45 (1H, m) CI-MS (m/z) : 251 (M++1) Preparation 3 To a solution of ethyl 7-fluoro-2,3,4,5-tetrahydro-5- oxo-1-benzoxepin-4-carboxylate (2.00 g) in ethanol (20 ml) was added sodium borohydride (0.225 g) at 0°C. The reaction mixture was stirred for 2 hours at ambient temperature, acidified with 1N hydrochloric acid (12 ml), and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed successively with brine, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of hexane and ethyl acetate to give colorless oil of ethyl 7-fluoro- 2,3,4,5-tetrahydro-5-hydroxy-1-benzoxepin-4-carboxylate (1.15 g).

IR (Film) : 3450, 1710, 1590 cm 1 NMR (CDCl3, #) : 1.15-1.35 (3H, m), 2.1-2.55 (2H, m), 2.7-3.15 (1H, m), 3.25-3.8 (2H, m), 4.0-4.4 (3H, m), 5.05-5.2 (1H, m), 6.8-7.3 (3H, m) CI-MS (m/z) : 255 (M++1), 237 Preparation 4 The following compounds were obtained according to a similar manner to that of Preparation 3.

(1) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-9-phenyl-1- benzoxepin-4-carboxylate IR (Film) : 3450, 1705, 1580 cm 1 NMR (CDC13, #) : 1.15-1.3 (3H, m), 2.1-2.6 (2H, m), 2.8-3.1 (1H, m), 3.2-3.5 (1H, m), 3.65-4.0 (1H,

m), 4.0-4.3 (3H, m), 5.2-5.3 (1H, m), 7.05-7.55 (8H, m) CI-MS (m/z) : 295 (M++1-H2O) (2) Ethyl 7-chioro-2,3,4,5-tetrahydro-5-hydrcxy-9- methoxy-1-benzoxepin-4-carboxylate IR (Film) : 3450, 1710, 1570 cm 1 NMR (CDC13, #) : 1.15-1.35 (3H, m), 2.1-2.55 (3H, m), 2.7-3.55 (3H, m), 3.89 (3H, s), 4.0-4.4 (3H, m), 5.05-5.2 (1H, m), 6.75-6.85 (1H, m), 6.9-7.0 (1H, m) CI-MS (m/z) : 283 (M++1-H2O) (3) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-7-methyl-1- benzoxepin-4-carboxylate IR (Film) : 3450, 1710 cm-1 NMR (CDCl3, #) : 1.25-1.35 (3H, m), 2.05-2.35 (1H, m), 2.30 (3H, s), 2.35-2.65 (1H, m), 2.7-3.0 (1H, m), 3.05-3.35 (1H, m), 3.75-4.35 (4H, m), 5.05-5.2 (1H, m), 6.87 (1H, d, J=8.OHz), 7.00 (1H, d, J=8.OHz), 7.26 and 7.30 (total 1H, each s) CI-MS (m/z) : 233 (M++1-H2O) (4) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-9-methyl-1- benzoxepin-4-carboxylate IR (Film) : 3460, 1720 cm 1 NMR (CDC13, #) : 1.15-1.3 (3H, m), 2.1-2.3 (4H, m), 2.8-3.4 (2H, m), 3.75-4.3 (4H, m), 5.1-5.2 (1H, m), 6.9-7.35 (3H, m) CI-MS (m/z) : 251 (M++1) (5) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-9-isopropyl-1- benzoxepin-4-carboxylate IR (Film) : 3470, 1720 cm 1

NMR (CDCl3, #) : 1.05-1.3 (9H, m), 2.05-2.3 (1H, m), 2.4-2.65 (1H, m), 2.75-3.0 (2H, m), 3.2-3.45 (1H, m), 3.7-4.35 (4H, m), 5.05-5.2 (1H, m), 6.9-7.35 (3H, m) CI-MS (m/z) : 261 (M++1-H2O) (6) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-9-iodo-1- benzoxepin-4-carboxylate IR (Film) : 3470, 1715 cm 1 NMR (CDCl3, 5) : 1.1-1.3 (3H, m), 2.1-2.9 (2H, m), 2.95-3.1 (1H, m), 3.75-4.35 (5H, m), 5.1-5.25 (1H, m), 6.75-6.9 (1H, m), 7.3-7.55 (1H, m), 7.65-7.75 (1H, m) CI-MS (m/z) : 362 (M++1), 345 (M++1-H2O) (7) Ethyl 2,3,4,5-tetrahydro-5-hydroxy-9-pyrrolidino-1- benzoxepin-4-carboxylate IR (Film) : 3480, 1715, 1585 cm 1 NMR (CDCl3, 5) : 1.25 and 1.26 (total 3H, each t, J=7.1Hz), 1.85-2.0 (4H, m), 2.0-2.7 (2H, m), 2.85-3.25 (5H, m), 3.75-3.95 (1H, m), 4.05-4.3 (4H, m), 5.15-5.25 (1H, m), 6.55-7.05 (3H, m) CI-MS (m/z) : 306 (M++1) (8) Methyl 2,3,4,5-tetrahydro-5-hydroxy-9-methoxy-1- benzoxepin-4-carboxylate iR (Neat) : 3502, 1732, 1716 cm 1 NMR (CDCl3, #) : 2.1-2.65 (2H, m), 2.8-3.4 (2H, m), 3.7 (3H, s), 3.85 (3H, s), 4.0-4.4 (2H, m), 5.15-5.25 (1H, m), 6.8-7.15 (3H, m) CI-MS (m/z) : 235 (M++1-H20) Preparation 5 To a solution of ethyl 7-fluoro-2,3,4,5,-tetrahydro-5- hydroxy-1-benzoxepin-4-carboxylate (1.00 g) in toluene (10

ml) was added p-toluenesulfonic acid monohydrate (?4.8 mg). The reaction mixture was stirred under reflux for 1.5 hours, quenched with triethylamine (0.082 ml) after cooling, diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified with medium performance liquid chromatography using a mixture of hexane and ethyl acetate as an eluent to give colorless solid of ethyl 7-fluoro- 2,3-dihydro-1-benzoxepin-4-carboxylate (0.8 g). mp : 56-57°C IR (Nujol) : 1685 cm 1 NMR (CDC13, #) : 1.35 (3H, t, J=7.lHz), 2.9-3.05 (2H, m), 4.15-4.35 (4K, m), 6.85-7.05 (3H, m), 7.47 (1H, s) CI-MS (m/z) : 237 (M++1) Preparation 6 The following compounds were obtained according to a similar manner to that of Preparation 5.

(1) Ethyl 2,3-dihydro-9-phenyl-1-benzoxepin-4-carboxylate IR (Film) : 1725, 1690, 1620, 1580 cm-1 NMR (CDCl3, #) : 1.35 (3K, t, J=7.1Hz), 2.9-3.05 (2H, m), 4.2-4.35 (4H, m), 7.0-7.55 (8H, m), 7.66 (1H, s) CI-MS (m/z) : 295 (N++1) (2) Ethyl 7-chloro-2,3-dihydro-9-methoxy-1-benzoxepin-4- carboxylate mp : 106-107°C IR (Nujol) : 1700, 1625, 1560 cm NMR (CDCl3, 5) : 1.34 (3H, t, J=7.1Hz), 2.95-3.05 (2H, m), 3.87 (3H, s), 4.2-4.4 (4H, m), 6.84 (1H, d, J=2.4Hz), 6.94 (1H, d, J=2.4Hz), 7.45

(1H, s) CI-MS (m/z) : 283 (M++1) (3) Ethyl 2,3-dihydro-7-methyl-1-benzoxepin-4-carboxylate IR (Film) : 1690, 1625, 1570 cm 1 NMR (CDCl3, #) : 1.35 (3H, t, J=7.1Hz), 2.29 (3H, s), 2.8-3.05 (2H, m), 4.15-4.35 (4H, m), 6.86 (1H, d, J=8.2Hz), 7.07 (1H, dd, J=1.9, 8.2Hz), 7.12 (1H, br s), 7.54 (1H, s) CI-MS (m/z) : 233 (M++1) (4) Ethyl 2,3-dihydro-9-methyl-1-benzoxepin-4-carboxylate IR (Film) : 1695, 1630 cm 1 NMR (CDC13, 5) : 1.35 (3H, , J=7.1Hz), 2.25 (3H, s), 2.9-3.0 (2K, m), 4.15-4.35 (4K, m), 6.91 (1H, dd, J=7.5, 7.5Hz), 7.15-7.25 (2H, m), 7.58 (1K, s) CI-MS (m/z) : 233 (M++1) (5) Ethyl 2,3-dihydro-9-isopropyl-1-benzoxepin-4- carboxylate IR (Film) : 1690, 1630, 1590 cm - NMR (CDCl3, #) : 1.21 (6H, t, J=6.9Hz), 1.35 (3H, t, J=7.1Hz), 2.9-3.05 (2H, m), 3.38 (1H, septet, J=6.9Hz), 4.15-4.35 (4H, m), 6.98 (1H, dd, J=7.5, 7.5Hz), 7.1-7.25 (2H, m), 7.59 (1H, s) CI-MS (m/z) : 261 (M++1) (6) Ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4-carboxylate IR (Film) : 1695, 1630 cm NMR (CDC13, #) : 1.35 (3H, t, J=7.1Hz), 2.95-3.05 (2H, m), 4.28 (2H, q, J=7.1Hz), 4.25-4.4 (2H, m), 6.76 (1H, dd, J=7.7, 7.7Hz), 7.32 (1H, dd, J=1.5, 7.7Hz), 7.51 (1H, s), 7.75 (1H, dd, J=1.5, 7.7Hz)

CI-MS (m/z) : 345 (M++1) (7) Ethyl 2,3-dihydro-9-pyrrolidino-1-benzoxepin-4- carboxylate IR (Film) : 1690, 1625 cm NMR (CDCl3, #) : 1.35 (3H, t, J=7.1Hz), 1.85-2.05 (4H, m), 2.9-3.05 (2H, m), 3.25-3.45 (4K, m), 4.15-4.35 (4H, m), 6.7-6.95 (3H, m), 7.58 (1H, s) CI-MS (m/z) : 288 (M++1) (8) Methyl 2,3-dihydro-9-methoxy-1-benzoxepin-4- carboxylate mp : 80-81°C IR (KBr) : 1689, 1635 cm 1 NMR (CDC13, #) : 2.95-3.05 (2H, m), 3.81 (3H, s), 3.88 (3H, s), 4.30-4.40 (2H, m), 6.85-7.0 (3H, m), 7.57 (1H, s) CI-MS (m/z) : 235 (M++1) Preparation 7 To a solution of ethyl 2,3-dihydro-7-methyl-1- benzoxepin-4-carboxylate (0.46 g) in ethanol (4.6 ml) was added 10% palladium-on-charcoal (46 mg, 50% wet). The reaction mixture was stirred for 5 hours under hydrogen atmosphere. The catalyst was filtered and the solvent was removed in vacuo. The residue was purified with silica gel column chromatography using a mixture of hexane and ethyl acetate as an eluent to give colorless oil of ethyl 2,3,4,5-tetrahydro-7-methyl-1-benzoxepin-4-carboxylate (0.47 g).

IR (Film) : 1725 cm 1 NMR (CDCl3, #) : 1.25 (3H, t, J=7.1Hz), 2.1-2.35 (2H, m), 2.27 (3H, s), 2.55-2.7 (1H, m), 2.94 (1H, dd, J=2.3, 14.1Hz), 3.10 (1K, dd, J=9.8,

14.1Hz), 3.7-3.85 (1H, m) , 4.14 (2H, q, J=7.lHz), 4.2-4.35 (1H, m), 6.85-7.0 (3H, m) CI-MS (m/z) : 235 (M++1) Preparation 8 To concentrated nitric acid (5 ml, d 1.42) was added a solution of ethyl 2,3-dihydro-1-benzoxepin-4-carboxylate (1.09 g) in acetic acid (0.5 ml) dropwise for 2 minutes at 0°C under ice-sodium chloride cooling. The reaction mixture was stirred for 1 hour at 0°C and for 1.5 hours at ambient temperature, poured into water, and extracted with ethyl acetate. The organic laver was washed successively with water, saturated aqueous sodium bicarbonate (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with medium performance liquid chromatography using a mixture of hexane and ethyl acetate as an eluent to give the following compounds (1) Ethyl 2,3-dihydro-7-nitro-1-benzoxepin-4-carboxylate (0.57 g) mp : 94-95°C IR (Nujol) : 1690, 1660, 1565 cm 1 NMR (CDCl3, #) : 1.37 (3H, t, J=7.1Hz), 2.9-3.1 (2H, m) , 4.15-4.4 (4H, m), 7.15 (1K, d, J=8.8Hz), 7.58 (1H, s), 8.09 (1H, dd, 3=2.8, 8.8Hz), 8.27 (1K, d, J=2.87Hz) CI-MS (m/z) : 264 (M++1) (2) Ethyl 2,3-dihydro-9-nitro-1-benzoxepin-4-carboxylate (0.16 g) mp : 77-78°C IR (Nujol) : 1690, 1600, 1520 cm 1 NMR (CDCl3, #) : 1.36 (3H, t, J=7.1Hz), 3.0-3.15 (2H, m), 4.30 (2H, q, J=7.1Hz), 4.35-4.45 (2H, m), 7.10 (1H, dd, J=7.9, 7.9Hz), 7.5-7.7 (3H, m)

CI-MS (m/z) : 264 (M++1) Preparation 9 o a suspension of iron (reduced, 8.22 g) and ammonium chloride (0.88 g) in 75% (v/v) ethanol (108 ml) was added ethyl 2,3-dihydro-7-nitro-1-benzoxepin-4- carboxylate (7.18 g) in portions under reflux. The reaction mixture was stirred for 1 hour under reflux. The inorganic salt was filtered and the solvent was removed in vacuo. The residue was diluted with ethyl acetate. The organic solvent was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, and evaporated to give orange solid of ethvl 2,3-dihydro-7-amino-1-benzoxepin-4-carboxylate (6.18 g). mp : 89-90°C IR (Nujol) : 3400, 3330, 1685, 1620 cm 1 NMR (CDCl3, #) : 1.34 (3H, t, J=7.1Hz), 2.85-3.0 (2H, m), 3.38 (2H, br s), 4.1-4.25 (2H, m), 4.26 (2H, q, J=?.lKz) , 6.55-6.7 (2H, m), 6 6.80 (1H, d, J=8.3Hz), 7.47 (1H, s) CI-MS (m/z) : 234 (M++l) Preparation 10 he following compound was obtained according to a similar manner to that of Preparation 9.

Ethyl 2,3-dihydro-9-amino-1-benzoxepin-4-carboxylate mp : 67-68°C IR (Nujol) : 3470, 3360, 1675, 1600 cm 1 NMR (CDC13, #) : 1.34 (3H, t, J=7.lHz), 2.9-3.05 (2H, m), 3.61 (2H, br s), 4.15-4.4 (4H, m), 6.65-6.9 (3H, m), 7.54 (1H, s) CI-MS (m/z) : 234 (M++1) Preparation il

A solution of a mixture of ethyl 2,3-dihydro-7-amino- l-benzoxepin-4-carboxylate (0.70 g), 2,5-dimethoxytetra- hydrofuran (0.49 ml) and 4-chloropyridine hydrochloride (45.0 mg) in 1,4-dioxane (18 ml) was heated under reflux for 3 hours. The reaction mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of hexane and ethyl acetate as an eluent to give yellow solid of ethyl 2,3-dihydro-7-(1-pyrrolyl)-1-benzoxepin-4-carboXvlate (0.61 g) mp : 112-114°C IR (Nujol) : 1690 cm 1 NMR (CDC13, #) : 1.36 (3H, t, J=7.1Hz), 2.95-3.1 (2H, m), 4.2-4.4 (4K, m), 6.3-6.4 (2H, m), 6.95- 7.1 (3H, m), 7.26 (1H, dd, J=2.7, 8.6Hz), 7.34 (1H, d, J=2.7Hz), 7.57 (1H, s) CI-MS (m/z) 284 (M++1) Preparation 12 The following compound was obtained according to a similar manner to that of Preparation 11.

Ethyl 2,3-dihydro-9-(1-pyrrolyl)-1-benzoxepin-4- carboxylate mp : 82-83°C IR (Nujol) : 1685 cm - NMR (CDC13, #) : 1.36 (3H, t, J=7.1Hz), 2.9-3.05 (2H, m), 4.2-4.35 (4H, m), 6.25-6.35 (2H, m), 6.9-7.0 (2H, m), 7.06 (1H, dd, J=7.7, 7.7Hz), 7.25-7.4 (2H, m), 7.64 (1H, s) CI-MS (m/z) : 284 (M++1)

Example 1 Sodium methoxide (4.5 ml, 28% in methanol) was added to a solution of methyl 6,7-dihydro-5-benzocycloheptene- 8-carboxylate (1.0 g) and guanidine hydrochloride (2.4 g) in dry N,N-dimethylformamide (10 ml), and the mixture was stirred for 20 hours at ambient temperature. To the reaction mixture was added a mixture of water and ethyl acetate. The separated organic layer was washed with a brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in a solution of methanol and diisopropyl ether and crystallized from a slight excess of methanesulfonic acid. The crystalline was collected by filtration and recrystallized rom a solution of methanol and diisopropyl ether to give (6,7- dihydro-5H-benzocycloheptene-8-carbonyl)guanidine methanesulfonate (0.58 g). mp : 142-143°C IR (Nujol) : 3360, 3130, 1700, 1598, 1180, 1053 cm 1 NMR (DMSO-d6, #) : 1.95-2.08 (2H, m), 2.38 (3H, s), 2.55 (2K, t, 3=6.5Hz), 2.75-2.85 (2K, m), 7.24- 7.35 (3K, m), 7.40-7.51 (1H, m), 7.49 (1H, s), 8.32 (4K, s), 10.97 (1K, s) Anal. Calcd. for C13H15N3O.CH4O3S C 51.68%, H 5.89%, N 12.91% Found : C 51.49%, H 5.91%, N 12.74% Example The following compounds were obtained according to a similar manner to that of Example 1.

(1) (2,3-Dihydro-1-benzoxepin-4-carbonyl)guanidine methanesulfonate mp : 190-192°C IR (Nujol) : 3330, 3130, 1680, 1600, 1200, 1040 cm 1 NMR (DMSO-d6, #) : 2.44 (3H, s), 2.91 (2H, t,

J=8.8Hz), 4.26 (2H, t, J=8.8Hz), 7.01 (1H, d, J=8.0Hz), 7.05-7.16 (1H, m), 7.29-7.40 (1H, m), 7.43 (1H, s), 7.52 (1H, dd, J=1.5Hz, 7.7Hz), 8.39 (4H, s), 11.03 (1H, s) Anal. Calcd. for C12H13N3O2.CH4O3S C 47.70%, H 5.23%, N 12.84% Found : C 47.66%, H 5.47%, N 12.80% (2) (2,3,4,5-Tetrahydro-1-benzoxepin-4-carbonyl)guanidine methanesulfonate mp : 189-191°C IR (Nujol) : 3345, 3100, 1700, 1590, 1205, 1040 cm 1 NMR (DMSO-d6, #) : 2.00-2.20 (2H, m), 2.45 (3H, s), 2.65-2.79 (1H, m), 2.90-3.03 (2H, m), 3.60-3.75 (1H, m), 7.28-7.42 (1H, m), 6.91-?.05 (2H, m), 7.12-7.26 (2H, m), 8.34 (4H, s), 11.44 (1H, s) Anal. Calcd. for C12H15N3O2.CH4O3S C 47.41%, H 5.81%, N 12.76% Found : C 47.52%, H 5.90%, N 12.53% Example 3 The following compounds were obtained according to a similar manner to that of Example 1.

(1) (7-Fluoro-2,3-dihydro-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 189-290°C (diisopropyl ether-methanol) IR (Nujol) : 3320, 3100, 1700 cm NMR (DMSO-d6, #) : 2.40 (3H, s), 2.92 (2H, t, J=4.5Hz), 4.25 (2H, t, J=4.5Hz), 7.03 (1H, dd, J=5.1, 9.0Hz), 7.21 (1H, ddd, J=3.0, 9.0, 9.0Hz), 7.36 (1K, s), 7.3-7.45 (1H, m), 8.33 (4H, br s), 11.00 (1H, br s) CI-MS (m/z) : 250 (M++1-MsOH) Anal Calcd. for C13H16FN3O5S

C 45.21%, H 4.67%, N 12.17% Found : C 45.17%, H 4.61%, N 11.97% (2) (2,3-Dihydro-9-phenyl-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 259-260°C (diisopropyl ether-methanol) IR (Nujol) : 3320, 3120, 1705, 1690, 1635 cm 1 NMR (DMSO-d6, #) : 2.38 (3H, s), 2.91 (2H, t, J=4.5Hz), 4.26 (2H, t, J=4.5Hz), 7.15-7.6 (9H, m), 8.31 (4K, br s), 10.97 (1K, br s) CI-MS (m/z) : 308 (M++1-MsOH) Anal Calcd. for C19H21N305S C 56.56%, H 5.25%, N 10.42% Found : C 56.64%, H 5.18%, N 10.40% (3) (2,3-Dihydro-7-methyl-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 240-241°C (diisopropyl ether-methanol) IR (Nujol) : 3310, 3100, 1685, 1450 cm 1 NMR (DMSO-d6, 5) : 2.27 (3H, s), 2.44 (3H, s), 2.89 (2H, t, J=4.6Hz), 4.22 (2H, t, J=4.6Hz), 6.90 (1H, d, J=8.2Hz), 7.15 (1H, dd, J=1.8, 8.2Hz), 7.30 (1H, br s), 7.38 (1H, s), 8.37 (4H, br s), 10.98 (1H, br s) CI-MS (m/z) : 246 (M++1-MsOH) Anal Calcd. for C14H19N305S C 49.26%, H 5.61%, N 12.31% Found : C 49.64%, H 5.63%, N 12.26% (4) (2,3-Dihydro-9-methyl-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 210-211°C (diisopropyl ether-methanol) IR (Nujol) : 3300, 3100, 1695, 1680, 1630 cm 1 NMR (DMSO-d6, #) : 2.21 (3H, s), 2.40 (3H, s), 2.75-2.95 (2H, m), 4.2-4.35 (2H, m), 7.00 (1H,

dd, J=7.5, 7.5Hz), 7.2-7.4 (2i, m), 7.30 (1H, br s), 7.40 (1H, s), 8.34 (4H, br s), 10.97 (1H, br s) CI-MS (m/z) : 246 (M++1-MsOH) Anal Calcd. for C14HlgN305S C 49.26%, H 5.61%, N 12.31% Found : C 49.76%, H 5.59%, N 12.32% (5) (2,3,4,5-Tetrahydro-7-methyl-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 253-254°C (diisopropyl ether-methanol) IR (Nujol) : 3320, 3100, 1720, 1680, 1600 cm 1 NMR (DMSO-d6, #) : 1.95-2.15 (2H, m), 2.22 (3H, s), 2.41 (3H, s), 2.55-2.75 (1H, m), 2.8-3.05 (2H, m), 3.5-3.7 (1H, m), 4.25-4.4 (1H, m), 6.83 (1H, d, J=8.0Hz), 6.97 (1H, d, J=8.1Hz), 7.02 (1H, s), 8.27 (4H, br s), 11.35 (1H, br s) CI-MS (m/z) : 248 (M++1-MsOH) Anal Calcd. for C14H21N3O5S C 48.97%, H 6.16%, N 12.24% Found : C 48.84%, H 6.21%, N 12.19% (6) (2,3-Dihydro-7-methoxy-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 217-218°C (diisopropyl ether-methanol) IR (Nujol) : 3330, 3125, 1685, 1580 cm 1 NMR (DMSO-d6, #) : 2.38 (3H, s), 2.89 (1H, t, J=4.4Hz), 3.?5 (3H, s), 4.20 (2H, t, J=4.5Hz), 6.94 (2H, s), 7.06 (1H, s), 7.39 (1H, s), 8.30 (4H, br s), 10,96 (1K, br s) CI-MS (m/z) : 262 (M++1-MsOH) Anal Calcd. for C14H19N306S C 47.05%, H 5.36%, N 11.76% Found : C 47.20%, H 5.36, N 11.74%

(7) (2,3-Dihydro-8-methoxy-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 192-193°C (diisopropyl ether-methanol) IR (Nujol) : 3330, 3125, 1700, 1680, 1605 cm 1 NMR (DMSO-d6, #) : 2.37 (3K, s), 2.88 (2H, t, J=4.3Hz), 3.79 (3H, s), 4.26 (2H, t, J=4.3Hz), 6.57 (1H, d, J=2.5Hz), 6.72 (1H, dd, J=2.5, 8.7Hz), 7.40 (1H, s), 7.42 (1H, d, J=8.7Hz), 8.27 (4H, br s), 10.86 (1K, br s) CI-MS (m/z) : 262 (M++1-MsOH) Anal Calcd. for C14H19N3O6S C 47.05%, H 5.36%, N 11.76% Found : C 46.88%, H 5.34%, N 11.57% (8) (2,3-Dihydro-9-methoxy-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 210-211°C (diisopropyl ether-methanol) IR (Nujol) : 3340, 3110, 1700, 1640, 1585 cm-1 NMR (DMSO-d6, #) : 2.37 (3K, s), 2.91 (2H, t, J=4.4Hz), 3.78 (3H, s), 4.27 (2H, t, J=4.4Hz), 7.0-7.15 (3H, m), 7.37 (1H, s), 8.28 (4H, br s), 10.94 (1H, br s) CI-MS (m/z) : 262 (M++1-MsOH) Anal Calcd. for C14H19N306S C 47.05%, H 5.36%, N 11.76% Found : C 46.70%, H 5.35%, N 11.57% (9) (7-Chloro-2,3-dihydro-9-methoxy-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 252-253°C (diisopropyl ether-methanol) IR (Nujol) : 3330, 3120, 1680 cm 1 NMR (DMSO-d6, #) : 2.39 (3H, s), 2.92 (2H, t, J=4.5Hz), 3.81 (3H, s), 4.27 (2H, t, J=4.5Hz), 7.1-7.2 (2H, m), 7.32 (1H, s), 8.30 (4H, br s), 10.96 (1H, br s)

CI-MS (m/z) : 296 (M++1-MsOH) Anal Calcd. for C14H18ClN306S C 42.92%, H 4.63%, N 10.72% Found : C 42.64%, H 4.58%, N 10.60% (10) (2,3-Dihydro-7-nitro-1-benzoxepin-4- carbonyl) guanidine methanesulfonate mp : 282-283°C (Dec.) (diisopropyl ether-methanol) IR (Nujol) : 3320, 1690 cm-1 NMR (DMSO-d6, #) : 2.38 (3H, s), 2.85-3.05 (2H, m), 4.3-4.5 (2H, m), 7.23 (1H, d, J=9.0Hz), 7.54 (1H, br s), 8.1-8.55 (6H, m), 11.04 (1H, br s) CI-MS (m/z) : 277 (M++1-MsOH) Anal Calcd. for C13H16N4O7S : C 41.93%, H 4.33%, N 15.05% Found : C 41.51%, H 4.24%, N 14.75% (11) (2,3-Dihydro-9-nitro-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 264-266°C (diisopropyl ether-methanol) IR (Nujol) : 3325, 3130, 1705, 1690 cm 1 NMR (DMSO-d6, 5) : 2.39 (3H, s), 2.99 (2K, t, J=4.5Hz), 4.40 (2H, t, J=4.5Hz), 7.29 (1H, dd, J=7.9, 7.9Hz), 7.47 (1H, s), 7.75-7.95 (2H, m), 8.32 (4H, br s), 11.07 (1H, br s) CI-MS (m/z) : 277 (M++1-MsOH) Anal Calcd. for C13H16N4°7S C 41.93%, H 4.33, N 15.05% Found : C 41.55%, H 4.23%, N 14.81% (12) (2, 3-Dihydro-9-iodo-1-benzoxepin-4-carbonyl) guanidine methanesulfonate mp : 257-258°C (diisopropyl ether-methanol) IR (Nujol) : 3330, 3140, 1700, 1680 cm 1 NMR (DMSO-d6, #) : 2.39 (3H, s), 2.85-3.0 (2H, m),

4.2-4.4 (2H, m), 6.90 (1H, dd, J=7.7, 7.7Hz), 7.36 (1H, s), 7.53 (1H, d, J=7.7Hz), 7.86 (1H, d, J=7.7Hz), 8.32 (4H, br s), 11.00 (1H, br s) CI-MS (m/z) : 358 (M++1-MsOH) Anal Calcd. for C13H16IN3O5S C 34.45%, H 3.56%, N 9.27% Found : C 34.90%, H 3.53%, N 9.23% (13) [2,3-Dihydro-7-(1-pyrrolyl)-1-benzoxepin-4- carbonyl]guanidine methanesulfonate mp : 241-242°C (diisopropyl ether-methanol) IR (Nujol) : 1670 cm-1 NMR (DMSO-d6, #) : 2.40 (3H, s), 2.85-3.0 (2H, m), 4.15-4.35 (2H, m), 6.2-6.3 (2H, m), .09 (1H, d, J=8.7Hz), 7.25-7.4 (2H, m), 7.50 (1H, s), 7.55 (1H, d, J=8.7Hz), 7.76 (1H, s), 8.33 (4H, br s), 11.01 (1K, br s) CI-MS (m/z) : 297 (M++1-MsOH) Anal Calcd. for C17H20N4O5S.0.5H2O C 50.86%, H 5.27%, N 13.96% Found : C 41.36, N 5.09%, N 13.93% (14) [2,3-Dihydro-9-(1-pyrrolyl)-1-benzoxepin-4- carbonyl]guanidine methanesulfonate mp : 217-218°C (diisopropyl ether-methanol) IR (Nujol) : 1700 cm-1 NMR (DMSO-d6, #) : 2.38 (3H, s), 2.85-3.0 (2H, m), 4.25-4.4 (2H, m), 6.15-6.25 (2H, m), 7.0-7.1 (2H, m), 7.16 (1H, dd, J=7.8, 7.8Hz), 7.42 (1H, d, J=7.8Hz), 7.47 (1H, s), 7.50 (1H, d, J=7.8Hz), 8.32 (4H, br s), 11.00 (1H, br s) CI-MS (m/z) : 297 (M++1-MsOH) Anal Calcd. for C14H19N3O5S.0.5H2O C 50.86%, H 5.27%, N 13.96% Found : C 50.62, r 5.28%, N 13.85%

(15) (2, 3-Dihydro-9-pyrrolidino-l-benzoxepin-4- carbonyl)guanidine dimethanesulfonate mp : 220-222°C (diisopropyl ether-methanol) IR (Nujol) : 1710, 1670 (br) cm 1 NMR (DMSO-d6, #) : 1.95-2.15 (4H, m), 2.39 (6H, s), 2.9-3.05 (2H, m), 3.4-3.65 (4H, m), 4.3-4.45 (2H, m), 7.1-7.25 (1H, m), 7.3-7.5 (3H, m), 8.37 (4H, br s), 11.07 (1H, br s) CI-MS (m/z) : 301 (M++1-2MsOH) Anal Calcd. for C18H28NtO7S2 C 43.89, H 5.73, N 11.37% Found : C 43.12%, H 5.81%, N 11.03% (16) (6,7-Dihydro-2-methoxy-5H-benzocycloheptene-8- carbonyl)guanidine methanesulfonte mp : 185-186°C (diisopropyl ether-methanol) IR (Nujol) : 3325, 3100, 1680, 1585 cm 1 NMR (DMSO-d6, #) : 1.9-2.05 (2H, m), 2.45-2.6 (2H, m), 2.65-2.8 (2H, m), 2.37 (3H, s), 3.76 (3H, s), 6.88 (1H, dd, J=2.7, 8.3Hz), 7.02 (1H, d, J=2.7Hz), 7.17 (1H, d, J=8.3Hz), 7.46 (1H, s), 8.31 (4H, br s), 10.9? (1, br s) CI-MS (m/z) : 260 (M++1-MsOH) Anal Calcd. for C15H21N305S C 50.69%, H 5.96%, N 11.82% Found : C 50.31%, H 5.98%, N 11.66% Example 4 To a mixture of ethyl 2,3-dihydro-9-isopropyl-1- benzoxepin-4-carboxylate (0.52 g) and guanidine hydrochloride (0.95 g) in N,N-dimethylformamide (5.2 ml) was added sodium methylate (0.54 ml, 28% in methanol) at ambient temperature. The reaction mixture was stirred overnight at the same temperature and partitioned between ethyl acetate and water. The organic layer was

successively with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was treated with 4N hydrochloride in 1,4-dioxane (0.75 ml). The reaction mixture was evaporated in vacuo. The residue was recrystallized from a mixture of methanol and diisopropyl ether to give colorless crystal of (2,3-dihydro-9- isopropyl-1-benzoxepin-4-carbonyl)guanidine hydrochloride mp : 179-180°C (diisopropyl ether-methanol) IR (Nujol) : 1665, 1615, 1570 cm 1 NMR (DMSO-d6, #) : 1.17 (6H, d, J=6.9Hz), 2.85-3.0 (2H, m), 3.25-3.45 (1H, m), 4.2-4.35 (2K, m), 7.0-7.15 (1H, m), 7.25-7.35 (1H, m), 7.4-7.5 (1H, m), 7.80 (1H, s), 8.25-8.8 (4H, m), 11.79 (1K, br s) CI-MS (m/z) : 274 (M++1-HCl) Anal Calcd. for C15H20C1N302 C 58.16%, H 6.51%, N 13.56% Found : C 58.27%, H 6.62%, N 13.48?- Example 5 The following compound was obtained according to a similar manner to that of Example 4.

(2,3-Dihydro-9-pyrrolidino-1-benzoxepin-4- carbonyl)guanidine dihydrochloride mp : 220-222°C (diisopropyl ether-methanol) IR (Nujol) : 1680 cm 1 NMR (CDC13, #) : 1.95-2.2 (4H, m), 2.85-3., (2K, m), 3.4-3.7 (4H, m), 4.25-4.5 (2H, m), 7.20 (1H, dd, J=7.9, 7.9Hz), 7.4-7.8 (2H, m), 7.92 (1H, s), 8.4-8.9 (4H, m), 12.11 (1H, br s) CI-MS (m/z) : 301 (M++1-2HCl) Anal Calcd. for C16H22Cl2N4O2 C 49.11%, H 6.18%, N 14.32% Found : C 49.58%, H .18, N 14.26%

Preparation 13 The mixture of ethyl 5-chlorosalicylate (7.7 g), ethyl 4-bromobutyrate (7.1 ml) and potassium carbonate (6.9 g) in N,N-dimethylformamide (54 ml) was stirred for 20 hours at ambient temperature. The mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 5-chloro-2- (3-ethoxycarbonylpropoxy)benzoate (12.0 g).

IR (Film) : 1734, 1705 cm 1 NMR (DMSO-d6, #) : 1.17 (3H, t, J=7.1Hz), .29 (3H, t, J=7.1Hz), 1.89-2.09 (2H, m), 2.43-2.54 (2H, m) , 3.99-4.12 (4H, m), 4.27 (2H, q, J=,.lHz), 7.17 (1H, d, J=8.9Hz), 7.56 (1H, dd, J=2.7, 8.9Hz), 7.63 (1H, d, J=2.7Hz) Preparation 14 The following compounds were obtained according to a similar manner to that of Preparation 13.

(1) Ethyl 4-chloro-2-(3-ethoxycarbonylpropoxy)benzoate IR (Film) : 1705, 1590 cm 1 NMR (DMSO-d6, #) : 1.83 (3H, t, J=7.1Hz), 1.29 (3H, t, J=7.1Hz), 1.89-2.04 (2H, m), 2.52 (2H, t, J=7.4Hz), 4.00-4.14 (4H, m), 4.26 (2H, q, J=7.1Hz), 7.08 (1H, dd, J=1.8, 8.3Hz), 7.23 (1H, d, J=1.8Hz), 7.68 (1H, d, J=8.3Hz) (2) Ethyl 3-chloro-2-(3-ethoxycarbonylpropoxy)benzoate IR (Film) : 1718 cm 1 NMR (DMSO-d6, #) : 1.19 (3H, t, J=7.lHz), 1.32 (3H, t, J=7.lHz), 1.93-2.10 (2H, m), 2.44-2.56 (2H, m), 3.99 (2H, t, J=6.2Hz), 4.07 (2H, q, J=7.1Hz), 4.31 (2H, q, J=7.1Hz), 7.25 (1H, dd, J=each 7.9Hz), 7.66 (1H, dd, J=1.7, 17.9Hz),

7.71 (1H, dd, J=1.7, 7.9Hz) (3) Methyl 2-(3-methoxycarbonylpropylthio)benzoate IR (Film) : 1734, 1711 cm 1 NMR (DMSO-d6, #) : 1.77-1.93 (2H, m), 2.49 (2H, t, J=7.2Hz), 2.98 (2H, t, J=7.1Hz), 3.60 (3H, s), 3.83 (3H, s), 7.24 (1H, m), 7.45-7.61 (2H, m), 7.86 (1H, dd, J=1.5, 7.8Hz) Preparation 15 Methyl 4-bromobutyrate (22.4 g) was added to the mixture of 3-methyl-2-mercaptobenzoic acid (20.8 g) and sodium bicarbonate (20.8 g) in N,N-dimethylformamide (210 ml) under ice-cooling and the mixture was stirred for 14 hours at ambient temperature. The mixture was added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 2 with 6N-hydrochloric acid. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 2-(3- methoxycarbonylpropylthio)-3-methylbenzoic acid (32.8 g).

IR (Film) : 1736, 1703 cm 1 NMR (DMSO-d6, #) : 1.59-1.74 (2H, m), 2.39 (2H, t, J=7.3Hz), 2.50 (3H, s), 2.76 (2H, t, J=7.1Hz), 3.55 (3H, s), 7.24-7.43 (3H, m), 13.03 (1H, s) Preparation 16 The mixture of 2-(3-methoxycarbonylpropylthio)-3- methylbenzoic acid (32.5 g), sodium bicarbonate (15.3 g) and methyl iodide (11.3 ml) in N,N-dimethylformamide (230 ml) was stirred for 16 hours at ambient temperature. The mixture was added to ethyl acetate and washed with water, dried over magnesium sulfate and evaporated in vacuo to give methyl 2-(3-methoxycarbonylpropylthio)-3- methylbenzoate (33.8 g).

IR (Film) : 1734 cm 1

NMR (DMSO-d6, 5) : 1.57-1.73 (2K, m), 2.38 (2H, t, J=7.3Hz), 2.51 (3H, s), 2.74 (2H, t, J=7.3Hz), 3.57 (3H, s), 3.82 (3H, s), 7.28-7.40 (2H, m), 7.43-7.48 (1H, m) Preparation 17 The following compounds were obtained according to a similar manner to that of Preparation 1.

(1) Ethyl 7-chloro-5-oxo-2,3,4,5-tetrahvdro- -oenzoxepin- 4-carboxylate IR (Film) : 1735, 1680, 1635, 1600 cm-1 NMR (DMSO-d6, #) : 1.10 (3H, t, J=7.1Hz), 2.39-2.50 (2H, m), 3.98-4.44 (5H, m), 7.10-7.18 (1H, m), 7.54-7.62 (2H, m) (2) Ethyl 8-chloro-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin- 4-carboxylate IR (Nujol) : 1730, 1630, 1590 cm 1 NMR (DMSO-d6, #) : 1.11 (3H, t, J=7.lHz), 2.37-2.52 (2H, m), 3.98-4.50 (5H, m), 7.20-7.26 (2H, m), 7.62-7.68 (1H, m) (3) Ethyl 9-chloro-5-oxo-2,3,a,5-tetranydro- -benzoxepin- 4- carboxylate IR (Film) : i743, 1689, 1645, 1614, 1591 cm-1 NMR (DMSO-d6, 5) : 1.11 (3H, t, J=7.1Hz), 2.41-2.58 (2H, m), 4.01-4.30 (4H, m), 4.30-4.50 (1H, m), 7.18 (1H, dd, J=each 7.8Hz), 7.61 (1H, dd, J=1.7, 7.8Hz), 7.73 (1H, dd, J=1.7, 7.8Hz) (4) Methyl 5-oxo-2,3,4-5-tetrahydro-1-benzothiepin-4- carboxylate IR (Film) : 1735, 1640 cm 1 NMR (DMSO-d6, 5) : 2.32-2.53 (2H, m), 2.65-2.83 (1H, m), 3.27-3.39 (1H, m), 3.64 (3H, s), 4.48 (1H,

dd, J=7.7, 10.0Hz), 7.34-7.65 (3H, m), 7.75 (1H, dd, J=1.4, 7.9Hz) (5) Methyl 9-methyl-5-oxo-2,3,4,5-tetrahydro-1- benzothiepin-4-carboxylate IR (Film) : 1747, 1680, 1647, 1614, 1579 cm-1 NMR (DMSO-d6, #) : 2.28-2.53 (2H, m), 2.37 (3H, s), 2.62-2.79 (1H, m), 3.29-3.41 (1H, m), 3.61 (3H, s), 4.47 (1H, dd, J=7.8, 10.1Hz), 7.24 (1H, dd, J=each 7.7Hz), 7.41 (1H, dd, J=1.8, 7.7Hz), 7.57 (1H, dd, J=1.8, 7.7Hz) (6) Ethyl 7-iodo-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4- carboxylate mp : 82-85°C IR (KBr) : 1743, 1683 cm 1 NMR (CDCl3, #) : 1.2-1.4 (3H, m), 2.55-2.75 (2H, m), 4.1-4.5 (4H, m), 6.7-7.1 (2H, m), 7.55-8.0 (1H, m), 8.1-8.3 (1H, m) Preparation 18 The following compounds were obtained according to a similar manner t that of Preparation 3.

(1) Ethyl 7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1- benzoxepin-4-carboxylate IR (Film) : 4448, 1730 cm 1 (2) Ethyl 8-chloro-5-hydroxy-2,3,4,5-tetrahydro-1- benzoxepin-4-carboxylate IR (Film) : 3400, 1710, 1590 cm 1 (3) Ethyl 9-chloro-5-hydroxy-2,3,4,5-tetrahydro-1- benzoxepin-4-carboxylate IR (Film) : 3470, 1720 cm 1

(4) Methyl 5-hydroxy-2,3,4,5-tetrahydro-1-benzothiepin-4- carboxylate IR (Film) : 3464, 1730 cm (5) Methyl 5-hydroxy-9-methyl-2,3,4,5-tetrahydro-1- benzothiepin-4-carboxylate IR (Film) : 3491, 1734 cm 1 NMR (DMSO-d6, #) : 1.95-2.10 (2H, m), 2.37 (3H, s), 2.81 (2H, t, J=5.9Hz), 3.08-3.17 (1H, m), 3.46 (3H, s), 5.39-5.46 (1H, m), 5.63 (1H, d, J=4.5Hz), 7.07-7.20 (2H, m), 7.31 (1H, dd, J=2.1, 7.1Hz) (6) Ethyl 7-iodo-5-hydroxy-2,3,4,5-tetrahydro-1- benzoxepin-4-carboxylate IR (Film) : 3470 (br), 1739, 1724, 1709 cm 1 NMR (CDCl3, 5) : 1.15-1.35 (3K, m), 2.1-2.45 (1H, m), 2.5-3.15 (1H, m), 3.3-3.45 (1H, m), 4.0-4.35 (4H, m), 5.05-5.25 (1H, m), 6.7-6.8 (1H, m), 7.4-7.45 (1H, m), 7.65-7.9 (1H, m) Preparation 19 The following compound was obtained according to a similar manner to that of Preparation 5.

(1) Ethyl 7-chloro-2,3-dihydro-1-benzoxepin-4-carboxylate mp : 70-72°C NMR (DMSO-d6, #) : 1.28 (3H, t, J=7.1Hz), 2.88 (2H, t, J=4.2Hz), 4.14-4.26 (4H, m), 6.99 (1H, d, J=8.7Hz), 7.32 (1H, dd, J=2.6, 8.7Hz), 7.50 (1H, s), 7.63 (1H, d, J=2.6Hz) (2) Ethyl 8-chloro-2,3-dihydro-1-benzoxepin-4-carboxylate mp : 71-73°C IR (Nujol) : 1691, 1592 cm 1

NMR (DMSO-d6, #) : 1.28 (3H, t, J=7.lHz), 2.88 (2H, t, J=4.3Hz), 4.15-4.27 (4H, m), 7.05 (1H, d, J=2.1Hz), 7.11 (1H, dd, J=2.1, 8.3Hz), 7.50 (1H, s), 7.52 (1H, d, J=8.3Hz) (3) Ethyl 9-chloro-2,3-dihydro-1-benzoxepin-4-carboxylate IR (Film) : 1705, 1635, 1591 cm 1 NMR (DMSO-d6, #) : 1.28 (3H, t, J=7.1Hz), 2.92 (2H, t, J=4.6Hz), 4.21 (2H, q, J=7.1Hz), 4.32 (2H, t, J=4.6Hz), 7.06 (1H, dd, J=each 7.8Hz), 7.44-7.54 (3H, m) (4) Methyl 2,3-dihydro-1-benzoxepin-4-carboxylate IR (Film) : 1712, 1630 cm-1 NMR (DMSO-d6, #) : 2.90 (2H, t, J=5.9Hz), 3.31 (2H, t, J=5.9Hz), 3.77 (3H, s), 7.22-7.37 (2H, m), 7.43-7.55 (2H, m), 7.73 (1H, s) (5) Methyl 2,3-dihydro-9-methyl-1-benzothiepin-4- carboxylate mp : 44-48°C IR (Film) : 1707, 1622 cm 1 NMR (DMSO-d6, #) : 2.38 (3H, s), 2.83-2.91 (2H, m), 2.07-3.14 (2H, m), 3.76 (3H, s, 7.11-7.27 (2H, m), 7.35 (1H, dd, J=2.6, 6.6Hz), 7.73 (1H, s) (6) Ethyl 2,3-dihydro-7-iodo-1-benzoxepin-4-carboxylate mp : 70-72°C IR (Film) : 1703, 1633 cm-1 NMR (CDCl3, #) : 1.35 (3H, t, J=7.1Hz), 2.9-3.05 (2H, m), 4.14-4.35 (4H, m), 6.73 (1H, dd, J=8.6Hz), 7.45 (1H, s), 7.48 (1H, dd, J=2.2, 8.6Hz), 7.64 (1H, d, J=2.2Hz) Preparation 20

To a suspension of sodium hydride (0.78 g, 60%) in benzene (150 ml) was added 2-iodobenzyl alcohol (3.06 g) under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature and thereto was added ethyl 2-(bromomethyl)acrylate (12.6 g). The reaction mixture was stirred overnight at ambient temperature, quenched with saturated sodium bicarbonate solution containing 1N aqueous ammonium chloride (6 drops), and washed with water. The aqueous solution was extracted with diethyl ether (X 4). The combined organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) as an eluent to give a colorless oil of ethyl 2-(2- iodophenylmethoxymethyl)acrylate (1.65 g).

IR (Film) : 1714, 1637 cam 1 NMR (CDC13, 5) : 1.35 (3H, t, J=7.1Hz), 2.9-3.05 (2K, m), 4.14-4.35 (4K, m), 6.73 (1K, dd, J=8.6Hz), 7.45 (1H, s), 7.48 (1H, dd, 3=2.2, 8.6Hz), 7.64 (1H, d, 3=2.2Hz) Preparation 21 The mixture of ethyl 2-(2-iodophenylmethoxymethyl)- acrylate (1.6 g) and molecular sieves (1.86 g, 4A, powder) was stirred at ambient temperature for 30 minutes under nitrogen atmosphere and thereto was added palladium(II) acetate (C.21 g), tetrabutylammonium chloride (1.28 g), and sodium bicarbonate (0.97 g). The reaction mixture was stirred overnight at 110°C and filtered off. The filtrate was evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:50) as an eluent to give ethyl 1,3-dihydro-2-benzoxepin-4-carboxylate (0.25 g) and ethyl 1,5-dihydro-2-benzoxepin-4-carboxylate (0.17

g).

(1) Ethyl 1,3-dihydro-2-benzoxepin-4-carboxylate IR (Film) : 1699, 1628 cm 1 NMR (CDCl3, #) : 1.27 (1K, s), 3.90 (2H, s), t.18 (2H, q, J=7.1Hz), 5.20 (2H, s), 7.15-?.35 (4H, m), 7.72 (3H, t, J=7.1Hz), (2) Ethyl 1,5-dihydro-2-benzoxepin-4-carboxylate IR (Film) : 1701, 1635 cm-1 NMR (CDC13, #) : 1.34 (3H, t, J=7.1Hz), 4.27 (2H, q, J=7.1Hz), 4.79 (2H, s), 4.80 (2H, d, J=1.8Hz), 7.1-7.5 (4H, m), 7.72 (1H, t, J=1.8Hz) Preparation 22 To conc. nitric acid (15 ml, d 1.42) was added in small portions ethyl 2,3-dihydro-9-iodo-1-benzoxepin-4- carboxylate (5.16 g) below 10°C under ice-sodium chloride cooling. The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:30) as an eluent to give a solid of ethyl 2,3-dihydro-9-iodo-7-nitro-benzoxepin-4- carboxylate (2.81 g). mp : 108-110°C IR (KBr) : 1695, 1518, 1346 cm NMR (CDCl3, #) : 1.37 (3H, t, J=7.1Hz), 3.0-3.15 (2H, m), 4.30 (2H, q, J=7.lHz), 7.53 (1H, s), 7.30 (1H, br s), 8.27 (1H, d, J=2.7Hz), 8.61 (1H, d, J=2.7Hz)

Preparation 23 To a mixture of iron (0.91 g, reduced) and ammonium chloride (97 mg) in aqueous ethanol (12 ml, 75% v/v) was added ethyl 2,3-dihydro-9-iodo-7-nitro-benzoxepin-4- carboxylate (1.18 g) under reflux. The reaction mixture was stirred for 20 minutes under reflux and filtered off.

The filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a solid of ethyl 7-amino-2,3- dihydro-9-iodo-1-benzoxepin-4-carboxylate (1.11 g) mp : 92-93°C IR (KBr) : 3644, 3361, 1699, 1624, 1597 cm-1 NMR (CDC13, 5) : 1.34 (3H, t, J=7.1Hz), 2.9-3.05 (2K, m), 3.94 (2K, br s), 4.15-4.35 (4E, m), 6.71 (1H, s), 7.19 (1H, s), 7.30 (1K, br s), 7.40 (1K, s) Preparation 24 To a mixture of ethyl 9-amino-2,3-dihydro-1- benzoxepin-4-carboxylate (0.70 g) and triethylamnne (0.63 ml) in chloroform (3.5 ml) was added methyl chloroformate (0.35 ml) at 0°C. The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:19) to give a solid o ethyl 2,3-dihydro-9-methoxycarbonyl- amino-1-benzoxepin-4-carboxylate (0.32 g). mp : 108-109°C IR (KEr) : 3431, 1735, 1695, 1631 cm 1

NMR (DMSO-d6, 5) : 1.27 (3H, t, J=7.lHz), 2.8-2.95 (2H, m), 3.67 (3H, s), 4.20 (2H, q, J=7.1Hz), 4.2-4.3 (2H, m), 7.02 (1H, dd, J=7.9, 7.9Hz), 7.20 (1H, dd, J=1.5, 7.9Hz), 7.51 (1H, s), 7.65- 7.8 (1H, m), 8.75 (1K, s) Preparation 25 To a solution of ethyl 2,3-dihydro-9-amino-1- benzoxepin-4-carboxylate (0.47 g) in toluene (2.3 ml) was added ethyl isocyanate (0.24 ml) at ambient temperature.

The reaction mixture was stirred overnight at the same temperature and partitioned between ethyl acetate (containing tetrahydrofuran) and 1N hvdrochloric acid.

The organic layer was washed successivelv with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give a solid of ethyl 2,3-dihydro-9-(N'-ethylureido)-1-benzoxepin-4- carboxylate (0.57 g). mp : 194-195°C (dec.) IR (KBr) : 3321, 3292, 1709, 1693, 1641 cm 1 NMR (DMSO-d6, 5) : 1.06 (3H, t, J=7.2Hz), 1.28 (3H, t, J=7.1Hz), 2.85-3.0 (2K, m), 3.0-3.2 (2H, m), 4.21 (2H, q, J=7.1Hz), 4.2-4.35 (2H, m), 6.75- 7.05 (3K, m), 7.48 (1K, s), 8.10 (1H, s), 8.15- 8.25 (1H, m) Preparation 26 The following compound was obtained according to a similar manner to that of Preparation 25.

Ethyl 2,3-dihydro-9-(N'-ethylthioureido)-1- benzoxepin-4-carboxylate mp : 137-139°C IR (KBr) : 3350, 3175, 1697, 1635 cm 1

NMR (DMSO-d6, #) : 1.12 (3H, t, J=7.1Hz), 1.28 (3H, t, J=7.1Hz), 2.8-2.95 (2H, m), 3.35-3.55 (2H, m), 4.21 (2K, q, J=7.1Hz), 4.2-4.35 (2K, m), 6.9-7.1 (1K, m), 7.2-7.35 (1H, m), 7.52 (1K, s), 7.85-8.1 (2H, m), 8.97 (1H, br s) Preparation 27 Ethyl 9-amino-2,3-dihydro-1-benzoxepin-4-carboxylate (0.47 g) was dissolved at 40°C in aqueous acetic acid (4 ml, 50% v/v). To the mixture was added a solution of sodium cyanate (0.26 g) in water (2 ml) dropwise at the same temperature. The reaction mixture was stirred for 2 hours at ambient temperature. The resulting precipitate was collected b filtration and recrystallized from ethanol to give a solid of ethyl 2,3-dihydro-9-ureido-1- benzoxepin-4-carboxylate (0.37 g). mp : 216-218°C (dec.) (ethanol) IR (KBr) : 3425, 3338, 1680 (br), 1604 cm 1 NMR (DMSO-d6, #) : 1.28 (3H, t, J=7.1Hz), 2.8-3.0 (2H, m), 4.21 (2H, q, J=7.1Hz), 4.25-4.4 (2H, m), 6.24 (1H, br s), 6.85-7.1 (2H, m), 7.48 (1H, s), 8.3-8.45 (2H, m) Preparation 28 To a solution of ethyl 9-amino-2,3-dihydro-1- benzoxepin-4-carboxylate (0.47 g) in N,N-dimethylformamide (2 ml) was added successively sodium carbonate (0.51 g), sodium iodide (0.30 g), and 2-chloroethyl ether (0.28 ml).

The reaction mixture was stirred at 85°C for 6.5 hours and partitioned between ethyl acetate and water. The organic layer was washed successively with water, 5% aqueous potassium bisulfonate, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica

gel) using a mixture of ethyl acetate and n-hexane (1:9) to give colorless oil of ethyl 2,3-dihydro-9-morpholino-1- benzoxepin-4-carboxylate (0.42 g).

IR (Film) : 1738, 1633 cm 1 NMR (DMSO-d6, #) : 1.35 (3H, t, J=7.1Hz), 2.9-3.2 (2K, m), 3.8-4.0 (4K, m), 4.2-4.4 (4H, m), 6.85- 7.1 (3H, m), 7.57 (1K, s) Preparation 29 To a mixture of ethyl 9-amino-2,3-dihydro-1- benzoxepin-4-carboxylate (0.70 g) and pyridine (0.15 ml) in dichloromethane (3.5 ml) was added acetyl chloride (0.13 ml) at 0°C. The reaction mixture was stirred for 1.5 hours at ambient temperature and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (2:3) to give a solid of ethyl 9-acetylamino-2,3-dihydro-1-benzoxepin-4- carboxylate (0.37 g). mp : 127-128°C IR (KBr) : 1684, 1639 cm 1 NMR (CDCl3, #) : 1.35 (3H, t, J=7.1Hz), 2.22 (3H, s), 2.95-3.1 (2H, m), 4.28 (2K, q, J=7.1Hz), 4.35-4.45 (2H, m), 6.95-7.1 (2H, m), 7.57 (1H, s), 7.93 (1H, br s), 8.3-8.45 (1H, m) Preparation 30 The following compound was obtained according to a similar manner to that of Preparation 29.

Ethyl 2,3-dihydro-9-methanesulfonylamino-1- benzoxepin-4-carboxylate

mp : 117-118°C IR (KBr) : 1705, 1690 cm-1 NMR (CDCl3, #) : 1.36 (3H, t, J=7.1Hz), 2.99 (3H, s), 3.0-3.1 (2H, m), 4.29 (2K, q, J=7.lHz), 4.3- 4.4 (2H, m), 7.0-7.25 (3H, m), 7.5-7.65 (2H, m) Example 6 The following compounds were obtained according to a similar manner to that of Example 1.

(1) (7-Chloro-2,3-dihydro-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 219-221°C IR (Nujol) : 3359, 3317, 3157, 1699, 1171, 1051 cm-1 NMR (DMSO-d6, #) : 2.45 (3H, s), 2.92 (2H, t, J=4.3Hz), 4.27 (2H, t, 3=4.3Hz), 7.04 (1H, d, J=8.7Hz), 7.38 (1H, dd, J=2.6, 8.7Hz), 7.39 (1H, s), 7.62 (1H, d, J=2.6Hz), 8.39 (4H, s), 11.05 (1H, s) (2) (8-Chloro-2,3-dihydro-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 231-233°C IR (KBr) : 3370, 3125, 1700, 1670, 1635, 1590, 1200, 1045 cm-1 NMR (DMSO-d6, #) : 2.42 (3H, s), 2.92 (2H, t, J=4.5Hz), 4.29 (2H, t, J=4.5Hz), 7.11 (1H, d, J=2.1Hz), 7.18 (1H, dd, J=2.1, 8.4Hz), 7.41 (1H, s), 7.54 (1H, d, J=8.4Hz), 8.34 (4H, s), 11.02 (1H, s) (3) (9-Chloro-2,3-dihydro-1-benzoxepin-4-carbonyl)- guanidine hydrochloride mp : 223-225°C IR (Nujol) : 3367, 3132, 1687, 1674, 1628, 1589 cm 1

NMR (DMSO-d6, #) : 2.96 (2H, t, J=4.5Hz), 4.36 (2H, t, J=4.5Hz), 7.11 (1H, dd, J=each 7.8Hz), 7.54 (1H, dd, J=1.4, 7.8Hz), 7.56 (1H, dd, J=1.4, 7.8Hz), 7.89 (1H, s), 8.47 (2H, s), 8.70 (2H, s), 11.97 (1H, s) (4) (2, 3-Dihydro-1-benzothiepin-4-carbonyl) guanidine methanesulfonate mp : 158-159°C IR (KBr) : 3330, 3110, 1697, 1600, 1175, 1047 cm 1 NMR (DMSO-d6, #) : 2.44 (3H, s), 2.91 (2K, t, J=5.7Hz), 3.22 (2H, t, J=5.7Hz), 7.26-7.42 (2H, m), 7.46-7.59 (2H, m), 7.54 (1H, s), 8.33 (2H, s), 8.47 (2H, s), 11.16 (1H, s) (5) (2,3-Dihydro-9-methyl-1-benzothiepin-4-carbonyl)- guanidine methanesulfonate mp : 188-190°C IR (Nujol) : 3350, 3151, 1699, 1655, 1593, 1194, 1173, 1051 cm-1 NMR (DMSO-d6, #) : 2.34 (3H, s), 2.45 (3H, s), 2.89 (2H, t, 3=5.9Hz), 3.19 (2H, t, J=5.9Hz), 7.21- 7.31 (2H, m), 7.37-7.45 (1H, m), 7.55 (1H, s), 8.34 (2H, br s), 8.50 (2H, br s), 11.13 (1H, s) (6) (1, 2-Dihydronaphthalen-3-carbonyl) guanidine methanesulfonate mp : 160-162°C IR (Nujol) : 3365, 3194, 1680, 1200, 1047 cm 1 NMR (DMSO-d6, #) : 2.44 (3H, s), 2.54 (2H, t, J=8.2Hz), 2.87 (2H, t, J=8.2Hz), 7.25-7.41 (4H, m), 7.59 (1H, s), 8.37 (4H, s), 11.00 (1H, s) (7) (2H-1-Benzopyran-3-carbonyl)guanidine methanesulfonate

mp : 227-229°C IR (Nujol) : 3330, 1701, 1668, 1603, 1194, 1043 cm 1 NMR (DMSO-d6, #) : 2.47 (3H, s), 4.95 (2H, s), 6.92 (1H, d, J=7.5Hz), 7.03 (1H, dd, J=each 7.5Hz), 7.30-7.40 (2H, m), 7.66 (1H, s), 8.10-8.56 (4H, br s), 11.18 (1K, s) (8) (6-Chloro-2H-1-benzopyran-3-carbonyl)guanidine methanesulfonate mp : 237-239°C IR (Nujol) : 3410, 3320, 3100, 1690, 1640, 1600, 1162, 1040 cm-1 NMR (DMSO-d6, #) : 2.49 (3H, s), 4.98 (2H, s), 6.95 (1H, d, J=8.6Hz), 7.37 (1H, dd, J=2.5, 8.6Hz), 7.45 (1H, d, J=2.5Hz), 7.62 (1K, s), 8.29 (2H, s), 8.45 (2H, s), 11.24 (1H, s) (9) (2H-1-Benzothiopyran-3-carbonyl)guanidine hydrochloride mp : 225-227°C IR (Nujol) : 3342, 3128, 3072, 1693, 1685, 1608 cm-1 NMR (DMSO-d6, #) : 3.76 (2K, s), 7.18-7.42 (4H, m), 8.05 (1H, s), 8.52 (2H, s), 8.64 (2H, s), 12.06 (1H, s) (10) (2,3-Dihydro-7-iodo-1-benzoxepin-4-carbonyl)guanidine methanesulfonate mp : 215-217°C (diisopropyl ether-methanol) IR (KBr) : 1699, 1645 cm-1 NMR (DMSO-d6, #) : 2.26 (3H, s), 2.85-3.0 (2H, m), 4.2-4.35 (2H, m), 6.84 (1H, d, J=8.5Hz), 7.34 (1H, s), 7.63 (1H, dd, J=2.2, 8.5Hz), 7.85 (1H, d, J=2.2Hz), 8.26 (4H, br s), 10.92 (1H, br s) (11) (1,3-Dihydro-2-benzoxepin-4-carbonyl)guanidine

methanesulfonate mp : 202-204°C (diisopropyl ether-methanol) IR (KBr) : 1703 cm 1 NMR (DMSO-d6, #) : 2.36 (3H, s), 4.2-5.1 (4H, m), 7.15-7.3 (5K, m), 8.27 (4H, br s), 11.41 (1K, br s) (12) (1,5-Dihydro-2-benzoxepin-4-carbonyl)guanidine methanesulfonate mp : 192-193°C (diisopropyl ether-methanol) IR (KBr) : 1697, 16?4, 1620 cm-1 NMR (DMSO-d6, #) : 2.37 (3H, s), 4.72 (2H, s), 4.73 (2X, s), 7.25-7.65 (5H, m), 8.30 (4H, br s), 11.11 (1K, br s) Example 7 The mixture of (2,3-dihydro-1-benzothiepin-4- carbonyl)guanidine methanesulfonate (0.6 g) and 3- chloroperbenzoic acid (0.83 g) in chloroform (50 ml) for 3 hours under ice-cooling. The isolated precipitate was collected by filtration and the precipitate was recrystallized from a mixture of methanol and diisopropyl ether to give 2,3-dihydro-4-guanidinocarbonyl-l- benzothiepin 1,1-dioxide methanesulfonate (0.43 g). mp : 200-202°C IR (Nujol) : 3346, 3325, 3099, 1701, 1606, 1176, 1146, 1051 cm 1 NMR (DMSO-d6, 5) : 2.43 (3H, s), 2.97 (2H, t, J=6.5Hz), 3.83 (2H, t, J=6.5Hz), 7.59-7.87 (4H, m), 8.06 (1H, d, J=7.4Hz), 8.31 (2H, br s), 8.47 (2H, br s), 11.32 (1H, s) Example 8 To a mixture of methyl 2,3-dihydro-9-methyl-1- benzothiepin-4-carboxylate (1.5 g) and guanidine

hydrochloride (3.1 g) in N,N-dimethylformamide (15 ml) was added sodium methoxide (5.8 ml, 28% in methanol) . The reaction mixture was stirred for 20 hours at ambient temperature and the mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate (60 ml) and methanol (10 ml), and thereto was added 3-chloroperbenzoic acid (3.5 g) under ice-cooling. The mixture was stirred for 2 hours at the same temperature. The mixture was diluted with water and the mixture was adjusted to pH 9 with 20% aqueous potassium carbonate. The separated organic layer was washed successively with a 1090 aqueous sodium thiosulfate and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in a mixture of methanol (6.5 ml) and diisopropyl ether (3 ml), and to the mixture was added a slight excess methanesulfonic acid. The isolated precipitate was collected by filtration and recrystallized from a mixture of methanol and diisopropyl ether to give 2,3-dihydro-4-guanidinocarbonyl-9-methyl-l-benzothiepin 1,1-dioxide methanesuifonate (0.64 g). mp : 237-239"C IR (Nujol) : 3336, 3145, 1703, 1657, 1595, 1194, 1169, 1049 cm 1 NMR (DMSO-d6, 5) : 2.41 (3H, s), 2.71 (3H, s), 2.88 (2H, t, J=6.5Hz), 3.84 (2H, t, J=6.5Hz), 7.t6 (1H, dd, J=1.7, 7.2Hz), 7.57-7.69 (3H, m), 8.13- 8.58 (4K, its), 11.23 (1K, s) Example 9 To a mixture of ethyl 2,3-dihydro-9-methoxycarbonyl- amino-l-benzoxepin-a-carboxylate (0.26 g) and guanidine hydrochloride (0.41 g) in N,N-dimethylformamide (2.6 ml)

was added sodium methoxide (0.81 ml, 28% in methanol) The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo.

The residue was dissolved in a mixture of methanol and diisopropyl ether and thereto was added methanesulfonic acid (0.069 ml). The resulting precipitate was collected by filtration and recrystallized from a mixture of methanol and diisopropyl ether to give a solid of (2,3- dihydro-9-methoxycarbonylamino-1-benzoxepin-4- carbonyl)guanidine methanesulfonate (0.13 g). mp : 224-226°C (dec.) (diisopropyl ether-methanol) IR (KBr) : 3370, 1741, 1705, 1637 cm 1 NMR (DMSO-d6, #) : 2.36 (3H, s), 2.85-3.0 (2H, m), 3.67 (3K, s), 4.2-4.35 (2H, m), 7.0-7.15 (1K, m), 7.15-7.25 (1H, m), 7.30 (1H, br s), 7.37 (1H, s), 8.28 (4H, br s), 8.80 (1K, s), 10.96 (1H, br s) Example 10 The following compounds were obtained according to a similar manner to that cf Example 9.

(1) [2,3-Dihydro-9-(N'-ethylthioureido)-1-benzoxepin-4- carbonyl]guanidine methanesulfonate mp : 217-218°C (diisopropyl ether-methanol) IR (KBr) : 3370, 3345, 1709, 1685, 1657, 1635 cm 1 NMR (DMSO-d6, #) : 1.12 (3H, t, J=7.2Hz), 2.36 (3H, s), 2.85-3.0 (2H, m), 3.35-3.55 (2H, m), 4.25- 4.4 (2H, m), 7.0-7.15 (1H, m), 7.2-7.35 (1H, m), 7.40 (1H, s), 7.9-8.15 (2H, m), 8.28 (4H, br s), 9.00 (1H, br s), 10.95 (1H, br s) (2) [2,3-Dihydro-9-(N'-ethylureido)-1-benzoxepin-4-

carbonyl]guanidine methanesulfonate mp : 244-245°C (dilsopropyl ether-methanol) IR (KBr) : 3340, 1707, 1691, 1649 cm 1 NMR (DMSO-d6, #) : 1.06 (3K, t, J=7.2Hz), 2.41 (3H, s), 2.85-3.0 (2H, m), 3.0-3.2 (2E, m), 4.25-4.4 (2H, m), 6.8-7.1 (3H, m), 7.36 (1K, s), 8.13 (1K, s), 8.15-8.5 (5H, m), 11.00 (1K, br s) (3) (2,3-Dihydro-9-ureido-1-benzoxepin-4- carbonyl)guanidine methanesulfonate mp : 236-237°C (dec.) (diisopropyl ether-methanol) IR (KBr) : 3440, 3354, 1707, 1687, 1668, 1610 cm-1 NMR (DMSO-d6, #) : 2.37 (3H, s), 2.9-3.05 (2H, m), 4.25-4.4 (2K, m), 6.27 (ii, br s), 6.9-7.1 (2K, m), 7.35 (1K, s), 8.1-8.45 (6H, m), 10.96 (1H, br s) Example 11 To a mixture of ethyl 7-amino-2,3-dihydro-9-iodo-1- benzoxepin-4-carboxylate (0.36 g) and guanidine hydrochloride (0.48 g) in N,N-dimethylformamide (3.6 ml) was added sodium methoxide (0.96 ml, 28% in methanol).

The reaction mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted twice wit ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,4-dioxane and thereto was added 4N hydrogenechloride (0.75 ml, in 1,4-dioxane.). The resulting precipitate was collected by filtration and recrystallized from a mixture of methanol and diisopropyl ether to give a solid of (7-amino-2,3-dihydro-9-iodo-1- benzoxepin-4-carbonyl)guanidine dihydrochloride (0.26 g). mp : >300°C (diisopropvl ether-methanol) IR (KBr) : 1709, 1687, 1624 cm 1

NMR (DMSO-d6, #) : 2.85-3.05 (2H, m), 4.2-4.4 (2H, m), 7.46 (1H, d, J=2.5Hz), 7.76 (1H, d, J=2.5Hz), 7.77 (1H, s), 8.4-8.9 (4H, m), 12.13 (1H, br s) Example 12 The following compounds were obtained according to a similar manner to that of Example 11.

(1) (2,3-Dihydro-9-morpholino-1-benzoxepin-4-carbonyl)- guanidine dihydrochloride mp : 285-288°C (dec.) (diisopropyl ether-methanol) IR (KBr) : 1703, 1687, 1620 cm-1 NMR (DMSO-d6, #) : 2.9-3.05 (2H, m), 3.05-3.2 (4H, m), 3.7-3.9 (4H, m), 4.25-4.4 (2H, m), 7.0-7.4 (3H, m), 7.85 (1H, s), 8.3-8.85 (4H, m), 11.93 (1H, br s) (2) (9-Acetylamino-2, 3-dihydro-1-benzoxepin-4- carbonyl)guanidine hydrochloride mp : 255-257°C (dec.) (diisopropyl ether-methanol) IR (KBr) : 1693, 1635 cm 1 NMR (DMSO-d6, #) : 2.11 (3H, s), 2.85-3.0 (2H, m), 4.25-4.4 (2H, 7.0-7.15 (1H, m), 7.25-7.35 (1H, m), 7.79 (1H, s), 8.05 (1H, d, J=7.7Hz), 8.3-8.75 (4H, m), 9.33 (1H, s), 11.79 (1H, br s) (3) (2,3-Dihydro-9-methanesulfonylamino-1-benzoxepin-4- carbonyl)guanidine hydrochloride mp : 261-264°C (dec.) (diisopropyl ether-methanol) IR (KBr) : 1670, 1620 cm 1 NMR (DMSO-d6, #) : 2.85-3.0 (2H, m), 3.00 (3H, s), 4.2-4.35 (2H, m), 7.0-7.15 (1H, m), 7.3-7.45 (2H, m), 7.79 (1H, s), 8.25-8.75 (4H, m), 9.14 (1K, s), 11.80 (1H, br s) Some of the object compound (I) of the present invention can be prepared by the following process.

Process (2) Fl oxidation 0 t N CIIN=CNH2 NH2 oxidation K2 xr (Ia) (Ib) or a salt thereof or a salt thereof wherein R1, R2, Y, Z and are each as defined above, X1 is -S-, and X2 is -SO2-.

The compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to oxidation reaction.

This reaction can be carried out in the manner disclosed in Example 7 or similar manners thereto.