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D E S C R I P T I O N

HETEROCYCLIC DERIVATIVES WITH IMMUNOMODUL.ATING ACTIVITY.

TECHNICAL FIELD

This invention relates to new heterocyclic derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.

BACKGROUND ART

Some heterocyclic derivatives have been known as described, for example, in WO 92/18483.

DISCLOSURE OF INVENTION

This invention relates to new heterocyclic derivatives. More particularly, this invention relates to new heterocyclic derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.

Accordingly, one object of this invention is to provide the new and useful heterocyclic derivatives and pharmaceutically acceptable salts thereof which possess a strong immunomodulating activity (e.g. an inhibitory activity on the production of an autoantibody, etc.), anti-inflammatory activity and anti-cancer activity. Another object of this invention is to provide processes for preparation of the heterocyclic derivatives and salts thereof.

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

Still further object of this invention is to provide a use of said heterocyclic derivatives or a pharmaceutically acceptable salt thereof as a medicament for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity.diseases, cancer and the like in human being and animals.

The object heterocyclic derivatives of the present invention are novel and can be represented by the following general formula (I) :

wherein R ³ is lower alkyl,

R° is hydroxy, protected hydroxy or halogen, -N ) is bicyclic heterocyclic group containing at least one nitrogen atom, which may have suitable substituent(s) , and Y is a bivalent radical selected from the group consisting of

R-

(in which R-*- is hydrogen or lower alkoxy,

R ² is hydrogen, lower alkyl, lower alkoxy, halogen, mono(or di or tri)halo(lower)alkoxy, amino, protected amino, mono(or di)(lower alkyl)amino, protected (lower)- alkylamino, hydroxy, protected hydroxy, aryloxy, heterocyclic group, or nitro,

R ³ is hydrogen, halogen or lower alkoxy, or

R ² and R ³ are linked together to form lower alkylene or a group of the formula :

,0\ _^

O,

R^ is hydrogen or lower alkoxy, or R^ and R5 are linked together to form lower alkylene) ,

R'

(in which R ⁷ is lower alkyl, or

R ⁵ and R ⁷ are linked together to form lower alkylene).

The object compound (I) of the present invention can epared by the following processes.

Process ( 1 )

R ^c

COOH

N

(II) or its reactive derivative at the carboxy group, or a salt thereof

tive derivative o group, or eof

(I) or a salt thereof

Process ( 2)

(la) or a salt thereof

elimination reaction of the hydroxy protective group

I 5

( lb ) or a salt thereof

Process (3)

^< R-

( Ic) or a salt thereof

- 6 -

elimination reaction of amino protective group

R-

fid) or a salt thereof

Process (4)

R-

(Ie) or a salt thereof

ereof

- 7 -

(If) or a salt thereof

wherein Y, _R !, _R 3, _R 4, _R 5, _R 6 _and . _{N are each aΞ} defined above, R| is protected (lower)alkylamino, 3 is lower alkylamino,

R is protected hydroxy, ^ is lower alkyl, and X is a leaving group.

Suitable pharmaceutically acceptable salts of the object compound (I) are 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, fumarate, methanesulfonate, 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.

The term "higher" is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.

Suitable "lower alkyl" and "lower alkyl moiety" in the terms "monofor di) (lower alkyl)amino", "lower alkylamino" and "protected (lower)alkylamino" 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 alkoxy" and "lower alkoxy moiety" in the term "mono(or di or tri)halo(lower)alkoxy" may include ethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy 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 which may have suitable substituent(s) (e.g., benzyl, trityl, etc.) or the like. Suitable "acyl" and "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 :

Carbamoyl ;

Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimeth lpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc. ) ; lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, 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)alkanoyl [e.g. , phenyl(lower)alkenoyl (e.g. , phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, 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) lkanoyl (e.g. , phenoxyacetyl, phenoxypropionyl, etc. ) ; arylcarbamoyl (e.g., phenylcarbamoyl, etc.); arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);

arylglyoxyloyl (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., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl; or the like; in which suitable "heterocyclic moiety" in the terms "heterocycliccarbonyl", "heterocyclic(lower)alkyl", heterocyclic(lower)alkenoyl" and "heterocyclicglyoxyloyl" as mentioned above means, in more detail, saturated or unsaturated, monocyclic 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, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H-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, guinolyl, 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, 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, t iazolidinyl, 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) heteromonocyclic 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 substituerit(s) such as lower alkyl (e.g., methyl, ethyl, propyl, etc.); lower alkoxy

(e.g., methoxy, ethoxy, propoxy, etc.); lower alkylthio (e.g., methylthio, ethylthio, etc.); lower alkylamino

(e.g., methylamino, ethylamino, propylamino, etc.); cyclo(lower)alkyl (e.g., cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g., cyclohexenyl, etc.); halogen

(e.g., fluorine, chlorine, bromine, iodine); amino, protected amino as mentioned above; hydroxy; protected hydroxy as mentioned below; cyano; nitro; carboxy; protected carboxy; sulfo; εulfamoyl; imino; oxo; amino(lower)alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoyloxy; hydroxy(lower)alkyl (e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc.), or the like.

Suitable "hydroxy protective group" in the term

"protected hydroxy" may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl

(e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.

Suitable "amino protective group" in the term "protected (lower)alkylamino" may include acyl as

mentioned above, and the like.

Suitable "aryl moiety" in the term "aryloxy" may include phenyl, naphthyl and 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. Suitable "halogen" and "halogen moiety" in the term "mono(or di or tri) alo(lower)alkoxy" may include fluorine, bromine, chlorine, iodine.

Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be Cη_-C4 alkylene.

Suitable "bicyclic heterocyclic group containing at least one nitrogen atom" may include isoindolyl, indolyl, indazolyl,- indolinyl, isoindolinyl, 1,2-dihydroguinolyl, tetrahydroquinolyl [e.g., 1,2,3,4-tetrahydroguinolyl, etc.], benzoxazinyl [e.g., 4H-l,4-benzoxazinyl, etc.], dihydrobenzoxazinyl [e.g., 3,4-dihydro-2H-l,4- benzoxazinyl, 2,3-dihydro-4H-l,3-benzoxazinyl, etc.], benzothiazinyl [e.g., 4H-l,4-benzothiazinyl, etc.], dihydrobenzothiazinyl [e.g. 3,4-dihydro-2H-l,4- benzothiazinyl, 2,3-dihydro-4H-l,3-benzothiazinyl, etc.], pyrazolopyridinyl [e.g., lH-pyrazolo[3,4-b]pyridinyl, etc.], dihydropyrazolopyridinyl [2,3-dihydro-lH- pyrazolo[3,4-b]pyridinyl, etc.], imidazopyrazolyl [e.g., lH-imidazo[l,2-b]pyrazolyl, etc.], dihydroimidazopyrazolyl [e.g. 2,3-dihydro-lH-imidazo[l,2-b]pyrazolyl, etc.], tetrahydropyrazoϊopyrimidinyl [4,5,6,7- tetrahydropyrazolo[l,5-a]pyrimidinyl, etc.], and the like. Suitable "heterocyclic group" can be referred to the

ones as exemplified above.

Suitable "substituent" in the term "bicyclic heterocyclic group containing at least one nitrogen atom, which may have suitable substituent(s)" may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methγlallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or tri)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2- bromoethyl, 1 or 2-chloroethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, etc.), halogen (e.g., chlorine, bromine, fluorine, iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc.), ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethy1, phenylpropy1, etc. ) , carboxy(lower)alkyl, protected carboxy(lower)alkyl, nitro, amino, protected amino, di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylmethylamino, ethylpropylamino, etc.), hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, cyano, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), imino, and the like.

The processes for preparing the object compound are 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(trimethylsilyDaceta ide [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 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.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g. methyl ester, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [ (CH3)2 =CH-] ester, vinyl

ester, ethyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-guinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)- 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, ethylene chloride, ethylene chloride, tetrahydrofuran, toluene, 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. When the base and/or the- starting compound are in liquid, they can be used also as a solvent.

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; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl- '-(3-dimethylaminopropyl)carbodiimide; , '-carbonyl-bis(2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-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; l-(p-chlorobenzenesulfonyloxy)-6- chloro-lH-benzotriazole; 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, pyridine, N- (lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.

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

Process (2) The compound (lb) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to elimination reaction of the hydroxy protective group.

This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo[4.3.0]non-5-ene, 1,4- diazabicycl[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7- ene, or the like.

Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. The elimination using Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agent [e.g. anisole, phenol, etc.], The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a ^' mixture thereof or any other solvent which does not adversely affect the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming. The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction. Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g.

reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ullman copper, etc.] and the like. The reduction is usually carried out in a conventional solvent which does not adversely affect the reaction such as water, methanol, ethanol, propanol, N,N- dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent, further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof. The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

Process (3) The compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the amino protective group.

This elimination can be carried out in a similar manner to that of the aforementioned Process (2) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (2) .

Process (4) The compound (If) or a salt thereof can be prepared by reacting the compound (le) or a salt thereof with the compound (IV) or a salt thereof.

This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene,

ethylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.

The reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium hydorgencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri(lower)alkylamine (e.g., trimethylamine, triethylamine, diisoprόpylethylamine, etc.), alkali metal hydride (e.g, sodium hydride, etc.), alkali metal (lower)alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower)alkylmorpholine, N,N- di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

When the base and/or the starting compound are in liquid, they can be used also as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under warming to heating. Suitable salts of the object and starting compounds and their reactive derivatives in Processes (1)~(4) can be referred to the ones as exemplified for the compound (I). The new heterocyclic derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention possess a strong immunomodulating activity (e.g. an inhibitory activity on the production of an autoantibody, etc.), anti-inflammatory activity and anti- cancer activity and therefore are useful as an immunomodulating agent (e.g. an inhibitor on the production of an autoantibody, etc. ) , anti-inflammatory agent and anti-cancer agent. Accordingly, the new heterocyclic derivatives (I) and

a pharmaceutically acceptable salt thereof can be used for the treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, cancer, and the like in human beings or animals, and more particularly for the treatment and/or prevention of inflammation and pain in joint and muscle [e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc.], inflammatory skin condition [e.g. sunburn, eczema, etc.], inflammatory eye condition [e.g. conjunctivitis etc.], lung disorder in which inflammation is involved [e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.], condition of the gastrointestinal tract associated with inflammation [e.g. aphthous ulcer, Crohn's disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.], gingivitis, (inflammation, pain and tumescence after operation or injury) , pyrexia, pain and other conditions associated with inflammation, rejection by transplantation, systemic lupus erythematosus, scleroderma, polymyositis, polychondritis, periarteritis nodosa, ankylosing spondytis, inflammatory chronic renal condition [e.g. glomerulonephritis, membranous nephritis, etc.], rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, dermatomyositis, chronic active hepatitis, myasthenia gravis, idiopathic sprue, Grave's disease, multiple sclerosis, primary biliary cirrhosis, Reiter's syndrome, autoimmune hematological disorders [e.g. hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenia, aplastic anemia, etc.], uveitis, contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Wegner's granulomatosis, Hodgkin's disease, cancer [e.g. lung carcinoma, stomach carcinoma, colon cancer, renal carcinoma, hepatoma, etc.] and the like.

In order to show the utilities of the heterocyclic derivatives (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the heterocyclic derivatives (I) are illustrated in the following.

Inhibitory activity on the production of an anti-DNA-antibody and on the leakage of a proteinuria.

1. Test method

Six weeks old female (57BL/6 x DBA/2)F ₁ and DBA/2 mice were used. Graft-versus-host (GVH) disease was induced in (57BL/6 x DBA/2)F _] _ mice with two injections of DBA/2 spleen cells given 5 days apart. Each injection contained 5 x 10 ⁷ cells. From 3 days after the second cell injection, drug was administered orally once a day for 8 weeks.

As an indication of autoimmune disease, 4 weeks after the last cell injection anti-single strand DNA antibodies were measured by enzyme-linked immunosorbent assay (ELISA) using the procedure reported by T. Fujitsu et al. (International J. Immunopharmacol, j3 897 (1986)). To assess the renal disease, 8 weeks after the last cell injection proteinuria were measured. The concentration of serum albumin in the urine was determined by the single radial immunodiffusion method using rabbit anti-mouse serum albumin antiserum. Ten mice were used per group. The activity of the compound was expressed as a % inhibition of anti-DNA antibody and proteinuria.

Test compound

1,2-Dihydro-6-hydroxy-5-(1-indolinylcarbonyl)-8- methoxy-4-oxo-4H-pyrrolo[3,2,1-ij ]quinoline

3. Test result

* : Significantly different from control group at P<0.05

For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used in a form of the conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.

The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the administering method.

Preferred embodiments of the object compound (I) are as follows. R is lower alkyl,

R^ is hydroxy, phenyl(lower)alkoxy which may have one or more suitable substituent(s) [more preferably benzyloxy] or halogen, -N ) is indolinyl, tetrahydroquinolyl, dihydrobenzoxazinyl, dihydrobenzothiazinyl, dihydroimidazopyrazolyl or tetrahydropyrazolopyrimidinyl, each of which may have 1 to 3 (more preferably one or two; most preferably one) suitable substituent(s)

[more preferably indolinyl which may have 1 to 3

(more preferably one or two; most preferably one) substituent(s) selected from the group consisting of halogen, lower alkoxy and lower alkylthio (more preferably indolinyl which may have halogen, lower alkoxy or lower alkylthio) ; tetrahydroquinolyl; dihydrobenzoxazinyl; dihydrobenzothiazinyl; dihydroimidazopyrazolyl; or tetrahydropyrazolopyrimidinyl] , and Y is a bivalent radical selected from the group consisting of

R4

(in which R ¹ is hydrogen or lower alkoxy, R ² is hydrogen, lower alkyl, lower alkoxy, halogen, trihalo(lower)alkoxy, amino, acylamino [more preferably lower alkanoylamino] , mono(or di)(lower alkyl)amino, N-acyl-N- lower alkylamino [more preferably N-

- 25 -

lower alkanoyl-N-lower alkylamino], hydroxy, phenyl(lower)alkoxy which may have one or more suitable substituent(s) [more preferably benzyloxy] , phenyloxy, pyrrolyl or nitro, R ³ is hydrogen, halogen or lower alkoxy, or R ² and R-^ are linked together to form lower alkylene or a group of the formula :

O

R^ is hydrogen or lower alkoxy, or R ⁴ and R^ are linked together to form lower alkylene),

(in which R' is lower alkyl, or R5 and R ⁷ are linked together to form lower alkylene).

The following Preparations. and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1

OH

-COOC Hc

N ¹ N

N NH N N 0

A mixture of 2,3-dihydro-lH-imidazo[1,2-b]pyrazole (3 g) and tri(ethoxycarbonyl)methane (11.3 ml) was stirred under a nitrogen atmosphere at 170°C for 2 hours. The reaction mixture was purified by column chromatography on silica gel (60 g) eluting with a mixture of ethyl acetate and methanol (10:1) to give colorless crystals of 5- ethoxycarbonyl-6,7-dihydro-l,7-ethylene-4-hydroxy-6-oxo- lH-pyrazolo[3,4-b]pyridine (2.7 g) . IR (Nujol) : 1700, 1635 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.27 (3H, t, J=7Hz) , 4.26 (2H, q, J=7Hz), 4.5-4.8 (4H, m) , 7.85 (1H, s), 13.9 (1H, s) Mass (m/z) : 249 (M ⁺ )

Preparation 2

The following compound was obtained according to a similar manner to that of Preparation 1.

6,7-Dihydro-l,7-dimethyl-5-ethoxycarbonyl-4-hydroxy- 6-oxo-lH-pyrazolo[3,4-b]pyridine

IR (Nujol) : 1650, 1635, 1610, 1570 em ^-1

NMR (DMSO-d ₆ , δ) : 1.26 (3H, t, J=7Hz) , 3.69 (3H, s), 4.15 (3H, s), 4.28 (2H, q, J=7Hz) , 7.90 (1H, s) Mass (m/z) :. 251 (M ⁺ >

Example 1

Phosphorus trichloride (0.398 ml) was added dropwise

to a solution of indoline (3.07 ml) in toluene (20 ml) under stirring. After the mixture was stirred for 30 minutes, 3-carboxy-1,2-dihydro-4-hydroxy-1-methyl-2- oxoquinoline (2 g) was added thereto. The mixture was heated at 100°C for 2 hours, and then cooled down. The reaction mixture was extracted with 2N sodium hydroxide solution. The extract was acidified with hydrochloric acid and extracted with chloroform. The extract was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was washed with acetone to give colorless crystals of l,2-dihydro-4-hydroxy-3-(1- indolinylcarbonyl)-l-methyl-2-oxoquinoline (2.4 g) . mp : 220-224°C

IR (Nujol) : 1650, 1635, 1595, 1585, 1555, 1500 cm ^-1 NMR (DMSO-d ₆ , δ) : 3.08 (2H, d, J=8Hz), 3.60 (3H, s), 3.89 (2H, t, J=8Hz), 6.8-8.3 (8H, ) , 11.5 (1H, s) MASS (m/z) : 320 (M ⁺ )

Elemental Analysis Calcd. for C^gH^g^O : C 71.23, H 5.04, N 8.75

Found : C 70.93, H 4.99, N 8.71

Example 2

The following compounds were obtained according to a similar manner to that of Example 1.

(1) l,2-Dihydro-4-hydroxy-3-[ (1,2,3,4-tetrahydroquinolin- 1-yl)carbonyl]-1-methyl-2-oxoquinoline mp : 164-168°C IR (Nujol) : 1650, 1630, 1595, 1570 cm ^"1

NMR (DMSO-d ₆ , δ) : 1.8-2.1 (2H, m) , 2.77 (2H, t,

J=7Hz), 3.50 (3H, s), 3.5-3.9 (2H, m) , 6.9-7.8 (7H, ), 8.00 (1H, d,_ J=8Hz), 11.4 (1H, m) Mass (m/z) : 334 (M ⁺ )

- 28 -

(2) 1,2-Dihydro-4-hydroxy-3-[ (3,4-dihydro-2H-l,4- benzoxazin-4-yl)carbonyl]-l-methyl-2-oxoquinoline mp : 194-197°C (dec.)

IR (Nujol) : 1640, 1590, 1565, 1495 cm ^"1 NMR (DMSO-d ₆ , δ) : 3.55 (3H, s), 3.6-3.9 (2H, m) ,

4.2-4.5 (2H, m), 6.6-8.5 (8H, m) , 11.6 (1H, s) Mass (m/z) : 336 (M ⁺ ) Elemental Analysis Calcd. for '•

C 67.85, H 4.80, N 8.33 Found : C 68.18, H 4.76, N 8.34

(3) 6-Chloro-l,2-dihydro-4-hydroxy-3-(1- indolinylcarbonyl)-l-methyl-2-oxoquinoline mp : 249-251°C (dec.) IR (Nujol) : 1660, 1630, 1610, 1575, 1555 cm ^-1

NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz), 3.59 (3H, s), 3.88 (2H, t, J=8Hz), 6.8-8.3 (7H, m) , 11.7 (1H, s) Mass (m/z) : 354 (M ⁺ )

(4) l,2-Dihydro-7-fluoro-4-hydroxy-3-(1- indolinylcarbonyl)-l-methyl-2-oxoquinoline mp : 206-208°C

IR (Nujol) : 1640, 1590, 1555 cm ^-1 NMR (DMSO-d ₆ , δ) : 3.08 (2H, t, J=8Hz), 3.57 (3H, s), 3.89 (2H, t, J=8Hz), 6.8-7.5 (5H, m) , 8.0- 8.3 (2H, m), 11.6 (1H, s) Mass (m/z) : 338 (M ⁺ )

Elemental Analysis Calcd. for Q^W^- c^^- - : C 67.45, H 4.47, N 8.28

Found : C 67.63, H 4.51, N 8.36

(5) 1,2-Dihydro-6-hydroxy-5-(1-indolinylcarbonyl)-4-oxo- 4H-pyrrolo[3,2,l-ij]quinoline mp : 248-250°C (dec.)

IR (Nujol) : 1650, 1600, 1545 cm-1

NMR (DMSO-d ₆ , δ) : 3.08 (2H, t, J=8Hz), 3.39 (2H, t, J=8Hz), 3.90 (2H, t, J=8Hz) , 4.27 (2H, t, J=8Hz), 6.8-7.6 (5H, m) , 7.77 (1H, d, J=8Hz), 8.18 (1H, d, J=8Hz), 11.3 (1H, s)

Mass (m/z) : 332 (M ⁺ )

( 6) 4,5-Dihydro-7-hydroxy-6-( 1-indolinylcarbonyl)-4- methyl-5-oxothieno[3 ,2-b]pyridine mp : 222-226°C

IR (Nujol) : 1650, 1605, 1570, 1530 cm ^-1 NMR (DMSO-d ₆ , 6) : 3.07 (2H, t, J=8Hz), 3.59 (3H, s), 3.91 (2H, t, J=8Hz), 6.9-7.3 (3H, m) , 7.38 (1H, d, J=5Hz), 8.03 (1H, d, J=5Hz), 8.14 (1H, d, J=8Hz), 11.6 (1H, s)

Mass (m/z) : 326 (M ⁺ )

(7) 1,2-Dihydro-5-[ ( 3,4-dihydro-2H-l,4-benzothiazin-4- yl)carbonyl]-6-hydroxy-4-oxo-4H-pyrrolo[3,2,1-ij ]- quinoline mp : 211-214°C (dec.)

IR (Nujol) : 1640, 1610, 1565 cm ^"1

NMR (DMSO-d ₆ , δ) : 3.2-4.1 (6H, m) , 4.20 (2H, t, J=8Hz), 6.7-7.5 (6H, m) , 7.71 (1H, d, J=8Hz), 11.3 (1H, s)

Mass (m/z) : 364 (M ⁺ )

Example 3

A mixture of l,2-dihydro-3-ethoxycarbonyl-7-chloro-4- hydroxy-l-methyl-2-oxoquinoline (2.3 g) and indoline (1.1 ml) in pyridine (11 ml) was stirred at 100°C for 4 hours. The solvent was evaporated and the residue was washed with ethanol to give colorless crystals of 1,2-dihydro-7- chloro-4-hydroxy-3-( 1-indolinylcarbonyl) -1-methyl-2- oxoquinoline (2.4 g) .

p : 250-252°C (dec.)

IR (Nujol) : 1640, 1630, 1600, 1575 cm ^"1 NMR (DMSO-d ₆ , δ) : 3.08 (2H, t, J=8Hz), 3.59 (3H, s), 3.88 (2H, t, J=8Hz), 6.8-8.2 (7H, m) , 11.6 (1H, s)

Mass (m/z) : 354 (M ⁺ )

Example 4

The following compounds were obtained according to a similar manner to that of Example 3.

( 1) l,2-Dihydro-6-fluoro-4-hydroxy-3-(1- indolinylcarbonyl)-l-methyl-2-oxoquinoline mp : 240-242°C IR (Nujol) : 1660, 1630, 1590, 1565, 1515 cm ^"1

NMR (DMSO-d ₆ , δ) : 3.08 (2H, t, J=8Hz) , 3.61 (3H, ε), 3.88 (2H, t, J=8Hz), 6.8-7.9 (6H, m) , 8.18 (1H, d, J=8Hz), 11.6 (1H, s) Mass (m/z) : 338 (M ⁺ )

( 2) l,2-Dihydro-6-hydroxy-5-[ ( 5-methylthioindolin-l- yl)carbonyl]-4-oxo-4H-pyrrolo[3,2,1-ij ]quinoline p : 222-227°C

IR (Nujol) : 1655, 1635, 1605, 1550 cm ^"1 NMR (DMSO-d ₆ , δ) : 2.47 (3H, s), 3.07 (2H, t,

J=8Hz), 3.39 (2H, t, J=8Hz) , 3.90 (2H, t,

J=8Hz), 4.27 (2H, t, J=8Hz), 6.8-7.6 (4H, m) ,

7.76 (1H, d, J=8Hz), 8.11 (1H, d, J=8Hz), 11.3 (1H, s) Mass (m/z) : 378 (M ⁺ )

( 3) 1,2-Dihydro-6-hydroxy-5-[ (5-methoxyindolin-l- yl)carbonyl]-4-oxo-4H-pyrrolo[3,2,1-ij ]quinoline mp : 227-230°C IR (Nujol) : 1645, 1630, 1595, 1540, 1490 cm ^"1

NMR (DMSO-d ₆ , δ) : 3.05 (2H, t, J=8Hz), 3.38 (2H, t, J=8Hz), 3.74 (3H, s), 3.89 (2H, t, J=8Hz), 4.26 (2H, t, J=8Hz), 6.7-7.6 (4H, m) , 7.76 (1H, d, J=8Hz), 8.09 (1H, d, J=8Hz), 11.2 (1H, s) Elemental Analysis Calcd. for C2iHι_gN2θ4 :

C 69.60, H 5.01, N 7.73 Found : C 69.35, H 5.05, N 7.65

(4) l,2-Dihydro-6-hydroxy-5-(1-indolinylcarbonyl)-8- methoxy-4-oxo-4H-pyrrolo[3,2,l-ij ]quinoline mp : 254-256°C

IR (Nujol) : 1650, 1600 cm ^"1

NMR (DMSO-D ₆ , δ) : 3.08 (2H, t, J=8Hz), 3.36 (2H, t,

J=8Hz), 3.80 (3H, s), 3.89 (2H, t, J=8Hz), 4.26 (2H, t, J=8Hz), 6.8-7.4 (5H, m) , 8.18 (1H, d,

J=8Hz), 11.2 (1H, s)

( 5) l,2-Dihydro-3-[ ( 5-fluoroindolin-1-yl)carbonyl]-4- hydroxy-6-methoxy-1-methyl-2-oxoquinoline mp : 256-258°C (dec.)

IR (Nujol) : 1650, 1605, 1580, 1550, 1510 cm ^-1 NMR (DMSO-d ₆ , δ) : 3.09 (2H, t, J=8Hz), 3.58 (3H, s), 3.84 (3H, s), 3.91 (2H, t, J=8Hz) , 6.9-7.6 (5H, m) , 8.1-8.3 (1H, m) Mass (m/z) : 369 (M+l)

Elemental Analysis Calcd. for C20 ^H l7 ^N 2 ^FO 4 ^:

C 65.21, H 4.65, N 7.61 Found : C 65.35, H 4.72, N 7.72

(6) l,2-Dihydro-4-hydroxy-3-( 1-indolinylcarbonyl)-6- methoxy-1-methyl-2-oxoquinoline mp : 240-242°C (dec.)

IR (Nujol) : 1650, 1610, .1585, 1550, 1510 cm ^"1

NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz), 3.59 (3H, s), 3.84 (3H, s), 3.88 (2H, t, J=8Hz), 6.8-7.6

( 6H , m ) , 8 . 19 ( 1H , d , J=8Hz ) , 11 . 4 ( 1H , s ) Mass ( m/ z ) : 350 ( M ⁺ )

(7) 1,2-Dihydro-3-[ (2,3-dihydro-lH-imidazo[1,2-b]pyrazol- 1-y1)carbonyl]-4-hydroxy-6-methoxy-1-methyl-2- oxoquinoline mp : 217-218°C (dec.)

IR (Nujol) : 1625, 1610, 1575, 1550, 1510 cm ^"1 Mass (m/z) : 341 (M+l)

(8) 5,6-Dihydro-8-hydroxy-7-(1-indolinylcarbonyl)-5- methyl-6-oxo-l,3-dioxolo[4,5-g]quinoline mp : 239-241°C

IR (Nujol) : 1640, 1600, 1560 cm ^"1 NMR (DMSO-d ₆ , δ) : 3.07 (2H, t, J=8Hz), 3.56 (3H, s), 3.89 (2H, t, J=8Hz), 6.17 (2H, s), 6.9-7.5 (5H, m) , 8.16 (1H, d, J=8Hz) , 11.1 (1H, s) Mass (m/z) : 364 (M ⁺ )

(9) 1,2,7,8-Tetrahydro-4-hydroxy-3-(1-indolinylcarbonyl)- l-methyl-2-oxo-6H-cyclopenta[g]quinoline mp : 206-209°C

IR (Nujol) : 1645, 1615, 1595, 1555 cm ^"1 NMR (DMSO-dg, δ) : 2.0-2.2 (2H, m) , 2.8-3.2 (6H, m) , 3.58 (3H, s), 3.88 (2H, t, J=8Hz) , 6.8-7.6 (4H, m) 7.88 (1H, ε), 8.18 (1H, d, J=8Hz), 11.2 (1H, s) Masε (m/z) : 360 (M ⁺ )

(10) l,2-Dihydro-4-hydrσxy-3-(1-indolinylcarbonyl)-1,6- di ethyl-2-oxoquinoline mp : 208-210°C

IR (Nujol) : 1630, 1585, .1565 cm ^"1

NMR (DMSO-dg, δ) : 2.40 (3H, ε), 3.08 (2H, t, J=8Hz), 3.58 (3H, s), 3.88 (2H, t, J=8Hz), 6.8-

7.9 (6H, m), 8.19 (1H, d, J=8Hz) , 11.4 (1H, s) Mass (m/z) : 334 (M ⁺ ) Elemental Analysiε Calcd. for C2oHχ8 ^N 2°3 ^:

C 71.84, H 5.43, N 8.38 Found : C 71.94, H 5.49, N 8.35

(11) 1,2-Dihydro-4-hydroxy-3-(1-indolinylcarbonyl)-7- methoxy-1-methyl-2-oxoquinoline mp : 235-237°C (dec.) IR (Nujol) : 1630, 1580, 1555, 1510 cm ^"1

NMR (DMSO-dg, δ) : 3.07 (2H, t, J=8Hz), 3.58 (3H, ε), 3.89 (2H, t, J=8Hz), 3.92 (3H, ε), 6.8-7.4 (6H, m), 7.97 (1H, d, J=9Hz) , 11.2 (1H, ε) Maεε (m/z) : 350 (M ⁺ )

(12) 1,2-Dihydro-4-hydroxy-3-(1-indolinylcarbonyl)-8- methoxy-1-methyl-2-oxoquinoline mp : 249-251°C (dec.)

IR (Nujol) : 1655, 1625, 1615, 1580 cm ^"1 NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz), 3.78 (3H, s), 3.90 (3H, ε), 3.88 (2H, t, J=8Hz), 6.8-7.5 (5H, m), 7.67 (1H, d, J=8Hz) , 8.18 (1H, d, J=8Hz) Mass (m/z) : 349 (M-l)

(13) 1,2-Dihydro-4-hydroxy-3-(1-indolinylcarbonyl)-5- methoxy-1-methyl-2-oxoquinoline mp : 218-220°C

IR (Nujol) : 1655, 1640, 1595, 1570 cm ^-1 NMR (DMSO-dg, δ) : 3.09 (2H, t, J=8Hz), 3.58 (3H, s), 3.90 (2H, t, J=8Hz), 4.03 (3H, s), 6.8-7.3 (5H, m), 7.66 (1H, t, J=8Hz), 8.16 (1H, d, J=8Hz) , 10.2 (1H, ε) Maεε (m/z) : 351 (M+l)

(14) 1,2-Dihydro-7-chloro-4-hydroxy-3-(1- indolinylcarbonyl)-6-methoxy-l-methyl-2-oxoquinoline p : 254-257°C (dec.)

IR (Nujol) : 1645, 1600, 1575, 1560 cm ^"1 NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz), 3.58 (3H, s), 3.88 (2H, t, J=8Hz), 3.93 (3H, ε), 6.8-8.2 (6H, m) Maεε (m/z) : 384 (M ⁺ )

Elemental Analysis Calcd. for C20H17N2CIO4 : C 62.42, H 4.45, N 7.28

Found : C 62.26, H 4.73, N 7.09

(15) l,2-Dihydro-4-hydroxy-3-(1-indolinylcarbonyl)-l- methyl-6-(trifluoromethoxy)-2-oxoquinoline p : >360°C

IR (Nujol) : 1660, 1620, 1600, 1580, 1520 cm ^"1 NMR (DMSO-dg, δ) : 2.9-3.2 (2H, m) , 3.53 (3H, ε),

3.8-4.2 (2H, m), 6.8-8.3 (7H, m) Mass (m/z) : 404 (M ⁺ )

(16) 1,2-Dihydro-6,7-dimethoxy-4-hydroxy-3-( 1- indolinylcarbonyl)-l-methyl-2-oxoquinoline mp : 238-241°C

IR (Nujol) : 1640, 1620, 1580, 1520 cm ^"1 NMR (DMSO-dg, δ) : 3.07 (2H, t, J=8Hz), 3.62 (3H, s), 3.83 (3H, ε), 3.96 (3H, s) , 3.8-4.0 (2H, m) , 6.9-7.3 (3H, m), 6.99 (1H, ε), 7.49 (1H, s), 8.18 (1H, d, J=8Hz), 11.2 (1H, br s) Maεε (m/z) : 294

( 17) 1,2-Dihydro-6-ethoxy-4-hydroxy-3-(1- indolinylcarbonyl)-l-methyl-2-oxoquinoline mp : 332-335°C (dec.)

IR (Nujol) : 1650, 1610, 1580, 1550, 1510 cm ^"1 NMR (DMSO-dg, δ) : 1.37 (3H, t, J=7Hz) , 3.08 (2H, t,

J=8Hz), 3.58 (3H, ε), 3.88 (2H, t, J=8Hz), 4.10 (2H, q, J=7Hz), 6.8-7.6 (6H, m) , 8.19 (1H, d, J=8Hz), 11.3 (1H, ε) Maεε (m/z) : 365 (M+l) Elemental Analyεiε Calcd. for C21H20N2O4 :

C 69.21, H 5.53, N 7.69 Found : C 69.42, H 5.47, N 7.66

(18) l,2-Dihydro-7-fluoro-4-hydroxy-3-(l- indolinylcarbonyl)-6-methoxy-l-methyl-2-oxoquinoline mp : 244-246°C (dec.)

IR (Nujol) : 1650, 1610, 1590, 1560, 1525 cm ^"1

NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz), 3.56 (3H, ε), 3.89 (2H, t, J=8Hz), 3.92 (3H, s), 6.8-7.8 (5H, m), 8.19 (1H, d, J=8Hz)

Maεε (m/z) : 369 (M+l)

(19) 1,2-Dihydro-4-hydroxy-3-(1-indolinylcarbonyl)-1- methyl-6-phenoxy-2-oxoquinoline mp : 220-225°C

IR (Nujol) : 1650, 1620, 1600, 1580, 1560, 1510 cm ^"1 NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz) , 3.61 (3H, s), 3.89 (2H, t, J=8Hz), 6.8-7.7 (11H, m) , 8.17 (1H, d, J=8Hz) Mass (m/z) : 413 (M+l)

Elemental Analysis Calcd. for C25H20 2O4 :

C 72.80, H 4.89, N 6.79 Found : C 72.60, H 5.00, N 6.81

(20) 6-Benzyloxy-l,2-dihydro-4-hydroxy-3-(l- indolinylcarbonyl)-l-methyl-2-oxoquinoline mp : 217-220°C (dec.)

IR (Nujol) : 1645, 1610, 1.585, 1560, 1510 cm ^"1

NMR (DMSO-dg, δ) ; 3.08 (2H, t, J=8Hz), 3.58 (3H, s), 3.88 (2H, t, J=8Hz), 5.19 (2H, ε), 6.8-7.7

(11H, m), 8.19 (1H, d, J=8Hz), 11.3 (1H, s) Mass (m/z) : 427 (M+l)

Elemental Analysis Calcd. for C2gH22 ^N 2°4 ^:

C 73.22, H 5.20, N 6.57 Found : C 73.22, H 5.22, N 6.77

( 21) l,2-Dihydro-4-hydroxy-3-( 1-indolinylcarbonyl) -1- methyl-6-nitro-2-oxoquinoline mp : 252-254°C (dec.) IR (Nujol) : 1645, 1625, 1590, 1525, 1500 cm ^"1

NMR (DMSO-dg, δ) : 3.10 (2H, t, J=8Hz), 3.66 (3H, s), 3.90 (2H, t, J=8Hz), 6.8-7.4 (3H, m) , 7.75 (1H, d, J=9Hz), 8.18 (1H, d, J=8Hz) , 8.46 (1H, dd, J=3Hz, 9Hz), 8.86 (1H, d, J=3Hz) Maεε (m/z) : 366 (M+l)

( 22) l,2-Dihydro-5-[ ( 2,3-dihydro-lH-imidazo[1,2-b]pyrazol- 1-yl)carbonyl]-6-hydroxy-4-oxo-4H-pyrrolo[3.2.1-ij ]- quinoline mp : 211-213°C (dec.)

IR (Nujol) : 3550, 1645, 1610, 1565 cm ^"1 Maεε (m/z) : 322 (M ⁺ )

(23) 1,2-Dihydro-6-hydroxy-8-methoxy-5-[ (5- methylthioindolin-1-yl)carbonyl]-4-oxo-4H- pyrrolo[3 ,2,1-ij ]quinoline p : 217-220°C

IR (Nujol) : 1650, 1635, 1600 cm ^"1 NMR (DMSO-dg, δ) : 2.46 (3H, ε), 3.06 (2H, t, J=8Hz), 3.36 (2H, t, J=7Hz) , 3.79 (3H, s), 3.89

(2H, t, J=8Hz), 4.25 (2H, t, J=7Hz) , 6.8-7.4 (4H, m), 8.11 (1H, d, J=8Hz), 11.2 (1H, br s) Maεε (m/z) : ^' 243

( 24 )

6,7-Dihydro-l,7-ethylene-4-hydroxy-5-( 1- indolinylcarbonyl) -6-oxo-lH-pyrazolo[3,4-b]pyridine mp : 225-228°C

IR (Nujol) : 1690, 1640, 1585 cm ^"1

NMR (DMSO-dg, δ) : 3.06 (2H, t, J=8Hz), 3.89 (2H, t, J=8Hz), 4.5-4.9 (4H, m) , 6.9-7.3 (3H, m) , 7.77 (1H, s), 8.0-8.3 (1H, m) , 11.9 (1H, s) Masε (m/z) : 322 (M ⁺ )

( 25) 6,7-Dihydro-l,7-dimethyl-4-hydroxy-5-( 1- indolinylcarbonyl)-6-oxo-lH-pyrazolo[3,4-b]pyridine mp : 243-245°C (dec. ) IR (Nujol) : 1645, 1615, 1550 cm ^"1

NMR (DMSO-dg, δ) : 3.06 (2H, t, J=8Hz) , 3.76 (3H, ε), 3.86 (2H, t, J=8Hz), 4.19 (3H, ε), 6.9-7.3 (3H, m), 7.95 (1H, ε), 8.1-8.2 (1H, m) Maεε (m/z) : 324 (M ⁺ )

Example 5

A mixture of l,2-dihydro-6-benzyloxy-4-hydroxy-3-(l- indolinylcarbonyl) -l-methyl-2-oxoquinoline (0.7 g) , 5% palladium-carbon (0.2 g) and acetic acid (1 ml) in tetrahydrofuran (100 ml) and methanol (20 ml) was εtirred under an atmoεphere of hydrogen for 8 hourε. The mixture waε filtered and the filtrate was concentrated to dryness. The residue was washed with ethanol to give pale brown crystals of 1, 2-dihydro-4,6-dihydroxy-3-(1- indolinylcarbonyl) -l-methyl-2-oxoquinoline (0.47 g) .

mp : 232-234°C (dec.)

IR (Nujol) : 3200, 1650, 1615, 1600, 1580, 1545,

1515 cm ^"1 NMR (DMSO-dg, δ) : 3.07 (2H, t, J=8Hz), 3.55 (3H, s), 3.88 (2H, t, J=8Hz), 6.8-7.5 (6H, m) , 8.18

(1H, d, J=8Hz), 9.61 (1H, s), 11.2 (1H, s) Mass (m/z) : 337 (M ⁺ +l)

Example 6 A .mixture of l,2-dihydro-4-hydroxy-3-( 1- indolinylcarbonyl)-l-methyl-6-nitro-2-oxoquinoline (0.5 g) and sodium hydride (60%; 60.4 mg) in N, ^' N-dimethylformamide (5 ml) was stirred at room temperature for 1 hour. Benzyl bromide (0.25 ml) was added thereto and the reεulting mixture waε εtirred at 60°C for 4 hourε. The reaction mixture waε poured into ice-water (80 ml) and the precipitates were collected by filtration and washed with water to afford pale brown crystals of 4-benzyloxy-l,2- dihydro-3-( 1-indolinylcarbonyl) -l-methyl-6-nitro-2- oxoquinoline (0.52 g) .

IR (Nujol) : 1645, 1610, 1525 cm ^"1

NMR (DMSO-dg, δ) : 3.05 (2H, t, J=8Hz) , 3.70 (3H, s), 3.91 (2H, t, J=8Hz), 5.32 (1H, d, J=llHz), 5.47 (1H, d, J=llHz), 6.8-8.7 (12H, m) Maεε (m/z) : 456 (M+l)

Example 7

A mixture of 4-benzyloxy-1,2-dihydro-3-( 1- indolinylcarbonyl)-l-methyl-6-nitro-2-oxoquinoline (0.56 g), iron powder (0.56 g) and ammonium chloride (56 mg) in ethanol (10 ml) and water (5 ml) waε refluxed with εtirring for 1 hour. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and ethanol (50:1) to

give a yellow powder of 6-amino-4-benzyloxy-l,2-dihydro-3- (1-indolinylcarbonyl)-l-methyl-2-oxoquinoline (0.43 g) .

IR (Nujol) : 3350, 3200, 1640, 1620, 1575, 1510 cm ^"1 NMR (DMSO-dg, δ) : 2.9-3.2 (2H, m) , 3.58 (3H, ε), 3.7-4.0 (2H, m), 5.19 (1H, d, J=llHz), 5.29 (2H, s), 5.32 (1H, d, J=llHz), 6.9-7.5 (11H, m) , 8.21 (1H, d, J=8Hz) Masε (m/z) : 426 (M+l)

Example 8

A mixture of acetic anhydride (0.49 ml) and formic acid (0.19 ml) waε εtirred at 50°C for 1 hour and then cooled. To the mixture was added 6-amino-4-benzyloxy-l,2- dihydro-3-(1-indolinylcarbonyl)-l-methyl-2-oxoquinoline (0.22 g) . The reεulting mixture waε εtirred at room temperature for 2 hours and poured into ice-water (20 ml). The precipitateε were collected and washed with water to give pale brown crystals of 4-benzyloxy-l,2-dihydro-6- formylamino-3-(1-indolinylcarbonyl)-l-methyl-2- oxoquinoline (0.19 g) .

IR (Nujol) : 3250, 1690, 1640, 1625, 1580 cm ^"1 NMR (CDC1 ₃ , δ) : 2.8-3.2 (2H, m) , 3.5-3.8 (1H, m) , 3.61 (3H, s), 3.9-4.2 (1H, m) , 5.28 (1H, d, J=llHz), 5.43 (1H, d, J=llHz), 6.8-8.5 (14H, m) Maεε (m/z) : 454 (M+l)

Example 9

A mixture of 4-benzyloxy-l,2-dihydro-6-formylamino-3- (1-indolinylcarbonyl)-l-methyl-2-oxoquinoline (1.1 g) , 5% palladium-carbon (0.22 g) and acetic acid (1.6 ml) in tetrahydrofuran (80 ml) and methanol (32 ml) waε εtirred under an atmosphere of hydrogen for 7 hours. The mixture was filtered and the inεoluble material was extracted twice with a hot mixture of chloroform (200 ml) and ethanol (50 ml). The filtrate and extracts were combined

and concentrated to drynesε. The residue (0.73 g) was washed with ethanol to give pale brown crystals of 1,2- dihydro-6-formylamino-4-hydroxy-3-(1-indolinylcarbonyl)-l- methyl-2-oxoquinoline (0.56 g) . mp : 248-250°C

IR (Nujol) : 1655, 1630, 1585, 1550 cm ^"1

NMR (DMSO-dg, δ) : 3.08 (2H, t, J=8Hz) , 3.58 (3H, s), 3.89 (2H, t, J=8Hz), 6.8-8.4 (8H, m) , 10.37 (1H, s) Maεs (m/z) : 364 (M+l)

Example 10

The following compounds were obtained according to a similar manner to that of Example 9. (1) 1,2-Dihydro-4-hydroxy-3-(1-indolinylcarbonyl)-1- methyl-6-(N-methyl-N-formylamino)-2-oxoquinoline mp : 225-227°C

IR (Nujol) : 1675, 1640, 1615, 1580, 1560 cm ^"1 NMR (DMSO-dg, δ) : 3.09 (2H, t, J=8Hz), 3.28 (3H, s), 3.62 (3H, s), 3.89 (2H, t, J=8Hz), 6.8-8.3

(7H, m), 8.56 (1H, ε) Mass (m/z) : 378 (M+l)

(2) l,2-Dihydro-6-dimethylamino-4-hydroxy-3-(1- indolinylcarbonyl)-l-methyl-2-oxoquinoline hydrochloride p : 177-181°C (dec.)

IR (Nujol) : 3350, 2500, 2350, 1640, 1590 cm ^"1 NMR (DMSO-dg, δ) : 3.09 (2H, t, J=8Hz) , 3.14 (6H, s), 3.61 (3H, s), 3.88 (2H, t, J=8Hz), 6.9-8.3

(7H, m) Mass (m/z) : 364 (M+l)

Example 11 A mixture of 4-benzyloxy-l,2-dihydro-6-formylamino-3-

( 1-indolinylcarbonyl) -l-methyl-2-oxoquinoline (0.68 g) and sodium hydride (60%, 67 mg) in N,N-dimethylformamide (1.8 ml) was stirred at 5°C for 40 minutes. To the mixture was added methyl iodide (0.19 ml) and the resulting mixture was stirred at 5°C for 1 hour and poured into ice-water. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over anhydrous magneεium sulfate and concentrated to give a powder of 1,2-dihydro-4-benzyloxy-3-(1-indolinylcarbonyl) -1-methyl- 6-(N-methyl-N-formylamino)-2-oxoquinoline (0.69 g) . IR (Nujol) : 1680, 1650, 1625, 1570 cm ^"1 NMR (DMSO-dg, δ) : 2.9-3.2 (2H, m) , 3.23 (3H, s), 3.66 (3H, ε), 3.7-4.0 (2H, m) , 5.29 (1H, d, J=llHz), 5.41 (1H, d, J=llHz), 6.9-8.3 (12H, m) , 8.52 (1H, ε)

Maεε (m/z) : 468 (M+l)

Example 12

A mixture of l,2-dihydro-4-hydroxy-3-( 1- indolinylcarbonyl) -l-methyl-6-(N-methyl-N-formylamino) -2- oxoquinoline (0.8 g) and 3N-hydrochloric acid (8 ml) in methanol (32 ml) was stirred at 60°C for 2 hours. The resulting εolution waε concentrated and the reεidue waε waεhed with ethanol to give pale brown cryεtals of 4- hydroxy-3-(1-indolinylcarbonyl)-1-methyl-6-methylamino-2- oxoquinoline hydrochloride (0.75 g) . mp : 221-224°C (dec.)

IR (Nujol) : 2550, 2350, 1640, 1590, 1510 cm ^"1 NMR (DMSO-dg, δ) : 2.93 (3H, ε), 3.08 (2H, t, J=8Hz), 3.60 (3H, ε), 3.89 (2H, t, J=8Hz), 6.8-

7.8 (5H, m) , 8.03 (1H, s), 8.19 (1H, d, J=8Hz) Mass (m/z) : 350 (M+l)

Example 13 A mixture of 1,2-dihydro-6-amino-4-benzyloxy-3-( 1-

indolinylcarbonyl)-l-methyl-2-oxoquinoline (1.3 g) , methyl iodide (0.48 ml) and potassium carbonate (1.3 g) in acetone (19 ml) was refluxed with εtirring for 4 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (60 g) eluting with a mixture of toluene and ethyl acetate (1:1) to give 1,2-dihydro-4- benzyloxy-6-(dimethylamino)-3-(1-indolinylcarbonyl)-1- methyl-2-oxoquinoline (0.63 g) . IR (CHC1 ₃ ) : 1640, 1600, 1570, 1510 cm ^"1

NMR (DMSO-dg, δ) : 2.89 (6H, s), 2.9-3.2 (2H, m) , 3.62 (3H, s), 3.7-4.0 (2H, m) , 5.23 (1H, d, J=llHz), 5.33 (1H, d, J=llHz), 6.9-7.6 (11H, m) , 8.23 (1H, d, J=8Hz) Masε (m/z) : 454 (M+l)

Example 14

A εolution of thionyl chloride (0.077 ml) in dichloromethane (0.5 ml) was added dropwise to a εolution of l,2-dihydro-3-carboxy-4-chloro-6-methoxy-l-methyl-2- oxoquinoline (0.27 g) and triethylamine (0.29 ml) in dichloromethane (2 ml) at -10°C. The mixture was stirred at -5°C for 1 hour. 4,5,6,7-Tetrahydropyrazolo[l,5- a]pyrimidine (0.15 g) was added thereto, and the resulting mixture was stirred at room temperature for 4 hourε. The reaction mixture waε washed with water, dried and evaporated to give a yellow powder of l,2-dihydro-4- chloro-6-methoxy-l-methγl-3-[ (4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-4-yl)carbonyl]-2- oxoquinoline (0.39 g) .

IR (Nujol) : 1600, 1630, 1565, 1535, 1500 cm ^"1 NMR (DMSO-dg, δ) : 2.0-2.2 (2H, m) , 3.6-3.8 (2H, m) , 3.67 (3H, s), 3.89 (3H, ε), 4.1-4.3 (2H, m) , 6.73 (1H, d, J=2Hz), 7.1-7.8 (4H, m) Maεε (m/z) : 373 (M+l)

Example 15

A mixture of 6-amino-4-benzyloxy-l, 2-dihydro-3-( 1- indolinylcarbonyl)-l-methyl-2-oxoquinoline (1.1 g) and 2 ,5-dimethoxytetrahydrofuran (0.41 g) in acetic acid (12 ml) was stirred under reflux for 30 minutes. The mixture was dissolved in chloroform, washed with water, and concentrated to dryness. The residue was washed with ether to give a pale brown powder of 4-benzyloxy-l,2- dihydro-3-( 1-indolinylcarbonyl)-l-methyl-6-( 1-pyrrolyl)-2- oxoquinoline (1.1 g) .

IR (Nujol) : 1635, 1580, 1510 cm ^"1 NMR (DMSO-dg, δ) : 2.9-3.1 (2H, m) , 3.68 (3H, s), 3.6-4.0 (2H, m) , 5.37 (2H, ABq, J=23, 11Hz), 6.2-6.4 (2H, m) , 7.0-7.5 (11H, m) , 7.6-7.8 (1H, m), 7.9-8.1 (2H, m) , 8.23 (1H, d, J=8Hz)

Mass (m/z) : 476 (M+l) ⁺

Example 16

The following compounds were obtained according to a similar manner to that of Example 9.

(1) 6-Amino-l,2-dihydro-4-hydroxy-3-( 1- indolinylcarbonyl)-l-methyl-2-oxoquinoline hydrochloride mp : 180-190°C (dec.)

IR (Nujol) : 2600, 2350, 1640, 1625, 1580 cm ^"1 NMR (DMSO-dg, δ) : 3.09 (2H, t, J=8Hz), 3.61 (3H, s), 3.89 (2H, t, J=8Hz), 6.9-7.5 (4H, m) , 7.6-7.8 (3H, m), 8.03 (1H, s), 8.19 (1H, d, J=8Hz)

Mass (m/z) : 336 (M+l) ⁺

( 2) l,2-Dihydro-4-hydroxy-3-( 1-indolinylcarbonyl)-1- methyl-6-(1-pyrrolyl) -2-oxoquinoline mp : 210-214°C

IR (Nujol) : 1650, 1615, 1580, 1510 cm ^"1 NMR (DMSO-dg, δ) : 3.09 (2H, t, J=8Hz), 3.63 (3H, s), 3.91 (2H, t, J=8Hz), 6.31 (2H, t, J=2Hz) , 6.8-7.4 (3H, m), 7.42 (2H, t, J=2Hz) , 7.6-8.3 (4H, ) Mass (m/z) : 386 (M+l) ⁺