KR860001959B1 - Process for preparing carbostyril compounds - Google Patents

Abstract

The title compds. I [R1=H, lower alkyl, alkenyl, alkynyl, Phlower alkyl; R2=H, lower alkoxy; R3=H, lower alkanoyl, pyrridyl carbonyl, lower alkoxy carbonyl, etc.!, useful as a heart medicines, were prepd. Thus, a mixt. contg. 14g N-(beta-bromopropionyl)- paminoaniline, 18 g bis(beta-bromoethyl)amine monohydrobromide, and 70 ml methanol was refluxed for 15 hrs. This mixt. was treated with 3.06 g KCO3 and refluxed for 8 hrs. to give 5.3 g N- (betabromopropionyl)-p-piperazinyl aniline [A!. A suspension contg. 2.2 g [A! and 28 g AlCl3 in 50 ml CS2 was refluxed for 4 hrs. to give 0.9 g 6-(1-piperazinyl)-3,4-dihydrocarbostyril-HBr.

Description

Process for preparing carbostyryl compound

The present invention relates to a process for the preparation of novel carbostyryl compounds of the general formula (I) and pharmaceutically acceptable salts thereof useful as cardiac agents:

In the above formula,

R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group;

R <^2> represents a hydrogen atom and a lower alkoxy group;

R ³ is a hydrogen atom, a lower alkanoyl group, a furoyl group, a pyridylcarbonyl group, a lower alkanesulfonyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, or a lower alkyl group on a benzene ring. A phenylsulfonyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a phenylcarbonyl group, a phenyl-lower alkyl group, or a phenyl lower alkanoyl group which may be substituted; , Phenyl-lower alkyl group and phenyl-lower alkanoyl group each of 1 to 3 lower alkoxy groups, halogen atoms, lower alkyl groups, cyano groups, nitro groups, amino groups, hydroxy groups, lower alkases in the benzene ring May be substituted by a noylamino group, a lower alkylthio group, or a lower alkanoyloxy group or a lower alkylenedioxy group;

The bond present between the 3 and 4 positions of the carbostyryl nucleus is a single bond or a double bond.

Japanese Patent Application (OPI) Nos. 130589/79, 135785/79, 138585/79, 141785/79, 76872/80, 49319/80, 53283/80, 53284/80, and 83781/80 lower blood pressure, platelets Various carbostyryl compounds have been described that have agglutination or allergic inhibition.

EP-Al Nos. 7525 and 8014 also describe isoquinoline compounds with cardiovascular action.

However, the carbostyryl compound according to the present invention is structurally different from conventional carbostyryl and isoquinoline compounds.

An object of the present invention is to provide a method for producing a carbostyryl compound having a cardiac strengthening action.

Another object of the present invention is to provide a pharmaceutical composition containing a carbostyryl compound in an amount of a cardiotensifying effect.

It is also an object of the present invention to provide carbostyryl compounds and pharmaceutically acceptable salts thereof.

The present invention also provides a cardiac agent composition containing a cardiac strengthening effective amount of the general formula (I) compound or a pharmaceutically acceptable salt thereof.

The present invention also provides general formula (I) compounds and pharmaceutically acceptable salts thereof.

The compound of general formula (I) according to the present invention and its pharmaceutically acceptable salts exhibit myocardial contractile stimulating effect or positive myopathic effect and coronary blood flow increasing activity, and as a cardiac agent for treating cardiac dysfunction such as congestive heart failure. useful. The compounds according to the invention have the advantage of not increasing the heart rate, or even slightly increasing them if any.

As used herein, the term "lower alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, for example methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl Group, pentyl group and hexyl group.

As used herein, the term "lower alkenyl" refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms, for example vinyl group, allyl group, 2-butenyl group, 3-butenyl group , 1-methylallyl group, 2-pentenyl group, 2-hexenyl group and the like.

As used herein, the term "lower alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, for example, an ethynyl group, 2-propynyl group, 2-butynyl group, 3 -Butynyl group, 1-methyl-2-propynyl group, 2-pentynyl group, 2-hexynyl group and the like.

As used herein, the term "phenyl-lower alkyl" refers to a phenyl-lower alkyl group containing a straight or branched chain alkyl group having 1 to 6 carbon atoms in the alkyl site, for example benzyl group, 2-phenylethyl group, 1 -Phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 1,1-dimethyl-2-phenylethyl group, 5-phenylpentyl group, 6-phenylhexyl group, 2-methyl-3-phenylpropyl group Etc.

The term "lower alkoxy" as used herein refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, for example methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group , Tert-butoxy group, pentyloxy group, hexyloxy group and the like.

As used herein, the term "lower alkanoyl" refers to a straight or branched chain alkanoyl group having 1 to 6 carbon atoms, for example, formyl group, acetyl group, propionyl group, butyryl group, isobuty And the aryl group, pentanoyl group, tert-butylcarbonyl group and hexanoyl group.

The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.

As used herein, the term "lower alkylenedioxy" refers to a straight or branched chain alkylenedioxy group having 1 to 4 carbon atoms, for example, methylenedioxy group, ethylenedioxy group, trimethylenedioxy group Etc.

As used herein, the term "lower alkanesulfonyl" refers to a straight or branched chain alkanesulfonyl group having 1 to 6 carbon atoms, for example, methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, Isopropanesulfonyl group, butanesulfonyl group, tert-butanesulfonyl group, pentanesulfonyl group, hexanesulfonyl group and the like.

The term "lower alkoxycarbonyl" refers to a straight or branched alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group , Isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group and the like.

The term “lower alkoxycarbonyl-lower alkyl” refers to a straight or branched chain lower alkoxycarbonyl-lower alkyl group containing 1 to 6 carbon atoms in the alkoxy moiety and 1 to 6 carbon atoms in the alkyl moiety, for example For example, methoxycarbonylmethyl group, 3-methoxycarbonylpropyl group, 4-ethoxycarbonylbutyl group, 6-propoxycarbonylhexyl group, 5-isopropoxycarbonylpentyl group, 1,1- Dimethyl-2-butoxycarbonylethyl group, 2-methyl-3-tert-butoxycarbonylpropyl group, 2-pentyloxycarbonylethyl group, hexyloxycarbonylmethyl group, and the like.

As used herein, the term “phenylsulfonyl group which may be substituted by lower alkyl group on benzene ring” refers to phenylsulfonyl group which may be substituted by straight or branched chain alkyl group having 1 to 6 carbon atoms on benzene ring. , For example, phenylsulfonyl group, p-toluenesulfonyl group, 2-methylphenylsulfonyl group, 3-ethylphenylsulfonyl group, 4-propylphenylsulfonyl group, 2-butylphenylsulfonyl group, 3- Tert-butylphenylsulfonyl group, 4-pentylphenylsulfonyl group, 2-hexylphenylsulfonyl group, and the like.

As used herein, the term “1 to 3 lower alkoxy groups, halogen atoms, lower alkyl groups, cyano groups, nitro groups, amino groups, hydroxy groups, lower alkanoylamino groups, lower alkylthio groups, or lower alkaes Phenylcarbonyl group substituted by a noyloxy group or substituted by a lower alkylenedioxy group ”is a straight or branched alkoxy group having 1 to 6 carbon atoms, a halogen atom, a straight or branched chain having 1 to 6 carbon atoms. Alkyl group, cyano group, nitro group, amino group, hydroxy group, straight or branched chain alkanoylamino group having 1 to 6 carbon atoms, straight or immediate chain alkylthio group having 1 to 6 carbon atoms, or carbon By straight or branched alkanoyloxy groups having 1 to 6 atoms, or by alkylenedioxy groups having 1 to 4 carbon atoms Phenylcarbonyl group, for example, 2-chlorobenzoyl group, 3-chlorobenzoyl group, 4-chlorobenzoyl group, 2-fluorobenzoyl group, 3-fluorobenzoyl group, 4-fluorobenzoyl group , 2-bromobenzoyl group, 3-bromobenzoyl group, 4-bromobenzoyl group, 2-iodobenzoyl group, 4-iodobenzoyl group, 3,5-dichlorobenzoyl group, 2,6-dichlorobenzoyl group, 3,4-dichlorobenzoyl group, 3,4-difluorobenzoyl group, 3,5-dibromobenzoyl group, 3,4,5-trichlorobenzoyl group, 2-methylbenzoyl group, 3-methylbenzoyl group , 4-methylbenzoyl group, 2-ethylbenzoyl group, 3-ethylbenzoyl group, 4-ethylbenzoyl group, 3-isopropylbenzoyl group, 4-hexylbenzoyl group, 3,4-dimethylbenzoyl group, 2,5- Dimethylbenzoyl group, 3,4,5-trimethylbenzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-methoxybenzoyl group, 2-ethoxybenzoyl group, 3-ethoxy Cybenzoyl group, 4-ethoxybenzoyl group, 4-isopropoxybenzoyl group, 4-hexyloxybenzoyl group, 3,4-dimethoxybenzoyl group, 3,4-diethoxybenzoyl group, 3,4,5- Trimethoxybenzoyl group, 2,5-dimethoxybenzoyl group, 2-nitrobenzoyl group, 3-nitrobenzoyl group, 4-nitrobenzoyl group, 2,4-dinitrobenzoyl group, 2-aminobenzoyl group, 3- Aminobenzoyl group, 4-aminobenzoyl group, 2,4-diaminobenzoyl group, 2-cyanobenzoyl group, 3-cyanobenzoyl group, 4-cyanobenzoyl group, 2,4-dicyanobenzoyl group, 3 , 4-methylenedioxybenzoyl group, 3,4-ethylenedioxybenzoyl group, 2,3-methylenedioxybenzoyl group, 3-methyl-4-chlorobenzoyl group, 2-chloro-6-methylbenzoyl group, 2 -Methoxy3-chlorobenzoyl group, 2-hydroxybenzoyl group, 3-hydroxybenzoyl group, 4-hydroxybenzoyl group, 3,4-dihydroxybenzoyl group, 3,4,5-trihydroxy Benzoyl group, 2-formylaminobenzoyl group, 3-acetylaminobenzoyl group, 4-acetylaminobenzoyl group, 2-acetylaminobenzoyl group, 3-propionylaminobenzoyl group, 4-butyrylaminobenzoyl group, 2- Isobutyrylaminobenzoyl group, 3-pentanoylaminobenzoyl group, tert-butylcarbonylamino group, 4-hexanoylaminobenzoyl group, 2,6-diacetylaminobenzoyl group, 2-methylthiobenzoyl group , 3-methylthiobenzoyl group, 4-methylthiobenzoyl group, 2-ethylthiobenzoyl group, 3-ethylthiobenzoyl group, 3-isopropylthiobenzoyl group, 4-hexylthiobenzoyl group, 3,4-dimethylthio Benzoyl group, 2,5-dimethylthiobenzoyl group, 3,4,5-trimethylthiobenzoyl group, 2-formyloxybenzoyl group, 3-acetyloxybenzoyl group, 4-acetyloxybenzoyl group, 2-acetyloxybenzoyl Group, 3-propionyloxybenzoyl group, 4-butylyloxybenzoyl group, 2 Isobutyryloxybenzoyl group, 3-pentanoyloxybenzoyl group, tert-butyryloxybenzoyl group, 4-hexanoyloxybenzoyl group, 3,4-diacetyloxybenzoyl group, 3,4,5 -Triacetyloxybenzoyl group, and the like.

As used herein, the term "lower alkoxy group, halogen atom, lower alkyl group, cyano group, nitro group, amino group, hydroxy group, lower alkanoylamino group, lower alkylthio group, lower alkanoyloxy group 1 to Phenyl-lower alkyl group substituted by 3 or substituted by lower alkylenedioxy group ”is a straight or branched chain alkoxy group having 1 to 6 carbon atoms, a halogen atom or a straight or branched chain having 1 to 6 carbon atoms. Alkyl group, cyano group, nitro group, amino group, hydroxy group, straight or branched chain alkanoylamino group having 1 to 6 carbon atoms, straight or branched chain alkylthio group or carbon atom having 1 to 6 carbon atoms Substituted by 1 to 3 straight or branched alkanoyloxy groups having 1 to 6 or substituted by alkylenedioxy groups having 1 to 4 carbon atoms. Phenyl-lower alkyl group, for example, 2-chlorobenzyl group, 2- (3-chlorophenyl) ethyl group, 1- (4-chlorophenyl) -ethyl group, 3- (2-fluorophenyl ) Propyl group, 4- (3-fluorophenyl (butyl group, 1,1--dimethyl-2- (4-fluorophenyl) ethyl group, 5- (2-bromophenyl) pentyl group, 6- ( 3-bromophenyl) -hexyl group, 2-methyl-3- (4-bromophenyl) -propyl group, 3-iodobenzyl group, 2- (4-iodophenyl) -ethyl group, 1- (3, 5-dichlorophenyl) ethyl group, 2- (3,4-dichlorophenyl) -ethyl group, 3- (2,6-dichlorophenyl) propyl group, 4- (3,4-dichlorophenyl) butyl group, 1, 1-dimethyl-2- (3,4difluorophenyl) ethyl group, 5- (3,5-dibromophenyl) pentyl group, 6- (3,4,5-trichlorophenyl) hexyl group, 4 -Methylbenzyl group, 2- (2-methylphenyl) ethyl group, 1- (3-methylphenyl) ethyl group, 3- (3-ethylphenyl) propyl group, 4- (2-ethylphenyl) butyl group, 5- ( 4-ethylphenyl) pentyl group, 6- (3-isopropylphenyl) hexyl group, 2-methyl -3- (4-hexylphenyl) propyl group, 2- (3,4-dimethylphenyl) ethyl group, 2- (2,5-dimethylphenyl) ethyl group, 2- (3,4,5-trimethylphenyl) Ethyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 3,4,5-trimethoxybenzyl group, 1- (3-methoxyphenyl) ethyl group, 2- (2-methoxy Phenyl) ethyl group, 3- (2-ethoxyphenyl) propyl group, 4- (4-ethoxyphenyl) butyl group, 5- (3-ethoxyphenyl) pentyl group, 6- (4-isopropoxyphenyl ) Hexyl group, 1,1-dimethyl-2- (4-hexyloxyphenyl) ethyl group, 2-methyl-3- (3,4-dimethoxyphenyl) propyl group, 2- (3,4-dimethoxyphenyl ) Ethyl group, 2- (3,4-diethoxyphenyl) ethyl group, 2- (3,4,5-trimethoxyphenyl) ethyl group, 1- (2,5-dimethoxyphenyl) ethyl group, 3- Nitrobenzyl group, 1- (2-nitrophenyl) ethyl group, 2- (4-nitrophenyl) ethyl group, 3- (2,4-dinitrophenyl) propyl group, 4- (2-aminophenyl) butyl group , 5- (3-aminophenyl) pentyl group, 6- (4-aminophenyl) hexyl group, 2,4-diaminobenzyl , 2-cyanobenzyl group, 1,1-dimethyl-2- (3-cyanophenyl) ethyl group, 2-methyl-3- (4-cyanophenyl) propyl group, 2,4-dicyanobenzyl group , 3,4-methylenedioxybenzyl group, 3,4-ethylenedioxybenzyl group, 2,3-methylenedioxybenzyl group, 2- (3,4-methylenedioxyphenyl) ethyl group, 1- (3 , 4-ethylenedioxyphenyl) ethyl group, 3-methyl-4-chlorobenzyl group, 2-chloro-6-methylbenzyl group, 2-methoxy-3-chlorobenzyl group, 2-hydroxybenzyl group, 2 -(3,4-dihydroxyphenyl) ethyl group, 1- (3,4-dihydroxyphenyl) ethyl group, 2- (3-hydroxyphenyl) ethyl group, 3- (4-hydroxyphenyl) Propyl group, 6- (3,4-dihydroxyphenyl) group, 3,4-dihydroxybenzyl group, 3,4,5-trihydroxybenzyl group, 2-formylaminobenzyl group, 3-acetyl Aminobenzyl group, 3- (2-acetylaminophenyl) propyl group, 4- (4-acetylaminophenyl) butyl group, 2-propionyl-aminobenzyl group, 3- (3-butyryl Nophenyl) propyl group, 4- (4-isobutyrylaminophenyl) butyl group, 5- (2-tert-butylcarbonylaminophenyl) pentyl group, 6- (3-pentanoylaminophenyl) hexyl group, (2,4-diacetylamino) benzyl group, 4-methylthiobenzyl group, 2- (2-methylthiophenyl) ethyl group, 1- (3-methylthiopheny) ethyl group, 3- (3-ethylthio Phenyl) propyl group, 4- (2-ethylthiophenyl) butyl group, 5- (4ethylthiophenyl) pentyl group, 6- (3-isopropylthiophenyl) hexyl group, 2-methyl-3- (4- Hexylthiophenyl) propyl group, 2- (3,4-dimethylthiophenyl) ethyl group, 2- (2,5-dimethylthiophenyl) ethyl group, 2- (3,4,5-trimethylthiophenyl) ethyl group , 4-acetyloxybenzyl group, 3,4-acetyloxybenzyl group, 3,4,5-triacetyloxybenzyl group, 1- (3 acetyloxyphenyl) ethyl group, 2- (2-acetyloxyphenyl) ethyl Group, 3- (2-propionyloxyphenyl) propyl group, 4- (4-pentanoyloxyphenyl) butyl group, 5- (3-propionyloxyphenyl) pentyl group, 6- (4-isobutyryloxyphenyl) hexyl group, 1,1-dimethyl-2- (4-hexanoyloxyphenyl) ethyl group, 4-butyryloxybenzyl group, and the like.

The term "lower alkanoylamino" as used herein refers to a straight or branched chain alkanoylamino group having 1 to 6 carbon atoms, for example formylamino group, acetylamino group, propionylamino group, butyryl Amino group, isobutyrylamino group, pentanoylamino group, tert-butylcarbonylamino group, hexanoylamino group and the like.

The term “lower alkylthio” refers to a straight or branched chain alkylthio group having 1 to 6 carbon atoms, for example methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, 3 Tert-butylthio group, pentylthio group, hexylthio group and the like.

The term "lower alkanoyloxy" as used herein refers to a straight or branched chain alkanoyl oxy group having 1 to 6 carbon atoms, for example, formyloxy group, acetyloxy group, propionyloxy group, buty Aryloxy group, isobutyryloxy group, pentanoyloxy group, tert-butylcarbonyloxy group, hexanoyloxy group and the like.

The term "phenyl-lower alkanoyl" as used herein refers to a phenylalkanoyl group containing a straight or branched chain alkanoyl group having 1 to 6 carbon atoms in the alkanoyl moiety, for example 2-phenylacetyl group, 3 -Phenyl propionyl group, 4-phenylbutyryl group, 2-phenylbutyryl group, 6-phenylhexanoyl group, 2-phenylpropionyl group, 3-phenylbutythyl group, 4-phenyl-3-methylbutyryl Group, 5-phenylpentanoyl group, 2-methyl-3-phenylpropionyl group, and the like.

As used herein, the term “lower alkoxy group”, halogen atom, lower alkyl group, cyano group, nitro group, amino group, hydroxy group, lower alkanoylamino group, lower alkylthio group or lower alkanoyloxy group 1 Phenyl-lower alkanoyl group substituted by 2 to 3 or lower alkylenedioxy group &quot; is a straight or branched alkoxy group having 1 to 6 carbon atoms, a halogen atom, a straight chain having 1 to 6 carbon atoms. Or branched alkyl group, cyano group, nitro group, amino group, hydroxy group, straight or branched chain alkanoylamino group having 1 to 6 carbon atoms, straight or branched chain alkylthio group having 1 to 6 carbon atoms or To alkylenedioxy groups having 1 to 4 carbon atoms or substituted by 1 to 3 straight or branched alkanoyloxy groups having 1 to 6 carbon atoms Substituted phenyl-lower alkanoyl group, for example 2- (2-chlorophenyl) acetyl group, 2- (3-chlorophenyl) acetyl group, 2- (4-chlorophenyl) acetyl group, 3- (2-fluorophenyl) propionyl group, 4- (3-fluorophenyl) butyryl group, 2- (4-fluorophenyl) acetyl group, 5- (2-bromophenyl) pentanoyl group, 6 -(3-bromophenyl) hexanoyl group, 2-methyl-3- (4-bromophenyl) propionyl group, 2- (3- iodophenyl) acetyl group, 2- (4-dodophenyl) acetyl group , 2- (3,5-dichlorophenyl) acetyl group, 2- (3,4-dichlorophenyl) acetyl group, 3- (2,6-dichlorophenyl) propionyl group, 4- (3,4-dichlorophenyl ) Butylyl group 2- (3,4-difluorophenyl) acetyl group, 5- (3,5-dibromophenyl) pentanoyl group, 6- (3,4,5-trichlorophenyl) hexanoyl Group, 2- (4-methylphenyl) acetyl group, 2- (2-methylphenyl) acetyl group, 2- (3-methylphenyl) acetyl group, 3- (3-ethylphenyl) propionyl group, 4- (2-ethyl Phenyl) butyryl group, 5- (4-ethylphenyl) pentanoyl group, 6- (3-isopropylenyl) hexanoyl group, 2-methyl-3- (4-hexylphenyl) propionyl group, 2- ( 3,4-dimethylphenyl) acetyl group, 2- (2,5-dimethylphenyl) acetyl group, 2- (3,4,5-trimethylphenyl) acetyl group, 2- (4-methoxyphenyl) acetyl group, 2- (3,4-dimethoxyphenyl) acetyl group, 2- (3,4,5-trimethoxyphenyl) acetyl group, 2- (3-methoxyphenyl) acetyl group, 2- (2-methoxy Phenyl) acetyl group, 3- (2-ethoxyphenyl) propionyl group, 4- (4-ethoxyphenyl) butyryl group, 5- (3-ethoxyphenyl) pentanoyl group, 6- (4-iso Propoxyphenyl) hexanoyl group, 2- (4-hexyoxyphenyl) acetyl group, 2-methyl-3- (3,4-dimethoxyphenyl) propionyl group, 2- (3,4-dimethoxyphenyl) Acetyl group, 2- (3,4-diethoxyphenyl) acetyl group, 2- (3,4,5-trimethoxyphenyl) acetyl group, 2- (2,5-dimethoxyphenyl) acetyl group, 2- (3-nitrophenyl) acetyl group, 2- (2-nitrophenyl) Tyl group, 2- (4-nitrophenyl) acetyl group, 3- (2,4-dinitrophenyl) propionyl group, 4- (2-aminophenyl) butyryl group, 5- (3-aminophenyl) penta Noyl group, 6- (4-aminophenyl) hexanoyl group, 2- (2,4-diaminophenyl) acetyl group, 2- (2-cyanophenyl) acetyl group, 2- (3-cyanophenyl) Acetyl group, 2-methyl-3- (4-cyanophenyl) propionyl group, 2- (2,4-dicyanophenyl) acetyl group, 2- (3,4-methylenedioxyphenyl) acetyl group, 2 -(3,4-ethylenedioxyphenyl) acetyl group, 2- (2,3-methylenedioxyphenyl) acetyl group, 2- (3,4-methylenedioxyphenyl) acetyl group, 2- (3,4 -Ethylenedioxyphenyl) acetyl group, 2- (3-methyl-4-chlorophenyl) acetyl group, 2- (2-chloro-6-methylphenyl) acetyl group, 2- (2-methoxy-3-chlorophenyl ) Acetyl group, 2- (2-hydroxyphenyl) acetyl group, 2- (2,4-dihydroxyphenyl) acetyl group, 2- (3-hydroxyphenyl) acetyl group, 3- (4-hydroxy Phenyl) propy Neyl group, 6- (3,4-dihydroxyphenyl) hexanoyl group, 2- (3,4-dihydroxyphenyl) acetyl group, 2- (3,4,5-trihydroxyphenyl) acetyl group , 2- (2-formylaminophenyl) acetyl group, 2- (3-acetylaminophenyl) acetyl group, 3- (2-acetylaminophenyl) propionyl group, 4- (4-acetylaminophenyl) butyryl Group, 2- (2-propionylaminophenyl) acetyl group, 3- (3-butyrylaminophenyl) propionyl group, 4- (4-isobutyrylaminophenyl) butyryl group, 5- (2-3 Tert-butylcarbonylaminophenyl) pentanoyl group, 6- (3-pentanoylaminophenyl) hexanoyl group, 2- (2,4-diacetylaminophenyl) acetyl group, 2- (4-methylthiophenyl) Acetyl group, 2- (2-methylthiophenyl) acetyl group, 2- (3-methylthiophenyl) acetyl group, 3- (3-ethylthiophenyl) propionyl group, 4- (2-ethylthiophenyl) buty Aryl group, 5- (4-ethylthiophenyl) pentanoyl group, 6- (3-isopropylthiophenyl) hexanoyl group, 2-meth Methyl-3- (4-hexylthiophenyl) propionyl group, 2- (3,4-dimethylthiophenyl) acetyl group, 2- (2,5-dimethylthiophenyl) acetyl group, 2- (3,4, 5-trimethoxyphenyl) acetyl group, 2- (4-acetyloxyphenyl) acetyl group, 2- (3,4-acetyloxyphenyl) acetyl group, 2- (3,4,5-triacetyloxyphenyl) Acetyl group, 2- (3-acetyloxyphenyl) acetyl group, 2- (2-acetyloxyphenyl) acetyl group, 3- (2-propionyloxyphenyl) propionyl group, 4- (4-pentanoyloxyphenyl ) Butyryl group, 5- (3-propionyloxyphenyl) pentanoyl group, 6- (4-isobutyryloxyphenyl) hexanoyl group, 2- (4-hexanoyloxyphenyl) acetyl group, 2-4 -Butyryloxyphenyl) acetyl group, and the like.

The compound of general formula (I) according to the present invention can be prepared by various methods. Preferred examples of these methods are those according to Scheme 1 below.

Scheme 1

In the above formulas,

X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralsulfonyloxy group, or a hydroxy group;

The bond present between the 3- and 4-positions of R ¹ , R ² , R ³ and carbostyryl nucleus has the meaning defined above.

In formula (III), examples of the halogen atom represented by X include chlorine, fluorine, bromine and iodine; Examples of lower alkanesulfenyloxy groups represented by X include methanesulfonyloxy group, ethanesulfonyloxy group, isopropanesulfonyloxy group, propanesulfonyloxy group, butanesulfonyloxy group, tert-butanesulfonyl Oxy group, pentanesulfonyloxy group, hexanesulfonyloxy group and the like; Examples of the arylsulfonyloxy group represented by X include substituted or unsubstituted arylsulfonyloxy groups such as phenylsulfonyloxy group, 4-methylphenylsulfonyloxy group, 2-methylphenylsulfonyloxy group, 4- Nitrosulfonyloxy group, 4-methoxyphenylsulfonyloxy group, 3-chlorophenylsulfonyloxy group, α-naphthylsulfonyloxy group and the like; Examples of the aralkylsulfonyloxy group represented by X include substituted or unsubstituted aralkylsulfonyloxy groups such as benzylsulfonyloxy group, 2-phenylethylsulfonyloxy group, 4-phenylbutylsulfonyloxy Group, 4-methylbenzylsulfonyloxy group, 2-methylbenzylsulfonyloxy group, 2-nitrobenzylsulfonyloxy group, 4-methoxybenzylsulfonyloxy group, 3-chlorobenzylsulfonyloxy group, α- Naphthylmethylsulfonyloxy group and the like.

When X is used as a starting material, a compound of the general formula (III) in which X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group is used. The reaction with the compound of formula (III) can generally be carried out with or without a basic condensing agent in a suitable inert solvent.

Examples of suitable inert solvents that can be used include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, lower alcohols such as methanol, ethanol, isopropanol, butanol, acetic acid, ethyl acetate, dimethyl sulfoxide, dimethylformamide, Hexamethylenephosphoric acid triamide and the like.

Examples of basic condensing agents include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; Metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; Metal alcoholates such as sodium methylate, sodium ethylate and the like; Tertiary amines such as pyridine, triethylamine and the like.

In the above reaction, the ratio of the general formula (III) compound to the general formula (II) compound is not particularly limited and can be varied in a wide range. Typically this reaction is carried out using at least equimolar amounts, preferably 1 to 5 moles, of the general formula (III) compound per mole of the general formula (II) compound. This reaction can usually be carried out at about 40 to 120 ° C., preferably 50 to 100 ° C., and is generally completed after about 5 to 30 hours.

On the other hand, when X is used as a starting material, the compound of the general formula (III) representing a hydroxy group, the reaction with the general formula (III) compound per compound of the general formula (II) is a solvent in the presence of a dehydrogen condensing agent It may be used unused or in a suitable solvent.

Examples of dehydrogen condensing agents include polyphosphoric acid, phosphoric acid (e.g., orthophosphoric acid, pyrophosphoric acid, metaphosphoric acid, etc.), phosphorous acid (e.g., orthophosphoric acid, etc.), phosphoric anhydride (e.g., phosphorus pentoxide, etc.), inorganic acids (e.g., hydrochloric acid, sulfuric acid). , Boric acid, and the like), metal phosphates (eg, sodium phosphate, boron phosphate, iron phosphate, aluminum phosphate, and the like), activated alumina, sodium hydrogen sulfate, ranickel and the like.

As the solvent, a high boiling point solvent such as dimethylformamide, tetralin and the like can be used.

In the above reaction, the ratio of the compound of the general formula (III) to the compound of the general formula (II) is not particularly limited and can be varied in a wide range. Typically, this reaction is carried out using at least equimolar amounts, preferably 1 to 2 moles, of the general formula (III) compound per mole of the general formula (II) compound.

The amount of dehydrogen condensing agent is also not particularly limited and may be used within a wide range. Usually, at least the catalytic amount of the dehydrogen condensing agent per mole of the compound of the general formula (II), preferably 0.5 to 5 moles is used.

Preferably, the reaction is carried out in a stream of inert gas such as carbon dioxide, nitrogen to prevent unwanted oxidation.

This reaction can be carried out at atmospheric pressure or under atmospheric pressure. This reaction is preferably carried out at atmospheric pressure.

This reaction is usually advantageously carried out at about 100 to 350 ° C., preferably 125 to 255 ° C., and is generally completed after about 3 to 10 hours.

It should be noted that the general formula (III) compounds can be used in the form of their pharmaceutically acceptable salts.

R ³ is a lower alkanoyl group, 1 to 3 lower alkoxy groups, a halogen atom, a lower alkyl group, a cyano group, a nitro group, an ano group, a lower alkanoylamino group, a lower alkylthio group, a lower alkane in a benzene ring Phenylcarbonyl group or phenyl-lower alkanoyl group, furoyl group, pyridylcarbonyl group, or lower alkoxycarbo which may be substituted by a noyloxy group or a hydroxy group or substituted by a lower alkylenedioxy group The compound represented by the formula (I) having a meaning as defined above, wherein the bond represented by the above formula represents a nil group, X ¹ represents a hydroxy group, and R ¹ , R ² and the 3- and 4- positions of the carbostyryl nucleus It may be prepared according to Scheme 2 below.

Scheme 2

In the above formulas,

R ³ ′ is a lower alkanoyl group, 1 to 3 lower alkoxy groups, a halogen atom, a lower alkyl group, a cyano group, a nitro group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a lower alkane in a benzene ring Phenylcarbonyl group or phenyl-lower alkanoyl group, furoyl group, pyridylcarbonyl group, or lower alkoxycarbo which may be substituted by a noyloxy group or a hydroxy group or substituted by a lower alkylenedioxy group It represents a Neal group,

X ¹ represents a hydroxy group;

The bond present between the 3- and 4-positions of R ¹ , R ² and the carbostyryl nucleus is as defined above.

The method shown in Scheme 2 is a reaction between a carbostyryl derivative of formula (IV) and a carboxylic acid of formula (V) using a conventional amido production reaction. This method can be readily accomplished using the conditions applied to known amido production reactions. Representative examples of this method are as follows:

(a) Mixed acid anhydride method

A method of reacting a compound of formula (V) with an alkylhaloformate to produce a mixed acid anhydride thereof, followed by reaction with an amine of formula (IV).

(b) active ester methods

The carboxylic acid compound of formula (V) is converted into a reactive ester such as p-nitrophenyl ester, N-hydroxy-succinimide ester, 1-hydroxybenzotriazole ester, and the like, followed by reaction with an amine of formula (IV). How to let.

(c) carbodiimide method

A method of condensing a carboxylic acid compound of formula (V) and an amine of formula (IV) in the presence of an activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole and the like.

(d) other methods

Converting the carboxylic acid compound of formula (V) to an acid anhydride using a dehydrating agent such as acetic anhydride and then reacting the product with an amine of formula (IV); A method of reacting a lower alcohol ester of a carboxylic acid compound of formula (V) with an amine of formula (IV) under high temperature pressurization conditions; Or converting the carboxylic acid compound of formula (V) to an acid halide using a halogenating agent and then reacting the product with an amine of formula (IV).

tten Baumann) 반응에 따라 제조할 수 있으며, 할 수 있으며, 이는 분리시키지 않고 일반식(Ⅳ)의 아민과 더 반응시켜 일반식(Ⅰa)의 화합물을 수득한다.In the mixed acid anhydride method, the mixed acid anhydride is prepared by the conventional Schatten-Baumann (Sch).

can be prepared according to the tten Baumann reaction, which can be further reacted with an amine of the general formula (IV) without separation to give a compound of the general formula (Ia).

The Schatten-Baumann reaction can be carried out in the presence of a basic compound. As the basic compound, any of the common basic compounds commonly used in the Schatten-Baumann reaction can be used. Examples of suitable basic compounds include, for example, triethylamine, trimethylamine, pyridine, N, N-dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] noden-5 ( DBN), organic bases such as 1,5-diazabicyclo [5,4,0] undecene-5 (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO) and potassium carbonate Inorganic bases such as sodium carbonate, potassium bicarbonate, sodium bicarbonate and the like.

The reaction may proceed at about −20 to 100 ° C., preferably 0 to 50 ° C., and may continue for about 5 to 10 hours and preferably 5 minutes to 2 hours.

The reaction of the mixed acid anhydride with the amine of the general formula (IV) can be carried out at about -20 to 150 ° C, preferably at 10 to 50 ° C for about 5 minutes to 10 hours, preferably 5 minutes to 5 hours. have.

Mixed acid anhydride methods can generally proceed in a solvent. As a solvent, any solvent conventionally used by the mixed acid anhydride method can be used. Examples of suitable solvents include halogenated hydrocarbons such as methylene chloride, chloroform dichloroethane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like; Esters such as methyl acetate, ethyl acetate and the like; And aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide and the like.

Examples of suitable alkyl haloformates that can be used in the mixed acid anhydride method include methylchloroformate, methylbromoformate, ethylchloroformate, ethylbromoformate, isobutylchloroformate and the like.

In the above reaction, the alkyl haloformate and the carboxylic acid compound of general formula (V) can be usually used in equimolar amounts relative to the amine of general formula (V). However, it is also possible to use 1 to 1.5 moles of alkyl haloformate or carboxylic acid compound of formula (V) per mole of amine of formula (IV).

On the other hand, the reaction of the carboxylic acid halide with the amine of the general formula (IV) can be carried out in the presence of a basic compound in a suitable solvent. Various well-known compounds can be used as a basic compound. For example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like can be used in addition to the basic compound used in the Sheton-Bauman reaction mentioned above. Examples of suitable solvents include alcohols (eg, methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, etc.), pyridine, in addition to the solvents used in the aforementioned Shetton-Bauman reaction. And acetone.

The ratio of carboxylic acid halide to amine of formula (IV) can be used in a wide range without limitation. Usually at least 1 mole, preferably 1 to 5 moles, of carboxylic acid halide per mole of amine of formula (IV) is used.

This reaction can usually be carried out at -20 to 180 ° C, preferably 0 to 150 ° C, and is generally completed in 5 minutes to 30 hours.

R ³ is a lower alkanesulfonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenylsulfonyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, which may be substituted by a lower alkyl group on benzeneation, or 1 to 3 lower alkoxy groups, lower alkyl groups, halogen atoms, nitro groups, cyano groups, amino groups, lower alkanoylamino groups, lower alkanoylamino groups, lower alkylthio groups, lower alkanoyloxy groups in the benzene ring Or a compound of formula (I) which represents a phenyl-lower alkyl group which may be substituted by a hydroxy group or substituted by a lower alkylenedioxy group, may be prepared according to the following scheme -3:

Scheme-3

In the formulas above, R ^{3 ″} is a lower alkanesulfonyl group, a lower alkoxycarbonyl-lower alkyl group, a phenylsulfonyl group which may be substituted by a lower alkyl group in the benzene ring, a lower alkyl group, a lower alkenyl group , Lower alkynyl group, or 1 to 3 lower alkoxy groups, lower alkyl groups, halogen atoms, nitro groups, cyano groups, amino groups, lower alkanoylamino groups, lower alkylthio groups, lower alkanoyloxy on the benzene ring Phenyl-lower alkyl group which may be substituted by a group or a hydroxy group or may be substituted by a lower alkylenedioxy group;

X ² represents a halogen atom;

The bond present between the 3- and 4-positions of R ¹ , R ² and the carbostyryl nucleus has the meaning as defined above. The reaction of the general formula (IV) compound with the general formula (VI) compound can be carried out under similar conditions as used in the reaction of the general formula (IV) compound with the carboxylic acid halide.

R ³ is lower alkoxycarbonyl-lower alkyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, or 1 to 3 lower alkoxy groups, lower alkyl group, halogen atom, nitro group, cyano on benzene ring General which represents a phenyl-lower alkyl group which may be substituted by a lower group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a lower alkanoyloxy group or a hydroxy group or substituted by a lower alkylenedioxy group The compound of formula (I) can be prepared according to the following Scheme -4.

Scheme 4

In the formulas above, R ^{3 ′ ″} is a lower alkoxycarbonyl-lower alkyl group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or one to three lower alkoxy groups, lower alkyl groups in the benzene ring Can be substituted by a halogen atom, a nitro group, a cyano group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a lower alkanoyloxy group or a hydroxy group or a lower alkenedioxy group Phenyl-lower alkyl group;

The bond present between the 3- and 4- positions of the R ¹ , R ² , X, X ² and carbostyryl nuclei is as defined above.

The reaction between the general formula (II) compound and the general compound (VII) can be carried out in the presence of a basic compound. Examples of the basic compound include various known compounds such as inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate and the like; Alcoholates such as sodium methylate, sodium ethylate and the like; And organic bases such as triethylamine, pyridine, N, N-dimethylaniline and the like.

This reaction can be carried out in the absence or presence of a solvent. As the solvent, any of inert solvents which do not adversely affect the reaction can be used. Examples of suitable inert solvents include alcohols such as methanol, ethanol, propanol, ethylene glycol and the like; Ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; Ketones such as acetone, methyl ethyl ketone and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Esters such as methyl acetate, ethyl acetate and the like; And aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide and the like.

This reaction is advantageously carried out in the presence of metal iodide, for example potassium iodide.

The ratio of the general formula compound to the general formula (II) compound is not particularly limited and may be used in a wide range. The general formula (VII) compound is usually used in large excess when the reaction proceeds in the absence of solvent, and when the reaction proceeds in the presence of solvent, 2 to 10 moles per mole of the compound of general formula (II), preferably Preference is given to using in amounts of 2 to 4 moles.

There is no particular restriction on the reaction temperature, but usually this reaction is carried out at room temperature to 200 ° C, preferably 50 to 160 ° C. Typically, this reaction is continued for 1 to 30 hours.

The reaction between the compound of formula (VII) and the compound of formula (III) can be carried out under the same conditions as the reaction between the compound of formula (II) and compound of formula (III).

R ³ is a lower alkoxycarbonyl-lower alkyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, or 1 to 3 lower alkoxy groups, lower alkyl group, halogen atom, nitro group, cyano on benzene ring General which represents a phenyl-loweralkyl group which may be substituted by a lower group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a lower alkanoyloxy group or a hydroxy group or a substituted by a lower alkylenedioxy group Compounds of formula (I) can be prepared according to the following scheme -5:

Scheme-5

In the above formulas, the bond between the 3- and 4- positions of R ¹ , R ² , R ^{3 '''} , X and the carbostyryl nucleus has the same meaning as defined above.

The reaction of the general formula (II) compound with the general formula (VII) compound can be carried out under similar conditions as used in the reaction of the general formula (II) compound with the general formula (III) compound.

The reaction of the general formula (XI) compound with the general compound (VII) may be carried out using an acid in the absence of a solvent or in the presence of a suitable solvent. Examples of the solvent that can be used include high boiling point solvents such as tetralin, dimethyl-formamide, dimethyl sulfoxide, hexamethyl phosphoric acid triamide and the like. As the acid, hydrochloric acid, sulfuric acid, bromic acid and the like can be used.

There is no restriction | limiting in particular in the ratio of a general formula (VII) compound with respect to general formula (XI) compound, It can use in a wide range ratio. Typically, at least about 1 mole, preferably 1 to 2 moles, of the general formula (VII) compound is used per mole of the general formula (XI) compound.

This reaction can typically be carried out at about 50 to 250 ° C., preferably 150 to 200 ° C., and is generally completed in about 1 to 24 hours. In addition, the general formula (I) compound can be prepared according to the following Scheme -6.

Scheme-6

In the above formulas, R ⁴ represents a halogen atom, and the bond present between R ¹ , R ² , R ³ , X and the 3- and 4- positions of the carbostyryl nucleus has the same meaning as defined above.

The reaction of the general formula (XII) compound with the general formula (III) compound can be carried out under similar conditions as used in the reaction of the general formula (II) compound with the general formula (III) compound. The reaction of the general formula (XIII) compound, generally called the Friedel Crafts reaction, can be carried out in the presence of Lewis acid in a solvent. As the solvent, solvents commonly used in this type of reaction may be used, such as carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane and the like.

In the above reaction, it may be advantageous to use conventionally used Lewis acids such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid and the like. The amount of Lewis acid used is not particularly limited and may be appropriately changed. Usually, about 2 to 4 moles, preferably 3 to 4 moles of Lewis acid per mole of the general formula (XIII) compound are used.

The reaction temperature can be changed appropriately, but is usually about 20 to 120 ℃, preferably 40 to 70 ℃. The reaction time depends on the starting material, catalyst, reaction temperature and the like and is not constant. Typically, this reaction is completed in about 0.5 to 6 hours. Compounds of general formula (I) can be prepared according to the following Scheme -7. :

Scheme-7

In the above formulas, the bond present between R ¹ , R ² , R ³ , X ² and the 3- and 4- positions of the carbostyryl nucleus has the meaning as defined above, provided that R ¹ and R ³ Cannot be a hydrogen atom at the same time.

The reaction of the compound of formula (If) with the compound of formula (XIV) is advantageously carried out, for example, in the presence of a basic compound in a suitable solvent.

As a basic compound, sodium hydride, potassium metal, sodium metal, sodium amide, potassium amide, etc. can be used, for example. Examples of the solvent include ethers such as dioxane, diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene, xylene and the like, and aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, and the like. .

There is no restriction | limiting in particular in the ratio of a general formula (If) compound with respect to a general formula (XIV) compound, It can change freely. Typically at least about 1 mole, preferably 1 to 2 moles of the general formula (XIV) compound is used per mole of the compound of general formula (If). This reaction can usually be carried out at about 0 to 70 ° C., preferably 0 ° C. to room temperature and is generally completed in about 0.5 to 12 hours.

The general formula (I) compound in which the bond between the 3- and 4- positions of the carbostyryl nucleus is a double bond (single bond) is derived from the corresponding compound in which the bond is a single bond (double bond). It may be prepared according to 8.

Reaction Scheme -8

In the above general formulae, R ¹ , R ² and R ³ have the same meaning as defined above. The reduction reaction of the general formula (Ii) compound can be carried out under conventional catalytic reduction conditions. Examples of catalysts that can be used include metals such as palladium, palladium-carbon, platinum, Raney nickel, and the like, and are generally used in catalytic amounts.

As a solvent, methanol, ethanol, isopropanol, dioxane, THF, hexane, cyclohexane, ethyl acetate, etc. can be used, for example. The reduction reaction can be carried out at atmospheric or excess atmospheric pressure of hydrogen gas. Typically, the reaction is carried out at atmospheric pressure to 20 kg / cm 2, preferably at atmospheric pressure to 10 kg / cm 2. The reaction temperature is generally about 0 to 150 ° C, preferably room temperature to 100 ° C.

The dehydrogenation of the compound of formula (Ih) can be carried out in an appropriate solvent using an oxidizing agent. Examples of suitable oxidizing agents are benzoquinones such as 2,3-dichloro-5,6-dicyanobenzoquinone, chloranyl (2,3,5,6-tetrachlorobenzoquinone), N-bromosuccinimide, N Halogenating agents such as chlorosuccinimide, bromine and the like, selenium dioxide, palladium-carbon, palladium-black, vanadium oxide, Raney nickel and the like.

The amount of the oxidizing agent is not particularly limited and can be changed photometrically. Generally, 1 to 5 moles, preferably 1 to 2 moles of oxidizing agent are used per mole of the compound of general formula (Ih). When using a hydrogenation catalyst, a hydrogenation catalyst is used in a normal catalyst amount. Examples of suitable solvents include ethers such as dioxane, THF, methoxyethanol, dimethoxyethane, aromatic hydrocarbons such as benzene toluene, xylene, cumene and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, butanol, Alcohols such as amyl alcohol, hexane and the like, protonic polar solvents such as acetic acid, and the like, aprotic polar solvents such as DMF, DMSO, hexamethyl phosphoric acid, triamide, and the like.

This reaction can generally be carried out at room temperature to 300 ° C., preferably room temperature to 200 ° C., and is generally completed in about 1 to 40 hours. A compound of formula (I) wherein R ¹ represents a hydrogen atom and the bond present between the 3- and 4- positions of the carbostyryl nucleus is a double bond is present in the form of a lactam-lactim tautomer as shown below. Can be.

In the formulas, R ² and R ³ have the same meanings as defined above. In addition, the general formula (I) compound can be prepared according to the following Scheme -9.

Scheme-9

In the formulas above, R ² and R ³ have the same meanings as defined above;

R ⁵ and R ^{5 '} each represent a lower alkyl group or R ⁵ and R ^5' together with the oxygen atom to which they are attached form a lower alkylenedioxy group;

X represents a halogen atom;

R ⁶ represents a hydroxy group or a lower alkyl group;

R ⁶ ′ represents lower alkoxy;

R ⁷ represents a lower alkanoyl group.

Examples of the halogen atom represented by X include fluorine, chlorine, bromine and iodine. Examples of the lower alkylenedioxy group include a methylenedioxy group, an ethylenedioxy group, a trimethylenedioxy group and the like.

Some of the general formula (XV) compounds are novel compounds and the remaining compounds are known compounds, for example, can be prepared by nitrating general formula (XIV ') compounds.

The nitration reaction of the general formula (XIV ′) compound can be carried out under similar conditions as used in conventional nitration reactions of aromatic compounds, for example, without the use of a solvent using a nitrating agent or in a suitable inert solvent. have.

Examples of inert solvents include acetic anhydride, concentrated sulfuric acid and the like, and nitrating agents include acids such as fuming nitric acid, concentrated nitric acid, mixed acids (mixtures of nitric acid with sulfuric acid, fuming sulfuric acid, phosphoric acid or acetic anhydride), And a mixture of sulfuric acid and alkali metal nitrate (e.g., potassium nitrate, sodium nitrate and the like). The amount of nitrating agent used is usually at least equimolar, preferably excess, relative to the starting compound, and this reaction is advantageously carried out at 0 ° C. to room temperature for 1 to 4 hours.

The acetylation reaction of formyl groups in general formula (XV) compounds can be carried out in the presence of an acetylating agent and an acid in a suitable solvent. In this reaction, any solvent can be used as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene and the like, alcohols such as methanol, ethanol and the like, dimethylformamide, dimethyl sulfoxide and the like.

Examples of acetylating agents include alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like, orthocarboxylic acid esters such as ethyl orthoformate and the like. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as p-toluene sulfonic acid.

The amount of acetylating agent used is at least 1 mole, preferably 1 to 1.5 moles of acetylating agent per mole of the general formula (XV) compound when using orthocarboxylic acid ester. On the other hand, when alcohol is used, at least 2 moles of acetylating agent per mole of the general formula (XV) compound, generally large excess, are used. This reaction can typically be carried out at 0-50 ° C., preferably at about room temperature and is completed in about 30 minutes to 5 hours.

The reaction of the general formula (XVI) compound with the general formula (XVII) compound can be carried out in the presence of a solvent. As the solvent, aromatic hydrocarbons such as benzene, toluene, xylene and the like; Lower alcohols such as methanol, ethanol, isopropanol and the like; Ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethyl ether and the like; Polar solvents such as N-methyl pyrrolidone, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide and the like.

More advantageously, this reaction can be carried out using basic compounds as acid acceptors. Examples of basic compounds include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines (e.g. triethylamine, tripropylamine, etc.), pyridine, quinoline and the like.

Suitable amounts of piperazine derivatives of the general formula (XVII) used in the reaction are typically 1 to 10 moles, preferably 3 to 7 moles of the general formula (XVII) compound per mole of the general formula (XVI) compound. This reaction can usually be carried out at 50 to 150 ° C., preferably 50 to 100 ° C., and is generally completed in about 1.5 to 10 hours.

The hydrolysis reaction of the general formula (XVIII) compound is carried out for 30 minutes to 3 hours using an inorganic acid such as hydrochloric acid, sulfuric acid, etc. at a reaction temperature from room temperature to the boiling point of the solvent used in alcohols such as methanol, ethanol and isopropanol. Can be performed while.

The reaction of the compound of formula (XIX) with malonic acid of formula (XX) can be carried out in the presence of a basic compound in a suitable solvent. As the solvent, any solvent that can be used in the reaction of the general formula (XVI) compound and the general formula (XVII) compound can be used. It is also possible to use a polar solvent such as pyridine. Examples of suitable basic compounds include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines (e.g. triethylamine, tripropylamine, piperidine, etc.), pyridine, quinoline and the like. Can be mentioned.

In the above reaction, the appropriate amount of malonic acid of the general formula (XX) is at least equimolar amount, preferably 2 to 7 moles of the general formula (XX) compound per mole of the general formula (XIX) compound. This reaction can usually be carried out at about 0 to 200 ° C., preferably at 70 to 150 ° C., and is usually completed in about 1 to 10 hours.

The esterification reaction of the general formula (XXI) compound is carried out in an alcohol such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and the like, an acid such as hydrochloric acid, sulfuric acid or the like at a reaction temperature of about 0 to 150 ° C, preferably 50 to 150 ° C, or It may be performed for about 1 to 10 hours in the presence of a halogenating agent such as thionyl chloride, phosphorus oxy chloride, phosphorus pentachloride, phosphorus trichloride, and the like.

In this reaction, the appropriate amount of acid used is usually 1 to 1.2 moles per mole of the general formula (XXI) compound and the halogenating agent is at least equimolar amount, preferably 1 to 5 moles per mole of the general formula (XXI) compound. Use in quantity.

Reduction reactions of general formula (XXI) and general formula (XXII) compounds can be carried out by (1) reduction using a catalyst for catalytic reduction in an appropriate solvent, or (2) a mixture of metals or metal salts with acids, metals or It can be carried out by reducing with a reducing agent such as a mixture of metal salts with alkali metal hydroxides, sulfates or ammonium salts and the like.

When using the catalytic reduction method (1), examples of solvents that can be used include water, acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. Diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, diethyl ether and the like), esters (e.g. ethyl acetate, methyl acetate and the like), aprotic polar solvents (e.g. N, N-dimethylformamide and the like). As a catalyst, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc. can be used. Suitable amounts of catalyst are from 0.02 to 1.00 parts by weight per part by weight of the general formula (XXI) or (XXII) compound. This reaction can be carried out at about -20 ° C to room temperature, preferably at 0 ° C to room temperature and hydrogen gas pressure of 1 to 10 atmospheres for about 0.5 to 10 hours.

On the other hand, in the case of using the above-mentioned reaction (2), a mixture of iron, zinc, tin or stannous chloride and an inorganic acid such as hydrochloric acid, sulfuric acid or the like as a reducing agent, or iron, ferrous sulfate, zinc or tin And a mixture of alkali metal hydroxides (eg sodium hydroxide), sulfates (eg ammonium sulfate), aqueous ammonia or ammonium salts (eg ammonium chloride) can be used. Examples of suitable inert solvents that may be used include water, acetic acid, methanol, ethanol, dioxane and the like.

The said reduction reaction conditions can be suitably selected according to the reducing agent used. For example, when a mixture of stannous chloride and hydrochloric acid is used as the reducing agent, it is advantageous to carry out this reaction at about 0 ° C. to room temperature for about 0.5 to 10 hours. Suitable amounts of reducing agent are at least equimolar amounts, preferably 1 to 5 moles, of reducing agent per mole of starting compound.

In addition, when the reaction (1) is preferably carried out at 50 to 150 ° C, the compound of general formula (I) may be obtained by directly ring-closing without separating the compound of general formula (XXIIIa) or (XXIIIb).

The acylation reaction of the compound of formula (XXIIIa) can be carried out under conditions similar to those which can be prepared for the compounds of formula (I) in which R ³ represents a lower alkanoylaminobenzoyl group as described below.

The reaction for preparing the compound of general formula (I) by ring closure of the compound of general formula (XXIIIa) or (XXIIIb) can be carried out in the presence or absence of a basic compound or acid in a suitable solvent, preferably in the presence of an acid.

Examples of suitable basic compounds include organic bases such as triethylamine, trimethylamine, pyridine, dimethyl aniline, N-methyl morpholine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1 , 5-diazabicyclo [5,4,0] undecene-5 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) and the like, inorganic bases such as potassium carbonate and sodium carbonate And sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.

Examples of suitable acids include hydrochloric acid, sulfuric acid, polyphosphoric acid, and the like.

As the solvent, any solvent may be used as long as it does not adversely affect the reaction. Examples of suitable solvents include alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, and the like; Pyridine; Acetone; Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; Aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as diethyl ether, tetrahydro-furan, dimethoxyethane and the like; Esters such as methyl acetate, ethyl acetate and the like; Aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethyl phosphoric acid triamide and the like; And mixtures thereof.

This reaction can usually be carried out at -20 to 150 ° C, preferably 0 to 150 ° C and is usually completed in 5 minutes to 30 hours.

Among the compounds of formula (If) according to the present invention, R ³ represents a phenylcarbonyl group, a phenyl-lower alkyl group or a phenyl-lower alkanoyl group, each containing 1 to 3 amino groups on the benzene ring. lower alkyl group or a ^phenyl-3 are each benzene phenylcarbonyl group, phenyl containing 1 to 3 nitro groups on the ring by reducing a corresponding compound showing a lower alkanoyl group can be easily prepared. This reduction reaction can be carried out in the same manner as a conventional reaction in which an aromatic nitro compound is reduced to obtain a corresponding aromatic amino compound, more particularly, a method using a reducing agent such as sodium nitrite, sulfurous acid gas, palladium-carbon, and the like. The catalytic reduction method using the same reductive catalyst can be used.

R ² represents the formula (Ⅰ) compound represents a hydrogen atom may also be prepared by R ² is an ether decomposition to the corresponding compound of formula (Ⅰ) to represent a lower alkoxy group. Ether decomposition can usually be carried out at temperatures of about -30 ° C to room temperature, in the presence of excess Lewis acid, such as boron tribromide, boron trifluoride, aluminum chloride, etc., relative to the starting material.

R ³ represents a phenylcarbonyl group, a phenyl-lower alkyl group or a phenyl-lower alkanoyl group each substituted by 1 to 3 lower alkanoylamino groups or lower alkanoyloxy groups on the benzene ring Is a compound of formula (I) wherein R ³ represents a phenylcarbonyl group, a phenyl-lower alkyl group or a phenyl-lower akanoyl group, each of which is substituted by one to three amino groups or hydroxy groups on the benzene ring; The compound of can be prepared by acylating.

Examples of the acylating agent include lower alkanoic acid, for example acetic acid, and lower alkanoic anhydrides, for example acetic anhydride, and lower alkanoic acid chlorides, for example acetyl chloride.

When lower alkanoic anhydride or lower alkanoic acid halide is used as the acylating agent, the acylation reaction can be carried out in the presence of a basic compound. Examples of the basic compound include alkali metals such as sodium metal and potassium metal, hydroxides thereof, carbonates and hydrogencarbonates, and aromatic amines such as pyridine and piperidine.

This reaction can be carried out in the absence or presence of a solvent. In general, this reaction can be carried out in a suitable solvent. Examples of the solvent include ketone diethyl ether such as acetone and methyl ethyl ketone, ether such as dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, water and the like.

Suitable amounts of acylating agent used are equimolar to macromolar excess, preferably 5 to 10 moles of acylating agent per mole of starting compound.

This reaction can proceed at 0-150 degreeC, Preferably it is 0-80 degreeC.

When lower alkanoic acid is used as the acylating agent, the reaction is preferably carried out in the presence of a dehydrating agent, for example, inorganic acids such as sulfuric acid, hydrochloric acid, sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid. It is advantageous to proceed while maintaining at 50-120 degreeC.

R ³ is, each of the phenylcarbonyl group and phenyl substituted by one to three hydroxy or amino group on the benzene ring-lower alkyl group or a phenyl-compound represented by the general formula (Ⅰ) represents the lower aka Russo group R ³ A corresponding general formula (I) which represents a phenylcarbonyl group, a phenyl-lower alkyl group or a phenyl-lower alkanoyl group each substituted by one to three lower alkanoylamino groups or a lower alkanoyloxy group on a benzene ring; Can be prepared by hydrolysis of the compound.

The hydrolysis reaction can be carried out in the presence of an acid or basic compound in a suitable solvent. Solvents include water, lower alcohols (e.g. methanol, ethanol, isopropanol and the like), ethers (e.g. dioxane, tetrahydrofuran and the like) and mixtures thereof. Examples of suitable acids include inorganic acids such as hydrochloric acid, sulfuric acid, bromic acid and the like, and examples of suitable basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like.

This reaction is advantageously carried out at room temperature to 150 ° C., preferably 80 to 120 ° C. and can generally be completed in about 1 to 15 hours.

Formula (I) compounds can also be prepared according to Scheme 10 below:

Reaction Scheme -10

In the above formulas,

R ¹ , R ² and R ³ have the same meanings as defined above;

(여기에서, R⁸및 R⁹은 각기 저급알킬 그룹을 나타낸다)의 그룹, 또는 CH

C-그룹을 나타낸다.A is a group of the general formula R ^{7 '} -CH = CH-, wherein R ^7' represents a lower alkoxy group or a halogen atom

(Wherein R ⁸ and R ⁹ each represent a lower alkyl group), or CH

C-group.

The compound of the general formula (XXIV) and the compound of the general formula (XXV) are known compounds and the reaction between these compounds can be carried out by the same method as the reaction of compound (IV) and compound (V) described above.

The ring closure of the aniline derivatives of general formula (XXVI) can be carried out in the presence of an acid or without using a solvent. The acid is not particularly limited and a wide range of commonly used inorganic and organic acids can be used. More particularly, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid and the like, Lewis acids, such as aluminum chloride, boron trifluoride, titanium tetrachloride and the like, organic acids such as formic acid, acetic acid, ethanesulfonic acid, p-toluene sulfide Phonic acid and the like can be used.

Of these acids, hydrochloric acid, bromic acid and sulfuric acid are preferred.

The amount of acid used is not particularly limited and may be appropriately selected within a wide range. Typically, at least equimolar amounts, preferably 10 to 50 parts by weight of acid, per weight part of the general formula ((XXVI) compound can be used.

As the solvent, any commonly used inert solvent can be used. Examples of suitable solvents include water, lower alcohols (e.g. methanol, ethanol, propanol, etc.), ethers (e.g. dioxane, tetrahydrofuran), aromatic hydrocarbons (e.g. benzene, toluene, etc.), halogenated hydrocarbons (e.g. methylene chloride). , Chloroform, carbon tetrachloride, etc.), acetone, dimethyl sulfoxide, dimethylformamide, hexamethyl phosphoric acid triamide, and the like. Of these solvents, water-soluble solvents such as lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide and the like are preferable.

The above-mentioned reaction can be carried out at 0 to 100 ° C., preferably at room temperature to 60 ° C. and can usually be completed in about 5 minutes to 6 hours.

In addition, the compound of formula (I) can be prepared according to the following reaction scheme-11.

Reaction Scheme -11

In the above formulas,

R ¹ , R ² , R ³ and X ² are as defined above.

The reaction of the general formula (XXVII) compound with the general formula (XXVVIII) compound can be carried out with or without addition of a basic condensing agent in a suitable inert solvent.

Inert solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; Alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve and the like; Pyridine; Acetone; Dimethyl sulfoxide; Dimethylformamide; Hexamethylphosphoric acid triamide and the like.

Examples of suitable basic reagents include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, triethylamine and the like.

The ratio of the general formula (XXVIII) compound to the general formula (XXVII) compound is not particularly limited and can be varied widely. Typically, at least about equimolar amounts, preferably 1 to 5 moles, of the general formula (XXVIII) compounds per mole of the general formula (XXVII) compounds are used.

This reaction can usually be carried out at room temperature to 180 ° C., preferably at 100 to 150 ° C., and is generally completed in about 3 to 30 hours. This reaction is also advantageously carried out in the presence of copper powder as catalyst.

Formula (II) compounds in which the amino group is in the 8-position can be prepared according to Scheme 12 below.

Scheme -12

In the above formulas,

R ¹⁰ represents a lower alkanoyl group;

R ¹¹ lower alkyl group;

X ² represents a halogen atom.

The acylation reaction of the general formula (XXVIII ') compound can be carried out in the same manner as in the acylation reaction of the general formula (XXIIIa) compound.

The reaction for reducing the nitro group in the general formula (XXIX) compound can be carried out in the same manner as in the reduction reaction of the general formula (XXI) compound or general formula (XXII) compound.

The reaction between the compound of formula (XXX) and the compound of formula (XXXI) may be carried out under the same conditions as those for reacting the compound of formula (IV) with the compound of formula (V). The reaction conditions using the carboxylic acid halide as the compound and the ratio used are different. This reaction can be carried out in the absence of a basic compound, but it is advantageously carried out using at least equimolar amounts, preferably 1 to 5 moles, of the general formula (XXX) compound per mole of the general formula (XXXI) compound.

The ring closure reaction of the general formula (XXXII) compound can be carried out under the same conditions as the case of performing the ring closure reaction of the general formula (XXVI) compound.

The reduction reaction of the carbostyryl derivative of the general formula (XXXIII) can be carried out according to the same method as in the reduction reaction of the carbostyryl derivative of the general formula (Ii).

The hydrolysis reaction of the carbostyryl derivative of the general formula (XXXIII) or (XXXIV) can be carried out in the same manner as in the reduction reaction of the compound of general formula (I) in which R ³ represents a lower alkanoylamino benzoyl group.

Formula (I) compounds according to the invention prepared as described above may form pharmaceutically acceptable salts with acids, and the scope of the invention also includes pharmaceutically acceptable salts. Pharmaceutically acceptable acids that can be used for salt formation include various inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, bromic acid, and organic acids, such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Can be.

The compounds of general formula (I) according to the invention can be converted into the corresponding salts by reacting the acid groups with pharmaceutically acceptable basic compounds when they contain acid groups. Examples of the basic compound include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogencarbonate and the like.

The compounds of formula (I) according to the invention and their salts are prepared from the respective reaction mixtures after completion of the reaction by conventional methods such as solvent extraction, dilution, precipitation, recrystallization, column chromatography, preparative thin layer chromatography. It can isolate | separate and refine | purify by graffiti etc.

As will be apparent to those skilled in the art, the compounds of formula (I) may exist in optically active form and such optical isomers are included within the scope of the present invention.

When the compounds of formula (I) and salts thereof according to the invention are used as therapeutic agents, these compounds can be formulated into pharmaceutical compositions with conventional pharmaceutically acceptable carriers. Suitable carriers that can be used are solvents or excipients, for example fillers, strata agents, binders, hydrating agents, disintegrants, surfactants and suspending agents, which depending on the dosage form are usually used in the preparation of such drugs.

Various dosage forms that can be used as cardiac agents can be selected for treatment purposes. Common dosage forms that can be used are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injectable solutions (solutions, suspensions, etc.).

In order to formulate pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, a wide variety of carriers known in the art can be used. Examples of suitable carriers include excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; Binders such as water, ethanol, propanol, single syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinyl pyrrolidone; Disintegrants such as dry starch, sodium alginate, agar powder, laminaria powder, sodium bicarbonate, calcium carbonate, Tween, sodium lauryl sulfate, stearic acid monoglycerides, starch and lactose; Disintegration inhibitors such as white sugar, stearic acid glyceryl esters, cacao butter and hardened oils; Absorption accelerators such as quaternary ammonium base and sodium lauryl sulfate; Humectants such as glycerol and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; And lubricants such as refined talc, stearate, boric acid powder, macrogol (trade name of polyethylene glycol manufactured by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycols.

Tablets may be coated as desired and may be prepared as dragees, gelatinous, enteric, film, or tablets containing two or more layers.

Pharmaceutical compositions can employ a wide variety of conventional carriers known in the art when formulated in pills. Examples of suitable carriers include excipients such as glucose, lactose, starch, cacao butter, hardened oil, kaolin and talc; Binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; And disintegrants such as laminaria and agar.

When formulating pharmaceutical compositions into suppositories, a wide variety of carriers known in the art can be used. Examples of suitable carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin and semisynthetic glycerides.

When formulating a pharmaceutical composition into an injectable preparation, it is desirable to sterilize the resulting solutions and suspensions and to make them isotonic with blood. When formulating pharmaceutical compositions into solutions or suspensions, any diluent conventionally used in the art can be used. Examples of suitable diluents include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters. Sodium chloride, glucose or glycerol may be incorporated into therapeutic agents such as nephritis agents in an amount sufficient to produce an isotonic solution. Therapeutic agents are conventional dissolution aids, buffers. And may further contain pain relief agents, and preservatives, and optionally colorants, fragrances, flavors, sweeteners, and other drugs.

The amount of the general formula (I) compound of the present invention and its pharmaceutically acceptable salts which can be mixed as an active ingredient to prepare a pharmaceutical composition useful as a cardiac stimulant is not particularly limited and can be varied widely. Appropriate effective therapeutically effective amounts of the compound of formula (I) according to the invention and pharmaceutically acceptable salts thereof are usually from about 1 to about 70% by weight, preferably from 1 to 30% by weight, based on the total composition.

There are no particular restrictions when used as a cardiovascular agent and can be administered by a route suitable for the specific form thereof.

For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injectable preparations may be administered alone or intravenously with conventional adjuvants such as glucose and amino acids. If necessary, the cardiac medicine may be easily administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories are administered rectally and ointments are applied to the skin.

The dosage of cardiac medicine is appropriately selected depending on the purpose of use and symptoms. Typically, the preferred dosage of a compound of the invention is about 0.1-10 mg / kg body weight. The active ingredient is preferably contained in an amount of 2 to 200 mg in a disposable unit dosage form.

The following control examples, examples and formulation examples of the present invention are described in more detail.

Control Example 1

29.3 ml of concentrated nitric acid is added dropwise to 500 ml of concentrated sulfuric acid with ice cooling and stirring. In addition, 50 g of m-chlorobenzaldehyde is added dropwise to the resulting mixture at 5 ° C or lower. After continuing stirring for 1 hour at room temperature, the reaction mixture is poured onto ice to precipitate a solid and collected by filtration. After washing with water, the obtained solid is dissolved in methylene chloride and the methylene chloride layer is washed with aqueous sodium hydroxide solution and water and dried over sodium sulfate. The solvent was distilled off to give 62.3 g of 2-nitro-5-chlorobenzaldehyde having a melting point of 65 to 69 ° C.

Control Example 2

After dissolving 100 g of 2-nitro-5-chlorobenzaldehyde in 1000 ml of toluene, 10 g of p-toluene sulfonic acid and 87.8 g of ethyl orthoformate are added to the resulting solution. The mixture is stirred at room temperature for 1 hour to neutralize the reaction mixture with aqueous sodium hydroxide solution. After washing with water the toluene layer was dried over anhydrous sodium sulfate and concentrated to give 138 g of an oily product of 2-nitro-5-chlorobenzaldehyde diethyl acetal.

Control Example 3

138 g of 2-nitro-5-chlorobenzaldehyde diethyl acetal is dissolved in 750 ml of dimethylformaldehyde (DMF), 250 g of anhydrous piperazine is added to the solution, and the mixture is stirred at 80 ° C. for 4 hours. After evaporation under reduced pressure to remove excess piperazine and DMF, the residue is dissolved by addition of aqueous sodium hydroxide solution. Next, the solution is extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulphate and the solvent is distilled off. 850 ml of isopropyl alcohol was added to the residue to dissolve, and 65 ml of concentrated hydrochloric acid was added to the solution, followed by heating under reflux for 1 hour.

The precipitated crystals were collected by filtration after cooling to give 93 g of 2-nitro-5-piperazinyl benzaldehyde hydrochloride having a melting point of 195 to 201 캜.

[Control Example 4]

47 g of 2-nitro-5-piperazinylbenzaldehyde hydrochloride is dissolved in 500 ml of pyridine, and 5 g of piperidine and 100 g of malonic acid are added to the solution, followed by heating under reflux for 5 hours. After cooling, the resulting crystals are filtered out. Collecting gives 42 g of 2-nitro-5-piperazinyl cinnamic acid with a melting point of 229 to 237 ° C.

Control Example 5

10 g of 2-nitro-5-piperazinyl cinnamic acid is suspended in 100 ml of ethyl alcohol, and 3 ml of thionyl chloride is added dropwise to the suspension with ice-cooling stirring. After completion of the dropwise addition, the mixture was heated to reflux for 3 hours and ethyl alcohol and thionyl chloride were distilled off. Isopropyl alcohol is added to the residue and heated to dissolve.

After cooling, the precipitated yellow crystals were collected by filtration to obtain 4.3 g of 2-nitro-5-piperazinyl cinnamic acid ethyl ester hydrochloride having a melting point of 210 to 220 캜.

Control Example 6

5 g of 2-nitro-5-piperazinylbenzaldehyde is suspended in 50 ml of DMF and 6 ml of triethylamine are added to the suspension. Next, a solution of 4.4 g of 3,4-dimethoxybenzoyl chloride in 20 ml of DMF was added dropwise while stirring with ice cooling externally, the mixture was stirred at room temperature for 2 hours, then poured into saturated brine and extracted with methylene chloride.

After washing with water the methylene chloride layer is dried over anhydrous sodium sulfate. The solvent was distilled off, methyl alcohol was added to the residue, the mixture was heated and cooled, and the resulting crystals were recrystallized from DMF. 2-nitro-5- [4- (3,4 having a melting point of 196 to 198 ° C. -Dimethoxybenzoyl) -1-piperazinyl] 4.5 g of benzaldehyde is obtained as yellow crystals.

Control Example 7

4 g of 2-nitro-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] benzaldehyde was dissolved in 200 ml of pyridine, 2.1 g of malonic acid and 0.4 ml of piperidine were added, and the mixture was 80 Stir at 4 ° C. for 4 hours. After evaporating pyridine and piperidine, the reaction mixture is poured into an aqueous dihydrochloride solution and extracted with methylene chloride. After washing the methylene chloride layer with water, the solvent is distilled off and methanol is added to the residue. After cooling, the resulting crystals were collected by filtration to give 3.7 g of 2-nitro-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] cinnamic acid having a melting point of 197 to 202 ° C. .

Control Example 8

12 g of 2-nitro-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] cinnamic acid was dissolved in 60 ml of concentrated hydrochloric acid, and a solution of 20 g of tin chloride in 40 ml of concentrated hydrochloric acid was added to the resulting solution at room temperature. Drop by After stirring for 2 hours, the precipitated crystals are collected by filtration. The crystals thus obtained are dissolved in 240 ml of methanol and the solution is neutralized with 10% aqueous sodium hydroxide solution to precipitate crystals which are then collected by filtration. The methanol solution was concentrated and the residue was recrystallized from ethanol to give 6.3 g of 2-amino-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] cinnamic acid having a melting point of 168 to 170.5 ° C. Obtained as a pale yellow powder.

Control Example 9

5 g of 2-amino-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] cinnamic acid are dissolved in a mixed solvent consisting of ethanol and water. After adding 0.5 g of 5% palladium-carbon, the mixture is reduced at atmospheric pressure of hydrogen gas. Once the theoretical hydrogen gas absorbed, the crystals are filtered off and the ethanol-water phase is concentrated to dryness. The residue was dissolved in chloroform and separated by silica gel column chromatography to obtain 3 [2-amino-5- ｛4- (3,4-dimethoxybenzoyl) -1-piperazinyl｝ phenyl] having a melting point of 98 to 101 ° C. 1.5 g propionic acid is obtained.

Control Example 10

4.4 g of 3- [2-amino-5- ｛4- (3,4-dimethoxybenzoyl) -1-piperazinyl｝ phenyl] propionic acid is dissolved in 40 ml of acetic acid. 1.1 g of acetic anhydride is added to the solution and the mixture is stirred for 1 hour at room temperature. After acetic acid is concentrated, water is added to the reaction mixture. The precipitated crystals were collected by filtration, washed with water, and then recrystallized from a mixed solvent consisting of acetone and water. 3- {2-acetylamino-5- [4- (3,4-dimethoxybenzoyl)-having a melting point of 78.5 to 80.5 占 폚. 1-pyrerazinyl] phenyl} -propionic acid is obtained.

Control Example 11

0-nitroaniline (300 g, 2.17 moles) is dissolved in 620 ml of acetic anhydride and stirred at 40-50 ° C. for 3 hours. Pour the reaction mixture into ice water. Next, the resulting crystals are collected by filtration and dried. The obtained 0-acetylaminonitrobenzene was suspended in 2.4 L of methanol. After addition of 20 g of 10% palladium-carbon the suspension is catalytically reduced at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to precipitate crystals which were then washed with ethanol and dried over phosphorus pentoxide under reduced pressure to give 248 g of o-amino-acetanilide.

Control Example 12

248 g (1.65 moles) of o-acetylaminoaniline are dissolved in 1 L of DMF, and a solution of 114 g (0.87 moles) of β-ethoxy-acrylchloride in 0.4 L of DMF is added dropwise to the mixture over 3.5 hours with stirring at room temperature. The resulting mixture is then stirred for 30 minutes at the same temperature. The reaction mixture is poured into ice water to precipitate crystals which are collected by filtration to give 84.9 g of 1-acetylamino-2- (β-ethoxyacryloylamide) -benzene.

Control Example 13

84.9 g (0.34 mole) of 1-acetylamino-2- (β-ethoxyacryloylamide) -benzene- was added dropwise to concentrated sulfuric acid with stirring at room temperature. After the addition was completed, the mixture was stirred at room temperature for 2 hours. do. The reaction mixture was poured into a large amount of ice water to precipitate crystals which were then collected by filtration to give 49.5 g of 8-acetylaminocarbostyryl.

Control Example 14

15.0 g (74.2 moles) of 8-acetylaminocarbostyryl is suspended in 300 ml of dioxane. After addition of 2.0 g of 10% palladium-carbon, the suspension is catalytically reduced under atmospheric pressure at 70 to 80 ° C. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to afford 14.3 g of 8-acetylamino-3,4-dihydrocarbostyryl.

Control Example 15

11.8 g (57.8 mol) of 8-acetylamino-3,4-dihydrocarbostyryl is suspended in 90 ml of 20% hydrochloric acid and the suspension is stirred with heating under reflux for 1 hour. The reaction mixture is poured into ice water, neutralized with 5N sodium hydroxide and adjusted to pH8. Filtration of the precipitated crystals gave 7.87 g of 8-amino-3,4-dihydrocarbostyryl.

Control Example 16

2.5 g (0.106 mol) of 8-acetylaminocarbostyryl is suspended in 190 ml of 20% hydrochloric acid and the suspension is stirred with heating under reflux for 1 hour. The reaction mixture is poured into ice water and neutralized 5N sodium hydroxide. Filtration of the crystals gave 15.47 g of 8-aminocarbostyryl.

Example 1

(a) 9.12 ml of triethylamine is added to a solution of 7.02 g of p-aminoaniline in 150 ml of toluene, and a solution of 11 g of β-bromopropionyl chloride in 30 ml of toluene is added dropwise while stirring at 80 ° C. After the mixture is reacted for 30 minutes, the resulting colored dendritic material is removed and the reaction mixture is washed with water and dried. Removal of the solvent by distillation yielded 10.1 g of N- (βbromopropionyl) -p-aminoaniline as an oily product. The production of compounds is confirmed by IR and NMR spectra.

Elemental Analysis:

Calculated Value (%): C 44.44, H 4.53, N 11.52

Found (%): 44.32, 4.61, 11.43

(b) A mixture of 14.0 g of N- (β bromopropionyl) -p-aminoaniline, 18 g of bis (β-bromoethyl) amine monohydrobromide and 70 ml of ethanol is stirred under reflux for 15 hours. After cooling, 3.06 g of potassium carbonate was added to the reaction mixture and stirred for 8 hours under reflux. After cooling, the resulting crystals are collected by filtration and washed with methanol to give 5.3 g of N- (β-bromopropionyl) -p-piperazinylaniline. The production of this compound is confirmed by IR and NMR spectra.

Elemental Analysis:

Calculated Value (%): C 50.00, H 5.77, N 13.46

Found (%): 49.91, 5.69, 13.41

(c) A suspension of 2.2 g of N- (β-bromopropionyl) -p-piperazinylaniline and 28 g of anhydrous aluminum chloride powder in 50 ml of carbon disulfide is stirred under reflux for 4 hours. The reaction mixture was poured into ice water and the precipitate was collected by filtration, then washed with water, then with ether, converted to hydrobromide and recrystallized from methanol-water 6 having a melting point of 289 to 293 ° C. (decomposition) (methanol-water). 0.9 g of-(1-piperazinyl) -3,4-dihydrocarbostyryl monohydrobromide is obtained as a colorless needle.

Elemental Analysis:

Calculated Value (%): C 50.00, H 5.77, N 13.46

Found (%): 49.96, 5.81, 13.51

Example 2

By the same method as in Example 1, 5- (1-piperazinyl) -3,4-dihydrocarbostyryl hydrochloride monohydrate having a melting point of 300 ° C. or higher (methanol) was obtained as a colorless needle.

Example 3

By the same method as Example 1, 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro having a melting point of 238 to 239.5 ° C using an appropriate starting material. 8.5 g of carbostyryl are obtained as a colorless granular material.

Elemental Analysis:

Calculated Value (%): C 66.84, H 6.33, N 10.63

Found (%): 66.71, 6.51, 10.52

[Examples 4 to 92]

According to the method of Example 1, the following compounds are prepared using appropriate starting materials.

Example 4

6- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 196-198 ° C. (ethanol) colorless acicular material.

Example 5

5- [4- (p-toluenesulfonyl) -1-piperazinyl] 3,4-dihydrocarbostyryl, melting point: 302 to 304 ° C. (dimethylformamide), colorless powder.

Example 6

6- (4-butyl-1-piperazinyl) -3,4-dihydrocarbostyrylyl hydrochloride 1/2 hydrate, melting point: 279 to 281 ° C. (decomposition) (methanol).

Example 7

5- (4-benzoyl-1-piperazinyl) -3,4-dihydrocarbostyryl, Melting point: 248-251 ° C. (ethanol), colorless acicular material.

Example 8

6- (4-benzoyl-1-piperazinyl) -3,4-dihydrocarbostyryl, Melting point: 221-222.5 ° C. (ethanol), pale yellow granular material.

Example 9

5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 207-208 DEG C (ethanol), colorless powder.

Example 10

5- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 250 to 251.5 ° C. (isopropanol), colorless granular material .

Example 11

6- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 180 to 182 ° C (isopropanol), colorless granular material .

Example 12

6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl 1/2 hydrate, melting point: 212 to 213 ° C (methanol), colorless acicular material.

Example 13

6- (4-acetyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 203 to 205 캜 (isopropanol), light yellow brown needle-like material.

Example 14

6- (4-furoyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 206.5 to 207.5 ° C. (ethanol), pale yellow granular material.

Example 15

6- [4- (2-propynyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 174-176 ° C. (isopropanol).

Example 16

6- [4- (4-chlorobenzoyl) -1-piperazinyl] 3,4-dihydrocarbostyryl, Melting point: 233-235 ° C. (methanol), pale yellow needle.

Example 17

5 [4- (3,4-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 250 to 252 ° C. (methanol), colorless powder.

Example 18

5- [4- (3,5-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 225 to 257 ° C (methanol-chloroform), colorless acicular material.

Example 19

6- [4- (4-bromobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 233-234.5 ° C. (methanol-chloroform), colorless granular material.

Example 20

5- [4- (4-cyanobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 266-269 ° C. (methanol-chloroform), colorless acicular material.

Example 21

6- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 235.5 to 236.5 ° C. (methanol-chloroform), yellow scale.

Example 22

6- [4- (3,5-Dinitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 262 to 264 ° C. (methanol-chloroform), dark red acicular material.

Example 23

6- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 244 to 246 ° C (ethanol), pale yellow needle.

Example 24

5- [4- (4-hydroxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 300 DEG C or more (methanol-chloroform), colorless granular material.

Example 25

6- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 191 to 192.5 ° C. (methanol), colorless acicular material.

Example 26

5- [4- (4-methylbenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 239.5 to 240 ° C. (chloroform-ether), colorless powder.

Example 27

6- [4-methanesulfonyl-1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 241.5-243 ° C. (methanol), colorless granular material.

Example 28

5- (4-ethyl-1-piperazinyl) -3,4-dihydrocarbostyryl monohydrochloride, Melting point: 293-296 ° C. (decomposition) (methanol), colorless granular material.

Example 29

6- (4-allyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 175-176 ° C. (chloroform-ether), colorless impression material.

Example 30

5- [4- (2-propynyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 225 to 226 ° C (chloroform), pale yellow powder.

Example 31

6- [4- (2-butenyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 242 to 245 ° C. (decomposition).

Example 32

1-benzyl-6- [4- (3,5-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl half-hydrate, melting point: 131.5-132.5 ° C. (ethanol), Yellow powder.

Example 33

1-allyl-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl half-hydrate, melting point: 120-122 degreeC (methanol-ether ), Colorless granular material.

Example 34

1- (2-propynyl) -6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 152 to 154 ° C. (ethanol) , Pale yellow needles.

Example 35

1-methyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 146.5 to 147.5 ° C. (isopropanol), pale yellow granular material .

Example 36

8-methoxy-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 162.5 to 163.5 ° C. (isopropanol), colorless needle matter.

Example 37

6- [4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 195 to 197.5 ° C. (methanol), colorless impression material.

Example 38

5- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 219-220 ° C. (methanol-chloroform), colorless acicular material.

Example 39

5- (4-ethoxycarbonylmethyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 206 to 208 캜 (methanol), colorless acicular material.

Example 40

5- (4-formyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 263 to 265 ° C., colorless granular material (methanol).

Example 41

6- (4-ethoxycarbonyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 182.5 to 184 ° C, colorless acicular material (isopropanol).

Example 42

5- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 194-196 ° C. (methanol) colorless acicular material.

Example 43

6- [4- (2-phenether) -1-piperazinyl] -3,4-dihydrocarbostyryl hydrochloride, Melting point: 274 to 276 ° C (decomposition) (methanol), colorless powder.

Example 44

6- [4- (4-chlorobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 190 to 191.5 ° C. (chloroform-methanol), colorless acicular material.

Example 45

5- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl monochloride monohydrate, Melting point: 298.5 to 300 ° C. (decomposition) (ethanol), colorless Granular material.

Example 46

5- [4- (4-nitrobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 268 to 271 ° C. (decomposition) (methanol), pale yellow powder.

Example 47

5- [4- (4-aminobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl dihydrochloride monohydrate, Melting point: 224-227 ° C. (decomposition) (methanol-ether), yellow granules Phase material.

Example 48

6- [4- (4-methylbenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl dihydrochloride, Melting point: 272 to 273 ° C. (decomposition) (methanol-water).

Example 49

5- [4- (3,4-dimethoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl dihydrochloride, melting point: 270 to 272.5 ° C. (decomposition).

Example 50

6- (4-ethoxycarbonyl-1-piperazinyl) carbostyryl, melting point: 223-224 DEG C (methanol), yellow needles.

Example 51

6- [4- (3chlorobenzoyl) -1-piperazinyl] carbostyryl, melting point: 250.5 to 252 ° C. (methanol-chloroform), yellow powder.

Example 52

6- [4- (4-chlorobenzoyl) -1-piperazinyl] carbostyryl, Melting point: 265 to 266 ° C (methanol-chloroform), yellow powder.

Example 53

6- [4- (4-methoxybenzoyl) -1-piperazinyl] carbostyryl, melting point: 230-233 ° C. (methanol-chloroform), yellow needles.

Example 54

6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] carbostyryl, melting point: 265 to 266.5 ° C. (decomposition) (methanol-chloroform), yellow granular material.

Example 55

6- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] carbostyryl, melting point: 249.5 to 250 ° C. (methanol-chloroform), yellow needles.

Example 56

6- [4- (4-cyanobenzoyl) -1-piperazinyl] carbostyryl, Melting point: 300-301 ° C. (decomposition) (ethanol-chloroform), yellow powder.

Example 57

6- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -carbostyryl, melting point: 266 to 267 ° C (decomposition) (methanol-chloroform), yellow powder.

Example 58

6- [4- (4-nitrobenzoyl) -1-piperazinyl] carbostyryl, melting point: 256 to 266 ° C. (decomposed) methanol-chloroform), yellow needles.

Example 59

6- [4- (4-aminobenzoyl) -1-piperazinyl] carbostyryl, Melting point: 287 to 290 ° C (chloroform-methanol), yellow powder.

Example 60

6- (4-benzoyl-1-piperazinyl] carbostyryl, melting point: 264-265 ° C. (ethanol-chloroform), yellow needles.

Example 61

5- [4- (4-acetylaminobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 300 DEG C or more (chloroform-ethanol), colorless powder.

Example 62

6- (4-formyl1-piperazinyl) carbostyryl, melting point: 286.5 to 288 ° C (methanol), yellow impression material

Example 63

6- [4- (4-methylthiobenzoyl) -1-piperazinyl] carbostyryl, melting point: 247.5 to 249.5 ° C. (chloroform-methanol), yellow needles.

Example 64

6- [4- (3-pyridylcarbonyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 250-252 ° C. (ethanol), yellow needles.

Example 65

6- [4- (4-methoxyphenylacetyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 266 to 268.5 ° C. (methanol), yellow powder.

Example 66

6- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyryl, Melting point: 189.5-191 ° C. (chloroform-methanol), yellow granular material.

Example 67

8- (4-benzoyl-1-piperazinyl) carbostyryl, melting point: 244 to 245 ° C. (ethanol), colorless powder.

Example 68

8- [4- (4-chlorobenzoyl) -1-piperazinyl] carbostyryl, Melting point: 255.5 to 257 ° C. (ethanol-chloroform), colorless powder.

Example 69

8- [4- (3-chlorobenzoyl) -1-piperazinyl] carbostyryl, melting point: 208 to 209 ° C (ethanol), colorless granular material.

Example 70

8- [4- (2-chlorobenzoyl) -1-piperazinyl] carbostyryl, melting point: 239 to 240.5 ° C. (ethanol), colorless acicular material.

Example 71

8- [4- (4-methoxy benzoyl) -1-piperazinyl] carbostyryl, melting point: 208 to 210 ° C (ethanol), colorless impression material.

Example 72

8- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] carbostyryl, Melting point: 197-198 ° C. (ethanol-ether), colorless impression material.

Example 73

8- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 195-197 ° C (ethanol), colorless impression material.

Example 74

8- [4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 152 to 154 ° C. (ethanol), colorless phosphor.

Example 75

8- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 145 to 148 ° C, colorless phosphorus (ethanol).

Example 76

8- [4- (4-methylthiobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 178 to 179.5 ° C., colorless granular material (ethanol).

Example 77

7- [4- (2-chlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 194 to 195.5 ° C. (methanol), colorless needles.

Example 78

7- [4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 136.5 to 138.5 ° C (ethanol), colorless powder.

Example 79

7- [4- (4-chlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 289-291 ° C, colorless powder (chloroform-methanol).

Example 80

7- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 231 to 233 ° C., colorless acicular substance (ethanol).

Example 81

7- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 207 to 208 캜 (ethanol), colorless powder.

Example 82

7- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 240 to 242 ° C (chloroform-methanol), yellow granular material.

Example 83

7- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 195 to 196.5 ° C. (methanol), colorless tetragonal crystal.

Example 84

7- (4-benzoyl) -1-piperazinyl) -3,4-dihydrocarbostyryl, Melting point: 264.5 to 265.5 ° C. (chloroform-methanol), colorless acicular material.

Example 85

7- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 118 to 120 ° C (ethanol: dried at 80 ° C for 5 hours under reduced pressure ), Colorless granular material.

Example 86

7- [4- (4-methylthiobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 258-260 ° C. (chloroform-methanol), colorless tetragonal crystal.

Example 87

7- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyryl, melting point: 183 to 184 ° C, colorless acicular substance (ethanol).

Example 88

6- [4- (4-methoxyphenylacetyl) -1-piperazinyl] carbostyryl, melting point: 224 to 225 ° C (ethanol), yellow needles.

Example 89

6- [4- (4-hydroxyphenylacetyl) -1-piperazinyl] carbostyryl, Melting point: 300 ° C or higher (DMF), Yellow powder.

Example 90

5- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 292-294 ° C. (decomposition) (methanol-chloroform), yellow granular material.

Example 91

5- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 285-287 ° C (decomposition) (ethanol-chloroform), colorless granular material.

Example 92

6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl) 3,4-dihydrocarbostyryl, Melting point: 238 to 239.5 ° C., colorless granular material.

Elemental Analysis:

Calculated Value (%): C 66.84, H 6.33, N 10.63

Found (%): 66.69 6.49 10.51

Example 93

(a) To a solution of 11 g of p- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] aniline in 100 ml of benzene, 4.56 ml of triethylamine was added and refluxed to β-methoxyacrylic chloride in 20 ml of benzene. 3.94 g of solution is added dropwise. At the end of the dropping, the mixture is refluxed for 1 hour. After the reaction is completed, the reaction mixture is washed with water and dried. The solvent was distilled off and the residue was purified by silica gel column chromatography to obtain N- (β-methoxyacryloyl) -p- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] aniline 10 g are obtained.

Elemental Analysis:

Calculated Value (%): C 64.92, H 6.40, N 9.88

Found (%): 64.77 6.50 9.75

(b) 50 ml of 60% H ₂ SO ₄ while stirring 5 g of N- (β-methoxyacryloyl) -p- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] aniline at room temperature with stirring Divide a little bit into After continuing to react for 2 hours, the reaction mixture was neutralized with 10N NaOH to precipitate crystals which were then collected by filtration and washed with water. When the crystals were recrystallized from chloroform-methanol, melting point was 256 to 266.5 ° C. (decomposition) 230 mg of 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] carbostyryl as yellow granular material. Obtained.

Elemental Analysis:

Calculated Value (%): C 67.16, H 5.89, N 10.68

Found (%): 67.03, 5.78, 10.81

Compounds obtained in Examples 50-53, 55-63, 67-72, 88 and 89 according to methods analogous to those of Example 93, using appropriate starting materials Prepare the same compound as.

[Examples 94 to 98]

According to the method of Example 1, the following compounds are prepared using appropriate starting materials:

Example 94

6- (1-piperazinyl) carbostyryl hydrobromide, melting point: 300 DEG C or more (water-ethanol), pale yellow tetragonal crystals.

Example 95

7- (1-piperazinyl) -3,4-dihydrocarbostyryl hydrobromide, Melting point: 174-177 DEG C, colorless granular material.

Example 96

8- (1-piperazinyl) -3,4-dihydrocarbostyryl hydrobromide, Melting point: 300 DEG C or more, colorless acicular material.

Example 97

8- (1-piperazinyl) carbostyryl hydrobromide, Melting point: 300 ℃ or higher, colorless impression material.

[Method of Table 1]

Isolation of Blood Flow Idiopathic Agents

This experiment is performed on both mature Mongrerel dog male and female. Isotropic preparations are obtained by anesthetizing dogs weighing between 8 and 13 kg with pentobarbital sodium (30 mg / kg, intravenously) and administering heparin sodium (1000 u / kg, intravenously) and then bleeding. The formulation consists mainly of the right atrium and is placed in a cold tie rod solution. The formulation is placed in a glass water jacket maintained at about 38 ° C. and blood is cross circulated to a constant pressure of 10 mmHg from the blood supply dog through the right coronary artery with the cannula inserted. Blood-feeding dogs weigh 18 to 27 kg and are anesthetized with pentobarbital sodium (30 mg / kg, intravenously). It is administered intravenously in an amount of 1000 u / kg sodium heparin. The tension in the right atrium is measured using a tension gauge transducer. About 1.5 g is loaded into the right atrium. The rate of motion induced by tension in the right atrium is measured using a long-term heart rate monitor. Blood flow through the right coronary artery is measured with an electromagnetic flow meter. The generated tension, copper heart rate and blood flow are recorded on the chart by ink-recording rectification graphs. A detailed description of this formulation is described in Chiba et al., (Japan, J. Pharmacol., 25, 433-439, 1975: Naunyn-Schmiedberg's Arch. Pharmacol. 289, 315-325 1975). 10-30 ml of compound are injected into the artery for 4 seconds. The cardiac contractile effect of this compound represents the tension generated as a percentage of the tension before compound injection. The effect of a compound on copper heart rate (beats / minute) or blood flow (ml / min) is expressed as the difference before and after injection of the compound. The results are shown in Table 1.

Test compound

1. 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

2. 6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

3. 6- (4-acetyl-1-piperazinyl) -3,4-dihydrocarbostyryl

4. 6- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

5. 6- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

6. 5- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

7. 6- [4- (4-Chlorobenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

8. 6- (1-piperazinyl) -3,4-dihydrocarbostyryl

9. 6- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

10. 6- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

11.6- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

12. 6- [4- (4-bromobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

13. 6- [4- (4-cyanobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

14. 5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

15. 8-methoxy-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

16. 1-Methyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

17. 6- (4-Furoyl-1-piperazinyl) -3,4-dihydrocarbostyryl

18. 6- (4-benzoyl-1-piperazinyl] -3,4-dihydrocarbostyryl

19. 1-benzyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl halfhydrate

20. 6- [4- (2-phenethyl) -1-piperazinyl] -3,4-dihydrocarbostyryl monohydrochloride

21. 6- (4-formyl-1-piperazinyl) -3,4-dihydrocarbostyryl

22. 6- (4-ethoxycarbonylmethyl-1-piperazinyl) -3,4-dihydrocarbostyryl

23. 6- (4-ethoxycarbonyl-1-piperazinyl) -3,4-dihydrocarbostyryl

24. 6- [4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

25. 6- (4-Methanesulfonyl-1-piperazinyl) -3,4-dihydrocarbostyryl

26. 6- [4- (4-Methylbenzyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

27. 5- [4- (3,4-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl monohydrochloride

28. 6- [4- (3,5-Dinitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

29. 6- (4-allyl-1-piperazinyl) -3,4-dihydrocarbostyryl

30. 5- [4- (2-propynyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

31. 5- (4-Ethyl-1-piperazinyl) -3,4-dihydrocarbostyryl monohydrochloride

32. 1-allyl-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl halfhydrate

33. 1- (2-propynyl) -6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

34. 5- [4- (p-toluenesulfonyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

35. 6- [4- (4-methylthiobenzoyl) -1-piperazinyl] carbostyryl

36. 8- [4- (3-pyridylcarbonyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

37. 6- [4- (4-methoxyphenylacetyl) -1-piperazinyl] -3,4-dihydrocarbostyryl 1/2 hydrate

38. 6- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyryl

39. 8- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] carbostyryl

40. 5- [4- (4-hydroxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

41. 6- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -carbostyryl

42. 6- [4- (3-chlorobenzoyl) -1-piperazinyl] carbostyryl

43. 6- [4- (3,4-Methylenedioxybenzoyl) -1-piperazinyl] -carbostyryl

44. 6- [4- (4-nitrobenzoyl) -1-piperazinyl] carbostyryl

45. 6- [4- (4-cyanobenzoyl) -1-piperazinyl] carbostyryl

46. 6- (4-benzoyl-1-piperazinyl) carbostyryl

47. 6- [4- (4-chlorobenzoyl) -1-piperazinyl] carbostyryl

48. 6- [4- (3,4,5-Trimethoxybenzoyl) -1-piperazinyl] -carbostyryl

49. 6- (4-ethoxycarbonyl-1-piperazinyl) carbostyryl

50. 6- [4- (4-aminobenzoyl) -1-piperazinyl] carbostyryl

51. 6- (4-formyl-1-piperazinyl) carbostyryl

52. 5- (4-benzyl-1-piperazinyl) -3,4-dihydrocarbostyryl monohydrochloride

53. 7- [4- (3,4-methylenedioxybenzoyl) | -1-piperazinyl] 3,4-dihydrocarbostyryl

54. 7- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] 3,4-dihydrocarbostyryl

55. 7- [4- (2-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

56. 7- (4-phenylpropionyl-1-piperazinyl) -3,4-dihydrocarbostyryl

57. 7- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl

58. Papaverine (Control)

59.Amurino (Control)

TABLE 1

[Method of Table 2]

Isolated Blood-Pulmonary Capillary Muscle Preparation

This experiment is performed on both mature Mongrerel dog male and female. Capillary muscle preparations are obtained by anesthetizing dogs weighing 8 to 13 kg with pentobarbital sodium (30 mg / kg intravenously) and then bleeding after administration of heparin sodium (1000 u / kg intravenous). This preparation consists mainly of an excised anterior capillary muscle and ventricular septum and is placed in a cold thyroid solution. The preparation is placed in a vitreous jacket maintained at about 38 ° and the blood is cross circulated at a constant pressure of 100 mmHg from the blood supply passage through the cannula-inserted anterior diaphragm artery. Blood pressure dogs are 18 to 27 kg in weight and anesthetized with pentobarbital sodium (30 mg / kg intravenously). Heparin sodium is administered intravenously at a dose of 1000 u / kg. The capillary muscle is induced at a constant speed of 120 / min through this polarizing electrode with a latency of about 5 msec at a pulse of about 1.5 times the threshold voltage (0.5 to 3 V). About 1.5 g is loaded in this root. Blood flow through the anterior septal artery is measured with an electromagnetic flow meter. The generated tension and blood flow ink-recording rectification graphs are recorded in the chart. A detailed description of this formulation is described in Endoh and Hashimoto (Am. J. Physiol. 218, 1459-1463, 1970). 10 ml to 30 ml volume of compound is injected into the artery for 4 seconds. The cardiac contractile effect of this compound represents the tension generated as a percentage of the tension before compound injection. The effect of the compound on blood flow is expressed as the difference (ml / min) before and after compound injection.

The results are shown in Table 2.

TABLE 2

[Formulation Example 1]

6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl]

-3,4-dihydrocarbostyryl 5mg

Starch 132mg

Magnesium Stearate 18mg

Lactose 45mg

Tablets each having the above composition are prepared according to a conventional method.

Formulation Example 2

6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-

Dihydrocarbostyryl 5mg

Starch 127mg

Magnesium Stearate 18mg

Lactose 45mg

Tablets each having the above composition are prepared according to a conventional method.

Formulation Example 3

6- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4

Dihydrocarbostyryl 500mg

0.3 g of polyethylene glycol (molecular weight: 4000)

0.9 g of sodium chloride

0.4 g polyoxyethylene sorbitan monooleate

0.1 g of sodium pyrosulfite

Methylparaben 0.18g

Propylparaben 0.02g

100ml distilled water for injection

The paraben, sodium pyrosulfite and sodium chloride are dissolved in distilled water with stirring at 80 占 폚. The resulting solution is cooled to 40 ° C. and the polyethylene glycol and polyoxyethylene sorbitan monooleate are dissolved. Distilled water for injection is added to adjust the final volume. The mixture is filtered using an appropriate filter paper, sterilized and filled into 1 ml ampoules to prepare an injectable preparation.

Formulation Example 4

6- [4- (3,4-dimethyloxybenzoyl) -1-piperazinyl] carbostyryl 5 mg

Starch 132mg

Magnesium Stearate 18mg

Lactose 45mg

Tablets each having the above composition are prepared in a conventional manner.

The present invention has been described in detail in conjunction with specific aspects thereof, and it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the scope of the present invention.

Claims (2)

A method for producing a carbostyryl compound of formula (Ie-1) or a pharmaceutically acceptable salt thereof, characterized by cyclization of a compound of formula (XIII-1).

Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group; R ² represents a hydrogen atom or a lower alkoxy group; R ³ is a hydrogen atom, a lower alkanoyl group, a furoyl group, a pyridylcarbonyl group, a lower alkanesulfonyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkyl group, or a lower alkyl group on a benzene ring. Substituted phenylsulfonyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, 1 to 3 lower alkoxy groups on the benzene ring, halogen atom, lower alkyl group, cyano group, nitro group, amino group , Phenylcarbonyl group which may be substituted by hydroxy group, lower alkanoylamino group or lower alkylthio group or substituted by lower alkylenedioxy group, 1 to 3 lower alkoxy groups on benzene ring, halogen atom , A phenyl-lower alkyl group which may be substituted by a lower alkyl group, a nitro group or an amino group, or a lower alkoxy group or a hydroxy group on a benzene ring. Phenyl-lower alkanoyl represents a group R ⁴ represents a halogen atom. A process for preparing a carbostyryl compound of formula (Ih-1) or a pharmaceutically nontoxic salt thereof, characterized in that the compound of formula (XXVI-1) is closed.

In which R ¹ represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group; R ² represents a hydrogen atom; R ³ may be substituted or lowered by one to three lower alkoxy groups, halogen atoms, cyano groups, nitro groups, amino groups or lower alkylthio groups on a hydrogen atom, a lower alkanoyl group, a lower alkoxy group, a benzene ring A phenylcarbonyl group which may be substituted by an alkylenedioxy group or a phenyl-lower alkanoyl group substituted by a lower alkoxy group or a hydroxy group on a benzene ring; A is a group of the general formula R ⁷ CH = CH-, wherein R ⁷ represents a lower alkoxy group or a halogen atom

Wherein R ⁸ and R ⁹ both represent a lower alkyl group, or CH≡C-group.