KR860001945B1 - Process for preparing carbostyril compounds - Google Patents

Abstract

The title compds. I [R1=H, lower alkyl, alkynyl, alkenyl, Phlower alkyl; R2=H, lower alkoxy; R3=H, lower alkanoyl, pyrridylcarbonyl, lower alkoxycarbonyl, lower alkane sulfonyl, etc.!, useful as cardiacs, were prepd. Thus, a mixt. contg. 29.3 ml conc. HNO3 and 500 ml conc. H2SO4 was treated with 50 g m-chlorobenzaldehydeand washed with H2O. The resulting solid material was dissolved in methylene chloride and washed with NaOH and H2O to give 62.3 g 2-nitro-5- chlorobenzaldehyde. A desirable dosage was 0.1-10 mg/Kg wt.

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 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. 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 alkanoyl groups on the benzene ring; May be substituted by an amino group, a lower alkylthio group, or a lower alkanoyloxy group or a lower alkylenedioxy group; The bond 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 are known to lower blood pressure and platelet aggregation. Various carbostyryl compounds with inhibitory or allergic action have been described.

In addition, EP-A1 Nos. 7525 and 8014 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 gabostyryl 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 a compound of formula (I) 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 heart disease such as congestive heart failure. useful. The compounds according to the invention have the advantage of not increasing the heart rate, or even increasing them only slightly.

The term "lower alkyl" as used herein 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 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.

The term "phenyl-lower alkyl" as used herein 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 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.

The term "lower alkylenedioxy" as used herein 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 a lower alkyl group on a benzene ring" refers to a phenylsulfonyl group which may be substituted by a straight or branched chain alkyl group having 1 to 6 carbon atoms on a 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 "1-3 lower alkoxy group, halogen atom, lower alkyl group, cyano group, nitro group, amino group, hydroxy group, lower alkanoylamino group, lower alkylthio group, or lower alka A 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 straight or branched chain having 1 to 6 halogen 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 having 1 to 6 carbon atoms, or carbon Substituted by 1 to 3 straight or branched alkanoyloxy groups having 1 to 6 atoms or substituted 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-dimethyl Benzoyl group, 3,4,5-trimethylbenzoyl group, 2-methoxybenzoyl group, 3-methoxybenzoyl group, 4-methoxybenzoyl group, 2-ethoxybenzoyl group, 3-ethoxybene Crude group, 4-ethoxybenzoyl group, 4-isopropoxybenzoyl group, 4-hexyloxybenzoyl group, 3,4-dimethoxybenzoyl group, 3,4-diethoxybenzoyl group, 3,4,5-tri Methoxybenzoyl group, 2,5-dimethoxybenzoyl group, 2-nitrobenzoyl group, 3-nitrobenzoyl group, 4-nitrobenzoyl group, 2,4-dinitrobenzoyl group, 2-aminobenzoyl group, 3-amino Benzoyl 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- Methoxy-3-chlorobenzoyl group, 2-hydroxybenzoyl group, 3-hydroxybenzoyl group, 4-hydroxybenzoyl group, 3,4-dihydroxybenzoyl group, 3,4,5-trihydroxybene Crude 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-butyryloxybenzoyl group, 2-di Sobutyryloxybenzoyl 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 or lower alkanoyloxy group 1 to Phenyl-lower alkyl group substituted by three or substituted by lower alkylenedioxy group "is a straight or branched chain 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 branched chain alkylthio group having 1 to 6 carbon atoms or carbon Substituted by 1 to 3 straight or branched alkanoyloxy groups having 1 to 6 atoms 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-fluoro Phenyl) 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- (3,4-difluorophenyl) 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-meth -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 Group, 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) hexyl group, 3,4-dihydroxybenzyl group, 3,4,5-trihydroxybenzyl group, 2-formylaminobenzyl group, 3- Acetylaminobenzyl group, 3- (2-acetylaminophenyl) propyl group, 4- (4-acetylaminophenyl) butyl group, 2-propionyl-aminobenzyl group, 3- (3- Thiylaminophenyl) propyl group, 4- (4-isobutynylaminophenyl) 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-methylthiophenyl) ethyl group, 3- (3-ethyl Thiophenyl) propyl group, 4- (2-ethylthiophenyl) butyl group, 5- (4-ethylthiophenyl) 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-acetyloxy Phenyl) ethyl group, 3- (2-propionyloxyphenyl) propyl group, 4- (4-pentanoyloxyphenyl) butyl group, 5- (3-propionyloxyphenyl) Butyl group, and the like 6- (4-isobutyryl-oxy-phenyl) hexyl group, 1, l-dimethyl-2- (4-hexanoyl-oxy) ethyl group, 4-butyryl-benzyl-oxy.

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, Tert-butylthio group, pentylthio group, hexylthio group and the like.

As used herein, the term "lower alkanoyloxy" refers to a straight or branched chain alkanoyloxy group having 1 to 6 carbon atoms, e.g. formyloxy group, acetyloxy group, propionyloxy group, butyryl Oxy 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-phenylbutynyl 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 to Phenyl-lower alkanoyl group substituted by three or substituted by lower alkylenedioxy group "is a straight or branched chain 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 or carbon having 1 to 6 carbon atoms By an alkylenedioxy group substituted by 1 to 3 straight or branched alkanoyloxy groups having 1 to 6 atoms or having 1 to 4 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) propynyl group, 2- (3- iodophenyl) acetyl group, 2- (4- iodophenyl) 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) hexa Noyl group, 2- (4-methylphenyl) acetyl group, 2- (2-methylphenyl) acetyl group, 2- (3-methylphenyl) acetyl group, 3- (3-ethylphenyl) propionyl group, 4- (2- Ethylpe ) Butylyl group, 5- (4-ethylphenyl) pentanoyl group, 6- (3-isopropylphenyl) 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-methoxyphenyl ) Acetyl group, 3- (2-ethoxyphenyl) propionyl group, 4- (4-ethoxyphenyl) butynyl group, 5- (3-ethoxyphenyl) pentanoyl group, 6- (4-isopro Foxyphenyl) hexanoyl group, 2- (4-hexyloxyphenyl) 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-trimethoxycyphenyl) acetyl group, 2- (2,5-dimethoxyphenyl) acetyl group, 2- (3-nitrophenyl) acetyl group, 2- (2-nitrophenyl) Cetyl group, 2- (4-nitrophenyl) acetyl group, 3- (2,4-dinitrophenyl) propionyl group, 4- (2-aminophenyl) butynyl 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-butynylaminophenyl) 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 Neyl group, 5- (4-ethylthiophenyl) pentanoyl group, 6- (3-isopropylpiophenyl) hexanoyl group, 2-meth -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 aralkylsulfonyloxy 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 meanings defined above.

In the general formula (III), examples of the halogen atom represented by X include chlorine, fluorine, bromine and iodine; Examples of lower alkanesulfonyloxy 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-methylphenylsufonyloxy group, 4- Nitrophenylsulfonyloxy 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) representing 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 may be used are, for example, aromatic hydrocarbons such as benzene, toluene, xylene, and lower alcohols such as methanol, ethanol, isopropanol, butanol, acetic acid, ethyl acetate, dimethylsulfoxide, dimethylformamide, hexamethylene Phosphoric acid triamide and the like.

Examples of the basic condensing agent 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 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 of the general formula (III) compound per mole, preferably 1 to 5 moles per mole. This reaction can usually be carried out at about 40 to 120 ° C., preferably 50 to 100 ° C., and is usually completed after about 5 to 30 hours.

On the other hand, when using a compound of the general formula (III) in which X represents a hydroxy group as a starting material, the reaction between the general formula (II) compound and the general formula (III) compound is carried out 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, etc.), metal phosphates (eg, sodium phosphate, boron phosphate, iron phosphate, aluminum phosphate, etc.), activated alumina, sodium hydrogen sulfate, Raney nickel, and the like.

As the solvent, a high boiling point solvent such as dimethylformamino, 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 changed photometrically. Typically, this reaction is carried out using at least equimolar amounts, preferably 1-2 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 formula (II) is used, preferably 0.5 to 5 moles.

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 lower alkanoyl group, 1-3 lower alkoxy group, halogen atom, lower alkyl group, cyano group, nitro group, amino group, lower alkanoylamino group, lower alkylthio group, lower alkanoyl on benzene ring Phenylcarbonyl group or phenyl-lower alkanoyl group, furoyl group, pyridylcarbonyl group, or lower alkoxycarbo which may be substituted by an oxy group or a hydroxy group or by a lower alkylenedioxy group A bond having a meaning as defined above, wherein the bond represents a nil group, X ¹ represents a hydroxy group, and R ¹ , R ^2, and the position between the 3- and 4- positions of the carbostyryl nucleus. The compound can 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, halogen atoms, lower alkyl groups, cyano groups, nitro groups, amino groups, lower alkanoylamino groups, lower alkylthio groups, lower alkanoyls on the benzene ring Phenylcarbonyl group or phenyl-lower alkanoyl group, furoyl group, pyridylcarbonyl group, or lower alkoxycarbonyl which may be substituted by oxy group or hydroxy group or substituted by lower alkylenedioxy group Represents a 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 easily accomplished using the conditions applied to known amido production reactions. Representative examples of this method are as follows.

(a) Mixed acid anhydride method

A compound of formula (V) is reacted with an alkyl haloformate 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) carbodiamide methods

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 the carboxylic acid compound of formula (V) is converted to an acid halide using a halogenating agent and then the product is reacted with an amine of formula (IV).

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

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] nonene-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 hydrogen carbonate, sodium hydrogen carbonate and the like.

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

The reaction of the mixed acid anhydride with the amine of general formula (IV) may 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. .

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 methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like.

In this reaction, the alkyl haloformate and the carboxylic acid compound of general formula (V) can be used typically 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 Schenten-Baumann reaction mentioned above. Examples of suitable solvents include alcohols (e.g., methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, etc.), in addition to the solvents used in the Schatten-Baumann reaction mentioned above, pyridine And acetone.

The ratio of carboxylic acid halide to amine of formula (IV) can be used in a wide range without limitation. Typically 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 at 0 to 150 ° C. and is usually completed in 5 minutes to 30 hours.

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 on a benzene ring, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or By 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 groups or hydroxy groups in the benzene ring The general formula (I) compound representing a phenyl-lower alkyl group which may be substituted or substituted by lower alkylenedioxy group may be prepared according to Scheme 3 below.

Scheme 3

Among the above general formulas,

R ^{3 ′ ''} is lower alkanesulfonyl group, lower alkoxycarbonyl-lower alkyl group, phenylsulfonyl group which may be substituted by lower alkyl group in benzene ring, lower alkyl group, lower alkenyl group, lower alkynyl 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 groups or hydroxy groups on a benzene ring Phenyl-loweralkyl group which may be substituted by a group or by lower alkylenedioxy group;

X ² represents a halogen atom;

The bond present between the 3- and 4-positions of R ¹ , R ² and 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 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 group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a lower alkanoyloxy group or a hydroxy group or which may be substituted by a lower alkylenedioxy group The compound of formula (I) can be prepared according to Scheme 4 below.

Scheme 4

In the above formulas,

R ^{3 ′ ''} is a lower alkoxycarbonyl-lower alkyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, or one to three lower alkoxy groups, lower alkyl group, halogen atom, nitro group on benzene ring , Phenyl-lower alkyl group which may be substituted by a cyano 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 Represents;

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

The reaction between the compound of formula (II) and the compound of formula (III) can be carried out in the presence of a basic compound. As a basic compound, various well-known compounds, for example, inorganic salts, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate, etc .; 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 can be used in a wide range without particular limitation. Formula compounds are usually used in large excess when the reaction proceeds in the absence of solvent, and 2 to 10 moles per mole of compound of formula (II), preferably when the reaction proceeds in the presence of a solvent. Preference is given to using in amounts of 2 to 4 moles.

There is no particular limitation 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 lasts for 1 to 30 hours.

The reaction between the compound of formula (III) 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, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or one to three lower alkoxy groups in the benzene ring, a lower alkyl group, or a lower alkoxy group in the benzene ring, Lower alkyl

Scheme 5

Can be substituted by a group, a halogen atom 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 alkylenedioxy group Compounds of general formula (I) which represent a phenyl-lower alkyl group can be prepared according to Scheme 5 below.

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

The reaction of the general formula (XI) with the general compound can 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.

The ratio of the general formula compound to the general formula (XI) compound is not particularly limited and can be used in a wide range. Typically, at least about 1 mole, preferably 1 to 2 moles of the general formula (IV) 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 at 150 to 200 ° C. and is generally completed in about 1 to 24 hours.

In addition, the compound of formula (I) may be prepared according to Scheme 6 below:

Scheme 6

To the above formulas,

R ⁴ represents a halogen atom,

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 ring closure 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 6 moles, preferably 3 to 4 moles of Lewis acid per mole of the general formula (XIII) compound is 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 formula (I) can be prepared according to Scheme 7, below:

Scheme 7

In the above formulas,

A bond existing between the 3- and 4-positions of R ¹ , R ² , R ³ , X ² and carbostyryl nucleus has the meaning as defined above, provided that R ¹ and R ³ are hydrogen atoms simultaneously There is no number.

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 and the like, 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 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 formula (If).

This reaction can usually be carried out at about 0-70 ° C., preferably at 0 ° C. to room temperature and is generally completed in about 0.5-12 hours.

Formula (I) compounds in which the bonds present between the 3- and 4-positions of the carbostyryl nucleus are double bonds (single bonds) are obtained from the corresponding compounds in which such bonds are single bonds (double bonds). It can be prepared according to.

Scheme 8

In the above formulas,

R ¹ , R ² and R ³ have the same meanings 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.

Dehydrogenation of the general formula (Ih) compound 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 chloroimide, bromine and the like, selenium dioxide, palladium-carbon, palladium-black, vanadium oxide, Raney nickel and the like.

The amount of oxidant used is not particularly limited and can be varied in a wide range. Generally, 1 to 5 moles, preferably 1 to 2 moles of oxidizing agent are used per mole of the formula (Ih) compound. When using a hydrogenation catalyst, a hydrogenation catalyst is used in normal catalyst amount.

Examples of suitable solvents include ethers such as dioxane, THF, methoxyethanol, dimethoxyethane and the like, aromatic hydrocarbons such as benzene, toluene, xylene, cumene and the like, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, butanol And protonic polar solvents such as alcohols such as amyl alcohol and hexanol, acetic acid and the like, and aprotic polar solvents such as DMF, DMSO, hexamethyl phosphoric acid and triamide.

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.

Compounds of formula (I) wherein R ¹ represents a hydrogen atom and the bond present between the 3- and 4-positions of the carbostyryl nucleus are double bonds exist in the form of lactam-lactim tautomers as shown below. Can be.

In the above formulas,

R ² and R ³ have the same meanings as defined above.

In addition, the compound of formula (I) can be prepared according to Scheme 9 below.

Scheme 9

In the above formulas,

R ² and R ³ have the same meaning 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 lower alkylenedioxy groups include methylenedioxy groups, ethylenedioxy groups, trimethylenedioxy groups, and the like.

Some of the compounds of general formula (XV) are novel compounds and the remaining compounds are known compounds, for example by nitration of compounds of general formula (XIV ′).

The nitration reaction of the general formula (XIV ′) compounds can be carried out under similar conditions as those 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. Can be.

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

The acetylation reaction of the formyl group in the compound of formula (XV) 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 the acetylating agent used is at least 1 mole, preferably 1 to 1.5 mole of acetylating agent per mole of the compound of formula (XV) 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 between the compound of formula (XVI) and the compound of formula (XVII) 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.

In the above reaction, the appropriate amount of the piperazine derivative of the general formula (XVIII) to be used is usually 1 to 10 moles, preferably 3 to 7 moles of the general formula (XVIII) 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 (X ') compound is carried out in an alcohol such as methanol, ethanol or isopropanol, using an inorganic acid such as hydrochloric acid or sulfuric acid at a reaction temperature from room temperature to the boiling point of the solvent used for 30 minutes to 3 minutes. Can run for hours.

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 of the solvents that can be used in the reaction between 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 ° 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 캜, preferably 50 to 150 캜 It may be carried out for about 1 to 10 hours in the presence of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and the like.

In this reaction, the appropriate amount of acid used is typically 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 compounds of formula (XXI) with compounds of formula (XXII) may 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, etc.), esters (e.g., ethyl acetate, methyl acetate, etc.), aprotic polar solvents (e.g., N, N-dimethylformamide, etc.) have. As the catalyst, palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used. Suitable amounts of catalyst are from 0.02 to 1.00 parts by weight per weight part of the general formula (XXI) or (XXII) compound. The 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 mixtures of alkali metal hydroxides (eg sodium hydroxide), sulfates (eg ammonium sulfate), aqueous ammonia or ammonium salts (eg ammonium chloride).

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 performed 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) may be carried out under conditions similar to those which can be prepared for compounds of formula (I) in which R ³ represents a lower alkanoylaminobenzoyl group as described below.

The reaction for preparing the compound of formula (I) by ring-closing the compound of 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, dimethylaniline, N-methyl morpholine, 1,5-diazabicyclo [4.3.0] nonen-5 (DBN), 1 , 5-diazabicyclo [5.4.0] undecene-5 (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, hydroxide Sodium, potassium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.

Examples of suitable acids include hydrochloric acid, sulfuric acid, polyvalent phosphoric 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, dimethyl sulfoxide, 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. can be prepared as follows for by reducing a corresponding compound showing a lower alkanoyl group, lower alkyl group or a ^phenyl-3 are each phenyl carbonyl group, phenyl containing 1 to 3 nitro groups on the benzene ring. This reduction reaction can be carried out in the same manner as in the conventional reaction in which the aromatic nitro compound is reduced to obtain the corresponding aromatic amino compound. More particularly, a method using a reducing agent such as sodium nitrite, sulfite gas, etc., a catalytic reduction method using a reducing catalyst such as palladium-carbon, or the like 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) which represent a lower alkoxy group. Ether decomposition can usually be carried out at temperatures of about −30 ° to room temperature, usually 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 alkanoyl group, each of which is substituted by one to three amino groups or hydroxy groups on the benzene ring; It can be prepared by acylating the compound

Examples of the acylating agent include lower alkanoic acid, such as acetic acid, and lower alkanoic anhydrides, such as acetic anhydride, and lower alkanoic acid chlorides, such as 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, carbonates and carbonates thereof, 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. Solvents include, for example, ethers such as acetone, methyl ethyl ketone diethyl ether, dioxane, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, 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 to 150 ° C, preferably 0 to 80 ° C.

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 to 120 ℃.

R ³ represents a phenylcarbonyl group, a phenyl-loweralkyl group or a phenyl-lower alkanoyl group each substituted by 1 to 3 hydroxy or amino groups on the benzene ring, wherein R ³ Is a corresponding general formula (I) which represents a phenyl carbonyl group, a phenyl-lower alkyl group or a phenyl-lower alkanoyl group, each substituted by one to three lower alkanoylamino groups or lower alkanoyloxy groups on the 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. Examples of the solvent include water, lower alcohols (eg, methanol, ethanol, isopropanol, etc.), ethers (eg, dioxane, tetrahydrofuran, etc.) 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.

The reaction is advantageously carried out at room temperature to 150 ° C., preferably at 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.

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

Where R ⁸ and R ⁹ each represent a lower alkyl group or a 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 the compound (IV) and the compound (V) described above.

The ring closure reaction of the aniline derivatives of general formula (XXVI) can be carried out in the presence of an acid or without a solvent, or in a suitable 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 sulphate 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. Among these solvents, water-soluble solvents such as lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, and the like are preferable.

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

In addition, the general formula (I) compound may be prepared according to the following Scheme 11.

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

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 present at 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 represents a lower alkyl group;

X ² represents a halogen atom.

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

Reduction of the nitro group in the general formula (XX ') compound may be carried out in the same manner as in the reduction reaction of the general formula (XXI) compound or the 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 and the ratios of using the carboxylic acid halide as the compound of are different. This reaction can be carried out in the absence of a basic compound but 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 when the ring-closure reaction of the general formula (XXVI) compound is carried out.

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, the scope of the invention also includes pharmaceutically acceptable salts. Pharmaceutically acceptable acids that can be used for salt formation can be 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. have.

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 hydrogen carbonate and the like.

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, for example solvent extraction, dilution, precipitation, recrystallization, column chromatography, preparative thin layer chromatography. It can isolate | separate and 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 such as fillers, extenders, binders, hydrating agents, disintegrants, surfactants and lubricants, which are usually used in the preparation of such drugs, depending on the dosage form.

Various dosage forms that can be used as cardiac agents can be selected depending on the therapeutic purpose. Common dosage forms that can be used are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injectable preparations (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, carboxymethyl cellulose, shellac, methyl cellulose, 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 suspending agents, such as refined talc, stearic acid salts, boric acid powders, Macrogol (trade name of polyethylene glycol manufactured by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycols.

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

When formulating pharmaceutical compositions into pills, a wide variety of conventional carriers known in the art can be used. Examples of suitable carriers include excipients such as glucose, lactose, starch, cacao butter, hardened oil, kaolin and talc; Binders such as gum arabic, trigacanth 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 pharmaceutical compositions into injectable preparations, it is desirable to sterilize the resulting liquids and suspending agents 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 a therapeutic agent such as a nephritis therapeutic agent in an amount sufficient to produce an isotonic solution. The therapeutic agent may further contain conventional dissolution aids, buffers, pain relief 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 irritant 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 entire 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, a 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 2-200 mg in a disposable unit dosage form.

The invention is further illustrated by the following control examples, examples and formulation examples.

Control Example 1

29.3mι of concentrated nitric acid is added dropwise to 500mι 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 an aqueous dilute 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 mM 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 are dissolved in 750 mM of dimethylformamide (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 a dilute 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 mι of isopropyl alcohol was added to the residue to dissolve, and 65 mι of concentrated hydrochloric acid was added to the solution and heated to 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 are 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 were collected by filtration to give 42 g of 2-nitro-5-piperazinyl cinnamic acid having 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 mM of DMF and 6 mM 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, 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 to give 2-nitro-5- [4- (3,4 having a melting point of 196 to 198 ° C. 4.5 g of -dimethoxybenzoyl) -1-piperazinyl] benzaldehyde is obtained as yellow crystals.

[Control Example 7]

4 g of 2-nitro-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] benzaldehyde is dissolved in 20 mι of pyridine, 2.1 g of malonic acid and 0.4 mι of piperidine are then added, and the mixture is 80 Stir at 4 ° C. for 4 hours. After evaporating pyridine and piperidine, the reaction mixture is poured into dilute hydrochloric acid solution and extracted with methylene chloride. The methylene chloride layer is washed with water, then 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 mM concentrated hydrochloric acid and a solution of 20 g of tin chloride in 40 mM 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 mmol of methanol and the solution is neutralized with 10% aqueous sodium hydroxide solution to precipitate the crystals and then collected by filtration. After concentration of the methanol solution, 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. Is 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 amount of hydrogen gas theory is 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 are dissolved in 40 mM acetic acid. 1.1 g of acetic anhydride is added to this 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 recrystallized from a mixed solvent composed 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-piperazinyl] phenyl} -propionic acid is obtained.

Control Example 11

0-nitroaniline (300 g, 2.17 mol) is dissolved in 620 mM acetic anhydride and stirred at 40-50 ° C. for 3 hours. The reaction mixture is poured into ice water. The resulting crystals are then collected by filtration and dried. The 0-acetyl aminonitrobenzene obtained is suspended in 2.4ι 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 removed by filtration 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 0-amino-acetanilide.

Control Example 12

248 g (1.65 moles) of 0-acetylaminoaniline are dissolved in DMF 1ι and a solution of 114 g (0.87 moles) of β-ethoxy-acryl chloride in DMF 0.4ι is added dropwise 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 mol) of 1-acetylamino-2- (β-ethoxyacryloylamido) benzene is added dropwise to concentrated sulfuric acid with stirring at room temperature. After completion of the dropwise addition, the mixture is stirred at room temperature for 2 hours. 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 pH 8. 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 with 5N sodium hydroxide. Filtration of the crystals gave 15.47 g of 8-aminocarbostyryl.

Example 1

3.5 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl monohydro bromide is suspended in 40 mg of dimethylformamide (hereinafter referred to as DMF). After adding 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes to convert the starting material to 6- (1-piperazinyl) -3,4-dihydro carbostyryl. Next, 2.34 mmol of triethylamine was added to the mixture, and the mixture was slowly added dropwise with 10 mM of a DMF solution containing 2.9 g of 3,4-dimethoxybenzoyl chloride while stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred for 30 minutes, poured into a large amount of saturated saline solution and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from chloroform-ethanol to give 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] 3,4-dihydro carbo having a melting point of 238 to 239.5 ° C. 3.8 g of styryl are obtained as a colorless granular material.

Elemental Analysis:

C H N

Calculated Value (%): 66.84 6.33 10.63

Found (%): 66.69 6.49 10.51

[Examples 2 to 58]

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

Example 2

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

Example 3

6- (4-benzoyl-1-piperazinyl) -3,4-dihydro carbostyryl, melting point: 221 to 222.5 ° C. (ethanol), pale yellow granular material.

Example 4

5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 207 to 208 ° C (ethanol), colorless powder.

Example 5

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

Example 6

6- [4- (3,4,5-tridimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 180 to 182 ° C (isopropanol), colorless granular material .

Example 7

6- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl half-hydrate, melting point: 212-213 degreeC (methanol), a colorless needle-like material.

Example 8

6- (4-acetyl-1-piperazinyl) -3,4-dihydro carbostyryl, melting point: 203-205 ° C. (isopropanol), light yellow brown needle-like material.

Example 9

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

Example 10

1-benzyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl 1/2 hydrate, melting point: 131.5 to 132.5 ° C. (ethanol), Yellow powder.

Example 11

1-allyl-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl 1/2 hydrate, melting point: 120-122 ° C. (methanol-ether ), Colorless granular material.

Example 12

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

Example 13

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

Example 14

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

Example 15

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

Example 16

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

Example 17

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

Example 18

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

Example 19

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

Example 20

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

Melting point: 265 to 266 ° C. (methanol-chloroform), yellow powder.

Example 21

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

Example 22

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

Example 23

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

Example 24

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

Example 25

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

Example 26

6- [4- (4-nitrobenzoyl) -1-piperazinyl] carbostyryl, melting point: 265 to 266 ° C. (decomposition) (methanol-chloroform), yellow needles.

Example 27

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

Example 28

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

Example 29

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

Example 30

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

Example 31

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

Example 32

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

Example 33

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

Example 34

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

Example 35

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

Example 36

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

Example 37

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

Example 38

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

Example 39

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

Example 40

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

Example 41

8- [4- (3-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, melting point: 152 to 154 ° C. (ethanol), colorless impression material.

Example 42

8- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 145 to 148 ° C, colorless impression material (ethanol).

Example 43

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

Example 44

7- [4- (2-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl, Melting point: 194-195.5 ° C. (methanol), colorless acicular material.

Example 45

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

Example 46

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

Example 47

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

Example 48

7- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, Melting point: 207-208 ° C. (ethanol), colorless powder.

Example 49

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

Example 50

7- [4- (3,4,5-trimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 195 to 196.5 ° C. (methanol), colorless rectangular crystals.

Example 51

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

Example 52

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

Example 53

7- [4- (4-methylthiobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, Melting point: 258-260 ° C. (chloroform-methanol), colorless rectangular crystals.

Example 54

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

Example 55

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

Example 56

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

Example 57

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

Example 58

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

Example 59

1 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl monohydrobromide is suspended in 15 mM of DMF. After adding 296 mg of sodium bicarbonate, the suspension is stirred for 30 minutes at room temperature to convert the starting material to 6- (1-piperazinyl) -3,4-dihydro carbostyryl. Then 0.62 mmol of triethylamine was added to the mixture, and the mixture was slowly added dropwise with 5 mM of a DMF solution containing 532 mg of m-chlorobenzoyl chloride while stirring at room temperature. After completion of the dropwise addition, the reaction mixture is stirred at room temperature for 1 hour, poured into a large amount of water and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol. 0.4 g of 6- [4- (3-chlorobenzoyl) -1-piperazinyl] -3, 4-dihydro carbostyryl having a melting point of 197 to 197.5 ° C. This colorless impression material is obtained.

Elemental Analysis:

C H N

Calculated Value (%): 65.04 5.42 11.38

Found (%): 64.99 5.35 11.45

Example 60

3.5 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl mono hydrobromide are suspended in 40 ml of DMF. After adding 960 mg of sodium bicarbonate, the suspension is stirred at room temperature for 30 minutes to convert the starting material to 6- (1-piperazinyl) -3,4-dihydro carbostyryl. Then, 2.34 mmol of triethylamine was added to the mixture, and 10 mM of the DMF solution containing 2.5 g of 4-chlorobenzoyl chloride was slowly added dropwise while stirring at room temperature. After the dropwise addition, the reaction mixture is stirred for 30 minutes, poured into a large amount of water and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol to give 0.7 g of 6- [4- (4-chlorobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl having a melting point of 233 to 235 ° C. Obtained as pale yellow needles.

Elemental Analysis:

C H N

Calculated Value (%): 65.04 5.42 11.38

Found (%): 64.89 5.30 11.51

Example 61

2.6 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl monohydrobromide and 2.34 mmol of triethylamine are dissolved in 40 mM of DMF. The mixture is slowly added dropwise with 10 mM of a DMF solution containing 2.5 g of 4-methoxybenzoyl chloride while stirring at room temperature. After the addition, the reaction mixture was stirred for 30 minutes, poured into a large amount of water, and extracted with chloroform. The extract is extracted successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol-chloroform to give 5- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbosti having a melting point of 219 to 220 캜. 1.1 g of reel are obtained as a colorless needle.

Elemental Analysis:

C H N

Calculated Value (%): 69.04 6.30 13.15

Found (%): 68.95 6.21 13.24

Example 62

3.5 g of 5- (1-piperazinyl) -3,4-dihydrocarbostyryl monohydrobromide are suspended in 40 mL of DMF. After adding 960 mg of sodium bicarbonate, the suspension is stirred for 30 minutes at room temperature to convert the starting material to 5- (1-piperazinyl) -3,4-dihydro carbostyryl. Then, 2.34 mmol of triethylamine was added to the mixture, and 10 mM of DMF solution containing 3.0 g of 3,5-dichlorobenzoyl chloride was slowly added dropwise while stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred for 40 minutes, poured into a large amount of saturated salt aqueous solution, and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol-chloroform to give 5- [4- (3,5-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbo having a melting point of 255 to 257 ° C. 1.8 g of styryl is obtained as a colorless needle.

Elemental Analysis:

C H N

Calculated Value (%): 59.55 4.71 10.42

Found (%): 59.43 4.83 10.31

Example 63

2.6 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl and 1 g of sodium bicarbonate were added to 50 mι of dimethylsulfoxide, and the mixture was cooled with ice and stirred with 3.2 g of 4-bromobenzoyl chloride. Slowly add 20mι of dimethylsulfoxide side solution. After completion of the dropwise addition, the reaction mixture is stirred for 60 minutes at room temperature, poured into a large amount of water and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol-chloroform to give 6- [4- (4-bromobenzoyl) -1-piperazinyl] -3,4-dihydro carbosti having a melting point of 233 to 234.5 ° C. 0.8 g of reel is obtained as a colorless granular material.

Elemental Analysis:

C H N

Calculated (%): 57.97 4.83 10.14

Found (%): 57.79 4.71 10.23

Example 64

2.6 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl and 2 mM of trimethylamine are added to 40 mM of DMF. While stirring the mixture at room temperature, slowly add 10mι of a DMF solution containing 2.4g of 4-cyanobenzoyl chloride. After completion of the dropwise addition, the reaction mixture is stirred for 30 minutes at 40 to 50 ° C. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol-chloroform to give 5- [4- (4-cyanobenzoyl) -1-piperazinyl] -3,4-dihydro carbosti with a melting point of 260 to 269 ° C. 1.9 g of reel are obtained as a colorless granular material.

Elemental Analysis:

C H N

Calculated Value (%): 70.00 5.56 15.56

Found (%): 70.14 5.71 15.43

Example 65

2.6 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl and 2 mmol of pyridine are added to 40 mL of DMF. While stirring the mixture at room temperature, slowly add 10mι of a DMF solution containing 2.7g of 4-nitrobenzoyl chloride. After the dropwise addition is complete, the reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed successively with saturated sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol-chloroform to give 6- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl having a melting point of 235.5 to 236.5 ° C. 2.4 g are obtained.

Elemental Analysis:

C H N

Calculated Value (%): 63.15 5.30 14.73

Found (%): 63.09 5.35 14.77

Example 66

2.6 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl and 2.34 mι of triethylamine were added to 40 mι of dimethylsulfoxide, and the mixture was stirred at room temperature with 3,5-dinitrobenzoyl chloride 3.3 10 mι of dimethyl sulfoxide solution containing g is slowly added dropwise. After the dropwise addition is complete, the reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract was washed successively with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, the chloroform was distilled off, and the residual crystals were recrystallized from methanol-chloroform to give 6- [4- (3, 0.3 g of 5-dinitrobenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyryl is obtained as a dark red needle.]

Elemental Analysis:

C H N

Calculated Value (%): 56.47 4.47 16.47

Found (%): 56.34 4.61 16.35

Example 67

400 mg of 6- [4- (4-nitrobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl was added to 20 mM of methanol and reduced using 50 mg of 10% palladium-carbon as catalyst at atmospheric pressure and room temperature. Let's do it. After absorption of hydrogen gas, the catalyst is filtered off. The filtrate is distilled off under reduced pressure and the residue is purified by silica gel column chromatography. Recrystallization from ethanol yields 210 mg of 6- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl with a melting point of 244 to 246 ° C. as a pale yellow needle.

Elemental Analysis:

C H N

Calculated Value (%): 68.57 6.29 16.00

Found (%): 68.70 6.18 16.14

In a similar manner as in Example 67, 5- [4- (4-aminobenzoyl) -1-piperazinyl] -3,4-dihydro carbosteel dihydrochloride monohydrate is prepared. Melting point: 224-227 ° C. (decomposition) (methanol-ether), yellow granular material.

Example 68

Methylene containing 226 mg of boron tribromide with 300 mg of 5- [4- (4-methoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl and 7mι of methylene chloride at 0-5 ° C. with stirring Slowly add 2mι of chloride solution. After the dropping is complete, the reaction mixture is stirred for 30 minutes at the same temperature and raised at room temperature for about 1 hour. Next, the reaction mixture is poured into a large amount of water and the precipitated crystals are collected by filtration. Recrystallization of the residual crystals with methanol-chloroform results in 150 mg of 5- [4- (4-hydroxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl having a melting point of 300 ° C. or higher, a colorless granular material. Is obtained.

Elemental Analysis:

C H N

Calculated Value (%): 63.38 5.98 11.97

Found (%): 68.21 6.11 11.83

Example 69

To 2.6 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl and 4 mL of DBU is added to 40 mL of DMF. The mixture was slowly added dropwise with 10 mM of a DMF solution containing 3.0 g of 3,4-chloroformbenzoyl chloride while stirring at room temperature. After the dropwise addition is complete, the reaction mixture is stirred for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed successively with sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol to give 5- [4- (3,4-dichlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbosti with a melting point of 250 to 252 ° C. 1.2 g of reel are obtained as a colorless powder.

Elemental Analysis:

C H N

Calculated Value (%): 59.55 4.71 10.42

Found (%): 59.38 4.82 10.34

Example 70

2.6 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl and 2.4 mmol of triethylamine are added to 40 mL of DMF. The mixture is slowly added dropwise with 10 mM of a DMF solution containing 2.7 g of 3,4-methylenedioxybenzoyl chloride while stirring at room temperature. After the dropwise addition is complete, the reaction mixture is stirred for 30 minutes at room temperature. Next, the reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed successively with sodium bicarbonate solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol to give 6- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydro carbo having a melting point of 191 to 192.5 ° C. 1.6 g of styryl is obtained as a colorless acicular material.

Elemental Analysis:

C H N

Calculated (%): 66.49 5.54 11.08

Found (%): 66.35 5.67 10.94

Example 71

2.6 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl and 2.34 mmol of triethylamine are added to 50 mmol of chloroform. The mixture is slowly added dropwise with 10 mM of a chloroform solution containing 2.3 g of 4-methylbenzoyl chloride while stirring at room temperature. After the dropwise addition is complete, the reaction mixture is stirred for 30 minutes. At the end of the reaction, 100 mM of chloroform and then a large amount of water are added to separate the chloroform, and the chloroform layer is washed successively with sodium hydrocarbon solution and water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from chloroform-ether to give 5- [4- (4-methylbenzoyl) -1-pyrazinyl] -3,4-dihydro carbostyryl having a melting point of 239.5 to 240 ° C. 1.8 g is obtained as a colorless powder.

Elemental Analysis:

C H N

Calculated Value (%): 72.21 6.59 12.03

Found (%): 72.34 6.44 11.94

Example 72

To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl 1.17 g potassium carbonate and DMF 20 mM, 720 mg of 4-methoxybenzyl chloride are added and the mixture is stirred at 80 ° C. for 2.5 h. . The reaction mixture is poured into a large amount of saturated brine solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Recrystallization from ethanol yields 950 mg of 6- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl with a melting point of 196-198 ° C. as a colorless needle.

Elemental Analysis:

C H N

Calculated Value (%): 70.00 7.22 11.67

Found (%): 69.91 7.15 11.71

Example 73

A mixture of 1.0 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.11 g of potassium carbonate, 760 mg of 4-methoxybenzyl chloride and 200 mM of DMF is stirred at 70-80 ° C. for 4 hours. . The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Recrystallization from methanol yields 60 mg of 5- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl with a melting point of 194-196 ° C. as a colorless needle.

Elemental Analysis:

C H N

Calculated (%): 71.79 7.12 11.97

Found (%): 71.84 7.05 11.89

Example 74

To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl and 1.17 g of potassium carbonate and 20 mM of DMF was added 646 mg of 2-felethyl chloride and the mixture was added at 80 to 100 ° C. for 2.5 hours. Stir. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Conversion to hydrochloride with methanol-hydrochloric acid followed by recrystallization from methanol yielded 6- [4- (2-phenethyl) -1-piperazinyl] -3,4-dihydro with a melting point of 274 to 276 ° C (decomposition). 0.6 g of carbostyryl is obtained as a colorless powder.

Elemental Analysis:

C H N

Calculated Value (%): 67.82 7.05 11.30

Found (%): 67.85 6.93 11.39

Example 75

To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium carbonate and 20 mM of DMF, 858 mg of 3,4-dimethoxybenzyl chloride was added and the mixture was stirred at 70 to 80 ° C. Stir for 2 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Conversion of the residue to hydrochloride resulted in 610 mg of 5- [4- (3,4-dimethoxybenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl having a melting point of 270 to 272.5 ° C. (decomposition). Obtained.

Elemental Analysis:

C H N

Calculated Value (%): 58.15 6.43 9.25

Found (%): 58.08 6.51 9.14

Example 76

780 mg of 4-chlorobenzyl chloride was added to a mixture of 1.0 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.11 g of potassium carbonate, and DMF 20 mM, and the mixture was stirred at 70 to 80 ° C. for 4 hours. Stir. The reaction mixture is poured into a large amount of water and extracted with chloroform. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Recrystallization from chloroform-methanol yields 500 mg of 6- [4- (4-chlorobenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl with a melting point of 190 to 191.5 ° C. as a colorless needle.

Elemental Analysis:

C H N

Calculated Value (%): 67.51 6.23 11.81

Found (%): 67.31 6.17 11.85

Example 77

To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium carbonate, and 20 mM of DMF, 895 mg of 3,4-dichlorobenzyl chloride was added and the mixture was stirred at 60 to 70 ° C. Stir for 3 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Conversion to hydrochloride with methanol-hydrochloric acid followed by recrystallization of the product from methanol yielded 5- [4- (3,4-dichlorobenzyl) -1-piperazinyl] -3, having a melting point of 298.5 to 300 ° C. (decomposition). 0.17 g of 4-dihydro carbostyryl is obtained as a colorless granular material.

Elemental Analysis:

C H N

Calculated Value (%): 54.00 5.44 9.45

Found (%): 53.73 5.57 9,29

Example 78

To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium carbonate and 50 mmol of benzene, 789 mg of 4-nitrobenzyl chloride are added and the mixture is stirred at reflux for 4 hours. After the reaction is complete, benzene is distilled off and the residue is dissolved in chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. When recrystallized from chloroform-ether, 0.26 g of 5- [4- (4-nitrobenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl having a melting point of 268 to 271 ° C (decomposition) is converted into a pale yellow powder. Obtained.

Elemental Analysis:

C H N

Calculated Value (%): 65.57 6.01 15.30

Found (%): 65.43 5.89 15.42

Example 79

To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium carbonate and 20 mM of dimethyl sulfoxide, 650 mg of 4-aminobenzyl chloride was added and the mixture was stirred at 80 ° C. for 2.5 hours. Stir. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. Conversion to hydrochloride with methanol-hydrochloric acid followed by recrystallization from methylol-ether 5- [4- (4-aminobenzyl) -1-piperazinyl] -3,4 with a melting point of 224 to 227 ° C. (decomposition). 0.4 g of dihydro carbostyryl is obtained as a yellow granular material.

Elemental Analysis:

C H N

Calculated Value (%): 56.20 6.60 13.11

Found (%): 56.19 6.57 13.31

Example 80

To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium carbonate and 20 mM of hexamethylphosphoric acid triamide, 651 mg of 4-hydroxybenzel chloride was added and the mixture was 90 Stir at 2.5 ° C. for 2.5 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified by silica gel column chromatography to give 0.3 g of 6- [4- (4-hydroxybenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl. .

Atomic analysis:

C H N

Calculated Value (%): 14.24 6.82 12.46

Found (%): 14.33 6.74 12.37

Example 81

To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium bicarbonate, and DMF 20 mM, 646 mg of 4-methylbenzyl chloride are added and the mixture is stirred at 80 ° C. for 2.5 hours. . The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography. After conversion to hydrochloride with methylol-hydrochloric acid, the product was recrystallized from methanol-water to give 6- [4- (4-methylbenzyl) -1-piperazinyl] -3, having a melting point of 272-273 ° C. (decomposition). 0.17 g of 4-dihydro carbostyryl is obtained as a colorless powder.

Elemental Analysis:

C H N

Calculated Value (%): 61.91 6.63 10.32

Found (%): 61.86 6.59 10.39

Example 82

To a mixture of 1.2 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium carbonate and 50 mM of benzene, 688 mg of 4-cyanobenzyl chloride are added and the mixture is refluxed and stirred for 3 hours. . The reaction mixture is poured into a large amount of saturated saline solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified by silica gel column chromatography to yield 105 mg of 5- [4- (4-cyanobenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl.

Elemental Analysis:

C H N

Calculated Value (%): 72.83 6.36 16.18

Found (%): 72.92 6.51 16.07

Example 83

To a mixture of 1.2 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 1.17 g of potassium bicarbonate, and DMF 20 mM, 785 mg of 3,4-methylenedioxybenzyl chloride was added and the mixture was heated to 80 to 90 ° C. Stir for 3.5 hours. The reaction mixture is poured into a large amount of saturated brine solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified by silica gel column chromatography to give 0.2 g of 6- [4- (3,4-methylenedioxybenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl. Is obtained.

Elemental Analysis:

C H N

Calculated Value (%): 69.04 6.30 11.51

Found (%): 68.89 6.43 11.42

Example 84

1.0 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl was added to a mixture of DMF 10mι and trimethylamine 0.85mι and the mixture was stirred at room temperature containing 1.07 g of P-toluenesulfonyl chloride. Slowly add 5mι of DMF solution. After the dropwise addition is complete, the reaction mixture is stirred at the same temperature for 30 minutes. The reaction mixture is poured into a large amount of saturated brine solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from DMF to give 5- [4- (P-toluenesulfonyl) -1-piperazinyl) -3,4-dihydro carbostyryl having a melting point of 302 to 304 ° C. 800 mg is obtained as a colorless powder.

Elemental Analysis:

C H N

Calculated Value (%): 62.34 5.97 10.91

Found (%): 62.43 5.89 10.79

Example 85

1.0 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl was added to a mixture of 10 mι DMF and 0.85 mι of trimethylamine, and the mixture was stirred at room temperature with 5 mι of a DMF solution containing 440 mg of methanesulfonyl chloride. Slowly dropwise. After the dropwise addition is complete, the reaction mixture is stirred at the same temperature for 30 minutes. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residual crystals were recrystallized from methanol. 0.17 g of 6- (4-methanesulfonyl-1-piperazinyl) -3,4-dihydro carbostyryl having a melting point of 241.5 to 243 ° C was colorless. Obtained as a granular material.

Elemental Analysis:

C H N

Calculated Value (%): 54.37 6.15 13.59

Found (%): 54.23 6.24 13.43

Example 86

To a mixture of 1 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 30 mM of DMF and 900 mg of potassium carbonate, 2 mM of butyl bromide are added and the mixture is stirred at 80 ° C. for 2.5 hours. The reaction mixture is poured into a large amount of saturated brine solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is then distilled off and the residue is purified by silica gel column chromatography. After conversion to hydrochloride with methanol-hydrochloric acid, the product is recrystallized from methanol to give 6- (4-butyl-1-piperazinyl) -3,4-dihydro carbosti with a melting point of 279 to 281 ° C (decomposition). 700 mg of reel hydrochloride 1/2 hydrate are obtained.

Elemental Analysis:

C H N

Calculated Value (%): 61.46 7.53 12.65

Found (%): 61.34 7.45 12.51

Example 87

To a mixture of 1 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 20 mM of DMSO and 1.7 g of potassium carbonate, 450 mg of ethyl bromide are added and the mixture is stirred at 70-100 ° C. for 4.5 h. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is then distilled off and the residue is purified by silica gel column chromatography. After conversion to hydrochloride with methanol-hydrochloric acid, the product is recrystallized from methanol to give 5- (4-ethyl-1-piperazinyl) -3,4-dihydro carbosti with a melting point of 293 to 296 ° C (decomposition). 0.14 g of reel monohydrochloride is obtained as a colorless granular material.

Elemental Analysis:

C H N

Calculated Value (%): 61.01 7.46 14.24

Found (%): 61.08 7.41 14.19

Example 88

To a mixture of 1 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl, 15 mM of DMF and 1.82 g of potassium carbonate was added 500 mg of allyl bromide, and the mixture was stirred at room temperature for 2 hours. The reaction mixture is poured into a large amount of water and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is then removed by distillation and the residue is purified by silica gel column chromatography and recrystallized from chloroform-ether to give 6- (4-allyl-1-piperazinyl) -3,4 with a melting point of 175 to 176 ° C. 0.43 g of dihydro carbostyryl is obtained as a colorless impression material.

Elemental Analysis:

C H N

Calculated Value (%): 70.84 7.75 15.50

Found (%): 70.73 7.81 15.38

Example 89

To a mixture of 1 g of 5- (1-piperazinyl) -3,4-dihydro carbostyryl, 30 mM of DMF and 900 mg of sodium carbonate, 491 mg of propargyl bromide are added and the mixture is stirred at 80 ° C. for 3 hours. The reaction mixture is poured into a large amount of saturated saline solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform was then distilled off and the residue was purified by silica gel column chromatography and recrystallized from chloroform to give 5- [4- (2-propynyl) -1-piperazinyl] -3 having a melting point of 225 to 226 ° C. 0.1 g of 4-dihydrocarbostyryl is obtained as a pale yellow powder.

Elemental Analysis:

C H N

Calculated Value (%): 71.38 7.06 15.61

Found (%): 71.23 7.14 15.48

Example 90

To a mixture of 30 g of 6- (1-pepyrazinyl) -3,4-dihydro carbostyryl 1 g DMF and 900 mg of sodium bicarbonate is added 600 mg of 3-methylallyl bromide and the mixture is stirred at 100 ° C. for 2.5 hours. The reaction mixture is poured into a large amount of saturated brine solution and extracted with chloroform. The extract is washed with water and dried over anhydrous sodium sulfate. The chloroform is then distilled off and the residue is purified by silica gel column chromatography. Conversion to hydrochloride with methanol-hydrochloric acid followed by recrystallization of the product from methanol yielded 6- [4- (2-butenyl) -1-piperazinyl] -3,4 with a melting point of 242 to 245 ° C. (decomposition). 0.4 g of dihydro carbostyryl dihydrochloride is obtained as a colorless impression material.

Elemental Analysis:

C H N

Calculated Value (%): 56.98 7.03 11.73

Found (%): 56.92 6.72 11.72

Example 91

A mixture of 2.6 g of 3,4-dimethoxybenzoic acid, 1,8-diazabicyclo- [5,4,0] undecene-71.65 g, and 100 mι of DMF was added dropwise with 1.5 mι of isobutyl chloroformate while ice-cooling stirring externally. do. After completion of the dropwise addition, the mixture was stirred for 30 minutes and a solution of 2.3 g of 6- (1-piperazinyl) -3,4-dihydro carbostyryl in 40 mL of DMF was added. After stirring for 5 hours at room temperature, the solvent is distilled off and the residue is extracted with about 30 mM chloroform. The extract is washed with dilute aqueous NaHCO ₃ solution, water, dilute hydrochloric acid and water in that order. Chloroform was distilled off and the residue was recrystallized from ethanol-chloroform to give 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro having a melting point of 238 to 239.5 ° C. 1.7 g of carbostyryl is obtained as a colorless granular material.

Elemental Analysis:

C H N

Calculated Value (%): 66.84 6.33 10.63

Found (%): 66.72 6.45 10.52

According to a method analogous to Example 91, the same compound as obtained in Examples 2 to 58 is obtained using an appropriate starting material.

[Examples 92 to 103]

According to a method analogous to Example 91, the following compounds are prepared using appropriate starting materials.

Example 92

6- [4- (4-methoxybenzyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 109-198 ° C. (ethanol). Colorless needles.

Example 93

6- [4- (4-chlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 233 to 235 ° C., (methanol) pale yellow needle.

Example 94

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

Example 95

5- [4- (3,5-dichloropobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl, melting point: 225 to 257 ° C (methanol-chloroform), colorless acicular material.

Example 96

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

Example 97

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

Example 98

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

Example 99

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

Example 100

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

Example 101

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

Example 102

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

Example 103

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

Example 104

A mixture of 1.22 mM acetic anhydride and 0.5 mM formic acid is stirred at 50-60 ° C. for 2 hours. After cooling to room temperature, 1.0 g of 5-piperazinyl-3,4-dihydro carbostyryl is added dropwise to the reaction mixture, during which the product solidifies. 5 ml of dichloromethane is added to this solid and stirred at room temperature for 2 hours. Next, a large amount of water is added, and the mixture is extracted with chloroform. The extract is washed with water, then dried over anhydrous sodium sulfate and chloroform is removed by distillation. Recrystallization of the residue from methanol yielded 420 mg of 5- (4-formyl-1-piperazinyl) -3,4-dihydro carbostyryl having a melting point of 263 to 265 ° C. as a colorless granular material.

Elemental Analysis:

C H N

Calculated Value (%): 64.84 6.61 16.21

Found (%): 64.64 6.57 16.22

Example 105

According to a method analogous to Example 104, the following compounds are prepared using the appropriate starting material: 6- (4-formyl-1-piperazinyl) carbostyryl, melting point: 286.5 to 288 ° C. (methanol), yellow Impression material.

Example 106

To a suspension of 1.0 g of 6- (1-piperazinyl-3,4-dihydro carbostyryl monohydrobromide in 10 mL of DMF was added 296 mg of sodium bicarbonate and stirred at room temperature for 30 minutes to give the starting compound 6- (1-P To ferrazinyl) -3,4-dihydro carbostyryl, add 0.62 mmol of triethylamine to it, and then slowly add dropwise dropwise addition of a solution of 605 mg of 4-acetyloxy benzoyl chloride in 5 mM of DMF to the mixture. When finished, the mixture is stirred for 1 hour at room temperature The reaction mixture is poured into a large amount of water and extracted with water The extract is washed successively with saturated aqueous sodium hydrogen carbonate solution and with water and dried over anhydrous sodium sulfate. 6- [4- (4-acetyloxy benzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl is obtained.

Elemental Analysis:

C H N

Calculated Value (%): 67.16 5.89 10.68

Found (%): 67.04 5.98 10.49

Example 107

2.0 g of 6- (1-piperazinyl) carbostyryl hydrobromide is suspended in 20 ml of DMF. After adding 2.34 ml of triethylamine, the mixture was added dropwise to a solution of 1.43 g of 3,4-methylenedioxybenzoyl chloride in 2 ml of DMF. After the addition, the mixture is stirred for 30 minutes at room temperature and the reaction mixture is poured into a large amount of water. The crystals formed are collected by filtration and dried. The crystals were then purified by silica gel column chromatography and recrystallized from chloroform-methanol to give 6- [4- (3,4-methylenedioxy benzoyl) -1-piperazinyl] carbo having a melting point of 266 to 267 ° C (decomposition). 1.9 g of styryl is obtained as a yellow powder.

Example 108

To a solution of 800 mg of 7- (1-piperazinyl) -3,4-dihydro carbostyryl hydrobromide in 10 ml of DMF was added 1.2 ml of triethylamine and to the mixture was stirred a solution of 730 mg of 4-chlorobenzoyl chloride in 2 ml of DMF. Add it down. At the end of the dropping, the mixture is stirred for 30 minutes at room temperature. The reaction mixture is poured into a large amount of water and the resulting crystals are collected by filtration, washed with water and dried. The crystals were purified by silica gel column chromatography and recrystallized from chloroform-methanol to yield 7- [4- (4-chlorobenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl having a melting point of 289 to 291 ° C. 700 mg is obtained as a colorless powder.

Example 109

0.7 g (2.26 mmol) of 8- (1-piperazinyl) carbostyryl and 0.2 g of sodium bicarbonate are suspended in 5 ml of DMF and the suspension is stirred at room temperature for 30 minutes. 0.4 ml of triethylamine was added to the resulting mixture, and then a solution of 0.47 g of 2-chlorobenzoyl chloride in 5 ml of DMF was added dropwise, followed by stirring at room temperature for 30 minutes. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is washed with water, washed with saturated aqueous sodium hydrogen carbonate and then dried over sodium sulfate. The solvent is distilled off and crystallized by adding ether to the residue. The crystal thus obtained is recrystallized from ethanol to give 0.24 g of 8- [4- (2-chlorobenzoyl) -1-piperazinyl] -carbostyryl having a melting point of 239 to 240.5 ° C. as a colorless needle.

[Method of Table 1]

Isolation of Blood Flow Idiopathic Agents

This experiment is performed on both mature Mongraral species male and female. Isotope formulations are obtained by anesthetizing dogs weighing 8 to 13 kg with pentobarbital sodium (30 mg / kg, intravenously), and then administering heparin sodium (1000 u / kg, intravenous) 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 cross-purified the blood from the blood supply dog through a right cannulated coronary artery to a constant pressure of 1000 mmHg. Blood-feeding dogs weigh between 18 and 27 kg and are anesthetized with pentobarbital sodium (30 mg / kg, intravenously). Sodium heparin is administered intravenously in an amount of 1000 u / kg. The tension in the right atrium is measured using a tension gauge transducer. About 1.5 g is loaded into the right atrium. The pulse rate 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. Details for this formulation are described in Chiba et al., (Japan, J. Pharmacol., 25, 433-439, 1975: Naunyn-Schmiedberg's Arch, Pharmacol, 289,315-325, 1975). 10-30 mM 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 a compound on copper heart rate (beats / minute) or blood flow (mι / min) is expressed as the difference between 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-dihydro carbostyryl

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

3. 6- (4-acetyl-1-piperazinyl) -3,4-dihydro carbostyryl

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

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

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

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

8. 6- (1-piperazinyl) -3,4-dihydro carbostyryl

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

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

11. 6- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl-3,4-dihydro carbostyryl

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

13. 6- [4- (4-cyanobenzoyl) -1-piperazinyl) -3,4-dihydro carbostyryl

14. 5- [4- (3,4-dimethoxybenzoin) -1-piperazinyl] -3,4-dihydro carbostyryl

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

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

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

18. 6- (4-benzoyl-1-piperazinyl) -3,4-dihydro carbostyryl

19. 1-benzyl-6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl 1/2 hydrate

20. 6- [4- (2-phenethyl) -1-piperazinyl-3,4-dihydro carbostyryl monohydrochloride

21. 6- (Formyl-1-piperazinyl) -3,4-dihydro carbostyryl

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

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

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

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

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

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

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

29. 6- (4-allyl-1-piperazinyl] -3,4-dihydro carbostyryl

30. 5- [4- (2-provinyl) -1-piperazinyl] -3,4-dihydro carbostyryl

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

32. 1-allyl-5- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl 1/2 hydrate

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

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

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

36. 6- [4- (3-pyridylcarbonyl) -1-piperazinyl] -3,4-dihydro carbostyryl

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

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

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

40. 5- [4- (4-hydroxybenzoyl) -1-piperazinyl-3,4-dihydro carbostyryl

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

42. 6- [4- (3-Chlorobenzoyl) -1-piperazyl] 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-dihydro carbostyryl monohydrochloride

53. 7- [4- (3,4-methylenedioxybenzoyl) -1-piperazinyl] -3,4-dihydro carbostyryl

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

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

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

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

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 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 administering heparin sodium (1000 u / kg intravenously) and then bleeding. The formulation consists mainly of an excised anterior capillary muscle and ventricular septum and is placed in a cold tyroid solution. The formulation is placed in an ultra-embroidered jacket maintained at about 38 ° and the blood is cross circulated at a constant pressure of 100 mmHg from the blood supply dog through the cannula-inserted anterior diaphragm artery. Blood-feeding 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. Capillary muscle has a pulse rate of 5 m, about 1.5 times the threshold voltage (0.5-3V). A latency of sec, induced at a constant rate of 120 times / minute through the bipolar electrode. About 1.5 g is loaded from this root. Blood flow through the anterior diaphragm artery is measured with an electromagnetic flow meter. Record on the chart by generated tension and blood flow ink-recording commutation graphs. A detailed description of this agent is described in Endoh and Hashimoto (Am. J. Physiol, 218, 1459-1463, 1970). 10-30 ml of the 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 (mι / 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-

Dehydro carbostyryl 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-

Dehydro carbostyryl 10mg

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-

Dehydro Carbostyryl 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

100mι 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 appropriate filter paper, sterilized and filled with 1 mM ampoule to prepare an injectable preparation.

Formulation Example 4

6- [4- (3,4-dimethyloxy benzoyl) -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 of preparing a carbostyryl compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof, characterized by reacting a compound of formula (IV-1) with a compound of formula (V).

R ^{3 '} X ¹ (V) 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 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 alkoxy group on a benzene ring. Lower on a phenylcarbonyl group, a furoyl group, a pyridylcarbonyl group, a lower alkoxycarbonyl group, or a benzene ring which may be substituted by a noyloxy group or a hydroxy group or substituted by a lower alkylenedioxy group A phenyl-lower alkanoyl group which may be substituted by an alkoxy group or a hydroxy group; The bond present between the 3- and 4- positions of the carbostyryl nucleus is a single bond or a double bond, and X ¹ represents a hydroxy group. A process for preparing a carbostyryl compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof, characterized by reacting a compound of formula (IV-1) with a compound of formula (VI).

R ^{3 "} X ² (VI) In the formula, R ¹ represents a hydrogen atom or a lower alkyl group; R ² represents a hydrogen atom; R ^{3 ″} is lower alkanesulfonyl group, lower alkoxycarbonyl-lower alkyl group, phenylsulfonyl group which may be substituted by lower alkyl group on benzene ring, lower alkyl group, lower alkenyl group, lower alkynyl group, Or phenyl which may be substituted by 1 to 3 lower alkoxy groups, lower alkyl groups, halogen atoms, nitro groups, cyano groups, amino groups or hydroxy groups on the benzene ring or by lower alkylenedioxy groups. A lower alkyl group is represented and the bond existing between 3- and 4-positions of the carbostyryl nucleus is a single bond or a double bond; X ² represents a halogen atom.