JPS647968B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to cardiotonic agents. More specifically, the present invention relates to the general formula [In the 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 ³ and R ⁴ are hydrogen atoms, lower alkyl groups, lower alkenyl groups, cycloalkyl groups, phenoxy lower alkyl groups, or lower alkyl groups, hydroxyl groups, lower alkoxy groups on the phenyl ring,
A group selected from the group consisting of a halogen atom, a nitro group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a sulfamoyl group, a carbamoyl group that may have a lower alkyl group, and a cyano group. represents a phenyl lower alkyl group which may have 1 to 3 or a lower alkylenedioxy group as a substituent. A represents a lower alkylene group. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril adjective represents a single bond or a double bond. The present invention relates to a cardiotonic agent characterized by containing a carbostyril derivative or a salt thereof as an active ingredient. The carbostyril derivative represented by the above general formula (1) and its salt have an effect of enhancing myocardial contraction (positive inotropic effect) and an effect of increasing coronary blood flow,
It is therefore useful as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. General formula (1) above
Carbostyril derivatives and salts thereof have excellent positive inotropic effects and coronary blood flow increasing effects, but are characterized by extremely weak heart rate increasing effects and low toxicity. More specifically, each group shown in this specification is as follows. Lower alkyl groups: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl groups, etc. Lower alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups, etc. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Cycloalkyl...cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc. Phenyl lower alkyl group...benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl- 3-phenylpropyl group, etc. Lower alkenyl group...vinyl, allyl, crotyl, 1-methylallyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-
Methyl-3-butenyl, 1-methyl-3-butenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-4-pentenyl, 1-methyl-4-pentenyl, 2-methyl- 3-pentenyl, 1-methyl-3-pentenyl, etc. Lower alkynyl group...ethynyl, 2-propynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-methyl-3-butynyl, 1-methyl-3-butynyl , 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 1-methyl-
3-pentynyl group, etc. Phenoxy lower alkyl group... phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, 1,1-dimethyl-2-phenoxyethyl, 5-phenoxypentyl, 6-phenoxyhexyl , 2-methyl-3-phenoxypropyl group, etc. Lower alkanoylamino group... formamide,
Acetamide, propionamide, butyramide, isobutyramide, pentanoylamino, hexanoylamino groups, etc. Lower alkoxycarbonyl group: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group, etc. Lower alkylthio groups: methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio groups, etc. Carbamoyl group that may have a lower alkyl group...carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-
tert-Butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-ethyl- N
-hexylcarbamoyl, N,N-dihexylcarbamoyl group, etc. Lower alkylenedioxy group...methylenedioxy, ethylenedioxy, trimethylenedioxy group, etc. Having a lower alkyl group, hydroxyl group, lower alkoxy group, halogen atom, nitro group, amino group, lower alkanoylamino group, lower alkylthio group, carboxyl group, lower alkoxycarbonyl group, sulfamoyl group, lower alkyl group on the phenyl ring A phenyl lower alkyl group which may have 1 to 3 groups selected from the group consisting of a certain carbamoyl group and a cyano group or a lower alkylenedioxy group as a substituent...benzyl, 2-phenylethyl, 1-phenylethyl, 3 -Phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl, 3,3 -diphenylpropyl,
1,1-dimethyl-2,2-diphenylethyl,
2-methylbenzyl, 3-methylbenzyl, 3-
Ethylbenzyl, 4-ethylbenzyl, 2-propylbenzyl, 3-isopropylbenzyl, 4-
tert-butylbenzyl, 3-hexylbenzyl,
2-(3-methylphenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(2-ethylphenyl)ethyl, 2-(3-butylphenyl)ethyl,
1-(4-ethylphenyl)ethyl, 1-(3-isopropylphenyl)ethyl, 3-(2-methylphenyl)propyl, 3-(4-methylphenyl)
Propyl, 3-(3-ethylphenyl)propyl,
3-(4-pentylphenyl)propyl, 2-methyl-3-(4-methylphenyl)propyl, 5
-(2-ethylphenyl)pentyl, 5-(3-butylphenyl)pentyl, 6-(4-methylphenyl)hexyl, 2-hydroxybenzyl, 4-
Hydroxybenzyl, 2-(3-hydroxyphenyl)ethyl, 2-(4-hydroxyphenyl)
Ethyl, 1-(2-hydroxyphenyl)ethyl,
3-(4-hydroxyphenyl)propyl, 1,
1-dimethyl-2-(4-hydroxyphenyl)
Ethyl, 5-(3-hydroxyphenyl)pentyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3-ethoxybenzyl, 2-propoxybenzyl, 3-isopropoxybenzyl, 4-tert-butoxybenzyl , 2-
(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(2-ethoxyphenyl)ethyl, 2-(3-butoxyphenyl)ethyl, 1-(4-ethoxyphenyl)ethyl ,3
-(2-methoxyphenyl)propyl, 2-methyl-3-(4-methoxyphenyl)propyl, 6
-(4-methoxyphenyl)hexyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-bromobenzyl, 2-iodobenzyl, 3-fluorobenzyl, 2-(3-chlorophenyl)ethyl, 2-
(4-chlorophenyl)ethyl, 2-(2-bromphenyl)ethyl, 2-(3-iodophenyl)
Ethyl, 1-(4-chlorophenyl)ethyl, 1
-(3-bromphenyl)ethyl, 3-(2-chlorophenyl)propyl, 3-(4-chlorophenyl)propyl, 3-(3-bromphenyl)propyl, 3-(4-iodophenyl)propyl, 5
-(3-chlorophenyl)pentyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-(3-nitrophenyl)ethyl, 2-(4-nitrophenyl)
Ethyl, 1-(2-nitrophenyl)ethyl, 3
-(4-nitrophenyl)propyl, 1,1-dimethyl-2-(4-nitrophenyl)ethyl, 6
-(3-nitrophenyl)hexyl, 3-aminobenzyl, 4-aminobenzyl, 2-(2-aminophenyl)ethyl, 2-(4-aminophenyl)
Ethyl, 1-(4-aminophenyl)ethyl, 3
-(4-aminophenyl)propyl, 2-methyl-3-(2-aminophenyl)propyl, 2-formamidobenzyl, 3-acetamidobenzyl, 4-acetamidobenzyl, 2-propionamidobenzyl, 4-propionamidobenzyl, 4- Pentylamidobenzyl, 2-(3-acetamidophenyl)ethyl, 2-(4-acetamidophenyl)ethyl, 2-(2-propionamidophenyl)ethyl, 1-(2-formamidophenyl)ethyl, 1 -(4-acetamidophenyl)ethyl, 3-(2-acetamidophenyl)propyl, 3-(4-pentylamidophenyl)propyl, 6-(4-acetamidophenyl)
hexyl, 2-methylthiobenzyl, 4-methylthiobenzyl, 3-ethylthiobenzyl, 4-ethylthiobenzyl, 2-propylthiobenzyl,
3-butylthiobenzyl, 4-pentylthiobenzyl, 2-(3-methylthiophenyl)ethyl,
2-(4-methylthiophenyl)ethyl, 2-(4
-ethylthiophenyl)ethyl, 1-(2-methylthiophenyl)ethyl, 3-(2-methylthiophenyl)propyl, 3-(4-methylthiophenyl)propyl, 3-(3-propylthiophenyl) ) propyl, 1,1-dimethyl-3-(3-methylthiophenyl)propyl, 5-(2-ethylthiophenyl)pentyl, 2-carboxybenzyl, 4-carboxybenzyl, 2-(3-carboxyphenyl) ) ethyl, 2-(4-carboxyphenyl)ethyl, 1-(2-carboxyphenyl)
Ethyl, 3-(4-carboxyphenyl)propyl, 5-(3-carboxyphenyl)pentyl,
2-methoxycarbonylbenzyl, 4-methoxycarbonylbenzyl, 3-ethoxycarbonylbenzyl, 4-ethoxycarbonylbenzyl, 2-
Propoxycarbonylbenzyl, 3-butoxycarbonylbenzyl, 4-pentyloxycarbonylbenzyl, 4-hexyloxycarbonylbenzyl, 2-(3-methoxycarbonylphenyl)
Ethyl, 2-(4-methoxycarbonylphenyl)
Ethyl, 2-(4-ethoxycarbonylphenyl)
Ethyl, 1-(2-methoxycarbonylphenyl)
Ethyl, 3-(2-methoxycarbonylphenyl)
Propyl, 3-(4-methoxycarbonylphenyl)propyl, 1,1-dimethyl-3-(3-methoxycarbonylphenyl)propyl, 6-(2
-ethoxycarbonylphenyl)hexyl, 2-
Sulfamoylbenzyl, 3-sulfamoylbenzyl, 4-sulfamoylbenzyl, 2-(3
-sulfamoylphenyl)ethyl, 2-(4-
Sulfamoylphenyl)ethyl, 1-(2-sulfamoylphenyl)ethyl, 3-(4-sulfamoylphenyl)propyl, 1,1-dimethyl-2-(4-sulfamoylphenyl) )ethyl,
2-carbamoylbenzyl, 4-carbamoylbenzyl, 2-(3-carbamoylphenyl)ethyl, 2-(4-carbamoylphenyl)ethyl,
1-(2-carbamoylphenyl)ethyl, 3-
(4-carbamoylphenyl)propyl, 1,1
-dimethyl-2-(4-carbamoylphenyl)
Ethyl, 5-(3-carbamoylphenyl)pentyl, 2-(N-methylcarbamoyl)benzyl,
-4-(N-methylcarbamoyl)benzyl, 3
-(N-ethylcarbamoyl)benzyl, 4-(N
-ethylcarbamoyl)benzyl, 2-(N-isopropylcarbamoyl)benzyl, 4-(N-
tert-butylcarbamoyl)benzyl, 3-(N
-hexylcarbamoyl)benzyl, 2-[3-
(N-methylcarbamoyl)phenyl]ethyl,
2-[4-(N-ethylcarbamoyl)phenyl]
Ethyl, 2-[4-(N-propylcarbamoyl)
Phenyl]ethyl, 1-[4-(N-methylcarbamoyl)phenyl]ethyl, 3-[2-(N-methylcarbamoyl)phenyl]propyl, 3-[4
-(N-ethylcarbamoyl)phenyl]propyl, 3-[4-(N-butylcarbamoyl)phenyl]propyl, 2-methyl-3-[4-(N-methylcarbamoyl)phenyl]propyl, 6-[2
-(N-ethylcarbamoyl)phenyl]hexyl, 2-(N,N-dimethylcarbamoyl)benzyl, 4-(N,N-diethylcarbamoyl)benzyl, 3-(N-methyl-N-ethylcarbamoyl)benzyl, 4 -(N,N-dibutylcarbamoyl)benzyl, 2-(N,N-dihexylcarbamoyl)benzyl, 2-[3-(N-methyl-
N-propylcarbamoyl)phenyl]ethyl,
1-[4-N,N-diethylcarbamoyl)phenyl]ethyl, 2-methyl-3-[4-(N,N-
dimethylcarbamoyl)phenyl]propyl, 5
-[2-(N,N-diethylcarbamoyl)phenyl]pentyl, 2-cyanobenzyl, 4-cyanobenzyl, 2-(3-cyanophenyl)ethyl,
2-(4-cyanophenyl)ethyl, 1-(2-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 1,1-dimethyl-2-(4-cyanophenyl)ethyl, 5-(3-cyanophenyl)pentyl , 2,3-methylenedioxybenzyl, 3,4-methylenedioxybenzyl, 2,3
-ethylenedioxybenzyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2-(2,3-methylenedioxyphenyl)ethyl, 2-(3,4-ethylenedioxybenzyl) phenyl)ethyl, 1-(3,4-methylenedioxyphenyl)ethyl, 3-(2,3-methylenedioxyphenyl)propyl, 3-(3,4-
ethylenedioxyphenyl)propyl, 1,1-
Dimethyl-2-(3,4-methylenedioxyphenyl)ethyl, 2-methyl-3-(3,4-ethylenedioxyphenyl)propyl, 2,4-dimethylbenzyl, 3,4,5-trimethyl Benzyl, 2-ethyl-3-propylbenzyl, 2-
(3,4-dimethylphenyl)ethyl, 2-(2,
4-diethylphenyl)ethyl, 3-(2,4-
dimethylphenyl)propyl, 3-(2-methyl-3-propylphenyl)propyl, 2,3-dihydroxybenzyl, 3,4-dihydroxybenzyl, 3,4,5-trihydroxybenzyl, 2
-(3,4-dihydroxyphenyl)ethyl, 2,
3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl,
2,4-diethoxybenzyl, 2-(3,4-diethoxyphenyl)ethyl, 2-(3,4,5-
trimethoxyphenyl)ethyl, 3-(2,3-
dimethoxyphenyl)propyl, 3-(3-methoxy-4-ethoxyphenyl)propyl, 1,1
-dimethyl-2-(3,4,5-trimethoxyphenyl)ethyl, 5-(3,4-dimethoxyphenyl)pentyl, 2,3-dichlorobenzyl,
3,4-dichlorobenzyl, 3,4,5-trichlorobenzyl, 2,4-dibromobenzyl, 3,
4-diiodobenzyl, 3,4-difluorobenzyl, 2-chloro-3-brombenzyl, 2-
(2,3-dichlorophenyl)ethyl, 2-(3,
4,5-trichlorophenyl)ethyl, 2-(3,
4-dibromphenyl)ethyl, 2-(2,4-
Diiodophenyl)ethyl, 1-(3,4-dichlorophenyl)ethyl, 1-(3,4,5-tribromphenyl)ethyl, 3-(2,4-dichlorophenyl)propyl, 3-(3,4-dibromphenyl) ) propyl, 5-(3,4-dichlorophenyl)pentyl, 2,4-dinitrobenzyl,
3,4-dinitrobenzyl, 3,4,5-trinitrobenzyl, 2-(3,4-dinitrophenyl)
Ethyl, 3-(2,4-dinitrophenyl)propyl, 3,4-diaminobenzyl, 3,4,5-
Triaminobenzyl, 2-(3,4-diaminophenyl)ethyl, 2-(2,4-diaminophenyl)ethyl, 4-(2,4-diaminophenyl)
Butyl, 2,4-diacetamidobenzyl, 3,
4,5-triacetamidobenzyl, 2-(2,
3-diformamidophenyl)ethyl, 2-(3,
4-Diacetamidophenyl)ethyl, 3-(3,
4-Diacetamidophenyl)propyl, 6-
(2,4-diacetamidophenyl)hexyl,
2,3-dimethylthiobenzyl, 3,4-dimethylthiobenzyl, 3,4,5-trimethylthiobenzyl, 3,4-diethylthiobenzyl, 2-
(3,4-dimethylthiophenyl)ethyl, 2-
(2,4-diethylthiophenyl)ethyl, 3-
(3,4-dimethylthiophenyl)propyl, 5
-(2,4-dimethylthiophenyl)pentyl,
2,4-dicarboxybenzyl, 3,4,5-tricarboxybenzyl, 2-(2,4-dicarboxyphenyl)ethyl, 3-(3,4-dicarboxyphenyl)propyl, 3,5- Di(methoxycarbonyl)benzyl, 2,4-di(ethoxycarbonyl)benzyl, 2-[2,4-di(ethoxycarbonyl)phenyl]ethyl, 3,4-disulfamoylbenzyl, 2,3,4- Sulfamoylbenzyl, 2-(2,4-disulfamoylphenyl)ethyl, 3-(3,4-disulfamoylphenyl)propyl, 2,4-dicarbamoylbenzyl, 2,4-di(N , N-dimethylcarbamoyl)benzyl, 2-[3,5-di(N-ethylcarbamoyl)phenyl]ethyl, 3-(N
-methyl-N-ethylcarbamoyl)-4-(N-
butylcarbamoyl)benzyl, 3-[3-(N-
ethylcarbamoyl)-5-(N-propylcarbamoyl)phenyl]propyl, 2,4-dicyanobenzyl, 3,4,5-tricyanobenzyl, 2
-(3,5-dicyanophenyl)ethyl, 3-
(2,4-dicyanophenyl)propyl, 2-hydroxy-4-nitrobenzyl, 2-nitro-3
-methoxybenzyl, 3-methyl-5-chlorobenzyl group, etc. Lower alkylene group...methylene, methylmethylene, ethylmethylene, propylmethylene, butylmethylene, pentylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1-isopropylethylene, 1-butylethylene, 1,1-
dimethylethylene, 1,1-diethylethylene,
trimethylene, 2-methyltrimethylene, 2-ethyltrimethylene, 2-propyltrimethylene,
2,2-dimethyltrimethylene, 1-methyltrimethylene, 1-ethyltrimethylene, 1-propyltrimethylene, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1-
Ethyltetramethylene, 2-ethyltetramethylene, pentamethylene, 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, hexamethylene groups, etc. Representative carbostyryl derivatives represented by the above general formula (1) are listed below. The 3,4-position dehydrogenated product of each compound refers to a compound in which the carbon-carbon bond at the 3- and 4-positions of the carbostyril skeleton is a double bond. Γ6-(1-oxo-2-aminoethyl)-3,4
-Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-(1-oxo-2-methylaminoethyl)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ6-[1-oxo-2-(N,N-diethylamino)ethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-(1-oxo-2-butyl aminoethyl)-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ6-(1-oxo-2-hexylaminoethyl)
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ6-[1-oxo-(2-N-methyl-N-propylamino)ethyl]-3,4-dihydrocarbostyryl and its 3, 4-position dehydrogenation product Γ6-(1-oxo-2-cyclopropylaminoethyl)-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-(1-oxo-2-cyclohexylaminoethyl)- 3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(N-cyclopropyl-
N-cyclohexylamino)ethyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenation Γ6-[1-oxo-2-(N-ethyl-N-cyclooctylaminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Γ6-[1-oxo-2-(2-phenoxyethyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1-oxo-2-(4-phenoxybutyl)amino Ethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ6-[1-oxo-2-(6-phenoxybutyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position Dehydrogenated Γ6-{1-oxo-2-[N-methyl-N-(2
-phenoxyethyl)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-ethyl-N-(1,
1-dimethyl-2-phenoxyethyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-cyclohexyl-
N-(3-phenoxypropyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-(1-oxo-2-benzylaminoethyl)
-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ6-[1-oxo-2-(1-methyl-3-phenylpropyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1-oxo-2-(5-phenylpentyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1-oxo- 2-(2-methylbenzylaminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[4-(4-methylphenyl)butylamino]ethyl}- 3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1-oxo-2-(4-hydroxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Γ6-{1-oxo-2-[3-(2-hydroxyphenyl)propylamino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[2-(2-methoxyphenyl)ethylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Dehydrogenated product Γ6-{1-oxo-2-[3-(4-methoxyphenyl)propylamino]ethyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenation Γ6-{1-oxo-2-[6-(3-methoxyphenyl)hexamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Element Γ6-{1-oxo-2-[3-(2-chlorophenyl)propylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2- [2-(4-bromphenyl)ethylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ6-{1-oxo-2-[4-(4-fluorophenyl)butyl Amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(4-iodobenzyl)
Aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[5-(3-chlorophenyl)pentylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1-oxo-2-(2-nitrobenzylaminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-{1-oxo- 2-[1,1-dimethyl-2
-(4-nitrophenyl)ethyl]aminoethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[2-(2-aminophenyl)ethylamino]ethyl} -3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ6-{1-oxo-2-[2-methyl-3-(2
-aminophenyl)propylamino]ethyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Γ6-[1-oxo-2-(3-acetamidobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Element Γ6-{1-oxo-2-[6-(4-acetamidophenyl)hexylamino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(3-butylthiobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[3-(2-methylthiophenyl)propylamino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[1-(2-carboxyphenyl)ethylamino]ethyl}-3,4-
Dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[1-(2-ethoxycarbonylphenyl)ethylamino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ6-[1-oxo-2-(4-sulfamoylbenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-{1-oxo-2 -[3-(2-sulfamoylphenyl)propylamino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[3-(2-galbamoylphenyl)propylamino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[3-(N-ethylcarbamoyl)benzylamino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-(3-[4-(N,N-dimethylcarbamoyl)phenyl]propylamino)ethyl}-3,4-dihydrocarbo Styryl and its 3,4-position dehydrogenation product Γ6-{1-oxo-2-[2-(4-cyanophenyl))ethylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-{1-oxo-2-[5-(3-cyanophenyl)pentylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(2 ,3-methylenedioxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[3-(3,4-ethylenedioxyphenyl) ) propylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(2,2-diphenylethyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1-oxo-2-[2,4-dimethylbenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-[1 -oxo-2-(3,4,5-trimethylbenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ6-{1-oxo-2-[3-(2- Methyl-3
-propylphenyl)propylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[2-(3,4-dihydroxyphenyl)ethylamino ]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(3,4,5-trihydroxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Dehydrogenated product Γ6-[1-oxo-2-[2,4-dimethoxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ6-[1-oxo-2- (3,4,5-trimethoxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[2-(3,4-diethoxy phenyl)ethylamino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[1,1-dimethyl-2
-(3,4,5-trimethoxyphenyl)ethylamino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[5-(3, 4-dimethoxyphenyl)pentylamino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(3,4,5-trichlorobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Dehydrogenated product Γ6-[1-oxo-2-(2,4-dibromobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ6-{1-oxo-2- [2-(2,4-diiodophenyl)ethylamino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[5-(3,4-difluorophenyl)pentylamino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[2-(3,4-dinitrophenyl)ethylamino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ6-[1-oxo-2-(2,4,6-trinitrobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position Dehydrogenated product Γ6-[1-oxo-2-(3,4,5-triaminobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenated product Γ6-{1-oxo- 2-[4-(2,4-diacetamidophenyl)butylamino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ6-[1-oxo-2-(3,4-dimethylthiobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-{1-oxo- 2-[3-(3,4-dicarboxyphenyl)propylamino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ6-[1-oxo-2-(3,4-disulfamoylbenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6-{1- Oxo-2-[2,4-di(methylaminocarbonyl)benzylamino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenation product Γ6-[1-oxo-2-(3-methylaminocarbonyl-5-butylaminocarbonylbenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation product Γ6- [1-oxo-2-(3,4,5-tricyanobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-(2- Hydroxy-4-
nitrobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-[1-oxo-2-(2-nitro-3-methoxybenzyl)aminoethyl]-3,4- Dihydrocarbostyryl and its 3,4-position dehydrogenation Γ6-[1-oxo-2-(3-methyl-5-chlorobenzyl)aminoethyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenation Body Γ6-{1-oxo-2-[N-benzyl-N-
(2,2-diphenylethyl)amino]ethyl}
-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-benzyl-N-
(4-hydroxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ6-{1-oxo-2-[N-benzyl-N-
[6-(3-methoxyphenyl)hexyl]amino)ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-benzyl-N-
(3-chlorobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-benzyl-N-
(2,4-dimethoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate
-methylbenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(4
-hydroxybenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-ethyl-N-(2
-methoxybenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-(N-methyl-N-[3
-(4-methoxyphenyl)propyl]amino)
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-[6
-(3-methoxyphenyl)hexyl]amino)
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-ethyl-N-(4
-Brombenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-propyl-N-
(2-nitrobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-[2
-Methyl-3-(2-aminophenyl)propyl]amino)ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-( 3
-acetamidobenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(3
-butylbenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-(N-pentyl-N-
[1-(2-carboxyphenyl)ethyl]amino)ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-ethyl-N-( 3
-ethylaminocarbonylbenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(2,
3-methylenedioxy)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(3,
4,5-trimethoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(2,
4-dimethoxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenated Γ6-{1-oxo-2-[N-methyl-N-[2
-(3,4-diethoxyphenyl)ethyl]amino)ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-propyl-N-
[5-(3,4-dimethoxyphenyl)pentyl]amino)ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N −(2,
4-dibromobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(3,
4,5-triaminobenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(2
-hydroxy-4-nitrobenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-ethyl-N-(2
-nitro-3-methoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-[N-methyl-N-(3
-Methyl-5-chlorobenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ6-[1-oxo-2-methyl-2-(N-ethyl-N-cyclohexyl) amino)ethyl-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2-methyl-2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl}-3,4-dihydro Carbostyryl and its 3,4-dehydrogenated product Γ6-{1-oxo-2-ethyl-2-[N-ethyl-N-(3,4-dimethoxybenzyl)amino]ethyl}-3,4-dihydrocarbo Styryl and its 3,4-position dehydrogenate Γ6-{1-oxo-3-[N-methyl-N-(3,
4-methylenedioxybenzyl)amino]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-3-[N-propyl-N-
(4-chlorobenzyl)amino]propyl}-
3,4-dihydrocarbostyryl and its 3,
4-position dehydrogenate Γ6-{1-oxo-4-[N-methyl-N-(2
-nitrobenzyl)amino]butyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-6-[N-methyl-N-(4
-methoxybenzyl)amino]hexyl}-3,
4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ6-{1-oxo-2,2-dimethyl-3-[N
-Methyl-N-(3,4-methylenedioxybenzyl)amino]propyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenase Γ1-methyl-6-{1-oxo-2-ethyl −
2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ1-ethyl-6-{1-oxo-2-[ N-Methyl-N-(4-allylbenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenator Γ1-butyl-6-{1-oxo-2-methyl-
2-[N-methyl-N-(3,4-dimethoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ1-hexyl-6-{1-oxo-2 1-allyl-6-[1-oxo-2-(4-cyanobenzylamino)ethyl]-3,4-dihydro Carbostyryl and its 3,4-position dehydrogenate Γ1-vinyl-6-[1-oxo-2-methyl-
3-(N-methyl-N-benzylamino]propyl]-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ1-(2-propynyl)-6-[1-oxo-2
-Methyl-2-(4-butoxybenzylamino)
ethyl]-3,4-dihydrocarbostyryl and its 3,4-dehydrogenated product Γ1-(3-pentynyl)-6-(1-oxo-3
-ethylaminopropyl)-3,4-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ1-(2-hexynyl)-6-{1-oxo-2
-Methyl-2-[N-methyl-N-(3,4-dimethoxybenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ1-benzyl-6-[1-oxo-3-(N-methyl-N-ethylamino)propyl]-3,4
-dihydrocarbostyryl and its 3,4-position dehydrogenate Γ1-(3-phenylpropyl)-6-[1-oxo-2-(3,4-methylenedioxybenzylamino)ethyl]-3,4- Dihydrocarbostyryl and its 3,4-position dehydrogenate The compound represented by the above general formula (1) is produced, for example, by the method shown in the following reaction scheme. Reaction formula-1 [In the formula, X represents a halogen atom. ^R1 , ^R3 , ^R4 ,
A and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] That is, the compound of the present invention represented by general formula (1) is
The carbostyril derivative represented by the general formula (2),
It is produced by reacting an amine derivative represented by general formula (3). The above reaction is carried out without a solvent or in a common inert solvent at a temperature of room temperature to about 200°C, preferably room temperature to 100°C, for several hours to 24 hours.
It will be completed in about an hour. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol,
Lower alcohols such as isopropanol, polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetone, and acetonitrile can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include tertiary amines such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, and quinoline. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in equimolar amounts to the former. The excess amount is preferably from equimolar to 5 times the mole, more preferably from 1 to 1.2 times the mole. Further, when the compound represented by the general formula (3) is used as a solvent, it is usually preferable to use a large excess amount. The compound of general formula (2) used as a starting material in Reaction Scheme-1 includes known compounds and new compounds, and is produced, for example, by the method shown in Reaction Scheme-2 below. Reaction formula-2 [In the formula, X′ represents a halogen atom. R ¹ , A, X, and the carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] That is, the compound of general formula (2) is produced by reacting the known compound of general formula (4) with the known compound of general formula (5) or the known compound of general formula (6). Compound of general formula (4) and general formula (5) or general formula (6)
The reaction with the compound is generally called the Friedel-Crafts reaction, and this reaction is carried out in a solvent in the presence of a Lewis acid. As the solvent used in this case, those commonly used in this type of reaction are advantageously used, and examples thereof include carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, and tetrachloroethane. Furthermore, conventionally used Lewis acids are preferably used, 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 to be used may be determined appropriately, but it is usually about 2 to 6 times the mole, preferably about 3 to 4 times the mole of the compound of general formula (4). General formula (5)
The amount of the compound or the compound of general formula (6) to be used is:
The amount used is usually at least equimolar, preferably equimolar to twice the molar amount of the compound of general formula (4). The reaction temperature is selected appropriately, but is usually 20~
The temperature is preferably about 120°C, preferably about 40 to 70°C. The reaction time for this reaction varies depending on the raw materials, catalyst, reaction temperature, etc., and cannot be generalized, but it is usually 0.5~
The reaction completes in about 24 hours. Reaction formula-3 [In the formula, R ¹ , R ³ , R ⁴ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. R ⁶ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ] According to Reaction Scheme-3, the compound represented by the general formula (1a) can also be produced by subjecting the carbostyril derivative represented by the general formula (7) to the Mannitz reaction with paraformaldehyde and the amine (3). Obtainable. The reaction is carried out without or in the presence of a solvent. As a solvent, a wide range of solvents that are not involved in the reaction can be used.
Examples include water, lower alcohols such as methanol, ethanol, and isopropanol, and lower fatty acids such as acetic acid and propionic acid. The ratio of amine (3) and paraformaldehyde to be used is usually about 1 to 3 times the molar amount, preferably about 1 molar amount, relative to compound (7). good. The reaction temperature is usually about 0 to 150°C, preferably room temperature to about 100°C, and the reaction is usually carried out at about 3 to 150°C.
It will be finished in 6 hours. In addition, the compound of general formula (7) which is a raw material compound is represented by general formula (5) or general formula (6) in the reaction scheme-2.
Instead of the compound of general formula (8) or (9) below, under the same conditions, the compound of general formula (8) or (9) is added. [In the formula, R ¹ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] can be easily obtained by reacting with a compound represented by: R ⁶ -CH ₂ -COX (8) (R ⁶ -CH ₂ -CO) ₂ O (9) [wherein R ⁶ and X are the same as above. ] Among the compounds of the present invention represented by general formula (1), R ³
Alternatively, a compound in which R ⁴ represents a phenyl lower alkyl group having a nitro group as a substituent on the phenyl ring can be reduced to lead to a corresponding amino group-substituted compound. The reaction is, for example,
water, acetic acid, methanol, ethanol, ether,
Catalytic reduction is carried out in a solvent such as dioxane in the presence of a catalyst such as palladium black, palladium carbon, platinum oxide, platinum black, Raney nickel, etc., usually at room temperature and pressure, or by catalytic reduction with ordinary iron, zinc or tin, stannous chloride and an acid ( (e.g. formic acid, acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid, etc.), iron, ferrous sulfate, zinc or tin and alkalis (alkali such as alkali metal hydroxides, alkali metal carbonates, ammonia, etc.),
This is easily done with sulfides, sodium dithionite, sulfites, etc. Moreover, the obtained amino group-substituted product can be led to the corresponding lower alkanoylamino group-substituted product by subjecting it to an N-acylation reaction. The reaction is carried out without a solvent or in a solvent such as pyridine, benzene, nitrobenzene, ether, acetone, dioxane, etc., using an alkali metal carbonate such as sodium carbonate or potassium carbonate, triethylamine, N,N-dimethylaniline,
Basic compounds such as 1,5-diazabicyclo[5,4,0]undecene-5 (DBU), sulfuric acid, p-
In the presence of acidic compounds such as toluenesulfonic acid,
This is carried out by reacting the obtained amino group-substituted product with a lower alkanecarboxylic acid anhydride or its acid halide. The amount of the lower alkanecarboxylic acid anhydride or its acid halide to be used is usually an equimolar to an excess molar amount, preferably an equimolar to 10 times the molar amount relative to the amino group-substituted product. The acylation reaction is carried out under cooling, at room temperature, or under heating, but is usually carried out at -10
The reaction is preferably carried out at about 150°C, preferably 0 to 100°C, and the reaction is generally completed in about 10 minutes to 10 hours. Furthermore, compounds in which R ³ or R ⁴ represents a phenyl lower alkyl group having a cyano group as a substituent on the phenyl ring can be hydrolyzed to lead to the corresponding carbamoyl group-substituted product or carboxyl group-substituted product. I can do it. The reaction leading to the carboxyl group-substituted product is carried out without a solvent or in a suitable solvent such as water, methanol, ethanol, isopropanol, acetic acid, etc. by reacting with an acid or alkali. Examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and examples of the alkali include sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate. The acid or alkali is preferably used in an amount of at least equimolar or more, usually in large excess, relative to the raw material compound. The reaction temperature is room temperature to 150℃,
It is usually best to set the temperature to about 50 to 100℃, and generally 0.5 to 100℃.
The reaction completes in about 10 hours. Further, a carbamoyl group-substituted product can be obtained by reacting with an acid for about 0.5 to 3 hours under the same conditions. Further, the obtained carboxyl group-substituted product can be led to a carbamoyl group-substituted product that may have a corresponding lower alkyl group by an amide bond forming reaction. As the amide bond forming reaction, conditions for known amide bond forming reactions can be applied. For example, (a) mixed acid anhydride method, that is, a method in which a carboxyl group-substituted product is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with an amine;
(b) Active ester method, that is, a method in which the carboxyl group-substituted product is an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and this is reacted with an amine; c) Carbodiimide method, that is, a method in which a carboxyl group-substituted product is subjected to dehydration condensation with an amine in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) Carboxylic acid halide method, that is, a carboxyl group-substituted product is converted into a halide form. (v) Another method is to convert the carboxyl group-substituted product into a carboxylic acid anhydride using a dehydrating agent such as acetic anhydride,
Examples include a method of reacting this with an amine, and a method of reacting an ester of a carboxyl group-substituted product with, for example, a lower alcohol, with an amine under high pressure and high temperature. Among these, the mixed acid anhydride method and the carboxylic acid halide method are preferred. Examples of the alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. The mixed acid anhydride is obtained by the usual Schotten-Baumann reaction, and by reacting it with an amine without isolation, a carbamoyl group-substituted product which may have a reactive lower alkyl group is produced. The Schotten-Baumann reaction is usually carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, for example,
Triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4,3,0]nonene-
5(DBN), 1,5-diazabicyclo[5,4,
0] Undecene-5 (DBU), organic bases such as 1,4-diazabicyclo[2,2,2]octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. . The reaction is usually carried out at -20 to 100°C
The reaction time is approximately 5 minutes to 10 hours. The reaction between the obtained mixed acid anhydride and amine is carried out at about -20 to 150°C.
It is preferably carried out at 10 to 50°C for about 5 minutes to 10 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used as the solvent, and specifically, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, etc. can be mentioned. The proportions of the carboxyl group-substituted product, alkylhalocarboxylic acid, and amine used in this method are usually equimolar, but the ratio of the alkylhalocarboxylic acid and amine to the carboxyl group-substituted product is 1 to 1.
You may use 1.5 times the molar amount. In the carboxylic acid halide method, a carboxyl group-substituted product is reacted with a halogenating agent to form a carboxylic acid halide, and this carboxylic acid halide is isolated and purified, or is reacted with an amine to form a lower alkyl group without isolation and purification. Carbamoyl group substituents, which may have groups, are prepared. The reaction between the carboxyl group-substituted product and the halogenating agent is carried out without a solvent or in the presence of a solvent. Any solvent can be used as long as it does not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, dioxane, Examples include ethers such as tetrahydrofuran and diethyl ether, dimethylformamide, and dimethyl sulfoxide. The halogenating agent changes the hydroxyl group of a carboxyl group into a halogen. Common halogenating agents can be used, such as thionyl chloride, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, and the like. The ratio of the carboxyl group-substituted product to the halogenating agent is not particularly limited and is selected as appropriate, but when the reaction is carried out without a solvent, the latter is usually used in a large excess amount relative to the former, or in the solvent. When carrying out the reaction, the latter is usually used in at least an equimolar amount to the former, preferably 2
~4 times the molar amount is used. The reaction temperature (and reaction time) is not particularly limited, but is usually room temperature to
At about 100℃, preferably 50-80℃, for 30 minutes
It will take about 6 hours. The reaction between the carboxylic acid halide obtained as described above and the amine is carried out in the presence of a dehydrohalogenating agent. As this dehydrohalogenating agent, a basic compound is usually used, such as an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, sodium Methylate, alcoholate such as sodium ethylate, triethylamine, pyridine, N,N-
Dimethylaniline, N-methylmorpholine, 4-
Dimethylaminopyridine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), 1,5-
Diazabicyclo[5,4,0]undecene-5
(DBU), 1,4-diazabicyclo[2,2,2]
Examples include organic bases such as octane (DABCO). Note that an excess amount of the amine can also be used as a dehydrohalogenating agent. The reaction may be carried out without a solvent or in the presence of a solvent. All inert solvents that do not adversely affect the reaction can be used as solvents, such as chloroform, methylene chloride, halogenated hydrocarbons such as carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran, and dioxane, benzene, toluene, Examples include aromatic hydrocarbons such as xylene, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The usage ratio of carboxylic acid halide and amine is not particularly limited, but
When the reaction is carried out in a solvent, the latter is usually added in at least an equimolar amount to the former, preferably,
It is used in an equimolar to twice molar amount. The reaction temperature and reaction time are also not particularly limited, but are usually about -30 to 100°C, preferably 0 to 50°C for 30
It takes about 12 minutes to 12 hours. Among the compounds of general formula (1), compounds in which the carbon-carbon bond at the 3- and 4-positions of the carbostyril skeleton is a single bond, and compounds in which the carbon-carbon bond is a double bond may be treated by dehydrogenation reaction or selective They can be mutually converted by carrying out a hydrogenation reaction. The carbostyril derivative produced in this way is
It can be easily converted into an acid addition salt by the action of a pharmaceutically acceptable acid, and the present invention also includes this acid addition salt. Examples of acids in the above include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, and methanesulfonic acid. Organic acids such as acid and benzoic acid can be used. Further, among the compounds of the present invention, compounds in which the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are double bonds include, for example, bases such as metal hydroxides such as potassium hydroxide, sodium hydroxide, and calcium hydroxide. It can be easily converted into a salt by reacting with a chemical compound, and the present invention also includes this salt. The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( liquid agents, suspension agents, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. absorption enhancers such as grade ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite,
Examples include adsorbents such as colloidal silicic acid, purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, dissolution-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used.
For example, glucose, lactose, starch, cocoa butter,
Examples include excipients such as hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminalan agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples include polyoxyethylene sorbitan fatty acid esters. In this case, the cardiotonic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and the usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the therapeutic agent, if necessary. The amount of the compound of general formula (1) to be contained in the cardiotonic agent of the present invention is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight based on the total composition. be. There are no particular restrictions on the method of administering the cardiac inotrope of the present invention, and the administration may be carried out in accordance with various formulations, age, sex and other conditions of the patient, degree of disease, etc.
For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly, intradermally, or intradermally.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally. The dosage of the cardiotonic agent of the present invention depends on the usage, the age of the patient,
The amount of the compound of general formula (1), which is the active ingredient, is preferably about 0.1 to 10 mg per kg of body weight per day, although it is selected as appropriate depending on gender and other conditions, the degree of disease, etc. Further, it is preferable that the dosage unit form contains 1 to 200 mg of the active ingredient. The results of pharmacological tests on the compounds of the present invention are listed below. Pharmacological Test Adult male and female mixed breed dogs weighing 8 to 13 kg are anesthetized by intravenously administering pentobarbital sodium salt at a rate of 30 mg/kg. heparin sodium salt
After intravenous administration at a rate of 1000U/Kg, death was caused by exsanguination.
The heart is removed into locks fluid. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Next, the animals were anesthetized with pentobarbital sodium salt (30 mg/Kg, intravenous administration) and treated with heparin (1000 U/Kg,
Blood is introduced from the carotid artery of a male-male mixed-breed adult dog weighing 18 to 27 kg (intravenous administration) via a peristaltic pump to a cannula inserted into the right coronary artery to perfuse the right atrium. The perfusion pressure is a constant pressure of 100 mmHg.
The movement of the right atrium is measured by measuring the contractile force of the atrial node via a force displacement transducer under a resting tension of 2 g. Coronary blood flow is measured using an electromagnetic flowmeter. All records shall be recorded on an ink recorder. The details of this method are reported by Hiba et al. [Japan, J.
Pkarmacol, 25 , 433–439 (1975), Naunyn−
Schmiedbergs Arch.Pharmacol, 289 , 315~
325 (1975)]. The test compound is injected into the artery in a volume of 10-30μ via a rubber tube connected proximally to a cannula inserted into the right coronary artery. The positive inotropic effect of the test compound was determined using the following formula. Positive inotropic action (%) = B-A/A /min). The results are shown in Table 1. Test compound 1 6-[1-oxo-2-(N-methyl-N-benzylamino)ethyl]-3,4-dihydrocarbostyryl monohydrochloride 2 6-(1-oxo-2-benzylaminoethyl )-3,4-dihydrocarbostyryl monohydrochloride 3 6-(1-oxo-2-methylaminoethyl)
-3,4-dihydrocarbostyryl monohydrochloride 4 6-[1-oxo-2-methyl-2-(1-methyl-2-phenoxyethyl)aminoethyl]
-3,4-dihydrocarbostyryl monohydrochloride 5 6-(1-oxo-2-methyl-2-benzylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride 1/3 ethanol6 6- [1-oxo-2-methyl-2-(1,1
-dimethyl-2-phenylethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride 7 6-[1-oxo-2-methyl-2-(1,1
-dimethyl-2-phenoxyethyl)aminoethyl]-3,4-dihydrocarbostyryl 1
Hydrobromide 8 6-[1-oxo-2-(2-phenylethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride 9 6-{1-oxo-2-[N-methyl- N-
(2-phenylethyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 1/2
Hydrate 10 6-[1-oxo-2-(4-methoxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 11 6-{1-oxo-2-[ N-methyl-N-
(4-methoxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride
Quarter hydrate 12 6-[1-oxo-2-(3-phenylpropyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride 13 6-{1-oxo-2-[N -methyl-N-
(4-cyanobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 14 1-Methyl-6-(1-oxo-2-methyl-2-benzylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate 15 6 -[1-oxo-2-ethyl-2-(2-phenylethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 16 6-[1-oxo-2-(N- Methyl-N-benzylamino)ethyl]carbostyryl monohydrochloride 3/2 hydrate 17 6-{1-oxo-2-methyl-2-[N-methyl-N-(4-methoxybenzyl)amino ]
ethyl}-3,4-dihydrocarbostyryl
Monohydrochloride 1/2 hydrate 18 6-{1-oxo-2-ethyl-2-[N-methyl-N-(4-methoxybenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl
Monohydrochloride/monohydrate 19 1-Methyl-6-{1-oxo-2-methyl-2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl}-3,4-dihydrocarbo Styryl monohydrobromide 20 6-[1-oxo-2-(N-cyclohexyl-N-benzylamino)ethyl]-3,4-dihydrocarbostyryl monohydrochloride 1/4 hydrate 21 6-{1-oxo-3-[N-methyl-N-
(4-motoxybenzyl)amino]propyl}-
3,4-dihydrocarbostyryl monohydrochloride
Quarter hydrate22 6-{1-oxo-2-[N-methyl-N-
(2-nitrobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride23 6-{1-oxo-2-[N-methyl-N-
(4-nitrobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride24 6-{1-oxo-2-[N-methyl-N-
(2-chlorobenzyl}amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride25 6-{1-oxo-2-[N-methyl-N-
(3,4-methylenedioxybenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl
1 hydrochloride 26 6-[1-oxo-2-(N-ethyl-N-benzylamino)ethyl]-3,4-dihydrocarbostyryl 27 6-[1-oxo-2-(N-isopropyl-
N-benzylamino)ethyl]-3,4-dihydrocarbostyryl28 6-{1-oxo-2-methyl-2-[N-benzylamino)ethyl]-3,3-diphenylpropyl
Amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride29 6-{1-oxo-2-ethyl-2-[N-methyl-N-(4-methoxybenzyl)amino]
Ethyl}carbostyryl monohydrochloride 1/4 hydrate 30 6-{1-oxo-2-[N-methyl-N-
(4-chlorobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 31 6-{1-oxo-2-methyl-2-[N-methyl-N-(4-methoxybenzyl)amino]
Ethyl}carbostyryl monohydrochloride 1/2 hydrate32 6-{1-oxo-2-[N-methyl-N-
(2-methoxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride33 6-{1-oxo-2-[N-methyl-N-
(3-methoxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride 34 6-[1-oxo-2-(4-sulfamoylbenzylamino)ethyl]-3,4-dihydrocarbostyryl monohydrochloride 35 6-[1- Oxo-2-(4-methylbenzylamino)ethyl]carbostyril monohydrochloride 36 6-[1-oxo-2-(4-chlorobenzylamino)ethyl]carbostyryl monohydrochloride
Quarter hydrate 37 6-{1-oxo-2-[N-methyl-N-
(4-aminobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl dihydrochloride monohydrate38 6-{1-oxo-2-[N-methyl-N-
(4-methoxybenzyl)amino]ethyl}carbostyryl monohydrochloride 5/4 hydrate 39 6-{1-oxo-2-[N-methyl-N-
(3,4,5-trimethoxybenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl
Monohydrochloride/monohydrate 40 6-{1-oxo-2-[N-methyl-N-
(3-nitrobenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 41 6-{1-oxo-2-[N-methyl-N-
(4-hydroxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride
Hemihydrate 42 6-{1-oxo-2-[N-methyl-N-
(4-methylbenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 43 6-{1-oxo-2-[N-methyl-N-
(3,4-dimethoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride44 6-{1-oxo-2-[N-methyl-N-
(2-nitro-3-methoxybenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl
1-hydrochloride 45 6-{1-oxo-2-[N-methyl-N-
(4-acetamidobenzyl)amino]ethyl}
-3,4-dihydrocarbostyryl monohydrochloride dihydrate 46 6-{1-oxo-4-[N-methyl-N-4
-methoxybenzyl)amino]butyl}-3,
4-dihydrocarbostyryl monohydrochloride 47 1-allyl-6-(1-oxo-2-butylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride 48 1-(2-propynyl)-6- (1-oxo-
2-Methylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride 49 1-benzyl-6-(1-oxo-2-butylaminoethyl)-3,4-dihydrocarbostyryl 50 6-{1- Oxo-2-[N-methyl-N-
(2-hydroxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride
Quarter hydrate 51 6-{1-oxo-2-[N-methyl-N-
(4-methylthiobenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride52 6-{1-oxo-2-[N-methyl-N-
(4-carboxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride
Quarter hydrate 53 6-{1-oxo-2-(N-methyl-N-
[4-(N,N-diethylcarbamoyl)benzyl]amino)ethyl}-3,4-dihydrocarbostyryl monohydrochloride54 6-{1-oxo-2-[N-methyl-N-
(4-ethoxycarbonylbenzyl)amino]
ethyl}-3,4-dihydrocarbostyryl
1-hydrochloride55 6-{1-oxo-2-[N-methyl-N-
(4-carbamoylbenzyl)amino]ethyl}
-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate 56 6-{1-oxo-2-methyl-3-[N-methyl-N-(4-methoxybenzyl)amino]
Propyl}-3,4-dihydrocarbostyryl monofumaric acid 1/2 hydrate 57 1-Methyl-6-(1-oxo-2-allylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloric acid Salt control compound 58 6-(1-oxo-2-methyl-2-isopropylaminoethyl)-8-chloro-3,4-
Dihydrocarbostyril monohydrochloride (Unexamined Japanese Patent Publication No. 1983)
-16478 Example 2) 59 8-Hydroxy-5-[α-(2-cyanoethylamino)propionyl]carbostyryl hydrochloride monohydrate (Production Example 5 of JP-A-53-112883) 60 8-Hydroxy- 5-(2-hydroxy-1,
1-dimethylethylaminoacetyl) carbostyryl hydrobromide (JP-A-53-112883 Production Example 2) 61 8-Hydroxy-5-[α-(2-chloroethylamino)propionyl] carbostyril hydrobromide ( JP-A-53-112883 Production Example 6) 62 8-Hydroxy-5-allylaminoacetylcarbostyryl hydrochloride (JP-A-53-112883 Production Example 17) 63 Amrinone

【table】

【table】

[Table] Acute toxicity test The test compound was orally administered to male rats, and the acute toxicity (LD ₅₀ , mg/Kg) was determined.

[Table] Reference examples, examples, and formulation examples are listed below. Reference Example 1 120 ml of γ-chlorobutyric acid chloride and 160 g of crushed anhydrous aluminum chloride were suspended in 300 ml of carbon disulfide, and a solution of 29.4 g of 3,4-dihydrocarbostyryl suspended in 100 ml of carbon disulfide was heated under reflux. After the dropwise addition took some time, the mixture was heated under reflux for 4 hours. The reaction solution was poured into ice water, the precipitate was collected, washed with water and ether, and then recrystallized from acetone to give yellow needle-like crystals of 6-(4-chloro-1-oxobutyl)-.
25.5 g of 3,4-dihydrocarbostyryl are obtained. Melting point: 158-160°C Reference Example 2 The following compound was obtained in the same manner as in Reference Example 1. Γ6-(1-oxo-2-bromopropyl)-3,
4-Dihydrocarbostyryl Pale yellow scaly crystals Melting point 192-193℃ (ethanol) Γ6-(1-oxo-2-chloroethyl)-3,4
-dihydrocarbostyryl Colorless needle crystals Melting point 230-231℃ (ethanol) Γ6-(1-oxo-2-chloroethyl)carbostyril Pale green needle crystals (ethanol) Melting point 275-277℃ Γ1-methyl-6-(1 -oxo-3-chloropropyl)-3,4-dihydrocarbostyryl Colorless needles (isopropanol) Melting point 121-123℃ Γ6-(1-oxo-2-brombutyl)carbostyryl Colorless needles (methanol) Melting point 227 ~228℃ (decomposed) Γ6-(1-oxo-2-bromopropyl) carbostyril Pale yellow needles (ethanol) Melting point 238-240℃ Γ6-(1-oxo-2-chloropropyl)-3,
4-dihydrocarbostyryl Colorless needle crystals (ethanol) Melting point 160-162℃ Γ6-(1-oxo-2-brombutyl)-3,4
-Dihydrocarbostyryl Colorless needle crystals (chloroform) Melting point 181-184℃ Γ1-methyl-6-(1-oxo-2-bromopropyl)-3,4-dihydrocarbostyryl Colorless granular crystals (ligroin) Melting point 84-86 °C Γ6-(1-oxo-3-bromopropyl)-3,
4-dihydrocarbostyryl Colorless granular crystals (chloroform-hexane) Melting point 158-160℃ Γ6-(1-oxo-3-chloropropyl)-3,
4-dihydrocarbostyryl Colorless granular crystals (chloroform-petroleum ether) Melting point 168-170°C Reference example 3 55 g of aluminum chloride and 25 g of propionyl chloride were dissolved in 30 ml of carbon disulfide, and 20 g of 3,4-dihydrocarbostyryl was dissolved under stirring under reflux. Add little by little. After addition, stir under reflux for 2 hours. After cooling, the reaction solution was poured into ice-water, and the precipitated crystals were collected and washed with water. Recrystallization from methanol yields 20 g of 6-propionyl-3,4-dihydrocarbostyryl. Melting point 175-177℃ Pale yellow prismatic crystals Example 1 6-chloroacetyl-3,4-dihydrocarbostyryl 5g, triethylamine 6.79g, N-methyl-4-hydroxybenzylamine monohydrochloride
4.66 g and 50 ml of acetonitrile were stirred at room temperature overnight, and after the reaction was completed, the mixture was stirred and cooled with ice water, and the precipitated crystals were collected. Dissolve the crystals in methanol and add concentrated hydrochloric acid.
Adjust the pH to approximately 1 and concentrate the solution to dryness. Add water to the residue to crystallize it and collect. This was recrystallized from water to give 6-{1-oxo-2-[N-methyl-N-(4
-hydroxybenzyl)amino]ethyl}-3,
4.13 g of 4-dihydrocarbostyryl monohydrochloride 1/2 hydrate was obtained. Colorless powdery crystals Melting point 169.0-171.0 (decomposed) Example 2 10 g of 1-allyl-6-chloroacetyl-3,4-dihydrocarbostyryl and 50 g of n-butylamine
ml and stirred at room temperature for 2 hours to react. Then, the reaction solution is concentrated, 200 ml of 5% hydrochloric acid is added, and the mixture is washed with chloroform. Add 0.5N aqueous sodium hydroxide solution to the aqueous layer to make it alkaline and extract with chloroform. After washing the extract with water and distilling off the chloroform, it is made acidic by adding hydrochloric acid and concentrated. The residue was recrystallized from ethanol to obtain 8.2 g of 1-allyl-6-(1-oxo-2-butylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride as colorless powder crystals. Elemental analysis value (as C ₁₈ H ₂₄ O ₂ N ₂・HCl) C H N Calculated value (%) 64.18 7.48 8.32 Analysis value (%) 64.01 7.62 8.10 Example 3 1-(2-propynyl)-6-chloroacetyl −
40 ml of 40% methylamine solution is added to 11.7 g of 3,4-dihydrocarbostyryl and the mixture is stirred at room temperature for 1 hour. Approximately 1/3 of the resulting reaction mixture
Concentrate to volume and adjust the pH to approximately 1 by adding hydrochloric acid. The precipitated crystals were collected and recrystallized from ethanol to obtain colorless powdery crystals of 1-(2-propynyl).
-6-(1-oxo-2-methylaminoethyl)-
3,4-dihydrocarbostyryl monohydrochloride 10g
get. Elemental analysis value (as C ₁₅ H ₁₆ O ₂ N ₂・HCl) C H N Calculated value (%) 61.54 5.85 9.57 Analysis value (%) 61.40 6.05 9.38 Example 4 1-Benzyl-6-chloroacetyl-3,4 −
14g of dihydrocarbostyril and n-butylamine
Add 50 ml and stir the mixture for 1 hour at room temperature.
The resulting reaction mixture is externally cooled on ice and the precipitated crystals are collected. This was recrystallized from chloroform-n-hexane to form colorless powdery crystals of 1-benzyl-6.
-(1-oxo-2-butylaminoethyl)-3,
6.7 g of 4-dihydrocarbostyryl are obtained. Elemental analysis value (as C ₂₂ H ₂₆ O ₂ N ₂ ) C H N Calculated value (%) 75.40 7.48 7.99 Analysis value (%) 75.45 7.44 8.02 Example 5 1-Methyl-6-chloroacetyl-3,4-dihydro 5g of carbostyril and 40ml of acetonitrile
Add 10 ml of arylamine and react at room temperature for 3 hours. The reaction solution was concentrated to dryness, the residue was dissolved in acetone, and concentrated hydrochloric acid was added to adjust the pH to 1. The precipitated crystals were collected and recrystallized from methanol-ether to give colorless powder crystals of 1-methyl-6-(1-oxo-2-arylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride. Obtained 1.87g. mp 173-175.5℃ (decomposed) Elemental analysis value (as C ₁₅ H ₁₈ O ₂ N ₂・HCl) C H N Calculated value (%) 61.14 6.50 9.50 Analysis value (%) 61.40 6.52 9.68 Example 6 Example 1 and Similarly, the following compounds are obtained. Γ6-(1-oxo-2-methyl-2-methylaminoethyl)carbostyryl monohydrochloride Colorless powder crystal (ethanol) Melting point 300-301℃ (decomposed) Γ6-(1-oxo-2-ethyl-2 -Methylaminoethyl) carbostyril monohydrochloride 1/4
Hydrate Colorless powder crystal (ethanol) Melting point 297-298℃ (decomposed) Γ6-(1-oxo-2-ethyl-2-isopropylaminoethyl) carbostyryl monohydrochloride monohydrate Colorless powder crystal (Isopropanol-water) Melting point 293-294℃ (decomposed) Γ6-(1-oxo-2isopropylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride Colorless flocculent crystals (ethanol-ether) Melting point 237-238 °C (decomposition) Γ6-(1-oxo-2-methyl-2-isopropylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol-ether) Melting point 265-267 °C (decomposition) Γ6-[1-oxo-2-ethyl-2-(tert-butylamino)ethyl]-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystal (ethanol-ether) Melting point 280-281℃ Γ6-( 1-oxo-2-ethyl-2-ethylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol-ether) Melting point 265-268°C (decomposition) Γ6-(1-oxo- 2-Ethyl-2-isopropylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride Pale yellow powder crystals (isopropanol-acetone) Melting point 297-298°C (decomposed) Γ6-[1-oxo-2-ethyl -2-(2-phenylethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless needle crystals (ethanol) Melting point 162-164℃ Γ6-(1-oxo-2-butyl aminoethyl)-
3,4-dihydrocarbostyryl Pale yellow needle crystals (methanol) Melting point 133-135℃ Γ6-(1-oxo-2-methylaminoethyl)-
3,4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (ethanol) Melting point 272-274℃ (decomposed) Γ6-[1-oxo-2-(tert-butyl)aminoethyl]-3,4-dihydrocarbo Styril・
Monohydrochloride Colorless amorphous crystal (isopropanol) Melting point 233-239℃ (decomposed) Γ6-[1-oxo-2-methyl-2-(1-methyl-2-phenoxyethyl)aminoethyl]-
3,4-dihydrocarbostyryl monohydrochloride Colorless amorphous crystal (ethanol) Melting point 238-240℃ (decomposed) Γ[1-oxo-2-methyl-2-(1-methyl-3-phenylpropyl)amino ethyl]-3,
4-dihydrocarbostyryl monohydrochloride Colorless amorphous crystal (methanol-ethyl acetate) Melting point 231.5-233℃ (decomposed) Γ6-(1-oxo-2-methyl-2-butylaminoethyl)-3,4-dihydro Carbostyryl monohydrochloride Colorless amorphous crystal (ethanol) Melting point 249-252℃ (decomposition) Γ6-{1-oxo-2-methyl-2-[N-benzyl-N-(3,3-diphenylpropyl) Amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride Pale yellow powder crystals (ethanol-chloroform-petroleum ether) Melting point 262-267℃ (decomposed) Γ6-[1-oxo-2-methyl-2- (1-phenylethyl)aminoethyl]-3,4-dihydrocarbostyryl Colorless prismatic crystals (chloroform-petroleum ether) Melting point 137.5-139.5℃ Γ1-methyl-6-[1-oxo-2-methyl-
2-(1-Methyl-2-phenoxyethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (ethanol) Melting point 205-209℃ Γ6-(1-oxo-2-methyl-2 -benzylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride 1/3 ethanol Colorless amorphous crystals (ethanol) Melting point 256-259℃ (decomposed) Γ6-[1-oxo-2-methyl-2- (1,1-
Dimethyl-2-phenylethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol) Melting point 281.5-282.5℃ Γ1-Methyl-6-[1-oxo-2-methyl-
2-(1,1-dimethyl-2-phenoxyethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrobromide Colorless powder crystal (ethanol) Melting point 193-196℃ Γ6-[1-oxo- 2-methyl-2-(1,1-
Dimethyl-2-phenoxyethyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrobromide Pale yellow powdery crystals Melting point 272-274℃ (Water) Γ6-[1-oxo-2-(N-methyl) -N-benzylamino)ethyl]-3,4-dihydrocarbostyryl monohydrochloride Colorless amorphous crystals (ethanol-petroleum ether) Melting point 239-241.5°C (decomposition) Γ6-(1-oxo-2-benzylaminoethyl ]
-3,4-dihydrocarbostyryl monohydrochloride Colorless amorphous crystal (ethanol-n-hexane) Melting point 238.5-242℃ (decomposed) Γ6-[1-oxo-2-(2-phenylethyl)
Aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (methanol-ether) Melting point 249.4-251.6°C (decomposed) Γ6-[1-oxo-2-(N-methyl-N-benzylamino) ) Ethyl] carbostyryl monohydrochloride 11/2 hydrate Pale yellow needle crystals (methanol-ether) Melting point 216.5-218.3℃ (decomposed) Γ6-{1-oxo-2-[N-methyl-N- (4
-methoxybenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 1/4
Hydrate Colorless needle crystals (water-acetone) Melting point 225.3-226.1℃ (decomposition) Γ6-[1-oxo-2-(3-phenylpropyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloric acid Salt Pale yellow powder crystal (water) Melting point 251.8-253℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N-(4
-cyanobenzyl)amino]ethyl}-3,4
-Dihydrocarbostyryl monohydrochloride 1/2 hydrate Colorless granular crystals (water-acetone) Melting point 234.4-235.5℃ Γ6-{1-oxo-2-(N-methyl-N-(2
-phenylethyl)amino]ethyl}-3,4
-Dihydrocarbostyryl monohydrochloride 1/2 hydrate Colorless powder crystal (ethanol) Melting point 160-162℃ (decomposed) Γ1-Methyl-6-(1-oxo-2-methyl-
2-Benzylaminoethyl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless powder crystals (water) Melting point 226.5-227.7°C (decomposition) Γ6-[1-oxo-2-(N- cyclohexyl
N-benzylamino)ethyl]-3,4-dihydrocarbostyryl monohydrochloride quarter hydrate Pale yellow powder crystals (ethanol) Melting point 224-226℃ Γ6-[1-oxo-2-(4 -Methoxybenzyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate Colorless powder crystal (water) Melting point 236-239℃ (decomposed) Γ6-{1-oxo-2-methyl- 2-[N-methyl-N-(4-methoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl 1
Hydrochloride / hemihydrate Colorless needle crystals (water-acetone) Melting point 202-205℃ (decomposition) Γ6-{1-oxo-2-ethyl-2-[N-methyl-N-(4-methoxy) benzyl)amino]ethyl}-3,4-dihydrocarbostyryl 1
Hydrochloride monohydrate Colorless granular crystals (ethanol) Melting point 164.5-167℃ Γ1-methyl-6-{1-oxo-2-methyl-
2-[N-Methyl-N-(4-methoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrobromide Colorless granular crystals (methanol-ether) Melting point 223-226°C (decomposed) Γ6-{1-oxo-2-[N-methyl-N-(2
-nitrobenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl monohydrochloride Pale yellow granular crystals (water-acetone) Melting point 227-230℃ (decomposed) Γ6-{1-oxo-2-ethyl-2-[N-methyl-N-(4-methoxybenzyl) )Amino]ethyl}carbostyryl monohydrochloride 1/4 hydrate Colorless powder crystals (ethanol) Melting point 203-205℃ (decomposed) Γ6-{1-oxo-2-(N-methyl-N-( 4
-nitrobenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl monohydrochloride Pale yellow granular crystals (methanol-1N-hydrochloride) Melting point 233-236℃ (decomposed) Γ6-{1-oxo-2-[N-methyl-N-(2
-chlorobenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl monohydrochloride Pale yellow granular crystals (water) Melting point 228-231℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N-(3,
4-Methylenedioxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (methanol-ether) Melting point 238-241℃ (decomposed) Γ6-{1-oxo-2-[ N-methyl-N-(4
-chlorobenzyl)amino]ethyl}-3,4
-Dihydrocarbostyryl monohydrochloride Colorless granular crystals (water) Melting point 238-240℃ Γ6-{1-oxo-2-methyl-2-[2-(3,
4-dimethoxyphenyl)ethylamino]ethyl}-3,4-dihydrocarbostyryl 1/2 fumaric acid 1/2 hydrate Colorless powder crystal (water-acetone) Melting point 135.5-138℃ (decomposition) Γ6 -{1-oxo-2-[N-methyl-N-(4
-Methoxybenzyl)amino]ethyl}carbostyryl monohydrochloride 5/4 hydrate Colorless powder crystals (methanol-ether) Melting point 215-218℃ (decomposition) Γ6-{1-oxo-2-[N- Methyl-N-(4
-methylbenzyl)amino]ethyl}-3,4
-Dihydrocarbostyryl monohydrochloride Colorless powder crystals (methanol) Melting point 246.5-248℃ (decomposition) Γ6-[1-oxo-2-(N-ethyl-N-benzylamino)ethyl]-3,4-dihydro Carbostyril Colorless needle crystals (methanol) Melting point 110.5-113℃ Γ6-[1-oxo-2-(N-isopropyl-N
-benzylamino)ethyl]-3,4-dihydrocarbostyryl Colorless needle crystals (methanol) Melting point 120-122℃ Γ6-{1-oxo-3-[N-methyl-N-(4
-methoxybenzyl)amino]propyl}-3,
4-dihydrocarbostyryl monohydrochloride 1/4
Hydrate Colorless granular crystals (methanol) Melting point 183.5-185℃ Γ6-{1-oxo-2-[N-methyl-N-(2
-methoxybenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (water-acetone) Melting point 228-230℃ (decomposed) Γ6-{1-oxo-2-[N-methyl-N-(3
-methoxybenzyl)amino]ethyl}-3,
4-Dihydrocarbostyryl monohydrochloride Pale yellow powder crystal (water) Melting point 226-228.5℃ (decomposed) Γ6-[1-oxo-2-(4-chlorobenzyl)
Aminoethyl carbostyril 1 hydrochloride 1/
Tetrahydrate Colorless flocculent crystals (water) Melting point 275.0-278.0℃ (decomposition) Γ6-[1-oxo-2-(4-methylbenzyl)
Aminoethyl] carbostyril monohydrochloride Colorless needle crystals (methanol) Melting point 282.0-284.0℃ (decomposed) Γ6-{1-oxo-2-methyl-2-[N-methyl-N-(4-methoxybenzyl) Amino]ethyl}carbostyryl monohydrochloride 1/2 hydrate Pale yellow granular crystals (ethanol-water) Melting point 224-226℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N- (3,
4-dimethoxybenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol) Melting point 210-212℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N-(3,
4,5-trimethoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride monohydrate Pale yellow granular crystals (water) Melting point 222-224℃ (decomposed) Γ6-{1-oxo -2-[N-methyl-N-(2
-hydroxybenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 1/4
Hydrate Colorless needle crystals (water) Melting point 169-171℃ Γ6-{1-oxo-2-[N-methyl-N-(2
-nitro-3-methoxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl 1
Hydrochloride Pale yellow needle crystals (water-methanol) Melting point 238-240.5℃ Γ6-{1-oxo-2-[N-methyl-N-(3
-nitrobenzyl)amino]ethyl}-3,4
-dihydrocarbostyryl monohydrochloride Pale yellow powder crystal (water-acetone) Melting point 237-239℃ (decomposed) Γ6-{1-oxo-2-[N-methyl-N-(4
-aminobenzyl)amino]ethyl}-3,4
-Dihydrocarbostyryl dihydrochloride monohydrate Colorless powder crystals (water-acetone) Melting point 190.5-193.5℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N-(4
-acetamidobenzyl)amino]ethyl}-
3,4-dihydrocarbostyryl monohydrochloride
Dihydrate Colorless powder crystal (water) Melting point 158.5-159.5℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N-(4
-methylthiobenzyl)amino]ethyl}-3,
4-Dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol-ether) Melting point 231-232℃ (decomposition) Γ6-{1-oxo-2-[N-methyl-N-(4
-carboxybenzyl)amino]ethyl}-3,
4-dihydrocarbostyryl monohydrochloride 1/4
Hydrate Colorless needle crystals (water) Melting point 264-266.5℃ (decomposition) Γ6-{1-oxo-2-(N-methyl-N-[4
-(N,N-diethylcarbamoyl)benzyl]
Amino)ethyl}-3,4-dihydrocarbostyryl monohydrochloride Colorless powder crystals (ethanol) Melting point 238.5-240.5℃ (decomposed) Γ6-[1-oxo-2-(4-sulfamoylbenzyl)aminoethyl ]-3,4-dihydrocarbostyryl monohydrochloride Colorless flocculent crystals (methanol) Melting point 271-273.5℃ Γ6-{1-oxo-4-[N-methyl-N-(4
-methoxybenzyl)amino]butyl}-3,
4-dihydrocarbostyryl monohydrochloride Colorless needle crystals (ethanol) Melting point 225-227℃ Γ6-{1-oxo-2-methyl-3-[N-methyl-N-(4-methoxybenzyl)amino]propyl }-3,4-dihydrocarbostyryl
1-fumaric acid 1/2 hydrate Colorless powder crystal (methanol-ether) Melting point 132.5-134℃ (decomposed) Γ6-[1-oxo-2-[N-methyl-N-(4
-Ethoxycarbonylbenzyl)aminoethyl]-3,4-dihydrocarbostyryl monohydrochloride Colorless flocculent crystals (ethanol) Melting point 233.5-235.5℃ (decomposed) Γ6-[1-oxo-2-[N-methyl-N -(4
-carbamoylbenzyl)aminoethyl]-3,
4-dihydrocarbostyryl monohydrochloride 1/2
Hydrate Colorless powder crystal (methanol) Melting point 240-242°C (decomposition) Example 7 6-propionyl-3,4-dihydrocarbostyryl 5 g, paraformaldehyde 4.5 g and N-methyl-methoxybenzylamine monohydrochloride
Add 5.5 g to 20 ml of glacial acetic acid and stir at 100°C for 7 hours. After the reaction, acetic acid was distilled off and chloroform-
After extraction with 0.5N sodium hydroxide solution, washing with water, and drying (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure. The residue was purified using a column (CHCl ₃ -MeOH), converted into a fumarate salt, and recrystallized from methanol-ether to give 6-{1
-oxy-2-methyl-3-[N-methyl-N-
(4-methoxybenzyl)amino]propyl}-
350 mg of 3,4-dihydrocarbostyryl monofumarate 1/2 hydrate is obtained. Colorless powdery crystals Melting point: 132.5-134°C (decomposed) Example 8 The following compound was obtained in the same manner as in Example 7. Γ6-{1-oxo-3-[N-methyl-N-(4
-methoxybenzyl)amino]propyl}-3,
4-dihydrocarbostyryl monohydrochloride 1/4
Hydrate Colorless granular crystals (methanol) Melting point 183.5-185°C Example 9 5.15 g of stannous chloride dihydrate (90% content) was dissolved in 10 ml of concentrated hydrochloric acid and 6-{1-oxo-2-[ N-
2 g of methyl-N-(4-nitrobenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride was added and stirred at room temperature for 2 hours. Add water and chloroform, and add 10N aqueous sodium hydroxide solution while stirring to bring the pH to about 9. The chloroform layer is separated, washed with water, dried, and concentrated to dryness. Dissolve this in methanol, add concentrated hydrochloric acid to bring the pH to about 1, and concentrate to dryness. Acetone-isopropanol is added to the residue to crystallize it. This was recrystallized from water-acetone to give 6-{1-oxo-2-[N-methyl-N-(4-aminobenzyl)amino]ethyl}-3,4-dihydrocarbostyryl dihydrochloride 1 1.41 g of hydrate is obtained. Colorless powdery crystals Melting point 190.5-193.5°C (decomposed) Example 10 3 g of 6-{1-oxo-2-[N-methyl-N-(aminobenzyl)amino]ethyl}-3,4-dihydrocarbostyryl and anhydrous Stir 20 ml of acetic acid at room temperature for 7 hours and calculate the amount of precipitate. This is suspended in methanol, concentrated hydrochloric acid is added to adjust the pH to about 2, and the solution is concentrated to dryness. Add acetone to the residue to crystallize it and collect. This was recrystallized from water and 6-
{1-oxo-2-[N-methyl-N-(4-acetamidobenzyl)amino]ethyl}-3,4-
Dihydrocarbostyril monohydrochloride dihydrate
Obtain 3.2g. Colorless powder crystal Melting point 158.5-159.5℃ (decomposed) Example 11 6-{1-oxo-2-[N-methyl-N-(4
-cyanobenzyl)amino]ethyl}-3,4-
Dihydrocarbostyril monohydrochloride 1/2 hydrate
Heat and stir 3.8 g and 30 ml of concentrated hydrochloric acid at 50°C for 2.5 hours. The reaction solution is concentrated to dryness, and methanol is added to crystallize it. This was recrystallized from methanol to obtain colorless powdery crystals of 6-{1-oxo-2-[N-methyl-N-(4-carbamoylbenzyl)amino].
ethyl}-3,4-dihydrocarbostyryl 1
Obtain 3.14 g of hydrochloride 1/2 hydrate. Melting point 240-242℃ (decomposition) Example 12 6-{1-oxo-2-[N-methyl-N-(4
7.35 g of -ethoxycarbonylbenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride, 50 ml of concentrated hydrochloric acid, and 50 ml of water were stirred at 100°C for 2 hours, and the reaction solution was cooled with ice water to remove the precipitated crystals. do.
This was recrystallized from water to form colorless needle crystals of 6-{1-
5.56 g of oxo-2-[N-methyl-N-(4-carboxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl monohydrochloride 1/4 hydrate
obtain. Melting point 264-266.5℃ (decomposition) Example 13 6-{1-oxo-2-[N-methyl-N-(4
-carboxybenzyl)amino]ethyl}-3,
Suspend 3 g of 4-dihydrocarbostyryl monohydrochloride 1/4 hydrate in 50 ml of dimethylformamide,
Add 1.95 g of triethylamine. Add 1.16 g of isobutyl chloroformate under ice-water cooling and stir at the same temperature for 1 hour. Add 650 mg of dimethylamine under ice-water cooling, and react at room temperature for 3 hours. The reaction solution was concentrated to dryness, chloroform and a 1N aqueous sodium hydroxide solution were added to the residue for extraction, and the chloroform layer was washed with water, dried, and then evaporated. Dissolve the residue in acetone and add concentrated hydrochloric acid.
Adjust the pH to approximately 2 and collect the precipitated crystals. This was recrystallized from ethanol to obtain colorless powdery crystals of 6-{1-oxo-2-[N-methyl-N-[4-(N,N-diethylcarbamoyl)benzyl]amino)ethyl}.
-3,4-dihydrocarbostyryl monohydrochloride
Obtain 1.2g. Melting point 238.8-240.5℃ (decomposition) Formulation example 1 6-{1-oxo-2-[N-methyl-N-(4-
methoxybenzyl)amino]ethyl}-3,4-
Dihydrocarbostyryl monohydrochloride 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation example 2 6-{1-oxo-2-methylaminoethyl)-
3,4-dihydrocarbostyryl monohydrochloride 10 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above composition were prepared in a conventional manner. Formulation example 3 6-{1-oxo-2-[N-methyl-N-(3,
4-Methylenedioxybenzyl)amino]ethyl}-3,4-dihydrocarbostyryl 500mg Polyethylene glycol (molecular weight: 4000) 0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 1000mg The above parabens, sodium metabisulfite and sodium chloride are dissolved in the above distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilization using a suitable filter paper, and then dispensed into ampoules in 1 ml portions to prepare an injection.

Claims (1)

[Claims] 1. General formula [In the formula, ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl lower alkyl group. R ³ and R ⁴ are hydrogen atoms, lower alkyl groups, lower alkenyl groups, cycloalkyl groups, phenoxy lower alkyl groups, or lower alkyl groups, hydroxyl groups, lower alkoxy groups on the phenyl ring,
A group selected from the group consisting of a halogen atom, a nitro group, an amino group, a lower alkanoylamino group, a lower alkylthio group, a carboxyl group, a lower alkoxycarbonyl group, a sulfamoyl group, a carbamoyl group that may have a lower alkyl group, and a cyano group. represents a phenyl lower alkyl group which may have 1 to 3 or a lower alkylenedioxy group as a substituent. A represents a lower alkylene group. The carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton represents a single bond or a double bond. ] A cardiotonic agent characterized by containing a carbostyril derivative or a salt thereof as an active ingredient.