JPH01117865A - Carbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H, phenylcarbonyl which may have 1-3 substituents selected from lower alkanoyl, furoyl, pyridylcarbonyl, lower alkansulfonyl, lower alkoxycarbonyl, or lower alkoxy or a lower alkylene- dioxy; R<2> is H, lower alkoxy; the bond between carbon atoms. between the 3 and 4 positions in the carbostyril skeleton] and its salts. EXAMPLE:6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbosty ril. USE:For example, heat muscle contraction enhancer (positively inotropic agent) which is used as a heart stimulant for treating cardiopathy such as congestive heart failure, with scarce increase of the pulse rate, and coronary blood flow increaser. PREPARATION:The cyclization of a compound of formula II (R<3> is H, lower alkanoyl; R<4> is H, lower alkyl; formula III is single or double bond) gives the compound of formula I.

Description

[Detailed description of the invention] Industrial applications The present invention relates to carbostyril derivatives.

DISCLOSURE OF THE INVENTION The carbostyril derivative of the present invention has the general formula [wherein R1 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, a phenyl group] It represents 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 have a lower alkyl group as a substituent on the ring. A lower alkoxy group, a halogen atom,
1 group selected from the group consisting of a lower alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group;
It may have ~3 or a lower alkylenedioxy group as a substituent. R2 represents a hydrogen atom or a lower alkoxy group. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ].

The carbostyryl derivative represented by the above general formula (1) and its salt are novel compounds that have not been described in any literature. This compound has the effect of increasing myocardial contraction (positive inotropy) and the effect of increasing coronary flow, and is characterized by not increasing heart rate or increasing the rate only to a small degree, such as congestion. It is an important compound as a cardiotonic agent for the treatment of heart diseases such as heart failure.

More specifically, the multiple groups shown in this specification are as follows.

Examples of lower alkyl groups include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl groups.

Examples of lower alkenyl groups include linear or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl groups. can.

Examples of lower alkynyl groups include straight chain or branched carbon atoms having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, and 2-hexynyl groups. Examples include alkynyl groups such as

Phenyl lower alkyl groups include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1.1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2 Examples include phenylalkyl groups in which the alkyl moiety is a linear or branched alkyl group having 1 to 6 carbon atoms, such as -methyl-3-phenylpropyl group.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups.
Examples include straight chain or branched alkoxy groups of 6.

Examples of lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,
Examples include straight chain or branched alkanoyl groups having 1 to 6 carbon atoms such as tert-butylcarbonyl and hexanoyl groups.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

Examples of the lower alkylenedioxy group include linear or branched alkylenedioxy groups having 1 to 4 carbon atoms, such as methylenedioxy, ethylenedioxy, and trimethylenedioxy.

A group selected from the group consisting of a lower alkoxy group, a halogen atom, a lower alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group as a substituent on the phenyl ring. Examples of the phenylcarbonyl group having 1 to 3 or a lower alkylenedioxy group include 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, 2-chlorobenzoyl,
-fluorobenzoyl, 3-fluorobenzoyl, 4-
Fluorobenzoyl, 2-brombenzoyl, 3-brombenzoino-14-brombenzoyl, 2-iodobenzoyl, 4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,4-dichlorobenzoyl Chlorobenzoyl, 3゜4-difluorobenzoyl, 3,
5-dibromobenzoyl, 3,4.5-)dichlorobenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-ethylbenzoyl, 3-
Ethylbenzoyl, 4-ethylbenzoyl, 3-isopropylbenzoyl, 4-hexylbenzoyl, 3,4-
Dimethylbenzoyl, 2,5-dimethylbenzoyl, 3
, 4.5-) dimethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxy Benzoyl, 3,4-dimethoxybenzoyl, 3,4-jethoxybenzoyl, 3.
4.5-trimethoxybenzoyl, 2.5-dimethoxybenzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, 2.4-dinitrobenzoyl, 2-aminobenzoyl, 3-aminobenzoyl,
4-aminobenzoyl, 2,4-diaminobenzoyl,
2-cyanobenzoyl, 3-cyanobenzoyl, 4-cyanobenzoyl, 2,4-dicyanobenzoyl, 3,4
-methylenedioxybenzoyl, 3゜4-ethylenedioxybenzoyl, 2.3-methylenedioxybenzoyl, 3-methyl-4-chlorobenzoyl, 2-chloro-6
-Methylbenzoyl, 2-methoxy-3-chlorobenzoyl, 2-hydroxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, 3,4-dihydroxybenzoyl, 3,4.5-)dihydroxybenzoyl, 2-formylaminobenzoyl , °3-acetylaminobenzoyl, 4-acetylaminobenzoyl, 2-
Acetylaminobenzoyl, 3-propionylaminobenzoyl, 4-butyrylaminobenzoyl, 2-isobutyrylaminobenzoyl, 3-pentanoylaminobenzoyl, 3-tert-butylcarbonylaminobenzoyl, 4-hexanoylaminobenzoyl, 2. 6-Diacetylaminobenzoyl, 2-methylthiobenzoyl, 3-methylthiobenzoyl, 4-methylthiobenzoyl, 2-ethylthiobenzoyl, 3-ethylthiobenzoyl, 4-ethylthiobenzoyl, 3-isopropylthiobenzoyl, 4-hexylthio Benzoyl, 3.4-
Dimethylthiobenzoyl, 2,5. -dimethylthiobenzoyl, 3゜4.5-)dimethylthiobenzoyl, 2-
Formyloxybenzoyl, 3-acetyloxybenzoyl, 4-acetyloxybenzoyl, 2-acetyloxybenzoyl, 3-propionyloxybenzoyl,
4-butyryloxybenzoyl, 2-isobutyryloxybenzoyl, 3-pentanoyloxybenzoyl, 3
- A substituent having 1 to 6 carbon atoms on the phenyl ring such as tert-butyryloxybenzoyl, 4-hexanoyloxybenzoyl, 3,4-diacetyloxybenzoyl, 3゜4.5-)lyacetyloxybenzoyl group, etc. Straight chain or branched alkoxy group, halogen atom, carbon number 1-
6 straight chain or branched alkyl group, cyano group, nitro group, amino group, hydroxyl group, straight chain or branched alkanoylamino group having 1 to 6 carbon atoms, straight chain or branched chain having 1 to 6 carbon atoms 1 to 3 groups selected from the group consisting of branched alkylthio groups and linear or branched alkanoyloxy groups having 1 to 6 carbon atoms;
An example thereof is a phenylcarbonyl group having an alkylene dioxy group having 1 to 4 carbon atoms.

Examples of lower alkanesulfonyl groups include straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, tert-butanesulfonyl, pentanesulfonyl, and hexanesulfonyl groups. An example is a sulfonyl group having a group.

Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, ter
Examples include carbonyl groups having a straight chain or branched alkoxy group having 1 to 6 carbon atoms, such as t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups.

Lower alkoxycarbonyl lower alkyl groups include methoxycarbonylmethyl, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, 6-propoxycarbonylhexyl, 5-isopropoxycarbonylpentyl, 1,1-dimethy; L/-2- Butoxycarbonylethyl, 2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl,
Examples include alkoxycarbonylalkyl groups in which the alkoxy moiety has 1 to 6 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, such as a hexyloxycarbonylmethyl group.

Examples of the phenylsulfonyl group that may have a lower alkyl group as a substituent on the phenyl ring include phenylsulfonyl, p-toluenesulfonyl, 2-methylphenylsulfonyl, 3-ethylphenylsulfonyl, 4-propylphenylsulfonyl, 2-butyl. Phenylsulfonyl which may have a straight chain or branched alkyl group having 1 to 6 carbon atoms as a substituent, such as phenylsulfonyl, 3-tert-butylphenylsulfonyl, 4-pentylphenylsulfonyl, 2-hexylphenylsulfonyl group, etc. Examples include groups.

A group selected from the group consisting of a lower alkoxy group, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group as a substituent on the phenyl ring. Examples of the phenyl lower alkyl group having 1 to 3 or lower alkylenedioxy groups include 2-chlorobenzyl, 2-(3-chlorophenyl)ethyl, 1-(4-chlorophenyl)ethyl, 3-(2-fluoro phenyl)
Propyl, 4-(3-fluorophenyl)butyl, 1
, 1-dimethyl-2-(4-fluorophenyl)ethyl, 5-(2-bromphenyl)pentyl, 6-(3
-bromphenyl)hexyl, 2-methyl-3-(4-
Bromphenyl)propyl, 3-iodobenzyl, 2-
(4-iodophenyl)ethyl, 1-(3,5-dichlorophenyl)ethyl, 2-(3,4-dichlorophenyl)ethyl, 3-(2,6-dichlorophenyl)propyl, 4-( 3,4-dichlorophenyl)butyl, 1
゜1-dimethyl-2-(3,4-difluorophenyl)
Ethyl, 5-(3,5-dibromphenyl)pentyl, 6-(3,4,5-)dichlorophenyl)hexyl, 4-methylbenzyl, 2-(2-methylphenyl)
Ethyl, 1-(3-methylphenyl)ethyl, 3-(
3-ethylphenyl)propyl, 4-(2-ethylphenyl)butyl, 5-(4-ethylphenyl)pentyl, 6-(3-isopropylphenyl)hexyl, 2-
Methyl-3-(4-hexylphenyl)propyl, 2-
(3゜4-dimethylphenyl)ethyl, 2- (2,
5-dimethylphenyl)ethyl, 2-(3,4,・5
-trimethylphenyl)ethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4.5-trimethoxybenzyl, 1-(3-methoxyphenyl)ethyl,
2-(2-methoxyphenyl)ethyl, 3-(2-
ethoxyphenyl)propyl, 4-(4-ethoxyphenyl)butyl, 5-(3-ethoxyphenyl)pentyl, 6-(4-isopropoxyphenyl)hexyl, 1,
1-dimethyl-2-(4-hexyloxyphenyl)ethyl, 2-methyl-3-(3,4-jethoxyphenyl)propyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3, 4-jethoxyphenyl)ethyl,
2-(3,4,5-1rimethoxyphenyl)ethyl,
1-(2,5-dimethoxyphenyl)ethyl, 3-nitrobenzyl, 1-(2-nitrophenyl/l/)ethyl, 2-(4-nitrophenyl)ethyl, 3-(2,
4-dinitrophenyl)propyl, 4-(2-aminophenyl)butyl, 5-(3-aminophenyl)pentyl, 6-(4-aminophenyl)hexyl, (2,4-
diamino)benzyl, 2-cyanobenzyl, 1,1-dimethyl-2-(3-cyanophenyl)ethyl, 2-methyl-3-(4-cyanophenyl)propyl, 2゜4-dicyanobenzyl, 3,4- methylenedioxybenzyl,
3.4-ethylenedioxybenzyl, 2.3-methylenedioxybenzyl, 2-(3゜4-methylenedioxyphenyl)ethyl, 1-(3,4-ethylenedioxyphenyl)ethyl, 3-methyl- 4-chlorobenzyl, 2
-chloro-6-methylbenzyl, 2-methoxy-3-chlorobenzyl, 2-hydroxybenzyl, 2- (3゜4-dihydroxyphenyl)ethyl, 1- (3゜4-
dihydroxyphenyl)ethyl, 2-(3-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 6-(3,4-hydroxyphenyl)hexyl, 31.4-dihydroxybenzyl, 3,4.5-
) dihydroxybenzyl, 2-formylaminobenzyl, 3-acetylaminobenzyl, 3-(2-acetylaminophenyl)propyl, 4-(4-acetylaminophenyl)butyl, 2-propionylaminobenzyl,
3-(3-butyrylaminophenyl)propyl, 4-(
4-isobutyrylaminophenyl)butyl, 5(2-t
ert-butylcarbonylaminophenyl)pentyl,
6-(3-pentanoylaminophenyl)hexyl,
(2,4-Diacetylamino)benzyl, 4-methylthiobenzyl, 2-(2-methylthiophenyl)ethyl, 1-(,3-methylthiophenyl)ethyl, 3-(
3-Ethylthiophenyl)propyl, 4-(2-ethylthiophenyl)butyl, 5-(4-ethylthiophenyl°)pentyl, 6-(3-isopropylthiophenyl)hexyl, 2-minor 3-(4 -hexylthiophenyl)propyl, 2-(3,4-dimethylthiophenyl)ethyl, 2-(2,5-dimethylthiophenyl)
ethyl, 2-(3,4,5-)dimethoxyphenyl)
Ethyl, 4-acetyloxybenzyl, 3,4-acetyloxybenzyl, 3,4゜5-triacetyloxybenzyl, 1-(3-acetyloxyphenyl)ethyl,
2-(2-acetyloxyphenyl)ethyl, 3-
(2-propionyloxyphenyl)propyl, 4-(
4-Pentanoyloxyphenyl)butyl, 5-(3
-propionyloxyphenyl)pentyl, 6-(4-
A straight chain with 1 to 6 carbon atoms as a substituent on the phenyl ring such as isobutyryloxyphenyl)hexyl, 1,1-dimethyl-2-(4-hexanoyloxyphenyl)ethyl, and 3-butyryloxybenzyl group. or a branched alkoxy group, a straight chain or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a straight chain or branched chain having 1 to 6 carbon atoms. alkanoylamino group,
1 to 3 groups selected from the group consisting of a straight chain or branched alkylthio group having 1 to 6 carbon atoms and a straight chain or branched alkanoyloxy group having 1 to 6 carbon atoms, or 1 to 4 carbon atoms Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms and having a phenyl group that may have a straight-chain or branched alkylenedioxy group.

Examples of lower alkanoylamino groups include formylamino,
Acetylamino, propionylamino, butyrylamino, isobutyrylamino, pentanoylamino, tert
Examples include straight-chain or branched alkanoylamino groups having 1 to 6 carbon atoms, such as -butylcarbonylamino and hexanoylamino groups.

Lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, te
Examples include straight-chain or branched alkylthio groups having 1 to 6 carbon atoms such as rt-butylthio, pentylthio, and hexylthio groups.

Examples of lower alkanoyl oxide groups include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, ter
Examples include straight chain or branched alkanoyloxy groups having 1 to 6 carbon atoms such as t-butylcarbonyloxy and hexanoyloxy groups.

Examples of phenyl lower alkanoyl groups include 2-phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 2-phenylbutyryl, 6-phenylhexanoyl, 2-phenylpropionyl, 3-phenylbutyryl, 4-phenyl- Examples include straight-chain or branched alkanoyl groups in which the alkanoyl moiety has 1 to 6 carbon atoms, such as 3-methylbutyryl, 5-phenylpentanoyl, and 2-methyl-3-phenylpropionyl groups.

A group selected from the group consisting of a lower alkoxy group, a lower alkyl group, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group as a substituent on the phenyl ring. The phenyl lower alkanoyl group having 1 to 3 or a lower alkylenedioxy group is 2- (2-
Chlorphenyl)acetyl, 2-(3-chlorophenyl)acetyl, 2-(4-chlorophenyl)acetyl, 3
-(2-fluorophenyl)propionyl, 4-(3-
fluorophenyl)butyryl, 2-(4-fluorophenyl)acetyl, 5-(2-bromphenyl)pentanoyl, 6-(3-bromphenyl)hexanoyl,
2-Methyl-3-(4-'bromphenyl)propanoyl, 2-(3-iodophenyl)acetyl, 2-(4
-iodophenyl)acetyl, 2- (3,5-dichlorophenyl)acetyl, 2- (3,4-dichlorophenyl)acetyl, 3-(2,6-dichlorophenylpionyl), 4- (3. 4-dichlorophenyl)butyryl,
2-(3,4-difluorophenyl)acelyl, 5-
(3,5-dibromphenyl)pentanoyl, 6-
(3.4.5-)dichlorophenyl)hexanoyl, 2
- (4-methylphenyl)acetyl, 2- (2-methylphenyl)acetyl, 2-(3-methylphenyl)
Acetyl, 3-(3-ethylphenyl)propionyl,
4-(2-ethylphenyl)butyryl, 5-(4-ethylphenyl)pentanoyl, 6-(3-isopropylphenyl)hexanoyl, 2-methyl-3-(4-hexylphenyl)propionyl, 2-(3.4 -dimethylphenyl)acetyl, 2-(2.5-dimethylphegol)acetyl, 2-(3, 4.5-trimethylphenyl)acetyl, 2-(4-methoxyphenyl)
Acetyl, 2-(3,4-dimethoxyphenyl)acetyl, 2-(3,4,5-trimethoxyphenyl)acetyl, 2-(3-methoxyphenyl)acetyl, 2-
(2-methoxyphenyl)acetyl, 3-(2-ethoxyphenyl)propionyl, 4-(4-ethoxyphenyl)butyryl, 5-(3-ethoxyphenyl)pentanoyl, 6-(4-isopropoxyphenyl)hexanoyl, 2 - (4-hexyloxyphenyl)acetyl, 2-methyl-3-(3,4-dimethoxyphenyl)propionyl, 2-(3,4-dimethoxyphenyl)acetyl, 2-(3,4-jethoxyphenyl) Acetyl, 2. (3,4,5-trimethoxyphenyl)acetyl, 2- (2,5-dimethoxyphenyl)acetyl, 2- (3-nitrophenyl)acetyl, 2- (
2-nitrophenyl)acetyl, 2-(4-nitrophenyl)acetyl, 3-(2,4-dinitrophenyl)
propionyl, 4-(2-aminophenyl)butyryl,
5-(3-aminophenyl)pentanoyl, 6-' (
4-aminophenyl)hexanoyl, (2,4-diamino)phenylacetyl, 2-cyanophenylacetyl,
2-(3-cyanophenyl)acetyl, 2-methyl-
3-(4-cyanophenyl)propionyl, 2-(2,
4-dicyanophenyl)acetyl, 2-(3,4-methyledidioxyphenyl)acetyl, 2-(3,4-
Ethylenedioxyphenyl)acetyl, 2,3-methylenedioxyphenylacetyl, 2-(3,4-methylenedioxyphenyl)acetyl, 2-(3,4-ethylenedioxyphenyl)acetyl, 2- (3- Methyl-
4-chlorophenyl)acetyl, 2-(2-chloro-
6-methylphenyl)acetyl, 2-(2-methoxy-
3-chlorophenyl)acetyl, 2-(2-hydroxyphenyl)acetyl, 2-(3,4-dihydroxyphenyl)acetyl, 2-(3-hydroxyphenyl)acetyl, 3-(4-hydroxyphenyl)propionyl,
6-(3,4-dihydroxyphenyl)hexanoyl,
2-(3,4,5-)dihydroxyphenyl)acetyl, 2-(2-formylaminophenyl)acetyl, 2
-(3-acetylaminophenyl)acetyl, 3-(2
-acetylaminophenyl)propionyl, 4-(4-
acetylaminophenyl)butyryl, 2-(2-propionylaminophenyl)acetyl, 3-(3-butyrylaminophenyl)propionyl, 4-(4-isobutyrylaminophenyl)butyryl, 5-(2-ter
t-butylcarbonylaminophenyl)pentanoyl,
6-(3-pentanoylaminophenyl)hexanoyl, 2-(2,4-diacetylaminophenyl)acetyl, 2-(4-methylthiophenyl)acetyl, 2-
(2-Methylthiophenyl)acetyl, 2-(3-methylthiophenyl)acetyl, 3-(3-ethylthiophenyl)propionyl, 4-(2-ethylthiophenyl)
Butyryl, 5-(4-ethylthiophenyl)pentanoyl, 6-(3-isopropylthiophenyl)hexanoyl, 2-methyl-3-(4-hexylthiophenyl)propionyl, 2-(3,4-dimethylthiophenyl) ) Acetyl, 2-(2,5-dimethylthiophenyl)acetyl, 2-(3,4,5-trimethoxyphenyl)acetyl, 2-(4-acetyloxyphenyl)
Acetyl, 2-(3,4-acetyloxyphenyl)acetyl, 2-(3,4,5-triacetyloxyphenyl)acetyl, 2-(3-acetyloxyphenyl)
Acetyl, 2-(2-acetyloxyphenyl)acetyl, 3-(2-propionyloxyphenyl)propionyl, 4-(4-pentanoyloxyphenyl)butyryl, 5-(3-propionyloxyphenyl)pentanoyl, 6-( A substituent having 1 to 6 carbon atoms on the phenyl ring such as 4-isobutyryloxyphenyl)hexanoyl, 2-(4-hexanoyloxyphenyl)acetyl, 2-(4-butyryloxyphenyl)acetyl group, etc. Straight chain or branched alkoxy group, straight chain or branched alkyl group having 1 to 6 carbon atoms, halogen atom, nitro group, cyano group, amino group, hydroxyl group, straight chain or branched chain having 1 to 6 carbon atoms 1 to 3 groups selected from the group consisting of a branched alkanoylamino group, a straight chain or branched alkylthio group having 1 to 6 carbon atoms, and a straight chain or branched alkanoyloxy group having 1 to 6 carbon atoms;
having a phenyl group which may have a linear or branched alkylene dioxy group having 1 to 4 carbon atoms or 1 to 4 carbon atoms
-6 linear or branched alkanoyl groups can be exemplified.

The compound of the present invention has the general formula, for example, where R1 and R2 are the same as above. R3 represents a hydrogen atom or a lower alkanoyl group. R4 represents a hydrogen atom or a lower alkyl group. - indicates a double bond or double bond. ]
It is produced by subjecting a carboxylic acid derivative represented by to a cyclization reaction.

General formula (2) used as a starting material in the present invention
The compound is produced, for example, by the method shown in the reaction formula below.

[In the formula or represents a halogen atom.] R5 and R5/ represent a lower alkyl group. R5 and R5/ may be bonded to each other together with the oxygen atom to which they are bonded to form a lower alkylenedioxy group. R4/ represents a lower alkyl group. R3/ represents a lower alkanoyl group. R1, R2,
R4 and = are the same as above. ] The nitration of the compound of general formula (3) is carried out under the usual nitration reaction conditions for aromatic compounds, for example, using a nitration agent without a solvent or in a suitable inert solvent. Examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of nitrating agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum, phosphoric acid, or acetic anhydride and nitric acid), potassium nitrate, sodium nitrate, etc. Examples include alkali metal nitrates and sulfuric acid. The amount of the above-mentioned nitrating agent used may be at least equimolar to the starting compound, usually in excess, and the reaction is preferably carried out at 0° C. to around room temperature for 1 to 4 hours.

An aceta of the aldehyde group of the compound of general formula (4).

The -formation reaction is carried out by reacting the acetalizing agent with an acid in a suitable solvent. The solvent used here may be any solvent as long as it does not affect the reaction, such as aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol and ethanol, dimethylformamide, dimethyl Examples include sulfoxide. As the acetalizing agent, for example, alcohols such as methanol, ethanol, isopropanol, and ethylene glycol, and orthoesters such as ethyl orthoformate are used. Examples of acids include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as para-toluenesulfonic acid.

The amount of the acetalizing agent used is based on general formula (4)
When using orthoesters for the compound,
It is best to use at least an equimolar amount, preferably 1 to 1.5 times the molar amount, and when using alcohols, at least 2 times the molar amount.
It is best to use twice the molar amount, usually in large excess. The reaction temperature is usually 0 to 50°C, preferably around room temperature.
The reaction is completed in about minutes to 5 hours.

The reaction between the compound of general formula (5) and the piperazine derivative of general formula (6) can be carried out in the presence of a solvent. Examples of solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and ethers such as dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, and diethyl ether. Class, N
-Methylpyrrolidone, dimethylformamide (DMF)
, dimethyl sulfoxide (DMSO), and hexamethyl phosphoric triamide.

The above reaction may be carried out more advantageously using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, natramamide, sodium hydride, tertiary amines such as triethylamine and tripropylamine, pyridine, quinolin, and the like. General formula (
The amount of piperazine derivative used in 6) is based on general formula (5).
) is used in an amount of usually 1 to 10 times the molar amount, preferably 3 to 7 times the molar amount of the compound. The reaction temperature is usually 50
The temperature is preferably 150°C to 150°C, preferably 50 to 100°C, and the reaction is generally completed in about 1.5 to 10 hours.

The hydrolysis reaction of the compound of general formula (7) is carried out in the presence of a mineral acid such as hydrochloric acid or sulfuric acid in an alcohol such as methanol, ethanol, or impropatol at a reaction temperature of room temperature to the boiling point temperature of the solvent. This is carried out by reacting for 30 minutes to 3 hours.

The reaction between the compound of general formula (8) and malonic acid (9) is carried out in a suitable solvent in the presence of a basic compound. As the solvent used, all the solvents used in the reaction between the compounds (5) and (6) can be used, and in addition, polar solvents such as pyridine can also be used. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, tertiary amines such as triethylamine, triethylamine, and piperidine, pyridine, and quinoline. Compound of general formula (8) and malonic acid (9)
The usage ratio of - to the compound of general formula (8) is:
It is preferable to use at least an equimolar amount, usually 2 to 7 times the molar amount. The reaction is usually carried out at 0 to 200°C, preferably 70 to 150°C.
The reaction is completed in about 1 to 10 hours.

The esterification reaction of the compound of general formula (10) can be carried out, for example, in alcohols such as methyl alcohol, ethyl alcohol, and isopropyl alcohol, in acids such as hydrochloric acid and sulfuric acid, or in thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, etc. The reaction is carried out in the presence of a halogenating agent, usually at a temperature of 0 to 150°C, preferably 50 to 100°C, for about 1 to 10 hours.

The amount of acid to be used is usually 1 to 1.2 times the molar amount of the compound of general formula (10), and the amount of halogenating agent to be used is at least 1 to 1.2 times the molar amount of the compound of general formula (10). It is preferable to use an equimolar amount, preferably 1 to 5 times the molar amount.

The reaction of reducing the compound of general formula (10) or (11) to obtain the compound of general formula (2a) includes, for example, (1) reduction using a catalytic reduction catalyst in an appropriate solvent, or (2) reduction using a suitable inert catalyst. The reduction is carried out by using a mixture of a metal or a metal salt and an acid or a metal or a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc. as a reducing agent in a solvent. When using the catalytic reduction described in (2), the solvents used include, for example, water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether. esters such as ethyl acetate and methyl acetate, and aprotic polar solvents such as N,N-dimethylformamide. Examples of the catalytic reduction catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite,
Raney nickel or the like is used. The Ω used for the catalyst is 0.0 for the compound of general formula (10) or (11).
It is better to have 2 to 1.00 times the mold weight. The reaction is usually -2
The reaction is carried out at a temperature of 0 DEG C. to around room temperature, preferably 0 DEG C. to around room temperature, and a hydrogen pressure of 1 to 10 atm, and the reaction takes about 0.5 to 10 hours.

In addition, when using the method (■), iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide such as sodium hydroxide, sulfide Sulfides such as ammonium, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride are used as reducing agents.

Examples of the inert solvent used include water, acetic acid, methanol, ethanol, and dioxane. The conditions for the above-mentioned reduction reaction may be appropriately selected depending on the reducing agent used. For example, when stannous chloride and hydrochloric acid are used as reducing agents, the conditions are preferably 0° C. to around room temperature, 0.5 to 10° C.
It is best to do a time window for about an hour. The amount of the reducing agent to be used is at least equimolar, usually equimolar to 5 times the molar amount of the raw material compound. In addition, in the method of ■5
When the reaction is carried out at around 0 to 150°C, compound (2a)
The compound of general formula (1) can be directly obtained through the following steps.

Acylation of the compound of general formula (2a) is carried out using a suitable acylating agent. Examples of the acylating agent include lower alkanoic acids such as acetic acid, lower alkanoic anhydrides such as acetic anhydride, and lower alkanoic acid halides such as acetyl chloride. When a lower alkanoic anhydride or a lower alkanoic acid halide is used as the acylating agent, the acylation reaction is carried out in the presence of a basic compound. Examples of the basic compounds used include alkali metals such as sodium metal and potassium metal, hydroxides, carbonates, and bicarbonates of these alkali metals, and aromatic amine compounds such as pyridine and piperidine.

Although the reaction proceeds either without a solvent or in a solvent, it is usually carried out using an appropriate solvent.

Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, and water. The acylating agent is used in equimolar to large excess relative to the raw material compound, but generally 5 to 10
It is better to use twice the molar amount. The reaction proceeds at a temperature of 0 to 150°C, but is generally preferably carried out at a temperature of 0 to 80°C. Furthermore, when using a lower alkanoic acid as an acylating agent, it is preferable to add a mineral acid such as sulfuric acid or hydrochloric acid or a sulfonic acid such as para-toluenesulfonic acid, benzenesulfonic acid or ethanesulfonic acid as a dehydrating agent to the reaction system. is 50-12
The acylation reaction proceeds advantageously by maintaining the reaction temperature at 0°C.

In producing the compound of the present invention, the compound of general formula (2) obtained above is cyclized. This cyclization is carried out in a suitable solvent in the presence or absence of a basic compound or acid, preferably an acid.

A wide range of known basic compounds can be used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4,3,Ocononene-5(
DBN), 1,5-diazabicyclo[5,4,OF Launssen-5 (DBU), 1,4-diazabicyclo[
Examples include organic bases such as octane (DABCO), and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium hydrogen carbonate, and sodium hydrogen carbonate. It will be done. Examples of acids include hydrochloric acid, sulfuric acid, hydrobromic acid,
Examples include inorganic acids such as nitric acid and polyphosphoric acid, and organic acids such as p-toluenesulfonic acid, ethanesulfonic acid and trifluoroacetic acid.

Any solvent can be used as long as it does not affect the reaction, such as alcohols such as methanol, ethanol, propatool, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, etc. Examples include pyridine and acetone. Halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, and diphenyl ether, and esters such as methyl acetate and ethyl acetate. ,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide, or mixed solvents thereof. The reaction is usually carried out at -20 to 150°C, preferably 0 to 150°C, and is generally completed in 5 minutes to 30 hours.

The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid.

Examples of chain acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, and benzoic acid. .

Further, among the carbostyril derivatives represented by the general formula (1) of the present invention, a compound having an acidic group can be easily formed into a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, and the like.

The carbostyryl derivative represented by the general formula (1) can be easily isolated and purified from the reaction mixture by conventional isolation means such as filtration, recrystallization, column chromatography, preparative thin layer chromatography, etc.

Example Reference examples and examples are listed below.

Reference Example 1 29.3 n of concentrated nitric acid was added to 500 g of concentrated sulfuric acid under external water cooling and stirring.
was added dropwise, and then 50 g of m-chlorobenzaldehyde was added dropwise.
The mixture was added dropwise at a temperature below 0.degree. C., and after stirring at room temperature for 1 hour, the reaction mixture was poured into water, and the precipitated solid was collected. After washing the precipitated solid with water, it is dissolved in methylene chloride, and the methylene chloride layer is washed with a dilute aqueous sodium hydroxide solution, and after further washing with water, it is dried over sodium sulfate, and the solvent is distilled off. 62.3 g of 2-nitro-5-chlorobenzaldehyde are obtained.

m965-69°C Reference Example 2 100 g of 2-nitro-5-chlorobenzaldehyde is dissolved in 1000 m2 of toluene. Next, 10 g of p-toluenesulfonic acid and 87.8 g of ethyl orthoformate were added,
Stir for 1 hour at room temperature.

The mixture was neutralized with a dilute aqueous sodium hydroxide solution, and the toluene layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 138 g of 2-nitro-5-chlorobenzaldehyde ethyl acetal in the form of an oil.

, Reference Example 3 138 g of 2-nitro-5-chlorobenzaldehyde diethyl acetal was dissolved in DMF 750111f2,
Add 250 g of anhydrous piperazine and stir at 80° C. for 4 hours. Excess piperazine and DMF are distilled off under reduced pressure, and a dilute aqueous sodium hydroxide solution is added to the residue, which is dissolved and extracted with methylene chloride. After washing the methylene chloride layer with water and drying with sodium sulfate, the solvent was distilled off. Add 850 g of isopropyl alcohol to the residue and dissolve. Add concentrated HCJ 65Tnf2 and heat to reflux for 1 hour. After cooling, the precipitated crystals are separated.

93 g of 2-nitro-5-piperazinylbenzaldehyde hydrochloride are obtained.

mp 195-201°C Reference Example 4 47 g of 2-nitro-5-piperazinylbenzaldehyde hydrochloride is dissolved in pyridine 500, 5 g piperidine and malonic acid 100 are added, and the mixture is heated under reflux for 5 hours. After cooling, the precipitated crystals are counted. Add 1,000 g of methanol to the crushed crystals and heat under reflux for 1 hour. Remove after cooling. 2 of 42g
-Ditro 5=piperazinylcinnamic acid is obtained.

m9229-237°C Reference Example 5 10 g of 2-nitro-5-piperazinylcinnamic acid is suspended in 100 w2 of ethyl alcohol, and 3 ml of thionyl chloride is added dropwise under external water cooling and stirring. Heat to reflux for 3 hours. Ethyl alcohol and thionyl chloride are distilled off, isopropanol is added to the residue, dissolved by heating, and cooled.

Count the number of yellow crystals that precipitate. 4.3 g of 2-nitro-5-piperazinyl cinnamic acid ethyl ester hydrochloride are obtained.

m p 210-220°C Reference Example 6 5 g of 2-nitro-5-piperazinylbenzaldehyde was suspended in 50 DMF, 6 wQ of triethylamine was added, and 4.4 g of 3,4-dimethoxybenzoyl chloride was suspended in DMF while stirring with external water cooling. Add the solution dissolved in 20 ml dropwise. Stir at room temperature for 2 hours, then pour into saturated brine. After extraction with methylene chloride and washing the methylene chloride layer with water,
Dry with anhydrous sodium sulfate. The solvent is distilled off, methyl alcohol is added, and the mixture is heated and then cooled. Recrystallized in DMF to obtain 4.5 g of 2-nitro-5-[4-(3,
Yellow crystals of 4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde are obtained.

m p 196-198°C Reference Example 7 4 g of 2-nitro-5-[4·=(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde was added with 20 g of pyridine and dissolved, and 2.1 g of malonic acid was added. , 0.4 mf2 of piperidine was added, and the mixture was stirred at 80°C for 4 hours. Pyridine and piperidine are concentrated, poured into dilute aqueous hydrochloric acid solution, and extracted with methylene chloride. Wash the methylene chloride layer with water and concentrate the solvent. Add methanol to the residue, cool it, and collect the precipitated crystals. 3. '7g of 2-nitro-5
-[4-(3,4-dimethoxybenzoyl)-1-piverazinylcocinnamic acid is obtained.

mp197-202°C Reference Example 8 12 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)piperazinococinnamic acid is dissolved in 60 m2 of concentrated hydrochloric acid. A solution prepared by dissolving 20 g of stannous chloride in 40 g of concentrated hydrochloric acid was added dropwise to the solution at room temperature. After stirring for 2 hours, the precipitated crystals are collected. The crystals were dissolved in 240 g of methanol, neutralized with a 10% aqueous solution of caustic soda, and the precipitated crystals were collected. Concentrate the methanol solution and recrystallize from ethanol.

6.3 g of 2-amino-5-[4-(3,4-dimethoxybenzoyl)piperazinococinnamic acid are obtained.

mp 168' to 170.5°C Pale yellow powder crystal Reference example 9 5 g of 2-amino-5-[4-(3,4-dimethoxybenzoyl)piperazinococinnamic acid was dissolved in an ethanol-water mixed solvent, and 5% palladium on carbon was dissolved. Add 0.5 g and reduce at normal pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered and the ethanol-water is concentrated to dryness. Dissolve in chloroform and separate by silica gel chromatography to obtain 1.5 g of 3-[2-amino-5-(4-(3,4-dimethoxybenzoyl)piperazino)phenylcoprobionic acid.

mp98-101°C Reference Example 10 3-[2-amino-5-(4-(3,4-dimethoxybenzoyl)piperazino)phenylcopropionic acid 4.4
g was dissolved in 40 g of acetic acid, 1.1 g of acetic anhydride was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the acetic acid, add water. Count the number of precipitated crystals. After washing with water, recrystallize from a mixed solvent of acetone and water.

1.5 g of 3-[2-aminoacetyl-5-(4-(3
,4-dimethoxybenzoyl)piperazino)phenyl]
Obtain propionic acid.

mp78. 5 to 80.5°C Example 1 1 g of 3-[2-amino-5-(4-(3,4-dimethoxybenzoyl)piperazino)phenyl]propionic acid was dissolved in a chloroform-methanol mixture and a solvent, and 1 g of concentrated hydrochloric acid was added. and stir for 1 hour at room temperature. Distill the solvent,
Recrystallized from ethanol-chloroform to give 500 mg of 6-[4-(3゜4-dimethoxybenzoyl)-1-
piperazinyl]-3,4-dihydrocarbostyryl is obtained.

mp238-239-5°C Colorless granular crystals Compounds of Examples 2 to 68 below are obtained in the same manner as in Example 1 using appropriate starting materials.

Example 2 5-(1-piperazinyl)-3,4-dihydrocarbostyryl monohydrochloride monohydrate mp 300°C or higher (methanol) Colorless needle crystals Example 3 6-[4-(4-methoxybenzyl) )-1-piperazinyl]-3,4-dihydrocarbostyryl mp 196
~198°C (ethanol) Colorless needles Example 4 57[4-(p-)luenesulfonyl)-1-piperazinyl]-3,4-dihydrocarbostyryl Example 5 6-(1-piperazinyl')-3 ,4-dihydrocarbostyryl hydrobromide m9289-293°C (decomposition) (methanol-water) Colorless needle crystals Example 6 6-(4-butyl-1-piperazinyl)-3°4-dihydrocarbo Styryl monohydrochloride/1/2 hydrate salt m p 279-281°C (decomposition) (methanol) Example 7 5-(4-benzoyl-1-piperazinyl)-3,4-
Dihydrocarbostyryl mp 248-251°C (ethanol) Colorless needle crystals Example 8 6-(4-benzoyl-1-piperazinyl)-3,4-
Dihydrocarbostyril mp 221-222.5°C (ethanol) pale yellow granules Example 9 5-[4-(3,4-dimethoxybenzoyl)-1-
piperazinyl]-3,4-dihydrocarbostyryl mp207-208°C (ethanol) Colorless powder Example 10 5-[4-(3,4,5-trimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl mp250-251.5°C (isopropatol) Colorless granular product Example 11 6-[4-(3,4,5-)dimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl m9 180-182°C (isopropatol) Colorless granular product Example 12 6-[4-(4-methoxybenzoyl)-1=piperazinyl]-3,4- Dihydrocarbostyryl l/2 hydrate mp 212-213°C (methanol) Colorless needle crystals Example 13 6-(4-acetyl-1-piperazinyl)-3°4-dihydrocarbostyryl mp 203-205°C (isopropyl Tool) Pale yellow brown acicular crystals Example 14 6-(4-furoyl-1-piperazinyl)-3゜4-dihydrocarbostyryl mp206.5-207.56C (ethanol) Pale yellow granules Example 15 6- [ 4-(2-propynyl)-1-piperazinyl]
-3,4-dihydrocarbostyryl mp174-176
°C (isopropanol) Example 16 6-[4-(4-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp233~
235°C (methanol) Pale yellow needles Example 1.7 5-[4-(3,4-dichlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp250-252°C (methanol) Colorless Powder Example 18 5-[4-(3,5-dichlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp255-257°C (methanol-chloroform) Colorless needle-like crystals Example 19 6 - [4-(4-bromobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp233~
234.5°C (methanol-chloroform) Colorless granular crystals Example 20 6-[4-(4-cyanobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl m p 26
6-269°C (methanol-chloroform) Colorless granules Example 21 6-[4-(4-nitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp235.
5-236.5°C (methanol-chloroform) Yellow flakes Example 22 6-[4-(3,5-dinitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp262-264°C ( methanol-chloroform) red-black needles Example 23 6-[4-(4-aminobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp244~
246°C (ethanol) pale yellow needle crystals Example 24 5-[4-(4-hydroxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl 300°C or higher (methanol-chloroform) colorless needle crystals Example 25 6-[4-(3,4-methylenedioxybenzoyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl mp 191-192.5°C (methanol) Colorless needles Example 26 5-[4-(4-methylbenzoyl)-1-piperazinyl]-3,4 -dihydrocarbostyril mp239.
5-240°C (Rioform-ether) Colorless powder product Example 27 6-[4-(methanesulfonyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp241.5-
243℃ (methanol) Colorless granular crystals Example 28 5-(4-ethyl-1-piperazinyl)-3゜4-dihydrocarbostyryl monohydrochloride mp 293-296℃ (
Decomposition) (methanol) Colorless granules Example 29 6-(4-allyl-1-piperazinyl)-3゜4-dihydrocarbostyryl mp 175-176°C (chloroform-ether) Colorless phosphorus flakes Example 30 5- [4-(2-propynyl)-1-piperazinyl]
-3,4-dihydrocarbostyryl mp225-226
°C (chloroform) pale yellow powder product Example 31 6-[4-(2-butenyl)-1-piperazinyl]-
3,4-dihydrocarbostyryl mp242-245℃
(Decomposition) Example 32 8-Methoxy-6-[4-(3,4-dimethoxydibenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp162.5-163.5°C (isopropanol) Colorless needle crystal Example 33 6-[4-(3-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl m p 19
5-197.5°C (methanol) Colorless phosphorus flakes Example 34 5-[4-(4-methoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp219-220°C (methanol-chloroform ) Colorless needle crystals Example 35 5-(4-ethoxycarbonylmethyl-1-piperazinyl)-3,4-dihydrocarbostyryl mp206-2
08°C (methanol) Colorless needles Example 36 5m [4-(4-formyl)-1-piperazinyl]-
3,4-dihydrocarbostyryl m p 263-26
5°C (methanol) Colorless granular crystals Example 37 6-(4-ethoxycarbonyl-1-piperazinyl)-
3,4-dihydrocarbostyryl mp182.5-18
4°C (isopropatol) colorless needles Example 38 5-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyryl m p 19
4-196°C (methanol) Colorless needle crystals Example 39 6-[4-(2-phenethyl)-1-piperazinyl]-
3,4-dihydrocarbostyryl 1-hydrochloride m p 274-276°C (decomposition) (methanol) Colorless powder crystal Example 40 6-[4-(4-chlorobenzyl)-1-piperazinyl]-3, 4-dihydrocarbostyryl mp190-1
91.5°C (liooform-methanol) Colorless needle crystals Example 41 5-[4-(3,4-dichlorobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyryl monohydrochloride. Monohydrate mp 298.5-300°C (decomposition) (methanol) Colorless granular product Example 42 5-[4-(4-nitrobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp 268-27
19C (decomposition) (methanol) pale yellow powder product Example 43 5-[4-(4-aminobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyryl dihydrochloride 1
Hydrate mp 224-227°C (decomposition) (methanol-ether) Yellow granular crystals Example 44 6-[4-(4-methylbenzyl)-1-piperazinyl]-3,4-dihydrocarbostyryl dihydrochloride mp 272 ~273°C (decomposition) (methanol-water) Colorless powder product Example 45 5- [4-(3,4-dimethoxybenzyl)-1-piperazinyl]-3,4-dimethoxybenzyl)-1-piperazinyl]- 3,4-dihydrocarbostyryl dihydrochloride mp 270-272.5°C (decomposition) Example 46 8-(4-benzoyl-1-piperazinyl) carbostyryl mp 244-245°C (1 tanol) Colorless powder product implementation Example 47 6-[4-(3-pyridylcarbonyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp 250-252°C (ethanol) Yellow needles Example 48 6-[4-(4-methoxyphenyl) acetyl)-1-
piperazinyl]-3,4-dihydrocarbostyryl mp 266-268.5°C (methanol) Yellow powdery field Example 49 6-(4-phenylpropionyl-1-piperazinyl)
-3,4-dihydrocarbostyryl mp189.5-1
91°C (Rioroform-methanol) Yellow granules Example 50 8-[4-(3,4-methylenedioxybenzoyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl m9 195-197°C (ethanol) Colorless granular product Example 51 8-[4-(3-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp152~1
54°C (ethanol) Colorless scale-like product Example 52 8-[4-(3,4-dimethoxybenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostyryl mp145-148°C (ethanol) colorless scaly crystals Example 53 8-[4-(4-methylthiobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp178 ~179.5°C (ethanol) Colorless granular crystals Example 54 7-[4-(2-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp194~
199.5°C (methanol) Colorless needles Example 55 7-[4-(3-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp136.
5-138.5°C (ethanol) Colorless powder product Example 56 7-[4-(4-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp289-2
91°C (chloroform-methanol) Colorless powder crystal Example 57 7-[4-(4-methoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl m p 231-233°C (ethanol) Colorless Needle crystal Example 58 7-[4-(3,4-methylenedioxybenzoyl)-
1-Piperazinyl]-3,4-dihydrocarbostyryl mp207-208°C (ethanol) Colorless powder crystal Example 59 7-[4-(4-nitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbo styril mp240~
242°C (chloroform-methanol) Yellow granules Example 60 7-[4-(3,4,5-trimethoxybenzoyl)-
1-Piperazinyl]-3,4-dihydrocarbostyryl mp195-196.5°C (methanol) Colorless edge-shaped crystals Example 61 7-(4-benzoyl-1-piperazinyl)-3,4-
Dihydrocarbostyril mp264.5-265.5°C (chloroform-methanol) Colorless needle crystals Example 62 7-[4-(3,4-dimethoxybenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostyryl mpH8-120°C (ethanol) Colorless granular product Example 63 7-[4-(4-methylthiobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mpH8-120 °C (chloroform-methanol) Colorless edge-shaped crystals Example 64 7-(4-phenylpropionyl-1-piperazinyl'
) -3,4-dihydrocarbostyryl mp183-1
84°C (ethanol) Colorless acicular crystals Example 65 7-(1-piperazinyl)-3,4-dihydrocarbostyryl hydrobromide mp 174-177°C (ethanol) Colorless granules Example 66 8-( 1-piperazinyl") -3,4-dihydrocarbostyryl hydrobromide m p 300°C or higher (methanol-ether) colorless needle crystals Example 67 5-[4-(4-nitrobenzoyl)-1 -piperazinyl]-3,4-dihydrocarbostyryl mp292~
294°C (decomposition) (methanol-chloroform) Yellow granules Example 68 5-[4-(4-aminobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl mp285-2
87°C (decomposition) (methanol-chloroform) Colorless granules Example 69 10 g of 3-[2-aminoacetyl-5-(4-(3°4-dimethoxybenzoyl)piperazino)phenyl]propionic acid is added to 100 g of diphenyl ether. Dissolved at 90~
Stir at 100°C.

After 8 hours of reaction, pour into water and collect the precipitated crystals monthly. This was separated by silica gel column chromatography and recrystallized from methanol-chloroform to give 1.2 g of 6-[4-(3,
4-dimethoxybenzoyl)-1-piperazinyl]-1
-piperazinyl]carbostyryl is obtained.

mp 265-266.5°C (decomposition) Yellow granules Compounds of Examples 70-92 are obtained in the same manner as in Example 69 using appropriate starting materials.

Example 70 6-(4-ethoxycarbonyl-1-piperazinyl) carbostyril mp 223-224°C (methanol) yellow needles Example 71 6-[4-(3-chlorobenzoyl)-1-piperazinyl] carbostyryl mp250.5-252°C (methanol-chloroform) Yellow powder Example 72 6-[4-(4-chlorobenzoyl)-1-piperazinyl]carbostyryl mp265-266°C (methanol-chloroform) Yellow powder Product Example 73 6-[4-(4-methoxybenzoyl)-1-piverazinyl colupostyril mp230-233°C (chloroform-methanol) Yellow needles Example 74 6-[4-(3,4,5- )dimethoxybenzoyl)−
1-piverazinylcocarbostyryl mp249.5-2
50°C (methanol-chloroform) Yellow needles Example 75 6-[4-(4-cyanobenzoyl)-1-piperazinyl]carbostyryl ml) 300-301°C (decomposition) (methanol-chloroform) Yellow powder Crystal Example 76 6-[4-(3,4-methylenedioxybenzoyl)-
1-piperazinyl] carbostyryl mp266-267
°C (decomposition) (methanol-chloroform) Yellow powder crystal Example 77 6-[4-(4-nitrobenzoyl)-1-piperazinyl]carbostyryl mp265-266 °C (decomposition) (methanol-chloroform) Yellow needle Crystalline Example 78 6-[4-(4-Aminobenzoyl)-1-piperazinyl]carbostyryl m p, 287-290°C (chloroform-methanol) Yellow powdery crystal Example 79 6-(4-benzoyl-1 -piperazinyl) carbostyryl m p 264-265°C (ethanol-chloroform) Yellow needles Example 80 5- [4-(4-acetylaminobenzoyl)-1-
Piperazinyl L-3,4-dihydrocarbostyryl m p 3009C or higher (chloroform-methanol)
Colorless powder crystal Example 81 6-[4-(4-formyl)-1-piperazinylcocarbostyryl mp286.5-288°C (methanol) Yellow scale Example 82 6-[4-(4- Methylthiobenzoyl)-1-piperazinyl] carbostyryl mp 247.5-249.5°C (chloroform-methanol) Yellow needles Example 83 8-(4-benzoyl-1-piperazinyl) carbostyryl mp 244-245°C (ethanol ) Colorless powdery crystal Example 84 8- [4-(4-chlorobenzoyl)-1-piperazinyl]carbostyryl mp255.5-257°C (ethanol-chloroform) Colorless powdery crystal Example 85 8- [4- (3-Chlorobenzoyl)-1-piperazinylcolupostyryl m9208-209°C (ethanol) colorless granular crystals Example 86 8-[4-(2-chlorobenzoyl)-1-piperazinylcolupostyril mp239-240.5°C ( Ethanol) colorless needle-like crystals Example 87 8-[4-(4-methoxybenzoyl)-1-piperazinyl colupostyryl m9208-210°C (ethanol) colorless scaly crystals Example 88 8,-[4-(3 ,4-dimethoxybenzoyl)-1
-Piperazinyl] carbostyryl mp 197-198°C (ethanol-ether) colorless scaly crystals Example 89 6-(1-piperazinyl) carbostyryl hydrobromide mp 300°C or higher (water-ethanol) light yellow ridge-like crystals Example 90 8-(1-piperazinyl)carbostyryl hydrobromide mp 300°C or higher (methanol-ether) colorless scaly crystals Example 91 8-[4-(4-methoxyphenylacetyl)-1-
Biberazinyl colupostyryl mp224-225°C (ethanol) Yellow needles Example 92 6-[4-(4-hydroxyphenylacetyl)-1
-piperazinyl] carbostyryl mp 300°C or higher (dimethylformamide) Yellow powder crystal Example 93 2-Amino-5-[4-(3,4-dimethoxybenzoyl)piperazinococinnamic acid 5 g was dissolved in DMF50me, and 5% palladium on carbon 0.5 g was added, a hydrogen pressure of 3 kg/cm2 was applied using a Parr, and the reaction was carried out at 80°C for 4 hours. After removing the hydrogen, take out the internal solution, remove the catalyst, concentrate the solution by half, and pour into a large amount of water. The precipitated crystals are collected monthly and recrystallized from ethanol-chloroform to obtain 2.9 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl.

mp238-239.5°C Colorless granules Compounds of Examples 2-68 are obtained in the same manner as in Example 93 using appropriate starting materials.

Example 94 3.5 g of 2-nitro-5-piperazinyl cinnamic acid ethyl ester hydrochloride was mixed with 150 g of ethyl alcohol and 45 g of water.
Dissolved in a mixed solvent of yoke and diluted with sodium hydroxide aqueous solution.
Add 2 g of Raney nickel catalyst as H well 7 and place in a glass autoclave. Hydrogen pressure 5kg/crfJ2
and stirred at 80°C for 4 hours. After removing hydrogen,
After taking out the solution and removing the catalyst, the solution is concentrated to dryness, methyl alcohol is added to the residue to crystallize it, and the precipitated crystals are filtered. Recrystallized from methanol to obtain 1.3 g of 6-(
1-piperazinyl)-3,4-dihydrocarbostyryl is obtained.

mp224-231.5°C Example 95 8.8g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)piperazinococinnamic acid was dissolved in DMF88mf2
1.6 g of Raney nickel catalyst was added, a hydrogen pressure of 3 kg/cm2 was applied using a Parr, and the mixture was reacted at 80° C. for 4 hours. After removing hydrogen, the internal solution is taken out, and after removing the catalyst, the solution is concentrated to dryness, and methanol is added to the residue for crystallization. The precipitated crystals were filtered, recrystallized with DMF, and further recrystallized with a chloroform-ethanol mixed solvent.
-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl at 5.8
g get.

mp238-239.5°C Colorless granular crystal Compounds of Examples 2-4.6-68 are obtained in the same manner as in Example 95.

(that's all)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 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 group An alkyl group, 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 have a lower alkyl group as a substituent on the phenyl ring. On the phenyl ring of the above phenylcarbonyl group, phenyl lower alkyl group and phenyl lower alkanoyl group, a lower alkoxy group,
halogen atom, lower alkyl group, cyano group, nitro group,
It may have 1 to 3 groups selected from the group consisting of an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group, or a lower alkylenedioxy group as a substituent. R^2 represents a hydrogen atom or a lower alkoxy group. The carbon-carbon bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. ]
A carbostyryl derivative represented by and its salt.