JPH0314023B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carbostyril derivatives. The carbostyril derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula. [In the formula, R ¹ represents a hydrogen atom. R ² represents a hydrogen atom. R ³ represents a hydrogen atom, a lower alkanoyl group, a pyridylcarbonyl group, a lower alkoxycarmonyl group, a phenylcarbonyl group, or a phenyl lower alkanoyl group. On the phenyl ring of the above phenyl carbonyl group and phenyl lower alkanoyl group, a lower alkoxy group, a halogen atom, a cyano group,
It may have 1 to 3 groups selected from the group consisting of a nitro group, 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. 3rd and 4th position of carbostyril skeleton
The carbon-carbon bond with the position represents a single bond or a double bond. However, when the carbon-carbon bond between the 3rd and 4th positions of the carbostyryl skeleton is a single bond, R ³ is a group consisting of a lower alkoxy group, a halogen atom, a cyano group, a nitro group, an amino group, and a hydroxyl group on the phenyl ring. It must not be a phenylcarbonyl group, a hydrogen atom, a lower alkanoyl group, or a lower alkoxycarbonyl group that may have one to three groups selected from the following, or a lower alkylenedioxy group. ] The compound of the present invention represented by the above general formula (1) is
It has an effect of increasing myocardial contraction (positive inotropic effect) and an effect of increasing coronary blood flow, and is useful as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. In particular, the compounds of the invention are characterized in that they do not increase heart rate or increase it only to a small degree. More specifically, each group shown in the above general formula (1) is as follows. Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Examples include straight chain or branched alkoxy groups having 1 to 6 carbon atoms such as tert-butoxy, pentyloxy, and hexyloxy groups. Lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl,
Examples include straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms, such as pentanoyl, 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. As a substituent on the phenyl ring, a lower alkoxy group, a halogen atom, a lower alkyl group, a cyano group,
The phenylcarbonyl group having 1 to 3 groups selected from the group consisting of a nitro group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group or a lower alkylenedioxy group is 2- Chlorbenzoyl, 3
-Chlorbenzoyl, 4-chlorobenzoyl, 2
-Fluorobenzoyl, 3-fluorobenzoyl, 4-fluorobenzoyl, 2-brombenzoyl, 3-brombenzoyl, 4-brombenzoyl, 2-iodobenzoyl, 4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,6 -dichlorobenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3,5-dibrombenzoyl, 3,4,5-trichlorobenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methyl Benzoyl, 2-ethylbenzoyl, 3-ethylbenzoyl, 4-ethylbenzoyl, 3-isopropylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl,
2,5-dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-methoxybenzoyl, 3
-Methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl, 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-diethoxybenzoyl , 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-
Trihydroxybenzoyl, 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-hexylthiobenzoyl, 3,4-
Dimethylthiobenzoyl, 2,5-dimethylthiobenzoyl, 3,4,5-trimethylthiobenzoyl, 2-formyloxybenzoyl, 3-acetyloxybenzoyl, 4-acetyloxybenzoyl, 2-acetyloxybenzoyl, 3-propionyloxy Benzoyl, 4-butyryloxybenzoyl, 2-isobutyryloxybenzoyl, 3-pentanoyloxybenzoyl, 3-
A straight chain with 1 to 6 carbon atoms as a substituent on the phenyl ring such as tert-butyryloxybenzoyl, 4-hexanoyloxybenzoyl, 3,4-diacetyloxybenzoyl, 3,4,5-triacetyloxybenzoyl group, etc. or branched alkoxy group, halogen atom, straight chain or branched alkyl group having 1 to 6 carbon atoms, cyano group, nitro 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 an 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. Alternatively, a phenylcarbonyl group having an alkylenedioxy group having 1 to 4 carbon atoms can be exemplified. Examples of lower alkoxycarbonyl groups include straight-chain or branched carbon atoms having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. An example is a carbonyl group having an alkoxy group. Examples of lower alkanoylamino groups include formylamino, acetylamino, propionylamino,
Examples include straight-chain or branched alkanoylamino groups having 1 to 6 carbon atoms, such as butyrylamino, isobutyrylamino, pentanoylamino, tert-butylcarbonylamino, and hexanoylamino groups. Examples of lower alkylthio groups include linear or branched alkylthio groups having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, and hexylthio groups. Examples of lower alkanoyloxy groups include formyloxy, acetyloxy, propionyloxy,
Examples include straight-chain or branched alkanoyloxy groups having 1 to 6 carbon atoms, such as butyryloxy, isobutyryloxy, pentanoyloxy, tert-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-3-
Methylbutyryl, 5-phenylpentanoyl, 2
Examples include straight-chain or branched alkanoyl groups in which the alkanoyl moiety has 1 to 6 carbon atoms, such as -methyl-3-phenylpropionyl group. As a substituent on the phenyl ring, a lower alkoxy group, a lower alkyl group, a halogen atom, a nitro group,
The phenyl lower alkanoyl group having 1 to 3 groups selected from the group consisting of a cyano group, an amino group, a hydroxyl group, a lower alkanoylamino group, a lower alkylthio group, and a lower alkanoyloxy group or a lower alkylenedioxy group is 2 -(2-chlorophenyl)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-dichlorophenyl)propionyl, 4-(3,4-dichlorophenyl)butyryl, 2-(3 ,4-difluorophenyl)acetyl, 5-(3,5-dibromphenyl)pentanoyl, 6-(3,4,5-trichlorophenyl)
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-dimethylphenyl)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-diethoxyphenyl)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-methylenedioxyphenyl)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-trihydroxyphenyl)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-tert-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-propionyloxy) phenyl)propionyl, 4-(4-pentanoyloxyphenyl(butyryl), 5-(3-
propionyloxyphenyl)pentanoyl, 6
-(4-isobutyryloxyphenyl)hexanoyl, 2-(4-hexanoyloxyphenyl)
Acetyl, 2-(4-butyryloxyphenyl)
A linear or branched alkoxy group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group as a substituent on the phenyl ring such as an acetyl group. group, amino group, hydroxyl group, straight chain or branched alkanoylamino group having 1 to 6 carbon atoms, straight chain or branched alkylthio group having 1 to 6 carbon atoms, and straight chain or branched chain having 1 to 6 carbon atoms. 1 to 6 carbon atoms having a phenyl group which may have 1 to 3 groups selected from the group consisting of branched alkanoyloxy groups or a linear or branched alkylenedioxy group having 1 to 4 carbon atoms; Examples include straight-chain or branched alkanoyl groups. The compound of the present invention can be produced by various methods, but one preferred example thereof is the method shown in Reaction Scheme-1 below. [In the formula, X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, an aralkylsulfonyloxy group, or a hydroxyl group.
R ¹ , R ² , R ³ and the 3rd and 4th positions of the carbostyryl skeleton
The carbon-carbon bond with the position is the same as above. ] In the general formula (3), specific examples of the halogen atom represented by Examples include isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy groups, and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4- Methylphenylsulfonyloxy, 2-
Examples include substituted or unsubstituted arylsulfonyloxy groups such as methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups. , and specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2
-Phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as -chlorobenzylsulfonyloxy and α-naphthylmethylsulfonyloxy groups. As a starting material, in the compound of general formula (3), X is a halogen atom, a lower alkanesulfonyloxy group,
When using a compound exhibiting an arylsulfonyloxy group or an aralkylsulfonyloxy group,
The reaction between the compound of general formula (2) and the compound of general formula (3) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of inert solvents that can be used include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, isopropanol, and butanol, acetic acid, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric triamide. etc. can be mentioned. Examples of basic condensing agents include carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium methylate;
Examples include metal alcoholates such as sodium ethylate, pyridine, and tertiary amines such as triethylamine. Compound of general formula (2) and general formula
The ratio of the compound (3) to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually used in at least an equimolar amount, preferably an equimolar to 5 times the molar amount of the former. Good. The reaction is usually carried out at a temperature of about 40 to 120°C, preferably 50 to 100°C, and is generally completed in about 5 to 30 hours. When using a compound of general formula (3) in which X represents a hydroxyl group as a starting material, the reaction between the compound of general formula (2) and the compound of general formula (3) is carried out in the presence of a dehydration condensation agent. It is carried out without a solvent or in a suitable solvent. Examples of the dehydration condensation agent used include condensed phosphoric acids such as polyphosphoric acid, orthophosphoric acid, pyrophosphoric acid,
Phosphoric acids such as metaphosphoric acid, phosphorous acids such as northophosphorous acid, phosphoric anhydrides such as phosphorus pentoxide, acids such as hydrochloric acid, sulfuric acid, boric acid, sodium phosphate, boron phosphate, ferric phosphate, Examples include metal phosphates such as aluminum phosphate, activated alumina, sodium bisulfate, and Raney nickel. Examples of the solvent used include high boiling point solvents such as dimethylformamide and tetralin. The ratio of the compound of general formula (2) and the compound of general formula (3) to be used is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in an equimolar amount or more to the former, It is preferable to use equimolar to twice the molar amount. The amount of the dehydration condensing agent to be used is not particularly limited and can be appropriately selected from a wide range, but it is usually used in a catalytic amount or more, preferably in an amount of about 0.5 to 5 times the molar amount of the compound of general formula (2). In the above reaction, in order to prevent advantageous oxidation reactions, it is desirable to carry out the reaction in an inert gas stream, such as a carbon dioxide or nitrogen stream. Although the above reaction can be carried out either under normal pressure or under increased pressure, it is preferable to carry out the reaction under normal pressure. The above reaction is usually carried out at a temperature of about 100 to 350°C, preferably at a temperature of about 125 to 350°C.
The reaction proceeds suitably at 255°C and is generally completed in about 3 to 10 hours. In addition, in the above reaction, the general formula
The compound (3) may be used in the form of a salt. [In the formula, R ³ ' is a lower alkanoyl group, and as a substituent on the phenyl ring, a lower alkoxy group, a halogen atom, 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 represents a phenylcarbonyl group, a phenyl lower alkanoyl group, a pyridylcarbonyl group, or a lower alkoxycarbonyl group which may have 1 to 3 groups selected from the group or a lower alkylenedioxy group. X ¹ represents a hydroxyl group. R ¹ , R ² and carbostyril skeleton 3
The carbon-carbon bond at position and 4-position is the same as above. However, when the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton is a single bond, R ³ ' is a lower alkoxy group, a halogen atom, a cyano group, a nitro group, an amino group, or a hydroxyl group on the phenyl ring. The group selected from the group must not be a phenylcarbonyl group, a lower alkanoyl group, or a lower alkoxycarbonyl group, which may have one to three groups or a lower alkylenedioxy group. ] The method shown by Reaction Scheme-2 is a method in which a carbostyril derivative represented by general formula (4) and a carboxylic acid represented by general formula (5) are reacted in a conventional amide bond forming reaction. As the amide bond forming reaction, conditions for known amide bond forming reactions can be easily applied. For example, (a) mixed acid anhydride method, that is, a method in which carboxylic acid (5) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, which is then reacted with amine (4), (b) active ester method, that is, carboxylic acid A method of converting (5) into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. and reacting this with amine (4); (c) carbodiimide method, i.e., carboxylic acid A method of condensing amine (4) with (5) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole,
(iv) Other methods include converting carboxylic acid (5) to carboxylic anhydride using a dehydrating agent such as acetic anhydride and reacting it with amine (4); Examples include a method in which 4) is reacted under high pressure and high temperature, and a method in which an acid halide of carboxylic acid (5), that is, a carboxylic acid halide is reacted with amine (4). The mixed acid anhydride used in the mixed acid anhydride method is obtained by the usual Schotten-Baumann reaction, and by reacting it with the amine (4) without isolation, the compound of the present invention of general formula (1a) can be obtained. Manufactured. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound used, compounds commonly used in the Schotten-Baumann reaction are used, such as triethylamine,
Trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 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), and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is carried out at -20 to 100°C, preferably 0 to 50°C, and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 2 hours.
done in time. The resulting mixed acid anhydride and amine
The reaction (4) is carried out at -20 to 150°C, preferably 10 to 50°C, and for a reaction time of 5 minutes to 10 hours, preferably 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. Any solvent commonly used in the mixed acid anhydride method can be used, and specifically, halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane,
Aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran,
Ethers such as dimethoxyethane, methyl acetate,
Examples include esters such as ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate,
Examples include ethyl bromoformate and isobutyl chloroformate. The ratio of carboxylic acid (5), alkylhalocarboxylic acid, and amine (4) used in this method is usually equivalent molar ratios, but the ratio of alkylhalocarboxylic acid and carboxylic acid (5) to amine (4) is 1 molar. ~1.5 times the molar amount may be used. Furthermore, when employing a method of reacting carboxylic acid halide with amine (4), the reaction is carried out in a suitable solvent in the presence of a basic compound. A wide range of known basic compounds can be used, including, for example, in addition to the basic compounds used in the Schotten-Baumann reaction, sodium hydroxide,
Potassium hydroxide, sodium hydride, potassium hydride, etc. can be mentioned. Examples of the solvent used include, for example, methanol, ethanol, propanol, butanol, 3-methoxy-
Examples include alcohols such as 1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, and acetone. The ratio of the amine (4) and carboxylic acid halide to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is at least equimolar to the former, preferably equimolar to 5 times the molar amount. It is better to use the amount. The reaction is usually carried out at about -20 to 180°C, preferably 0 to 150°C, and is generally completed in 5 minutes to 30 hours. [In the formula, R ⁴ represents a halogen atom. ^R1 , ^R2 , ^R3
and X are the same as above. ] The reaction between the compound of general formula (12) and the compound of general formula (3) is carried out under the same conditions as the reaction between the compound of general formula (2) and the compound of general formula (3). The ring-closing reaction of the compound of general formula (13) is generally called Friedel-Crafts reaction,
This reaction is carried out in the presence of a Lewis acid in a solvent. As the solvent used in this case, those commonly used in this type of reaction are advantageously used, such as carbon disulfide, nitrobenzene, chlorobenzene,
Examples include 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 appropriately determined, 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 (13). The reaction temperature is appropriately selected, but is usually about 20 to 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 usually
The reaction is completed in about 0.5 to 6 hours. [In the formula, R ¹ , R ² and R ³ are the same as above. ] Conventional catalytic reduction conditions are applied to the reduction of the compound of general formula (1i). Examples of catalysts that can be used include metals such as palladium, palladium-carbon, platinum, and Raney nickel, and it is preferable to use such metals in normal catalytic amounts. Examples of solvents that can be used include methanol, ethanol, isopropanol, dioxane, THF, hexane, cyclohexane, and ethyl acetate. The reduction reaction can be carried out either at normal pressure or under increased pressure, but it is usually carried out at normal pressure to 20 kg/cm ³ , preferably at normal pressure to 10 kg/cm ³ . The reaction temperature is usually about 0 to 150°C, preferably room temperature to 100°C. In addition, the dehydrogenation reaction of the compound of general formula (1h) is
This is carried out using an oxidizing agent in a suitable solvent. The oxidizing agent used is, for example, 2,3-dichloro-
5,6-dicyanobenzoquinone, chloranil (2,3,5,6-tetrachlorobenzoquinone)
Examples include benzoquinones such as N-bromosuccinimide, N-chlorosuccinimide, halogenating agents such as bromine, hydrogenation catalysts such as selenium dioxide, palladium carbon, palladium black, palladium oxide, and Raney nickel. The amount of the halogenating agent to be used is not particularly limited and may be appropriately selected from a wide range, but it is usually 1 to 5 times the molar amount, preferably 1 to 2 times the amount of the compound of general formula (1h).
It is better to use twice the molar amount. Further, when a hydrogenation catalyst is used, it is preferable to use a normal amount of the catalyst. Examples of solvents include ethers such as dioxane, tetrahydrofuran, methoxyethanol, and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, and cumene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, and butanol. Examples include alcohols such as amyl alcohol and hexanol, polar protic solvents such as acetic acid, and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The reaction is usually carried out at room temperature to 300°C, preferably room temperature to 200°C, and is generally completed in about 1 to 40 hours. Furthermore, among the compounds of the present invention represented by the general formula (1), compounds in which R ¹ represents a hydrogen atom and the carbon bonds at the 3- and 4-positions of the carbostyril skeleton are double bonds can be expressed by the following reaction scheme - As shown in Figure 5, lactam-lactim tautomerism can occur. [In the formula, R ² and R ³ are the same as above. ] The compound of the present invention represented by the general formula (1) can also be produced by the method shown in the following reaction scheme-6. [In the formula, R ⁵ and R ⁵ ' represent a lower alkyl group. ^R5
and R ⁵ ' may be bonded to each other together with the oxygen atom to which they are bonded to form a lower alkylenedioxy group. R ⁶ represents a hydrogen atom or a lower alkyl group. R ⁶ ' represents a lower alkyl group. R ¹ ' represents a lower alkanoyl group. 〓 indicates a single bond or a double bond. R ¹ , R ⁴ and X ² are the same as above. ] The nitration of the compound of general formula (15) is carried out under the usual nitration reaction conditions for aromatic compounds, for example, without a solvent or using a nitration agent in a suitable inert solvent. Examples of inert solvents include acetic acid, acetic anhydride, concentrated sulfuric acid, etc., and examples of nitration agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum,
Examples include phosphoric acid or acetic anhydride and nitric acid), alkali metal nitrates such as potassium sulfate and sodium nitrate, and sulfuric acid. The amount of the nitrating agent used may be an equimolar or more excess amount relative to the starting compound, and the reaction is preferably carried out at a temperature of 0 to about room temperature for 1 to 4 hours. The acetalization reaction of the aldehyde group of the compound of general formula (16) is carried out by reacting it with an acetalizing agent in the presence of 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, xylene, etc.
Examples include alcohols such as methanol and ethanol, dimethylformamide, and dimethyl 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 to be used is at least equimolar, preferably 1 to 1 molar, when orthoesters are used, based on the compound of general formula (16).
It is best to use 1.5 times the mole, and when using alcohols, it is best to use at least 2 times the mole, usually in large excess. The reaction temperature is usually 0 to 50℃,
The temperature is preferably around room temperature, and the reaction is completed in about 30 minutes to 5 hours. The reaction between the compound of general formula (17) and the piperazine derivative of general formula (18) 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, isopropanol, dioxane, tetrahydrofuran (THF), ethers such as ethylene glycol dimethyl ether, diethyl ether, N-methylpyrrolidone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethyl phosphoric acid Polar solvents such as triamides can be mentioned. 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 hydrogen carbonate, sodium amide, sodium hydride,
Examples include tertiary amines such as triethylamine and tripropylamine, pyridine, and quinoline.
The amount of the piperazine derivative of general formula (18) to be used is usually 1 to 10 times the molar amount, preferably 3 to 7 times the molar amount of the compound of general formula (17). The reaction temperature is usually 50-150℃, preferably 50℃
The temperature is preferably ~100°C, and the reaction is generally completed in about 1.5 to 10 hours. The hydrolysis reaction of the compound of general formula (19) is carried out for 30 minutes at a reaction temperature of room temperature to the boiling point temperature of the solvent in an alcohol such as methanol, ethanol, or isopropanol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid. ~
This is carried out by reacting for 3 hours. The reaction between the compound of general formula (20) and malonic acid (21) is carried out in an appropriate solvent in the presence of a basic compound. As the solvent used, all the solvents used in the reaction of the compounds (17) and (18) 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 hydrogen carbonate, sodium amide,
Examples include sodium hydride, triethylamine, tripropylamine, tertiary amines such as piperidine, pyridine, and quinoline. The proportion of the compound of general formula (20) and malonic acid (21) to be used is preferably at least equimolar, usually 2 to 7 times the molar amount of the compound of general formula (20). The reaction is usually carried out at a temperature of 0 to 200°C, preferably about 70 to 150°C, and is completed in about 1 to 10 hours. The esterification reaction of the compound of general formula (22) can be carried out, for example, in an alcohol such as methyl alcohol, ethyl alcohol, or isopropyl alcohol,
In the presence of an acid such as sulfuric acid or a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, or phosphorus trichloride, usually 0 to 150°C, preferably 50 to 100°C.
It takes about 1 to 10 hours. The amount of acid used is usually 1 for the compound of general formula (22).
The halogenating agent can be used in an amount of up to 1.2 times the molar amount, and the amount of the halogenating agent to be used is at least equimolar, preferably 1 to 5 times the molar amount of the compound of general formula (22). The reaction of reducing the compound of general formula (22) or (23) to obtain the compound of general formula (24) includes, for example, reduction using a catalytic reduction catalyst in an appropriate solvent, or reduction in an appropriate inert solvent. 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. When using catalytic reduction, the solvents used include, for example, water, alcohols such as acetic acid, methanol, ethanol, and isopropanol, hydrocarbons such as hexane and cyclohexane, and ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether. esters such as ethyl acetate, methyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide. The catalytic reduction catalyst used is, for example, palladium, palladium-
Black, palladium-carbon, platinum, platinum oxide, copper chromite, Raney nickel, etc. are used. The amount of catalyst to be used is preferably 0.02 to 1.00 times the weight of the compound of general formula (22) or (23). The reaction is usually carried out at -20 to around room temperature, preferably 0 to around room temperature, and the hydrogen pressure is 1 to 10 atm.
It will be completed in about 10 hours. When using the method, iron, zinc, tin or stannous chloride and hydrochloric acid,
Mineral acids such as sulfuric acid, or mixtures of iron, ferrous sulfate, zinc or tin with alkali metal hydroxides such as sodium hydroxide, sulfides such as ammonium sulfide, ammonium salts such as ammonia water, ammonium chloride, etc. Used as a base agent. Inert solvents used include, for example, water, acetic acid, methanol,
Examples include 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 reaction is advantageously carried out at 0 to about room temperature for about 0.5 to 10 hours. It is better. The amount of the reducing agent used is at least equimolar, usually equimolar to 5 times the molar amount of the raw material compound. In another method, when the reaction is carried out at around 50 to 150°C, the compound (24) is converted to the general formula (1).
can be obtained directly. Acylation of the compound of general formula (24) 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 a suitable 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 an equimolar to large excess amount relative to the raw material compound, but it is generally preferred to use 5 to 10 times 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. The acylation reaction proceeds advantageously by maintaining the reaction temperature at 50 to 150°C. The reaction to obtain the compound of general formula (1) by cyclizing the compound of general formula (24) or (25) is carried out in an appropriate solvent in the presence or absence of a basic compound or acid, preferably an acid. It will be done. A wide range of known basic compounds can be used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5
-diazabicyclo[4,3,0]nonene-5
(DBN), 1,5-diazabicyclo[5,4,0]
Organic hydrochloric acid such as undecene-5 (DBU), 1,4-diazabicyclo[2,2,2]octane (DABCO), potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride,
Examples include inorganic bases such as potassium hydride, potassium hydrogen carbonate, and sodium hydrogen carbonate. Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, 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.
For example, methanol, ethanol, propanol,
Examples include alcohols such as butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, and acetone. Halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, diphenyl ether, methyl acetate, ethyl acetate, etc. Examples include esters, aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide, and 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. Furthermore, among the compounds of the present invention represented by general formula (1f), compounds in which the substituent on the phenyl ring is an amino group can be easily produced by reducing a compound in which the substituent on the phenyl ring is a nitro group. Ru.
For this reduction, for example, the usual conditions for reducing an aromatic nitro group to an aromatic amine group can be adopted, and more specifically, a method using a reducing agent such as sodium sulfite or sulfur dioxide gas, or a method using a reducing catalyst such as palladium on carbon. A catalytic reduction method or the like can be used. Among the compounds of the present invention represented by the above general formula (1), a compound in which R ² is a hydrogen atom can also be produced by ether decomposition of a corresponding compound in which R ² is a lower alkoxy group. This ether decomposition is carried out in the presence of a Lewis acid such as boron tribromide, boron trifluoride or aluminum chloride. It is usually preferable to use such a Lewis acid in an excess amount relative to the raw material compound. Further, the reaction temperature is usually about -30°C to room temperature. Among the compounds of the present invention represented by general formula (1)
A compound in which R ³ represents a hydroxyl group or an amino group can also be produced by hydrolyzing a corresponding compound in which R ³ represents a lower alkanoyloxy group or an amino group having a lower alkanoyl group as a substituent. This hydrolysis is carried out in a suitable solvent in the presence of an acid or basic compound. Examples of solvents include water, lower alcohols such as methanol, ethanol, and isopropanol, dioxane,
Examples include ethers such as tetrahydrofuran, mixed solvents thereof, and the like. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and examples of basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. . The reaction normally proceeds suitably at room temperature to 150°C, preferably 80 to 120°C, and is generally completed in about 1 to 15 hours. Furthermore, among the compounds of the present invention represented by the general formula (1), compounds in which R ³ is a lower alkanoylamino group or a lower alkanoyloxy group can be prepared by acylating a compound in which R ³ is an amino group or a hydroxyl group. Manufactured. This acylation reaction is preferably carried out under the same reaction conditions as for the acylation of the compound of general formula (24). The compound of general formula (1) can also be produced by the method shown in Reaction Scheme-7. [In the formula, A is R ⁷ CH=CH- (R ⁷ is a lower alkoxy group or a halogen atom),

[Formula] (R ⁸ and R ⁹ are lower alkyl groups) or CH≡C-.
R ¹ , R ² and R ³ are the same as above. ] The reaction between the compound of general formula (26) and the compound of general formula (27) is carried out under the same reaction conditions as the reaction between the compound of general formula (4) and the compound of general formula (5). Cyclization of the compound of general formula (28) is carried out in the presence of an acid in the absence of a solvent or in a suitable solvent. The acid is not particularly limited, and a wide range of ordinary inorganic acids and organic acids can be used. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, Lewis acids such as aluminum chloride, boron trifluoride, titanium tetrachloride, etc. Examples include organic acids such as acid, formic acid, acetic acid, ethanesulfonic acid, and p-toluenesulfonic acid. Among these acids, hydrochloric acid, hydrobromic acid, sulfuric acid, etc. are preferred. The amount of such acid to be used is usually at least the same weight, preferably 10 to 50 times the weight of the compound of general formula (28). A wide range of common inert solvents can be used as the solvent, such as water, lower alcohols such as methanol, ethanol, and propanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, methylene chloride, Chloroform, halogenated hydrocarbons such as carbon tetrachloride, acetone, dimethyl sulfoxide,
Examples include dimethylformamide and hexamethylphosphoric triamide. Among these, water-soluble solvents such as the lower alcohols, ethers, acetone, dimethyl sulfoxide, dimethyl formamide, and hexamethyl phosphoric triamide are preferred. The reaction is usually carried out at 0 to 100°C, preferably at room temperature to
The reaction is carried out at 60°C, and usually completes in about 5 minutes to 6 hours. The compound of general formula (1) can also be produced by the method shown in Reaction Scheme-8. [In the formula, R ¹ , R ² , R ³ , X ² and the carbon-carbon bonds between the 3rd and 4th positions of the carbostyryl skeleton are the same as above. ] The reaction between the compound of general formula (29) and the compound of general formula (18) is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of inert solvents used include benzene,
Aromatic hydrocarbons such as toluene and xylene, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, dimethyl sulfoxide, dimethyl formamide, hexamethyl phosphorus Acid triamides and the like can be mentioned. Examples of basic condensing agents include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride,
Examples include potassium hydride and triethylamine. The ratio of the compound of general formula (29) and the compound of general formula (18) to be used is not particularly limited and may be appropriately selected within a wide range, but the latter is usually at least equimolar to the former, preferably is preferably used in an equimolar to 5-fold molar amount. The reaction is usually carried out at room temperature to about 180°C, preferably 100 to 150°C.
The reaction is carried out at a temperature of 0.degree. C., and the reaction is generally completed in about 3 to 30 hours. Further, in this reaction, when copper powder is used as a catalyst, the reaction proceeds advantageously. Among the compounds of general formula (2) above, compounds in which the amino group is substituted at the 8-position (compounds of general formula (37) or (38)) can also be produced by the method shown in the following reaction scheme-13. [In the formula, R ¹⁰ represents a lower alkanoyl group, and R ¹¹ represents a lower alkyl group. X ² is the same as above. ] Acylation of the compound of general formula (30) is carried out under the same reaction conditions as for the acylation of the compound of general formula (24). The reduction of the nitro group of the compound of general formula (31) is carried out under the same reaction conditions as for the reduction of general formula (22) or (23). In the reaction between the compound of general formula (32) and the compound of general formula (33), the former is usually used in at least an equimolar amount, preferably 1 to 5 times the molar amount of the latter. The reaction with (5) may be carried out under the same conditions as the reaction using a carboxylic acid halide as compound (5), but the reaction proceeds even in the absence of a basic compound. The cyclization reaction of the compound of general formula (34) is
It can be carried out under the same reaction conditions as the cyclization reaction of the compound of general formula (28). The reduction of the carbostyril derivative of general formula (35) can be carried out under the same reaction conditions as for the reduction of the carbostyril derivative of general formula (1i). The hydrolysis reaction of the carbostyryl derivative of general formula (35) or 36 is
The reaction can be carried out under the same reaction conditions as the hydrolysis reaction of the compound of general formula (1) in which R ³ represents a lower alkanoylamino group. The carbostyryl derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a medically acceptable acid. Examples of the acid 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 carbostyryl 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 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, polyvinylpyrrolidone, etc. Binders, dry starch, sodium alginate, agar powder, laminaran powder, Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch,
Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch,
Examples include adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. In addition, tablets may be coated with a conventional coating, such as sugar-coated tablets,
It can be a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include binders such as 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,
Examples include gelatin and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents are used. All those commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the cardiotonic agent, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, if necessary, colorant,
Preservatives, fragrances, flavors, sweeteners, and other pharmaceutical agents may also be included in the therapeutic agent. 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 administration may be carried out in a manner depending on various formulation forms, 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
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 2 to 200 mg of the active ingredient. Reference examples and examples are listed below. Reference example 1 Add 29.3 ml of concentrated nitric acid to 500 ml of concentrated sulfuric acid under external ice cooling and stirring.
was added dropwise, and further m-chlorobenzaldehyde 50
g is added dropwise at a temperature below 5°C. After stirring at room temperature for 1 hour, the reaction mixture was poured into ice 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. mp65-69℃ Reference example 2 2-nitro-5-chlorobenzaldehyde 100
Dissolve g in 1000ml of toluene. Next, 10 g of p-toluenesulfonic acid and 87.8 g of ethyl orthoformate were added, and the mixture was stirred at room temperature for 1 hour. 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 diethylacetal in the form of an oil. Reference Example 3 138 g of 2-nitro-5-chlorobenzaldehyde diethyl acetal was dissolved in 750 ml of DMF, 250 g of anhydrous piperazine was added, and the mixture was stirred at 80°C for 4 hours. Excess piperazine and DMF were distilled off under reduced pressure,
Add a dilute aqueous caustic soda solution to the residue, dissolve it, and then extract with methylene chloride. After washing the methylene chloride layer with water,
After drying with sodium sulfate, the solvent is distilled off. Add 850 ml of isopropyl alcohol to the residue and dissolve. Add 65 ml of concentrated HCl and heat to reflux for 1 hour. After cooling, collect the precipitated crystals. 93g of 2-nitro-
5-piperazinylbenzaldehyde hydrochloride is obtained. mp195-201°C Reference Example 4 47 g of 2-nitro-5-piperazinylbenzaldehyde hydrochloride is dissolved in 500 ml of pyridine, 5 g of piperidine and 100 g of malonic acid are added, and the mixture is heated under reflux for 5 hours. After cooling, take the precipitation results. Add 1000 ml of methanol to the collected crystals and heat under reflux for 1 hour. Remove after cooling. 42 g of 2-nitro-5-piperazinylcinnamic acid are obtained. mp229-237°C Reference Example 5 10 g of 2-nitro-5-piperazinylcinnamic acid is suspended in 100 ml of ethyl alcohol, and 3 ml of thionyl chloride is added dropwise under external ice-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. Collect the yellow crystals that precipitate. 4.3 g of 2-nitro-5-piperazinyl cinnamic acid ethyl ester hydrochloride are obtained. mp210-220℃ Reference Example 6 5 g of 2-nitro-5-piperazinylbenzaldehyde was suspended in 50 ml of DMF, 6 ml of triethylamine was added, and 4.4 g of 3,4-dimethoxybenzoyl chloride was dissolved in 20 ml of DMF under external ice cooling and stirring. drip. Stir at room temperature for 2 hours, then pour into saturated brine. Extract with methylene chloride, wash the methylene chloride layer with water, and then dry over anhydrous sodium sulfate. The solvent is distilled off, methyl alcohol is added, and the mixture is heated, cooled, and taken. Recrystallized in DMF and 4.5 g of 2-nitro-5-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Yellow crystals of benzaldehyde are obtained. mp196-198℃ Reference Example 7 Add 20 ml of pyridine to 4 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]benzaldehyde, dissolve, and dissolve malonic acid.
Add 2.1 g and 0.4 ml of piperidine, and stir 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. 3.7 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid are obtained. mp197～202℃ Reference example 8 12g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)piperazino]cinnamic acid was dissolved in concentrated hydrochloric acid at 60°C.
Dissolve in ml. A solution of 20 g of stannous chloride dissolved in 40 ml of concentrated hydrochloric acid was added dropwise to the solution at room temperature. After stirring for 2 hours, collect the precipitated crystals. Dissolve the crystals in 240 ml of methanol, neutralize with 10% caustic soda aqueous solution, and record the precipitation results. Concentrate the methanol solution and recrystallize from ethanol. 6.3g of 2-
Amino-5-[4-(3,4-dimethoxybenzoyl)piperazino]cinnamic acid is obtained. mp168-170.5℃ Pale yellow powder crystal Reference example 9 Dissolve 5 g of 2-amino-5-[4-(3,4-dimethoxybenzoyl)piperazino]cinnamic acid in an ethanol-water mixed solvent, and add 5% palladium on carbon.
Add 0.5g and reduce at normal pressure. After a theoretical amount of hydrogen has been absorbed, the catalyst is filtered and the ethanol-water is concentrated to dryness. Dissolved in chloroform and separated by silica gel chromatography to obtain 1.5 g of 3-[2-amino-5-{4-(3,4-dimethoxybenzoyl)piperazino}phenyl]propionic acid. mp98～101℃ Reference example 10 Dissolve 4.4 g of 3-[2-amino-5-{4-(3,4-dimethoxybenzoyl)piperazino}phenyl}propionic acid in 40 ml of acetic acid, and dissolve 1.1 g of acetic anhydride.
and stirred at room temperature for 1 hour. After concentrating the acetic acid,
Add water. Take the precipitated crystals. After washing with water, it is recrystallized from a mixed solvent of acetone and water. 1.5g of 3-
[2-Aminoacetyl-5-{4-(3,4-dimethoxybenzoyl)pepyrazino}phenyl]propionic acid is obtained. mp78.5-80.5°C Reference Example 11 300 g of o-nitroaniline is dissolved in 620 ml of acetic anhydride and stirred at 40-50°C for 3 hours. The reaction mixture was poured into ice water, and the precipitated crystals were collected and dried.
The obtained o-acetylaminonitrobenzene was suspended in 2.4 methanol, 20 g of 10% Pd/C was added,
Catalytic reduction is carried out at room temperature and pressure. After the reaction is completed, the catalyst is separated and the solvent is distilled off under reduced pressure to obtain crystals. This is washed with ethanol, and the resulting crystals are dried under reduced pressure over phosphorus pentoxide to obtain 248 g of o-aminoacetanilide. Reference Example 12 248 g of o-acetylaminoaniline is dissolved in 1 part of dimethylformamide, and a solution of 114 g of β-ethoxyacrylic acid chloride in 400 ml of dimethylformamide is added dropwise over 3.5 hours while stirring at room temperature. After that, stir for an additional 30 minutes at the same temperature. The reaction mixture was poured into ice water and the precipitated crystals were collected to obtain 84.9 g of 1-acetylamino-2-(β-ethoxyacryloylamide)benzene. Reference Example 13 84.9 g of 1-acetylamino-2-(β-ethoxyacryloylamide)benzene was gradually added to concentrated sulfuric acid under stirring at room temperature. After the addition is complete, the mixture is further stirred at room temperature for 2 hours. The reaction mixture was poured into a large amount of ice water and the precipitated crystals were collected to obtain 49.5 g of 8-acetylaminocarbostyryl. Reference Example 14 15.0 g of 8-acetylaminocarbostyryl was suspended in 300 ml of dioxane, 2.0 g of 10% Pd/C was added, and catalytic reduction was carried out at 70 to 80°C under normal pressure. After the reaction was completed, the catalyst was separated, the solvent was distilled off under reduced pressure, and 8-
14.3 g of acetylamino-3,4-dihydrocarbostyryl are obtained. Reference Example 15 11.8 g of 8-acetylamino-3,4-dihydrocarbostyryl was suspended in 90 ml of 20% hydrochloric acid and stirred under heating under reflux for 1 hour. The reaction mixture was poured into ice water, neutralized with 5N sodium hydroxide, and saturated aqueous sodium bicarbonate was added to adjust the pH to 8. The precipitated crystals were collected to obtain 7.87 g of 8-amino-3,4-dihydrocarbostyryl. Reference example 16 21.5g of 8-acetylaminocarbostyryl
% hydrochloric acid and stirred for 1 hour while heating under reflux. The reaction mixture is poured into ice water and neutralized with 5N sodium hydroxide. Take the precipitated crystals,
15.47 g of 8-aminocarbostyryl are obtained. Reference example 17 6-amino-3,4-dividrocarbostyryl
9.36g, N,N-(di-β-bromoethyl)-3,
A mixture of 18.3 g of 4-dimethoxybenzamide and 70 ml of methanol is stirred and refluxed for 15 hours. After cooling, 3.06 g of potassium carbonate was added and the mixture was stirred and refluxed for 8 hours. After cooling, collect the crystals that precipitate. Wash with methanol and recrystallize with ethanol-chloroform to give 8.5
g of 6-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl was obtained. mp238-239.5°C Colorless granular crystal elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.71 6.51 10.52 Compounds of Examples 1 to 29 were obtained in the same manner as in Example 3. Example 1 6-(4-ethoxycarbonyl-1-piperazinyl) carbostyryl mp223-224°C (methanol) Yellow needles Example 2 6-[4-(3-chlorobenzoyl)-1-piperazinyl] carbostyril mp250 .5-252℃ (Methanol-Chloroform) Yellow powder crystal Example 3 6-[4-(4-chlorobenzoyl)-1-piperazinyl]carbostyryl mp265-266℃ (Methanol-Chloroform) Yellow powder crystal Example 4 6-[4-(4-methoxybenzoyl)-1-piperazinyl]carbostyryl mp230-233℃ (Chloroform-methanol) Yellow needles Example 5 6-[4-(3,4-dimethoxybenzoyl)-
1-Piperazinyl]carbostyryl mp265-266.5℃ (decomposition) (methanol-chloroform) Yellow granular crystal Example 6 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl]carbostyryl mp249.5 ~250℃ Methanol-Chloroform) Yellow needle-like crystal Example 7 6-[4-(4-cyanobenzoyl)-1-piperazinyl] carbostyril mp300-301℃ (decomposition) (Ethanol-Chloroform) Yellow powdery crystal Example 8 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]carbostyryl mp266-267℃ (decomposition) (methanol-chloroform) Yellow powder crystal Example 9 6-[4-(4- Nitrobenzoyl)-1-piperazinyl]carbostyryl mp265-266℃ (decomposed) (methanol-chloroform) Yellow needles Example 10 6-[4-(4-aminobenzoyl)-1-piperazinyl]carbostyryl mp287-290 °C (chloroform-methanol) Yellow powder crystal example 11 6-(4-benzoyl-1-piperazinyl]carbostyryl mp264-265 °C (ethanol-chloroform) Yellow needle crystal example 12 5-[4-(4- acetylaminobenzoyl)-
1-piperazinyl]-3,4-dihydrocarbostyryl mp300℃ or higher (chloroform-methanol) Colorless powder crystal Example 13 6-[4-(4-formyl)-1-piperazinyl]
Carbostyril mp286.5-288℃ (methanol) Yellow scaly crystals Example 14 6-[4-(4-methylthiobenzoyl)-1-
Piperazinyl]carbostyryl mp247.5-249.5℃ (chloroform-methanol) Yellow needle crystal Example 15 6-[4-(3-pyridylcarbonyl)-1-piperazinyl]3,4-dihydrocarbostyryl mp250-252℃ ( ethanol) yellow needles Example 16 6-[4-(4-methoxyphenylacetyl)-
1-Piperazinyl]-3,4-dihydrocarbostyryl mp266-268.5℃ (methanol) Yellow powder crystal Example 17 6-(4-phenylpropionyl-1-piperazinyl)-3,4-dihydrocarbostyryl mp189.5 ~191°C (chloroform-methanol) Yellow granular crystal Example 18 8-(4-benzoyl)-1-piperazinyl)carbostyryl mp244~245°C (ethanol) Colorless powder crystal Example 19 8-[4-(4- (Chlorobenzoyl)-1-piperazinyl]carbostyryl mp255.5-257℃ (ethanol-chloroform) Colorless powder crystal Example 20 8-[4-(3-chlorobenzoyl)-1-piperazinyl]carbostyryl mp208-209℃ (Ethanol) Colorless granular crystal Example 21 8-[4-(2-chlorobenzoyl)-1-piperazinyl]carbostyryl mp239-240.5℃ (Ethanol) Colorless needle crystal Example 22 8-[4-(4-methoxy) Benzoyl)-1-piperazinyl]carbostyryl mp208-210℃ (ethanol) Colorless scaly crystals Example 23 8-[4-(3,4-dimethoxybenzoyl)-
1-Piperazinyl]carbostyryl mp197-198℃ (ethanol-ether) Colorless scaly crystals Example 24 8-[4-(4-methylthiobenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostyryl mp178-179.5℃ (ethanol) Colorless granular crystal Example 25 7-[4-(4-methylthiobenzoyl)-1-
Piperazinyl]-3,4-dihydrocarbostyryl mp258-260℃ (Chloroform-methanol) Colorless edge-like crystals Example 26 6-[4-(4-methoxyphenylacetyl) 1
-Piperazinyl]carbostyryl mp224-225℃ (ethanol) Yellow needle-like crystals Example 27 6-[4-(4-hydroxyphenylacetyl)
-1-Piperazinyl]carbostyryl mp300℃ or above (dimethylformamide) Yellow powdery crystal reference example 18 6-(1-piperazinyl)-3,4-dihydrocarbostyryl monohydrobromide (3.5g) was added to dimethylformamide (dimethylformamide) Suspend in 40 ml (abbreviated as "DMF"), add 960 mg of sodium hydrogen carbonate, and leave at room temperature.
After stirring for 30 minutes, 6-(1-piperazinyl)-3,4-
After dihydrocarbostyril was prepared, 2.34 ml of triethylamine was added, and the mixture containing 2.9 g of 3,4-dimethoxybenzoyl chloride was stirred at room temperature.
Gradually add 10 ml of DMF solution dropwise. Stir for 30 minutes after addition. Pour into a large amount of saturated saline and extract with chloroform. Wash with saturated sodium bicarbonate solution, then water, and dry over anhydrous sodium sulfate. Distill the chloroform,
The residual crystals were recrystallized from chloroform-ethanol to give 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4 at mp238-239.5°C.
- 3.8 g of dihydrocarbostyril are obtained. Colorless granular crystal elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.69 6.49 10.51 Example 2-12, 14-
27 compounds are obtained. Example 28 25 g of 6-aminocarbostyryl, 50 g of bis(β-bromoethyl)amine hydrobromide and
Stir the DMF mixture at 80-90°C for 3 hours.
After cooling to room temperature, add 8.2g of sodium carbonate and
Stir at ~90°C for 4 hours. Cool to room temperature, collect precipitated crystals, wash with ethanol, dry, and recrystallize from ethanol-water to obtain 6-(1-piperazinyl).
22 g of carbostyril hydrobromide are obtained. mp300℃ or higher Pale yellow edge-shaped crystals Example 29 2 g of 6-(1-piperazinyl)carbostyryl hydrobromide was suspended in 20 ml of DMF, 2.34 ml of triethylamine was added, and 3,4-methylenedioxy was dissolved under stirring at room temperature. 1.43g of benzoyl chloride
Gradually add 2 ml of DMF solution dropwise. After dropping, stir at room temperature for 30 minutes, then pour into a large amount of water to remove precipitated crystals. After drying, purify with a silica gel column,
Recrystallized from chloroform-methanol, mp266~
1.9 g of 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]carbostyryl at 267°C (decomposed) is obtained. Yellow powder crystal Example 30 8-Aminocarbostyryl 15.47g and bis(β-dibromoethyl)amine hydrobromide 33
g in DMF and stirred at 70-80°C for 10 hours. Add 5.1 g of sodium carbonate to this and stir at the same temperature for 7 hours. After distilling off the solvent under reduced pressure, methanol is added to the residue and crystallized to obtain crude crystals.
This was recrystallized from methanol-ether and 8-
5.1 g of (1-piperazinyl)carbostyryl hydrobromide is obtained. mp300℃ or higher Colorless scaly crystal Example 31 8-(1-piperazinyl)carbostyryl 0.7g
and 0.2 g of sodium hydrogen carbonate were suspended in 5 ml of DMF and stirred at room temperature for 30 minutes. 0.4 ml of triethylamine is added to this liquid, and a solution of 0.47 g of 2-chlorobenzoyl chloride in 5 ml of DMF is added dropwise, and the mixture is further stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform. Wash the organic layer with water,
Next, the mixture is washed with saturated brine, dried over sodium sulfate, the solvent is distilled off under reduced pressure, and ether is added to crystallize. Recrystallized from ethanol to give 8-[4-(2-
0.24 g of chlorobenzoyl)-1-piperazinyl]carbostyryl is obtained. mp239-240.5℃ Colorless needle crystals Example 19 (a) Dissolve 9.36 g of 6-amino-3,4-dihydrocarbostyryl in 70 ml of methanol, and di-β-
Add 13.5 g of bromoethyl ether and stir and reflux for 10 hours. After cooling, add 3.06 g of potassium carbonate and reflux for 10 hours, then cool and collect the precipitated crystals.
Dissolve the crystals in 40 ml of water and make slightly alkaline with dilute sodium hydroxide solution. The mother liquor is distilled off, and isopropanol is added to the residue to collect precipitated crystals. 4.7 g of 6-(4-morpholino)-
3,4-dihydrocarbostyryl is obtained. IR
It was confirmed by the NMR spectrum. Elemental analysis C H N Calculated value (%) 67.24 6.90 12.07 Actual value (%) 67.12 7.02 11.98 (b) 6-morpholino-3,4-dihydrocarbostyryl 2.32 g, 4-methoxybenzylamine
Put 14.7g into a sealed tube and heat at 170-200°C for 5 hours. 4-Methoxybenzylamine was distilled off by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography and recrystallized from ethanol to give 6-[4] as colorless needle crystals at mp196-198℃.
0.35 g of -(4-methoxybenzyl)-1-piperazinyl]3,4-dihydrocarbostyryl is obtained. Elemental analysis C H N Calculated value (%) 71.79 7.12 11.97 Actual value (%) 71.65 6.98 12.10 Example 1 to 28, 30 in the same manner as Example 135
The compound is obtained. Reference example 20 6-[bis-(2-chloroethyl)amino]-3,
A mixture of 14.5 g of 4-dihydrocarbostyryl, 8.0 g of 4-methoxybenzylamine, and 70 ml of methanol was stirred and refluxed for 15 hours. Sodium carbonate after cooling
Add 3.06 g and stir and reflux for 8 hours. After cooling, collect the crystals that precipitate. Recrystallized from ethanol,
mp196-198℃, colorless needle-like crystals of 6-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-
8.1 g of dihydrocarbostyril are obtained. Elemental analysis C H N Calculated value (%) 71.79 7.12 11.97 Actual value (%) 71.62 7.21 11.82 In the same manner as Example 136, the above Examples 28 and 30
The compound is obtained. Reference Example 21 (a) 82 g of ethylene chlorohydrin is added to 81 g of 6-amino-3,4-dihydrocarbostyryl and stirred at about 160°C for 10 hours. After cooling, 100 ml of 10N-NaOH water is added to the reaction solution to separate the layers, and the organic layer is dried with KOH. The KOH is removed and the mother liquor is distilled under reduced pressure. 90 g of 6-[bis-(2-hydroxyethylamino)]-3,4-dihydrocarbostyryl are obtained. Confirmed by IR and NMR spectra. Elemental analysis C H N Calculated value (%) 62.40 7.20 11.20 Actual value (%) 62.27 7.09 11.34 (b) 6-[bis-(2-hydroxyethyl)amino]-3,4-dihydrocarbostyryl 9 g,
A mixture of 4.1 g of 4-methoxybenzylamine and 7.6 g of polyphosphoric acid is reacted at 160-170°C for about 6 hours. After that, the reaction solution was allowed to cool, and water
ml dropwise and dissolve. Neutralize with 48% sodium hydroxide and extract with chloroform. After dehydration with potassium carbonate, chloroform was distilled off and recrystallized from ethanol to give colorless needle-shaped crystals of 6-[4-(4-methoxybenzyl)-1-
8 g of piperazinyl]-3,4-dihydrocarbostyryl are obtained. Elemental analysis C H N Calculated value (%) 71.79 7.12 11.97 Actual value (%) 71.91 7.01 11.86 Compounds of Examples 28 and 30 are obtained in the same manner as in Reference Example 2. Reference example 22 6-amino-3,4-dihydrocarbostyryl
2.7g, N,N-(di-2-hydroxyethyl)-
3,4-dimethoxybenzamide 5.9g and 85%
8.6 g of phosphoric acid was reacted with stirring at 165-175°C for 4.5 hours. After cooling, about 50 ml of water is added dropwise to dissolve, neutralized with 48% aqueous sodium hydroxide solution, and extracted with chloroform. After dehydration with potassium carbonate, chloroform was distilled off and recrystallized with ethanol-chloroform.
4.7 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl were obtained. mp238-239.5°C Colorless granular crystal elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.95 6.23 10.51 Compounds of Examples 1-28 and 30 are obtained in the same manner as in Reference Example 22. Reference example 23 (a) 7.02g of p-aminoaniline in 150ml of toluene
and add 9.12 ml of triethylamine.
Next, a solution of 11 g of β-bromopropionyl chloride in 30 ml of toluene was added dropwise at 80° C. with stirring. Subsequently, after reacting for 30 minutes, the colored substance was removed, washed with water, dried, and the solvent was distilled off to form an oily N.
-(β-bromopropionyl)-p-amino-aniline is obtained. The yield was 10.1 g, confirmed by IR and NMR spectra. Elemental analysis C H N Calculated value (%) 44.44 4.53 11.52 Actual value (%) 44.32 4.61 11.43 (b) N-(β-bromopropionyl)-p-amino-aniline 14.0 g, bis-(β-bromoel)
A mixture of 18 g of amine monobromate and 70 ml of methanol was stirred and refluxed for 15 hours. After cooling, 3.06 g of sodium carbonate was added and the mixture was stirred and refluxed for 8 hours. After cooling, collect the crystals that precipitate and wash them with methanol.
5.3 g N-(β-bromopropionyl)-p-
Piperazinyl-aniline was obtained. IR and NMR
Confirmed from spectrum. Elemental analysis C H N Calculated value (%) 50.00 5.77 13.46 Actual value (%) 49.91 5.69 13.41 (c) 2.2 g of N-(β-bromopropionyl)-p-piperazinyl-aniline and 28 g of crushed anhydrous aluminum chloride were Suspended in 50ml of carbon sulfide,
Heat to reflux for 4 hours. The reaction solution was poured into ice water, the precipitate was collected, washed with water and ether, converted into a hydrobromide salt, recrystallized from methanol-water, and 0.9 g of 6-(1-piperazinyl)-3,4
-Dihydrocarbostyryl monohydrobromide is obtained. mp289-293℃ (decomposition) (methanol-water) Colorless needle crystal elemental analysis C H N Calculated value (%) 50.00 5.77 13.46 Actual value (%) 49.96 5.81 13.51 Example 1-28 in the same manner as Reference Example 23 , yielding 30 compounds. Reference Example 24 Add 2.6 g of 3,4-dimethoxybenzoic acid and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7 to 100 ml of dimethylformamide, and add chloroformic acid to 100 ml of dimethylformamide while stirring with external ice cooling. Add 1.5 ml of isobutyl dropwise. After dropping, stir for 30 minutes and add 6-(1-piperazinyl)-
A solution of 2.3 g of 3,4-dihydrocarbostyryl dissolved in 40 ml of dimethylformamide is added and stirred at room temperature for 5 hours. After the reaction, the solvent was distilled off, the residue was extracted with about 300 ml of chloroform, and diluted with dilute NaHCO ₃
Wash with water, water, dilute hydrochloric acid, and water. After chloroform was distilled off, the residue was recrystallized from ethanol-chloroform and mp238-239.5°C. 6-[4-(3,
4-dimethoxybenzoyl-1-piperazinyl]
1.7 g of -3,4-dihydrocarbostyril is obtained. Colorless granular crystal elemental analysis C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.72 6.45 10.52 Example 1-12, 14-
27 compounds are obtained. Reference example 25 A mixture of 1.22 ml of acetic anhydride and 0.5 ml of formic acid was heated to 50 to 60 ml.
Stir at ℃ for 2 hours. Cool to room temperature and add 5-piperazinyl-3,4-dihydrocarbostyryl.
Gradually add 1.0g. The reactants solidify. Add 5 ml of dichloromethane and stir at room temperature for 2 hours. Add a large amount of water and extract with chloroform.
After washing with water, it is dried over anhydrous sodium sulfate and chloroform is distilled off. The residue was recrystallized with methanol,
mp263-265℃ 5-(4-formyl-1-piperazinyl)-3,4-dihydrocarbostyryl 420 mg
I got it. Colorless granular crystals The compound of Example 13 is obtained in the same manner as in Reference Example 25. Reference example 26 8.8 g of 2-nitro-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid
Dissolve in 88 ml of DMF, add 1.6 g of Raney nickel catalyst, apply hydrogen pressure of 3 kg/cm ² using a Parr, and react 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 collected, recrystallized with DMF, and further recrystallized with a chloroform-methanol mixed solvent to obtain 6-[4-(3,
4-dimethoxybenzoyl)-1-piperazinyl]
5.8 g of -3,4-dihydrocarbostyril are obtained. mp238-239.5°C Compounds of Examples 15-17, 24, and 25 are obtained in the same manner as in Reference Example 26. Example 32 1.0 g of 6-piperazinyl-3,4-dihydrocarbostyryl monohydrobromide was suspended in DMF,
Add 296 mg of sodium hydrogen carbonate and stir at room temperature (30 minutes) to obtain 6-piperazinyl-3,4-dihydrocarbostyryl, then add triethylamine.
After adding 0.62 ml, the solution is gradually added dropwise to 605 ml of 4-acetyloxybenzoyl chloride in 5 ml of DMF. After dropping, stir at room temperature for 1 hour. Pour into a large amount of water and extract with chloroform. After sequentially washing with saturated sodium hydrogen carbonate and water, drying with anhydrous sodium sulfate. Distill off the chloroform and add 6-
[4-(4-acetyloxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyryl is obtained. Elemental analysis (as C ₂₂ H ₂₃ N ₃ O ₄ ) C H N Calculated value (%) 67.16 5.89 10.68 Actual value (%) 67.04 5.98 10.49 Example 33 (a) p-[4-(3,4-dimethoxybenzoyl) )
-1-Piperazinyl] 11g of aniline in benzene
Dissolve in 100ml and add 4.56ml of triethylamine. Next, a solution of 3.94 g of β-methoxyacrylic acid chloride in 20 ml of benzene was added dropwise under reflux.
Reflux for 1 hour after addition. After the reaction is completed, the reaction solution is washed with water, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography to obtain N-(β-
methoxyacryloyl)-p-[4-(3,4-
dimethoxybenzoyl)-1-piperazinyl]
Obtain 10 g of aniline. Elemental analysis (as C ₂₃ H ₂₇ N ₃ O ₅ ) C H N Calculated value (%) 64.92 6.40 9.88 Actual value (%) 64.77 6.51 9.75 (b) N-(β-methoxyacryloyl)-p-[4
-(3,4-Dimethoxybenzoyl)-1-piperazinyl] 5 g of aniline was added to 60% sulfuric acid with stirring at room temperature.
Gradually add to 50ml. Continue the reaction for 2 hours.
The reaction solution was neutralized with 10N-NaOH, the precipitated crystals were collected, washed with water, and then recrystallized with chloroform-methanol to give 6-[4-(3,
230 mg of 4-dimethoxybenzoyl)-1-piperazinyl]carbostyril are obtained. Elemental analysis of yellow granular crystals (as C ₂₂ H ₂₃ N ₃ O ₄ ) C H N Calculated value (%) 67.16 5.89 10.68 Actual value (%) 67.03 5.78 10.81 Example 1 to 28, 30 in the same manner as Example 33 The compound is obtained. Example 146 6-bromo-3,4-dihydrocarbostyryl
5.6g, 4-(3,4-dimethoxybenzoyl)-
Mix 2.9 g of 1-piperazine, 1.8 g of potassium carbonate, and 0.2 g of copper powder with 60 ml of 3-methoxybutanol,
Reflux for 5 hours. The reaction solution was filtered, the mother liquor was concentrated to dryness under reduced pressure, and the residue was extracted with methanol-chloroform. The chloroform layer is distilled off, and the resulting residue is purified by preparative silica gel thin layer chromatography. Recrystallize from chloroform-ethanol to obtain 6-[4-(3,
4-dimethoxybenzoyl)-1-piperazinyl]
489 mg of -3,4-dihydrocarbostyril is obtained. Colorless granular crystal elemental analysis (as C ₂₂ H ₂₅ N ₃ O ₄ ) C H N Calculated value (%) 66.84 6.33 10.63 Actual value (%) 66.70 6.48 10.53 Example 1, 2, 4 in the same manner as Example 146
~91, 128, 130, 132, 133 are obtained. Reference example 28 Dissolve 1 g of 3-{2-amino-5-[4-(3,4-dimethoxybenzoyl)piperazino]phenyl}propionic acid in a mixed solvent of chloroform and methanol, add 1 ml of concentrated hydrochloric acid, and bring to room temperature. Stir for 1 hour. The solvent was distilled off and recrystallized from ethanol-chloroform to give 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-
Obtain 500 mg of dihydrocarbostyril. mp238-239.5°C Colorless granular crystals In the same manner as Reference Example 28, Examples 15-17, 24,
Compounds 25, 28, and 30 are obtained. Example 34 3-{2-aminoacetyl-5-[4-(3,4
- Dimethoxybenzoyl)piperazino]phenyl}propionic acid 10g to diphenyl ether 100g
ml and stir at 90-100°C. After reacting for 8 hours, pour into water and collect the precipitated crystals. This was separated by silica gel column chromatography, recrystallized from methanol-chloroform, and 6-[4-(3,4
-dimethoxybenzoyl)-1-piperazinyl]
Obtain Carbostyril. Yield 1.2g mp265-266.5℃ (decomposition) Yellow granular crystals Produced in the same manner as in Example 34, above Examples 1-4, 6-
Compounds 14, 18-23, 28, 30 are obtained. Reference example 29 5g of 2-amino-5-[4-(3,4-dimethoxybenzoyl)piperazino]cinnamic acid in DMF50
ml, add 0.5g of 5% palladium on carbon,
A hydrogen pressure of 3 kg/cm ² was added using a pearl, and the mixture was reacted 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 were collected 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 granular crystals Compounds of Examples 15-17, 24, and 25 are obtained in the same manner as in the examples. Pharmacological test (a) Pentobarbital sodium salt is intravenously administered at a rate of 30 mg/Kg to male and female mixed-breed adult dogs weighing 8 to 13 kg and anesthetized. After intravenously administering heparin sodium salt at a rate of 1000 U/Kg, the animals were bled to death and the hearts were removed into a lock solution. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Then, pre-prepared sodium salt of pentobarbital (30
Anesthetized with heparinized (1000U/Kg, intravenous) body weight 18~
Blood from the carotid artery of a 27 kg male-male mixed-breed adult dog is guided 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 muscle 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 have been reported by Chiba et al. [Japan, J.
Pharmacol, 25 , 433-439 (1975), Naunyn-
Schmiedberg's 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 a test compound is expressed as a percent change in tension developed before compound administration, and the change in coronary blood flow is expressed as an absolute value (ml/min) from before administration. The results are shown in Table 1 below. (b) Anesthetize an adult male and female mixed breed dog weighing 8 to 13 kg by intravenously administering pentobarbital sodium salt at a rate of 30 mg/kg. After intravenously administering heparin sodium salt at a rate of 1000 U/Kg, the animals were bled to death and the hearts were removed. The specimen mainly consisted of papillary muscles and ventricular septum, and was made using blood drawn from a donor dog through a cannula inserted into the anterior septal artery.
Perfusion is performed at a constant pressure of mmHg. Donor dogs weigh 18~
The patient weighs 27 kg and is anesthetized by intravenously administering 30 mg/Kg of pentobarbital sodium salt, and 1000 U/Kg of heparin sodium salt intravenously. Using bipolar electrodes, apply a voltage 1.5 times the value (0.5
~3V), stimulate the papillary muscles with a square wave with a stimulation width of 5 msec and a stimulation frequency of 120 times per minute. The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of generated tension and blood flow are recorded on an ink recorder.
The details of this method have already been reported by Endo and Hashimoto (Am.J.Physiol., 218 , 1459~
1463, 1970). The test compound is administered intra-arterially in a volume of 10-30 μ over 4 seconds. The inotropic effect of the test compound is expressed as a % change in the tension generated before drug administration. The effect on coronary blood flow is expressed as the change in absolute value (ml/min) from before administration. The results are shown in Table 2 below. Test compound No. 1 6-[4-(4-methylthiobenzoyl)-1
-piperazinyl]-carbostyryl 2 6-[4-(3-pyridylcarbonyl)-1-
piperazinyl]-3,4-dihydrocarbostyryl 3 6-[4-(4-methoxyphenylacetyl)
-1-piperazinyl]-3,4-dihydrocarbostyryl 1/2 hydrate 4 6-(4-phenylpropionyl-1-piperazinyl)-3,4-dihydrocarbostyryl 5 8-[4-(3 ,4-dimethoxybenzoyl)
-1-piperazinyl]carbostyryl 6 6-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]carbostyryl 7 6-[4-(3-chlorobenzoyl)-1-piperazinyl]carbostyryl 8 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]carbostyryl 9 6-[4-(4-nitrobenzoyl)-1-piperazinyl]carbostyryl 10 6-[4-(4-cyanobenzoyl)-1-piperazinyl]carbostyryl 11 6-(4-benzoyl-1-piperazinyl)
Carbostyryl 12 6-[4-(4-chlorobenzoyl-1-piperazinyl) Carbostyryl 13 6-[4-(3,4,5-trimethoxybenzoyl-1-piperazinyl] Carbostyryl 6-(4-ethoxycarbonyl) -1-piperazinyl)carbostyryl 15 6-[4-(4-aminobenzoyl)-1-piperazinyl]carbostyryl 16 6-[4-(4-formyl)1-piperazinyl]carbostyryl 17 7-(4-piperazinyl)carbostyryl 17 Enylpropionyl-1-piperazinyl)-3,4-dihydrocarbostyryl 18 Papaverine (control compound) 19 Amrinone (control compound)

【table】

【table】

[Table] Formulation example 1 6-[4-(3,4-dimethoxybenzoyl)
-1-piperazinyl]carbostyryl 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.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom. R ² represents a hydrogen atom. R ³ represents a hydrogen atom, a lower alkanoyl group, a pyridylcarbonyl group, a lower alkoxycarbonyl group, a phenylcarbonyl group, or a phenyl lower alkanoyl group. On the phenyl ring of the above phenyl carbonyl group and phenyl lower alkanoyl group, a lower alkoxy group, a halogen atom, a cyano group,
It may have 1 to 3 groups selected from the group consisting of a nitro group, 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. 3rd and 4th position of carbostyril skeleton
The carbon-carbon bond with the position represents a single bond or a double bond. However, when the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton is a single bond, R ³ is a group consisting of a lower alkoxy group, a halogen atom, a cyano group, a nitro group, an amino group, and a hydroxyl group on the phenyl ring. It must not be a phenylcarbonyl group, a hydrogen atom, a lower alkanoyl group, or a lower alkoxycarbonyl group that may have one to three groups selected from the following, or a lower alkylenedioxy group. ] A carbostyryl derivative represented by these and its salt.