JPS649315B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel carbostyryl derivatives and salts thereof. The galbostyryl derivative of the present invention has the following general formula:
It is expressed as (1). [In the formula, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom,
Phenoxy lower alkyl group, lower alkyl group, lower alkyl group substituted with one phenyl group, which may have 1 to 3 groups selected from lower alkyl groups and halogen atoms as substituents on the phenyl ring, or on the phenyl ring 1 halogen atom as a substituent
It shows a benzoyl group having ~3 benzoyl groups. ] The carbostyril derivative represented by the above general formula (1) has an effect of enhancing myocardial contraction (positive inotropic effect) and an effect of increasing coronary blood flow, such as congestive heart failure, mitral valvular heart disease, atrial It is effective as a cardiotonic agent for the treatment of various heart diseases such as fibrillation, flutter, and paroxysmal atrial tachycardia. In particular, the derivative of the present invention represented by the above general formula (1) has an excellent positive inotropic effect and an effect of increasing coronary blood flow, but is characterized in that it has almost no effect of increasing heart rate. Specific examples of each group defined by R ¹ and R ² in the above general formula (1) are illustrated below. Lower alkyl group...methyl, ethyl, propyl,
Alkyl groups having 1 to 6 carbon atoms such as isopropyl, butyl, tert-butyl, pentyl, hexyl, etc. Phenoxy lower alkyl group... phenoxymethyl, 2-phenoxyethyl, 2-phenoxypropyl, 3-phenoxypropyl, 1-methyl-2
-Phenoxyethyl, 2-phenoxybutyl, 3
-Phenoxybutyl, 4-phenoxybutyl,
1,1-dimethyl-2-phenoxybutyl, 2-
Phenoxypentyl, 3-phenoxypentyl,
An alkyl group having 1 to 6 carbon atoms having a phenoxy group such as 4-phenoxyhexyl as a substituent. A lower alkyl group substituted with one phenyl group, which may have 1 to 3 groups selected from lower alkyl groups and halogen atoms...benzyl, 2-phenylethyl, 3-phenylpropyl, 6-phenylhexyl, 4-phenylbutyl , C1-C6 alkyl having one unsubstituted phenyl group such as 5-phenylpentyl, 2-chlorobenzyl, 3
-bromobenzyl, 4-iodobenzyl, 2-
(4-fluorophenyl)ethyl, 1-(3-chlorophenyl)ethyl, 6-(4-bromophenyl)hexyl, 5-(3,4-dichlorophenyl)pentyl, 1,1-dimethyl-2-(2 ,5
-dibromphenyl)propyl, 2- or 3
-Methylbenzyl, 2-(4-methylphenyl)
Ethyl, 2-ethylbenzyl, 1-(3-ethylphenyl)ethyl, 3-(4-ethylphenyl)
Propyl, 6-(4-isopropylphenyl)hexyl, 4-(4-hexylphenyl)butyl,
1,1-dimethyl-2-(3,4-dimethylphenyl)ethyl, 5-(3,4-diethylphenyl)pentyl, 6-(3,5-dimethylphenyl)hexyl, 2-methyl-3 -(2,5-dimethylphenyl)propyl, 3-methyl-4-chlorobenzyl, 2-chloro-6-methylbenzyl,
Phenyl(4-chlorophenyl)methyl, 3,
4,5-trimethylbenzyl, 3,4,5-trichlorobenzyl, etc. having 1 to 6 carbon atoms on the phenyl ring
An alkyl group having 1 to 6 carbon atoms and having one phenyl group having 1 to 3 substituents selected from the group consisting of an alkyl group and a halogen atom. One halogen atom as a substituent on the phenyl ring
~3 benzoyl groups...2-, 3- or 4-chlorobenzoyl, 2-, 3- or 4-
Fluorobenzoyl, 2-, 3- or 4-brombenzoyl, 2-, 3- or 4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,
6-dichlorobenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3,5
- One halogen atom on the phenyl ring of dibromobenzoyl, 3,4,5-trichlorobenzoyl, etc.
~3 benzoyl groups. The derivative of the present invention can be used, for example, in the following reaction scheme-1.
It can be manufactured by the following method. [In the formula, R ¹ and R ² are the same as above. ] The method shown in the above reaction scheme-1 is based on the general formula
This is carried out by reacting the carbostyril derivative represented by (2) or its carboxy group-activated derivative with the piperazyl derivative represented by general formula (3) in a conventional amide bond forming reaction.
The amide bond formation reaction can be carried out using various known methods such as (a) mixed acid anhydride method, that is, the carbostyryl derivative (2) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, which is then reacted with the piperazine derivative (3). Method: (b) Active ester method, i.e. carbostyryl derivative (2) is converted into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and piperazine derivative (3) is added to this. ); (c) carbodiimide method, that is, a method of condensing the carbostyril derivative (2) with the piperazine derivative (3) in the presence of an activating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole; (d) other methods For example, carbostyryl derivative (2) is converted into carboxylic acid anhydride using a dehydrating agent such as acetic anhydride, and this is reacted with piperazine derivative (3). ) under high pressure and high temperature,
This can be carried out by, for example, a method in which an acid halide of the carbostyril derivative (2), that is, a carboxylic acid halide, is reacted with the piperazine derivative (3). Alternatively, the carbostyryl derivative (2) can be activated with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and then reacted with the piperazine derivative (3). In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is obtained by the usual Schotten-Baumann reaction, and by reacting it with the piperazine derivative (3) without isolation, the general formula The compound of the present invention (1) is produced. Short story
The Baumann reaction is usually carried out using basic compounds commonly used in the Schotten-Baumann reaction, 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),
In the presence of an organic base such as 1,4-diazabicyclo[2,2,2]octane (DABCO) and an inorganic ash base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc., at approximately -20 to 100 °C
It is preferably carried out at 0 to 50°C for about 5 minutes to 10 hours, preferably 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the piperazine derivative (3) is carried out at about -20 to 150°C, preferably 10 to 50°C, for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. be exposed. In addition, the above mixed acid anhydride method generally uses solvents commonly used in this type of mixed acid anhydride method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate, ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc. It is done in a solvent. Examples of the alkylhalocarboxylic acids used in the production of the mixed acid anhydride include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc., and these are usually carbostyril derivatives ( 2)
at least equimolar amounts, preferably about 1 to 2
Used in twice the molar amount. The proportion of the piperazine derivative (3) to be used is usually at least equimolar, preferably about 1 to 2 times the molar amount of the carbostyril derivative (2). The active ester method shown in (b) above, for example when N-hydroxysuccinimide ester is used, is carried out in a suitable solvent that does not affect the reaction. Examples of the solvent include halogen hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, methyl acetate, Esters such as ethyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The reaction is 0
The process is completed in 5 to 30 hours at a temperature of ~150°C, preferably 10 to 100°C. The ratio of piperazine derivative (3) and N-hydroxysuccinimide ester to be used is usually at least equimolar, preferably equimolar to twice molar, of the former to the latter. When employing the method of reacting the piperazine derivative (3) with a carboxylic acid halide among the other methods shown in (d) above, the reaction is carried out in a suitable solvent in the presence of a basic compound. As the basic compound, a wide variety of known compounds can be used, including, for example, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc., in addition to the basic compounds used in the above-mentioned Schodzden-Baumann reaction. In addition to the solvents used in the Schotten-Baumann reaction described above, examples of the solvent include methanol, ethanol, propanol, butanol,
Examples include alcohols such as -methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, etc., and mixed solvents of two or more of the above solvents. The ratio of the piperazine derivative (3) and the carboxylic acid halide to be used is not particularly limited and is appropriately selected within a wide range, but the former is usually used in at least an equimolar amount, preferably an equimolar to twice the molar amount, of the latter. It is better. The reaction is usually carried out at about -20 to 180°C, preferably about 0 to 150°C, and is generally completed in 5 minutes to 30 hours. Further, a method of activating the carbostyril derivative (2) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and reacting it with the piperazine derivative (3) can be carried out in an appropriate solvent. Any solvent can be used as long as it does not affect the reaction, but specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether,
Examples include ethers such as tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. In the above reaction, since the piperazine derivative (3) itself acts as a basic compound, the reaction proceeds well by using it in excess of the theoretical amount, but if necessary, other basic compounds such as triethylamine may be used. , trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, DBU,
Organic bases such as DABCO and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. can also be used. The reaction is carried out at about 0-150°C, preferably about 0-100°C, and the reaction time is about 1-30 hours. The ratio of the phosphorus compound and the piperazine derivative (3) to the carbostyryl derivative (2) is usually at least equimolar, preferably 1 to 3 times the molar amount. In addition, compounds belonging to a certain group among the derivatives of the present invention (the following general formulas (1-a), (1-b) and (1-c)
) can also be produced by the methods shown in the following reaction schemes -2 to -5, respectively. [In each formula, R ¹ is the same as above. R ² ' is a lower alkanoyl group, a lower alkoxycarbonyl group, a furoyl group, or a phenyl ring having 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, and a cyano group as substituents, or Indicates a benzoyl group that may have a lower alkylenedioxy group. X ¹ represents a hydroxyl group. ] That is, the derivative of the present invention represented by the general formula (1-a) above is produced by reacting the compound of the general formula (4) with the compound of the general formula (5) or a compound whose carboxyl group is activated. Ru. The above reaction can be carried out under the same operation and conditions as the reaction between the carbostyryl derivative represented by the general formula (2) shown in the reaction scheme-1 and the piperazine derivative represented by the general formula (3). . [In each formula, R ¹ is the same as above. R ² ″ is a lower alkenyl group, a lower alkynyl group, a lower alkanesulfonyl group, a phenoxy lower alkyl group, a lower alkyl group that may have a cyano group or a carbamoyl group as a substituent, a lower alkyl group as a substituent on the phenyl ring, 1 group selected from a lower alkoxy group, a halogen atom, a nitro group, an amino group, a lower alkanoylamino group, and a lower alkylthio group.
Indicates a phenyl lower alkyl group which may have ~3 phenyl lower alkyl groups, or a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. X ² represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group]. That is, the derivative of the present invention represented by general formula (1-b) is produced by reacting a compound represented by general formula (4) with a compound represented by general formula (6). This reaction can be carried out under the same operation and conditions as the method of reacting the piperazine derivative (3) with the carboxylic acid halide described above. In addition, in the compound represented by the above general formula (6),
Specifically, the halogen atom defined by X ² is chlorine,
These are fluorine, bromine, and iodine atoms, and examples of lower alkanesulfonyloxy groups include methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy, and pentanesulfonyloxy. , hexanesulfonyloxy group, etc., and specific examples of the arylsulfonyloxy group include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy,
Examples include substituted or unsubstituted arylsulfonyloxy groups such as 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and α-naphthylsulfonyloxy groups, and specific examples of aralkylsulfonyloxy groups include benzylsulfonyl Oxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy. [In each formula, R ¹ is the same as above. R ² is a lower alkenyl group, a lower alkynyl group, a phenoxy lower alkyl group, a lower alkyl group that may have a cyano group or a carbamoyl group as a substituent, or a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent on the phenyl ring. , nitro group, amino group,
It represents a phenyl lower alkyl group which may have 1 to 3 groups selected from a lower alkanoylamino group and a lower alkylthio group. X is the above X ¹ and
Indicates the same group as X ² group. ] That is, the derivative of the present invention represented by the general formula (1-c) is obtained by reacting the compound of the general formula (2) with the compound of the general formula (7), and reacting the compound of the general formula (8) thus obtained with the general formula ( It can be produced by reacting the compound of 9). The reaction in the first step is carried out by the general formula
The reaction is carried out under the same operation and conditions as the reaction between the compound (2) and the compound of general formula (3). The second step following the first step is carried out as follows depending on the type of X in the compound of general formula (8). That is, when using a compound in which X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group as the compound of the general formula (8), the compound of the general formula (8) and the general formula (9) The reaction with the compound is generally carried out in a suitable inert solvent in the presence or absence of a basic condensing agent. Examples of inert solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, methanol, ethanol,
Examples include lower alcohols such as isopropanol and butanol, acetic acid, ethyl acetate, dimethyl sulfoxide, dimethylformamide, and hexamethylphosphoric triamide. 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, and metals such as sodium methylate and sodium ethylate. Examples include alcoholates, pyridine, tertiary amines such as triethylamine, and the like. The ratio of the compound of general formula (8) and the compound of general formula (9) to be used is not particularly limited and can be appropriately selected within a wide range, and usually the latter is at least equimolar to the former, preferably equimolar to It is preferable to use 5 times the molar amount. The reaction is usually carried out at a temperature of about 40 to 120°C.
The temperature is preferably 50 to 100°C, and generally 5 to 100°C.
The reaction completes in about 30 hours. In addition, when a compound in which X represents a hydroxyl group is used as the compound of general formula (8), the reaction between the compound of general formula (8) and the compound of general formula (9) may be carried out in the presence of a dehydration condensation agent in the absence of a solvent or It is carried out in a suitable solvent. Examples of the dehydration condensation agent include condensed phosphoric acids such as polyphosphoric acid, phosphoric acids such as orthophosphoric acid, pyrophosphoric acid, and metaphosphoric acid, phosphorous acids such as orthophosphorous acid, phosphoric anhydrides such as phosphorus pentoxide, Examples include acids such as hydrochloric acid, sulfuric acid, and boric acid, metal phosphates such as sodium phosphate, boron phosphate, ferric phosphate, and aluminum phosphate, activated alumina, sodium bisulfate, and Raney nickel. Examples of the solvent include high boiling point solvents such as dimethylformamide and tetralin. The ratio of the compound of general formula (8) and the compound of general formula (9) to be used is not particularly limited and can be appropriately selected within a wide range, and usually the former is used in an amount of about 0.8 molar or more relative to the latter, preferably 0.8 molar.
It is preferable to use a molar 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, and is usually at least a catalytic amount for the compound of general formula (8),
It is preferable to use about 0.5 to 5 times the molar amount.
The above reaction may advantageously be carried out in a stream of inert gas such as CO ₂ or N ₂ to prevent oxidation reactions.
The reaction is usually carried out under normal pressure, preferably at about 100 to 350°C.
It is carried out at 125-255°C for about 3-10 hours. [In each formula, R ¹ and R ² are the same as above. ] The derivative of the present invention represented by the general formula (1-c) can also be obtained by reacting the compound of the general formula (2) with morpholine (10) to obtain a morpholine derivative (11) as described above, and then adding the compound of the general formula (1-c) to the morpholine derivative (11). It can also be produced by reacting the compound 9). In the above, the compound of general formula (2) and morpholine (10)
The reaction between the compound of the general formula (2) and the general formula
It can be carried out under the same operation and conditions as the reaction with compound (3). The reaction between the thus obtained compound of general formula (11) and the compound of general formula (9) is carried out without a solvent or in the presence of an acid in a suitable solvent. As the solvent, for example, a high boiling point solvent such as tetralin, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, etc. can be used. As the acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc. can be used. The ratio of the compound of general formula (11) and the compound of general formula (9) to be used is not particularly limited and can be appropriately selected within a wide range, and usually the latter is at least equimolar to the former, preferably equimolar. It is preferable to use up to 2 times the molar amount. The reaction is usually carried out at a temperature of about 50 to 250°C, preferably 150 to 200°C, and is generally completed in about 1 to 24 hours. Furthermore, R ¹ in the derivative of the present invention represented by general formula (1)
is a group other than a hydrogen atom (general formula (1-
Compound e) can also be produced from a compound in which R ¹ is a hydrogen atom (compound of general formula (1-d)) by the method shown in the following reaction scheme-6. [In each formula, R ² and X ² are the same as above. R ¹ ′ represents an R ¹ group other than a hydrogen atom. However, R ² is not a hydrogen atom. ] In the above, the reaction between the compound of general formula (1-d) and the compound of general formula (12) is preferably carried out, for example, in the presence of a basic compound in a suitable solvent. Here, examples of basic compounds include sodium hydride,
Potassium, sodium, sodium amide, potassium amide, etc. can be mentioned. Examples of the solvent include ethers such as dioxane, diethylene glycol, and dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of the compound of general formula (1-d) and the compound of general formula (12) to be used is not particularly limited and can be appropriately selected within a wide range, and usually the latter is at least equimolar to the former, preferably equimolar. It is preferable to use about 2 to 2 times the mole amount. The reaction is usually carried out at around 0 to 70°C, preferably around 0 to room temperature, and generally at a temperature of 0.5 to 12
The reaction completes in about an hour. Furthermore, among the compounds of the present invention represented by general formula (1-d), compounds in which R ² is a group having an amino group as a substituent on the phenyl ring are those in which the substituent on the phenyl ring is a nitro group. It can also be easily produced by reducing a compound. This reduction can be carried out under conventional conditions for reducing aromatic nitro groups to aromatic amino groups. More specifically, a method using a reducing agent such as sodium sulfite or sulfur dioxide gas, a catalytic reduction method using a reduction catalyst such as palladium-carbon, etc. may be used. In the reaction schemes -1, -4 and -5 detailed above, the general formula used for the production of the derivative of the present invention
The compounds in (2) include some new compounds,
This compound can be produced, for example, by the method shown in Reaction Scheme-7 below. [In the formula, R ¹ and X are the same as above. R ³ is an aromatic amine residue, R ³ -H is an aromatic amine, or
X ² ′ represents a halogen atom. ] In the above, the reaction to obtain the compound of general formula (15) can be carried out by reacting the compound of general formula (13) with aromatic amines (14) in a suitable solvent or in the absence of a solvent. Any solvent can be used as long as it does not affect the reaction, such as halogenated hydrocarbons such as methylene chloride, chloroform, and dichloromethane, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and acetic acid. Esters such as methyl and ethyl acetate, N,N-dimethylformamide,
Examples include aprotic polar solvents such as dimethyl sulfoxide and hexamethyl phosphoric triamide. Examples of aromatic amines include pyridine and quinoline. The amount of the aromatic amine used is
It is preferable to use at least an equimolar amount, preferably a large excess amount, relative to the compound of general formula (13). The reaction temperature is 50-200°C, preferably 70-150°C,
The reaction is completed in 3 to 10 hours. Furthermore, the hydrolysis reaction of the compound of general formula (15) obtained above is as follows:
Using an inorganic base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or hydrobromic acid in water or an alcohol such as methanol or ethanol, it takes about 1 to 10 hours at room temperature to 150°C. It is done. In addition, the piperazine derivative represented by the general formula (3) used as the other raw material in Reaction Scheme-1 also includes a new compound as a part of it, and this compound is a combination of the compound of the general formula (4) and the general formula It can be easily obtained by substituting piperazine for the compound of general formula (4) in the reaction with the compound of general formula (5) or general formula (6). Among the carbostyryl derivatives represented by the general formula (1) of the present invention, compounds having a basic group can be easily converted into acid addition salts by the action of a pharmaceutically 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. . The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like. Incidentally, the present invention naturally also includes optical isomers. The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( liquid agents, suspension agents, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. absorption enhancers such as grade ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite,
Examples include adsorbents such as colloidal silicic acid, purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used.
Examples include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar. When forming into a suppository, a wide range of conventionally known carriers can be used, including polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, 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 may be included in the preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavors, sweeteners, and other pharmaceuticals may be included in the preparation, if necessary. The amount of the compound of general formula (1) to be contained in the pharmaceutical preparation (cardiotonic agent) thus prepared is not particularly limited and can be selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 70% by weight of the total pharmaceutical composition. The content is preferably 1 to 30% by weight. There are no particular restrictions on the method of administering the above-mentioned cardiotonic agent, and it is administered 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 intradermally.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally. The dosage of the above-mentioned cardiotonic agent is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of general formula (1), which is the active ingredient, is usually about 1 kg per 1 kg of body weight per day. The dose is preferably 0.01 to 10 mg. It also contains 0.1 of the active ingredient in dosage unit form.
It is best to contain ~200mg. Reference examples and examples are listed below. Reference example 1 6-(α-pyridinium acetyl)-3,4-
Suspend 50 g of dihydrocarbostyryl chloride and 50 g of sodium hydroxide in 1 part of water, and heat at 90 to 100°C.
Stir for 3 hours. After the reaction is complete, add concentrated hydrochloric acid to adjust the pH.
The precipitated crystals were collected and recrystallized from dimethylformamide to obtain 19.1 g of 6-carboxy-3,4-dihydrocarbostyryl. mp.300℃ or higher Pale yellow powdery crystal Reference example 2 6-carboxy-3,4-dihydrocarbostyryl 10g and N-hydroxysuccinimide 6.0
Suspend g in 200 ml of dioxane. Next, under ice-cooling stirring, 12.4 g of dicyclohexylcarbodiimide
Add 50 ml of dioxane solution dropwise. Then further
Heat and stir at 90°C for 4 hours. After the reaction is completed, the mixture is allowed to cool to room temperature, the precipitated crystals are removed, and the mother liquor is distilled off. Recrystallization from dimethylformamide-ethanol yields 10.8 g of succinimide, 3,4-dihydrocarbostyryl-6-carboxylate. mp.234.5-236℃ Colorless flaky crystal Reference example 3 127 mg of succinimide 3,4-dihydrocarbostyryl-6-carboxylate and 39 mg of diethanolamine are dissolved in 2 ml of dimethylformamide and stirred overnight. Water is added to the reaction mixture, extracted with chloroform, and washed sequentially with water and saturated brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure, and acetone was added to the residue to crystallize it.
48 mg of (diethanolaminocarbonyl)-3,4-dihydrocarbostyril is obtained. mp.131~134
°C Reference example 4 6-(diethanolaminocarbonyl)-3,
Add 30 ml of thionyl chloride to 2.2 g of 4-dihydrocarbostyril, stir at room temperature for 5 hours, concentrate under reduced pressure, and add 50 ml of benzene. The operation of concentrating under reduced pressure is repeated three times to obtain 6-{[di-(2-chloroethyl)]aminocarbonyl}-3,4-dihydrocarbostyryl. Reference example 5 1.0 g of succinimide 3,4-dihydrocarbostyryl-6-carboxylate and morpholine
Dissolve 0.37g in 2ml of dimethylformamide,
Stir for 3 hours. Water is added to the reaction mixture, extracted with chloroform, and washed sequentially with water and saturated brine. After drying over sodium sulfate, the solvent is distilled off under reduced pressure, and acetone is added to the residue for crystallization. This gives 6-morpholinocarbonyl-3,4-dihydrocarbostyryl. Yield: 150 mg mp. 206-207°C (ethanol) Colorless granular crystals Example 1 127 mg of succinimide 3,4-dihydrocarbostyryl-6-carboxylate and 93 mg of benzylpiperazine are dissolved in 2 ml of dimethylformamide and stirred overnight. Water is added to the reaction mixture, extracted with chloroform, and washed with water and saturated brine. After drying over sodium sulfate, the solvent is distilled off under reduced pressure, and acetone is added to the residue for crystallization. Recrystallized from ethanol to give 6-(4-benzyl-1-
130 mg of piperazinylcarbonyl-3,4-dihydrocarbostyryl are obtained. mp. 198-200°C Colorless needle crystals In the same manner as in Example 1, using appropriate starting materials, the following compounds of Examples 2 to 16 are obtained. Example 2 6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp. 271-274°C (decomposition) Colorless needle crystals Example 3 6 -(1-piperazinylcarbonyl)-3,4
-Dihydrocarbostyryl mp. 211.5-213℃ Colorless phosphorus flakes Example 4 6-[4-(4-methylbenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp 280-283℃ (decomposition) Colorless phosphorus flake Example 5 6-[4-(3,4-dichlorobenzyl)-1
-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp. 284-287℃ (decomposition) Colorless phosphorus flakes Example 6 6-[4-(4-chlorobenzyl)-1-pipe Radinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp. Colorless needle crystals above 300°C Example 7 6-[4-(3-chlorobenzoyl)-1-piperazinylcarbonyl]-3, 4-dihydrocarbostyryl mp. 258.5-260℃ Colorless powder crystal Example 8 6-[4-(4-brombenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl mp. 265.5-267.5 °C Colorless powder crystal Example 9 6-[4-(3,4-dichlorobenzoyl)-
1-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl mp. 265-267℃ (decomposition) Colorless granular crystals Example 10 6-(4-Methyl-1-piperazinylcarbonyl)-3,4-dihydro Carbostyryl 1 hydrogen iodide mp. 258-259.5℃ (decomposition) Colorless powder crystal Example 11 6-(4-n-hexyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1 Hydrochloride mp. 276-280℃ (decomposition) Colorless flaky crystals Example 12 6-(4-isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.
Monohydrochloride mp. 292-293.5℃ (decomposition) Colorless phosphorus flakes Example 13 6-[4-(3-phenoxypropyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp. 151-153℃ (decomposition) Colorless powder crystal Example 14 6-[4-(6-phenoxyhexyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp. 254-257℃ (decomposition) Colorless powder crystal Example 15 6-[4-(2-phenylethyl)-1-piperazinylcarbonyl ]-3,4-dihydrocarbostyryl monohydrochloride half hydrate mp. 269-272℃ (decomposition) Colorless powder crystal Example 16 6-[4-(3-phenylpropyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate mp.257-259℃ (decomposition) Colorless powder crystal Example 17 6-(1-Piperazinylcarbonyl )-3,4
- 3.0 g of dihydrocarbostyril, 2.9 g of triethylalumine, 2.7 g of β-chlorophenetol and 2.1 g of sodium iodide were suspended in a mixed solvent of 20 ml of acetonitrile and 20 ml of dimethylformamide,
Heat to reflux with stirring for 15 hours. Concentrate the solvent, extract with a mixed solvent of saturated sodium bicarbonate water and chloroform,
The organic layer is washed successively with water and saturated brine. After drying over sodium sulfate, the solvent is distilled off under reduced pressure. Concentrated hydrochloric acid is added to the residue to adjust the pH to approximately 1 to obtain the hydrochloride. Recrystallize from ethanol-water to obtain 6-[4-(2-
2.13 g of phenoxyethyl-1-piperazinylcarbonyl-3,4-dihydrocarbostyryl monohydrochloride was obtained. mp.271-274°C (decomposition) Colorless needle crystals In the same manner as in Example 17, the following compounds (Examples 18 to 20) are obtained using appropriate raw materials. Example 18 6-(4-methyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydriodide mp.258-259.5℃ (decomposition) Colorless powder crystal Example 19 6- [4-(3-phenoxypropyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.151-153℃ (decomposition) Colorless powder crystal Example 20 6-[4-(6-phenoxyhexyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.254-257℃ (decomposition) Colorless powder crystal Example 21 6-(1-piperazinylcarbonyl)-3,4
-Dihydrocarbostyril 2.6g, triethylamine 3.0g and 4-methylbenzyl chloride
Suspend 2.18g in acetonitrile and heat at 50-55℃ for 2 hours.
Stir for an hour. After evaporating the solvent, the residue is extracted with chloroform and washed successively with water and saturated brine.
After drying with sodium sulfate, the solvent is distilled off. Concentrated hydrochloric acid is added to the residue to adjust the pH to approximately 1 to obtain the hydrochloride. Ethanol - recrystallized from water to give 6-[4-(4-methylbenzyl)-1-piperazinylcarbonyl]
-3,4-dihydrocarbostyryl monohydrochloride
Obtain 1.13g. mp.280-283°C (decomposition) Colorless flaky crystals In the same manner as in Example 21, using appropriate starting materials, the compounds of Examples 27 and 28 below are obtained. Example 22 6-[4-(3,4-dichlorobenzyl)-1
-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.284-287℃ (decomposition) Colorless phosphorus flakes Example 23 6-[4-(4-chlorobenzyl)-1-pipe Radinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.300℃ or higher Colorless needle crystals Example 24 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl mp.198-200℃ Colorless needle crystal Example 25 6-(4-n-hexyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride mp.276-280℃ (decomposition) Colorless flake crystal Example 26 6-(4-isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.
Monohydrochloride mp.292-293.5 (decomposition) Colorless flaky crystal Example 27 6-[4-(2-phenylethyl)-piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride 1/ Dihydrate mp.269-272℃ (decomposition) Colorless powder crystal Example 28 6-[4-(3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl 1 Hydrochloride 1/2 hydrate mp.257-259℃ (decomposition) Colorless powder crystal Example 29 6-(1-piperazinylcarbonyl)-3,4
- Suspend 3.0 g of dihydrocarbostyril and 4.0 ml of triethylamine in 20 ml of dichloromethane, and add 3.05 g of 3-chlorobenzoyl chloride while stirring under ice cooling.
20 ml of dichloromethane solution is added dropwise. Then stir at room temperature for 1 hour. The reaction mixture was poured into saturated sodium hydrogen chloride solution, extracted with chloroform, and washed successively with water and saturated brine. After drying with sodium sulfate, the solvent is distilled off. Recrystallize from ethanol-chloroform-diethyl ether to obtain 6-[4-
(3-chlorobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl
Obtain 3.6g. mp.258.5-260°C Colorless powder crystals Compounds of Examples 30 to 31 are obtained in the same manner as in Example 29 using appropriate starting materials. Example 30 6-[4-(4-brombenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl mp.265.5-267.5℃ Colorless powder crystal Example 31 6-[4-(3 ,4-dichlorobenzoyl)-
1-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl mp. 265-267°C (decomposition) Colorless granular crystals Example 32 6-morpholinocarbonyl-3,4-dihydrocarbostyryl 2.62 g and 4-methylbenzylamine Put 13.5g into a sealed tube and heat at 170-200°C for 5 hours. 3,4-dimethoxybenzylamine is distilled off by concentration under reduced pressure, and the residue is separated and purified by silica gel column chromatography, and then converted into a hydrochloride using concentrated hydrochloric acid. This was recrystallized from ethanol-water to produce 6-[4-(4-methylbenzyl)-1-piperazinylcarbonyl]-3,4-
0.26 g of dihydrocarbostyril monohydrochloride is obtained. mp.280-283°C (decomposition) Colorless scale crystals Compounds of Examples 33 to 43 are obtained in the same manner as in Example 32 using appropriate starting materials. Example 33 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl mp.198-200℃ Colorless needle crystals Example 34 6-[4-(2-phenoxyethyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.271-274℃ (decomposition) Colorless needle crystals Example 35 6-[4-(3,4-dichlorobenzyl)-1
-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.284-287℃ (decomposition) Colorless phosphorus flakes Example 36 6-[4-(4-chlorobenzyl)-1-pipe Radinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.300℃ or higher Colorless needle crystals Example 37 6-(4-n-hexyl-1-piperazinylcarbonyl)-3,4-dihydro Carbostyryl monohydrochloride mp. 276-280℃ (decomposed) Colorless phosphorus flakes Example 38 6-(4-isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl
Monohydrochloride mp.292-293.5℃ (decomposition) Colorless phosphorus flakes Example 39 6-[4-(3-phenoxypropyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.151-153℃ (decomposition) Colorless powder crystal Example 40 6-[4-(6-phenoxyhexyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.254-257℃ (decomposition) Colorless powder crystal Example 41 6-[4-(2-phenylethyl)-1-piperazinylcarbonyl ]-3,4-dihydrocarbostyryl monohydrochloride half hydrate mp.269-272℃ (decomposition) Colorless powder crystal Example 42 6-[4-(3-phenylpropyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate mp.257-259℃ (decomposition) Colorless powder crystal Example 43 6-(4-methyl-1- piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1-hydriodide mp.258-259.5℃ (decomposition) Colorless powder crystal Example 44 6-[Bis-(2-hydroxyethyl)aminocarbonyl] -3,4-dihydrocarbostyryl
A mixture of 10 g of 4-methylbenzylamine, 3.4 g of polyphosphoric acid, and 7.6 g of polyphosphoric acid is reacted by heating at 160 to 170° C. for about 6 hours. After that, the reaction solution was allowed to cool, and water
Add 500ml dropwise and dissolve. Neutralize with 48% sodium hydroxide and extract with chloroform. After dehydration with potassium carbonate, chloroform is distilled off and the hydrochloride is prepared with concentrated hydrochloric acid. Ethanol - Recrystallized from water 6-
5.7 g of [4-(4-methylbenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride is obtained. mp.280-283°C (decomposition) Colorless scale crystals Compounds of Examples 45 to 55 are obtained in the same manner as in Example 44 using appropriate starting materials. Example 45 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl mp.198-200℃ Colorless needle crystals Example 46 6-[4-(2-phenoxyethyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.271-274℃ (decomposition) Colorless needle crystals Example 47 6-[4-(3,4-dichlorobenzyl)-1
-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.284-287℃ (decomposition) Colorless phosphorus flakes Example 48 6-[4-(4-chlorobenzyl)-1-pipe Radinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.300℃ or higher colorless needle crystals Example 49 6-(4-methyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl・1-hydriodide mp.258-259.5℃ (decomposition) Colorless powder crystal Example 50 6-(4-n-hexyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1-hydrochloric acid Salt mp.276-280℃ (decomposition) Colorless phosphorus flakes Example 51 6-(4-isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.
Monohydrochloride mp.292-293.5℃ (decomposition) Colorless phosphorus flakes Example 52 6-[4-(3-phenoxypropyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.151-153℃ (decomposition) Colorless powder crystal Example 53 6-[4-(6-phenoxyhexyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.254-257℃ (decomposition) Colorless powder crystal Example 54 6-[4-(2-phenylethyl)-1-piperazinylcarbonyl ]-3,4-dihydrocarbostyryl monohydrochloride half hydrate mp.269-272℃ (decomposition) Colorless powder crystal Example 55 6-[4-(3-phenylpropyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate mp.257-259℃ (decomposition) Colorless powder crystal Example 56 6-[Bis-(2-chloroethyl )Aminocarbonyl]-3,4-dihydrocarbostyryl 15.9
A mixture of 7.4 g of 4-methylbenzylamine and 70 ml of methanol is 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. Make the hydrochloride with concentrated hydrochloric acid. Ethanol - Recrystallized from water 6-
5.5 g of [4-(4-methylbenzyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride is obtained. mp.280-283°C (decomposition) Colorless scale crystals Compounds of Examples 57 to 67 are obtained in the same manner as in Example 56 using appropriate starting materials. Example 57 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl mp.198-200℃ Colorless needle crystals Example 58 6-[4-(2-phenoxyethyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.271-274℃ (decomposition) Colorless needle crystals Example 59 6-[4-(3,4-dichlorobenzyl)-1
-Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.284-287℃ (decomposition) Colorless phosphorus flakes Example 60 6-[4-(4-chlorobenzyl)-1-pipe Radinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.300℃ or higher Colorless needle crystals Example 61 6-(4-Methyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl・1-hydriodide mp.258-259.5℃ (decomposition) Colorless powder crystal Example 62 6-(4-n-hexyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 1-hydrochloric acid Salt mp.276-280℃ (decomposition) Colorless phosphorus flakes Example 63 6-(4-isobutyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl.
Monohydrochloride mp.292-293.5℃ (decomposition) Colorless phosphorus flakes Example 64 6-[4-(3-phenoxypropyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.151-153℃ (decomposition) Colorless powder crystal Example 65 6-[4-(6-phenoxyhexyl)-1-
Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride mp.254-257℃ (decomposition) Colorless powder crystal Example 66 6-[4-(2-phenylethyl)-1-piperazinylcarbonyl ]-3,4-dihydrocarbostyryl monohydrochloride half hydrate mp.269-272℃ (decomposition) Colorless powder crystal Example 67 6-[4-(3-phenylpropyl)-1 -Piperazinylcarbonyl]-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate mp.257-259℃ (decomposition) Colorless powder crystal Example 68 6-carboxy-3,4-dihydro Carbostyril 1.0g, DCC 1.3g and benzylpiperazine
Suspend 1.1 g in 10 ml of dioxane and stir at 60-70°C for 5 hours. After the reaction is complete, the solvent is distilled off, and ether is added to remove the precipitated crystals. After concentrating the mother liquor,
Add chloroform to dissolve the residue, and wash with water and saturated brine. After drying with sodium sulfate, the solvent is distilled off. Recrystallize from ethanol to obtain 6-
(4-benzyl-1-piperazinylcarbonyl)
330 mg of -3,4-dihydrocarbostyril is obtained. mp.198-200°C Colorless needle crystals In the same manner as in Example 68, using appropriate starting materials, the compounds of Examples 2 to 16 are obtained. Example 69 1.0 g of 6-carboxy-3,4-dihydrocarbostyryl and 0.8 ml of triethylamine were suspended in 10 ml of tetrahydrofuran (THF), and 1.0 g of diethyl chlorophosphate was added under stirring at room temperature.
Add 10 mg of THF solution dropwise and stir at room temperature for 3 hours.
This stuff contains 1.1g of benzylpiperazine in 10ml of THF.
Add the solution dropwise and stir for a further 10 hours at room temperature. After the reaction is complete, the precipitated crystals are removed, the mother liquor is concentrated, and the residue is poured with saturated sodium hydrogen chloride solution and extracted with chloroform.
The organic layer is washed with water and saturated brine, dried over sodium sulfate, and then the solvent is distilled off. Recrystallization from ethanol yields 1.07 g of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl. mp.198-200°C Colorless needle crystals In the same manner as in Example 69, using appropriate starting materials, the compounds of Examples 2 to 16 are obtained. Example 70 A solution of 3.87 g of isobutyl chloroformate in 2 ml of dimethylformamide is added dropwise to a solution of 5.0 g of 6-carboxy-3,4-dihydrocarbostyryl and 4 ml of triethylamine in 50 ml of dimethylformamide. After stirring at room temperature for 30 minutes, a solution of 5.5 g of benzylpiperazine in 3 ml of dimethylformamide is added dropwise, followed by stirring at room temperature for 30 minutes and then at 50-60° C. for 1 hour. Pour the reaction mixture into a large amount of saturated saline,
Extract with chloroform, wash with water, and dry. The solvent was distilled off, diethyl ether was added to the residue for crystallization, and the resulting crude crystals were recrystallized from ethanol to give 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl. 3.4
get g. mp.198-200°C Colorless needle crystals Compounds of Examples 2 to 76 are obtained in the same manner as in Example 70 using appropriate starting materials. Example 71 6-ethoxycarbonyl in 100ml of ethanol
3,4-dihydrocarbostyryl 2.0g, sodium ethylate 0.5g and benzylpiperazine 1.6
g and in an autoclave, 110 atm, 140~
React at 150°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in 200 ml of chloroform, washed successively with a 1% aqueous potassium carbonate solution, diluted hydrochloric acid, and water, dried over sodium sulfate, the solvent was distilled off, and the residue was applied to a silica gel column. Chromatography (silica gel: Wako C-200, eluent:
Chloroform:methanol (V/V) = 20:1)
and recrystallize the crude crystals from ethanol.
300 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl is obtained. mp.198-200°C Colorless needle crystals In the same manner as in Example 71, using appropriate starting materials, the compounds of Examples 2 to 16 are obtained. Example 72 1.9 g of 6-carboxy-3,4-dihydrocarbostyryl was suspended in 200 ml of methylene chloride, 2 ml of pyridine was added, and 1.4 g of thionyl chloride was added with stirring while maintaining the internal temperature between 0 and 20°C. Drip. After the addition was completed, the mixture was stirred at the same temperature for 1 hour, and a solution of 1.74 g of benzylpiperazine in 10 ml of methylene chloride was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 4 hours. The reaction solution is thoroughly washed with an aqueous potassium carbonate solution, washed with water and diluted hydrochloric acid, dried over sodium sulfate, and then the solvent is distilled off. The obtained residue was subjected to silica gel column chromatography (silica gel: Wako C-200,
Eluent: Chloroform:methanol (V/V)=
20:1) and then recrystallized from ethanol to obtain 325 mg of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl. mp.198-200°C Colorless needle crystals In the same manner as in Example 72, using appropriate starting materials, the compounds of Examples 2 to 16 are obtained. Example 73 In 100 ml of dimethylformamide, 2.2 g of 3-chlorobenzoic acid and 1,8-diazabicyclo[5,4,
0] 1.65 g of undecene-7 was added, and 1.5 ml of isobutyl chloroformate was added dropwise to this while stirring while externally cooling with ice. After dropping, stir for 30 minutes, add a solution of 2.6 g of 6-(1-piperazinyl)carbonyl-3,4-dihydrocarbostyryl dissolved in 40 ml of dimethylformamide, and stir at room temperature for 5 hours. After the reaction, the solvent is distilled off and the residue is extracted with about 300 ml of chloroform and washed successively with a dilute aqueous sodium bicarbonate solution, water, and dilute hydrochloric acid. After chloroform was distilled off, the residue was recrystallized from ethanol-chloroform-diethyl ether to give 6-[4-(3-chlorobenzoyl)-1-piperazinylcarbonyl]-3,
1.5 g of 4-dihydrocarbostyryl is obtained. mp.258.5-260°C Colorless powder crystals In the same manner as in Example 73, the following compounds of Examples 74 to 75 are obtained from appropriate starting materials. Example 74 6-[4-(4-brombenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl mp.265.5-267.5℃ Colorless powder crystal Example 75 6-[4-(3 ,4-dichlorobenzoyl)-
1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl mp. 265-267℃ (decomposition) Colorless granular crystals Example 76 Succinimide 3,4-dimethoxybenzoate 112 mg and 6-(1-piperazinylcarbonyl )
-3,4-dihydrocarbostyril (137 mg) was dissolved in dimethylformamide (2 ml) and stirred overnight. Water is added to the reaction mixture, extracted with chloroform, and washed with water and saturated brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-chloroform-diethyl ether to give 6-[4-(3-chlorobenzoyl)-1
-Piperazinylcarbonyl]-3,4-dihydrocarbostyril (90 mg) was obtained. mp.258.5-260°C Colorless powder crystal Example 77 A solution of 3.87 g of isobutyl chloroformate in 2 ml of dimethylformamide is added dropwise to a solution of 4.12 g of 3-chlorobenzoic acid and 4 ml of triethylamine in 50 ml of dimethylformamide. After stirring at room temperature for 30 minutes, 6-(1-piperazinylcarbonyl)-3,
A solution of 8.1 g of 4-dihydrocarbostyril in 3 ml of dimethylformamide was added dropwise, and the solution was continued for 30 minutes at room temperature.
Stir at 50-60°C for 1 hour. The reaction mixture is poured into a large amount of saturated brine, extracted with chloroform, washed with water, and then dried. The solvent was distilled off and the residue was recrystallized from ethanol-chloroform-diethyl ether to give 6-[4-(3-chlorobenzoyl)-1-
2.2 g of piperazinylcarbonyl]-3,4-dihydrocarbostyryl are obtained. mp.258.5-260℃ Colorless powder crystal Example 78 To 100ml of ethanol, 1.7g of ethyl 3,4-dimethoxybenzoate and 0.5g of sodium ethylate.
g and 6-(1-piperazinylcarbonyl)-
Add 2.4 g of 3,4-dihydrocarbostyryl,
6 at 110 atm, 140-150℃ in autoclave
Allow time to react. After cooling, the reaction solution was concentrated under reduced pressure.
The residue was dissolved in 200 ml of chloroform, washed sequentially with a 1% aqueous potassium carbonate solution, dilute hydrochloric acid and water, dried over sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (silica gel: Wako C- 200, eluent: chloroform:methanol (V/V) = 20:1), and the crude crystals were recrystallized from ethanol-chloroform-diethyl ether to obtain 6-[4-(3-
224 mg of chlorobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl is obtained. mp.258.5-260℃ Colorless powder crystal Example 79 1.55 g of 3,4-dimethoxybenzoic acid and 6-(1
-Piperazinylcarbonyl)-3,4-dihydrocarbostyryl (2.75 g) was added to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride, and N,N-dicyclohexylcarbodiimide was added under external ice cooling and stirring.
A solution of 2.1 g dissolved in 5 ml of methylene chloride is added to
Drop while keeping at 20℃. After dropping, stir at the same temperature for 3.5 hours. The precipitated crystals were removed, and the liquid was concentrated to dryness under reduced pressure. The resulting residue was dissolved in methylene chloride.
Dissolve the organic layer in 100ml of 5% aqueous hydrochloric acid solution, 5%
After washing with an aqueous sodium bicarbonate solution and water in that order, and drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform-ethanol.
Recrystallized from diethyl ether to give 6-[4-(3
-Chlorobenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl 0.78g
get. mp.258.5-260°C Colorless powdery crystals Examples of formulations and pharmacological tests using the compounds of the present invention are listed below. Formulation example 1 6-[4-(2-phenoxyethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyryl 10mg Starch 127mg Magnesium stearate 18mg Lactose 45mg Total 200mg The above composition in one tablet by the usual method Manufactured into tablets. Formulation example 2 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl
500mg polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 100ml Dissolve the above parabens, sodium metabisulfite and sodium chloride in distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, and the compound of the present invention, polyethylene glycol, and polyoxyethylene sorbitan monooleate were sequentially dissolved therein, and then distilled water for injection was added to the solution to adjust the final volume. , sterilize using appropriate filter paper, and dispense 1 ml into ampoules to prepare an injection. <Pharmacological test> Male and female mixed-breed adult dogs weighing 8 to 13 kg are anesthetized by intravenously administering pentobarbital sodium salt at a rate of 30 mg/kg. heparin sodium salt
After intravenous administration at a rate of 1000U/Kg, death was caused by exsanguination.
The heart is removed in locks fluid. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Next, the patient was anesthetized with pentobarbital sodium salt (30 mg/Kg, intravenous administration) and treated with heparin (1000 U/Kg).
In an adult male-male mixed-breed dog weighing 18-27 kg (intravenous administration), blood is guided from the carotid artery 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 under a resting tension of 2 g.
Measure the contractile force of the atrial muscle via a force displacement transducer. 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 the tension developed before compound administration, and the change in coronary blood flow is expressed as a
Expressed as absolute value (ml/min) from before administration. The results are shown in Table 1 below. <Test compound> Compound No. Compound name 1 6-(1-piperazinylcarbonyl)-
3,4-dihydrocarbostyryl 2 6-[4-(2-phenoxyethyl)-
1-piperazinylcarbonyl]-3,
4-dihydrocarbostyryl 3 6-(4-methyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl 4 6-[4-(3-chlorobenzoyl)-
1-piperazinylcarbonyl]-3,
4-dihydrocarbostyryl 5 6-[4-(3,4-dichlorobenzoyl)-1-piperazinylcarbonyl]
-3,4-dihydrocarbostyryl 6 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyryl monohydrochloride 7 6-[4-(4-methylbenzyl)-1
-piperazinylcarbonyl]-3,4
-dihydrocarbostyryl 8 6-[4-(4-chlorobenzyl)-1
-piperazinylcarbonyl]-3,4
-Dihydrocarbostyryl monohydrochloride 9 Amrinone (control compound) [Table]

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, R ² represents a hydrogen atom,
Phenoxy lower alkyl group, lower alkyl group, lower alkyl group substituted with one phenyl group, which may have 1 to 3 groups selected from lower alkyl groups and halogen atoms as substituents on the phenyl ring, or on the phenyl ring represents a benzoyl group having 1 to 3 halogen atoms as a substituent. ] A carbostyryl derivative represented by these and its salt.