JPH0240658B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel carbostyril derivatives and salts thereof. 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 (1). [In the formula, R is a hydroxyl group, a lower alkoxy group, or a group

[Formula] is shown. R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl lower alkyl group. However, when R is a hydroxyl group or a lower alkoxy group, R ¹ must not be a hydrogen atom or a lower alkyl group. ] The carbostyril derivative represented by the above general formula (1) and its salt have the effect of enhancing myocardial contraction (positive inotropic effect), the effect of increasing coronary blood flow, and the effect of lowering blood pressure. As an intermediate for synthesizing the compound represented by general formula (26) below, which is useful as a cardiotonic agent for the treatment of various heart diseases such as capillary heart disease, atrial fibrillation, flutter, and paroxysmal atrial tachycardia. Useful. In this specification, the lower alkyl group is
Examples include alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl. Lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Examples include alkoxy groups having 1 to 6 carbon atoms such as tert-butoxy, pentyloxy, and hexyloxy. Lower alkenyl groups include vinyl, allyl,
Examples include alkenyl groups having 2 to 6 carbon atoms such as 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl. Examples of lower alkynyl groups include alkynyl groups having 2 to 6 carbon atoms such as ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, and 2-hexynyl. Examples of phenyl lower alkyl groups include benzyl,
2-phenylethyl, 1-phenylethyl, 3-
Phenylpropyl, 4-phenylbutyl, 1,1
-Dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-
Examples include phenyl alkyl groups in which the alkyl moiety has 1 to 6 carbon atoms, such as 3-phenylpropyl. Among carbostyril derivatives represented by general formula (1), compounds in which R represents a hydroxyl group (i.e., general formula (1a))
The compound) is produced, for example, by the method shown in Reaction Scheme 1 or 2 below. Reaction equation 1 [In the formula, R ¹ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. R ² represents an aromatic amine residue, and X represents a halogen atom. ] In the above, the reaction to obtain the compound of general formula (4) can be carried out by reacting the compound of general formula (2) with the aromatic amine (3) 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 methanol, ethanol, isopropanol,
Alcohols such as butanol, halogenated hydrocarbons such as methylene chloride, chloroform, dichloromethane, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate, ethyl acetate, N,N-dimethylformamide, dimethyl Examples include sulfoxide, aprotic polar solvents such as hexamethylphosphoric triamide, acetonitrile, and the like. Examples of aromatic amines include pyridine and quinoline. The amount of the aromatic amine to be used is at least equimolar, preferably in large excess, relative to the compound of general formula (2). Reaction temperature is 50-200℃
The temperature is preferably 70-150°C, and the reaction is completed in 3-10 hours. Also, the general formula (4) obtained from the above
The hydrolysis reaction of the compound is carried out in water using an inorganic base such as sodium hydroxide or potassium hydroxide at room temperature to 150°C for about 1 to 10 hours. Reaction equation 2 [In the formula, R ¹ , X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reaction between the compound of general formula (5) and a halogen is usually carried out in a solvent. Examples of solvents that can be used include ethers such as tetrahydrofuran and dioxane, carboxylic acids such as acetic acid and propionic acid, aromatic hydrocarbons such as benzene, dimethylformamide, and dimethyl sulfoxide. In this reaction, calcium carbonate or the like may be added as a deoxidizing agent to remove by-produced hydrogen halide.
The compounding ratio of the compound of general formula (5) and the halogen is not particularly limited and is appropriately selected within a wide range, but usually the latter is 2 to 5 times the former by mole, preferably 2
It is preferable to use up to 3 times the molar amount. The reaction is usually 0~
It is best to carry out the reaction at 50°C, and the reaction is usually completed in about several hours to 24 hours. The reaction for obtaining the compound of general formula (1a) from the compound of general formula (6) is preferably carried out in an aqueous solvent in the presence of a basic compound. As the basic compound, a wide variety of known compounds can be used, such as alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide. The amount of the basic compound to be used is not particularly limited and can be selected within a wide range, but it is generally preferred to use it in an amount of 2 times to a large excess of the compound of general formula (6). The reaction is usually 50~
It is best to carry out at 150℃, preferably 70-120℃,
The reaction usually completes in about 1 to 12 hours. In the above reaction schemes -1 and -2, the compounds of general formulas (2) and (5) used as raw materials include new compounds, for example, the following reaction schemes -
It is manufactured according to the method shown in 3.-4. Reaction equation 3 [In the formula, R ¹ , X and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. X ¹ represents a hydrogen atom or a halogen atom. ] Compound of general formula (7) and general formula (8) or general formula (9)
The reaction with the compound is generally called the Friedel-Crafts reaction, and this reaction is carried out in a solvent in the presence of a Lewis acid. As the solvent used in this case, those commonly used in this type of reaction are advantageously used, and examples thereof include carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, and tetrachloroethane. Furthermore, conventionally used Lewis acids are preferably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used may be 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 (7). General formula (8)
The amount of the compound or the compound of general formula (9) to be used is:
The amount used is usually at least equimolar, preferably equimolar to 3 times the molar amount of the compound of general formula (7). The reaction temperature is selected appropriately, but is usually 20~
The temperature is preferably about 120°C, preferably about 40 to 70°C. The reaction time for this reaction varies depending on the raw materials, catalyst, reaction temperature, etc., and cannot be generalized, but it is usually 0.5~
The reaction completes in about 24 hours. Reaction equation 4 [In the formula, X and X ¹ are the same as above. R ¹ ' represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl lower alkyl group. R ³ represents a hydrogen atom or a lower alkyl group. ] The reaction between the compound of general formula (12) and the compound of general formula (8) or (9) is the reaction of the compound of general formula (7) with the compound of general formula (8) or
It can be carried out in the same manner as the reaction with compound (9). However, the reaction temperature is usually -50 to 120
The temperature is preferably about 0°C to 70°C. Further, although the reaction time varies depending on the raw materials, catalyst, reaction temperature, etc., and cannot be generalized, the reaction is usually completed in about 0.5 to 24 hours. The nitration reaction of compound (13) is carried out under 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 nitrating agents include fuming nitric acid, concentrated nitric acid, mixed acids (sulfuric acid, oleum, phosphoric acid, or acetic anhydride and nitric acid), potassium nitrate, sodium nitrate, etc. Examples include alkali metal nitrates and sulfuric acid. The amount of the nitrating agent used may be an equimolar or more excess amount relative to the raw material compound,
The reaction is usually carried out at -30℃ to around room temperature, preferably -30℃
It is carried out for 5 minutes to 4 hours before and after. The benzene derivative of the general formula (14) is reduced and ring-closed to give the carbostyril derivative of the general formula (15). This reaction can be carried out by reduction using a catalytic reduction catalyst in a suitable solvent, or by reducing it in a suitable 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, examples of solvents used include water, acetic acid,
Alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, THF and diethyl ether, esters such as ethyl acetate and methyl acetate, aprotic polarity such as DMF Examples include solvents. Examples of the catalytic reduction catalyst used include palladium, palladium-black, palladium-carbon, platinum, platinum oxide, copper chromite, and Raney nickel. The amount of catalyst to be used is preferably 0.02 to 1.00 times the weight of compound (14). The reaction is carried out at -20 to 100°C, preferably from 0 to 50°C.
℃, hydrogen pressure is 1 to 10 atm, and generally completes in about 0.5 to 10 hours. In this reaction, the reaction proceeds advantageously when a basic compound such as sodium hydroxide or potassium hydroxide is present in the reaction system. Alternatively, when using iron, zinc, tin or stannous chloride and a mineral acid such as hydrochloric acid or sulfuric acid, or iron, ferrous sulfate, zinc or tin and an alkali metal hydroxide such as sodium hydroxide, sulfide Sulfides such as ammonium, aqueous ammonia, and mixtures with ammonium salts such as ammonium chloride are used as reducing agents. Inert solvents used include water,
Examples include acetic acid, methanol, ethanol, and dioxane. The conditions for the above reduction reaction may be appropriately selected depending on the reducing agent used, and are usually -
The reaction proceeds at 50 to 100°C and is completed in about 0.5 to 10 hours. For example, when stannous chloride and hydrochloric acid are used as reducing agents, the reaction is advantageously carried out at around -20 to 50°C. The amount of the reducing agent to be used is preferably at least equimolar, usually equimolar to 3 times the molar amount of the raw material compound.
In the above reaction, the compound of general formula (14) is first converted from the nitro group to an amino group by a reducing agent, and then the compound of general formula (14) is [In the formula, R ³ and X ¹ are the same as above. ] It is thought that a benzene derivative represented by the formula (15) is produced, and then this compound is ring-closed to produce a carbostyril derivative of the general formula (15). Further, in reducing compound (14), the carbonyl group is not changed in the above case, but in the case of , the carbonyl group may be converted to a methylene group. However, it is of course possible to maintain the carbonyl group as it is by appropriately selecting reaction conditions. The reaction between the compound of general formula (15) and the compound of general formula (16) is preferably carried out, for example, in the presence of a basic compound in a suitable solvent. Examples of the basic compound include sodium hydride, potassium, sodium, sodium amide, potassium amide, and the like. Examples of the solvent include ethers such as dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. The ratio of the compound of general formula (15) and the compound of general formula (16) to be used is not particularly limited and can be appropriately selected within a wide range, and usually the latter is at least about equimolar to the former, preferably equimolar to 2. It is best to use about double the mole. The reaction is usually carried out at a temperature of about 0 to 70°C, preferably from about 0°C to room temperature, and is generally completed in about 0.5 to 12 hours. Also, some of the compounds of general formula (1) are produced by the methods shown in the following reaction schemes -5 and -6. Reaction equation 5 [In the formula, R ³ and X ¹ are the same as above. ] The nitration of the compound of general formula (13) can be carried out in the same manner as the nitration of general formula (13) in the reaction scheme-4. However, the reaction temperature is preferably -10°C to around room temperature. The reaction to obtain the compound of general formula (1b) by reducing and ring-closing the compound of general formula (19) is carried out under the same conditions as the reaction for obtaining the compound of general formula (15) from the compound of general formula (14). can be done. In this reaction, the nitro group of the compound of general formula (19) is first converted to an amino group by a reducing agent to form the compound of general formula (19). [In the formula, R ³ is the same as above. ] It is thought that a benzene derivative represented by the formula (1b) is produced, and then this compound is ring-closed to produce a carbostyryl derivative of the general formula (1b). Reaction equation 6 [In the formula, R ³ and X are the same as above. R ⁴ represents a lower alkyl group. ] The reaction between the compound of general formula (21) and the compound of general formula (22) is usually carried out in a suitable solvent in the presence or absence of a dehydrohalogenating agent. As this dehydrohalogenation agent, a common basic compound is used, and a wide range of known basic compounds can be used, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine. ,
1,5-diazabicyclo[5,4,0]-undecene-5[DBU], 1,4-diazabicyclo[2,
Organic bases such as 2,2]octane (DABCO), 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, Examples include inorganic bases such as potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, and alcoholates such as sodium methylate and sodium ethylate. Furthermore, compound (21)
It can also be used as a dehydrohalogenating agent by using an excess amount. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, and methyl cellosolve, diethyl ether, tetrahydrofuran, Ethers such as dimethoxyethane, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, pyridine, acetone, acetonitrile, etc., or the above solvents. Examples include a mixed solvent of two or more solvents. Compound of general formula (21) and general formula (22)
The proportion of the compound to be used is not particularly limited and is appropriately selected within a wide range, but usually the former is used in at least an equimolar amount of the latter, preferably equimolar to 5.
It is better to use twice the molar amount. The reaction is usually −30 to
The reaction is carried out at about 180°C, preferably about 0 to 150°C, and the reaction is generally completed in 5 minutes to 30 hours. The cyclization reaction of the compound of general formula (23) is carried out in the presence of an acid without 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, hydrochloric acid, hydrobromic acid,
Examples include inorganic acids such as sulfuric acid, Lewis acids such as aluminum chloride, boron trifluoride, and titanium tetrachloride, and organic acids such as 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 not particularly limited and may be appropriately selected within a wide range, but it is usually at least the same weight, preferably 10 to 50 times the weight of the compound of general formula (23). Good. As the solvent, a wide range of common inert solvents can be used, 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, Examples include halogenated hydrocarbons such as chloroform and carbon tetrachloride, acetone, dimethylsulfoxide, dimethylformamide, and hexamethylphosphoric triamide. Among these, water-soluble solvents such as the lower alcohols, ethers, acetone, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide are preferred. The reaction is usually carried out at 0 to 100°C, preferably at room temperature to 60°C, and is usually completed in about 5 minutes to 6 hours. In addition, in the compound of general formula (1), R is a lower alkoxy group or a group

The compound represented by the formula (ie, the compound represented by the general formula (1d)) can be produced, for example, by the method shown in the following reaction scheme-7. Moreover, the compound of general formula (1d) can be converted to the compound of general formula (1a) by hydrolyzing it. Reaction equation 7 [In the formula, R ¹ is the same as above. R′ is lower alkoxy group or group

[Formula] is shown. ] For the reaction between the compound of general formula (1a) and the compound of general formula (24), any reaction conditions for normal esterification reactions can be adopted, but for example, dehydration condensation in a solvent in the presence of a dehydrating agent or acid Alternatively, it may be carried out in a suitable solvent in the presence of a basic catalyst.
In this method, examples of solvents used include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Examples include ethers, aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the dehydrating agent include dicyclohexylcarbodiimide and carbonyldiimidazole. The ratio of the compound of general formula (24) to the compound of general formula (1a) is at least equimolar, preferably equimolar to 1.5 times the molar amount. The amount of dehydrating agent used is
It is preferable to use the compound in an amount of at least equimolar, preferably equimolar to 1.5 times the molar amount of the compound of general formula (1a). The reaction temperature is usually room temperature to 150°C, preferably around 50 to 100°C, and the reaction is generally carried out at 1
Finishes in ~10 hours. In this method, the acids used include, for example, hydrochloric acid gas, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trichloromethanesulfonic acid, naphthalenesulfonic acid, p -Organic acids such as tosylic acid, benzenesulfonic acid and ethanesulfonic acid, acid anhydrides such as trichloromethanesulfonic anhydride and trifluoromethanesulfonic anhydride, thionyl chloride, acetone and dimethyl acetal. Acidic ion exchange resins may also be used. Examples of basic catalysts used include potassium carbonate, sodium carbonate, potassium hydrogen carbonate,
Examples include inorganic bases such as sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, and silver carbonate, and alcoholates such as sodium methylate and sodium ethylate. The reaction is carried out without a solvent or in the presence of a solvent. As the solvent, solvents commonly used in esterification reactions are used, such as aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, diethyl ether, and tetrahydrofuran. , dioxane, ethylene glycol monomethyl ether, and other ethers. Further, the above reaction is advantageously carried out using a desiccant such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, phosphorus pentoxide, or the like. In the above reaction, the ratio of the compound of general formula (1a) and the compound of general formula (24) to be used is not particularly limited and can be appropriately selected from a wide range. If a solvent is used, the latter should be used in a large excess of the former to 5 times the mole, preferably equimolar to 5 times the former.
It is preferable to use twice the molar amount. The reaction temperature is not particularly limited, but usually about -20 to 200°C, preferably about 0 to 150°C. Moreover, the reaction is 1
It will be completed in about 10 hours. In addition, the hydrolysis reaction of the compound of general formula (1d) is
It is preferable to carry out the reaction in an aqueous solution in the presence of an acid or basic compound. The acids used include mineral acids such as hydrochloric acid and sulfuric acid, and the basic compounds include potassium carbonate,
Examples include sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide. The amount of the acid or basic compound to be used is usually a large excess amount relative to the compound of general formula (1d). The reaction is usually carried out at room temperature to 200°C, preferably room temperature to 150°C.
It is best to carry out the reaction at around 10°C, and the reaction is generally completed in about 1 to 10 hours. The compound of general formula (1d) can also be obtained by reacting the compound of general formula (4) in Reaction Scheme-1 with the compound of general formula (24) in the presence of a basic compound without a solvent or in a solvent. can be obtained. The basic compound used is the general formula (21) above.
All those used in the reaction of compounds (22) and (22) can be used. Further, as the solvent to be used, all those used in the reaction of the compounds of the general formulas (1a) and (24) can be used. As for the ratio of the compound of general formula (24) to the compound of general formula (4), in the case of no solvent, use a large excess of the latter to the former, and in the case of using a solvent, use the latter in equimolar amount to the former. It is preferable to use about 5 to 5 times the mole amount, preferably about 1 to 2 times the mole amount. The reaction can be carried out usually at room temperature to 200°C, preferably room temperature to about 150°C, and is generally completed in about 30 minutes to 5 hours. The amount of the basic compound to be used is preferably at least a catalytic amount, preferably 0.9 to 1.5 times the molar amount of the compound of general formula (4). Reaction equation 8 [In the formula, R and R ¹ are the same as above. ] Normal catalytic reduction conditions are applied to the reduction of the compound of general formula (1f). Examples of the catalyst 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 water, methanol, ethanol, isopropanol, dioxane, THF, hexane,
Examples include cyclohexane, ethyl acetate, and mixed solvents thereof. The reaction can be carried out either at normal pressure or under increased pressure, but usually at normal pressure to 20°C.
Kg/cm ² , preferably normal pressure to 10 Kg/cm ² . The reaction temperature is usually about 0 to 150°C, preferably room temperature to 100°C. Further, the dehydrogenation reaction of the compound of general formula (1e) 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, and dehydrogenation catalysts such as selenium dioxide, palladium carbon, palladium black, palladium oxide, and Raney nickel. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but in the case of a halogenating agent, it is usually 1 to 5 times the molar amount of the compound of general formula (1e),
It is preferable to use 1 to 2 times the molar amount, and in the case of a dehydrogenation catalyst, it is usually good to use an excess amount. 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; Examples include alcohols such as butanol, 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. Further, among the compounds 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 are shown in the following reaction scheme-9. It can have lactam-lactim type tautomerism. Reaction equation 9 [In the formula, R is the same as above. ] Reaction equation 10 [In the formula, R, R ¹ ', X and 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position is the same as above. ] The reaction between the compound of general formula (1i) and the compound of general formula (16) can be carried out under the same conditions as the reaction between the compound of general formula (15) and the compound of general formula (16). . 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 a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, and a preparative thin layer chromatography. Incidentally, the present invention naturally also includes optical isomers. The carbostyril derivative represented by the general formula (1) of the present invention can be derived into the carbostyril derivative represented by the general formula (26), which is useful as a cardiotonic agent, according to the method shown in the following reaction scheme-11. Reaction equation 11 [In the formula, R ⁵ is a lower alkyl group, which may have 1 to 3 groups selected from the group consisting of a halogen atom, a lower alkoxy group, and a lower alkyl group, or a lower alkylene dioxy group as a substituent on the phenyl ring. 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group, an amino group, a lower alkanoylamino group, and a lower alkylthio group as substituents on the phenoxy lower alkyl group or the phenyl ring, or Indicates a phenyl lower alkyl group which may have a lower alkylenedioxy group. R, R ¹ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyryl skeleton are the same as above. ] For the reaction between the compound of general formula (1) and the compound of general formula (25), any ordinary amide bond forming reaction can be applied, and for example, a mixed acid anhydride method or an active ester method can be adopted. In the mixed acid anhydride method, the mixed acid anhydride used is obtained by the usual Schotten-Baumann reaction, and it is usually converted into compound (25) without isolation.
A compound of general formula (26) is produced by reacting with. The Schotten-Baumann reaction is usually carried out using basic compounds commonly used in the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4,3,0]nonene. -5 (DBN),
1,5-diazabicyclo[5,4,0]undecene (DBU), 1,4-diazabicyclo[2,2,
2] Organic bases such as octane (DABCO) and potassium carbonate, sodium carbonate, potassium hydrogen carbonate,
In the presence of an inorganic base such as sodium bicarbonate, approximately -
It is carried out at 20 to 100°C, preferably 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 compound (25) is carried out at about -20 to 150°C, preferably at 10 to 50°C, for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. . The above mixed acid anhydride is generally a solvent 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, and dimethoxyethane, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide. carried out in the presence or absence of 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 carbostyryl derivatives ( It is used in at least an equimolar amount, preferably about 1 to 2 times the molar amount of 1). In addition, the proportion of compound (25) used is usually that of carbostyryl derivatives.
At least equimolar to (1), preferably about 1 to 2
It is preferable to double the molar amount. In the active ester method, for example, when N-hydroxysuccinimide ester is used, the reaction is carried out in a suitable solvent that does not affect the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and 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 compound (25) and N-hydroxysuccinimide ester to be used is usually at least equimolar, preferably equimolar to twice the molar amount of the former to the latter. Reference examples and examples are listed below. Reference Example 1 100 g of m-aminobenzoic acid is suspended in ether 1, and 44.6 g of β-ethoxyacrylic acid chloride is added dropwise at room temperature with stirring. After dropping, react at 40°C for 5 hours and collect the precipitate. The crystals were washed with water three times, dried and recrystallized from methanol to give m-carboxy-N-(β-ethoxyacryloyl)aniline 60
get g. mp 200.5-202.0℃ Colorless flocculent reference example 2 Methyl 3-phenylpropionate 50g, chloroacetyl chloride 51.6g and dichloromethane
Cool 250 ml of the mixture to 0°C. While stirring at 0-10°C, 122g of aluminum chloride is gradually added.
Then stir at room temperature for 2 hours. After standing overnight at room temperature, the reaction mixture was poured into ice-concentrated hydrochloric acid and extracted with chloroform. The chloroform layer is washed with water and dried, and the chloroform is distilled off. The residue is crystallized by adding isopropyl ether, and the crystals are collected and recrystallized from ethanol to obtain 53.4 g of methyl 3-(4-chloroacetylphenyl)propionate. mp 90.0~92.0℃ Colorless needle crystals Reference example 3 36.26 g of methyl 3-(4-chloroacetylphenyl)propionate was dissolved in 300 ml of concentrated sulfuric acid, and 20.9 g of fuming nitric acid (d=1.52) was stirred under cooling with ice water. While dripping. After stirring for 3 hours at room temperature, the reaction mixture is poured into ice water and extracted with chloroform. After washing the chloroform layer with water and drying, the chloroform is distilled off. The residue is purified by silica gel column chromatography and crystallized by adding ether. Take the crystals and recrystallize them from methanol to obtain 3-(4-
26.7 g of methyl carboxy-2-nitrophenyl)propionate are obtained. mp 120.0 to 122.0°C Pale yellow prism crystal reference example 4 To a solution of 467 g of chloroacetyl chloride in 400 ml of dichloromethane, add 735 g of aluminum chloride in 1/3 portions at a temperature below 30°C while stirring. Next, add 200 g of carbostyril at the same temperature and stirring. Thereafter, the mixture is heated under reflux for 6 hours. After the reaction, the reaction mixture is poured into ice-concentrated hydrochloric acid and the precipitated crystals are collected. This was washed with methanol and hot methanol to obtain 153 g of 6-chloroacetylcarbostyril. The mother liquor was concentrated to dryness, and the residue was purified by silica gel column chromatography and recrystallized from methanol to obtain 35.41 g of 8-chloroacetylcarbostyryl. mp 177.5-179.0°C Pale yellow needle-like crystals Reference Example 5 Mix 30 g of 8-chloroacetylcarbostyryl and 300 ml of pyridine, and heat and stir at 80-90°C for 2.5 hours. Cool the reaction solution with ice water and collect the precipitated crystals. Wash with ether and recrystallize from methanol to obtain 8-
40.85 g of (α-pyridinium acetyl)carbostyryl chloride is obtained. mp 261.5-264.0℃ (decomposition) Colorless needle crystals Reference example 6 6-carboxy-3,4-dihydrocarbostyryl 64g and triethylamine 60ml DMF 600ml
Dissolve 51.4 ml of isobutyl chloroformate under ice-cooling and stirring.
drip. After stirring at room temperature for 1 hour, a solution of 40 g of 4-isobutylpiperazine in 36 ml of DMF was added dropwise, followed by stirring at room temperature for 5 hours and at 40-50°C for 2 hours. The reaction mixture was poured into ice water 4 to remove the precipitated crystals, and the liquid was extracted with a 5N-sodium hydroxide-chloroform mixed solvent. After washing the organic layer with water, it is dried with magnesium sulfate. The solvent is distilled off, and methanol/concentrated hydrochloric acid is added to the residue to obtain a hydrochloride. Recrystallize from water-acetone to obtain 30 g of 6-(4-isobutyl-1-piperazinylcarbonyl)-3,4-
Dihydrocarbostyril monohydrochloride is obtained. mp 292-293.5°C (decomposed) Colorless phosphorus flakes Reference example 7 Succinimide 127 mg of 3,4-dihydrocarbostyryl-6-carboxylate and 93 mg of benzylpiperazine were dissolved in 2 ml of dimethylformamide and stirred overnight. Add water to the reaction mixture,
Extract with chloroform and wash with water and saturated saline. 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 Reference example 8 To a solution of 29.5 g of methyl m-aminobenzoate in 300 ml of diethyl ether is added dropwise 11.53 g of β-ethoxyacrylic acid chloride at 17-27°C with stirring. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and the precipitated crystals were collected.
After washing with ether, the crude crystals are dissolved in chloroform and washed with 0.5N hydrochloric acid, saturated sodium bicarbonate, and saturated saline. After drying, chloroform was distilled off, the residue was purified by silica gel column chromatography, and then recrystallized from methanol.
13.63 g of m-methoxycarbonyl-N-(β-
ethoxyacryloyl)aniline is obtained. mp 108-110℃ Colorless prismatic crystal Example 1 10 g of 6-carboxy-3,4-dihydrocarbostyryl and 6.0 g of N-hydroxysuccinimide
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°C Colorless scale flake reference example 9 8 g of m-carboxy-N-(β-ethoxyacryloyl)aniline is added to 80 ml of concentrated sulfuric acid, and the mixture is stirred at room temperature for 2 hours and then at 50°C for 1 hour. Pour the reaction solution into ice and adjust the pH to 3 with 10N aqueous sodium hydroxide solution.
Adjust to ~4. Take the precipitated crystals, wash with water, and add DMF
Recrystallized from 5-carboxycarbostyryl
Obtain 4.26g. mp 320℃ or higher Pale yellow powder crystal NMR (DMSO) δ 6.58 (d, J=9.5Hz,
1H), 7.40-7.80 (m, 3H), 8.69 (d,
J=9.5Hz, 1H) Example 2 Using 56.6 g of 1-allyl-6-(α-pyridinium acetyl)-3,4-dihydrocarbostyryl chloride as the starting material, the same procedure as in Reference Example 9 was carried out to obtain 20.5 1-allyl-6-carboxy- of g
3,4-dihydrocarbostyryl is obtained. Elemental analysis value (as C ₁₄ H ₁₅ NO ₃ ) C H N Calculated value (%) 68.55 6.16 5.71 Actual value (%) 68.42 6.27 5.82 Example 3 1-Benzyl-6-(α-pyridinium acetyl)-3,4 -Using 64.9 g of dihydrocarbostyryl chloride as a starting material, the same procedure as in Reference Example 9 is carried out to obtain 28.7 g of 1-benzyl-6-carboxy-3,4-dihydrocarbostyryl. Elemental analysis value (as C ₁₈ H ₁₇ NO ₃ ) C H N Calculated value (%) 73.20 5.80 4.74 Actual value (%) 73.11 5.68 4.87 Example 4 1-Propargyl-6-(α-pyridinium acetyl)-3,4 -Using 56.3 g of dihydrocarbostyryl chloride as a starting material, the procedure was repeated in the same manner as in Reference Example 9 to obtain 23.1 g of 1-propargyl-6-carboxy-3,4-dihydrocarbostyryl. Elemental analysis value (as C ₁₄ H ₁₃ NO ₃ ) C H N Calculated value (%) 69.12 5.39 5.76 Actual value (%) 69.03 5.45 5.68

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydroxyl group, a lower alkoxy group, or a group [Formula]]. R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl lower alkyl group. However, when R is a hydroxyl group or a lower alkoxy group, R ¹ must not be a hydrogen atom or a lower alkyl group. ] A carbostyryl derivative represented by these and its salt.