JPH0239488B2 - KYOSHINZAI - Google Patents

Description

[Detailed description of the invention]

The present invention relates to cardiotonic agents. The cardiotonic agent of the present invention is characterized in that it contains at least one kind selected from carbostyril derivatives represented by the following general formula (1) and salts thereof as an active ingredient. [In the formula, R ¹ represents a hydrogen atom. R is a lower alkanoyl group, a lower alkoxycarbonyl group, a furoyl group, a lower alkasulfonyl group, a lower alkyl group, a lower alkoxy group as a substituent on the phenyl ring,
Having 1 to 3 groups selected from halogen, cyano, amino, and nitro groups, or a benzoyl group that may have a lower alkylene dioxy group, or 1 to 3 lower alkoxy groups as a substituent on the phenyl ring. represents a certain phenyl lower alkenyl carbonyl group or phenoxy lower alkyl group.
A represents a lower alkylene group. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. ] Examples of each group defined by R ¹ , R and A in the above general formula (1) include the following groups. 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 phenylalkyl groups having a straight chain or branched alkyl group having 1 to 6 carbon atoms such as 3-phenylpropyl group. Lower alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl,
Examples include straight chain or branched alkanoyl groups having 1 to 6 carbon atoms such as pentanoyl, tert-butylcarbonyl, and hexanoyl groups. Examples of lower alkoxycarbonyl groups include linear or branched carbon atoms having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. An example is an alkoxycarbonyl group having an alkoxy group. Examples of lower alkanesulfonyl groups include straight-chain or branched alkanesulfonyl groups having 1 to 6 carbon atoms, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, tert-butanesulfonyl, pentanesulfonyl, and hexanesulfonyl groups. Examples include groups. Examples of the benzoyl group which may have one to three groups selected from lower alkyl, lower alkoxy, halogen, cyano, amino and nitro groups or a lower alkylene dioxy group as substituents on the phenyl ring include benzoyl, 2 -,3- or 4-chlorobenzoyl, 2-,3- or 4-
fluorobenzoyl, 2-, 3- or 4-brombenzoyl, 2- or 4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,6-dichlorobenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3,5-dibromobenzoyl, 3,4,5-trichlorobenzoyl, 2-,3- or 4-methylbenzoyl, 2-,3- or 4-ethylbenzoyl,
3-isopropylbenzoyl, 4-hexylbenzoyl, 3,4-dimethylbenzoyl, 2,5-
Dimethylbenzoyl, 3,4,5-trimethylbenzoyl, 2-,3- or 4-methoxybenzoyl, 2-,3- or 4-ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl, 3,4- Dimethoxybenzoyl, 3,4-diethoxybenzoyl, 3,
4,5-trimethoxybenzoyl, 2,5-dimethoxybenzoyl, 2-,3- or 4-nitrobenzoyl, 2,4-dinitrobenzoyl, 2
-,3- or 4-aminobenzoyl, 2,4
-Diaminobenzoyl, 2,3-diaminobenzoyl, 3,4-diaminobenzoyl, 2,5-diaminobenzoyl, 3,4,5-triaminobenzoyl, 2-,3- or 4-cyanobenzoyl, 2,4- Dicyanobenzoyl, 3,4-methylenedioxybenzoyl, 3,4-ethylenedioxybenzoyl, 2,3-methylenedioxybenzoyl, 3-methyl-4-chlorobenzoyl, 2
- Straight chain or branched alkyl group having 1 to 6 carbon atoms on the phenyl ring, straight chain or branched chain having 1 to 6 carbon atoms, such as chloro-6-methylbenzoyl, 2-methoxy-3-chlorobenzoyl group, etc. 1 to 3 groups selected from the group consisting of alkoxy groups, halogen atoms, cyano groups, amino groups, and nitro groups, or 1 to 4 carbon atoms
An example is a benzoyl group which may have a linear or branched alkylenedioxy group as a substituent. Examples of phenyl lower alkenyl carbonyl groups that may have 1 to 3 lower alkoxy groups as substituents on the phenyl ring include cinnamoyl, 4
-Phenyl-3-butenoyl, 4-phenyl-2
-butenoyl, 5-phenyl-4-pentenoyl, 5-phenyl-3-pentenoyl, 5-phenyl-2-pentenoyl, 6-phenyl-5-hexenoyl, 6-phenyl-4-hexenoyl,
6-phenyl-3-hexenoyl, 6-phenyl-2-hexenoyl, 2-methyl-4-phenyl-3-butenyl, 2-methyl-cinnamoyl, 1
-Methyl-cinnamoyl, 2-, 3- or 4
-Methoxycinnamoyl, 2-, 3- or 4
-Ethoxycinnamoyl, 2-, 3- or 4
-Propoxycinnamoyl, 2-butoxycinnamoyl, 3-(tert-butoxy)cinnamoyl,
4-pentyloxycinnamoyl, 3-hexyloxycinnamoyl, 3,5-dimethoxycinnamoyl, 2,6-dimethoxycinnamoyl, 3,
4-dimethoxycinnamoyl, 3,4-diethoxycinnamoyl, 3,5-diethoxycinnamoyl, 3,4,5-trimethoxycinnamoyl, 4
-Ethoxyphenyl-3-butenoyl, 4-(3
-tert-butoxyphenyl)-2-butenoyl,
5-(4-hexyloxyphenyl)-4-pentenoyl, 6-(3,4-dimethoxyphenyl)
-5-hexenoyl, 2-methyl-(2,5-diethoxyphenyl)cinnamoyl, 1-methyl-
(3-methoxyphenyl)cinnamoyl, 6-
(3,4,5-triethoxyphenyl) - A phenyl group that may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms on the phenyl ring such as -3-hexenoyl group. Examples include straight chain or branched alkenylcarbonyl groups having 3 to 6 carbon atoms. Examples of the phenoxy lower alkyl group include phenoxymethyl, 2-phenoxyethyl, 2-phenoxypropyl, 3-phenoxypropyl, 1-methyl-2-phenoxyethyl, 2-phenoxybutyl, 3-phenoxybutyl, 4-phenoxybutyl, 1,1 -dimethyl-2-phenoxybutyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms having a phenoxy group as a substituent, such as 2-phenoxypentyl, 3-phenoxypentyl, and 4-phenoxyhexyl groups. The lower alkylene group defined by A in general formula (1) is specifically, for example, methylene, ethylene,
trimethylene, 2-methyltrimethylene, 2,2
-Dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene, hexamethylene, and other linear or branched alkylene groups having 1 to 6 carbon atoms are exemplified. Furthermore, the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton in the above general formula (1) may be a single bond or a double bond, and furthermore, the carbon bond between the 3rd and 4th positions of the carbostyryl skeleton may be a single bond or a double bond.

[Reaction equation 1]

[In each formula, R, R ¹ , A and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton are the same as above. ^X1
represents a halogen atom] That is, the compound of the present invention is a compound of the general formula (2) which is known or can be obtained, for example, by the method shown in the reaction scheme 9 described below, and a piperazine derivative of the general formula (3). It is produced by reacting.
The reaction may be carried out without solvent or in a common inert solvent.
The process is completed in about 1 to 24 hours at a temperature of room temperature to about 200°C, preferably room temperature to 120°C. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and diethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, dimethylformamide, and dimethyl. Polar solvents such as sulfoxide, hexamethylphosphoric triamide, ayaton, acetonitrile, etc. can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. The basic compound also includes the piperazine derivative itself used as a raw material,
If this is used in excess, there is no need to use other basic compounds, such as potassium carbonate, sodium carbonate, sodium hydride, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, Tertiary amines such as quinoline can be used. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide or hexamethylphosphoric acid triamide as a reaction promoter, if necessary. The ratio of the compound of general formula (2) and the piperazine derivative 3 used in the above reaction is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in an equimolar amount to an excess amount, preferably an equimolar amount to the former. It is preferable to make it 5 times the molar amount. The piperazine derivative represented by the general formula (3) used as a raw material in the above includes some new compounds, and these can be converted into the general formula ( It can be easily produced in the same manner using piperazine instead of the carbostyryl derivative represented by 4). [Reaction equation 2] [In each formula, A, R ¹ and 3 of the carbostyril skeleton
The carbon-carbon bond between position and 4-position is the same as above. R' is a lower alkanoyl group, a lower alkoxycarbonyl group, a furoyl group, and 1 to 3 groups selected from lower alkyl, lower alkoxy, halogen, cyano, amino, and nitro groups as substituents on the phenyl ring.
This refers to a benzoyl group which may have one or lower alkylenedioxy groups, or a phenyl lower alkenylcarbonyl group which may have one to three lower alkoxy groups as substituents on the phenyl ring. ] That is, among the compounds of the present invention, those represented by the above general formula (1-a) can be obtained by reacting the carbostyril derivative of the general formula (4) with the carboxylic acid of the general formula (5) or an active compound of the carboxy group thereof. It can also be manufactured by The above reaction may be carried out by a conventional amide bond forming reaction. Examples of the amide bond forming reaction include the following method. (a) Mixed acid anhydride method, that is, a method in which carboxylic acid (5) is reacted with an alkylhalocarboxylic acid to form a mixed acid anhydride, and this is reacted with a derivative of general formula (4). (b) Active ester method, that is, carboxylic acid (5) is converted into p-
A method in which an active ester such as nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc. is reacted with a derivative of general formula (4). (c) Carbodiimide method, that is, a method in which a derivative of general formula (4) is condensed with carboxylic acid (5) in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole. (d) Other methods, such as converting carboxylic acid (5) into carboxylic anhydride using a dehydrating agent such as acetic anhydride, and reacting this with a derivative of general formula (4), or combining carboxylic acid (5) with a lower alcohol. A method of reacting a derivative of general formula (4) with an ester of (4) under high pressure and high temperature, a method of reacting a derivative of general formula (4) with an acid halide of carboxylic acid (5),
Methods such as activating carboxylic acid (5) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and reacting this with a derivative of general formula (4). The mixed acid anhydride used in the mixed acid anhydride method shown in (a) above is obtained by the usual Schotten-Baumann reaction, and is usually reacted with the derivative of general formula (4) without isolation. , the present compound of general formula (1-a) is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. As the basic compound, the derivative of the above general formula (4) itself or a compound 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),
Examples include organic bases such as 1,4-diazabicyclo[2,2,2]octane (DABCO) and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, and sodium hydrogen carbonate. The reaction is -20
The reaction is carried out at a temperature of -100°C, preferably 0 - 50°C, and the reaction time is about 5 minutes - 10 hours, preferably about 5 minutes - 2 hours. The reaction between the obtained mixed acid anhydride and the derivative of general formula (4) is carried out at about -20 to 150°C, preferably about
The reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 hours. Mixed anhydride methods are generally carried out in a solvent. The solvent used is a solvent commonly used in the mixed acid anhydride method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran, and dimethoxy. Ethers such as ethane, esters such as methyl acetate and ethyl acetate,
Examples include aprotic polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. The alkylhalocarboxylic acids used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate,
Examples include ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. Carboxylic acid (5) in this method, alkylhalocarboxylic acid and general formula
The ratio of the derivative (4) to be used is usually at least an equimolar amount of the latter to the former, preferably about 1 to 1.
It is assumed to be twice the molar amount. In addition, the carboxylic acid halide shown in (d) above and the general formula
When adopting the method of reacting with the derivative of (4),
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. For example, in addition to the basic compounds used in the above-mentioned Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. can be mentioned. Examples of solvents include, in addition to the solvents used in the above Schotten-Baumann reaction, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, acetonitrile, etc. Alternatively, a mixed solvent of two or more of the above solvents may be used. The ratio of carboxylic acid halide to the derivative of general formula (4) is not particularly limited and may be appropriately selected within a wide range.
It is usually advisable to use at least an equimolar amount, preferably an equimolar to 5 times the molar amount. The reaction is usually -20
The reaction is carried out at about 180°C, preferably 0 to 150°C, and is generally completed in 5 minutes to 30 hours. [Reaction equation 3] [In each formula, A, R ¹ and 3 of the carbostyril skeleton
The carbon-carbon bond between position and 4-position is the same as above. R'^' represents a phenoxy lower alkyl group or a lower alkanesulfonyl group. It can also be produced by reacting a styryl derivative with a compound represented by general formula (6). General formula detailed in Equation-2
The reaction is carried out under the same conditions as the reaction of the derivative (4) with a carboxylic acid halide. The compound of the present invention can also be produced as follows. [Reaction equation 4] [In each formula, X ¹ , R, R ¹ , A and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton are the same as above.
R ² is

[Formula] or

[Reaction equation 5]

[In the formula, R, R ¹ , A, X ¹ and the carbon-carbon bonds at the 3- and 4-positions of the carbostyril skeleton are the same as above. ] The reaction between the carbostyril derivative of general formula (12) and the compound of general formula (13) is generally carried out in the presence of a Lewis acid in a solvent according to a reaction called Friedel-Crafts reaction. As the solvent, those commonly used in this type of reaction, such as carbon disulfide, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, etc., can be used. Any conventional Lewis acid can be suitably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used may be determined as appropriate, but it is usually about 2 to 6 times the amount of carbostyryl derivative (12), preferably about 2 to 4 times the amount of the carbostyryl derivative (12). The amount of the compound of general formula (13) to be used relative to the carbostyril derivative (12) is usually at least an equimolar amount, preferably an equimolar amount to twice the molar amount. The reaction temperature is selected appropriately, but is usually 0.
The temperature is preferably about 0 to 70°C, preferably about 0 to 70°C. Although the reaction time varies depending on the raw materials, catalyst, reaction temperature, etc. and is not constant, the reaction is usually completed in about 0.5 to 6 hours. [Reaction equation 6] [In the formula, R, R ¹ and A are the same as above. ] Normal catalytic reduction conditions are applied to the reduction of the compound of general formula (1-d). Catalysts used include palladium, palladium-carbon, platinum,
Examples include metals such as Raney nickel, and such metals are preferably used in conventional catalytic amounts. Examples of the solvent that can be used include methanol, ethanol, isopropanol, dioxane, THF, hexane, cyclohexane, and ethyl acetate. The reduction reaction can be carried out both at normal pressure and under increased pressure, but it is usually carried out at normal pressure to 20 kg/
cm ² , preferably at normal pressure to 10 kg/cm ² . In addition, the reaction temperature is usually about 0 to 150℃,
The temperature is preferably room temperature to 100°C. Further, the dehydrogenation reaction of the compound of general formula (1-c) is carried out using an oxidizing agent in a suitable solvent. Examples of the oxidizing agent used include 2,3-dichloro-5,6-dicyanobenzoquinone and chloranil (2,3,5,6-tetrachlorobenzoquinone).
Examples include benzoquinones such as N-bromosuccinimide, N-chlorosuccinimide, halogenating agents such as bromine, hydrogenation catalysts such as selenium dioxide, palladium carbon, palladium black, palladium oxide and Raney nickel. The amount of the oxidizing agent to be used is not particularly limited and may be appropriately selected from a wide range, but it is usually 1 to 5 times the molar amount, preferably 1 to 2 times the molar amount of the compound of general formula (1-d). Good to use. Further, when a hydrogenation catalyst is used, a normal amount of catalyst may be used. Examples of solvents include ethers such as dioxane, THF, methoxyethanol, and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene, xylene, and cumene; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride;
Alcohols such as butanol, amyl alcohol, hexanol, polar protic solvents such as acetic acid,
Examples include polar aprotic solvents such as DMF, DMSO, and hexamethylphosphoric triamide. The reaction is usually carried out at room temperature to 300°C, preferably room temperature to 200°C, and is generally completed in about 1 to 40 hours. Furthermore, among the compounds of the present invention, compounds in which R ¹ is a hydrogen atom and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton is a double bond can be expressed by the following reaction scheme -
As shown in Figure 7, lactam-lactim tautomerism is possible. [Reaction equation 7] [In the formula, R and A are the same as above. ] Among the compounds of the present invention, compounds having an amino group as a substituent on the phenyl ring can also be easily produced by reducing a corresponding compound in which the substituent on the phenyl ring is a nitro group. can be done. 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. The compound of general formula (2) described in the reaction scheme-1 is a known compound described in West German Patent No. 3107601, for example, or a new compound. These can be produced, for example, by the method shown in Reaction Scheme 8 below. [Reaction equation 8] [In the formula, R ¹ , X ¹ and 3 of the carbostyril skeleton
The carbon-carbon bond at position and 4-position is the same as above. X′ represents a halogen atom. ] The reaction between the carbostyril derivative of general formula (12) and the compound of general formula (15) is carried out according to the reaction scheme-5 above.
It can be carried out under the same reaction conditions as the reaction described in . The compound of the present invention thus obtained can be easily converted into an acid addition salt by reacting it with 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 the present invention represented by general formula (1) or a salt thereof is usually used in the form of a common pharmaceutical preparation.
The formulation contains commonly used fillers, extenders, binders,
It is prepared using diluents or excipients such as wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, etc.
Examples include suppositories, injections, (solutions, suspensions, etc.). When forming into a tablet, a wide variety of carriers known in the art for this decomposition can be used.
For example, lactose, white sugar, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution,
Binders such as starch liquid, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone,
Dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, white sugar, stearyl, cocoa butter, hydrogen disintegration inhibitors such as added oil, absorption enhancers such as quaternary ammonium bases, sodium lauryl sulfate,
Moisturizers such as glycerin and starch, starch,
Adsorbents such as lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate,
Lubricants such as boric acid powder and polyethylene glycol can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, intestinal fluid-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers that are conventionally known for this decomposition can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, gum arabic powder,
Binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar can be used. When forming into suppository form,
A wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, ester fats of higher alcohols, gelatin, semi-synthetic glycerides, and the like. 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 decomposition can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution may be included in the cardiotonic agent, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, and other pharmaceutical agents may be included in the pharmaceutical preparation, if necessary. The amount of the compound of general formula (1) or its salt to be contained in the cardiotonic agent of the present invention is not particularly limited and can be selected from a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight based on the total composition. % by weight. There are no particular restrictions on the method of administering the cardiac inotrope of the present invention, and administration may be carried out in a manner depending on various formulation forms, age, sex and other conditions of the patient, degree of disease, etc.
For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly, intradermally, or
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally. The dosage of the cardiotonic agent of the present invention depends on the usage, the age of the patient,
The amount of the compound of general formula (1), which is the active ingredient, is usually about 0.01 to 10 mg per kg of body weight per day, although it is appropriately selected depending on gender, other conditions, and the degree of disease. It also contains the active ingredient in dosage unit form.
It is preferable to contain 0.1 to 200 mg. Reference examples and production examples of the compounds of the present invention are listed below as examples. Reference example 1 200g of 3,4-dihydrocarbostyryl, 160mg of chloroacetyl chloride and 300ml of carbon disulfide
460 g of pulverized anhydrous aluminum chloride was gradually added to the mixture under ice-cooling and stirring at an internal temperature of 5 to 15°C.
After addition, stir under reflux for 40 minutes. After removing CS ₂ by decantation, pour the residue into a large amount of ice water to remove precipitated crystals, wash thoroughly with water, then methanol and dry.
280g of 6-(2-chloroacetyl)-3,4-
Obtain dihydrocarbostyril. Recrystallize from ethanol to obtain colorless needle crystals. mp 230-231°C Reference Example 2 Add 4.4 g of piperazine and 5 ml of triethylamine to a solution of 6.7 g of 6-(α-chloroacetyl)-3,4-dihydrocarbostyryl and 60 ml of anhydrous dimethylformamide, and stir at 50-60°C for 1 hour. do.
The reaction solution was poured into a large amount of water and extracted with chloroform. After washing the chloroform layer with water and dehydrating, chloroform was distilled off, the residue was suspended in methanol-chloroform, and converted into a hydrochloride with hydrochloric acid/methanol to form colorless needle-like crystals of 6-[4-(1-piperazinyl)acetyl]- 3,4-dihydrocarbostyryl 1
Obtain 3.5 g of hydrochloride trihydrate. mp 265-267℃ (decomposition) Reference example 3 1.9 g of hexamine was added to a suspension of 3.0 g of 6-chloroacetyl-3,4-dihydrocarbostyryl in 20 ml of dimethylformamide while stirring at room temperature.
Gradually add 20 ml of dimethylformamide solution. After dropping, stir at 50-60°C for 2 hours. The precipitated crystals were collected, washed with methanol, and dried to obtain 3.5 g of crude crystals of 6-hexaminium acetyl-3,4-dihydrocarbostyryl chloride. Next 6-
Add 15 ml of ethanol and 6 ml of concentrated hydrochloric acid to 3.5 g of crude crystals of hexaminium acetyl-3,4-dihydrocarbostyryl chloride, and stir at room temperature for 12 hours. The crystals were collected and recrystallized with methanol-water to obtain 1.2 g of 6-aminoacetyl-3,4-dihydrocarbostyryl monohydrochloride in the form of colorless powder crystals. mp 300℃ or higher Example 1 To a solution of 6.7 g of 6(α-chloroacetyl)-3,4-dihydrocarbostyryl in 60 ml of anhydrous dimethylformamide, 14.3 g of 4-(3,4,5-trimethoxybenzoyl)piperazine and triethylamine were added. Add 5 ml and stir at 50-60°C for 1 hour. The reaction solution was poured into a large amount of water, and the organic layer was extracted with chloroform. After washing the chloroform layer with water and dehydrating it,
Distill off the chloroform. Crystallize the residue with ethanol and collect the crystals. The crystals were suspended in methanol-chloroform, converted to hydrochloride with hydrochloric acid/methanol, and recrystallized from ethanol to give colorless needle-like crystals of 6[4-(3,4,5-trimethoxybenzoyl)].
6.3 g of -1-piperazinylacetyl]-3,4-dihydrocarbostyryl monohydrochloride 3/2 hydrate was obtained. mp 213-217°C (decomposition) Colorless needles Compounds of Examples 2-24 are obtained in the same manner as in Example 1 using appropriate starting materials.

【table】

【table】

【table】

[Table] * -...Single bond =...Double bond Example 25 6-(1-piperazinyl)acetyl-3,4-
Dissolve 2.0 g of dihydrocarbostyril and 1.4 ml of triethylamine in 20 ml of dimethylformamide,
A solution of 2.2 g of 3,4,5-trimethoxybenzoyl chloride in 5 ml of dimethylformamide was gradually added dropwise to the mixture at room temperature with stirring. After stirring at room temperature for 30 minutes, the reaction mixture was poured into a large amount of saturated brine and extracted with chloroform. After washing with water, dry over anhydrous sodium sulfate, and chloroform is distilled off. The residue is crystallized and collected from ethanol. The crystals are suspended in a mixed solvent of methanol and chloroform, and converted into a hydrochloride with hydrochloric acid/ethanol. The solvent is distilled off, and ethanol is added to the residue for crystallization. Recrystallize from ethanol to obtain 6-[4-(3,4,5-trimethoxybenzoyl-1-piperazinylacetyl)]-
3,4-dihydrocarbostyryl monohydrochloride 3/
1.2 g of dihydrate are obtained. mp 213-217°C (decomposition) Colorless needle crystals In the same manner as in Example 25, using appropriate starting materials, the compounds of Examples 2-12, 15-21, 23 and 24 are obtained. Example 26 6-(1-piperazinyl acetyl)-3,4-
1.6 g of dihydrocarbostyril and 1.5 g of triethylamine were suspended in 10 ml of dichloromethane, and 1.4 g of p-toluenesulfonyl chloride was added under stirring under ice cooling.
Add dropwise 10 ml of dichloromethane solution. Thereafter, the mixture was stirred for an additional 3 hours at room temperature and then for 1 hour under ice cooling.
The precipitated crystals were collected and recrystallized from chloroform-ether to give 6-[4-p-toluenesulfonyl)-
0.4 g of 1-piperazinylacetyl]-3,4-dihydrocarbostyryl is obtained. mp 254-256°C (decomposition) Colorless powder crystals In the same manner as in Example 26, using appropriate starting materials, the compounds of Examples 13 and 22 are obtained. Example 27 5.0 g of 6-(α-aminoacetyl)-3,4-dihydrocarbostyryl, 10.8 g of (3,4,5-trimethoxybenzoyl)[di-(2-hydroxyethyl)]amine and 7.6 g of polyphosphoric acid The mixture of g is reacted at 160-170°C for about 6 hours. Thereafter, the reaction solution was allowed to cool, and about 500 ml of water was added dropwise to dissolve it. 48
Neutralize with % 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 ethanol, mp213-217℃ (decomposition), colorless needle crystals of 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinylacetyl]-3,4-dihydro 1.5 g of carbostyril monohydrochloride 3/2 hydrate was obtained. The compounds of Examples 2 to 24 are obtained in the same manner as in Example 27 using appropriate starting materials. Example 28 A mixture of 11.9 g of 6-(α-aminoacetyl)-3,4-dihydrocarbostyryl, 17.0 g of 3,4,5-trimethoxybenzoyl[bis(2-chloroethyl)]amine and 70 ml of methanol was heated for 15 hours. Stir and reflux. 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. The hydrochloride salt was prepared with concentrated hydrochloric acid/ethanol and recrystallized from ethanol to give colorless needle-like crystals of 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazine], mp213-217℃ (decomposition). Ruacetyl] -
3,4-dihydrocarbostyryl monohydrochloride 3/
7.3 g of dihydrate are obtained. The compounds of Examples 2 to 24 are obtained in the same manner as in Example 28 using appropriate starting materials. Example 29 3,4,5- in 100 ml of dimethylformamide
Add 3.6 g of trimethoxybenzoic acid and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7, and add isobutyl chloroformate under external cold stirring.
Drop 1.5ml. After dropping, stir for 30 minutes and add 6
A solution of 2.27 g of -(1-piperazinylacetyl)-3,4-dihydrocarbostyryl dissolved in 40 ml of dimethylformamide is added, and the mixture is stirred 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 with dilute NaHCO ₃ water, water, dilute hydrochloric acid, and water. After chloroform is distilled off, the residue is made into a hydrochloride with hydrochloric acid/ethanol. Recrystallized from ethanol, mp213-217℃ (decomposition) 6
- Obtain 2.1 g of [4-(3,4,5-trimethoxybenzoyl-1-piperazinyl acetyl)-3,4-dihydrocarbostyryl monohydrochloride 3/2 hydrate. Colorless needle crystals. The compounds of Examples 2 to 24 are obtained in the same manner as in Example 29 using appropriate starting materials. Example 30 6-(1-piperazinyl acetyl)-3,4-
2.76 g of dihydrocarbostyryl and 2.25 g of 3,4,5-trimethoxybenzoic acid were added to a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride, and 2.1 g of N,N'-dicyclohexylcarbodiimide was chlorinated under external ice cooling and stirring. A solution dissolved in 5 ml of methylene is added dropwise while maintaining the temperature at 10 to 20°C. At the same temperature after dropping
Stir for 3.5 hours. The precipitated crystals were removed, and the liquid was concentrated to dryness under reduced pressure. The obtained residue was dissolved in 100 ml of methylene chloride, and the organic layer was dissolved in 5% aqueous hydrochloric acid solution,
After sequentially washing with a 5% aqueous sodium bicarbonate solution and water, drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was converted into a hydrochloride with hydrochloric acid/methanol. Recrystallization from ethanol yields colorless needle-like crystals of 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyryl monohydrochloride 3/ dihydrate 0.8
get g. Melting point: 213-217°C (decomposition) In the same manner as in Example 30, the compounds of Examples 2-12, 15-21, 23 and 24 are obtained from appropriate starting materials. Example 31 136 mg of succinimide 3,4,5-trimethoxybenzoate and 144 mg of 6-(1-piperazinyl acetyl)-3,4-dihydrocarbostyryl 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 with sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was diluted with hydrochloric acid/
Constitute the hydrochloride with methanol. Recrystallized from ethanol to give 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinylacetyl]-
3,4-dihydrocarbostyryl monohydrochloride 3/
110 mg of dihydrate are obtained. mp 213-217°C (decomposition) Compounds of Examples 2-12, 15-21, 23 and 24 are obtained from appropriate starting materials in the same manner as in Example 31. Example 32 6-ethoxycarbonyl 3, in 100ml of ethanol
2.19 g of 4,5-trimethoxybenzoate, 0.5 g of sodium ethylate, and 2.48 g of 6-(1-piperazinyl acetyl)-3,4-dihydrocarbostyryl were added in an autoclave at 110 atm.
React at 140-150°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 200 ml of chloroform, washed successively with a 1% K ₂ CO ₃ aqueous solution, diluted hydrochloric acid, and water, dried over Na ₂ SO ₄ , and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (silica gel: Wako C-200, eluent: chloroform:methanol (V/V) = 20:
After purification in step 1), it is converted into a hydrochloride with hydrochloric acid/methanol. Recrystallization from ethanol gave colorless needle-like crystals of 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl]-3,4.
- Obtain 250 mg of dihydrocarbostyril monohydrochloride 3/2 hydrate. mp 213-217°C (decomposition) Using appropriate starting materials in the same manner as in Example 32, the compounds of Examples 2-12, 15-21, 23 and 24 are obtained. Example 33 1.0 g of 6-(1-piperazinyl)acetylcarbostyryl and 0.67 ml of triethylamine in DMF10
A solution of 780 mg of m-chlorobenzoyl chloride in 2 ml of DMF is gradually added dropwise to the ml solution under ice-cooling and stirring.
After dropping, stir at room temperature for 2 hours. The reaction mixture was poured into a large amount of half-saturated saline and extracted with chloroform. After washing with water, it is dried over anhydrous sodium sulfate, and chloroform is distilled off under reduced pressure. The residue is crystallized from ether, filtered and then recrystallized from ethanol. Dissolve the crystals in methanol-chloroform and make the hydrochloride with concentrated hydrochloric acid/ethanol. After distilling off the solvent, the residue was crystallized with ethanol, and then recrystallized with methanol to obtain 370 mg of 6-[4-(3-chlorobenzoyl).
-1-piperazinyl acetyl carbostyryl
Obtain hydrochloride/hydrate. mp 212-215°C (decomposition) Colorless powdery crystals Compounds of Examples 34-42 below are obtained in the same manner as in Example 33.

【table】

[Table] Example 43 6-(α-chloroacetyl)carbostyryl
In a solution of 6.6 g in 60 ml of anhydrous dimethylformamide,
Add 14.3 g of 4-(3,4,5-trimethoxybenzoyl)piperazine and 5 ml of triethylamine.
Stir at 50-60°C for 1 hour. The reaction solution was poured into a large amount of water, and the organic layer was extracted with chloroform. After the chloroform layer is washed with water and dehydrated, the chloroform is distilled off. Crystallize the residue with ethanol and collect the crystals. The crystals were suspended in methanol-chloroform, converted to hydrochloride with hydrochloric acid/ethanol, and recrystallized from methanol to give colorless powdery crystals of 6-[4-
(3,4,5-trimethoxybenzoyl)-1-
6.0 g of piperazinyl acetyl carbostyryl monohydrochloride 3/2 hydrate was obtained. mp201-204°C (decomposition) Compounds of Examples 33, 34-39, 41 and 42 are obtained in the same manner as in Example 43 using appropriate starting materials. Example 44 6-(α-aminoacetyl)carbostyryl
4.9g, (3,4,5-trimethoxybenzoyl)
A mixture of 10.8 g of [di-(2-hydroxyethyl)]amine and 7.6 g of polyphosphoric acid is reacted at 160-170°C for about 6 hours. After that, the reaction solution was allowed to cool, and water
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 methanol, mp201-204℃ (decomposition), colorless powder crystal 6
- Obtain 1.4 g of [4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl] carbostyril monohydrochloride 3/2 hydrate. Compounds of Examples 33, 34-39, 41 and 42 are obtained in the same manner as in Example 44 using appropriate starting materials. Example 45 6-(α-aminoacetyl)carbostyryl
A mixture of 11.8 g, 17.0 g of 3,4,5-trimethoxybenzoyl[bis(2-chloroethyl)]amine and 70 ml of methanol was stirred and refluxed for 15 hours. After cooling, 3.06 g of sodium carbonate was added and the mixture was stirred and refluxed for 8 hours. After cooling, collect the crystals that precipitate. The hydrochloride salt was prepared with concentrated hydrochloric acid/ethanol, and recrystallized from methanol.mp201-204℃ (decomposition), 6-
[4-(3,4,5-trimethoxybenzoyl)
-1-piperazinyl acetyl carbostyryl
7.1 g of monohydrochloride 3/2 hydrate is obtained. The compounds of Examples 33 to 39, 41 and 42 are obtained in the same manner as in Example 45 using appropriate starting materials. Example 46 3,4,5- in 100ml of dimethylformamide
3.6 g of trimethoxybenzoic acid and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7 are added, and 1.5 ml of isobutyl chloroformate is added dropwise under external ice cooling and stirring. After the dropwise addition, the mixture was stirred for 30 minutes, and a solution of 2.25 g of 6-(1-piperazinyl acetyl)carbostyryl dissolved in 40 ml of dimethylformamide was added thereto, followed by stirring 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 with dilute NaHCO ₃ water, water, dilute hydrochloric acid, and water. After chloroform is distilled off, the residue is made into a hydrochloride with hydrochloric acid/ethanol. Recrystallized from methanol to give 6-[4-(3,
4,5-trimethoxybenzoyl-1-piperazinyl acetyl carbostyril monohydrochloride 3/2
Obtain 2.0 g of hydrate. Colorless powder crystals The compounds of Examples 33 to 39, 41 and 42 are obtained in the same manner as in Example 46 using appropriate starting materials. Example 47 27.4 g of 6-(1-piperazinyl acetyl)carbostyryl and 3,4,5-trimethoxybenzoic acid
In addition to a mixed solvent of 2.25 g, 20 ml of dioxane, and 20 ml of methylene chloride, N,N′-
A solution of 2.1 g of dicyclohexylcarbodiimide dissolved in 5 ml of methylene chloride is added dropwise while maintaining the temperature at 10 to 20°C. 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 obtained residue was dissolved in 100 ml of methylene chloride,
The organic layer is washed successively with a 5% aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is converted into a hydrochloride with hydrochloric acid/ethanol. Recrystallized from methanol to give colorless powdery crystals of 6-[4-(3,
4,5-trimethoxybenzoyl)-1-piperazinyl acetyl carbostyryl monohydrochloride 3/
0.8 g of dihydrate is obtained. Melting point 201-204°C (decomposition). In the same manner as in Example 47, the compounds of Examples 33 to 39, 41 and 42 are obtained from appropriate starting materials. Example 48 136 ml of succinimide 3,4,5-trimethoxybenzoate and 143 mg of 6-(1-piperazinyl acetyl)carbostyryl are dissolved in 2 ml of dimethylformamide and stirred for one day. 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 converted into a hydrochloride with hydrochloric acid/ethanol. Recrystallize from methanol to obtain 6-[4
-(3,4,5-trimethoxybenzoyl)-1
- Piperazinyl acetyl] carbostyril monohydrochloride 3/2 hydrate was obtained (103 mg). mp 201-204°C (decomposed) Colorless powdery crystals Compounds of Examples 33-39, 41 and 42 are obtained from appropriate starting materials in the same manner as in Example 48. Example 49 6-ethoxycarbonyl 3, in 100 ml of ethanol
Add 2.19 g of 4,5-trimethoxybenzoate, 0.5 g of sodium ethylate, and 2.46 g of 6-(1-piperazinyl acetyl)carbostyryl, and heat in an autoclave at 110 atm and 140 to 150°C for 6 hours.
Allow time to react. After cooling, the reaction solution was concentrated under reduced pressure.
Dissolve the residue in 200ml of chloroform and dilute to 1%
After washing in the order of K ₂ CO ₃ aqueous solution, dilute hydrochloric acid, and water,
After drying with Na ₂ SO ₄ , the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (silica gel: Wako C-200, eluent: chloroform: methanol (V/V) = 20:1). After that, it is made into a hydrochloride with hydrochloric acid/ethanol. Recrystallized from methanol to give colorless powdery crystals of 6-[4
-(3,4,5-trimethoxybenzoyl)-1
- 232 mg of piperazinyl acetyl] carbostyril monohydrochloride 3/2 hydrate was obtained. mp 201-204°C (decomposition) Using appropriate starting materials in the same manner as in Example 49, the compounds of Examples 33-39, 41 and 42 are obtained. Example 50 3,4-dihydrocarbostyryl 20g, 4-
(3,4,5-trimethoxybenzoyl)-1-
46 g of pulverized anhydrous aluminum chloride is gradually added to a mixture of 71.5 g of piperazinyl acetyl chloride and 30 ml of carbon disulfide while cooling with ice and stirring at an internal temperature of 5 to 15°C. After addition, stir under reflux for 40 minutes. After carbon disulfide is removed by decantation, the residue is poured into a large amount of ice water to remove precipitated crystals, which are thoroughly washed with water and then with methanol. After drying, the crystals were suspended in methanol-chloroform, converted to hydrochloride with hydrochloric acid/methanol, and recrystallized with ethanol to obtain colorless needle-like crystals of 6-[4-(3,4,5-trimethoxybenzoyl)-1. -Piperazinyl acetyl]-3,4-
Dihydrocarbostyril monohydrochloride 3/2 hydrate
Obtain 6.3g. mp 213-217°C (decomposition) Colorless needle crystals Compounds of Examples 2-24 are obtained in the same manner as in Example 50. Example 51 Anhydrous aluminum chloride ground into a mixture of 19.7 g of carbostyril, 71.5 g of 4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl chloride and 30 ml of carbon disulfide while stirring under ice cooling.
Gradually add 46g at an internal temperature of 5-15℃. 40 after addition
Stir to reflux. After carbon disulfide is removed by decantation, the residue is poured into a large amount of ice water to remove precipitated crystals, which are thoroughly washed with water and then with methanol.
After drying, the crystals were suspended in methanol-chloroform, converted to hydrochloride with hydrochloric acid/ethanol, and recrystallized from methanol to give colorless powdery crystals of 6-[4-
(3,4,5-trimethoxybenzoyl)-1-
6.2 g of piperazinyl acetyl carbostyryl monohydrochloride 3/2 hydrate was obtained. mp 201-204℃ (decomposition) Colorless needle-like crystals In the same manner as in Example 51, the above-mentioned Examples 33-39, 41
and 42 compounds are obtained. Example 52 6-[4-(2-phenoxyethyl)-1-piperazinylacetyl]-3,4-dihydrocarbostyryl 498 mg, 50% oily sodium hydride 70 mg
was mixed in 5 ml of dimethylformamide, stirred at room temperature for 1 hour, and then a solution of 0.17 ml of benzyl chloride in 3 ml of dimethylformamide was gradually added dropwise, followed by stirring at room temperature for 4 hours. The reaction solution is poured into a large amount of water, organic substances are extracted with chloroform, the chloroform layer is washed with water, dried, and the chloroform is distilled off. Concentrated hydrochloric acid was added to the residue to obtain white crystals of 1-benzyl-6-[4-(2-phenoxyethyl)-1].
-Piperazinylacetyl]-3,4-dihydrocarbostyryl monohydrochloride (150 mg) was obtained. mp 230-234℃ (decomposition) Elemental analysis value (as C ₃₀ H ₃₃ N ₃ O ₃・HCl) C H N Calculated value (%) 69.28 6.59 8.08 Actual value (%) 69.08 6.74 7.98 Example 53 6-[4 -(2-phenoxyethyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyryl 498 mg, 50% oily sodium hydride 70 mg
was mixed in 5 ml of dimethylformamide, and after stirring at room temperature for 1 hour, a solution of 0.23 g of methyl iodide in 3 ml of dimethylformamide was gradually added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction solution is poured into a large amount of water, organic substances are extracted with chloroform, the chloroform layer is washed with water, dried, and the chloroform is distilled off. Concentrated hydrochloric acid was added to the residue to obtain white crystals of 1-methyl-6-[4-(2-phenoxyethyl)-1-].
132 mg of piperazinyl acetyl]-3,4-dihydrocarbostyryl monohydrochloride was obtained. mp 115-120℃ (decomposition) Elemental analysis value (as C ₂₄ H ₂₉ N ₃ O ₃・HCl) C H N Calculated value (%) 70.56 7.40 10.29 Actual value (%) 70.41 7.51 10.09 Example 54 6-[4 -(2-phenoxyethyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyryl 498 mg, 50% oily sodium hydride 70 mg
was mixed in 5 ml of DMF and stirred at room temperature for 2 hours, then 0.17 g of propargyl chloride was added and stirred at room temperature for 7 hours. The reaction solution was poured into 13 ml of saturated saline solution, organic substances were extracted with chloroform, the chloroform layer was washed with water, dehydrated, and the chloroform was distilled off. The residue was purified by silica gel column chromatography, and concentrated hydrochloric acid was added to make the hydrochloride, giving white crystals of 1-(2-propynyl)-6-[4-(3,
4-dimethoxybenzoyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyryl
85 mg of monohydrochloride is obtained. mp 209-211℃ (decomposition) Elemental analysis value (as C ₂₆ H ₂₉ N ₃ O ₃・HCl) C H N Calculated value (%) 66.73 6.46 8.98 Actual value (%) 66.48 6.66 9.19 Example 55 6-[4 -(2-phenoxyethyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyril 498 mg, sodium amide 0.05 g
After mixing in 5 ml of DMF and stirring at room temperature for 2 hours,
Add 0.17 g of allyl chloride and stir at room temperature for 10 hours. The reaction solution is poured into 13 ml of saturated saline solution, organic substances are extracted with chloroform, the chloroform layer is washed with water, dehydrated, and the chloroform is distilled off. The residue was purified by silica gel column chromatography, converted to hydrochloride with concentrated hydrochloric acid, and white crystals of 1-allyl-5-[4-(3,4-dimethoxybenzoyl) were obtained.
91 mg of -1-piperazinyl acetyl]-3,4-dihydrocarbostyryl monohydrochloride was obtained. mp 107-110℃ (decomposition) Elemental analysis value (as C ₂₆ H ₃₁ N ₃ O ₃・HCl) C H N Calculated value (%) 66.44 6.86 8.94 Actual value (%) 66.14 6.61 9.15 Example 56 8-(α 14.3 g of 4-(3,4,5-trimethoxybenzoyl)piperazine and 5 ml of triethylamine were added to a solution of 6.7 g of -chloroacetyl)-3,4-dihydrocarbostyryl in 60 ml of anhydrous dimethylformamide at 50 to 60°C for 1 hour. Stir. The reaction solution was poured into a large amount of water, and the organic layer was extracted with chloroform. After the chloroform layer is washed with water and dehydrated, the chloroform is distilled off. Crystallize the residue with ethanol and collect the crystals. The crystals were suspended in methanol-chloroform and converted into a hydrochloride with hydrochloric acid/methanol to form white crystals of 8-[4-(3,4,5
-trimethoxybenzoyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyryl
4.7 g of monohydrochloride are obtained. mp 158-162℃ Elemental analysis value (as C ₂₅ H ₂₉ N ₃ O ₆・HCl) C H N Calculated value (%) 64.09 6.45 8.97 Actual value (%) 64.26 6.34 9.09 Example 57 5-(α-chloroacetyl 14.3 g of 4-(3,4,5-trimethoxybenzoyl)piperazine and 5 ml of triethylamine are added to a solution of 6.7 g of )-3,4-dihydrocarbostyril in 60 ml of anhydrous dimethylformamide, and the mixture is stirred at 50 to 60°C for 1 hour. The reaction solution was poured into a large amount of water, and the organic layer was extracted with chloroform. After the chloroform layer is washed with water and dehydrated, the chloroform is distilled off. Crystallize the residue with ethanol and collect the crystals. The crystals were suspended in methanol-chloroform and converted into a hydrochloride with hydrochloric acid/methanol to form white crystals of 5-[4-(3,4,5
-trimethoxybenzoyl)-1-piperazinyl acetyl]-3,4-dihydrocarbostyryl
4.3 g of monohydrochloride are obtained. mp 157-162℃ Elemental analysis value (as C ₂₅ H ₂₉ N ₃ O ₆・HCl) C H N Calculated value (%) 64.09 6.45 8.97 Actual value (%) 64.26 6.34 9.09 Pharmacological test (a) Weight of 8-13 kg Adult male and female mixed breed dogs are anesthetized by intravenously administering pentobarbital sodium salt at a rate of 30 mg/Kg. After intravenously administering heparin sodium salt at a rate of 1000 U/Kg, the animals were bled to death and the hearts were removed into a lock solution. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Then, pre-prepared sodium salt of pentobarbital (30
Anesthetized with heparinized (1000U/Kg, intravenous) body weight 18~
Blood from the carotid artery of a 27 kg male-male mixed-breed adult dog is guided via a peristaltic pump to a cannula inserted into the right coronary artery to perfuse the right atrium. The perfusion pressure is a constant pressure of 100 mmHg. The movement of the right atrium is measured by measuring the contractile force of the atrial muscle via a force displacement transducer under a resting tension of 2 g. Coronary blood flow is measured using an electromagnetic flowmeter. All records shall be recorded on an ink recorder. The details of this method have been reported by Chiba et al. [Japan, J.Pharmacol., 25 , 433-439
(1975), Naunyn Schmiedberg′s Arch.
Pharmacol., 289 , 315-325 (1975)]. The test compound is injected into the artery in a volume of 10-30 μl through a rubber tube connected proximally to a cannula inserted into the right coronary artery. The positive inotropic effect of a test compound is expressed as a percent change in tension generated before compound administration, and the change in coronary blood flow is expressed as an absolute value (ml/min) from before administration. The results are shown in Table 1 below. (b) Anesthetize an adult male and female mixed breed dog weighing 8 to 13 kg by intravenously administering pentobarbital sodium salt at a rate of 30 ml/kg. After intravenously administering heparin sodium salt at a rate of 1000 U/Kg, the animals were bled to death and the hearts were removed. The specimen mainly consisted of papillary muscles and ventricular septum, and was made using blood drawn from a donor dog through a cannula inserted into the anterior septal artery.
Perfused at a constant pressure of mmHg. Donor dogs weigh 18~
The patient weighs 27 kg and is anesthetized by intravenously administering 30 mg/Kg of pentobarbital sodium salt, and 1000 U/Kg of heparin sodium salt intravenously. Using bipolar electrodes, voltage 15 times the threshold (0.5 to 3 V), stimulation width 5 msec and stimulation frequency 120 per minute.
Stimulates the papillary muscles with square waves. The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement transducer. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of generated tension and blood flow are recorded on an ink recorder.
The details of this method have already been reported by Endo and Hashimoto (Am.J.Physiol., 218 , 1459~
1463, 1970). The test compound is administered intra-arterially in a volume of 10-30 μl over 4 seconds. The inotropic effect of the test compound is expressed as a % change in the tension generated before drug administration. The effect on coronary blood flow is expressed as an absolute change (ml/min) from before administration. The results are shown in Table 2 below. (c) Male and female mixed-breed adult dogs weighing 9 to 15 kg were used. Pentobarbital sodium 30mg/Kg for dogs
The animals were anesthetized by intravenous administration of pentobarbital sodium, followed by continuous intravenous infusion of 4 mg/Kg/hr of sodium pentobarbital to maintain a constant depth of anesthesia. Using a ventilator, breathing rate 18 times per minute, 20ml/Kg
Artificial respiration was performed with an inspiratory volume of , and the chest was opened. Left ventricular contractile force was measured via an arch-shaped strain gauge attached to the outer wall of the left ventricle. A polyethylene tube was inserted into the left femoral artery, systemic blood pressure was measured via a pressure transducer, and a heart rate tachometer was driven by the blood pressure pulse wave to measure heart rate. All parameters were recorded on an ink recorder. Drugs were administered via a catheter inserted into the femoral vein. The inotropic effect of the test compound was expressed as a percent change in the tension generated before compound administration. Changes in blood pressure (mmHg) and heart rate (number of times/min) were expressed as absolute values from before administration. The results are shown in Table 3. (d) The following test compounds 1 to 27 were orally administered to male rats, and their acute toxicity (LD ₅₀ mg/Kg) was determined. All test compounds 1 to 27 had an LD ₅₀ of 3000 mg/Kg or more. <Test compound> No. Compound name 1 6-[4-(4-methylbenzoyl)-1-
piperazinyl acetyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 2 6-[4-(4-cyanobenzoyl)-1-
piperazinyl acetyl]-3,4-dihydrocarbostyryl 1/2 hydrate 3 6-[4-(4-methoxybenzoyl)-1
-Piperazinyl acetyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 4 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl acetyl]-3,
4-dihydrocarbostyryl monohydrochloride monohydrate 5 6-[4-(4-nitrobenzoyl)-1-
Piperazinyl acetyl]-3,4-dihydrocarbostyryl 1 hydrochloride 6 6-(4-acetyl-1-piperazinyl acetyl)-3,4-dihydrocarbostyryl 1
Hydrochloride 1/2 hydrate 7 6-[4-ethoxycarbonyl-1-piperazinylacetyl)-3,4-dihydrocarbostyryl monohydrochloride 8 6-(4-methanesulfonyl-1-piperazinyl) 6-(4-formyl-1-piperazinylacetyl)-3,4-dihydrocarbostyryl 10 6-[4 -(3,4-dimethoxybenzoyl)-1-piperazinyl acetyl]-3,4-
Dihydrocarbostyryl 11 6-[4-(3-chlorobenzoyl)-1-
Piperazinylacetyl]-3,4-dihydrocarbostyryl 1/2 hydrate 12 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinylacetyl]carbostyryl 1/2 Hydrate 13 6-[4-(3,4-dichlorobenzoyl)
-1-Piperazinylacetyl]-3,4-dihydrocarbostyryl monohydrochloride 1/2 hydrate 14 6-(4-furoyl-1-piperazinylacetyl)-3,4-dihydrocarbostyryl・1
Hydrochloride 15 6-(4-benzoyl-1-piperazinyl acetyl)-3,4-dihydrocarbostyryl
Quarter hydrate 16 6-[4-(3-chlorobenzoyl)-1-
Piperazinyl acetyl] carbostyril, hydrochloride, hydrate 17 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl acetyl] carbostyril, hydrochloride, 3/2 hydrate 18 6 -[4-(4-methoxybenzoyl)-1
-Piperazinyl acetyl]carbostyryl hydrochloride 3/2 hydrate 19 6-[4-(4-methylbenzoyl)-1-
Piperazinyl acetyl] carbostyril hydrochloride 3/2 hydrate 20 6-(4-benzoyl-1-piperazinyl acetyl) carbostyril hydrochloride 3/2 hydrate 21 6-[4-( 4-cyanobenzoyl)-1-
Piperazinyl acetyl] carbostyryl hydrochloride 3/2 hydrate 22 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl] carbostyril hydrochloride 3/ Dihydrate 23 6-[4-(4-nitrobenzoyl)-1-
Piperazinyl acetyl] carbostyryl hydrochloride 1/2 hydrate 24 6-[4-(4-methoxycinnamoyl)-
1-Piperazinylacetyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 25 6-(4-cinnamoyl-1-piperazinylacetyl)-3,4-dihydrocarbostyryl monohydrochloride Salt 1/2 hydrate 26 6-[4-(4-aminobenzoyl)-1-
Piperazinyl acetyl]carbostyryl dihydrochloride monohydrate 27 6-[4-(2-phenoxyethyl)-1-
Piperazinyl acetyl]-3,4-dihydrocarbostyryl dihydrochloride 1/2 hydrate 28 Amrinone (control compound) 29 Dobutamine (control compound)

【table】

【table】

[Table] Examples of formulations using the compounds of the present invention are listed below. Formulation example 1 6-[4-(4-methylbenzoyl)-1-piperazinylacetyl]-3,4-dihydrocarbostyryl monohydrochloride monohydrate 5mg Starch 132mg Magnesium stearate 18mg Lactose 45mg total 200mg tablets of the above composition were manufactured in a conventional manner. Formulation example 2 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl]-3,4
-Dihydrocarbostyril 10mg Starch 127mg Magnesium stearate 18mg Lactose 45mg Total 200mg Tablets containing the above composition were prepared in a conventional manner. Formulation example 3 6-[4-(4-nitrobenzoyl)-1-piperazinyl acetyl]-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 the above distilled water at 80°C with stirring. The resulting solution was cooled to 40°C, and the compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, were dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, sterilized by sterilization using a suitable filter paper, and the solution is dispensed into 1 ml ampoules to prepare an injection. Formulation example 4 6-[4-(3,4,5-trimethoxybenzoyl)-1-piperazinyl acetyl]carbostyryl monohydrochloride 3/2 hydrate 10mg Starch 127mg Magnesium stearate 18mg Lactose 45mg A total of 200 mg of each tablet was prepared using the above composition in a conventional manner.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom. R is a lower alkanoyl group, a lower alkoxycarbonyl group, a furoyl group, a lower alkanesulfonyl group, a lower alkyl group, a lower alkoxy group as a substituent on the phenyl ring,
Having 1 to 3 groups selected from halogen, cyano, amino, and nitro groups, or a benzoyl group that may have a lower alkylene dioxy group, or 1 to 3 lower alkoxy groups as a substituent on the phenyl ring. represents a certain phenyl lower alkenyl carbonyl group or phenoxy lower alkyl group.
A represents a lower alkylene group. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. ] A cardiotonic agent containing as an active ingredient at least one selected from carbostyril derivatives represented by the following and salts thereof.