JPS6254404B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to cardiotonic agents. More specifically, the present invention relates to the general formula [In the formula, R represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, A represents a lower alkylene group, and X
represents a halogen atom, and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond, respectively. ] This relates to a cardiotonic agent characterized by containing a carbostyril derivative represented by the following as an active ingredient. A compound in which R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, A represents a -(CH ₂ ) ₃ - group, and X represents a halogen atom among the carbostyryl derivatives represented by the above general formula (1). is a known compound, and it is already a known fact that this compound has antibacterial action, anti-inflammatory action, and platelet aggregation inhibiting action (see Japanese Patent Application Laid-Open No. 54-30180). As a result of further research, the present inventors found that the carbostyril derivative of general formula (1) has an effect that could not be predicted from its antibacterial, anti-inflammatory, and platelet aggregation inhibitory effects, namely, the effect of enhancing myocardial contraction (positive It has been found that it has an inotropic effect) and an effect of increasing coronary blood flow, and is therefore effective as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. The present invention was completed based on this knowledge. The characteristics of the carbostyril derivative of the general formula (1) are that, while it has excellent positive inotropic action and coronary blood flow increasing action, it has extremely weak action to increase heart rate and has extremely low toxicity. In this specification, each group represented by R, A and X is more specifically as follows. Lower alkyl group...methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,
pentyl, hexyl groups, etc. Lower alkanoyl group...formyl, acetyl,
Propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl groups, etc. Lower alkylene group...methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,
2-dimethyltrimethylene, 1-methyltrimethylene, tetramethylene, pentamethylene, hexamethylene groups, etc. Halogen atoms: fluorine, chlorine, bromine and iodine atoms. Representative carbostyryl derivatives represented by the above general formula (1) are listed below. Γ 6-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl bromide Γ 6-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl chloride Γ 6-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl iodide Γ 6-(2-pyridinium ethoxy)3,4-
Dihydrocarbostyryl bromide Γ 6-(4-pyridinium butoxy)3,4-
Dihydrocarbostyryl chloride Γ 6-(2-methyl-3-pyridinium propoxy) 3,4-dihydrocarbostyryl bromide Γ 6-(2,2-dimethyl-3-pyridinium propoxy) 3,4-dihydrocarbostyryl chloride Γ 6 -(3-Methyl-3-pyridiniumpropoxy)-3,4-dihydrocarbostyryl bromide Γ 6-(5-pyridiniumpentyloxy)-
3,4-dihydrocarbostyryl chloride Γ 6-(6-pyridiniumhexyloxy)-
3,4-dihydrocarbostyryl bromide Γ 6-(3-pyridinium propoxy) carbostyryl bromide Γ 6-(3-pyridinium propoxy) carbostyryl chloride Γ 6-(3-pyridinium propoxy) carbostyryl iodide Γ 6-(2 -pyridinium ethoxy) carbostyryl bromide Γ 6-(4-pyridinium butoxy) carbostyryl chloride Γ 6-(2-methyl-3-pyridinium propoxy) carbostyryl bromide Γ 6-(2,2-dimethyl-3-pyridinium propoxy) Carbostyryl chloride Γ 6-(3-methyl-3-pyridiniumpropoxy) carbostyryl bromide Γ 6-(5-pyridiniumpentyloxy) carbostyryl chloride Γ 6-(6-pyridiniumhexyloxy) carbostyryl bromide Γ 6-[3 -(3-formylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 6-[3-(3-formylpyridinium)propoxy]carbostyryl bromide Γ 6-[3-(3-acetylpyridinium)propoxy]- 3,4-dihydrocarbostyryl bromide Γ 6-[3-(2-acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl chloride Γ 6-[3-(4-acetylpyridinium)propoxy]-3,4- Dihydrocarbostyryl iodide Γ 6-[4-(3-acetylpyridinium)butoxy]-3,4-dihydrocarbostyryl bromide Γ 6-[3-(3-acetylpyridinium)propoxy]carbostyryl bromide Γ 6-[3 -(2-acetylpyridinium)propoxy]carbostyryl bromide Γ 6-[3-(4-acetylpyridinium)propoxy]carbostyryl iodide Γ 6-[3-(3-isobutyrylpyridinium)
Propoxy] carbostyryl bromide Γ 6-[3-(3-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl iodide Γ 6-[3-(2-methylpyridinium)propoxy]-3,4-dihydrocarbo Styryl bromide Γ 6-[3-(4-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 6-[3-(2-methylpyridinium)propoxy]carbostyryl bromide Γ 6-[3-(3 -Methylpyridinium)propoxy]carbostyryl bromide Γ 6-[3-(4-methylpyridinium)propoxy]carbostyryl iodide Γ 6-[3-(2-ethylpyridinium)propoxy]carbostyryl bromide Γ 6-[3- (4-Butylpyridinium)propoxy]carbostyryl iodide Γ 6-[4-(2-methylpyridinium)butoxy]carbostyryl bromide Γ 7-(3-pyridiniumpropoxy)-3,4
-dihydrocarbostyryl bromide Γ 7-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl chloride Γ 7-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl iodide Γ 7-(2-pyridinium ethoxy)-3,4-
Dihydrocarbostyryl bromide Γ 7-(4-pyridinium butoxy)-3,4-
Dihydrocarbostyryl chloride Γ 7-(2-Methyl-3-pyridinium propoxy)-3,4-dihydrocarbostyryl bromide Γ 7-(2,2-dimethyl-3-pyridinium propoxy)-3,4-dihydrocarbostyryl chloride Γ 7-(3-methyl-3-pyridiniumpropoxy)-3,4-dihydrocarbostyryl bromide Γ 7-(5-pyridiniumpentyloxy)-
3,4-dihydrocarbostyryl chloride Γ 7-(6-pyridiniumhexyloxy)-
3,4-dihydrocarbostyryl bromide Γ 7-(3-pyridinium propoxy) carbostyryl bromide Γ 7-(3-pyridinium propoxy) carbostyryl chloride Γ 7-(3-pyridinium propoxy) carbostyryl iodide Γ 7-(2 -pyridinium ethoxy) carbostyryl bromide Γ 7-(4-pyridinium butoxy) carbostyryl chloride Γ 7-(2-methyl-3-pyridinium propoxy) carbostyryl bromide Γ 7-(2,2-dimethyl-3-pyridinium propoxy) Carbostyryl chloride Γ 7-(3-methyl-3-pyridiniumpropoxy) carbostyryl bromide Γ 7-(5-pyridiniumpentyloxy) carbostyryl chloride Γ 7-(6-pyridiniumhexyloxy) carbostyryl bromide Γ 7-[3 -(3-acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 7-[3-(2-acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl chloride Γ 7-[3-(4- acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl iodide Γ 7-[4-(3-acetylpyridinium)butoxy]-3,4-dihydrocarbostyryl bromide Γ 7-[3-(3-acetylpyridinium) Propoxy]carbostyryl bromide Γ 7-[3-(2-acetylpyridinium)propoxy]carbostyryl bromide Γ 7-[3-(4-acetylpyridinium)propoxy]carbostyryl iodide Γ 7-[3-(3-iso butyrylpyridinium)
Propoxy]carbostyryl bromide Γ 7-[3-(2-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 7-[3-(3-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl Iodide Γ 7-[3-(4-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 7-[3-(2-methylpyridinium)propoxy]carbostyryl bromide Γ 7-[3-(3 -Methylpyridinium)propoxy]carbostyryl bromide Γ 7-[3-(4-methylpyridinium)propoxy]carbostyryl iodide Γ 7-[3-(2-ethylpyridinium)propoxy]carbostyryl bromide Γ 7-[3- (4-Butylpyridinium)propoxy]carbostyryl iodide Γ 7-[4-(2-methylpyridinium)butoxy]carbostyryl bromide Γ 7-[3-(3-formylpyridinium)propoxy]-3,4-dihydrocarbo Styryl bromide Γ 7-[3-(3-formylpyridinium)propoxy]carbostyryl bromide Γ 5-(3-pyridiniumpropoxy)-3,4
-dihydrocarbostyryl bromide Γ 5-(2-pyridinium ethoxy)-3,4-
Dihydrocarbostyryl bromide Γ 5-(4-pyridinium butoxy)-3,4-
Dihydrocarbostyryl chloride Γ 5-(2-methyl-3-pyridinium propoxy)-3,4-dihydrocarbostyryl bromide Γ 5-(3-pyridinium propoxy) carbostyryl bromide Γ 5-(3-pyridinium propoxy) carbostyryl chloride Γ 5-(3-pyridinium propoxy) carbostyryl iodide Γ 5-(2-pyridinium ethoxy) carbostyryl bromide Γ 5-(4-pyridinium butoxy) carbostyryl chloride Γ 5-(2-methyl-3-pyridinium propoxy) Carbostyryl bromide Γ 5-[3-(3-acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 5-[3-(3-acetylpyridinium)propoxy]carbostyryl bromide Γ 5-[3-( 2-Methylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 5-[3-(2-methylpyridinium)propoxy]carbostyryl bromide Γ 5-[3-(4-methylpyridinium)propoxy]carbostyryl io Dydo Γ 8-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl bromide Γ 4-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl chloride Γ 8-(3-pyridinium propoxy) carbostyryl bromide Γ 4-(3-pyridinium propoxy) carbostyryl bromide Γ 4-(2-pyridinium ethoxy) carbostyryl bromide Γ 8-(4-pyridinium butoxy) Carbostyryl chloride Γ 8-(2-methyl-3-pyridiniumpropoxy)carbostyryl bromide Γ 8-[3-(3-acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 4-[3-(3 -acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl chloride Γ 8-[3-(3-acetylpyridinium)propoxy]carbostyryl bromide Γ 4-[3-(3-acetylpyridinium)propoxy]carbostyryl bromide Γ 8-[3-(2-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide Γ 4-[3-(2-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl iodide Γ 8-[ 3-(2-Methylpyridinium)propoxy]carbostyryl bromide Γ 4-[3-(2-methylpyridinium)propoxy]carbostyryl bromide The carbostyryl derivative represented by the general formula (1) is, for example, the following reaction scheme -1 It is easily produced by the method shown in . [In the formula, X' represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group, or an aralkylsulfonyloxy group. R,
The carbon-carbon bonds between A, X and the 3rd and 4th positions of the carbostyril skeleton are the same as above. ] In the above general formula (3), the lower alkanesulfonyloxy group represented by
Examples include -butanesulfonyloxy, pentanesulfonyloxy, hexanesulfonyloxy groups, etc., and specific examples of arylsulfonyloxy groups include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-Nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-chlorophenylsulfonyloxy, α-
Examples include substituted or unsubstituted arylsulfonyloxy groups such as naphthylsulfonyloxy groups, and specific examples of aralkylsulfonyloxy groups include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, and 4-phenylbutylsulfonyloxy. , 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4
Examples include substituted or unsubstituted aralkylsulfonyloxy groups such as -nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and α-naphthylmethylsulfonyloxy. The reaction between the known compound of general formula (2) and the known compound of general formula (3) is carried out without a solvent or in a common inert solvent at a temperature of room temperature to about 200°C, preferably 60 to 120°C. Under certain conditions, it can be completed within a few hours to 24 hours. Examples of inert solvents include ethers such as dioxane, tetrahydrofuran, ethylene glycol, and dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, and lower alcohols such as methanol, ethanol, and isopropanol.
dimethylformamide, dimethyl sulfoxide,
Polar solvents such as hexamethylphosphoric triamide can be used. The above reaction is more advantageously carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include tertiary amines such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium amide, sodium hydride, triethylamine, tripropylamine, pyridine, and quinoline. 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 represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is not particularly limited and is appropriately selected within a wide range, but the latter is usually equal to the former. The amount is preferably about 1 molar to about 2 times the molar amount. The reaction between the compound of general formula (4) and the known compound of general formula (5) is carried out without a solvent or in a solvent.
Any solvent can be used as long as it does not participate in the reaction. Typical solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and ethylene glycol, ethers such as dimethyl ether, tetrahydrofuran, and dioxane, acetone, methyl ethyl ketone, cyclohexanone,
Examples include ketones such as acetophenone, esters such as methyl acetate and ethyl acetate, aprotic polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide, and hexamethyl phosphate triamide, and nitriles such as acetonitrile. The ratio of the compound of general formula (4) and the compound of general formula (5) to be used is not particularly limited and is appropriately selected from a wide range, but when the reaction is carried out without a solvent, the former is usually compared to the latter. It is preferable to use an equimolar to large excess amount of the former, and when the reaction is carried out in a solvent, the latter is usually used in an equimolar to 5 times the molar amount, preferably an equimolar to twice the molar amount of the former. good. The reaction generally proceeds well at a temperature of 0 to 200°C, preferably 50 to 150°C, and is usually completed within 10 minutes to 10 hours, and at most 24 hours. After completion of the reaction, the target product can be separated and purified from the reaction solution by conventional separation methods such as filtration, concentration, crystallization, recrystallization, column chromatography, etc. The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( liquid agents, suspension agents, etc.). When forming tablets, a wide variety of carriers conventionally known in this field can be used, including carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder , disintegrants such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc. absorption enhancers such as grade ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite,
Examples include adsorbents such as colloidal silicic acid, purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used.
For example, glucose, lactose, starch, cocoa butter,
Examples include excipients such as hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminalan agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter,
Higher alcohols, esters of higher alcohols,
Examples include gelatin and semi-synthetic glycerides. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when formed into solutions, emulsions, and suspensions, diluents may be used. All those commonly used in this field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the cardiotonic agent may contain a sufficient amount of salt, glucose, or glycerin to adjust the isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. Good too. Furthermore, if necessary, colorant,
Preservatives, fragrances, flavors, sweeteners, and other pharmaceutical agents may also be included in the therapeutic agent. The amount of the compound of general formula (1) to be contained in the cardiotonic agent of the present invention is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 30% by weight based on the total composition. be. There are no particular restrictions on the method of administering the cardiac inotrope of the present invention, and administration can be done in a manner that is appropriate for various formulations, age, sex and other conditions of the patient, degree of disease, and the like.
For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. In the case of injections, they are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and if necessary, they can also be administered intramuscularly, intradermally, or intradermally.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally. The dosage of the 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 an active ingredient, is usually about 0.1 to 10 mg per 1 kg of body weight per day, although it is appropriately selected depending on gender and other conditions, the severity of the disease, etc. Further, it is preferable that the dosage unit form contains 1 to 200 mg of the active ingredient. Reference examples, production examples, formulation examples, and pharmacological test results are listed below. Reference example 16.4 g of 6-hydroxy-3,4-dihydrocarbostyryl and 9 g of potassium hydroxide were mixed in 150 ml of isopropanol and stirred at 70 to 80°C for 30 minutes.
Next, 25 g of 1,3-dibromopropane was added and the mixture was heated under reflux for 6 hours. After the reaction is completed, the reaction solution is poured into 200 ml of 2N aqueous sodium hydroxide solution, and insoluble materials are removed, washed with water, and dried. Recrystallization of the crude crystals from methanol yields 17 g of 6-(3-bromopropoxy)-3,4-dihydrocarbostyryl having a melting point of 121-124°C. Production example 1 2 g of 5-(3-bromopropyloxy)-3,4-dihydrocarbostyryl and 10 ml of pyridine were heated at 90°C.
After heating and stirring for 2 hours and cooling, the precipitated crystals were collected. Wash with isopropanol and ether to obtain crude crystals. This was recrystallized from methanol and 5-(3-
2.0 g of pyridinium propoxy)-3,4-dihydrocarbostyryl bromide are obtained. Melting point: 251.0-252.5°C Production example 2 2 g of 6-(3-bromopropyloxy) carbostyril and 10 ml of pyridine were heated and stirred at 75-80°C for 6 hours, and after cooling, the precipitated crystals were collected and washed with isopropanol and ether. to obtain crude crystals. This was recrystallized from ethanol to yield 1.8 g of 6-(3-pyridinium propoxy)carbostyryl bromide.
get. Melting point: 189.0-190.5°C Production example 3 2 g of 7-(3-bromopropyloxy)-3,4-dihydrocarbostyryl and 10 ml of pyridine were heated at 90°C.
When heated and stirred for 2 hours, an oily substance precipitates out.
This was crystallized by stirring under ice-cooling to obtain 1.9 g of 7-(3-pyridinium propoxy)-3,4-dihydrocarbostyryl bromide. Melting point: 213.5°C to 215.5°C Production example 4 2 g of 8-(3-bromopropyloxy)-3,4-dihydrocarbostyryl and 10 ml of pyridine were heated at 90°C.
The mixture was heated and stirred for 2 hours, and after cooling, the precipitated crystals were collected.
Wash with isopropanol and ether to obtain crude crystals. This was recrystallized from ethanol and 8-(3
2.2 g of -pyridiniumpropoxy)-3,4-dihydrocarbostyryl bromide are obtained. Melting point 200.0-202.5℃ Production example 5 6-(3-bromopropoxy)-3,4-dihydrocarbostyryl 1g and 3-acetylpyridine 3
Stir the ml mixture at 90-100°C for 10 hours. After cooling, the precipitated crystals were collected, washed with chloroform, and recrystallized twice from ethanol to give 6-[3-(3
-acetylpyridinium)propoxy]-3,4
- 310 mg of dihydrocarbostyryl bromide are obtained. Melting point: 172°C to 174°C Formulation Example 1 6-(3-pyridiniumpropoxy)carbostyryl bromide 5mg Starch 132mg Magnesium stearate 18mg Lactose 45mg Total 200mg Tablets of the above composition were prepared in a conventional manner. Formulation example 2 7-(3-pyridinium propoxy)-3,4
-Dihydrocarbostyryl bromide 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-(3-pyridinium propoxy) carbostyril 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 about half the amount of distilled water above at 80°C with stirring. do. 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. The solution was then adjusted to the final volume by adding distilled water for injection.
Sterilize by sterilization using a suitable filter paper, and prepare an injection by dispensing 1 ml into ampoules. Pharmacological Test Adult male and female mixed breed dogs weighing 8 to 13 kg are anesthetized by intravenously administering pentobarbital sodium salt at a rate of 30 mg/kg. heparin sodium salt
After intravenous administration at a rate of 1000U/Kg, death was caused by exsanguination.
The heart is removed into locks fluid. A cannula is inserted from the right coronary artery toward the sinus node artery, and the right atrium is removed together with the cannula. Next, the animals were anesthetized with pentobarbital sodium salt (30 mg/Kg, intravenous administration) and treated with heparin (1000 U/Kg,
Blood is introduced from the carotid artery of a male-male mixed-breed adult dog weighing 18 to 27 kg (intravenous administration) 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 to 30 μl through a rubber tube connected closely to a cannula inserted into the right coronary artery. The positive inotropic effect of the test compound is expressed as a percent change in tension developed before compound administration, and the change in coronary blood flow is expressed as an absolute value (ml/min) from before administration. The results are shown in Table 1 below. Test compound No. 1 5-(3-pyridinium propoxy)3,4
-dihydrocarbostyryl bromide 2 6-(3-pyridinium propoxy) carbostyryl bromide 3 7-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl bromide 4 6-(3-pyridinium propoxy)-3,4
-dihydrocarbostyryl bromide 5 6-[3-(3-acetylpyridinium)propoxy]-3,4-dihydrocarbostyryl bromide 6 6-[3-(2-methylpyridinium)propoxy]-3,4-dihydrocarbostyryl Bromide 7 8-(3-pyridiniumpropoxy)-3,4
-dihydrocarbostyryl bromide

[Table] Acute toxicity test Each test compound is orally administered to male rats to determine its acute toxicity (LD ₅₀ , mg/Kg). The results are shown in Table 2.

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, A represents a lower alkylene group, and X
represents a halogen atom, and the carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond, respectively. ] A cardiotonic agent characterized by containing a carbostyril derivative represented by the following as an active ingredient.