JPH07215873A - Cardiotonic - Google Patents

Abstract

PURPOSE:To obtain a cardiotonic containing a specific carbostyril derivative and a catecholamine as active components and free from a side effect such as cardiac rate increase and arrhythmia and capable of increasing a myocardial contraction power and a stroke volume. CONSTITUTION:This cardiac contains a compound selected from carbostyril derivatives expressed by the formula (R<1> is H or a lower alkyl; R<2> is a phenyl- substituted lower alkyl) and their salts {preferably 6-[3-(3,4-dimethoxybenzyl) amino-2-hydroxypropoxy]carbostyril or its salt} and (B) a catecholamine (preferably dobutamine) as active components. Further, the daily doses of the component A and B are each, preferably, 0.1-10mg/1kg of body weight. A unit preparation for administration preferably contains 1-200mg each of the components A and B.

Description

Detailed Description of the Invention

[0001]

This invention relates to cardiotonic agents.

[0002]

2. Description of the Related Art General formula (1)

[0003]

[Chemical 2]

[In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² represents a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring. ] The carbostyril derivative and its salt represented by the above are known compounds, for example, EP Publication No. 35558.
No. 3 specification. In addition, JP-A-3-8686
Japanese Patent Publication No. 4 discloses that the above carbostyril derivative and its salt have a positive inotropic effect, a coronary blood flow increasing effect and a blood pressure lowering effect.

On the other hand, catecholamine is used as a therapeutic drug for heart failure because it has a myocardial contractile force enhancing action. However, in general, catecholamine has a myocardial contractile force enhancing action and a heart rate increasing action as a β1 action, a peripheral vasodilator action as a β2 action, a peripheral vasoconstrictor action as an α action, and various catecholamines cause a β1 action, a β2 action and The strength of each α-action is different, and even with the same catecholamines, the intensity of each of the above-mentioned actions is different depending on the concentration. Therefore, it is necessary to exercise caution when using catecholamines. In particular, when the dose of catecholamine is increased to enhance the cardiotonic action, on the other hand, side effects such as an increase in heart rate and arrhythmia are unavoidable, which results in a sufficient increase in myocardial contraction force and cardiac output. Sometimes did not get an increase.

[0006] The present inventor has earnestly conducted research to develop a cardiotonic agent capable of achieving a sufficient increase in myocardial contraction force and an increase in cardiac output without causing side effects such as increase in heart rate and arrhythmia. As a result, it was found that the combined use of the carbostyril derivative of the general formula (1) or a salt thereof and catecholamine can increase the myocardial contractile force and cardiac output without causing side effects such as an increase in heart rate and arrhythmia. ,
The present invention has been completed here.

That is, the present invention is characterized by containing at least one compound selected from the group consisting of carbostyril derivatives represented by the above general formula (1) and salts thereof and catecholamine as active ingredients. Pertain to.

More specifically, each group represented by the above general formula (1) is as follows.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, butyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. be able to.

The phenylalkyl group which may have a lower alkoxy group as a substituent on the phenyl ring includes
For example, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,
1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl, 2- (3-methoxyphenyl) ethyl, 1-
(4-methoxyphenyl) ethyl, 2-methoxybenzyl, 3- (2-ethoxyphenyl) propyl, 4- (3
-Ethoxyphenyl) butyl, 1,1-dimethyl-2-
(4-ethoxyphenyl) ethyl, 5- (4-isopropoxyphenyl) pentyl, 6- (4-hexyloxyphenyl) hexyl, 3,4-dimethoxybenzyl,
A linear or branched alkyl group having 1 to 6 carbon atoms in the alkyl moiety such as 3,4,5-trimethoxybenzyl, 2.5-dimethoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl group , And 1 carbon atom on the phenyl ring
The phenylalkyl group which may have 1-3 linear or branched alkoxy groups of -6 can be mentioned.

The compound of the general formula (1) includes a compound in which R ¹ is a hydrogen atom and R ² is a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring; R ¹ is a lower alkyl group. Group, a compound in which R ² is a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring. Especially 6-
[3- (3,4-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril or a salt thereof is preferable.

Examples of catecholamines include epinephrine, norepinephrine, isopreterenol, dopamine and dobutamine. Among these, dopamine and dobutamine are preferable, and dobutamine is particularly preferable.

The carbostyril derivative of the general formula (1) and its salt, which are the active ingredients of the present invention, and catecholamine can be administered as separate preparations or as one preparation.

Among the carbostyril derivatives of the general formula (1) used as the active ingredient in the present invention, the compound having a basic group can easily form a salt with a usual pharmacologically acceptable acid. Examples of such an acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid. Examples thereof include citric acid, succinic acid, and benzoic acid. Further, among the carbostyril derivatives of the general formula (1), the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Examples of such basic compounds include sodium hydroxide, potassium hydroxide, lithium hydroxide,
Metal hydroxides such as calcium hydroxide, sodium carbonate,
Examples thereof include alkali metal carbonates or bicarbonates such as sodium hydrogen carbonate, and alkali metal alcoholates such as sodium methylate and potassium ethylate.

The carbostyril derivative of the general formula (1) used as an active ingredient in the present invention naturally includes optical isomers.

The cardiotonic agent of the present invention is used in the form of a general pharmaceutical preparation. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used.

Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
Suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned. When molding into tablets, various carriers well known in the art can be widely used as carriers. Examples thereof include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid,
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, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agent such as lactose, sucrose, stearin, cocoa butter, hydrogenated oil Disintegration inhibitors such as quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite,
Adsorbents such as colloidal silicic acid, and lubricants such as purified talc, stearates, boric acid powder, and polyethylene glycol can be used. Further, the tablets may be tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. In the case of molding in the form of pills, widely known carriers in this field can be used as carriers. Examples include glucose, lactose, starch, cocoa butter,
Excipients such as hardened vegetable oil, kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, disintegrating agents such as laminaran and agar can be used.
In the case of molding in the form of suppositories, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. Capsules are usually prepared by mixing the active ingredient compound with various carriers exemplified above and filling hard gelatin capsules, soft capsules and the like. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood, and when molded into these forms, those conventionally used in this field as a diluent Can be used, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, grape or the like or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent and the like and other pharmaceuticals can be contained in the pharmaceutical preparation.

The amount of the carbostyril derivative of the general formula (1) or a salt thereof to be contained in the cardiotonic agent of the present invention is not particularly limited and may be appropriately selected from a wide range, but it is usually 0. The amount is preferably about 1 to 70% by weight, preferably about 0.1 to 30% by weight.

When catecholamine is formulated alone,
The carbostyril derivative of the general formula (1) and a salt thereof are prepared in the same manner as in the case of preparing them alone. The amount of catecholamine to be contained in such a formulation is not particularly limited and may be appropriately selected from a wide range, but is usually about 0.1 to 70% by weight, preferably 0.1 to 3% by weight in the formulation composition.
It is preferable to set it to about 0% by weight.

Further, when the carbostyril derivative of the general formula (1) and its salt and catecholamine are formulated as one preparation, the carbostyril derivative of the general formula (1) and its salt are formulated individually. It is similarly formulated. The ratio of the carbostyril derivative of the general formula (1) and its salt and catecholamine to be contained in such a preparation is not particularly limited, but usually the former: the latter = 1: 0.1 by weight ratio. -10, preferably the former: the latter = 1: 0.5-5. The amount of the carbostyril derivative of the general formula (1) and its salt and catecholamine to be contained in such a formulation is not particularly limited and may be appropriately selected from a wide range, but it is usually the total amount of both in a pharmaceutical composition. About 0.1 to 70% by weight, preferably 0.1.
It is preferable to set it to about 1 to 30% by weight.

The administration method of the cardiotonic agent of the present invention is not particularly limited, and it may be administered according to various preparation forms, patient's age, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replacement fluid such as glucose or amino acid, and may be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally alone if necessary. In the case of suppositories, it will be administered rectally.

The dose of the cardiotonic agent of the present invention is appropriately selected according to the usage, the age of the patient, the sex and other conditions, the degree of disease, etc., but the carbostyril derivative of the general formula (1) which is an active ingredient and its derivative are usually selected. Salt per 1 kg of body weight per day,
The amount is preferably about 0.1 to 10 mg, and the other active ingredient, catecholamine, is preferably about 0.1 to 10 mg per 1 kg of body weight per day. Further, it is preferable that the carbostyril derivative of the general formula (1) and a salt thereof are contained in the dosage unit form in the range of about 1 to 200 mg, and catecholamine in the range of about 1 to 200 mg.

[0024]

[Examples] The present invention will be further clarified with reference to the results of pharmacological tests and formulation examples.

Pharmacological test A miscellaneous dog weighing 9 to 12.5 kg was anesthetized with thiopental sodium (30 mg / kg), a tube was inserted into the trachea, and a nitrogen gas and a mixed gas (95% oxygen, 5% carbon dioxide) were ventilated. (SN-480-3: Shinano Seisakusho) was used for ventilation. Blood pressure and heart rate are monitored from the left femoral artery via left ventricular pressure and left ventricular end diastolic pressure (LV).
dP / dt is a catheter (MPC-500: Millar instrument) from the left carotid artery into the left ventricle.
(manufactured by ts Inc). The drug is an infusion pump (STC-523: Terumo Corp., SP10) from the left femoral artery and the right femoral artery, respectively.
0: JMS). The electrocardiogram is monitored by the second lead, and a recorder (Cardio Logger is used.
322: manufactured by NEC Sanei Co., Ltd.). Hemodynamic 1
The test was conducted after stabilizing for 5 minutes or more. The drug used is 6
-[3- (3,4-dimethoxybenzyl) amino-2-
Hydroxypropoxy] carbostyril, dopamine (Kyowa Hakko Kogyo Co., Ltd.), dobutamine (Shionogi Pharmaceutical Co., Ltd.) 5
It was diluted with a% glucose solution before use.

(1) Combination of 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril (hereinafter referred to as "Compound A") and dobutamine The drug administration groups are as follows. The test was conducted by dividing into 3 groups.

Group 1: Compound A alone (10 μg / kg /
Min) 60 min administration 2 group: dobutamine alone (10 μg / kg / min) administration 30
5 minutes later, additional administration of 5% glucose solution for 60 minutes 3 groups: Dobutamine alone (10 μg / kg / min) administration 30
Minutes later, compound A (10 μg / kg / min) is additionally administered for 60 minutes

[0028]

[Table 1]

(2) Combination of Compound A and Dopamine The drug administration group was divided into 3 groups (7 animals in each group) as shown below, and the test was conducted.

Group 1: Dopamine alone (5 μg / kg / min)
30 minutes after administration, additional administration of 5% glucose solution for 30 minutes 2 group: Dopamine alone (5 μg / kg / min) 30 minutes after administration, compound A (10 μg / kg / min) was additionally administered for 30 minutes 3 group: Dopamine alone (5 μg / Kg / min) 30 minutes after administration, additional administration of dopamine (5 μg / kg / min) for 30 minutes

[0031]

[Table 2]

Formulation Example 1 6- [3- (3-Methoxybenzyl) amino-2-hydroxypropoxy] carbostyryl hydrochloride 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg According to a conventional method, the above-mentioned components are contained in one tablet. Was produced.

Formulation Example 2 Isoprenaline hydrochloride 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets containing the above components in one tablet were produced by a conventional method.

Formulation Example 3 6- [3- (3-Methoxybenzyl) amino-2-hydroxypropoxy] carbostyryl hydrochloride 5 mg Isoprenaline hydrochloride 5 mg Starch 127 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg According to a conventional method, 1 tablet A tablet containing the above ingredients was prepared.

Formulation Example 4 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 500 mg Polyethylene glycol (molecular weight: 4000) 300 mg Sodium chloride 900 mg Polyoxyethylene sorbitan monooleate 400 mg Metabisulfite Sodium 100 mg Methyl-paraben 180 mg Propyl-paraben 20 mg Distilled water for injection 100 ml The above parabens, sodium metabisulfite and sodium chloride were dissolved in the above distilled water at 80 ° C with stirring.
The obtained solution was cooled to 40 ° C., and 6- [3- (3,4
-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril, polyethylene glycol and polyoxyethylene sorbitan monooleate are sequentially dissolved, and then distilled water for injection is added to the solution to adjust the final volume, and a suitable filter is used. Sterile filtration was performed using paper and 1 ml was dispensed into ampoules to prepare injections.

Formulation Example 5 Dopamine hydrochloride 400 mg Polyethylene glycol (molecular weight: 4000) 300 mg Sodium chloride 900 mg Polyoxyethylene sorbitan monooleate 400 mg Sodium metabisulfite 100 mg Methyl-paraben 180 mg Propyl-paraben 20 mg Distilled water for injection 100 ml Same as Formulation Example 4 Then, an injection was prepared.

Formulation Example 6 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 500 mg Dopamine hydrochloride 300 mg Polyethylene glycol (molecular weight: 4000) 300 mg Sodium chloride 900 mg Polyoxyethylene sorbitan monooleate 400 mg Sodium metabisulfite 100 mg Methyl-paraben 180 mg Propyl-paraben 20 mg Distilled water for injection 100 ml An injection was prepared in the same manner as in Preparation Example 4.

Formulation Example 7 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 500 mg Dobutamine hydrochloride 500 mg Polyethylene glycol (molecular weight: 4000) 300 mg Sodium chloride 900 mg Polyoxyethylene sorbitan monooleate 400 mg Sodium metabisulfite 100 mg Methyl-paraben 180 mg Propyl-paraben 20 mg Distilled water for injection 100 ml An injection was prepared in the same manner as in Preparation Example 4.

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² represents a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring. ] A cardiotonic agent comprising catecholamine as an active ingredient and at least one compound selected from the group consisting of carbostyril derivatives represented by the following and salts thereof.