JP2711437B2 - Carbostyril derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to carbostyryl derivatives.

[0002]

DISCLOSURE OF THE INVENTION The carbostyril derivative of the present invention is a novel compound which has not been described in the literature and has the following general formula:

[0003]

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6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril or a salt thereof.

[0005] The carbostyril derivative represented by the above formula (1) and a salt thereof have an action of enhancing myocardial contraction (positive inotropic action) and are useful as a therapeutic agent for congestive heart failure. In particular, the above-mentioned compound of the present invention has an excellent positive inotropic effect, but has a characteristic of hardly increasing the heart rate. The compound of the present invention has low toxicity and central side effects such as vomiting, decreased motor function, convulsions,
It also has the feature of little tremor. Further, the compound of the present invention is excellent in absorbability and long in duration.

The carbostyril derivative represented by the above formula (1) and its salt have an effect of increasing coronary blood flow, lowering blood pressure, suppressing vasoconstriction by norepinephrine, and having an anti-inflammatory effect. It is useful as an anti-inflammatory agent.

Compounds similar to the carbostyril derivative of the present invention are described in, for example, JP-A-56-8319, JP-A-56-95115, JP-A-103589,
It is described in JP-A-51-222077.
However, all of the carbostyril derivatives described in these publications are β-blockers.

On the other hand, the carbostyril derivative of the present invention has a cardiotonic effect, ie, an effect of enhancing myocardial contractility (positive inotropic effect), and is useful for treating heart failure based on a decrease in myocardial contractility. It differs from β-blockers in the following points.

That is, β-adrenaline has effects such as enhancement of cardiac contractility (positive inotropic effect), increase of heart rate (positive chronotropic effect), increase of automatic excitability, promotion of atrioventricular conduction (illustration). Pharmacology p112, 114). β-blockers block the binding of adrenaline to the receptor and prevent the above effects of adrenaline. Therefore, β-blockers have a pharmacological action different from that of the positive inotropic action, and are completely opposite actions.

The above publications disclose that the carbostyril derivatives described in each publication have a β-adrenergic blocking action (β-blocker) and can be used as a therapeutic agent for arrhythmia and angina. Not just. There is no suggestion in any of these publications that these carbostyril derivatives have a positive inotropic effect of enhancing the contractile force of the myocardium, and it is completely difficult to predict from the description in the publication. Actually, a positive inotropic test was conducted on the carbostyril derivatives specifically described in these publications, but the compound did not substantially have a positive inotropic effect (see pharmacological test A described later).

Japanese Patent Application Laid-Open No. 57-80322 discloses that a compound similar to the carbostyril derivative of the present invention has a positive inotropic effect. However, the positive inotropic effect of the carbostyril derivative described in this publication is significantly different from that of the carbostyril derivative of the present invention.

[0012] The carbostyril derivatives of the present invention have a strong atrial muscle contraction action and ventricular muscle contracting action (positive inotropic effect), in particular a much lower ED ₃₀ values than amrinone ED ₃₀ values for the ventricular muscle contracting action And its positive inotropic effect is strong (see pharmacological test A below).

On the other hand, Japanese Patent Application Laid-Open No. 57-80322 discloses that the carbostyril derivative described in the publication has a positive inotropic effect. Only effects, ventricular muscle contraction effects have not been tested. Publication to test the ventricular muscle contracting action for some of the compounds specifically disclosed, it was compared and the ED ₃₀ value and ED ₃₀ value of amrinone, amrinone equal to or less than the either, or ED ₃₀ The value was not reached (see Pharmacological Test A below).

Further, the carbostyril derivative of the present invention does not show any central side effects such as tremor and convulsions, but the carbostyril derivative described in JP-A-57-80322 has remarkable tremors and convulsions. Side effects were observed (see pharmacological test B below).

The carbostyril derivative of the present invention represented by the above formula (1) can be produced by various methods.
If one example is shown, for example, it can be easily produced according to the method shown by the following reaction formula.

[Reaction formula-1]

[0017]

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[Wherein X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group. The reaction between the compound of the general formula (2) and the compound of the formula (3)
The reaction is carried out without solvent or in a suitable solvent in the presence or absence of a basic compound. The reaction is usually carried out at room temperature to 200 ° C, preferably at room temperature to 150 ° C,
It ends in about an hour. Examples of the solvent used here include dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, ethers such as diethyl ether, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, ethanol, lower alcohols such as isopropanol, and dimethyl. Formamide (DM
F), dimethylsulfoxide (DMSO), hexamethylphosphoric triamide, pyridine, acetone and other polar solvents. Further, as the basic compound used,
For example, inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium amide, sodium hydride, potassium hydride and the like; and organic bases such as triethylamine, tripropylamine, pyridine and quinoline. Bases and the like can be exemplified. The reaction proceeds advantageously by adding an alkali metal iodide such as potassium iodide or sodium iodide to the reaction system of the reaction. The compound of the formula (3) is generally used at least in an equimolar amount, preferably in an equimolar to 5-fold molar amount, relative to the compound of the general formula (2).

In the above reaction formula-1, the lower alkanesulfonyloxy group represented by X is, specifically, methanesulfonyloxy, ethanesulfonyloxy, isopropanesulfonyloxy, propanesulfonyloxy, butanesulfonyloxy, tert-butane Sulfonyloxy, pentane sulfonyloxy, hexanesulfonyloxy group and the like can be exemplified, and as the arylsulfonyloxy group, specifically, phenylsulfonyloxy,
4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 3-
Chlorophenylsulfonyloxy, a substituted or unsubstituted arylsulfonyloxy group such as α-naphthylphenylsulfonyloxy group can be exemplified, and specific examples of the aralkylsulfonyloxy group include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-
Substitution of phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, α-naphthylmethylsulfonyloxy group, etc. Alternatively, an unsubstituted aralkylsulfonyloxy group can be exemplified.

[Reaction formula-2]

[0021]

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Wherein X is the same as above. Y is a group

[0023]

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Is shown. The reaction of the compound of the formula (4) with the epihalogenohydrin of the general formula (5) is carried out in the presence of a basic compound, in a suitable solvent or without solvent. Examples of the basic compound used herein include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metal sodium, metal potassium, and sodium amide; Examples thereof include organic bases such as piperidine, pyridine, and triethylamine. Examples of the solvent used include methanol, ethanol, lower alcohols such as isopropanol, acetone, ketones such as methyl ethyl ketone, diethyl ether, dioxane, ethers such as diethylene glycol dimethyl ether, benzene, toluene,
Examples include aromatic hydrocarbons such as xylene and water. The compound of the general formula (5) is usually used at least in an equimolar amount, preferably 5 to 10 times the molar amount of the compound of the formula (4). The reaction proceeds usually at 0 to 150 ° C., preferably at about 50 to 100 ° C., and is generally completed in about 1 to 10 hours.

By the above reaction, the hydroxyl group of the compound of the formula (4) reacts with the epihalogenohydrin of the general formula (5) to give a (2,3-epoxy) propoxy group and a 3-halogeno-
A compound converted to a 2-hydroxypropoxy group is obtained as a mixture, and this mixture is subjected to a reaction with a compound of the following formula (3) without purification and separation. Alternatively, a compound having a (2,3-epoxy) propoxy group or a 3-halogeno-2-hydroxypropoxy group is separated and purified by a conventional means such as recrystallization and column chromatography, and then reacted with the compound of the formula (3). You may.

The reaction of the compound of the formula (6) with the compound of the formula (3) is carried out in the presence of a basic compound, in the presence or absence of a solvent. The reaction is usually performed at room temperature to 200 ° C.
Preferably, the reaction is carried out at around 60 to 120 ° C.
The reaction is completed in about 24 hours. As the solvent and the basic compound to be used, any of the solvent and the basic compound used in the reaction of the compound of the general formula (2) and the compound with the formula (3) in the above Reaction Scheme-1 can be used. The compound of the general formula (3) is usually used at least in an equimolar amount, preferably in an equimolar to 5-fold molar amount, relative to the compound of the general formula (6).

[Reaction formula-3]

[0028]

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Wherein X is as defined above. The reaction between the compound of the formula (4) and the compound of the general formula (7)
In a suitable solvent, a basic compound is preferably used as a dehydrohalogenating agent, and is usually at room temperature to 200 ° C, preferably at 50 to 1 ° C.
The reaction is performed at a temperature of 50 ° C. for about 1 to 15 hours.
Suitable solvents in the above include, for example, methanol,
Lower alcohols such as ethanol and isopropanol,
Examples thereof include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether, dioxane and diethylene glycol dimethyl ether, aromatic hydrocarbons such as toluene and xylene, DMF, DMSO, and hexamethylphosphoric triamide. Examples of the basic compound that can be used as a dehydrohalogenating agent include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metal potassium, sodium Examples include inorganic bases such as amides, and organic bases such as pyridine, quinoline, triethylamine, and tripropylamine. In the reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide may be added to the reaction system as a reaction accelerator. The amount of the compound of the general formula (7) is not particularly limited, but is usually 1 to 5 times, preferably 1 to 2 times the molar amount of the compound of the formula (4). .

The reaction of the compound of the formula (4) with the compound of the formula (8) is carried out under the same reaction conditions as the reaction of the compound of the formula (4) with the compound of the general formula (5) in the above reaction formula-2. Done.

[Reaction formula-4]

[0032]

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Wherein X is the same as above. The reaction between the compound of the formula (9) and the compound of the general formula (10) is carried out under the same reaction conditions as the reaction between the compound of the general formula (2) and the compound of the formula (3) in the aforementioned reaction formula-1. I can do it.

The carbostyril derivative of the present invention represented by the formula (1) can be easily converted into an acid addition salt by acting 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 compound having an acidic group among the carbostyril derivatives represented by the formula (1) of the present invention can easily form a salt by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The target compound thus obtained in each step can be easily isolated and purified by ordinary separation means. Examples of the separation means include a solvent extraction method, a dilution method, a recrystallization method, column chromatography, and preparative thin-layer chromatography.

The present invention naturally includes optical isomers.

The compound of the formula (1) is usually used in the form of a general pharmaceutical preparation. The formulation is a commonly used filler,
It is prepared using a diluent or excipient such as a bulking agent, a binder, a humectant, a disintegrant, a surfactant, and a lubricant. As this pharmaceutical preparation, various forms can be selected according to the purpose of treatment,
Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions,
Suspending agents). For molding into tablets, those conventionally known in the art can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipient, water, ethanol, propanol, simple syrup, dextrose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dried starch, sodium alginate,
Disintegrators such as agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium uraryl sulfate, stearic acid monoglyceride, starch, lactose, sucrose, stearin, cocoa butter, hydrogenated oil, etc. Inhibitors, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin, starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, Lubricants such as boric acid powder and polyethylene glycol can be exemplified. Further tablets are tablets coated with ordinary skin as required, such as sugar-coated tablets,
Gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets can be used. In molding into the form of pills, carriers conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, and a disintegrant such as laminaran agar. For shaping in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. When prepared as an injection, the liquid preparations and suspensions are preferably sterilized and isotonic with blood, and when formed into these liquid preparations, pills and suspensions, they may be used as diluents. All those commonly used in this field can be used, such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples thereof include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, fructose or glycerin for preparing an isotonic solution may be contained in the inotropic agent, and a usual solubilizing agent, buffer, soothing agent and the like may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like or other pharmaceuticals may be contained in the therapeutic agent.

Formula (1) to be contained in the above pharmaceutical preparation
The amount of the compound is not particularly limited and is selected over a wide range,
Usually, it is 1 to 70% by weight, preferably 1 to 30% by weight in the whole composition.

The administration method of the pharmaceutical preparation containing the carbostyril derivative of the present invention as an active ingredient is not particularly limited, and is administered by a method according to various preparation forms, patient age, gender and other conditions, degree of disease, and the like. You. For example, tablets, pills, solutions,
Suspensions, emulsions, granules and capsules are administered orally. In the case of an injection, it is intravenously administered alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dose of the above pharmaceutical preparation is appropriately selected depending on the usage, age of the patient, gender and other conditions, degree of disease, etc., but the amount of the compound of the formula (1), which is usually the active ingredient, is 1%.
It is preferable to use about 0.1 to 10 mg per kg of body weight per day. In addition, the active ingredient in a dosage unit form is 1 to 200 mg.
It is good to contain.

[0042]

EXAMPLES Reference examples, production examples, examples, pharmacological test results and formulation examples are listed below.

Reference Example 1 3.5 g of 6-hydroxycarbostyril and S-(+)
-Epichlorohydrin (5 g) is added to methanol (100 ml), triethylamine (0.5 ml) is added, and the mixture is heated under reflux for 8 hours. After allowing to cool, chloroform was added, the mixture was dusted on silica gel, and purified by column chromatography (silica gel chloroform: methanol = 100: 0 to 100: 3) to obtain 1.13 g of S-6- (3-chloro-2-). (Hydroxypropoxy) carbostyril is obtained.

Reference Example 2 Using R-(-)-epichlorohydrin, R-6- (3-chloro-2-hydroxypropoxy) carbostyril was obtained in the same manner as in Reference Example 1.

Reference Example 3 0.65 g of 85% potassium hydroxide was added to 30 ml of methanol.
Was dissolved in water, and 1.03 g of R-6- (3-chloro-2-hydroxypropoxy) carbostyril was added at room temperature.
Stir at the same temperature for 5 hours. After the reaction, the mixture is cooled on ice, neutralized with 1N hydrochloric acid, and then concentrated under reduced pressure at room temperature. Add water to the residue,
Filter the crystals. After heating in 15 ml of methanol for 2 to 3 minutes, the mixture is allowed to cool to obtain 0.5 g of S-6- (2,3-epoxypropoxy) carbostyril.

Reference Example 4 Using S-6- (3-chloro-2-hydroxypropoxy) carbostyril, the procedure of R-6 was carried out in the same manner as in Reference Example 3.
(2,3-Epoxypropoxy) carbostyril is obtained.

Production Example 1 6- (2,3-epoxypropoxy) carbostyril 1
A suspension of 5 g and 11 g of N-methylbenzylamine in 150 ml of methanol is heated under reflux for 2.5 hours. Methanol is distilled off under reduced pressure, diethyl ether is added to the residue obtained, and the precipitated crystals are collected by filtration. Silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1 /
After purification in 25), recrystallization from ethanol gave 7.6 g of 6- [3- (N-methyl-N-benzylamino) -2-.
[Hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Production Example 2 5.05 g of 6- (3-chloro-2-hydroxypropoxy) carbostyril and N-methylbenzylamine
0 g of a 50 ml solution of dimethylformamide in 50-60
Stir at 5 ° C. for 5 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/25), and recrystallized from ethanol to obtain 2.5 g of 6- [ 3-
(N-methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Production Example 3 1.6 g of 6-hydroxycarbostyril and 1 g of sodium hydride (50% oil) in dimethylformamide 30
ml solution at room temperature in 1-chloro-2-hydroxy-
3- (N-methyl-N-benzylamino) propane
After dropping 2 g, the mixture is heated and stirred at 70 to 80 ° C. for 3 hours. The reaction mixture is poured into water, extracted with chloroform, and dried over magnesium sulfate. After the chloroform was distilled off, the resulting residue was subjected to silica gel column chromatography (eluent; methanol / chloroform = 1/100 to 1/100).
After purification in 25), recrystallization from ethanol gave 0.76 g.
6- [3- (N-methyl-N-benzylamino) -2
-Hydroxypropoxy] carbostyril is obtained.

White powder, mp. 129-132 ° C.

Production Example 4 A 70 ml methanol solution of 4.4 g of 6- (2,3-epoxypropoxy) carbostyril was heated and refluxed in a 50 ml methanol solution of 21 g of N-methylbenzylamine.
Drop in 30 minutes. After the completion of the dropwise addition, the mixture is further heated under reflux for 2 hours. After the reaction mixture was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography (eluent; methanol /
After purification with chloroform = 1/100 to 1/25), recrystallization from ethanol gives 5 g of 6- [3- (N-methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril.

White powder, mp. 129-132 ° C.

Production Example 5 S- (2,3-epoxypropoxy) carbostyril 1
A suspension of 5 g and 11 g of N-methyl-N-benzylamine in 150 ml of methanol is heated under reflux for 2 hours. Methanol is distilled off under reduced pressure, diethyl ether is added to the residue obtained, and the precipitated crystals are collected by filtration. Silica gel column chromatography (eluent; methanol / chloroform = 1/100-
After purification in 1/25), recrystallization twice with ethanol 9.
3g 4S-(-)-6- [3- (N-methyl-N-benzylamino) -2-hydroxypropoxy] carbostyril is obtained.

Colorless prism, mp. 142-144 ° C [α] _D = -32.20 (c = 1.0, chloroform).

Example 1 Using the appropriate starting materials, the following compounds were obtained in the same manner as in Production Examples 1 to 4.

6- [3- (3,4-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril White powder (recrystallized from methanol), mp. 156.
0-157.0 ° C.

Example 2 The following compounds were obtained in the same manner as in Production Example 5 using appropriate starting materials.

R-(+)-6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril colorless needles (recrystallized from methanol), mp. 153-1
55 ° C. [α] _D ²⁰ = + 9.5 ° (c = 0.44, methanol) S-(−)-6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril colorless Needle-like (recrystallized from methanol), mp. 154-1
^{_{55 ℃ [α] D 20 =}} -9.4 DEG (c = 0.51, methanol).

Pharmacological test A (blood-perfused excised papillary muscle specimen) Adult male and female mongrel dogs weighing 8 to 13 kg were anesthetized by intravenous administration of pentoparbital sodium salt at a rate of 30 mg / kg. 1000 U of heparin sodium salt
After intravenous administration at a rate of / kg, blood was killed and the heart was excised. Specimens consisted mainly of papillary muscle and ventricular septum, and were perfused with blood derived from a donor dog at a constant pressure of 100 mmHg from a cannula inserted into the anterior septum artery. The blood donated dogs weighed 18-27 kg, were anesthetized with 30 mg / kg of pentoparbital sodium salt intravenously in advance, and had been intravenously administered 1000 U / kg of heparin sodium salt. Using a bipolar electrode, a voltage 1.5 times the threshold (0.5 to
3V) The papillary muscle was stimulated with a square wave having a stimulation width of 5 msec and a stimulation frequency of 120 times per minute. The resting tension of papillary muscle is 1.
At 5 g, the generated tension of the papillary muscle was measured via a force displacement exchanger. The recording of the generated tension was recorded on an ink writing recorder. Details of this method have already been reported by Endo and Hashimoto (Am. J. Physiol., 218 , 1459-146).
3, 1970).

The test compound was administered intraarterially in a volume of 10/30 μl for 4 seconds. Regression analysis was performed at 10, 100, and 1000 nmoles, and the ED ₃₀ value was determined from the regression equation. ED
_{The 30} value is the dose of the test compound when the contractile force was increased by 30% with respect to the control value.

Using amrinone as a control,

[0064]

(Equation 1)

Was obtained. The results were as shown in Table 1 below.

Test compound a: 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy]
Carbostyril (the compound of the present invention) Test compound b: 6- [2-hydroxy-3- (N-methyl-N-benzylamino) propoxy] -3,4-dihydrocarbostyril (Japanese Patent Application Laid-Open No. 56-8319) Compound 35 described in (1) Test compound c: 5- [2-hydroxy-3- (N-methyl-N-benzylamino) propoxy] -3,4-dihydrocarbostyril (see JP-A-56-8319). Compound 5 described) Test compound d: 5- [2-hydroxy-3- (N-methyl-N-benzylamino) propoxy] carbostyril (Compound 36 described in JP-A-56-8319) Test Compound e: 5- (2-hydroxy-3-benzylamino) propoxy-3,4-dihydrocarbostyril (compound C described in JP-A-56-95115) f: 6- (3- benzylamino propoxy)
Carbostyril (Reference A: Test compound 3 described in JP-A-57-80322) Test compound g: 6- [3- (N-methyl-N-benzylamino) propoxy] carbostyril (JP-A-57-80322) -8
No. 0322) Compound h: 6-
[3- (4-chlorobenzylamino) propoxy]-
3,4-dihydrocarbostyril (JP-A-57-803)
Test compound 25 described in Japanese Patent Publication No. 22) Test compound i: 6- {3- [N-methyl-N- (4-methoxybenzyl) amino] propoxy} -3,4-dihydrocarbostyril (Japanese Unexamined Patent Application Publication No. Test compound 28 described in JP-A-57-80322)

[0067]

[Table 1]

Pharmacological test B (Trecus / convulsive action) SD rats (body weight 160-170 g) were used. The test compound a or the test compound b was intravenously administered once, and the state of the rat was observed every 5 minutes until 1 hour after the administration. Table 2 shows the results.

[0069]

[Table 2]

The animals were SD rats (body weight 200-300).
g) was used. The above test compound f or test compound g
Intravenous administration was performed, and the state of the rat was observed until 1 hour after the administration. Table 3 shows the results.

[0071]

[Table 3]

Formulation Example 1 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg The above composition in one tablet by a conventional method. Tablets containing were produced.

Formulation Example 2 6- [3- (3,4-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyryl 500 mg Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g sodium metabisulfite 0.1 g methyl-paraben 0.18 g propyl-paraben 0.02 g distilled water for injection 100 ml The above parabens, sodium metabisulfite and sodium chloride were added to the above distilled water at 80 ° C. while stirring. Dissolved. The obtained solution is cooled to 40 ° C., and the compound of the present invention,
Polyethylene glycol and polyoxyethylene sorbitan monoolate are sequentially dissolved, and the resulting solution is adjusted to the final volume by adding distilled water for injection, sterile filtered using an appropriate filter paper, and dispensed into ampoules in 1 ml portions. Then, an injection was prepared.

 ──────────────────────────────────────────────────続 き Continuing on the front page Referee number Hei 8-19152

Claims (2)

(57) [Claims] (1) Formula (1) 6- [3- (3,4-dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril represented by the formula: or a salt thereof. 2. 6- [3- (3,4-Dimethoxybenzyl) amino-2-hydroxypropoxy] carbostyril.