JPH08157366A - Curing agent for brain edema - Google Patents

Abstract

PURPOSE: To obtain a curing agent for brain edema containing a carbostyril derivative as an active component. CONSTITUTION: This curing agent contains a compound of the formula (R<1> is OANR<2> R<3> ; A is a lower alkylene; R<2> and R<3> are each H or a lower alkanoyl; a bond between carbons at 3 and 4 positions of carbostyril ring is a single bond or a double bond) or its salt in an amount of 1-70wt.%, preferably 5-50wt.% as an active component. As the compound of the formula, 1- 1-[4-(3- acetylaminopropoxy)benzoyl]-4-piperydinyl}-3,4-dihydrocarbostyril can be used. The active component can be formulated into an oral agent, an injection, a suppository, etc., after compounding with an arbitrary component in an adequate amount by a conventional method. The agent is administered at a dose of 0.6-50mg/kg/day in terms of the active component. The compound of the active component is preferably contained in a unit administration formulation in an amount of 10-1000mg.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for cerebral edema.

[0002]

2. Description of the Related Art Cerebral edema occurs in various brain diseases such as cerebral hemorrhage, cerebral infarction, brain tumor, encephalitis, etc., and also when the brain is damaged by heat stroke or traffic accident. Cerebral edema shows serious symptoms such as consciousness disorder and convulsions, and thus urgent treatment is required.

At present, hyperosmolar drugs such as mannitol and glyceol are used for the treatment of cerebral edema, and the development of safer and more effective drugs is desired.

On the other hand, the general formula

[0005]

Embedded image

[In the formula, R ¹ represents a group —OA—NR ² R ³ . A represents a lower alkylene group. R ² and R ³ are
The same or different, a hydrogen atom or a lower alkanoyl group is shown. The carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton represent a single bond or a double bond. ] The carbostyril derivative represented by the formula and salts thereof are known compounds, and it is also known that these compounds have vasopressin antagonistic action and oxytocin antagonistic action (JP-A-3-17).
3870 and JP-A-6-87747).

[0007]

DISCLOSURE OF THE INVENTION The present inventors have conducted various studies to develop a safe and effective therapeutic agent for cerebral edema, and as a result, the carbostyril derivative represented by the general formula (1) and a salt thereof have the above pharmacological actions. Have an unexpected effect of suppressing cerebral edema and found that it can be suitably used as a therapeutic agent for cerebral edema. The present invention has been completed based on such knowledge.

That is, the present invention relates to a therapeutic agent for cerebral edema containing as an active ingredient at least one selected from the group consisting of carbostyril derivatives represented by the above general formula (1) and salts thereof.

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

Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene. Number of carbon atoms such as 1
Examples of the straight chain or branched chain alkylene group of 6

As the lower alkanoyl group, formyl,
Examples thereof include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups.

The active ingredient compound (1) of the present invention can be easily produced by a known method, for example, the method described in JP-A-3-173870.

Among the compounds (1) used as an active ingredient in the present invention, the compound having an acidic group can form a salt with a pharmacologically acceptable basic compound. Examples of such basic compounds include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate and sodium hydrogencarbonate, and sodium methyl carbonate. Examples thereof include alkali metal alcoholates such as citrate and potassium ethylate. In addition, in the compound (1) as an active ingredient in the present invention, a basic compound 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 and hydrobromic acid, acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, citric acid, succinic acid and benzoic acid. Organic acids can be exemplified. These salts can also be used as the active ingredient compound in the present invention similarly to the compound (1) in the free form. The above compound (1)
Include stereoisomers and optical isomers, and the like can be similarly used as active ingredient compounds.

The active ingredient compound of the present invention represented by the above general formula (1) is effective as a therapeutic agent for cerebral edema, and the therapeutic agent 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 can be selected as the pharmaceutical preparation depending on the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). 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, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, etc., sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, and Phosphorus, moisturizing agents such as starch, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used. Further, the tablet may be a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet or a double-layered tablet or a multi-layered tablet. In the case of molding in the form of pills, widely known carriers in this field can be used as carriers. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc., gum arabic powder, tragacanth powder, gelatin, binders such as ethanol, disintegrants such as laminaran, agar and the like 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 the art as diluents 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, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. 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 active ingredient compound to be contained in the therapeutic agent for cerebral edema of the present invention is not particularly limited and may be appropriately selected from a wide range, but it is usually about 1 to 70% by weight, preferably in a pharmaceutical composition. Is preferably about 5 to 50% by weight.

The method for administering the therapeutic agent for cerebral edema of the present invention is not particularly limited, and it may be administered according to various dosage 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, they are administered rectally.

The dose of the therapeutic agent for cerebral edema of the present invention is appropriately selected according to the usage, the age, sex and other conditions of the patient, the degree of the disease, etc. Usually, the amount of the active ingredient compound is 1 kg of body weight per day, It is preferable to set the amount to about 0.6 to 50 mg. In addition, it is desirable that the active ingredient compound is contained in the dosage unit form in the range of about 10 to 1000 mg.

[0018]

EXAMPLES In order to explain the present invention in more detail, formulation examples of the agent for treating cerebral edema of the present invention will be given below, followed by test examples of active ingredient compounds.

Formulation Example 1 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 150 g Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g corn starch 30 g stearin Magnesium acid 2 g Hydroxypropyl methyl cellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Ethanol 40 g After mixing and polishing the active ingredient compound of the present invention, Avicel, corn starch and magnesium stearate, sugar coating R10m
tablet with m. The obtained tablets were treated with hydroxypropyl methylcellulose, polyethylene glycol-600.
A film-coated tablet is produced by coating with a film-coating agent consisting of 0, castor oil and ethanol.

Formulation Example 2 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 150 g Citric acid 1.0 g Lactose 33.5 g Dicalcium phosphate 70.0 g Pluronic F-68 30.0 g Sodium lauryl sulfate 15.0 g Polyvinylpyrrolidone 15.0 g Polyethylene glycol (Carbowax 1500) 4.5 g Polyethylene glycol (Carbowax 6000) 45.0 g Corn starch 30.0 g Dry sodium stearate 3 0.0 g Dry magnesium stearate 3.0 g Ethanol Appropriate amount The active ingredient compound of the present invention, citric acid, lactose, dicalcium phosphate, Pluronic F-68 and sodium lauryl sulfate are mixed.

The above mixture is sieved through a No. 60 screen and wet granulated with an alcoholic solution containing polyvinylpyrrolidone, Carbowax 1500 and 6000. Alcohol is added as needed to make the powder a pasty mass. Add corn starch and continue mixing until uniform particles are formed. The mixture is passed through a No. 10 screen, placed in a tray and placed in an oven at 100 ° C for 1
Dry for 2-14 hours. The dry particles are screened through a No. 16 screen, dry sodium lauryl sulphate and dry magnesium stearate are added and mixed and compressed to the desired shape on a tablet machine.

The core is treated with varnish and sprinkled with talc to prevent moisture absorption. The undercoat layer is coated around the core. Apply varnish a sufficient number of times for internal use. A further subbing layer and a smooth coating are applied to make the tablet completely round and smooth. Color coating is applied until the desired shade is obtained. After drying, the coated tablets are polished into tablets of uniform gloss.

Formulation Example 3 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril 5 g Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0 9.9 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 10.0 ml Parabens, sodium metabisulfite and sodium chloride Is dissolved in about half of the above distilled water at 80 ° C. with stirring. The resulting solution is cooled to 40 ° C., and the active ingredient compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, are dissolved in the above solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilizing with an appropriate filter paper to prepare an injection.

Pharmacological test 1 (action of the compound of the present invention in a frozen brain injury model) Liquid nitrogen was sufficiently applied to the right cerebral hemisphere of male SD rats (body weight 250 to 350 g) anesthetized with pentobarbital (25 mg / kg, ip). A chilled copper column was applied to cause frozen brain injury. 1, 9, and 17 hours after causing the frozen brain injury, the drug (1-
{1- [4- (3-Acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,4-dihydrocarbostyril) was intraperitoneally administered at 50 mg / kg or 100 mg / kg. After 24 hours, the head was decapitated, the right and left cerebral hemispheres were taken out, and the water content in the brain was determined according to the following formula. The brain water content was determined in the same manner as above for the drug-non-administered group.

[0025]

[Equation 1]

From the brain water content of the drug-administered group and the drug-non-administered group, the rate of suppression of the increase in the water content in the brain and the suppression rate (%) were determined according to the following equation.

[0027]

[Equation 2]

The results are shown in FIG.

It can be seen from FIG. 1 that the increase of the water content in the brain can be suppressed by administering the active ingredient compound of the present invention.

[Brief description of drawings]

FIG. 1 is a graph showing the relationship between the dose of the active ingredient compound of the present invention and the inhibition rate of cerebral water content.

Claims (2)

[Claims] 1. A compound of the general formula [In formula, R < ¹ > shows group -OA-NR < ² > R < ³ >. A represents a lower alkylene group. R ² and R ³ are the same or different and each represents a hydrogen atom or a lower alkanoyl group. The carbon-carbon bonds at the 3-position and 4-position of the carbostyril skeleton represent a single bond or a double bond. ] A therapeutic agent for cerebral edema containing as an active ingredient at least one selected from the group consisting of carbostyril derivatives represented by and a salt thereof. 2. 1- {1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidinyl} -3,
A therapeutic agent for cerebral edema containing as an active ingredient at least one selected from the group consisting of 4-dihydrocarbostyril and salts thereof.