JPH07165720A - Carbostyril derivative and therapeutic agent for schizophrenia containing the same derivative - Google Patents

Abstract

PURPOSE:To obtain a new carbostyril derivative useful as a therapeutic agent for schizophrenia, having little antiepinephrine action as an index of alpha-locking action to be as an adverse effect and high selectivity of main action. CONSTITUTION:A carbostyril derivative of formula I [R is a group of formula II (R<1> is a 1-3C alkoxy), a group of formula III (R<2> and R<3> are each Cl or Br; R<4> is H or Cl), 2-methyl-3-nitrophenyl, 3,5-dichlorophenyl, a group of formula IV (R<5> is Cl or Br; R<6> is methyl) with the proviso that in the case of the bond at the 3- and 4-positions being a single bond, the group R in the formula I wherein R<1> is ethoxy and the group of formula II wherein R<2> and R<3> are each Cl at the same time and R<4> is H should not exist] or its salt, such as 7-[4-[4-(2,3- dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The compound of formula I is obtained, for example, by reacting a compound of formula V (X<1> is a halogen, mesityloxy, etc.) with a compound of formula VI.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carbostyril derivative and a therapeutic agent for schizophrenia containing the derivative.

[0002]

2. Description of the Related Art The derivatives according to the present invention are novel.

[0003]

The carbostyril derivative of the present invention is represented by the following general formula (1).

[0004]

[Chemical 5]

[Wherein R is a group

[0006]

[Chemical 6]

(R ¹ is a C _1-3 alkoxy group), a group

[0008]

[Chemical 7]

(R ² and R ³ are chlorine atom or bromine atom at the same time, R ⁴ is hydrogen atom or chlorine atom), 2-methyl-3
-Nitrophenyl group, 3,5-dichlorophenyl group, group

[0010]

[Chemical 8]

(R ⁵ is a chlorine atom or a bromine atom, and R ⁶ is a methyl group). The bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. However, when the bond at the 3 and 4 positions is a single bond, R is a group represented by the formula 1 in which R ¹ is an ethoxy group, R ² and R ³ are chlorine atoms at the same time, and R ⁴ is a hydrogen atom. It cannot be a group represented by Chemical formula 2. The therapeutic agent for schizophrenia of the present invention contains a carbostyril derivative represented by the above general formula (1) or a salt thereof as an active ingredient.

[0012] Schizophrenia is believed to be caused by overactivity of the central dopaminergic nervous system (dopamine excess hypothesis; Tetsuo, Metabolism, Vol. 22, p49 (198).
5), Pharmacia Review, No. 10, “Kokoro to Yaku” edited by the Pharmaceutical Society of Japan, etc.), phenothiazines such as chloropromazine, butyrophenones represented by haloperidol, and benzamide compounds such as sulpiride. A large number of drugs having an antidopaminergic action, that is, a central dopamine receptor blocker action have been developed and widely used for the purpose of improving so-called acute positive symptoms such as hallucinatory delusion and excitement of schizophrenia.

However, many of these drugs are said to be ineffective for improving positive symptoms in the chronic stage and so-called negative symptoms such as apathy of emotions, flattening of emotions, and thought dismantling. In addition, these drugs block the striatal dopamine receptors, resulting in akathisia, dystonia,
There are many serious side effects such as Parkinson's dyskinesia and tardive dyskinesia, and side effects such as hyperprolactinemia have become a problem (GM Simpson, EHPi, JJSra
Mek, Jr. Drugs, 21, p138 (1981)), and the development of safer and clinically effective drugs is desired.

The present inventor has developed a therapeutic drug for schizophrenia, which is effective not only in improving the negative symptoms of schizophrenia but also in improving the positive symptoms and has few side effects as existing drugs have. For the purpose, we have conducted intensive studies to find a carbostyril derivative having a strong dopamine receptor blocking action. Here, the side effects that conventional drugs have are, in phenothiazine drugs, orthostatic hypotension and oversedation based on a strong α-blocking action, and in drugs having a strong dopamine receptor blocking action, It is a side effect such as so-called extrapyramidal symptom of catalepsy, acacia, dystonia, etc. by blocking the linear dopamine receptor. In the course of the research, the strength of the α-blocking effect was shown by the dose of a compound required to suppress the lethality of mice by administration of epinephrine by 50% (ED ₅₀ mg / kg, oral administration), and the main effect was the dopamine receptor. Dosage of a compound required to suppress the stereotyped behavior of mice, which is induced by administration of a dopamine agonist apomorphine, by 50% (ED ₅₀ mg / kg, oral administration)
, The dopamine receptor blockade is strong and α
We have succeeded in finding a compound represented by the general formula (1) as a compound having a weak blocking action. The present invention has been completed based on such knowledge.

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

[Reaction Formula-1]

[0017]

[Chemical 9]

[Wherein R and carbostyril skeleton 3,
The bond at the 4-position is the same as above. X ¹ represents a halogen atom or a group such as a mesityloxy group and a tosyloxy group which causes the same substitution reaction as a halogen atom. The reaction of the compound represented by the general formula (3) with the compound represented by the general formula (4) is carried out at room temperature to 200 ° C., preferably 60 to 120 ° C., in the absence of a solvent or an ordinary inert solvent. It will be completed in several hours to 24 hours under the conditions. Examples of the inert solvent include ethers such as dioxane, tetrahydrofuran and ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol and isopropanol, dimethylformamide (DMF) and dimethyl. Any polar solvent such as sulfoxide (DMSO) or acetonitrile can be used. The above reaction is more preferably carried out using a basic compound as the dehydrohalogenating agent. Examples of the basic compound that can be used include inorganic bases such as calcium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, and organic bases such as triethylamine, tripropylamine, pyridine, and quinoline. . The above reaction can be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction accelerator, if necessary.
The ratio of the compound represented by the general formula (3) to the compound represented by the general formula (4) in the above reaction is usually equimolar or more, preferably equimolar to 5 times the molar amount of the former with respect to the former. It may be equimolar to 1.2 times the molar amount.

[Reaction formula-2]

[0020]

[Chemical 10]

[Wherein R and carbostyril skeleton 3,
The bond at the 4-position is the same as above, and X ² is a halogen atom. The reaction of the compound represented by the general formula (5) with the compound represented by the general formula (6) in Reaction Scheme-2 is preferably carried out by using a basic compound as a dehydrohalogenating agent in a suitable solvent at room temperature to 200 ° C. C., preferably 50 to 150.degree. C., within a few hours to 15 hours. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol, isopropanol, acetone, ketones such as methyl ethyl ketone, dioxane, ethers such as diethylene glycol dimethyl ether, toluene, aromatic hydrocarbons such as xylene, DMF, Examples include DMSO and hexamethylphosphoric triamide. Examples of basic compounds that can be used as dehalogenated hydrocarbons include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, potassium metal, and sodium. Examples include tertiary amines such as amide, pyridine, quinoline, triethylamine and tripropylamine. In the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can be used as a reaction accelerator. The ratio of the compound represented by the general formula (5) to the compound represented by the general formula (6) is not particularly limited, but 1 mol or more of the latter per 1 mol of the former, usually 1 to 5 mol, preferably 1 mol. It is preferable to use about 1.2 mol.

[Reaction Formula-3]

[0023]

[Chemical 11]

[In the formula, the bonds at the 3,4 positions of R, X ² and the carbostyril skeleton are the same as described above. The reaction of the compound of the general formula (7) with the compound of the general formula (8) is carried out in a suitable solvent,
It is carried out in the presence or absence of a basic compound. Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, lower alcohols such as methanol, ethanol, propanol and butanol,
Examples thereof include pyridine, acetone, DMF, DMSO, hexamethylphosphoric triamide and the like. As the basic compound used, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide,
Examples thereof include inorganic bases such as potassium hydroxide, sodium hydride and potassium hydride, organic bases such as triethylamine and the like. The amount of the compound of the general formula (8) used is at least equimolar, preferably equimolar to 3 times the molar amount of the compound of the general formula (7). The reaction is usually at room temperature to 180 ° C., preferably around 80 to 150 ° C.
The reaction is completed in about 3 to 30 hours.

[Reaction Formula-4]

[0026]

[Chemical 12]

[In the formula, the bonds at the 3,4 positions of R, X ¹ and the carbostyril skeleton are the same as above. The reaction between the compound of general formula (9) and the compound of general formula (10) can be carried out in a suitable solvent in the presence or absence of a basic compound.
As the solvent used here, water, lower alcohols such as methanol, ethanol, isopropanol, butanol, etc., aromatic hydrocarbons such as benzene, toluene, xylene, acetic acid, ethyl acetate, DMF, DMSO, hexamethylphosphoric triamide, etc. Can be illustrated. Examples of the basic compound used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, 1,5-diazabicyclo [4,3,0] nonene- 5
-(DBN), 1,8-diazabicyclo [5,4,0]
An inorganic base such as undecene-7 (DBU) or 1,4-diazabicyclo [2,2,2] octane (DABCO);
Examples thereof include organic bases such as pyridine and triethylamine. The amount of the compound of the general formula (10) used is equal to that of the general formula (9)
It is usually preferable to use at least an equimolar amount, preferably an equimolar to 5-fold molar amount with respect to the above compound. The reaction is usually 4
1 at 0 to 120 ° C., preferably 70 to 100 ° C.
The reaction is completed in about 15 hours.

[Reaction Formula-5]

[0029]

[Chemical 13]

[In the formula, R, X ¹ and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as described above. The reaction of the compound of general formula (11) with the compound of general formula (12) is carried out under the same conditions as the reaction between the compound of general formula (9) and the compound of general formula (10).

In the above reaction formula-1, the compound of the general formula (4) used as a starting material is produced, for example, by the method shown in the following reaction formula-6.

[Reaction Formula-6]

[0033]

[Chemical 14]

[In the formula, R and X ¹ are the same as defined above. ] The reaction of the compound of general formula (10) and the compound of general formula (13) is
The reaction is carried out under the same conditions as the reaction of the compound of the general formula (9) with the compound of the general formula (10).

The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted to an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid,
Organic acids such as tartaric acid, citric acid and benzoic acid can be mentioned.

Further, among the carbostyril derivatives represented by the general formula (1) of the present invention, the compound having an acidic group can be easily formed into 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 a conventional separation means. Examples of the separating means include a solvent extraction method, a dilution method, a recrystallization method, a column chromatography, and a proparative thin layer chromatography.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared by using a diluent or excipient which is usually used such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, liquids,
Suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned.

In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Binders such as potassium phosphate, 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, lactose, etc. Disintegrant, sucrose, stearin, cocoa butter, disintegration inhibitor such as hydrogenated oil, quaternary ammonium base, absorption enhancer such as sodium lauryl sulfate, glycerin, moisturizer such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, refined talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. Further, the tablet is a tablet coated with a usual coating as necessary, for example, sugar-coated tablet, gelatin-coated tablet, enteric-coated tablet, film-coated tablet or double tablet,
It can be a multilayer tablet.

In the case of molding in the form of pills, those 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, Arabic and the like. Examples thereof include rubber powder, tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthantene, and the like.

In the case of molding 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 semisynthetic glycerides. it can.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When the solution, pill and suspension are formed into a form, All diluents customary in the art can be used, such as water, ethyl alcohol,
Examples thereof include 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 contained in the drug of the present invention, and a usual solubilizer, buffer, soothing agent, etc. are added. You may.

If necessary, coloring agents, preservatives, fragrances,
Flavoring agents, sweetening agents and the like and other pharmaceutical agents may be included in the treatment.

The amount of the compound of the general formula (1) to be contained in the therapeutic agent for schizophrenia of the present invention is not particularly limited and may be selected in a wide range, but it is usually 1 to 70% by weight in the total composition, preferably Is 1 to 30% by weight.

The method of administration of the therapeutic agent for schizophrenia 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. Further, in the case of an injection, it is administered alone or mixed with an ordinary replenisher such as glucose or amino acid, and then intravenously administered. Furthermore, if necessary, it is intramuscularly, intradermally, subcutaneously or intraperitoneally administered. In the case of suppositories, it will be administered rectally.

The dose of the therapeutic agent for schizophrenia 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 it is usually the general formula (1) which is an active ingredient.
The amount of the compound is about 0.1 to 10 per 1 kg of body weight per day.
It is recommended to use mg. In addition, it is preferable to contain 1 to 200 mg of the active ingredient in the dosage unit form.

In the above general formula (1), the C _1-3 alkoxy group is, for example, methoxy, ethoxy, propoxy,
A linear or branched alkoxy group having 1 to 3 carbon atoms such as an isopropoxy group is shown, and of these, a methoxy group and an ethoxy group are preferable, and an ethoxy group is particularly preferable. The bond at the 3rd and 4th positions of the carbostyril skeleton is preferably a single bond.

[0048]

[Examples] Reference examples, examples, pharmacological test results and formulation examples are listed below.

Reference Example 1 2-chloro-3-methylaniline 6.08 g, di (2-
Bromoethyl) amine / hydrobromide 9 g and water 4 ml
A solution of 0.8 g of potassium hydroxide in 2.5 ml of water is added to the mixed solution of 3 times at 100 ° C. at 1 hour intervals, and the mixture is stirred at the same temperature for 9 hours. The reaction mixture is made alkaline with potassium hydroxide, extracted with ethanol, washed with water, and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: 5% methanol / chloroform),
3.41 g of 4- (2-chloro-3-methylphenyl)
Get piperazine.

Pale purple oily ¹ H-NMR (CDCl ₃ ) δ; 2.38 (3 H, s), 3.04 (8 H, m),
6.93 (2H, m), 7.12 (1H, dd, J =
7.7 Hz, 7.7 Hz) Reference Examples 2 to 5 In the same manner as in Reference Example 1, using the appropriate starting material, the following first
The compounds given in the table are obtained.

[0051]

[Table 1]

Reference Example 6 To a solution of 4.06 g of potassium carbonate in 400 ml of water was added 40 g of 7-hydroxy-3,4-dihydrocarbostyril and 158 g of 1,4-dibromobutane, and the mixture was heated under reflux for 3 hours. The reaction mixture is extracted with dichloromethane, dried over magnesium sulfate, and the solvent is evaporated. The obtained residue was purified by silica gel column chromatography (eluent; dichloromethane) and then recrystallized from n-hexane-ethanol to give 50 g of 7- (4-bromobutoxy) -3,
4-dihydrocarbostyril is obtained.

Colorless needle crystals mp 110.5-111.0 ° C. Example 1 A suspension of 47 g of 7- (4-bromobutoxy) -3,4-dihydrocarbostyril and 35 g of sodium iodide in 600 ml of acetonitrile is heated for 30 minutes. Bring to reflux. 1 more
40 g of-(2,3-dichlorophenyl) piperazine and 33 ml of triethylamine are added, and the mixture is heated under reflux for 3 hours. After distilling off the solvent, the obtained residue is dissolved in chloroform, washed with water and dried over magnesium sulfate. The residue obtained by distilling off the solvent was recrystallized twice from ethanol and
7.1 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril are obtained.

Colorless scale-like crystals mp 139.0-139.5 ° C. 7- {4- [4- (2,3-dichlorophenyl) -1-
1.0 g of piperazinyl] butoxy} -3,4-dihydrocarbostyril was dissolved by heating in 20 ml of ethanol,
With stirring, a saturated hydrochloric acid ethanol solution was added, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 0.75 g of 7- {4- [4- (2,3-dichlorophenyl) -1-.
Piperazinyl] butoxy} -3,4-dihydrocarbostyril hydrochloride is obtained.

Mp 214-222 ° C. (decomposition) white powder 7- {4- [4- (2,3-dichlorophenyl) -1-
1.0 g of piperazinyl] butoxy} -3,4-dihydrocarbostyril was dissolved in 10 ml of ethanol, and sulfuric acid-ethanol (1 ml concentrated sulfuric acid / 10 ml ethanol) 4
ml is added and the solvent is distilled off. Add 10 ml of ethanol and 30 ml of water, heat to make a solution, recrystallize, collect the crystals by filtration, and then recrystallize from ethanol-water to obtain 1.02.
g of 7- {4- [4- (2,3-dichlorophenyl)-
1-Piperazinyl] butoxy} -3,4-dihydrocarbostyryl sulfate is obtained.

Mp 220-225 ° C. white powder 7- {4- [4- (2,3-dichlorophenyl) -1-
Piperazinyl] butoxy} -3,4-dihydrocarbostyril (1.0 g) and fumaric acid (290 mg) were treated in the same manner as the above-mentioned sulfate, and recrystallized from ethanol to give 0.2.
97 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyryl fumarate are obtained.

Mp196-198 ° C. white powder 7- {4- [4- (2,3-dichlorophenyl) -1-
Piperazinyl] butoxy} -3,4-dihydrocarbostyril (1.0 g) and maleic acid (290 mg) were treated in the same manner as the sulfate, and recrystallized from ethanol to give 0.98 g of 7- {4- [4 -(2,3-Dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyryl maleate is obtained.

Mp172-180 ° C. White powder The compound shown in Table 2 below is obtained in the same manner as in Example 1 using appropriate starting materials. In addition, Example N in Table 2
o. Compounds 11-14 are all in the form of the hydrochloride salt.

[0059]

[Table 2]

[0060]

[Table 3]

Pharmacological Test Method a) Anti-Apomorphine Action in Mice Experiments were carried out with 6 mice per group. One hour after the oral administration of the test compound, apomorphine (1.25 mg / kg) was subcutaneously administered, and the stereotyped behavior to be expressed was described by Puech et al.
Pharmacology, Vol. 20, p1279, 1981), and the anti-apomorphine action of the test compound was examined using the score as an index. A score of 50% or less of the average score of the control group was determined to be positive for anti-apomorphine action in animals, and the 50% effective dose (ED
₅₀ values) were calculated.

B) Antiepinephrine lethal action in mice Janssen, P. et al. Arzneim. Forsch., 13 , 205 (19).
According to 63), the experiment was conducted with 6 animals per group. One hour after the oral administration of the test compound, a lethal dose of epinephrine (1.5 mg / kg) was intravenously administered, and 4 hours later, the presence or absence of survival of the mouse was observed. Surviving mice were determined to be positive for lethality of anti-epinephrine, and 50% effective dose (ED
₅₀ values) were calculated.

The results are shown in Table 3 below.

The following compounds were used as test compounds.

No. 1: Compound of Example 1 (free) No. 2: Compound of Example 2 No. 3: Compound of Example 3 No. 4: Compound of Example 4 No. 5: Example 5 Compound No. 6: Compound No. 7 of Example 12: Compound No. 7 of Example 8: Compound No. 9 of Example 8: Compound No. 10 of Example 9: Compound No. 11 of Example 10: Compound No. 12 of Example 11: Compound No. 13 of Example 13: Compound No. 14 of Example 14: 7- {3- [4- (2-methylphenyl) -1
-Piperazinyl] propoxy} -3,4-dihydrocarbostyryl (Example 143 of JP-A-55-127371)
No. 15: 7- {3- [4- (2-methoxyphenyl)-
1-piperazinyl] propoxy} -3,4-dihydrocarbostyril (Example 8 of JP-A-62-149664)
JP-A-56-46812, Example 50, JP-A-55-1
27371 Example 50, JP-A-55-124766, Example 50 and JP-A-54-130587, Example 66.
No. 16: 7- {3- [4- (2-ethoxyphenyl)-
1-piperazinyl] propoxy} -3,4-dihydrocarbostyryl (Example 44, JP-A-56-46812,
JP-A-55-127371, Example 44, JP-A-55-55
No. 124766 Example 44 and JP-A-54-13058
No. 7 compound of Example 77) No. 17: 7- [4- (4-phenyl-1-piperazinyl) butoxy] -3,4-dihydrocarbostyril (JP-A-62-149664 Example 9, Kaisho 56-46
812 Example 54, JP-A-55-127371, Example 54, JP-A-55-124766, Example 54 and JP-A-54-130587, Example 71) No. 18: 7- {3- [4- (3-chlorophenyl) -1
-Piperazinyl] propoxy} -3,4-dihydrocarbostyryl (No. 6, JP-A-62-135423),
Example 7 of JP-A-62-149664, JP-A-56-
No. 19: 7- {4-Compounds of No. 46812 Example 48, No. 55-127371 Example 48, No. 55-124766 Example 48 and No. 54-130587 Example 64) No. 19: 7- {4- [4- (2-nitrophenyl) -1
-Piperazinyl] propoxy} -3,4-dihydrocarbostyril (Compound described in JP-A-56-49361) No. 20: 7- {3- [4- (3-chlorophenyl) -1
-Piperazinyl] propoxy} carbostyril (the compounds described in JP-A-55-2693)

[0066]

[Table 4]

However, in Table 3, * indicates% control value after oral administration at 3 mg / kg (50 at 3 mg / kg administration).
% Effective dose cannot be reached), ** indicates 64 mg /
% control value after oral administration of kg (also 64 mg /
50% effective dose cannot be reached with kg administration).

From Table 3 above, the compound of the present invention has an anti-aporphine action (A) as an index of the main action, the dopamine receptor-blocking action, as compared with the respective compounds to be compared (Nos. 14 to 20). In Table 3, it is clear that each of them is 3.4 times or more stronger (excluding test compound No. 9).

Moreover, it can be seen that all the compounds of the present invention have little anti-epinephrine action (B) as an index of the α-blocking action which is a side effect, and have high selectivity for the main action (A). By the way, the test compound No. No. 9 has the main action (A), which is the best among comparative compounds. Approximately 2.8 compared to 16 but B / A showing the above selectivity is 100
It is distant by about 0 times, and it is clear that the selectivity of the main action is very high.

Formulation Example 1 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg According to a conventional method A tablet containing the above composition in one tablet was produced.

Formulation Example 2 7- {4- [4- (2-ethoxyphenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril 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 While stirring the parabens, sodium metabisulfite and sodium chloride 80 It was dissolved in the above distilled water at ℃. The obtained solution is cooled to 40 ° C.,
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, sterile filtration is performed using an appropriate filter paper, and 1 ml aliquots are dispensed into ampoules. Then, an injection was prepared.

Claims (2)

[Claims] 1. A general formula: [Wherein R is a group (R ¹ is a C _1-3 alkoxy group), a group (R ² and R ³ are chlorine atom or bromine atom at the same time, R ⁴ is hydrogen atom or chlorine atom), 2-methyl-3-nitrophenyl group, 3,5-dichlorophenyl group, group (R ⁵ is a chlorine atom or a bromine atom, and R ⁶ is a methyl group). The bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond. However, when the bond at the 3 and 4 positions is a single bond, R is a group represented by the formula ^{1 in} which R ¹ is an ethoxy group and R ² and R ³ are chlorine atoms at the same time and R ⁴
Cannot be a group represented by Chemical formula 2 in which is a hydrogen atom. ] The carbostyril derivative or its salt represented by these. 2. A therapeutic agent for schizophrenia, which comprises the carbostyril derivative according to claim 1 or a salt thereof.