JPH02191256A - Carbostyryl derivative and remedy for schizophrenia containing the same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is group of formula II (R<1> is 1-3C alkoxy), formula III (R<2> and R<3> are Cl or Br at the same time; R<4> is H or Cl), 2-methyl-3-nitrophenyl, 3,5-dichlorophenyl, etc.; the bond between 3- and 4-positions of carbostyryl skeleton is single or double bond] or its salt. EXAMPLE:7-{4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro carbostyryl. USE:Remedy for schizophrenia having strong dopamine receptor blocking action and weak alpha-blocking action. PREPARATION:The compound of formula I can be produced by reacting a compound of formula IV (X<1> is halogen or a group causing substitution reaction similar to halogen such as mesityloxy or tosyloxy) with a compound of formula V preferably in the presence of a base (e.g. triethylamine) in the absence of solvent or in an inert solvent (e.g. acetonitrile) at room temperature - 200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel carbostyril derivative and a therapeutic agent for schizophrenia containing the derivative.

DISCLOSURE OF THE INVENTION The carbostyryl derivative of the present invention has the following - soft formula % (% hydrogen atom or bromine atom, R4 is a hydrogen atom or chlorine atom),
2-methyl-3-nitrophenyl group, 3,5-dichlorophenyl group, 5 R6 R6 is a methyl group). 3,4 of carbostyril skeleton
The bond at position represents a single bond or a double bond. Furthermore, the therapeutic agent for schizophrenia of the present invention contains the carbostyril derivative represented by the above formula (1) or a salt thereof as an active ingredient.

Schizophrenia is said to be caused by overactivity of the central dopaminergic nervous system (dopamine excess hypothesis; Yumichio 9 Metabolism, Vol. 22, p. 49 (1985), Pharmacia Review, No., IQ).

(Refer to “Mind and Medicine” edited by the Pharmaceutical Society of Japan, etc.), antidopaminergic effects of phenothiazines such as chloropromacin, butyrophenones such as haloperidol, and benzamides such as sulpiride, that is, central dopamine receptors. Many drugs with blocking effects have been developed and are widely used for the purpose of improving the so-called acute-phase positive symptoms of schizophrenia, such as hallucinations, delusions, and excitement.

However, many of these drugs are said to be ineffective in improving the positive symptoms of the chronic phase and so-called negative symptoms such as dulling of emotions, flattening of emotions, and disorganized thinking. By blocking dopamine receptors in the linear body, drugs have many serious side effects such as akathisia, cystonia, Parkinson-like movement disorders, and tardive dyskinesia, and side effects such as hyperprolactinemia are also a problem. (G, M, Simpson, E, H,
Pi, J., and Sramek.

Jt, Drugs, 21. p138 (198
1)), the development of safer and more clinically effective drugs is desired.

The present inventor not only improved the negative symptoms of schizophrenia, but also
With the aim of developing a drug for treating schizophrenia that is effective in improving positive symptoms and has fewer side effects than conventional drugs, we are working diligently to discover carbostyril derivatives that have strong dopamine receptor blocking effects. I've done a lot of research.

Here, the side effects of conventional drugs include orthostatic hypotension and excessive sedation due to the strong α-blocking effect of phenothiazine drugs, and the side effects of drugs with strong dopamine receptor blocking effects. This is a side effect of so-called extrapyramidal symptoms such as catalepsy, akathisia, and cystonia caused by blocking dopamine receptors in the striatum. In the course of this research, the strength of the α-blocking effect was demonstrated by the dose of the compound required to inhibit 50% of mouse mortality due to epinephrine administration (ED 5gmg/kg1 oral administration).
The strength of the main action, dopamine receptor blocking effect, is the dose of the compound required to suppress by 50% the constant behavior in mice induced by administration of apomorphine, a dopamine agonist (ED 56 mg/kg, oral administration)
When shown as , the dopamine receptor blocking effect is strong and α
They succeeded in finding a compound with weak blocking effect. The present invention was completed based on this knowledge.

The carbostyril derivative represented by the above-mentioned formula (1) can be produced by various methods, and for example, it can be produced according to the method shown in the following reaction formula.

[Reaction formula-1] [In the formula, R and the bond at the 3.4-position of the carbostyril skeleton are the same as above. Xl represents a halogen atom or a group that undergoes the same substitution reaction as a halogen atom, such as mesityloxy or tosyloxy group. ] In the above, the reaction between the compound represented by the general formula (3) and the compound represented by the general formula (4) is carried out without a solvent or in a normal inert solvent, at room temperature to 200°C,
Preferably under a temperature condition of 60 to 120°C for several hours to 24 hours.
It will be completed in about an hour. Examples of inert solvents 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, and dimethylformamide (DMF). , dimethyl sulfoxide (DM
Any polar solvent such as SO) or acetonitrile can be used. The above reaction is more advantageously carried out using a basic compound as dehydrohalogenating agent. Examples of the basic compound include inorganic bases such as calcium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, and sodium hydride, triethylamine,
Organic bases such as tripropylamine, pyridine, quinoline, etc. can be used. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary. The ratio of the compound represented by general formula (3) and the compound represented by general formula (4) in the above reaction is usually at least equimolar to the former, preferably equimolar to 5 times the latter, more preferably The amount may be equal to 1 or 2 times the mole.

[Reaction Formula-2] [In the formula, R and the bonds at the 3rd and 4th positions of the carbostyril skeleton are the same as above, and x2 represents a halogen atom. ] In Reaction Formula-2, the reaction between the compound represented by the general formula (5) and the compound represented by the general formula (6) is preferably carried out using a basic compound as a dehydrogenating agent, in an appropriate solvent at room temperature. It is carried out at ~200°C, preferably from 50 to 150°C, within a few hours to 15 hours. In the above, suitable solvents include, for example, lower alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; ethers such as dioxane and diethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene and xylene; Examples include DMF, DMSO, hexamethylphosphoric triamide, and the like. Basic compounds that can be used as dehalogenated hydrocarbons include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, metallic potassium,
Inorganic bases such as sodium amide, alkali metal alcoholades such as sodium methoxide, sodium ethoxide, potassium ethoxide, pyridine, quinoline,
Examples include organic bases such as triethylamine and tripropylamine. In the above reaction, an alkali metal iodide compound such as potassium iodide or sodium iodide can also be used as a reaction promoter. - The proportion of the compound represented by the soft formula (5) and the compound represented by the general formula (6) is not particularly limited, but the latter is used per 1 mole of the former at least 1 mole, usually 1 to 5 moles, preferably 1 mole. It is preferable to use about 1.2 mol.

[Reaction formula-3] [In the formula, R1X2 and the bond at the 3° and 4-positions of the carbostyryl skeleton are the same as above. ] The reaction between the compound of general formula (7) and the compound of general formula (8) is carried out in a suitable solvent in the presence or absence of a basic compound. Examples of solvents used include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, propatool, and butanol, pyridine, acetone, DMF, and DMS.
Examples include O, hexamethylphosphoric triamide, and the like. Basic compounds used include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride,
Examples include inorganic bases such as potassium hydride and organic bases such as triethylamine.

The amount of the compound of soft formula (8) to be used is -at least equimolar, preferably equimolar to the compound of soft formula (7)-
It is preferable to use 3 times the molar amount. The reaction is usually carried out at room temperature to 1
3-30℃ at 80℃, preferably around 80-150℃
The reaction completes in about an hour.

[Reaction formula-4] [In the formula, R, XI and the bonds at the 3rd and 4th positions of the carbostyryl 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. Solvents used here include water, lower alcohols such as methanol, ethanol, isopropanol, and butanol, aromatic hydrocarbons such as benzene, toluene, and xylene, acetic acid, ethyl acetate, and DMFS.
Examples include DMSO and hexamethylphosphoric triamide.

The basic compounds used include, for example, inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, alkali metal alcoholades such as sodium methylate and sodium ethylate, 1,5- Diazabicyclo[4,3,O] nonene-5-(DBN), 1,8-diazabicyclo[5,4
, OFLunsen-7 (DBU), 1,4-diazabicyclo[2°2.2]octane (DABCO), pyridine, and triethylamine. −
The amount of the compound of general formula (10) to be used is usually at least equimolar, preferably equimolar to ~10,000 molar relative to the compound of general formula (9).
It is preferable to use 5 times the molar amount. The reaction is usually 40 to 1
1 to 15 at 20°C, preferably around 70 to 100°C
The reaction completes in about an hour.

[Reaction formula-5] [Reaction formula-6] [In the formula, R, XI and the bonds at the 3 and 4 positions of the carbostyril skeleton are the same as above. ] The reaction between the compound of general formula (11) and 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 Reaction Formula-1 above, the compound of general formula (4) used as a starting material is produced, for example, by the method shown in Reaction Formula-6 below.

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

The carbostyril derivative represented by the general formula (1) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid.

Examples of nucleic acids 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.

Further, among the carbostyril derivatives represented by the general formula (1) of the present invention, a 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 compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, proprietary thin layer chromatography, and the like.

The compound of general formula (1) is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders,
It is prepared using diluents or excipients such as binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquid , suspending agents, etc.). When forming into tablet form,
As carriers, a wide variety of carriers can be used that are conventionally known in this field.
For example, lactose, white sugar, sodium chloride, glucose, urea,
Starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propatool,
Simple syrup, glucose solution, starch solution, gelatin solution,
Binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearin acid monoglyceride,
Disintegrants such as starch and lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, and lactose. Examples include adsorbents such as , kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming an emulsion, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include tragacanth powder, gelatin, binders such as ethanol, and disintegrants such as laminar agar.

When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, the drug of the present invention may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers,
A soothing agent or the like may be added. Furthermore, coloring agents, preservatives, perfumes, flavors, sweeteners, etc., and other pharmaceuticals may be included during the treatment, if necessary.

The general formula (
The amount of the compound 1) is not particularly limited and can be selected within a wide range, but it is usually 1 to 70% by weight, preferably 1 to 3% by weight of the total composition.
It is 0% by weight.

There are no particular restrictions on the method of administering the therapeutic agent for schizophrenia of the present invention, and the administration method is determined depending on various formulation forms, age, sex and other conditions of the patient, severity of the disease, and the like. For example, tablets, powders, solutions, suspensions, emulsions, granules, and capsules are administered orally.

In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. If it is partially opened, it is administered rectally.

The dosage of the schizophrenia therapeutic agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, the degree of the disease, etc., but the amount of the compound of general formula (1) which is the active ingredient is usually The amount is preferably about 0.1 to 10 mg per kg of body weight per day. It is also possible to contain 1 to 200 doses of the active ingredient in a dosage unit form.
It is preferable to contain mg.

In the above general formula (1), the C1-3 alkoxy group refers to a straight or branched alkoxy group having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, etc., and preferred among these are can be exemplified by a methoxy group and an ethoxy group, particularly preferably an ethoxy group. Further, the bond at the 3.4-position of the carbostyril skeleton is preferably a single bond.

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

Reference example 1 6.08 g of 2-chloro-3-methylaniline.

To a mixture of 9 g of di(2-bromoethyl)amine hydrobromide and 4 zl of water was added a solution of 0.8 g of potassium hydroxide in 2.511 g of water at 100°C three times at 1 hour intervals, Stir at the same temperature for 9 hours. The reaction mixture was made alkaline by adding potassium hydroxide, extracted with diethyl ether, washed with water, and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is purified by silica gel column chromatography (eluent: 5% methanol/chloroform) to obtain 3.41 g of 4-(2-chloro-3methylphenyl)piperazine.

Light purple oil H-NMR (CDC13) δ; 2. 38 (3H, s) 3.04 (8H, m) 6, 93 (2H, m) 7, 12 (LH, dd, J 7.7Hz, 7.7Hz) Appropriate starting materials in the same manner as Reference Example 1 Use the following 1st
The compounds shown in the table are obtained.

Table 1 Reference Example 6 Potassium carbonate 4.06g water 400z! 40 g of 7-hydroxy-3,4-dihydrocarbostyryl and 1
, 158 g of 4-dibromobutane were added, and the mixture was heated under reflux for 3 hours. The reaction mixture was extracted with dichloromethane, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane) and then recrystallized from n-hexane-ethanol to obtain 50 g of 7-(4-bromobutoxy)-3゜4.
- Obtain dihydrocarbostyril.

Colorless needle crystals mpH 0.5-111.0°C Example 1 A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyryl and 35 g of sodium iodide in 600 y of acetonitrile is heated under reflux for 30 minutes. . 1 more
Add 40 g of -(2,3-dichlorophenyl)piperazine and 3311 g of triethylamine, and heat under reflux for 3 hours. After distilling off the solvent, the resulting residue was dissolved in chloroform, washed with water, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was recrystallized twice from ethanol to obtain 57
．． 1 g of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydrocarbostyryl is obtained.

Colorless scaly crystals mp139.0-139.5℃ 7-(4-[4-(2,3-dichlorophenyl)-1
1.0 g of -piperazinyl]butoxy)-3,4-dihydrocarbostyryl was dissolved in 2011 ethanol by heating, and while stirring, a saturated hydrochloric acid solution in ethanol was added, the precipitated crystals were collected, and this was recrystallized from ethanol. 0.75g
7-(4-[4-(2,3-dichlorophenyl)-
1-Piperazinyl]butoxy)-3,4-dihydrocarbostyryl hydrochloride is obtained.

mp214-222℃ (decomposition) White powder 7-(4-[4-(2,3-dichlorophenyl)-1
101! Dissolve in ethanol, sulfuric acid-ethanol (11! Concentrated sulfuric acid/1 oin ethanol)
411 was added and the solvent was distilled off.

Ethanol 101! and water 3011, heated to form a solution, recrystallized, collected the crystals in a furnace, and recrystallized from ethanol-water to obtain 1.02 g of 7-(4-[4-(2,
3-Dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydrocarbostyryl sulfate is obtained.

mp220-225℃ White powder 7-(4-[4-(2,3-dichlorophenyl)-1
-Piperazinyl]butoxy)-3,4-dihydrocarbostyryl (1.0 g) and fumaric acid (290 μl) were treated in the same manner as the sulfate salt, and recrystallized from ethanol.
97 g of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydrocarbostyryl fumarate are obtained.

m p 19'6-198℃ White powder 7-(4-[4-(2,3-dichlorophenyl)-1
Using 1.0 g of -piperazinyl]butoxy)-3,4-dihydrocarbostyryl and 290 mg of maleic acid,
Treated in the same manner as for the sulfate salt and recrystallized from ethanol to obtain 0.98 g of 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy)-3,4-dihydrocarbostyryl.・Obtain maleate.

mp172-180°C Using appropriate starting materials in the form of white powder, the compounds shown in Table 2 below are obtained in the same manner as in Example 1. The compounds of Examples Nα11 to 14 in Table 2 are all in the form of hydrochloride.

Table 1: Pharmacological test method a) Anti-apomorphine effect in mice Experiments were conducted with 6 mice per group. One hour after oral administration of the test compound, apomorphine (1.25 μ/kg) was subcutaneously administered, and the developed open behavior was measured using the method of Puech et al.
armacolog7. Vol, 20. p1
279.1981), and the anti-apomorphine effect of the test compound was examined using the score as an index. An animal with a score of 50% or less of the average score of the control group was determined to be positive for anti-apomorphine activity;
The % effective dose (ED5° value) was determined.

b) Antiepinephrine lethal effect in mice Jans
sen P, cl al, Atxneim, For
Scb, 13°205 (1963), experiments were conducted with 6 animals per group. One hour after oral administration of the test compound, a lethal dose of epinephrine (1.5 μ/kg) was administered.
) was administered intravenously, and the survival of the mice was observed 4 hours later. The surviving mice were determined to be positive for anti-epinephrine lethal action, and the 50% effective dose (ED5° value) was determined.

The results are shown in Table 3 below.

Test compound No. 1: Compound (free) No. of Example 1, 2: Compound No. of Example 2, 3: Compound No. of Example 3, 4: Compound No. of Example 4, 5: Example 5 6: Compound No. of Example 12, 7: Compound No. of Example 7, 8: Compound No. of Example 8, 9: Compound No. of Example 9, 10: Compound No. of Example 1O, 11 : Compound No. of Example 11, 12: Compound No. of Example 13, 13: Compound of Example 14 Table 3 Formulation Example 1 7- (4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy)-3,4-dihydrocarbostyryl starch Magnesium stearate Lactose Total 5■ 132■ 18■ 45■ 200■ Polyethylene glycol 0.3g (molecular weight:
4000) Sodium chloride 0.9g Polyoxyethylene sorbitan 0.4g Noolate Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection
100z/Tablets each containing the above composition were manufactured by a conventional method.

Formulation Example 2 7-(4-[4-(2-ethoxy 500 phenyl)-1-piperazinylcobutoxy)-3,4-dihydrocarbostyryl While stirring the above parabens, sodium metabisulfite and sodium chloride It was dissolved in the above distilled water at 80°C. The obtained solution was cooled to 40°C, and the compound of the present invention, polyethylene glycol, and polyoxyethylene sorbitan monooleate were sequentially dissolved. Next, distilled water for injection was added to the solution to adjust the final volume to an appropriate amount. The mixture was sterilized by filtration using filter paper and dispensed into ampoules in 1 xi portions to prepare injections.

(Hereafter Up)

Claims (10)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is a group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R
^1 is a C_1_~_3 alkoxy group), the group ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (R^2 and R^3 are both chlorine or bromine atoms, R^4 is hydrogen or chlorine atom),
2-methyl-3-nitrophenyl group, 3,5-dichlorophenyl group, Group ▲ Numerical formula, chemical formula, table, etc. ▼ (R^5 is a chlorine atom or bromine atom, 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. ] A carbostyryl derivative or a salt thereof represented by: (2) R is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1
The carbostyril derivative or its salt according to claim (1), wherein is the same as defined above. (3) R is the group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R ^
2, R^3 and R^4 are the same as above)
) or a salt thereof. (4) R is 2-methyl-3-nitrophenyl group or 3,
The carbostyril derivative or salt thereof according to claim (1), which is a 5-dichlorophenyl group. (5) R is the group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R ^
5 and R^6 are the same as defined above). The carbostyryl derivative or salt thereof according to claim 1. (6) 7-{4-[4-(2,3-dichlorophenyl)
The carbostyril derivative or salt thereof according to claim 1, which is -1-piperazinyl]butoxy}-3,4-dihydrocarbostyryl. (7) 7-{4-[4-(2-ethoxyphenyl)-1
-piperazinyl]butoxy}-3,4-dihydrocarbostyryl or a salt thereof according to claim (1). (8) A therapeutic agent for schizophrenia, comprising the carbostyril derivative or salt thereof according to claim (1). (9) 7-{4-[4-(2,3-dichlorophenyl)
The therapeutic agent for schizophrenia according to claim (8), which contains -1-piperazinyl]butoxy}-3,4-dihydrocarbostyryl. (10)7-{4-[4-(2-ethoxyphenyl)-
The agent for treating schizophrenia according to claim (8), which contains 1-piperazinyl]butoxy}-3,4-dihydrocarbostyryl.