JPH07304740A - Carbostyril derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful especially as a therapeutic agent for schizophrenia, having strongly blocking action on dopamine receptor and weak alpha blocking action as adverse action. CONSTITUTION:A compound of formula I (R is 2,3-dichlorophenyl) or its salt such as 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbosty ril. The compound of formula I is obtained by reacting a compound of formula II (X<1> is a halogen or a group such as mesyloxy or tosyloxy to cause the same substitution reaction as that of a halogen) with a compound of formula III in the absence of a solvent or in an inert solvent (e.g. dioxane) in the presence of a base (e.g. potassium hydroxide) at room temperature to 200 deg.C. The base compound is used as a dehydrohalogenating agent and optionally an alkali metal iodide compound is added as a reaction promoter to carry out the reaction. A dose of the compound of formula I is 0.1-10mg/kg/day.

Description

Detailed Description of the Invention

[0001]

The present invention relates to carbostyril derivatives,
More specifically, it relates to a particular carbostyril derivative which is particularly useful as a therapeutic agent for schizophrenia.

[0002]

2. Description of the Related Art Schizophrenia is believed to be caused by overactivity of the central dopaminergic nervous system (dopamine excess hypothesis; tract man, metabolism, Vol. 22, p49.
(1985), Pharmacia Review, No. 10,
"Kokoro to Yaku" (edited by the Pharmaceutical Society of Japan, etc.), phenothiazines such as chloropromazine, butyrophenone represented by haloperidol and benzamide compounds such as sulpiride, etc., that is, central dopamine receptors. Many drugs having a blocking action have been developed and widely used for the purpose of improving so-called positive symptoms in the acute phase such as hallucinations and delusions of schizophrenia and excitement.

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 blunt emotion, 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)), 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.

However, various carbostyril derivatives have hitherto been used, for example, as antihistamines (Japanese Patent Laid-Open No. 54-130).
587, JP-A-55-127371, JP-A-55-124766, etc.), central nerve inhibitor or analgesic (JP-A-54-130587, JP-A-56-46812). , JP-A-56-49361, JP-A-62-149664, etc.), antiallergic agents (see JP-A-55-2693, etc.), therapeutic agents for hypoxia (JP-A-62-135423). (See No.
Have been proposed and developed for pharmaceutical use such as, and some of them have been suggested to be used as therapeutic agents for schizophrenia (JP-A-56-46812 and JP-A-56-49).
No. 361), but the carbostyril derivatives specifically disclosed in each of these publications are still insufficient in the dopamine receptor blocking action, which is the most important action required for a therapeutic agent for schizophrenia. Moreover, they have a very strong side-effect of α-blocking action, and their narrow safe use range has made their clinical use difficult as a therapeutic agent for schizophrenia.

That is, the strength of the above α-blocking action is 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 action is the dopamine receptor. When the strength of the blocking action is shown by the dose of a compound required to suppress stereotyped behavior of mice induced by administration of apomorphine, which is a dopamine agonist, by 50% (ED ₅₀ mg / kg, oral administration), The carbostyril derivatives disclosed in the publication generally have too weak a dopamine receptor blocking action, and those having a strong action also have a strong α-blocking action, which is a side effect, and are not practical in terms of desired therapeutic effect and safety. There wasn't.

[0007] However, as a result of the subsequent studies conducted by the present inventors, a certain carbostyril derivative not specifically disclosed in the above-mentioned publications was surprisingly surprisingly strong in the dopamine receptor blocking action and α-blocking. It was discovered that the action is weak and that it is effective as a schizophrenia therapeutic agent which meets the purpose. The present invention has been completed based on such knowledge.

[0008]

That is, the present invention provides a carbostyril derivative represented by the following formula (1) and a salt thereof.

[0009]

[Chemical 2]

[In the formula, R represents a 2,3-dichlorophenyl group. The carbostyril derivative represented by the above formula (1) can be produced by various methods, and if one example thereof is shown, it is produced, for example, according to the method shown by the following reaction formula.

[0011]

[Chemical 3]

[Wherein R 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. ] In the above, the reaction between the compound represented by the formula (3) and the compound represented by the 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 within a few hours to 24 hours. 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 formula (3) and the compound represented by the formula (4) in the above reaction is usually equimolar or more, preferably equimolar to 5 times, more preferably equimolar to the former. It may be about 1.2 times mol.

[0013]

[Chemical 4]

[In the formula, R is the same as above, and X ² is a halogen atom. In the reaction formula-2, the reaction between the compound represented by the formula (5) and the compound represented by the formula (6) is preferably carried out by using a basic compound as a dehydrohalogenating agent in a suitable solvent at room temperature to 200 ° C. Preferably at 50 to 150 ° C. for several hours to 15
Will be done in time. 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 the basic compound that can be used as a dehalogenated hydrocarbon include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride,
Examples thereof include tertiary amines such as metal potassium, sodium 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 formula (5) to the compound represented by the formula (6) is not particularly limited, but 1 mol or more, usually 1 to 5 mol, preferably 1 to 1 mol of the latter per 1 mol of the former. It is preferable to use about 2 mol.

[0015]

[Chemical 5]

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

[0017]

[Chemical 6]

[In the formula, R and X ¹ are the same as defined above. The reaction between the compound of formula (9) and the compound of 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 and butanol, aromatic hydrocarbons such as benzene, toluene and xylene, acetic acid, ethyl acetate, DMF and DMS.
Examples thereof include O and hexamethylphosphoric triamide. 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 [4,3,3].
0] nonene-5- (DBN), 1,8-diazabicyclo [5,4,0] undecene-7 (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO) and other inorganic bases, Examples thereof include organic bases such as pyridine and triethylamine. The amount of the compound of formula (10) used is usually at least equimolar, preferably equimolar to 5 times the molar amount of the compound of formula (9). The reaction is
The reaction is usually completed at 40 to 120 ° C., preferably at 70 to 100 ° C. in about 1 to 15 hours.

[0019]

[Chemical 7]

[In the formula, R and X ¹ are the same as defined above. The reaction between the compound of formula (11) and the compound of formula (12) is carried out under the same conditions as the reaction between the compound of formula (9) and the compound of formula (10).

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

[0022]

[Chemical 8]

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

The carbostyril derivative represented by the formula (1) of the present invention can be easily converted into 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, 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 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 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 formula (1) is usually used in the form of a general pharmaceutical preparation. Formulations are commonly used fillers,
It is prepared using a diluent or excipient such as 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,
Typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions,
Suspension agents, etc.) and the like. 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, etc. Forming agent, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate,
Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, disintegration of sucrose, stearin, cocoa butter, hydrogenated oil, etc. Inhibitors, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, humectants such as starch, starch, lactose, kaolin, bentonite, adsorbents such as colloidal silicic acid, purified talc, stearate, Lubricants such as boric acid powder and polyethylene glycol can be exemplified. Further, the tablet is a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet,
It may be a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer 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, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, excipients such as kaolin and talc, gum arabic powder, Examples thereof include tragacanth powder, a binder such as gelatin and ethanol, and a disintegrating agent such as laminaranthantene. 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. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solutions, pills and suspensions, they are used as diluents. All those conventionally 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, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent,
A buffering agent, a soothing agent, etc. may be added. Further, if necessary, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the treatment.

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

There is no particular limitation on the method of administration of the above-mentioned therapeutic agent for schizophrenia, and it may be administered according to various dosage forms, age, sex and other conditions of the patient, 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 a normal replacement fluid such as glucose or amino acid, and then intravenously administered.
It is administered intradermally, subcutaneously or intraperitoneally. In the case of suppositories, it will be administered rectally.

The dose of the above schizophrenia therapeutic agent is as follows:
The amount of the compound of formula (1) which is an active ingredient is usually about 0.1 to 10 mg per 1 kg of body weight per day, though it is appropriately selected depending on the age, sex and other conditions of the patient, the degree of disease and the like. . In addition, 1 to 2 active ingredients in the dosage unit form
It is recommended to contain 00 mg.

[0031]

[Examples] Examples, results of pharmacological tests and formulation examples are listed below.

[0032]

Example 1 (1) 7-hydroxy-3,4-dihydrocarbostyril 40 was added to a solution of 4.06 g of potassium carbonate in 400 ml of water.
g and 158 g of 1,4-dibromobutane are added, and the mixture is 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 needles mp. 110.5 to 111.0 ° C (2) 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 under reflux for 30 minutes. Further, 40 g of 1- (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 to give 57.1 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4.
To obtain dihydrocarbostyril.

Colorless scaly crystals mp 139.0 to 139.5 ° C. (3) 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyryl 1. 0 g was dissolved in 20 ml of ethanol by heating, saturated ethanol solution of hydrochloric acid was added under stirring, the precipitated crystals were collected by filtration, and recrystallized from ethanol to obtain 0.75 g of 7- {4- [4- (2, 3-Dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyryl hydrochloride is obtained.

Mp 214-222 ° C. (decomposition) white powder (4) 1.0 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril It is dissolved in 10 ml of ethanol, 4 ml of sulfuric acid-ethanol (1 ml concentrated sulfuric acid / 10 ml ethanol) is added, and the solvent is distilled off. Ethanol 1
0 ml and 30 ml of water were added, heated to form a solution, recrystallized, and the crystals were collected by filtration and further 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.

Mp 220-225 ° C. white powder (5) 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril 1.0 g and fumaric acid 290 mg In the same manner as the above-mentioned sulfate, and recrystallized from ethanol to give 0.97 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4.
Obtaining dihydrocarbostyryl fumarate.

Mp196-198 ° C. white powder (6) 1.0 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril and 290 mg of maleic acid. In the same manner as the above-mentioned sulfate, and recrystallized from ethanol to give 0.98 g of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy}-.
The 3,4-dihydrocarbostyryl maleate salt is obtained.

Mp172 to 180 ° C. white powder

[0039]

[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.

Table 1 below shows the results of the above-mentioned test using the compound (free) obtained in (2) of Example 1 (referred to as compound 1 in the table) as a test compound.

Table 1 also shows the results obtained by carrying out the same test using the following comparative compounds for comparison and chloropromazine as a control, respectively.

Comparison No. 1: 7- {3- [4- (2-methylphenyl) -1-piperazinyl] propoxy]-
3,4-Dihydrocarbostyril (Japanese Patent Application Laid-Open No. 55-127)
371 Compound of Example 143) Comparative No. 2: 7- {3- [4- (2-methoxyphenyl) -1-piperazinyl] propoxy] -3,4-dihydrocarbostyril (JP-A-62-149664, Example 8, JP-A-56-46812). Example 50, JP-A-5
No. 5,127,371 Example 50, JP-A-55-1247
No. 66 Example 50 and the compound of Example 66 of JP-A No. 54-130587) Comparative No. 3: 7- {3- [4- (2-ethoxyphenyl) -1-piperazinyl] propoxy] -3,4-dihydrocarbostyril (JP-A-56-46812, Example 44, JP-A-55-127371). Example 44, JP-A-55-124766 Example 44 and JP-A-54-13
No. 0587 Compound of Example 77) Comparative No. 4: 7- {4- [4-phenyl-1-piperazinyl] butoxy] -3,4-dihydrocarbostyril (JP-A-62-149664, Example 9, JP-A-56-
No. 46812, Example 54, JP-A-55-127371, Example 54, JP-A-55-124766, Example 54 and JP-A-54-130587, Example 71) Comparative No. 5: 7- {3- [4- (3-chlorophenyl) -1-piperazinyl] propoxy] -3,4-dihydrocarbostyril (N in JP-A-62-135423)
o. 6, JP-A-62-149664, Example 7, JP-A-56-46812, Example 48, and JP-A-55-1273.
71, Example 48, JP-A-55-124766, Example 48 and JP-A-54-130587, Example 64) Comparative No. 6: 7- {4- [4- (2-nitrophenyl) -1-piperazinyl] propoxy] -3,4-dihydrocarbostyril (compound described in JP-A-56-49361) Comparative No. 7: 7- {3- [4- (3-chlorophenyl) -1-piperazinyl] propoxy] carbostyril (Compound described in JP-A-55-2693)

[0044]

[Table 1]

However, in Table 1, * indicates% control value after oral administration of 3 mg / kg (50 mg at 3 mg / kg administration).
% Effective dose is not reached), ** indicates 64 mg / k
% control value after oral administration (also 64 mg / k
g dose does not reach 50% effective dose).

From Table 1 above, the compounds of the present invention were
o. Both of the compounds 1 to 7 and chloropromazine used as a control, the anti-apomorphine action (A), which is an index of the main action of dopamine receptor blocking action, is very excellent, and side effects The anti-epinephrine action (B), which is an index of α-blocking action, is also very small, and the B / A showing the selectivity of the main action is also significantly superior to all comparative compounds and control compounds. It is clear that

[0047]

[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 By a conventional method, A tablet containing the above composition in one tablet was produced.

Claims (2)

[Claims] 1. The formula: [In the formula, R represents a 2,3-dichlorophenyl group. ] The carbostyril derivative or its salt represented by these. 2. The derivative according to claim 1, which is 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril.