JP2608788B2 - Schizophrenia remedy - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a therapeutic agent for schizophrenia.

Prior Art and its Challenges Schizophrenia has been attributed to overactivity of the central dopaminergic nervous system (Dopamine hyperhypothesis; Maruho 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 antidopaminergic action of benzamide compounds such as sulpiride. Many drugs having a dopamine receptor 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.

However, many of these drugs are said to be ineffective for improving so-called negative symptoms such as positive symptoms in the chronic phase and dull feelings, flattening of emotions and disorganization of thoughts.
Further, these drugs have many serious side effects such as akathisia, dystonia, Parkinson-like movement disorders and tardive dyskinesia by blocking the striatal dopamine receptors, and further have side effects such as hyperprolactinemia. (GMSimpson, EHPi, JJSramek, Jr. Drug
s, 21, p138 (1981)), and the development of safer and clinically effective drugs is desired.

The present inventor aims to develop a therapeutic drug for schizophrenia that is effective not only for the improvement of the negative symptoms of schizophrenia but also for the improvement of the positive symptoms, and that has few side effects as conventional drugs have. In order to find a carbostyril derivative having a strong dopamine receptor blocking action, intensive studies have been made. Here, the side effects of conventional drugs are phenothiazine drugs, which are orthostatic hypotension and hypersedation based on a strong α-blocking action, and drugs having a strong dopamine receptor blocking action, It is a side effect such as so-called extrapyramidal symptoms such as catalepsy, akathisia, dystonia, etc. due to the blockade of linear dopamine receptors.

Therefore, various carbostyril derivatives have been
For example, antihistamines (see JP-A-54-130587, JP-A-55-127371, JP-A-55-124766, etc.), central nervous system depressants or analgesics (JP-A-54-130587, JP-A-56-46812, JP-A-56-49361, JP-A-62-149664, etc.), antiallergic agent (JP-A-55-2693, etc.), hypoxia treatment It has been proposed and developed for pharmaceutical use of agents (see JP-A-62-135423, etc.), and some of them have been suggested to be used as therapeutic agents for schizophrenia (JP-A-56-56). -46812 and JP-A-56-49361), the carbostyril derivatives specifically disclosed in these publications are dopamine receptors which are the most important actions required for therapeutic agents for schizophrenia. The blocking action is still insufficient, and the α-blocking action, which is a side effect, is quite strong, and the Halfbeak, clinical use as schizophrenia therapeutic agents has been difficult.

That is, the strength of the α-blocking action is indicated by the dose of the compound required to suppress 50% of the lethality of mice by epinephrine administration (ED ₅₀ mg / kg, oral administration). The strength was determined by the dose of the compound required to inhibit 50% of the stereotypic behavior of mice induced by administration of the dopamine agonist apomorphine (ED ₅₀
(mg / kg, oral administration), the carbostyril derivatives disclosed in the above publications generally have too weak a dopamine receptor-blocking action, and those with a strong action also have a strong α-blocking action as a side effect. The desired therapeutic effect and safety were not practical.

However, as a result of subsequent studies, the present inventors have found that certain carbostyril derivatives not specifically disclosed in the above-mentioned publications surprisingly surprisingly have a strong dopamine receptor blocking effect and a weak α-blocking effect. Discovered that it is effective as a schizophrenia treatment that meets its purpose. The present invention has been completed based on such findings.

That is, the present invention provides a therapeutic agent for schizophrenia containing, as an active ingredient, at least one selected from a carbostyril derivative represented by the following formula (1) and a salt thereof. .

[Wherein R represents a 2,3-dichlorophenyl group. ] The carbostyril derivative represented by the above formula (1) is
It can be produced by various methods. For example, it is produced according to the method shown by the following reaction formula.

[Reaction formula-1] [Wherein R is the same as above. X ¹ represents a halogen atom or a group that causes the same substitution reaction as a halogen atom such as a mesityloxy or tosyloxy group. In the above, the compound represented by the formula (3) and the compound represented by the formula (4)
The reaction with the compound represented by is completed in a solvent-free or ordinary inert solvent at room temperature to 200 ° C., preferably 60 to 120 ° C., for several 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 advantageously carried out using a basic compound as a 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) to the compound represented by the formula (4) in the above reaction is usually at least equimolar, preferably equimolar to 5 times, and more preferably equimolar to the former. The molar ratio may be up to 1.2 times mol.

[Reaction formula-2] [In the formula, R is the same as above, and X ² represents 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. It is preferably carried out at 50 to 150 ° C. within several hours to 15 hours. Suitable solvents in the above, for example, methanol, ethanol, lower alcohols such as 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, for example, sodium hydroxide,
Tertiary amines such as potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium hydride, metallic potassium, sodium amide, pyridine, quinoline, triethylamine, tripropylamine, etc. Can be illustrated. In the above reaction, an alkali metal iodide compound such as potassium iodide and 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 is preferably 1 mol or more per 1 mol of the former, usually 1 to 5 mol.
It is good to use 1 mol to 1 mol, preferably 1 to 1.2 mol.

[Reaction Formula-3] [In the formula, R and X ² are the same as defined above. The reaction between the compound of the formula (7) and the compound of the 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,
Examples thereof include aromatic hydrocarbons such as toluene and xylene, lower alcohols such as methanol, ethanol, propanol and butanol, pyridine, acetone, DMF, DMSO, and hexamethylphosphoric triamide. As the basic compound used, sodium carbonate, potassium carbonate,
Examples include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride, and organic bases such as triethylamine. The amount of the compound of the formula (8) used is at least equimolar, preferably equimolar to 3 times the molar amount of 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.

[Reaction formula-4] Wherein R and X ¹ are the same as above. The reaction between the compound of the formula (9) and the compound of the formula (10) can be carried out in a suitable solvent in the presence or absence of a basic compound. Examples of the solvent 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, DMF, DMSO, hexamethylphosphoric triamide and the like. Can be exemplified. Examples of the basic compound used include, for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, 1,5-diazabicyclo [4,3,0] nonene- 5- (DB
N), 1,8-diazabicyclo [5,4,0] undecene-7 (D
BU), 1,4-diazabicyclo [2,2,2] octane (DABC
Examples thereof include inorganic bases such as O) and organic bases such as pyridine and triethylamine. The amount of the compound of the formula (10) used is
It is usually good to use at least equimolar, preferably equimolar to 5-fold molar amount to the compound of the formula (9). The reaction is usually carried out at 40 to 120 ° C., preferably around 70 to 100 ° C.
The reaction is completed in about 15 hours.

[Reaction formula-5] [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 scheme-1, the compound of formula (4) used as a starting material is produced, for example, by the method shown in the following Reaction scheme-6.

[Reaction formula-6] [In the formula, R and X ¹ are the same as defined above. The reaction between the compound of formula (10) and the compound of formula (13) is carried out under the same conditions as the reaction between 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 to an acid addition salt by acting a pharmaceutically acceptable acid. Examples of the acid include:
Examples thereof 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,
Examples thereof include sodium carbonate and potassium hydrogen carbonate.

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 formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions,
Granules, capsules, suppositories, injections (solutions, suspensions, etc.)
And the like. For molding into tablets, those conventionally known in the art can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose,
Excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, binders such as shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate, Agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters,
Disintegrating agents such as sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption accelerators such as sodium lauryl sulfate,
Humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid;
Lubricants such as purified talc, stearates, powdered boric acid, and polyethylene glycol can be exemplified. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. When molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, excipients such as kaolin and talc, gum arabic powder, Examples include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran agar. 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 liquid preparations and suspensions are preferably sterilized and isotonic with blood. In forming these liquid preparations, pills and suspensions, they may be used as diluents. All those commonly used in this field can be used, for example, 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 for preparing an isotonic solution may be contained in the drug of the present invention, and a usual solubilizer, buffer, soothing agent, etc. are added. May be. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be added during the treatment, if necessary.

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

There is no particular limitation on the method of administration of the therapeutic agent for schizophrenia of the present invention, various formulation forms, patient age, gender and other conditions,
It is administered by a method depending on the degree of disease and the like. Tablets, for example
In the case of pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally. In the case of an injection, it is administered alone or mixed with a normal replenisher such as glucose and amino acids for intravenous administration.
It is administered subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

The dose of the therapeutic agent for schizophrenia of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease, and the like. It is recommended that the daily dose should be about 0.1-10 mg / kg. In addition, it is preferable to contain 1 to 200 mg of the active ingredient in a dosage unit form.

Examples Hereinafter, production examples of the active ingredient compound of the present invention will be described as examples, followed by pharmacological test results and formulation examples.

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

Colorless needle crystals mp.110.5-111.0 ° 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. 1- (2,3
40 g of 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-dihydrocarbostyril is obtained.

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

mp214-222 ° C (decomposition) white powder (4) 7- {4- [4- (2,3-dichlorophenyl)
1.0 g of [-1-piperazinyl] butoxy} -3,4-dihydrocarbostyril 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. Add 10 ml of ethanol and 30 ml of water, heat to make a solution, recrystallize, collect the crystals by filtration, and recrystallize from ethanol-water to obtain 1.02 g of 7- {4- [4- (2,3-
Dichlorophenyl) -1-piperazinyl] butoxy}-
3,4-Dihydrocarbostyril sulfate is obtained.

mp220-225 ° C white powder (5) 7- {4- [4- (2,3-dichlorophenyl)
-1-Piperazinyl] butoxy} -3,4-dihydrocarbostyril and 1.0 mg of fumaric acid were treated in the same manner as the above sulfate, and recrystallized from ethanol to obtain 0.97 g of 7- {4- [4 -(2,3-Dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbostyril fumarate is obtained.

mp196-198 ℃ White powder (6) 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 above-mentioned sulfate and recrystallized from ethanol to give 0.98.
g of 7- {4- [4- (2,3-dichlorophenyl) -1-
[Piperazinyl] butoxy} -3,4-dihydrocarbostyril maleate.

mp 172 to 180 ° C. White powder Pharmacological test method a) Anti-apomorphine action in mice Experiments were performed with 6 mice per group. One hour after oral administration of the test compound, apomorphine (1.25 mg / kg) was subcutaneously administered, and the stereotypical behavior that occurred was determined by the method of Puech et al. (Neuropharmaco
, Vol. 20, p1279, 1981), and the anti-apomorphine effect of the test compound was examined using the score as an index. An animal was determined to have a score of 50% or less of the average score of the control group as an anti-apomorphine effect positive,
The 50% effective dose (ED ₅₀ value) was determined.

b) Anti-epinephrine lethal action in mice According to Janssen, P. et al. Arzneim. Forsch., 13 , 205 (1963), experiments were carried out with 6 mice per group. One hour after the oral administration of the test compound, a lethal dose of epinephrine (1.5 m
g / kg) was administered intravenously, and the survival of the mice 4 hours later was observed. The surviving mice were determined to have a positive anti-epinephrine lethal effect, and the 50% effective dose (ED ₅₀ value) was determined.

The results of the above test obtained using the compound (free) obtained in Example 1 (2) (referred to as compound 1 in the table) as a test compound are shown in Table 1 below.

For comparison, Table 1 also shows the results obtained by performing the same tests using the following comparative compounds and chloropromazine as a control.

Comparison No. 1: 7- {3- [4- (2-methylphenyl) -1
-Piperazinyl] propoxy] -3,4-dihydrocarbostyril (Compound of Example 143 of JP-A-55-127371) Comparative No. 2: 7- {3- [4- (2-methoxyphenyl)-
1-piperazinyl] propoxy] -3,4-dihydrocarbostyril (Example 8 in JP-A-62-149664;
46812 Example 50, JP-A-55-127371, Example 50, JP-A-55-124766, Example 50 and JP-A-54-130587
66 compound) Comparative No. 3: 7- {3- [4- (2-ethoxyphenyl)-
1-piperazinyl] propoxy] -3,4-dihydrocarbostyril (Example 44 of JP-A-56-46812, JP-A-55-1)
(Compound No. 27371, Example 44, JP-A-55-124766, Example 44 and JP-A-54-130587, Example 77) Comparative No. 4: 7- {4- [4-phenyl-1-piperazinyl] butoxy ] -3,4-Dihydrocarbostyril (JP-A-62-149664, Example 9; JP-A-56-46812, Example 5)
4, compound of Example 54 of JP-A-55-127371, Example 54 of JP-A-55-124766 and Example 71 of JP-A-54-130587) Comparative No. 5: 7- {3- [4- (3-chlorophenyl) -1
-Piperazinyl] propoxy] -3,4-dihydrocarbostyril (No. 6 of JP-A-62-135423, JP-A-62-1496)
No. 64, Example 7, JP-A-56-46812, Example 48, JP-A-55-46812
-127371 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
55-2693 compound) In Table 1, * indicates% control value after oral administration of 3 mg / kg (3 mg / kg administration does not reach 50% effective dose), and ** indicates% control after oral administration of 64 mg / kg. The value (also 50% effective dose is not reached with 64 mg / kg administration) is shown.

As shown in Table 1, the compound of the present invention exhibited an anti-apomorphine effect as an indicator of a dopamine receptor blocking effect, which is a main effect, on both of the compounds of Comparative Nos. 1 to 7 and chloropromazine as a control ( In A), it is very excellent, and the anti-epinephrine action (B), which is an index of the α-blocking action which is a side effect, is also very small, and B / A showing the selectivity of the main action is all It is clear that it is significantly superior to the comparative compound and the control compound.

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 One tablet in a conventional manner. Tablets containing the above composition therein were prepared.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP 54-130587 (JP, A) JP 55-2693 (JP, A) JP 55-127371 (JP, A) JP 55- 124766 (JP, A) JP 56-46812 (JP, A) JP 56-49361 (JP, A) JP 62-135423 (JP, A) JP 62-149664 (JP, A)

Claims (2)

(57) [Claims] (1) Expression [In the formula, R represents a 2,3-dichlorophenyl group. ] A therapeutic agent for schizophrenia comprising as an active ingredient at least one selected from the carbostyril derivatives represented by the following formulas and salts thereof. 2. The active ingredient is 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4.
-A schizophrenia therapeutic agent according to claim 1, which is dihydrocarbostyril.