JP3036789B2 - Novel heterocyclic compounds and pharmaceutical compositions - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel heterocyclic compound having excellent anti-serotonin action and anti-dopamine action, and a pharmaceutical composition containing the compound as an active ingredient.

[Conventional technology]

Conventionally, in order to treat and prevent psychiatric disorders,
Although pharmacotherapy with various psychotropic drugs, neuroactive drugs and neurotrophic drugs is widely practiced, there are few drugs that can satisfy both efficacy and safety at the same time. Safe and easy-to-use drugs that are immediate-acting, long-lasting, have novel mechanisms of action, have a distinct spectrum of efficacy, such as a broad spectrum of action, a different pattern of action from conventional drugs, There is a long-awaited need for drugs having a novel spectrum of action, etc., and also have a novel chemical structure so as to be effective not only in the acute phase but also in chronic conditions.

Recently, as a compound having an anti-serotonin action, JP-A-58-18390 discloses a 4H-pyrido [1,2-a] pyrimidin-4-one group having a 5H-thiazolo [3,2-a] pyrimidine-5-one group. ON; 5H-1,3,4-thiadiazolo [3,2-a] pyrimidin-5-one or 3,4-dihydro-2H, 6H-pyrimido [2,1-b] [1,3] thiazine-6 Disclosed are compounds attached to -one, which compounds also have antihistamine activity.

[Problems to be solved by the invention]

An object of the present invention is to provide a novel heterocyclic compound having excellent antiserotonin action and antidopamine action.

The present inventors have synthesized a large number of heterocyclic compounds, performed in vitro and in vivo screening tests to evaluate their respective anti-serotonin activity, anti-dopamine activity, and the like, and obtained a compound represented by the general formula (I). Have excellent activity and low toxicity, and have completed the present invention.

[Means for solving the problem]

The present invention relates to a compound of the formula (I) [Where m represents an integer of 1 to 3, n is zero or 1 to
X represents CH or N; Y represents CO or S; Is the formula ~ (Where R ¹ is Or represents a lower alkoxy group, R ² represents a lower alkoxycarbonyl group, R ³ represents a lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl carbonyl group, R ⁵ is a hydrogen atom, a lower alkyl group or a lower Represents an alkoxy group, R ⁶ represents a lower alkyl group, R ⁷ represents a lower alkyl group, R ⁸
Represents a lower alkyl group, R ⁹ represents a benzyl group or a hydrogen atom, R ¹⁰ represents a lower alkyl group, R ¹¹ represents a lower alkyl group, R ¹² represents a lower alkyl group, and R ¹³ represents a lower alkyl group. Represents a residue of a heterocyclic compound represented by the following formula: Is a formula, X is CH, Y is CO, n is zero and R ⁴
When R is a hydrogen atom, R ⁵ represents a lower alkoxy group].

The present invention further provides a pharmaceutical composition comprising, as an active ingredient, a compound selected from the group consisting of the novel heterocyclic compound shown above and a pharmaceutically acceptable acid addition salt thereof or a stereoisomer thereof. Offer things.

Next, Table 1 shows representative compounds included in the general formula (I) of the present invention.

The compound (I) of the present invention can be produced by the following method.

[Production method 1] Among the compounds of the present invention, general formula (I-1) (Wherein R ¹ , R ² , m, n, X and Y have the same meanings as described above)
For example, when m is 1, the compound represented by the following formula can be produced according to the following reaction formula.

That is, the present applicant reacts compound (II) and compound (III) shown in JP-A-61-65873 in the presence of a base.

Compound (III) is used in an amount of 0.5 to 10 moles, preferably 1 to 5 moles, based on Compound (II). Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, and amines such as triethylamine and pyridine. Among them, potassium carbonate is preferably used. The amount of the base to be used is 0.5 to 5 moles per mole of Compound (III), but usually 1.1 moles. One solvent is an aromatic hydrocarbon such as benzene or toluene; an alcohol such as methanol, ethanol, i-propanol or t-butanol; an ether such as ethyl ether, i-propyl ether, tetrahydrofuran or 1,4-dioxane; Ketones such as acetone and methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide and the like are used.
Usually, 2 to 50 times, preferably 3 to 50 times the amount of compound (II).
Use 10 times the amount.

The reaction is carried out at a temperature of 20 to 180 ° C, preferably 80 to 130 ° C, for a reaction time of 0.5 to 48 hours, usually 5 to 24 hours.

After the reaction, the reaction product is treated according to a conventional method, and isolated and purified by a method such as recrystallization or column chromatography to obtain the desired product.

[Production method 2] Among the compounds of the present invention, general formula (I-2) (Wherein, m, n, X and Y have the same meanings as described above), for example, when m is 3, can be produced according to the following reaction formula.

In Step A, the compound shown in JP-A-61-65873 (I
I ') is reacted with 3-amino-prol alcohol. 3-Amino-propanol is used in an amount of 0.5 to 10 times, preferably 1 to 3 times the mole of Compound (II '). Examples of the solvent include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol, i-propanol and t-butanol, dimethylformamide,
Dimethyl sulfoxide or the like is used, and it is usually used in an amount of 2 to 50 times, preferably 3 to 10 times the amount of compound (II ').

Step B is a reaction for converting the compound (IV) into a sulfonic acid ester (V) using methanesulfonyl chloride, which can be carried out by a commonly used method.

Step C involves reacting compound (V) with compound (III) in the presence of a base, and can be carried out in the same manner as in [Production method 1].

[Production method 3] Among the compounds of the present invention, general formula (I-3) (Wherein, R ³ , m, n, X and Y have the same meanings as described above), for example, when m is 1, the compound can be produced according to the following reaction formula.

In step A, the present applicant reduces compound (VI) shown in JP-A-61-50982 using a borohydride compound to synthesize compound (VII).

As the borohydride compound, sodium borohydride, sodium cyanoborohydride, or the like can be used, and it is used in an amount of 0.3 to 10 times, preferably 0.5 to 2 times the mole of Compound (VI). Examples of the solvent include alcohols such as methanol, ethanol, i-propanol and t-butanol, ethers such as ethyl ether, i-propyl ether, tetrahydrofuran and 1,4-dioxane, and ketones such as acetone and methyl isobutyl ketone. And these may be used as a mixture. These solvents are generally used in an amount of 2 to 50 times, preferably 5 to 30 times the amount of compound (VI).

The reaction is carried out at a temperature of 3 to 100 ° C, preferably 20 to 60 ° C, for a reaction time of 0.1 to 10 hours, usually 0.5 to 3 hours. After the reaction, the reaction product is treated according to a conventional method, and isolated and purified by a method such as recrystallization or column chromatography to obtain the desired product.

Step B is a reaction for converting compound (VII) into sulfonic acid ester (VIII) using methanesulfonyl chloride, and can be carried out by a method generally used.

Step C involves reacting compound (VIII) with compound (III) in the presence of a base.
Can be performed in the same manner as described above.

[Production method 4] Among the compounds of the present invention, general formula (I-4) (Wherein, R ⁴ , R ⁵ , m, n, X and Y have the same meanings as described above)
For example, when m is 2, the compound represented by the following formula can be produced according to the following reaction formula.

Compound (I-) is prepared from compound (IX) and compound (III).
Regarding the method of synthesizing 4), when R ⁴ is a hydrogen atom, R ⁵ is an alkyl group, n is zero, X is CH, and Y is CO,
No. 58-18390, when R ⁴ is a hydrogen atom or a lower alkylcarbonyl group and R ⁵ is a hydrogen atom, a lower alkoxy group or a lower alkyl group, a method similar to [Production method 1] is used. Can be manufactured. Compound (XI) which can be synthesized from compound (X) and methanesulfonyl chloride by a conventional method is compound (III) and [Preparation method
The compound (I-4) can be converted by reacting under the reaction conditions described in 1).

[Production Method 5] Among the compounds of the present invention, general formula (I-5) (Wherein R ⁶ , m, n, X and Y have the same meanings as described above), for example, when m is 2, can be produced according to the following reaction formula.

Step A involves reacting compound (XII) synthesized by reacting ethyl acetoacetate with thiourea in the presence of a base with compound (XIII) in the presence of a base.

The compound (XIII) is used in a molar amount of 1 to 2 times, preferably 1 to 1.5 times the molar amount of the compound (XII). Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, and amines such as triethylamine and pyridine. Among them, potassium carbonate is preferably used. The amount of the base to be used is 0.5 to 5 moles per 1 mole of Compound (XII), but it is usually 1.1 moles. Examples of the solvent include water, alcohols such as methanol, ethanol, i-propanol and t-butanol, ethers such as ethyl ether, i-propyl ether, tetrahydrofuran and 1,4-dioxane, and acetone and methyl isobutyl ketone. Ketones, dimethylformamide, dimethylsulfoxide and the like are used, and these may be used as a mixture. Usually, 2 to 50 times the amount of the compound (XII), preferably 3 to 10 times
Use twice as much. The reaction temperature is 20 to 120 ° C, preferably 40 to 1
The reaction is carried out at 00 ° C. for a reaction time of 1 to 24 hours, usually 3 to 10 hours. After completion of the reaction, post-treatment is carried out by a conventional method, and the desired product (XIV) can be isolated by recrystallization, silica gel column chromatography or the like.

Step B is a reaction for converting the compound (XIV) into a sulfonic acid ester (XV) using methanesulfonyl chloride, and can be carried out by a commonly used method. Step C is for reacting the compound (XV) with the compound (III) and can be performed under the reaction conditions described in [Production method 1].

[Production method 6] Among the compounds of the present invention, general formula (I-6) (Wherein R ⁷ , m, n, X and Y have the same meanings as described above), for example, when m is 2, can be synthesized according to the following reaction formula.

Step A involves reacting ethyl 2-cyclohexanonecarboxylate (XVI) with compound (XVII) in the presence of a base.

Compound (XVII) is used 1 to 3 times, preferably 1 to 1.5 times, the moles of compound (XVI). As the base, hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, sodium ethoxide, potassium t-
Alkoxides of alkali metals such as butoxide, alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, and amines such as triethylamine and pyridine can be used. Among them, potassium t-butoxide is preferably used. . The amount of the base to be used is 0.5 to 5 moles per mole of Compound (XVI), but is usually 1 to 2 moles.
Used twice as much. Examples of the solvent include aromatic hydrocarbons such as benzene and toluene; alcohols such as methanol, ethanol, i-propanol and t-butanol; and ethers such as ethyl ether, i-propyl ether, tetrahydrofuran and 1,4-dioxane. And ketones such as acetone and methyl isobutyl ketone, dimethylformamide, dimethylsulfoxide and the like, which are usually used in 2 to 50 times, preferably 3 to 10 times the amount of compound (XVI).

The reaction is carried out at a temperature of 20 to 180 ° C, preferably 80 to 130 ° C, for a reaction time of 0.5 to 48 hours, usually 5 to 24 hours.

Step B comprises compound (XVIII) and 1-chloro-2-
The compound (XI) is reacted with bromoethane in the presence of a base.
X).

1-Chloro-2-bromoethane is used in an amount of 1 to 10 times, preferably 2 to 5 times the moles of the compound (XVIII). As the base, sodium hydride, potassium t-butoxide, potassium carbonate, triethylamine and the like can be used, and among them, sodium hydride is preferable.

The amount of the base to be used is 0.5 to 10-fold the molar amount of compound (XVIII), but usually it is 1 to 5-fold the molar amount. Examples of the solvent include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol, i-propanol and t-butanol, ethyl ether, i-propyl ether,
Ethers such as tetrahydrofuran and 1,4-dioxane, ketones such as acetone and methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide and the like are used, and usually 2 to 50 times, preferably 3 to 50 times the amount of compound (XVIII). Use 10 times the amount.

The reaction is carried out at a temperature of 20 to 180 ° C, preferably 80 to 130 ° C, for a reaction time of 0.5 to 48 hours, usually 5 to 24 hours.

Step C involves reacting compound (XIX) with compound (III) and can be carried out in the same manner as in [Production method 1].

[Production method 7] Among compounds of the present invention, general formula (I-7) (Wherein R ⁸ , m, n, X and Y have the same meanings as described above), for example, when m is 2, can be synthesized according to the following reaction formula.

Step A is a reaction in which compound (XX) is reacted with 1-chloro-2-bromoethane in the presence of a base to obtain compound (XXI), and can be performed in the same manner as in step B of [Production method 6]. . Step B involves reacting compound (XXI) with compound (III), and can be carried out in the same manner as in [Production method 1].

[Production method 8] Among the compounds of the present invention, general formula (I-8) (Wherein R ⁹ , m, n, X and Y have the same meanings as described above), for example, when m is 2, can be synthesized according to the following reaction formula.

Step A comprises reacting compound (XXII) with formamidine hydrochloride in the presence of potassium carbonate to form compound (XXII)
This is the reaction to obtain I). Step B comprises compound (XXIII)
And 1-chloro-2-bromoethane in the presence of a base to obtain a compound (XXIV), which can be carried out in the same manner as in Step B of [Production method 6]. Step C involves reacting compound (XXIV) with compound (III), and can be carried out in the same manner as in [Production method 1].

[Production method 9] Among the compounds of the present invention, general formula (I-9) (Where m, n, X and Y have the same meanings as described above), for example, when m is 2, can be synthesized according to the following reaction formula.

Step A comprises reacting compound (X) with 2-bromoethanol in the presence of potassium carbonate to form compound (XXV)
This is a reaction to synthesize Step B is for compound (XXV)
Is reacted in an aqueous HBr solution to synthesize compound (XXVI). Step C is a reaction for reacting compound (XXVI) with tetrahydroisoquinoline in the presence of a base to synthesize compound (I-9). The reaction can be carried out in the same manner as in [Production method 1].

[Production method 10] Among the compounds of the present invention, general formula (I-10) (Wherein, R ¹⁰ , m, n, X and Y have the same meanings as described above), for example, when m is 2, can be synthesized according to the following reaction formula.

Step A comprises 2-alkylphthalazide (XXVII)
1,2-dihalogenoethane (XXVIII) is reacted in the presence of a base. Compound (XVIII) is compound (XXVI)
It is used in an amount of 1 to 50 times, preferably 1.5 to 20 times the mole of I). Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and triethylamine and pyridine. Of these, potassium carbonate is preferably used. The amount of the base used is the amount of the compound (XXVI
It is 0.5 to 5 moles compared to I), but is usually used at 1 to 2 moles. Solvents include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol, isopropanol and t-butanol, ethers such as ethyl ether, isopropyl ether, THF and 1,4-dioxane, acetone and methyl isobutyl ketone. And the like, or DMF, DMSO or the like is used, and is usually 1 to 50 times by weight, preferably 3 to 2 times, the weight of the compound (XXVII).
Use 0 weight times. The reaction temperature is 0 to 180 ° C, preferably 50
At ~ 120 ° C, the reaction time is 5 minutes to 10 hours, usually 15 minutes to 2 hours.
Let react for hours.

Step B involves reacting compound (XXIV) with compound (III), and can be carried out in the same manner as in [Production method 1].

[Production method 11] Among the compounds of the present invention, general formula (I-11) (Wherein R ¹¹ , m, n, X and Y have the same meanings as described above), for example, when m is 2, can be synthesized according to the following reaction formula.

Step A involves reacting phthalic anhydride (XXX) with 2-hydroxyethylhydrazine (XXXI). Compound (XXXI) is 0.8 to 5 times the molar amount of compound (XXX),
Preferably, it is used in an amount of 1 to 2 moles. Solvents include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol, isopropanol and t-butanol, ethyl ether, isopropyl ether and TH.
Ethers such as F, 1,4-dioxane, or DMF, DMS
O or the like is used, and it is usually used 1 to 50 times by weight, preferably 3 to 20 times by weight relative to compound (XXX). The reaction temperature is-
10 to 180 ° C, preferably 20 to 100 ° C, and the reaction time is 5 minutes to
The reaction is carried out for 10 hours, usually 15 minutes to 2 hours.

Step B involves reacting 2- (2-hydroxyethyl) phthalazide (XXXII) with an alkylating agent in the presence of a base. Examples of the alkylating agent include alkyl halides such as methyl chloride, methyl bromide, methyl iodide, ethyl bromide, and ethyl iodide, and dialkyl sulfates such as dimethyl sulfate and diethyl sulfate. It is 0.8 to 20 times, preferably 1 to 5 times the mole of (XXXII). Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Of which potassium carbonate is preferred.
The amount of the base to be used is 0.5 to 5 moles per 1 mole of Compound (XXXII), but it is usually 1 to 2 moles. As the solvent, aromatic hydrocarbons such as benzene and toluene, ethers such as ethyl ether and isopropyl ether, THF and 1,4-dioxane, ketones such as acetone and methyl isobutyl ketone, and DMF and DMSO are used. Usually 1 to 50 times by weight, preferably 3 times, the weight of the compound (XXXII)
Use up to 20 times the weight.

The reaction temperature is 0 to 180 ° C, preferably 50 to 140 ° C, and the reaction time is 30 minutes to 10 hours, usually 1 hour to 5 hours.

Step C is 4-alkoxy-2- (2-hydroxyethyl) -1,2-dihydrophthalazin-1-one (XXXII
This is the halogenation reaction of I). As the halogenating agent, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfuryl chloride and the like can be used. The amount of the halogenating agent to be used is 0.8 to 10-fold mol, preferably 1-fold mol, relative to compound (XXXIII).
５5 times mol. Hexane, heptane,
Aliphatic hydrocarbons such as decane, aromatic hydrocarbons such as benzene and toluene, ethers such as ethyl ether, isopropyl ether, THF and 1,4-dioxane, and ketones such as acetone and methyl isobutyl ketone are used. Usually, it is used 1 to 50 times by weight, preferably 3 to 20 times by weight, relative to compound (XXXIII). Reaction temperature is -10
~ 100 ° C, preferably 10 ~ 80 ° C, reaction time is 30 minutes ~ 10
The reaction is carried out for an hour, usually 1 hour to 5 hours.

Step D is a step of reacting compound (XXXIV) with compound (III), and can be performed in the same manner as in [Production method 1].

As is evident from the general formula (I), the compounds of the present invention have optical isomers, and the present invention encompasses all of them and can be used by separating or isolating the isomers as required, and It can also be used as an acceptable acid addition salt.

The present invention is based on the finding that the compound represented by the general formula (I) has excellent anti-serotonin action, anti-dopamine action, neurite outgrowth action and the like.

Accordingly, compounds of formula (I) are useful for treating diseases caused by or involving serotonin and dopamine, for example,
Schizophrenia, sickness, depression, delirium, anxiety, epilepsy,
Psychiatric diseases such as Parkinson's disease and dementia, or neurological diseases such as central or peripheral neuropathy, such as various neuropsychiatric diseases and hypertension, arrhythmia, angina, allergy, asthma, migraine, gastrointestinal disorders, platelet coagulation It is expected to be useful as an agent for treating and preventing various diseases such as insufficiency.

The compound of the general formula (I) is usually used in the form of a pharmaceutical composition and is orally, subcutaneously, intramuscularly, intravenously, intraduodenal, intranasally,
It is administered by various routes, such as the ophthalmic, sublingual, skin permeation and rectal routes.

The present invention includes a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound of the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutically acceptable salts include, for example, acid addition salts.

Examples of the pharmaceutically acceptable salts of the general formula (I) include, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, oxalate, and maleate Acid salts,
Fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, sugar, cyclohexylsulfamate, methanesulfonate, p-toluenesulfonate, naphthalene Includes salts formed from acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions such as sulfonates or hydrates thereof.

Examples of the quaternary ammonium salt include salts of an alkyl halide and a compound of the general formula (I).

Pharmaceutical compositions of the present invention include, for example, tablets, capsules, powders, granules, troches, sublingual tablets, cachets, elixirs,
Emulsions, solutions, syrups, suspensions, aerosols, ointments,
It can be in the form of eye drops, sterile syringes, molded paps, tapes, soft and hard gelatin capsules, suppositories and sterile packaged powders. Examples of pharmaceutically acceptable carriers include lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, acacia, calcium phosphate, alginate, calcium silicate, calcium sulfate, microcrystalline cellulose, polyvinylpyrrolidone, tragacanth gum, Gelatin, syrup, methylcellulose, carboxymethylcellulose, sodium benzoate, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, water or mineral oil, injectable peanut oil, and more Suppository bases such as glyceride;

Either solid or liquid compositions can contain fillers, binders, lubricants, wetting agents, disintegrating agents, emulsions and suspending agents, preservatives, sweetening or flavoring agents and the like, as described above. The compositions may also be formulated so that the active ingredient is released rapidly, sustained or delayed after administration to the patient.

For oral administration, the compounds of general formula (I) are mixed with carriers and diluents and formed into tablets, capsules and the like. For parenteral administration, the active ingredient is dissolved in 10% aqueous glucose solution, isotonic saline, sterile water or similar liquids, and administered in a vial or ampoule for intravenous infusion or injection or by intramuscular injection. Sealed. Advantageously, solubilizing agents and local anesthetics, preservatives and buffers can also be included in the vehicle. To increase stability, the composition can be lyophilized after injection into a vial or ampoule. In other cases of parenteral administration, there are preparations for transdermal administration as ointments and cataplasms. In this case, a molded pulp or a tape is advantageous.

The compositions may contain from 1 μg to 1 g, more usually 10 μg to 500 mg, of the active ingredient per unit dosage form.

The compounds of general formula (I) are effective over a wide dosage range. For example, the daily dose is usually 0.1 μg
/ kg to 100mg / kg. The actual amount of compound administered will depend on the compound being administered, as well as the age, weight, and response of the individual patient, the severity of the patient's condition (eg, in the case of central nervous system disease or hypertension, the degree of previous symptoms, etc.), and It is determined by the doctor and veterinarian depending on the route and the like. Accordingly, the above dosage ranges do not limit the scope of the invention. The appropriate number of times of administration per day is 1 to 6, usually 1 to 4 times.

The pharmaceutical composition of the present invention can be administered, if necessary, in combination with one or more other same drugs. Such additional agents include, for example, haloperidol, butyrophenone, thiothixene, sulpiride, sultprid, zotepine, thioridazine hydrochloride, lithium carbonate, chlorpromazine, fluphenazine hydrochloride, oxypertin,
Clothiapine, spiperone, chlorprothixen, timiperone, hydroxyzine hydrochloride, pimozide, bromperidol, perphenazine, carpipramine maleate, carpipramine hydrochloride, clocapramine hydrochloride, imipramine, desipramine, amitriptyline, nortriptyline, amoxapine, doxepin, maprotiline, maprotiline, maprotiline , Viloxazine, L-5-HT
P, pipamperon, etizolam, lofuepramine, trimipramine, diazepam, medazepam, lorazepam, flutazolam, clothazepam, promazepam, mexazolam, chlordiazepoxide, cloxazolam, oxazolam, alprazolam, calcium hopatenate, lisulido-aminoacetate, β-lactam, piracetam, piracetam, piracetam , Fevalbamate, idebenone, tiapride, biphemeran, phenytoin, barbituric acid preparations, clonazepam, valproic acid, amantadine preparations,
Psychotropic and neuropathic drugs such as biperiden, mecobalamin and ganglioside preparations, as well as nifedipine, nicardipine, nimodipine, pindolol, propranolol,
Formulations such as methyldopa, prazosin, disopyramide, aplindine and ketotifen are exemplified.

Examples are shown below to explain the production method of the compound of the present invention and the preparation method of the pharmaceutical composition according to the compound.

Example 1 4- {4- (4-fluorobenzoyl) -1-piperidinomethyl} -2- (4-benzylpiperazino) pyrimidine-5-carboxylic acid ethyl ester (Compound No. 100)
2.0 g (5.3 mmol) of 4-chloromethyl-2- (4-benzylpiperazino) pyrimidine-5-carboxylic acid ethyl ester synthesized by the method described in JP-A-61-65873.
And (4-fluorobenzoyl) -1-piperidine hydrobromide 1.5 g (5.3 mmol), and potassium carbonate 0.7
3 g (5.3 mmol) was added to 50 ml of methyl isobutyl ketone, and the mixture was heated under reflux for 20 hours. After completion of the reaction, the solid was removed by filtration under reduced pressure, the filtrate was concentrated under reduced pressure, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (developing solvent: methylene chloride / methanol = 40/1). This gave 2.30 g of the desired product as an oil. (Yield: 80%).

Hereinafter, the compounds shown in Table 2 were synthesized in the same manner, and the spectrum data was also described.

Example 2 6- {4- (4-Fluorobenzoyl) -1-piperidinomethyl} -2- (4-benzylpiperazino) -5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d Production of Pyrimidine (Compound No. 102) 2.0 g (5.3 g) of 4-chloromethyl-2- (4-benzylpiperazino) pyrimidine-5-carboxylic acid ethyl ester synthesized by the method described in JP-A-61-65873. Mmol)
And 0.48 g (6.4 mmol) of 3-aminopropanol were added to 300 ml of ethanol, and the mixture was heated under reflux for 4 hours. After the reaction, ethanol was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: chloroform / methanol = 30/1) to give 6- (hydroxypropyl) -2- (4-benzyl) as an intermediate. Piperazino) -5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine was synthesized (yield 0.70 g).

0.5 g (1.4 mmol) of this intermediate, 0.2 g (1.7 mmol) of methanesulfonyl chloride, 0.5 g of triethylamine
(5.0 mmol) was stirred in 50 ml of THF at −70 ° C. for 10 minutes, then heated to room temperature, and stirred for 30 minutes. When the reaction solution became yellow, 1.5 g (5 mmol) of 4- (fluorobenzoyl) -1-piperidine hydrobromide was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure,
The residue was separated and purified by silica gel column chromatography (developing solvent: chloroform-ethyl acetate) to obtain 0.3 g of the desired product as a solid (yield: 42%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.60 to 2.20 (8H, m), 2.20 to 2.64 (6H, m), 2.80 to 3.30
(3H, m), 3.40 ~ 3.72 (4H, m), 3.92 (4H, t, J = 7Hz), 4.
20 (2H, s), 7.12 (2H, dd, J = 7Hz), 7.32 (5H, s), 7.92
(2H, dd, J = 7 Hz), 8.64 (1H, s) Example 3 5,6-dihydro-8- {4- (4-fluorobenzoyl) -1-piperidinomethyl} -6-methyl-2- (4
-Benzylpiperazino) -5-oxo-pyrido [4,3-
d] Production of pyrimidine (Compound No. 104) 5,6-Dihydro-6-methyl-2- (4-benzylpiperazino)-synthesized by the method described in JP-A-61-50982.
Dissolve 2.8 g of 5-oxo-pyrido [4,3-d] pyrimidine-8-carbaldehyde in 50 ml of methanol and 100 ml of THF,
2.0 g of sodium borohydride was added, and the mixture was stirred at 40 ° C for 10 minutes.

After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and after removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (developing solvent: acetone / hexane = 1/4) to be an intermediate.
5,6-dihydro-8-hydroxymethyl-6-methyl-
2.3 g of solid 2- (4-benzylpiperazino) -5-oxo-pyrido [4,3-d] pyrimidine were obtained.

0.5 g of this intermediate was converted to methanesulfonic acid ester in the same manner as in Example 2 to give (4-fluorobenzoyl) -1
-Reaction with piperidine hydrobromide afforded 0.35 g of the desired product as a white solid (yield: 48%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.60 to 1.96 (4H, m), 2.28 to 2.70 (7H, m), 2.68 to 3.22
(6H, m), 3.38-3.70 (4H, m), 3.72-4.08 (4H, t, J = 4H
z), 7.10 (2H, dd, J = 7Hz), 7.28 (5H, s), 7.92 (2H, dd,
J = 7 Hz), 8.78 (1H, s) Example 4 6- [2- {4- (4-Fluorobenzoyl) -1-piperazinyl} ethyl] -2,3-dihydro-7-methyl-5
Preparation of H-thiazolo- [3,2-a] pyrimidin-5-one (Compound No. 200) 1.0 g of 4- (4-fluorobenzoyl) -1-formylpiperazine was added to 45 ml of methanol and 5 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature. For 10 hours. After completion of the reaction, the mixture was made alkaline with an aqueous sodium hydroxide solution (3N) and extracted with ethyl acetate.
The ethyl acetate layer was dried over anhydrous sodium sulfate, and the sodium sulfate was filtered. The solvent was distilled off from the filtrate under reduced pressure to obtain 0.8 g of 4- (4-fluorobenzoyl) -1-piperazine (yield: 91%).

4- (4-fluorobenzoyl) -1-piperazine 1.
0-g (5.6 mmol), 6- (2-bromoethyl) -2,3 synthesized by a method similar to that described in JP-A-58-18390.
-Dihydro-7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one 1.69 g (6.1 mmol), potassium carbonate 4.0 (g) (29 mmol), potassium iodide 0.3 (g)
Was added to 60 ml of methyl isobutyl ketone, and the mixture was refluxed for 14 hours.

After completion of the reaction, post-treatment and purification were conducted in the same manner as in JP-A-58-18390 to obtain 1.2 g of the desired product as a solid (yield: 53
%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 2.20 (3H, s ), 2.32~2.76 (8H, m), 3.30~3.72 (6H,
m), 4.34 (2H, t, J = 7 Hz), 7.18 to 7.60 (4H, m) Example 5 6- [2- {4- (4-fluorobenzoyl) -1-piperidinyl} ethyl] -2,3 Preparation of -dihydro-7-methoxy-5H-thiazolo- [3,2-a] pyrimidin-5-one (Compound No. 208) 2-oxo-3-ethoxycarbonyl-tetrahydrofuran 1.58 g (10 mmol), 2-amino Dissolve 1.53 g (15 mmol) of -4,5-dihydro-thiazole and 1.12 g (10 mmol) of potassium t-butoxide in 15 ml of DMF, and add
For 2 hours. After the temperature of the reaction solution was lowered to room temperature, 1.5 ml of methyl iodide was added, and the mixture was heated at 60 ° C. for 30 minutes. After completion of the reaction, the reaction solution was poured into 30 ml of water and extracted three times with 20 ml of chloroform. The chloroform layer was dried over magnesium sulfate to remove magnesium sulfate, and the filtrate was concentrated. The residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol = 5/1).
0.17 g of the intermediate 6-hydroxyethyl-2,3-dihydro-7-methoxy-5H-thiazolo- [3,2, a] pyrimidin-5-one was obtained.

0.29 g (1.27 mmol) of the intermediate thus obtained and 0.26 g (2.54 mmol) of triethylamine were dissolved in 3 ml of methylene chloride and stirred under ice-cooling.

0.29 g (1.9%) of methanesulfonyl chloride was added to this solution.
2 mmol of methylene chloride solution was added dropwise over 10 minutes.
Stir for 1 hour. After the temperature was raised to room temperature and stirred for 1 hour, the mixture was washed successively with 10 ml of a 5% hydrochloric acid solution and 10 ml of a saturated aqueous solution of sodium bicarbonate, and the methylene chloride layer was dried over magnesium sulfate. After magnesium sulfate was filtered, methylene chloride was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing dissolution: ethyl acetate) to obtain an intermediate 6-methanesulfonylethyl-.
2,3-dihydro-7-methoxy-5H-thiazolo- [3,2,
a] Pyrimidin-5-one (0.23 g, yield: 59%) was obtained.

0.23 g (0.75 mmol) of this intermediate, 0.29 g of 4- (4-fluorobenzoyl) -1-piperidine hydrobromide
(1.0 mmol), potassium carbonate 0.28 g (2.0 mmol)
Was reacted in 4 ml of DMF at 80 ° C. for 4 hours.

After completion of the reaction, pour the reaction solution into 50 ml of water, and add
Extracted twice with ml. The ethyl acetate layer is dried by a conventional method, concentrated under reduced pressure, separated and purified by silica gel column chromatography (developing solvent: methylene chloride / methanol = 30/1), and the target substance is converted to an amorphous solid by 0.27%.
g (yield: 86%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.78~2.00 (4H, m ), 2.08~2.36 (2H, m), 2.40~2.80
(4H, m), 2.88-3.26 (3H, m), 3.44 (2H, t, J = 7Hz), 3.
88 (3H, s), 4.44 (2H, t, J = 7Hz), 7.12 (2H, dd, J = 7H
z), 7.98 (2H, dd, J = 7Hz) Example 6 6- [2- {4- (4-fluorobenzoyl) thio-1
Synthesis of -piperazinyl {ethyl] -3-acetyl-2,3-dihydro-7-methyl-5H-thiazolo- [3,2, a] pyrimidin-5-one (Compound No. 210) 3,4-dichloro-2 While cooling 25 ml of an ethanol solution of 2.82 g (20 mmol) of -oxo-butane under cooling with ice, 5 ml of an ethanol solution of 2.13 g of triethylamine was added dropwise over 1 hour. 3.72 g (20 mmol) of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol and 5.53 g (40 mmol) of potassium carbonate were added to this solution,
The reaction was performed for 10 hours under ice cooling, the temperature was raised to room temperature, and the reaction was further performed for 10 hours.

After the completion of the reaction, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. A 50 ml solution of ethyl acetate / ethanol = 4/1 was added to 4.97 g of the obtained viscous liquid, followed by recrystallization, whereby 2.81 g of a solid was obtained. The mother liquor was further concentrated under reduced pressure, and recrystallized in the same manner to give 0.4 g of a solid. A total of 3.30 g (yield 65%) of the intermediate, 3-acetyl-6- (hydroxyethyl)- 2,3-dihydro-7
-Methyl-5H-thiazolo- [3,2, a] pyrimidine-5
On was obtained.

Using 2.54 g (10 mmol) of this intermediate, 1.37 g (12 mmol) of triethylamine, and 1.37 g (12 mmol) of methanesulfonyl chloride, the intermediate 3-acetyl-6-methanesulfonylethyl- was obtained in the same manner as in Example 5.
2,3-dihydro-7-methyl-5H-thiazolo- [3,2, a]
2.95 g of pyrimidin-5-one (96% yield) were obtained.

0.50 g (1.6 mmol) of this intermediate, 0.44 g (2.1 mmol) of 4-{(4-fluorobenzene) thio} -1-piperidine, and potassium carbonate (4.3 mmol) were dissolved in 8 ml of DMF. 0.10g of reaction, post-treatment and target substance
(Yield: 14%) was obtained. ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.70 to 2.12 (4H, m), 2.12 (6H, s), 2.48 to 2.90 (5H,
m), 2.90-3.30 (4H, m), 3.42 (1H, dd, J = 5Hz), 3.70
(1H, t, J = 7Hz), 5.38 (1H, dd, J = 5Hz), 7.14 (2H, t, J
= 7 Hz), 7.92 (2H, dd, J = 7 Hz) Example 7 6- [2- {4- (4-fluorobenzene) thio-1-]
Production of piperazinyldiethyl] -2,3-dihydro-5H-thiazolo [3,2, a] pyrimidin-5-one (Compound No. 212) 5 g (58 mmol) of γ-butyrolactone, ethyl formate 4.
100 ml of a dry diethyl ether solution of 3 g (58 mmol)
0% sodium hydride (2.44 g, 61 mmol) in a dry diethyl ether suspension was added dropwise at room temperature for 1 hour.
Stir for 30 minutes.

After completion of the reaction, the precipitated solid was collected by filtration and washed with 30 ml of diethyl ether to obtain 4.72 g (yield 57%) of a sodium salt.

2.0 g (14.2 mmol) of this sodium salt and 0.78 g (7.0 mmol) of potassium t-butoxide were suspended in 20 ml of ethanol, and 1.18 g (15.5 mmol) of thiourea was added at room temperature and stirred for 30 minutes.

The mixture was further heated under reflux for 2 hours, cooled to room temperature, and then the solvent in the reaction solution was distilled off under reduced pressure. The residue is water 50ml
And 3N hydrochloric acid was added dropwise under ice-cooling to make it slightly acidic. Since a solid was precipitated, the crystal was filtered, washed with water, and dried under reduced pressure to obtain 0.75 g (yield 31%) of an intermediate 4-hydroxy-2-mercapto-5-pyrimidine ethanol.

1.71 g of this intermediate was reacted with dibromoethane by the method described in JP-A-58-18390, and then the hydroxyl group was brominated with hydrobromic acid to give 6- (2-bromoethyl)-.
2,3-dihydro-5H-thiazolo- [3,2, a] pyrimidine-
1.42 g (42% yield) of 5-one hydrobromide was obtained.

This 6- (2-bromoethyl) -2,3-dihydro-5H
-Thiazolo- [3,2, a] pyrimidin-5-one hydrobromide 0.50 g (1.5 mmol), (4-fluorobenzene)
0.31 g (1.5 mmol) of thio-1-piperidine, 0.10 g (5.8 mmol) of potassium iodide and 0.40 g (2.9 mmol) of potassium carbonate were added to 50 ml of methyl isobutyl ketone, and the reaction and post-treatment were carried out in the same manner as in Example 4. Thereafter, 0.5 g of the desired product (yield 87
%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.60~2.20 (4H, m ), 2.60 (4H, s), 2.80~3.24 (5H,
m), 3.48 (2H, t, J = 7 Hz), 4.48 (2H, t, J = 7 Hz), 7.00
(2H, dd, J = 7Hz), 7.40 (2H, dd, J = 7Hz), 7.64 (1H, s) Example 8 3- [2- {4- (4-fluorobenzoyl) -1-piperidinyl} ethyl -6-methyl-2,3-dihydro-5
Preparation of H-thiazolo [3,2, a] pyrimidin-5-one (Compound No. 206) 1, which was synthesized by reacting 3,4-dibromo-butan-1-ol with acetic anhydride in the presence of a sulfuric acid catalyst. Acetoxy-3,4-dibromobutane 7.25 g (25 mmol),
3.51 g (25 mmol) of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidine, 3.12 g of potassium carbonate (23
(Mmol) was stirred in 31 ml of DMF at 60 ° C for 7 hours. After completion of the reaction, DMF was distilled off, 30 ml of water was added, and acetic acid was added dropwise to adjust the pH to 7.

The obtained aqueous solution was extracted twice with 50 ml of ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After the sodium sulfate was removed from the ethyl acetate layer by filtration, ethyl acetate was distilled off under reduced pressure.

The obtained residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/1 → ethyl acetate) to obtain an intermediate 3- (2-acetoxyethyl) -6-methyl-2. , 3-Dihydro-5H-thiazolo [3,
2,3] pyrimidin-5-one (3.63 g, yield 54%) was obtained.

0.1 g of the obtained intermediate was heated and refluxed with 9 times the amount of 48% hydrobromic acid to give intermediate 3- (2-bromoethyl)-.
It was converted to 6-methyl-2,3-dihydro-5H-thiazolo [3,2, a] pyrimidin-5-one (yield 0.78 g, 73
%).

3- (2-bromoethyl) -6-methyl-2,3-dihydro-5H-thiazolo [3,2, a] pyrimidin-5-one 0.7
8 g (2.8 mmol), 4- (4-fluorobenzoyl)
-1-piperidine 0.66 g (2.3 mmol), potassium carbonate
1.59 g (11.6 mmol) and 0.05 g of potassium iodide were heated and refluxed in 40 ml of methyl isobutyl ketone for 8 hours.

After completion of the reaction, 50 ml of water was added, and the mixture was extracted three times with 50 ml of chloroform. The chloroform layer is dried and concentrated by a conventional method, and then subjected to silica gel column chromatography (developing solvent:
Separation and purification were performed using ethyl acetate / methanol = 20/3) to obtain 0.05 g (yield 6%) of the desired product. ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.40 to 2.16 (8H, m), 2.20 (3H, s), 2.48 (2H, t, J = 7H
z), 2.66-3.14 (3H, m), 3.28 (1H, d, J = 10Hz), 3.66
(1H, dd, J = 10Hz), 5.10 (1H, q, J = 7Hz), 5.96 (1H,
s), 7.00 (2H, dd, J = 7 Hz), 7.40 (2H, dd, J = 7 Hz) Example 9 3- [2- {4- (4-fluorobenzoyl) -1-piperidinyl} ethyl] -2 -Methyl-4-one-3,4,5,
Preparation of 6,7,8-hexahydroquinazoline (Compound No. 300) 16.1 g (170 mmol) of acetamidine hydrochloride, 38.17 g (340 mmol) of potassium t-bitoxylate in ethanol 500
ml and stirred at room temperature. To this solution, 29 g (170 mmol) of ethyl 2-oxo-cyclohexanecarboxylate was added dropwise at room temperature, and after completion of the addition, the mixture was refluxed for 5 hours. After completion of the reaction, 300 ml of ethanol was distilled off under reduced pressure, 200 ml of water was added, the mixture was acidified with 3N HCl, and extracted with 300 ml of chloroform. The aqueous layer was further extracted with 300 ml of chloroform, and the combined chloroform layers were dried over magnesium sulfate. After removing the magnesium sulfate, the chloroform layer was concentrated to give the intermediate 2-methyl-4-one-3,4,5,
18.5 g (66% yield) of 6,7,8-hexahydroquinazoline was obtained.

A solution of 25.0 g (152 mmol) of this intermediate and 200 ml of dimethyl sulfoxide was added to 1-chloro-2-bromo-ethane 100
g (697 mmol) and 6.1 g (153 mmol) of 60% sodium hydride were added dropwise over 30 minutes under ice-cooling and stirred for 1 hour. After the temperature was raised to room temperature, 100 ml of water and 200 ml of methylene chloride were added, the methylene chloride layer was separated, and the methylene chloride layer was dried over magnesium sulfate. After removing magnesium sulfate, methylene chloride was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol = 30/1) to give intermediate 3- {2- ( 1-chloro) ethyl {-2-methyl-4-
7.5 g (22% yield) of on-hexahydroquinazoline was obtained.

1.0 g (4.4 mmol) of this intermediate, 1.2 g of 4- (4-fluorobenzoyl) -1-piperidine hydrobromide (4.
4 mmol), 1.22 g (8.8 mmol) of potassium carbonate, 0.15 g of potassium iodide and 50 ml of methyl isobutyl ketone in the same manner as in Example 8, and 0.65 g (yield: 37.2%) of the target compound by post-treatment. Obtained. ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.50 to 2.10 (8H, m), 2.10 to 2.40 (3H, m), 2.40 to 2.88
(8H, m), 2.90-3.38 (3H, m), 4.14 (2H, t, J = 7Hz), 7.
16 (2H, dd, J = 7 Hz), 8.00 (2H, dd, J = 7 Hz) Example 10 3- [2- {4- (4-fluorobenzoyl) -1-piperidinyl} ethyl] -2-methyl- 4-one-3,4-
Production of dihydroquinazoline (Compound No. 304) 89 mg (0.72 mmol) of ethylacetoimidate hydrochloride and 0.1 g (0.72 mmol) of potassium carbonate in methanol
The mixture was added to 10 ml and stirred at room temperature for 30 minutes. To this solution was added 0.1 g (0.72 mmol) of a 2-amino acid benzoic acid, and the mixture was stirred at room temperature for 6 hours and reacted at 70 ° C. for 7 hours. After completion of the reaction, methanol was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / methanol =
20/1), and the intermediate 2-methyl-4-one-3,
0.06 g (yield: 52%) of 4-dihydroquinazoline was obtained.

This intermediate was chlorethylated and reacted with 4- (4-fluorobenzoyl) -1-piperazine hydrobromide according to the method described in Example 9 to synthesize the desired compound (yield). 58%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.60~2.00 (4H, m ), 2.08~2.44 (2H, m), 2.72 (3H,
s), 2.72 (2H, t, J = 7 Hz), 2.88 to 3.36 (3H, m), 4.24 (2
H, t, J = 7Hz), 7.12 (2H, dd, J = 7Hz), 7.30-7.78 (4H,
m), 7.96 (2H, dd, J = 7 Hz), 8.22 (1H, d, J = 7 Hz) Compounds 302, 306, 308, 309, 310, and 312 were synthesized in the same manner. Table 3 summarizes the spectral data.

Example 11 6- (2- (4- (4-fluorophenylthio) -1-)
Piperidino) ethyl) -2,3-dihydro-7-methyl-5
Production of H-thiazolo [3.2.a] pyrimidin-5-one (Compound No. 202) 3.4 g of 4-chloro-1-methylpiperidine hydrochloride (20 mm
ol), 2.56 g of 4-fluorophenylmercaptan (20 mmo
l), a mixture of 6.07 g (44 mmol) of potassium carbonate and 20 ml of DMF were stirred at 100 ° C. for 4 hours. 100g of ice water plus 1N-NaO
After adjusting the pH to 12 with H, the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. By molecular distillation of the residue, 4- (4
3.58 g of -fluorophenylthio) -1-methylpiperidine was obtained as a pale yellow oil (bp 135-145 ° C / 7mmH
g).

A mixed solution of 2.58 g (23.8 mmol) of ethyl chloroformate and 3 ml of toluene was added dropwise to a mixed solution of 3.54 g (15.8 mmol) of 4- (4-fluorophenylthio) -1-methylpiperidine and 30 ml of toluene at room temperature. Heated to reflux for an hour. After allowing to cool, the mixture was added to 50 ml of aqueous sodium bicarbonate and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography to give 1-ethoxycarbonyl-4- (4-
0.97 g of (fluorophenylthio) piperidine was obtained as a colorless oil.

A mixture of 0.97 g (3.4 mmol) of 1-ethoxycarbonyl-4- (4-fluorophenylthio) piperidine and 5 ml of 47% aqueous HBr was stirred at 130 ° C for 3 hours. After cooling, the mixture was added to 100 g of ice water, adjusted to pH 12 with 1N-NaOH, and extracted twice with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated to obtain 0.66 g of 4- (4-fluorophenylthio) piperidine as a colorless oil.

In the same manner as in Example 1, 6- (2-bromoethyl)
-2,3-dihydro-7-methyl-5H-thiazolo [3.2.a]
Pyrimidin-5-one hydrobromide 1.1 g (3.1 mmol) and 4- (4-fluorophenylthio) piperidine 0.66
g (3.0 mmol) to give 0.83 g of the desired product
Was obtained (60% yield). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.52 to 2.15 (6H, m), 2.23 (3H, s), 2.32 to 2.78 (4H,
m), 2.83 to 3.06 (3H, m), 3.41 (2H, t, J = 9 Hz), 4.42 (2
H, t, J = 9Hz, 6,98 (2H, t, J = 9Hz), 7.41 (2H, dd, J = 5.
Example 12 6- (2- (3- (4-fluorophenylthio) -8-)
Azabicyclo [3.2.1] octan-8-yl) ethyl)
-2,3-dihydro-7-methyl-5H-thiazolo [3.2.a]
Production of pyrimidin-5-one (Compound No. 204) 3-Hydroxy-8-methyl-8-azabicyclo [3.
2.1] 10 g (71 mmol) of octane was dissolved in 20 ml of chloroform, and a mixed solution of 10.4 ml of ice-cooled methanesulfonyl chloride and 20 ml of chloroform was added dropwise over 1 hour. After further stirring at room temperature for 2 hours, the mixture was added to 50 ml of a 10% aqueous sodium carbonate solution, and the organic layer extracted twice with chloroform was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated to give 3-methanesulfonyloxy. 4.01 g of -8-methyl-8-azabicyclo [3.2.1] octane was obtained as a colorless oil. Next, using this as a raw material, 3- (4-fluorophenylthio) -8-azabicyclo [3.2.1] octane was obtained in three steps in the same manner as in Example 11.

In the same manner as in Example 1, 6- (2-bromoethyl)
-2,3-dihydro-7-methyl-5H-thiazolo [3.2.a]
By reacting 1.1 g (3.1 mmol) of pyrimidin-5-one hydrobromide and 0.63 g (2.7 mmol) of 3- (4-fluorophenylthio) -8-azabicyclo [3.2.1] octane, Was obtained as pale yellow oil (yield 39%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.5 to 2.1 (8H, m), 2.27 (3H, s), 2.3 to 2.7 (4H, m), 3.0
Up to 3.4 (3H, m), 3.43 (2H, t, J = 8Hz), 4.44 (2H, t, J = 8H)
z), 6.99 (2H, t, J = 9 Hz), 7.42 (2H, dd, J = 5.9 Hz) Example 13 4- (2- (4- (4-fluorobenzoyl) -1-piperidino) ethoxy) Production of 2-methyl-1,2-dihydrophthalazin-1-one (Compound No. 400) 0.88 g (5 mmol) of 2-methylphthalazide, 6.9 g (48 mmol) of 2-bromochloroethane, 0.76 g (5.5 mm) of potassium carbonate
ol) and 10 ml of DMF were stirred at 80 ° C. for 30 minutes. After allowing to cool, the mixture was added to 50 g of ice water and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography to give 0.91 g of 4- (2-chloroethoxy) -2-methyl-1,2-dihydrophthalazin-1-one as pale yellow crystals.

In the same manner as in Example 1, 4- (2-chloroethoxy) -2-methyl-1,2-dihydrophthalazin-1-one 0.8 g (3.4 mmol) and 4- (4-fluorobenzoyl) piperidine 0.82 g (2.9 mmol) to give 0.78 g of the desired product as a pale yellow oil (yield 57
%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.7 to 2.1 (4H, m), 2.34 (1H, m), 2.86 to 3.23 (6H, m),
3.74 (3H, s), 4.46 (2H, t, J = 9Hz), 7.13 (2H, t, J = 9H)
z), 7.70-8.05 (5H, m), 8.40 (1H, dd, J = 3.6 Hz) Example 14 2- (2- (4- (4-fluorophenylthio) -1-)
Production of (piperidino) ethyl) -4-methoxy-1,2-dihydrophthalazin-1-one (Compound No. 404) A mixture of 11.84 g (80 mmol) of phthalic anhydride and 80 ml of ethanol was added to ice-cooled 2-hydroxyethyl. Hydrazine 6.68
g (88 mmol) and a mixed solution of ethanol 20 ml are added dropwise.
Stirred for hours. The precipitated crystals were filtered, washed with ethanol, and dried to obtain 10.59 g of 2- (2-hydroxyethyl) phthalazide.

10.59 g of 2- (2-hydroxyethyl) butazide (5
1.4 mmol), 7.83 g (57 mmol) of potassium carbonate, 77 ml of DMF and 8.08 g (64 mmol) of dimethyl sulfate at 120 ° C. for 3 hours.
Stirred for hours. After allowing to cool, the mixture was added to 300 g of ice water and extracted twice with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, concentrated and then recrystallized from methylene chloride-hexane to give 2- (2-hydroxyethyl) -4-methoxy-
4.82 g of 1,2-dihydrophthalazin-1-one was obtained.

2- (2-hydroxyethyl) -4-methoxy-1,2
-Dihydrophthalazin-1-one 4.82 g (21.8 mmol),
5.11 g (43 mmol) of thionyl chloride and ethyl ether 100
The ml mixture was stirred at room temperature for 1.5 hours. Crystals precipitated by adding 50 ml of hexane to the reaction mixture and cooling with ice were filtered, washed with hexane, dried and dried to give 2- (2-chloroethyl) -4-methoxy-1,2-dihydrophthalazine-.
4.21 g of 1-one was obtained.

In the same manner as in Example 1, 2- (2-chloroethyl)
-4-methoxy-1,2-dihydrophthalazin-1-one
By reacting 0.57 g (2.4 mmol) and 0.5 g (2.4 mmol) of 4- (4-fluorophenylthio) piperidine, 0.23 g of the desired product was obtained as a pale yellow oil (yield 23).
%). ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.48 to 2.33 (4H, m), 2.73 to 3.10 (7H, m), 3.96 (3H,
s), 4.26 (2, t, J = 7 Hz), 6.97 (2H, t, J = 9 Hz), 7.41 (2
H, dd, J = 5,9Hz), 7.66 ~ 8.01 (3H, m), 8.38 (1H, dd, J =
Example 15 Production of 2- (2- (4- (4-fluorobenzoyl) -1-piperidino) ethyl) -4-methoxy-1,2-dihydrophthalazin-1-one (Compound No. 402) ) In the same manner as in Example 1, 2- (2-chloroethyl)
-4-methoxy-1,2-dihydrophthalazin-1-one
By reacting 0.4 g (1.7 mmol) and 0.48 g (1.7 mmol) of 4- (4-fluorobenzoyl) piperidine hydrobromide, 0.2 g of the desired product was obtained as a pale yellow oil (yield 24%). . ¹ H-NMR spectrum (CDCl ₃ solution, ppm) 1.70~2.42 (6H, m ), 2.88 (2H, t, J = 8Hz), 3.05~3.31
(3H, m), 3.98 (3H, s), 4.30 (2H, t, J = 8Hz), 7.12 (2
H, t, J = 9Hz), 7.70 ~ 8.04 (5H, m), 8.40 (1H, dd, J = 3.6
Hz) Example 16 (Either X or Y is N and the other is CH) 10 g (6.71 mmol) of 2,3-pyridinedicarboxylic anhydride (A)
l) was dissolved in 80 ml of ethanol (partially insoluble), and 3.4 g of methylhydrazine in which 20 ml of ethanol was dissolved under ice melting.
(74 mmol) was added dropwise. Stir for 3 hours under ice cooling,
Then, it was left at room temperature overnight. The precipitated crystals were filtered to obtain 5.19 g of compound (B) (44% yield).

3.00 g (16.9 mmol) of compound (B), 2-bromo-1-
12 g (85 mmol) of chloroethane and 2.1 g of potassium carbonate (34 m
mol) was added to 30 ml of DME and reacted at 60 ° C. for 2 hours. After cooling, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated. The obtained crude crystals were dissolved in chloroform, hexane was added, and the precipitated crystals were collected by filtration to obtain 0.97 g of compound (C) (yield 24%).

Compound (C) 0.80 g (3.34 mmol), 4- (4'-fluorobenzoyl) -piperidine 0.96 g (3.34 mmol), potassium carbonate 0.46 g (3.34 mmol) and potassium iodide 0.2 g
(1.2 mmol) was added to 10 ml of DMF and reacted at 80 ° C. for 6 hours. After cooling, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated. The resulting crude product was purified by column chromatography (silica gel 60, chloroform / ethanol = 20/1) to obtain 0.45 g of compound (D) (33% yield).

_{NMR (CDCl 3) δ: 1.7~2.1} (4H), 2.1~2.5 (4H),
1.9 to 2.4 (3H), 3.77 + 3.82 (S + S, 3H), 4.12 (q, 2
H, J = 5.8Hz), 7.15 (t, 2H, J = 9Hz), 7.72 (dd, 1H, J _{1
= 9.4Hz J 2 = 4.7Hz),} 7.9-8.1 (2H), 8.33 + 8.73 (d
_{d + dd, 1H, J 1} = 8.6HZ J 2 = 1.8Hz), 9.0~9.2 (1H) mp: oil Example 17 (Either A or B is N and the other is CH) 3,4-pyridinedicarboxylic acid (E) 5.00 g (29.9 mmol)
l), 1.38 g (29.9 mmol) of methylhydrazine and 12.3 g of DCC
(60 mmol) was added to 50 ml of THF under ice cooling. The mixture was stirred for 1 hour under ice cooling and overnight at room temperature, and the deposited precipitate was collected by filtration. The product was recrystallized from ethanol to obtain 12 g of crude crystals. The obtained crude crystals were added to 20 ml of a 10% aqueous sodium hydroxide solution, and insolubles were filtered. The filtrate was made slightly acidic using concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and dried to obtain 3.17 g of compound (F).

Compound (G) was synthesized from compound (F) in the same manner as in Example 16 (15% yield), and further compound (H) was synthesized (56% yield).

_{NMR (CDCl 3) δ: 1.7~2.1} (6H), 2.1~2.6 (2H),
2.9-3.3 (3H), 3.76 (S, 3H), 4.4-4.6 (2H), 7.0
Up to 7.4 (2H), 7.6 to 8.3 (3H), 9.0 (d, 1H, J = 5.4H)
z), 9.68 (1H) Melting point: 115-130 ° C. Example 18 A tablet containing 10 mg of active ingredient is prepared as follows.

Active ingredient per tablet 10mg Maize starch 55mg Crystalline cellulose 35mg Polyvinylpyrrolidone (as 10% aqueous solution) 5mg Carboxymethylcellulose calcium 10mg Magnesium stearate 4mg Talc 1mg Total 120mg Active ingredient, starch and crystalline cellulose are thoroughly mixed through 80 mesh sieve I do. The obtained powder is mixed with a polyvinylpyrrolidone solution, granulated, and passed through an 18-mesh sieve. The granules thus produced are dried at 50-60 ° C. and sized again with an 18 mesh sieve. The carboxymethylcellulose calcium and magnesium stearate and talc are pre-sieved through an 80 mesh sieve and added to the granules and mixed, after which tablets are weighed 120 mg each with a tablet machine.

Example 19 A tablet containing 100 mg of active ingredient is prepared as follows.

Active ingredient per tablet 100 mg Corn starch 50 mg Microcrystalline cellulose 42 mg Light anhydrous silicic acid 7 mg Magnesium stearate 1 mg Total 200 mg The above ingredients are thoroughly mixed through an 80 mesh sieve. The resulting powder is compression molded to produce tablets weighing 200 mg.

Example 20 A capsule containing 50 mg of the active ingredient is prepared as follows.

Active ingredient per capsule 50mg Corn starch 40mg Lactose 5mg Magnesium stearate 5mg Total 100mg Combine the above ingredients, pass through 80 mesh sieve and mix thoroughly. The resulting powder is filled into capsules in 100 mg increments.

Example 21 A vial-containing injectable injection containing 5 mg of the active ingredient is produced as follows.

When using 5 mg of active ingredient per vial and 50 mg of mannitol, dissolve in 1 ml of distilled water for injection and use.

Example 22 An injectable ampoule containing 20 mg of the active ingredient is produced as follows.

Active ingredient per ampoule 20 mg Sodium chloride 18 mg Distilled water for injection qs 2 ml Example 23 A sticky patch preparation containing 17.5 mg of active ingredient is prepared as follows.

Dissolve 10 parts of ammonium polyacrylate in 60 parts of water. On the other hand, 2 parts of glycerin diglycidyl ether are dissolved in 10 parts of water while heating. On the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water and 1 part of the active ingredient are stirred and dissolved. Then, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution of the active ingredient of polyethylene glycol were added and mixed, and a solution for a drug-containing hydrogel was added to a flexible plastic film. mg, and the surface was covered with release paper and cut into 35 square centimeters to give a preparation.

Example 24 An adhesive patch containing 10 mg of the active ingredient is produced as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin,
150 parts of water, trialpoxypropyl isocyanurate 0.2
Parts, ethanol 100 parts, isopropyl myristate 25
Parts, propylene glycol 25 parts and an active ingredient 15 parts to prepare a mixed aqueous sol solution. Next, this sol solution was applied to a nonwoven fabric surface of a composite film composed of a rayon nonwoven fabric and a polyethylene film to a thickness of 100 μm to form a drug-containing pressure-sensitive adhesive layer. The content of auxiliary release substances (isopropyl myristate and propylene glycol) contained in this layer is about 20
% By weight. Thereafter, crosslinking was carried out at 25 ° C. for 24 hours, a release film was adhered to the above adhesive interface, and this was cut into 35 square centimeters to obtain a preparation.

〔The invention's effect〕

The compound (I) of the present invention was confirmed to have excellent anti-serotonin action and anti-dopamine action by in vitro and in vivo pharmacological tests.

That is, in the in vitro test, the anti-serotonin effect was determined by preparing a frontal cortex membrane fraction from rat brain, and replacing the affinity activity of the compound of the present invention for the serotonin 2 receptor with the membrane fraction of [ ³ H] ketanserin from the membrane fraction. The dopamine action was measured by preparing a striatal membrane fraction from rat brain and measuring the affinity of the compound of the present invention for dopamine 2 receptor [ ³ H].
The displacement ability of spiperone from the membrane fraction was measured as an index.

In the in vivo test, using a mouse, the anti-serotonin effect was evaluated by the effect of the compound of the present invention on the quipazine-induced headswitch, and the anti-dopamine effect was evaluated by the effect of the compound of the present invention on the apomorphine-induced climbing behavior. However, all the results agreed well with the results of the in vitro test, and showed excellent anti-serotonin and anti-dopamine effects. When the antihypertensive effect of the compound of the present invention was tested on spontaneously hypertensive rats, it showed a stronger antihypertensive effect than the control ketanserin. Furthermore, a toxicity test of the compound of the present invention revealed that the compound had relatively low toxicity and could be used as a drug with a wide safety margin.

Hereinafter, Test Examples will be shown to explain the pharmacological activity of the compound of the present invention in detail.

Test Example 1 (affinity for serotonin 2 receptor) ^[3 H] Affinity activity to serotonin 2 receptors ketanserin binding the active compounds of the present invention, the frontal cortex membrane fraction prepared from brains of Wistar male rats [ ^[3 H] Ketanserin was evaluated based on its ability to displace.

The rat was decapitated, the brain was removed, and the frontal cortex was removed. The frontal cortex was treated with 40 volumes of 50 mM Tris-HCl buffer (pH 7.
6) Homogenized and then centrifuged. The pellet was rehomogenized in 100 volumes of the same buffer and used for the binding test.
The binding test was performed by the following method. That is, the wet tissue weight of the frontal cortex was 1 mg / ml, 100 μm of the test drug and 1 nM [ ³ H] ketanserin were added to a 50 mM Tris / HCl buffer (pH 7.
Incubated at 37 ° C for 10 minutes in 6). After completion, filter the reaction mixture with a glass fiber filter (Whatman GF / B)
, And washed three times with buffer.

The filter was placed in a scintillation cocktail (ACS II, Amersham), left to stand overnight after mixing, and the radioactivity retained on the filter was counted with a liquid scintillation counter. Non-specific binding was measured in the presence of 1 μM methyselide, and the concentration of a drug that inhibits specific binding by 50% was determined from the graph and defined as IC ₅₀ . Ki was determined by the following equation.

The results of this test are shown in Table 4.

Test Example 2 (Affinity to Dopamine 2 Receptor) [ ³ H] Spiperone-Binding Activity The affinity activity of the compound of the present invention for dopamine 2 receptor was determined from the striatal membrane fraction prepared from the brain of male Wistar rats. Evaluation was based on the ability to replace [ ³ H] spiperone.

The rat was decapitated, the brain was removed, and the striatum was removed.
The striatum was homogenized in 40 volumes of 50 mM Tris-HCl buffer (pH 7.6) and then centrifuged. The pellet was re-homogenized in 50 volumes of the same buffer and used for binding studies. The binding test was performed by the following method. That is, the striatal raw tissue weight of 20 mg / ml, 100 μl of the test agent and 0.5 nM [ ³ H] spiperone were incubated in 50 mM Tris / HCl buffer (pH 7.6) at 37 ° C. for 10 minutes. After completion, the reaction solution was suction-filtered through a glass fiber filter (Whatman GF / B) and washed three times with a buffer solution.

The filter was placed in a scintillation cocktail (ACS II, Amersham), left to stand overnight after mixing, and the radioactivity retained on the filter was counted with a liquid scintillation counter. Non-specific binding was measured in the presence of 1 μM (+) butaclamol, and the concentration of the drug that inhibits the specific binding by 50% was determined from the graph and defined as IC ₅₀ . Ki was determined by the following equation.

The results of this test are shown in Table 4.

Test Example 3 (Antipsychotic Action) Five or more 5-week-old ddY male mice were used in groups of 10 or more, and the anti-serotonin action (hereinafter referred to as anti-5-HT) and the anti-dopamine action (hereinafter referred to as anti-DA) were examined by the following method. Was.

All doses of the test drug were 1 mg / ml, and the dose volume was 0.
The suspension was suspended in 0.5% carboxymethylcellulose (CMC) / physiological saline at 1 ml / 10 g and administered intraperitoneally.

Effect of quipazine on head twitch (anti-5-HT effect) Kipazine (3 mg / kg) was intraperitoneally administered 30 minutes after intraperitoneal administration of test drug, and 10 minutes, 20 minutes, and 30 minutes after administration The number of head twitch of each mouse was measured for 2 minutes each time. The results are shown as the inhibition rate (%) with respect to the control.

 The results of this test are shown in Table 5.

Effect of apomorphine on climbing behavior (anti-DA action) Apomorphine (3 mg / k) 30 minutes after intraperitoneal administration of test drug
g) was administered subcutaneously, and 20 minutes later, the climbing action time of each mouse was measured. The results are shown as the inhibition rate (%) with respect to the control.

 The results of this test are shown in Table 5.

Test Example 4 (Antihypertensive effect) One male SHR (spontaneously hypertensive rat) of 20 to 25 weeks old
Groups used 3 or more animals. The test drug was administered intraperitoneally for 30 minutes,
Blood pressure was measured non-invasively 60 minutes later. Blood pressure is measured using a non-invasive blood pressure measuring device for rats (Muromachi Kikai MK-1000 type). After placing the rat in a 36 ° C incubator for 10 minutes, measure the systolic blood pressure from the pulse wave of the tail vein. Was performed. The results were expressed as a value obtained by subtracting the blood pressure before administration of the test drug.

 The results of this test are shown in Table 6.

Test Example 5 (Acute toxicity) Three to six ddy male mice (body weight 25 to 30 g) were used per group. The test drug was intraperitoneally administered, and one day later, death was observed. The 50% lethal dose LD ₅₀ (mg / kg) was calculated, and the results are shown in Table 7.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/519 A61K 31/519 A61P 1/00 A61P 1/00 7/02 7/02 9/00 9/00 11/06 11 / 06 25/00 25/00 27/14 27/14 43/00 114 43/00 114 C07D 401/06 C07D 401/06 451/02 451/02 471/04 117 471/04 117N 119 119 471/08 471 / 08 487/04 140 487/04 140 513/04 355 513/04 355 519/00 301 519/00 301 (72) Inventor Takeshi Ishidoku 6-1-2 Waki, Waki-machi, Kuga-gun, Yamaguchi Prefecture Mitsui Petrochemical (72) Inventor Akira Mizuchi 3-11-6, Tobudai, Mobara City, Chiba Prefecture 1541 Yabe-cho, Totsuka-ku, Yokohama-shi (56) References International Publication 88-2365 ( O, A1) (58) investigated the field (Int.Cl. ^7, DB name) C07D 403/06 C07D 401/06 C07D 451/02 C07D 471/04 C07D 471/08 C07D 487/04 C07D 513/04 C07D 519 / 00 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. The compound of the general formula (I) [Where m represents an integer of 1 to 3, n is zero or 1 to
X represents CH or N; Y represents CO or S; Is the formula ~ (Where R ¹ is Or represents a lower alkoxy group, R ² represents a lower alkoxycarbonyl group, R ³ represents a lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl carbonyl group, R ⁵ is a hydrogen atom, a lower alkyl group or a lower Represents an alkoxy group, R ⁶ represents a lower alkyl group, R ⁷ represents a lower alkyl group, R ⁸
Represents a lower alkyl group, R ⁹ represents a benzyl group or a hydrogen atom, R ¹⁰ represents a lower alkyl group, R ¹¹ represents a lower alkyl group, R ¹² represents a lower alkyl group, and R ¹³ represents a lower alkyl group. Represents a residue of a heterocyclic compound represented by the following formula: Is a formula, X is CH, Y is CO, n is zero and R ⁴
R ⁵ represents a lower alkoxy group when is a hydrogen atom]. 2. Formula (I) [Where m represents an integer of 1 to 3, n is zero or 1 to
X represents CH or N; Y represents CO or S; Is the formula ~ (Where R ¹ is Or represents a lower alkoxy group, R ² represents a lower alkoxycarbonyl group, R ³ represents a lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl carbonyl group, R ⁵ is a hydrogen atom, a lower alkyl group or a lower Represents an alkoxy group, R ⁶ represents a lower alkyl group, R ⁷ represents a lower alkyl group, R ⁸
Represents a lower alkyl group, R ⁹ represents a benzyl group or a hydrogen atom, R ¹⁰ represents a lower alkyl group, R ¹¹ represents a lower alkyl group, R ¹² represents a lower alkyl group, and R ¹³ represents a lower alkyl group. Represents a residue of a heterocyclic compound represented by the following formula: Is a formula, X is CH, Y is CO, n is zero and R ⁴
When R is a hydrogen atom, R ⁵ represents a lower alkoxy group.) A pharmaceutical composition for anti-serotonin, comprising as an active ingredient. 3. A compound of the general formula (I) [Where m represents an integer of 1 to 3, n is zero or 1 to
X represents CH or N; Y represents CO or S; Is the formula ~ (Where R ¹ is Or represents a lower alkoxy group, R ² represents a lower alkoxycarbonyl group, R ³ represents a lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl carbonyl group, R ⁵ is a hydrogen atom, a lower alkyl group or a lower Represents an alkoxy group, R ⁶ represents a lower alkyl group, R ⁷ represents a lower alkyl group, R ⁸
Represents a lower alkyl group, R ⁹ represents a benzyl group or a hydrogen atom, R ¹⁰ represents a lower alkyl group, R ¹¹ represents a lower alkyl group, R ¹² represents a lower alkyl group, and R ¹³ represents a lower alkyl group. Represents a residue of a heterocyclic compound represented by the following formula: Is a formula, X is CH, Y is CO, n is zero and R ⁴
When R is a hydrogen atom, R ⁵ represents a lower alkoxy group.) A pharmaceutical composition for anti-dopamine, comprising: