JPH0454181A - New heterocyclic compound and pharmaceutical composition - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [m is 1-3; n is 0-2; X is (CH or N; Y is CO or S; Het is group of formula II to formula VI (R<1> is group of formula VII or alkoxy; R<2> is alkoxycarbonyl; R<3> is alkyl; R<4> is H or alkylcarbonyl; R<5> is H, alkyl or alkoxy), etc.]. EXAMPLE:4-{4-(4-Fluorobenzoyl)-1-piperidinomethyl}-2-(4benzylpiperazino) pyrimidine-5-carboxylic acid ethyl ester. USE:It has excellent antiserotonin action and antidopamine action and is useful for the remedy and prevention of various psychoneurotic diseases and various diseases such as hypertension, arrhythmia, stenocardia and allergy. PREPARATION:The compound of formula I wherein Het is group of formula II and m is 1 can be produced e.g. by reacting a compound of formula VIII with a compound of formula IX in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel heterocyclic compound having excellent anti-serotonin and anti-dopamine effects, and a pharmaceutical composition containing the compound as an active ingredient.

[Conventional technology]

Conventionally, in order to treat and prevent neuropsychiatric diseases, drug therapy using various psychotropic drugs, neuroagonists, and neurotropic drugs has been widely used, or drugs that can satisfy both efficacy and safety. Currently, there are very few, and therefore,
Drugs that are safer and easier to use with fewer side effects, have an immediate effect, are long-lasting, have a novel mechanism of action, have a distinctive drug efficacy spectrum, such as a broad spectrum of action, or a spectrum of action with a pattern different from that of conventional drugs. The emergence of drugs with a purely single action spectrum, etc., and drugs with novel chemical structures that are effective not only in the acute phase but also in chronic symptoms is eagerly awaited.

Recently, as a compound having an anti-serotonin effect, 4H to pyrido [1゜2-a
] The pyrimidin-4-one group was replaced with 5H-thiazolo(3,2
-a) Pyrimidin-5-one, 5H-1,3,4
Thiadiazolo(3,2-a)pyrimidin-5-one or 3,4-dihydro-2H,6H-pyrimidoC2゜1-
Compounds conjugated to bl C1,3) thiazin-6-one are disclosed, and these compounds are also disclosed to possess antihistamine activity.

[Invention or problem to be solved]

An object of the present invention is to provide a novel heterocyclic compound having excellent anti-serotonin and anti-dopamine effects.

The present inventors synthesized a large number of heterocyclic compounds and evaluated their anti-serotonin activity, anti-dopamine activity, etc. in vitro and in viv.

A screening test was conducted and it was discovered that the compound represented by the general formula (I) has excellent activity and low toxicity, and the present invention was completed.

[Means to solve the problem]

The present invention represents the general formula (1) zero or an integer of 1 to 2, X represents CI (or N,
Y represents CO or S, ■ is the formula % formula % () [However, in the formula, m represents an integer of 1 to 3, n represents ■ ■ ■ ■ or a lower alkoxy group, and R2 is a lower alkoxycarbonyl group , R3 represents a lower alkyl group, R4
represents a hydrogen atom or a lower alkylcarbonyl group, R5
represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, R6 represents a lower alkyl group, R7 represents a lower alkyl group, R8 represents a lower alkyl group, R9 represents a benzyl group or a hydrogen atom, RIG represents a (represents a lower alkyl group, R1+ represents a lower alkyl group, RI2 represents a lower alkyl group, RI3 represents a lower alkyl group), provided that [Yes] 〇- [Phase] A novel heterocyclic formula represented by 0 or formula ■, when X or CH and Y or CO and n or zero and R4 is a hydrogen atom, R5 represents a lower alkoxy group] provide a compound.

The present invention further provides a pharmaceutical composition comprising as an active ingredient a compound selected from the group consisting of the above-mentioned novel heterocyclic compounds, their pharmaceutically acceptable acid addition salts, or their stereoisomers. provide something.

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

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

[Manufacturing method part 1]

Among the compounds of the present invention, the compound represented by the general formula (I-1) (I-1) (wherein R'J R21m, nl X and Y have the same meanings as above), for example, m is 1 In this case, it can be produced according to the following reaction formula.

(II) (I) That is, the compound (II) disclosed in JP-A No. 61-65873 by the present applicant and the compound (II[) are reacted in the presence of a base.

Compound (I) is used in an amount of 0.5 to 10 times mole, preferably 1 to 5 times mole, relative to compound (II). Bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and sodium carbonate.

Alkali metal carbonates such as potassium carbonate and sodium hydrogen carbonate, and amines such as triethylamine and pyridine can be used, and among these, potassium carbonate is preferably used. The amount of base used is 0.5 to compound (I).
~5 times the mole, or usually 1.1 times the mole.

As a solvent, aromatic hydrocarbons such as benzene and toluene, methanol, ethanol, i-propertool, t-
Alcohols such as butanol, ethyl ether, i-
Ethers such as probyl ether, tetrahydrofuran, and 1,4-dioxane, ketones such as acetone and methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide, etc. are used, and usually compound (II)
The amount used is 2 to 50 times, preferably 3 to 10 times.

The reaction temperature is 20-180°C, preferably 80-130°C.
°C, reaction time is 0.5 to 48 hours, typically 5 to 24 hours.
Allow time to react.

After the reaction, the desired product is obtained by processing according to conventional methods, and isolating and purifying the product by methods such as recrystallization and column chromatography.

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

(■') (N> (V) In step A, the compound (■') shown in JP-A No. 61-65873 is reacted with 3-amino-propyl alcohol. 3-amino-propanol is reacted with the compound (■ ') is used in moles of 0.5 to 10 times, preferably 1 to 3 times.Solvents include aromatic hydrocarbons such as benzene and toluene, methanol, ethanol, i-propanol, and t-butanol. Alcohols, dimethylformamide, dimethyl sulfoxide, etc. are used, and are usually used in an amount of 2 to 50 times, preferably 3 to 50 times the amount of compound (■').
Use 10 times.

Step B is a reaction of converting compound (IV) to sulfonic acid ester (V) using methanesulfonyl chloride, and can be carried out by a commonly used method.

Step C involves reacting compound (V) and 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) (VI) <C■) (I-3) (wherein, R'+ L nI X and Y have the same meanings as above) ) can be produced according to the following reaction formula, for example in the case of m or 1.

Step A is to synthesize compound (■) by reducing the compound (VI) disclosed in JP-A No. 61-50982 by the present applicant using a boron hydride compound.

As the borohydride compound, sodium borohydride, sodium cyanoborohydride, etc. can be used, and it is used in a molar amount of 0.3 to 10 times, preferably 0.5 to 2 times, relative to compound (VI). be done.

As a solvent, alcohols such as methanol, ethanol, i-propanol, t-butanol, ethyl ether, i-propyl ether, tetrahydrofuran, 1
, 4-dioxane, and ketones such as acetone and methyl isobutyl ketone are used, and a mixture of these may be used. These solvents are usually compounds (
VI) in an amount of 2 to 50 times, preferably 5 to 30 times.

The reaction temperature is 3 to 100°C, preferably 20 to 60°C, and the reaction time is 0.1 to 10 hours, usually 0.5 to 3 hours. After the reaction, the desired product is obtained by processing according to conventional methods, and isolating and purifying the product by methods such as recrystallization and column chromatography.

Step B is a reaction of converting the compound (■) into a sulfonic acid ester (■) using methanesulfonyl chloride, and can be carried out by a commonly used method.

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

[Production method 4] Among the compounds of the present invention, compounds represented by the general formula (I-4) (I-4) (wherein, R'+ R6+ ml rL X and Y have the same meanings as above) The compound is, for example, m or 2
In this case, it can be produced according to the following reaction formula.

(Margins below this page) (IX) (III) (I-4) It can be converted into compound (I-4).

[Production method 5] Among the compounds of the present invention, general formula (E-5) (X)
(X I) Compound (IX) and compound (
Regarding the method of synthesizing compound (■-4) from I), R4 is a hydrogen atom, R5 is an alkyl group, n or zero, and X is C
When H and Y are CO, it is already described in JP-A-58-18390, and when R4 is a hydrogen atom or a lower alkylcarbonyl group, and R5 is a hydrogen atom, a lower alkoxy group, or a lower alkyl group, It can be manufactured by the same method as [Manufacturing method 1]. Compound (XI), which can be synthesized by a conventional method from compound (X) and methanesulfonyl chloride, can be obtained by reacting compound (I [[) with (I-5) under the reaction conditions shown in [Production method part 1]. The compound represented by (wherein R@+L rL

(XI[) (XI[) (XIV) Step A is to react compound (XII) synthesized by reacting ethyl acetoacetate and thiourea in the presence of a base with compound <xm> in the presence of a base. It is something.

Compound (XI[[) is 1 to 2 with respect to compound (XI[)
It is used twice in mole, preferably 1 to 1.5 times in mole.

As the base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, and sodium bicarbonate, and amines such as triethylamine and pyridine can be used. Among these, potassium carbonate is preferably used. The amount of base used is 0.5 to 0.5 to compound (XI[)
It is 5 times the molar amount, but usually 1.1 times the molar amount is used. In addition to water, solvents include alcohols such as methanol, ethanol, i-propanol, and t-butanol, ethers such as ethyl ether, i-propyl ether, tetrahydrofuran, and 1,4-dioxane, acetone, and methyl isobutyl ketone. Ketones, dimethylformamide, dimethyl sulfoxide, etc. are used, and these may be used in combination. It is usually used in an amount of 2 to 50 times, preferably 3 to IO times, the amount of compound (XTI). The reaction temperature is 20-120°C, preferably 40-100'
c, the reaction time is 1 to 24 hours, usually 3 to 10 hours. After the reaction is completed, post-treatment is carried out by conventional methods, followed by recrystallization,
The target compound (XIV) can be isolated by silica gel column chromatography or the like.

Step B is a reaction of converting compound (XIV) to sulfonic acid ester (XV) using methanesulfonyl chloride, and can be carried out by a commonly used method. Step C consists of compound (XV) and compound (III).
) and can be carried out under the reaction conditions shown in [Production method 1].

[Production method 6] Among the compounds of the present invention, the compound represented by the general formula (I-6) (I-6) (wherein, R7+ L rL X and Y have the same meanings as above), for example, In the case of m or 2, it can be synthesized according to the following reaction formula.

(XVI) (X■) (X■) (XIX) Step A involves reacting ethyl 2-cyclohexanonecarboxylate (XVI) and compound (X■) in the presence of a base.

Compound (X) is used in a molar amount of 1 to 3 times, preferably 1 to 1.5 times, relative to compound (XVI).

Examples of bases 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, potassium carbonate, and sodium hydrogen carbonate. Amines such as salts, triethylamine, and pyridine can be used, among which t
-Butoxypotassium is preferably used. The amount of the base to be used is 0.5 to 5 times the mole of compound (XVI), but usually 1 to 2 times the amount by mole. Examples of solvents include aromatic hydrocarbons such as pentene and toluene, alcohols such as methanol, ethanol, i-propanol, and t-butanol, and ethyl ether.

i-propyl ether, tetrahydrofuran, l.

Ethers such as 4-dioxane, ketones such as acetone and methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide, etc. are used, and usually compounds (
XVI) is used in an amount of 2 to 50 times, preferably 3 to 10 times.

The reaction temperature is 20-180°C, preferably 80-130°C.
°C, reaction time is 0.5 to 48 hours, usually 5 to 24 hours.
Allow time to react.

Step B involves reacting compound (X■) and 1-chloro-2-bromoethane in the presence of a base to form compound (XIX).
This is the reaction that yields .

1-chloro-2-bromoethane is used in an amount of 1 to 10 times, preferably 2 to 5 times, the amount of compound (X). As the base, sodium hydride, potassium t-butoxy, potassium carbonate, triethylamine, etc. can be used, and among these, sodium hydride is preferred.

The amount of the base to be used is 0.5 to 10 times the molar amount of compound (X), or usually 1 to 5 times the molar amount.

Examples of solvents include aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol, ethanol, l-propanol, and t-butanol, and ethers such as ethyl ether, i-propyl ether, tetrahydrofuran, and 4-dioxane. Ketones such as acetone, methyl isobutyl ketone, dimethylformamide, dimethyl sulfoxide, etc. are used, and are usually used in an amount of 2 to 50 times, preferably 3 to 10 times, the amount of compound (X).

The reaction temperature is 20-180°C, preferably 80-130°C.
The reaction time is 0.5 to 48 hours, usually 5 to 24 hours.
Allow time to react.

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

[Production method 7] Among the compounds of the present invention, compounds represented by the general formula (I-7) (I-7) (wherein R'', m, n, X and Y have the same meanings as above) For example, in the case of m or 2, the compound can be synthesized according to the following reaction formula.

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

[Production method 8] Among the compounds of the present invention, a compound represented by the general formula (I-8) (XX) (I-8) (wherein, R9+ L n+ X and Y have the same meanings as above) For example, in the case of m or 2, it can be synthesized according to the following reaction formula.

(XX I) Step A is to react compound (XX) and 1-chloro-2-bromoethane in the presence of a base to form compound (XXI).
This is a reaction to obtain the following, and it can be carried out in the same manner as Step B of [Production Method 6]. (XXII) (XXI[) U <xxrv> Step A is to react the compound (XXI[) and formamidine hydrochloride in the presence of potassium carbonate to form the compound (X
This is a reaction to obtain XI[I]. Step B consists of compound (
This is a reaction in which XXI[) and 1-chloro-2-bromoethane are reacted in the presence of a base to obtain compound (XX■), and it can be carried out in the same manner as Step B of [Production Method 6]. Step C consists of compound (XXIV) and compound (I
[) and can be carried out in the same manner as [Production method part 1].

[Production method 9] Among the compounds of the present invention, compounds represented by the general formula (I-9) (blank below the essence) (I-9) (where m, n, X and Y have the same meanings as above) For example, when m is 2, the compound can be synthesized according to the following reaction formula.

(XXV) Step A comprises adding compound (X) to the compound (X) in the presence of potassium carbonate;
This is a reaction in which compound (XXV) is synthesized by reacting with 2-bromoethanol. Step B is the compound (XXV)
This is a reaction in which compound (XXVI) is synthesized by reacting in an aqueous HBr solution. Step C is compound (XXVI)
and tetrahydroisoquinoline in the presence of a base to synthesize compound (I-9).
The reaction can be carried out in the same manner as in Part 1].

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

(Margin below the essence) (For XX) (X IX :X', Z=CI, Br, I)
(XX■') Step A consists of 2-alkyl phthalazide (for XX) and 1
．． 2-dihalogenoethane (for XX) is reacted in the presence of a base. Compound (X) is used in a molar amount of 1 to 50 times, preferably 1.5 to 20 times, the amount of compound (for XX). Bases 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, or triethylamine. , pyridine and other amines can be used, among which potassium carbonate is preferred. The amount of the base to be used is 0.5 to 5 times the mole of compound (XX■), but usually 1 to 2 times the mole. As a solvent, aromatic hydrocarbons such as benzene and toluene, methanol, ethanol,
Alcohols such as isopropanol, t-butanol, ethyl ether, isopropyl ether, THF,
1. Ethers such as 4-dioxane, ketones such as acetone and methyl isobutyl ketone, or DMF.

DMSO or the like is used, and is usually used in an amount of 1 to 50 times, preferably 3 to 20 times, the weight of compound (XX). The reaction temperature is 0 to 180°C, preferably 50 to 120°C.
At °C, reaction times range from 5 minutes to 10 hours, typically from 15 minutes to 2 hours.
Allow time to react.

Step B involves reacting compound (XXIV) with compound (II), 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) (I-
11) The compound represented by (wherein R''+ L n+ X and Y have the same meanings as above) can be synthesized according to the following reaction formula, for example, in the case of m or 2.

<XXX> (XXX I ) (XXXK) (XXXIII) (XXXIV; Compound (XXXI) is used in an amount of 0.8 to 5 times, preferably 1 to 2 times, mole relative to compound <XXX>. Benzene as a solvent.

Aromatic hydrocarbons such as toluene, alcohols such as methanol, ethanol, isopropanol, t-butanol, ethyl ether, isopropyl ether, TH
F, ethers such as 1,4-dioxane, or DMF, DMSO, etc. are used, and usually the compound (XX
It is used 1 to 50 times by weight, preferably 3 to 20 times by weight relative to X). The reaction temperature is -10 to 180°C, preferably 20 to 100°C, and the reaction time is 5 minutes to 10 hours, usually 15 minutes to 2 hours.

Step B involves reacting 2-(2-hydroxyethyl)phthalazide (XXXIl[) with an alkylating agent in the presence of a base. As an alkylating agent, methyl chloride,
Alkyl halides such as methyl bromide, methyl iodide, ethyl bromide, and ethyl iodide, dialkyl sulfates such as dimethyl sulfate and diethyl sulfate, etc. can be used, and the amount used is 0.000% relative to compound (XXXII). The amount is 8 to 20 times by mole, preferably 1 to 5 times by mole. As the base, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium ethoxide and potassium t-butoxide, or alkali metal carbonates such as sodium carbonate and potassium carbonate may be used. Among these, potassium carbonate is preferably used. The amount of the base to be used is 0.5 to 5 times the mole of compound (XXXII), or usually 1 to 2 times the mole. Solvents include aromatic hydrocarbons such as benzene and toluene, ethyl ether, and isopropyl ether.

Ethers such as THF and 1,4-dioxane, ketones such as acetone and methyl isobutyl ketone, or DMF and DMSO are used, and usually compounds (
XXXII) 1 to 50 times by weight, preferably 3 to 50 times
Use 20 times the weight.

Reaction temperature is 0 to 180°C, preferably 50 to 140°
C, reaction time is 30 minutes to 10 hours, usually 1 hour to 5 hours.
Allow time to react.

Step C is 4-alkoxy-2-(2-hydroxyethyl)-1,2-dihydrophthalazin-1-one (XX
This is a halogenation reaction of XI[). As the halogenating agent, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfuryl chloride, etc. can be used, and the amount used is 0.8 to 10 times the mole of compound (XXXI[),
Preferably it is 1 to 5 times the mole. Solvents include aliphatic hydrocarbons such as hexane, heptane, decane, Hensen,
Aromatic hydrocarbons such as toluene, ethers such as ethyl ether, isopropyl ether, THF, and 1,4-dioxane, or ketones such as acetone and methyl isobutyl ketone are used.
XXIII) 1 to 50 times by weight, preferably 3 to 50 times
Use 20 times the weight. Reaction temperature is -1O~100°C1
Preferably at 10-80°C, the reaction time is 30 minutes-10
The reaction time is usually 1 to 5 hours.

Step D involves reacting compound (XXXIV) with compound (I) and can be carried out in the same manner as [Production method part 1].

As is clear from the general formula (I), whether the compound of the present invention has optical isomers or not, the present invention includes all of them,
The isomers can be separated or isolated if desired, and can also be used as pharmaceutically acceptable acid addition salts.

The present invention is based on the discovery that the compound represented by the general formula (I) has excellent anti-serotonin and anti-dopamine effects, as well as neurite extension effects.

Therefore, the compound of formula (I) can be used to treat various diseases caused by or associated with serotonin and dopamine, such as schizophrenia, psychosis, depression, delirium, anxiety, epilepsy, Parkinson's disease, dementia and other psychosis. , or treatment of neurological diseases such as various central or peripheral neurological disorders, that is, various psychiatric and neurological diseases, and various diseases such as hypertension, arrhythmia, angina pectoris, allergies, asthma, migraines, gastrointestinal disorders, and platelet coagulation dysfunction. It is expected to be useful as a preventive agent.

Compounds of general formula (I) are usually used in the form of pharmaceutical compositions and can be administered by various routes such as oral, subcutaneous, intramuscular, intravenous, intraduodenal, intranasal, intravenous, sublingual, percutaneous and rectal routes. Medication is administered.

The present invention encompasses pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Pharmaceutically acceptable salts include, for example, acid addition salts.

Pharmaceutically acceptable salts of general formula (I) include, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, oxalate, maleic acid salt, Acid salt, fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, saccharide, cyclohexylsulfamate, methanesulfonate, p-toluenesulfonate salts, salts formed from acids that form non-toxic acid addition salts with pharmaceutically acceptable anions, such as naphthalene sulfonate, or hydrates thereof.

Examples of quaternary ammonium salts include salts of alkyl halides and compounds of general formula (I).

The pharmaceutical composition of the present invention can be used, for example, in tablets, capsules, powders,
Granules, troches, sublingual tablets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, eye drops, sterile syringes, molded poultices, tapes, soft and hard gelatin capsules, herbal medicines and sterile packaging. It can also be made into powder form.

Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, microcrystalline cellulose, gum arabic, calcium phosphate, alginate, calcium silicate, calcium sulfate, microcrystalline cellulose, polyvinylpyrrolidone, Gum tragacanth, gelatin, syrup, methylcellulose, carboxymethylcellulose, sodium benzoate, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, water or mineral oil, injectable peanuts. These include oils and even half-based bases such as glycerides.

Either solid or liquid compositions may contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweetening or flavoring agents, and the like, such as those mentioned above. The compositions can also be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

For oral administration, compounds of general formula (I) are mixed with carriers and diluents and placed in the form of tablets, capsules, and the like. For parenteral administration, the active ingredient is dissolved in 10% aqueous dextrose, isotonic saline, sterile water, or similar liquid;
It is sealed in a vial or ampoule to be administered intravenously by infusion or injection, or by intramuscular injection. Advantageously, solubilizing agents, local anesthetics, preservatives and buffers may also be included in the vehicle. To increase stability, after pouring the composition into a vial or ampoule,
Freeze drying is also possible. Other examples of parenteral administration include formulations administered transdermally in the form of ointments and pa-nobu preparations. In this case, molded poultices or tapes are advantageous.

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

Compounds of general formula (I) are effective over a wide dosage range. For example, the dosage per day is usually 0.1
It falls within the range of ug/kg to 100mg/kg.

The actual amount of compound administered will depend on the compound administered and on the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms (e.g., central nervous system disease, high direct pressure, symptoms, pre-existing conditions, etc.). , determined by the physician and veterinarian, depending on the route of administration, etc. Therefore, the above dosage ranges are not intended to limit the scope of the invention. - The number of doses per day is 1 to 6 times,
Usually 1 to 4 times is appropriate.

The pharmaceutical composition according to the present invention can be administered in combination with one or several other equivalent drugs, if necessary. Such additional agents include, for example, haloperidol, butyrophenone, thiothixene, sulpiride, suldobride,
Zotepine, thioridazine hydrochloride, lithium carbonate, chlorpromazine, fluphenazine hydrochloride, oxypertine, clotiapine, spiverone, chlorpromazine, timiperone, hydroxyzine hydrochloride, bimozide, bromberidol,
Verphenazine, carpipramine maleate, carbipramine hydrochloride, clocabramine hydrochloride, imipramine, desipramine, amitributyline, nortributyline, amoxapine, doxepin, maprotiline, mianserin,
nomifensine, hyloxazine, L-5-HTP, pivamperone, etizolam, lofepramine, trimipramine, diazepam, medasepam, lorazepam, flutazolam, clotiapinum, promazepam, mexazolam, chlordiazepoxide, cloxazolam, oxazolam,
Albrasillam, calcium hopatenate, lisuride, piracetam, aniracetam, γ-amino-β-hydroxybutyric acid, febarbamate, idebenone, tiapride, pihemelan, phenytoin, barbituric acid preparations, clonazepam, palproic acid, amantadine preparations, piperiden, mecobalamin Examples include psychotropic and neurotropic drugs such as ganglioside preparations, as well as preparations such as nifedipine, nicardipine, nimodipine, pindolol, propranolol, methyldopa, prazosin, sisopyramide, abrindin, and ketotifen.

Examples are shown below to explain the method for producing the compound of the present invention and the method for preparing a pharmaceutical composition related to the compound.

Example 1 4-+4-(4-fluorobenzoyl)-1-piperidinomethyl l-2-(4-benzylpiperazino)pyrimidine-5-carboxylic acid ethyl ester (compound number 100
) Production of 4- synthesized by the method described in JP-A No. 61-65873
Chloromethyl-2-(4-benzylpiperazino)pyrimidine-5-carboxylic acid ethyl ester 2.0 g (5,3
1.5 g (5.3 mmol) of (4-fluorobenzoyl)-1-piperidine hydrobromide and a further 0.73 g (5.3 mmol) of potassium carbonate in methyl isobutyl ketone 50. The mixture was added and heated under reflux for 20 hours. After 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 using silica gel column chromatography (developing solvent: methylene chloride/methanol = 40/l). 2.30 g of the target product was obtained as an oil. (Yield: 80%).

Hereinafter, the compounds shown in Table 2 were synthesized in the same manner, and their spectral data are also listed.

Table 2 Example 2 6-(4-(4-), fluorobenzoyl)-1-piperidinopropyl)-2-(4-benzylpiperazino)-5
-oxo-5,6-dihydro(7H)pyrrolo(3,4
-d) Production of pyrimidine (compound number 102) 4-
Chloromethyl-2-(4-benzylpiperazino)pyrimidine-5-carboxylic acid ethyl ester 2.0 g (5,3
mmol) and 3-aminopropatol 0.48 g (
6.4 mmol) in 300 ml of ethanol,
The mixture was heated to reflux for an hour. After the reaction, ethanol was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent:
The intermediate 6-(hydroxypropyl)-2-
(4-Benzylpiperazino)-5oxo-5,6-dihydro(7H)pyrrolo[3,4d]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, and 0.5 g (5.0 mmol) of triethylamine were dissolved in THF 5 (
After stirring in W at -70°C for 10 minutes, the mixture was heated to room temperature and stirred for 30 minutes. When the reaction solution turns yellow, 4
1.5 g (5 mmol) of -(fluorobenzoyl)-1-piperidine hydrobromide was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent is distilled off under reduced pressure, and the residue is separated and purified by silica gel column chromatography (developing solvent: chloroform-ethyl acetate) to obtain the desired product as a solid.
．． 3g was obtained (yield=42%).

'H-NMR spectrum (CDCI3 solution, p
pm) 1.60-2.20 (8H, m), 2.20
~2.64 (6H, m), 2.80~3.30 (3
N, 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=7Hz), 8.64 (
IH,s) Example 3 5.6-Sihydro8-14-(4-fluorobenzoyl)-1-piperidinomethyl)-6-methyl-2-(4
-benzylpiperazino)-5-oxo-pyrido(4,3
-d) Production of pyrimidine (compound number] 04) 5 synthesized by the method described in JP-A No. 61-50982,
2.8 g of 6-hydro-6-methyl-2-(4-benzylpiperazino)-5-oxo-pyrido[4,3-d)pyrimidine-8-carbaldehyde in methanol 5O-1T
HF 10 (dissolved in W, sodium borohydride 2.
Og was added, and the mixture was stirred at 40°C for 10 minutes.

After the reaction was completed, water was added and the mixture was extracted with ethyl acetate.

The ethyl acetate layer was dried over anhydrous sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure.

The residue was separated and purified by silica gel column chromatography (developing solvent, acetone/hexane = 1/4) to obtain the intermediate 5,6-dihydro-8hydroxymethyl-6-
2.3 g of solid methyl-2-(4-benzylpiperazino)-5-oxo-pyrido(4,3-d]pyrimidine were obtained.

0.5 g of this intermediate was converted into methanesulfonic acid ester in the same manner as in Example 2, and (4-fluorobenzoyl)-
By reacting with 1-piperidine hydrobromide,
0.35g of the target product was obtained as a white solid (yield: 48%).
).

'H-NMR spectrum (CDC1, solution, p
pm) 1.60-1.96 (4H, m), 2.28-
2.70 (7H, m), 2.68-3.22 (6H,
m), 3.38-3.70 (4H, m), 3.72
~4.08 (4H, t, J=4Hz), 7.10 (2
H, dd, J=7Hx), 7.28(5H,s),
7.92 (2H.

dd, J=7Hz), 8.78 (IH, s) Example 4 6- (2-(4-(4-fluorobenzoyl)-1-
piperazinyl)ethyl)-2,3-dihydro-7-methyl-5H-thiazolo-(3,2-a)pyrimidine-5-
(Compound No. 200) 1.0 g of 4-(4-fluorobenzoyl)-1-formylpiperazine was added to 45 mt' of methanol and 5 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 10 hours. After the reaction is complete, add sodium hydroxide aqueous solution (3
The mixture was made alkaline with N) and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the sodium sulfate was filtered off.

When the solvent was distilled off from the filtrate under reduced pressure, 4-(4
0.8 g of -fluorobenzoyl)-1-piperazine was obtained (yield 91%).

4-(4-fluorobenzoyl)-1-piperazine 1.
0 g (5.6 mmol), 6-(2-bromoethyl')-2,3-dihydro-7-methyl-58-thiazolo(3 ,2-a) pyrimidin-5-one 1.69g
(6.1 mmol), potassium carbonate 4. (](g)(
29 mmol) and potassium iodide (0.3 g) were added to 6W of methyl isobutyl ketone, and the mixture was heated under reflux for 14 hours.

After the reaction was completed, the product was post-treated and purified in the same manner as in JP-A-58-18390 to obtain 1.2 g of the target product as a solid (yield: 53%).

'H-NMR spectrum (CDC1, solution, l)l
) m) 2.20 (3H, S), 2.32-2.76 (
8H, m), 3.30-3.72(6)1゜m),
4.34 (2H, t, J=7Hz'), 7.18~7
．． 60(4)1. rn) Example 5 6-(2-(4-(4-fluorobenzoyl)-■-
piperidinyl)ethyl)-2,3-dihydro-7-medoxy5H-thiazoo-(3,2,a)pyrimidine-5
-one (Compound No. 208) 2-oxo-3-ethoxycarbonyl-tetrahydrofuran 1.58 g (1
0 mmol), 1.53 g (15 mmol) of 2-amino-4,5-dihydro-thiazole, and 1.12 g (10 mmol) of t-butoxypotassium were dissolved in DMF15- and reacted at 100° C. for 2 hours. After lowering the temperature of the reaction solution to room temperature, 1.5-methyl iodide was added and heated at 60° C. for 30 minutes. After the reaction was completed, the reaction solution was poured into 30 ml of water and extracted three times with chloroform 2O-. The chloroform layer was dried over magnesium sulfate, the magnesium sulfate was removed, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate/methanol =
5/1) to separate and purify the intermediate 6-hydroxyethyl-
2゜3-dihydro-7-medoxy5H-thiazolo(3
, 2, a) Pyrimidin-5-one O, 17 g was obtained.

0.29 g of the intermediate thus obtained (1,27
mmol) and triethylamine 0.26 g (2,
54 mmol) was dissolved in 5rILl of methylene chloride and stirred under water cooling.

0.29 g of methanesulfonyl chloride was added to this solution.
A methylene chloride solution 2- (1.91 mmol) was added dropwise over 10 minutes and stirred for 1 hour. Raise the temperature to room temperature,
After stirring for 1 hour, it was washed successively with 1 ml of 5% hydrochloric acid solution, 10 ml of saturated aqueous sodium bicarbonate solution, and the methylene chloride layer was dried over magnesium sulfate. After filtering the magnesium sulfate, methylene chloride was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (developing and dissolving: ethyl acetate), resulting in the intermediate 6-methanesulfonylethyl-2,3-dihydro- 7-methoxy5H-thiazo-C3,2,a)pyrimidine-5-
0.23 g (yield: 59%) of ion was obtained.

0.23 g (0.75 mmol) of this intermediate, 4-(
4fluorobenzoyl)-1-piperidine hydrobromide 0.29 g (1.0 mmol), potassium carbonate 0.28
g (2.0 mmol) in DMF4mj' at 80°C, 4
Allowed time to react.

After the reaction was completed, the reaction solution was poured into 50ml of water and extracted twice with 50ml of ethyl acetate. The ethyl acetate layer was dried by a conventional method, concentrated under reduced pressure, and subjected to silica gel spring chromatography (developing solvent: methylene chloride/methanol = 30
/1) to obtain 0.27 g of the target product as an amorphous solid (yield: 86%).

'H-NMR spectrum (CDC13 solution, p
pm) 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=7
Hz), 7.12 (2H, ddj7Hz), 7゜98 (2H, dd, J=7Hz) Example 6 6- (2-(4-(4-fluorobenzene)thio l-
Synthesis of pyrimidin-5-one (compound no. 21O) 3.4-dichloro-2-oxo- Butane 2. a2g(
While cooling 25 mj' of an ethanol solution of 20 mmol) with water, 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-pyrimidine ethanol and 5.53 g (40 mmol) of potassium carbonate were added to this solution, and the mixture was cooled with water for 10 min.
The mixture was reacted for an hour, heated to room temperature, and further reacted for 10 hours.

After the reaction was completed, the solids were filtered off and the filtrate was concentrated under reduced pressure. To 4.97 g of the obtained viscous liquid was added ethyl acetate/
Recrystallization was performed by adding a 5 (W) solution of ethanol = 4/l, and 2.81 g of solid was obtained.

The mother liquor was further concentrated under reduced pressure and recrystallized in the same manner to obtain 0.4 g of solid, for a total of 3.30 g.
(65% yield) intermediate, 3-acetyl-6-(hydroxyethyl)-2,3-dihydro-7-methyl-5H
-thiazolo-(3,2,a)pyrimidin-5-one was obtained.

Using 2.54 g (IO 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-methane was prepared in the same manner as in Example 5. 2.95 g (yield 96%) of sulfonylethyl-2,3-dihydro-7-methyl-5H-thiazolo-(3,2,a)pyrimidin-5-one was obtained.

0.50 g (1.6 mmol) of this intermediate, 4-((4
-fluorobenzene)thio)-1-piperidine 0.44
g (2.1 mmol) and potassium carbonate (4.3 mmol) were dissolved in 8 rnl of DMF, and the reaction and work-up were carried out in the same manner as in Example 5, and the desired product was added to 0.1 mmol. 10g (yield: 14%) was obtained.

H-NMI? Spectrum (CDCI2 solution,
ppm) 1.70 to 2.12 (4H, m), 2.
12 (6H, s), 2.48-2.90 (5H.

m), 2.90-3°30 (4H, m), 3.42
<IH, dd, J=5Hz), 3.70 (IH, t,
J=71(Z), 5.38(IH, dd, J=5Hz
), 7.14 (2H, t.

J=7H1), 7.92<2H, dd, J=7H1
) Example 7 6-(2-(4-(4-fluorobenzene)thio-1
-piperidinyl)ethyl)-2,3-dihydro-5H-
Preparation of thiazolo(3,2,a)pyrimidin-5-one (Compound No. 2I2) A solution of 5 g (58 mmol) of γ-butyrolactone and 4.3 g (58 mmol) of ethyl formate in dry diethyl ether was added to 100 ml of 60% sodium hydride. 2.44g (6
The mixture was added dropwise to a suspension of 1 mmol of dry diethyl ether at room temperature over 1 hour, and the mixture was further stirred for 30 minutes.

After the reaction, the precipitated solid was collected by filtration and washed with 30 rJ of diethyl ether to give 4.72 g of sodium salt (yield: 5
7%).

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

Furthermore, after heating under reflux for 2 hours and lowering the temperature to room temperature,
The solvent in the reaction solution was distilled off under reduced pressure. Water the residue with 507r
The solution was dissolved in Ll, and 3N hydrochloric acid was added drop by drop under water cooling to make it slightly acidic. Since a solid precipitates out, the intermediate 4-hydroxy-2-
75 g (yield 31%) of mercapto-5-pyrimidine ethanol was obtained.

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

This 6-(2-bromoethyl)-2,3-dihydro-
5H-Thiazo o-[3,2,a)pyrimidin-5-one hydrobromide 0.50 g (1.5 mmol), (4-
fluorobenzene)thio-1-piperidine 0.31g (
1.5 mmol), potassium iodide 0.10 g (5.8 mmol), potassium carbonate 0.40 g (2.9 mmol)
was added to methyl isobutyl ketone 5 (7), and after reaction and post-treatment in the same manner as in Example 4, 0.5 g of the target product (yield 8
7%).

'H-NMR spectrum (CDCI3 solution, p
pm) 1.61) ~ 2.20 (4H, m), 2.6
0 (4H, s), 2.80-3.24 (5H.

m), 3.48 (2H, t, J=7Hz), 4
．． 48 (2H, t, J・7Hz), 7.00 (2H
, dd, , J=7Hz), 7.40(2H, dd,
J-7Hz), 7.64(IH,s) Example 8 3-(2-(4-(4-fluorobenzoyl)-1-
piperidinyl)ethyl-6-methyl-2゜3-dihydro-5H-thiazolo(3,2,a)pyrimidine-
Production of 5-one (Compound No. 206) 3. l-acetoxy-3,4 synthesized by reacting 4-dibromo-butan-1-ol and acetic anhydride in the presence of a sulfuric acid catalyst.
-dibromobutane 7.25 g (25 mmol), 4-
Hydroxy-2-mercapto-6-methyl-5-pyrimidine 3.51 g (25 mmol), potassium carbonate 3.1
2g (23 mmol) in DMF 31mj at 60°
C. Stirred for 7 hours. After the reaction, DMF was distilled off and water
After adding 0 m/, acetic acid was added dropwise to bring the pH to 7.

The resulting aqueous solution was extracted twice with 50 mt' of ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After removing sodium sulfate 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/l → ethyl acetate) 5, and the intermediate 3-(2-acetoxyethyl)-6-methyl-2 ,3-dihydro-5H-thiazolo[3,2,a)pyrimidin-5-one 3.63g (
A yield of 54% was obtained.

0.1 g of the obtained intermediate was heated under reflux with 9 times the amount of 48% hydrobromic acid to form the intermediate 3-(2-bromoethyl)-6-methyl-2,3-dihydro-5H-thiazolo(
3,2,a) Converted to pyrimidin-5-one (yield 0.78 g, yield 73%).

3-(2-bromoethyl)-6-methyl-2,3-dihydro-5H-thiazolo(3,2,a)pyrimidine-5
-one 0.78 g (2,8 mmol), 4-(4-fluorobenzoyl)-1-piperidine 0.66 g (2,3
1.59 g (11.6 mmol) of potassium carbonate and 0.05 g of potassium iodide were heated under reflux in 40 mt' of methyl isobutyl ketone for 8 hours.

After the reaction is complete, add 50 mt of water and add 50 mt of chloroform.
1 was extracted three times. The chloroform layer was dried using a conventional method.
After concentration, separation by silica gel column chromatography (developing solvent: ethyl acetate/methanol = 2073),
Purification was performed to obtain 0.05 g (yield: 6%) of the target product.

H-NMR spectrum (CDC13 solution, pp
m) 1.40-2.16 (8H, m), 2.20 (
3H,s), 2.48 (2H,t, J7Hz),
2.66-3.14 (3H, m), 3.28 (IH
, d, J=10Hz).

3.66 (IH, dd, J=10Hz), 5.10 (
IH, q, J=7Hz), 5.96 (IH, s),
7.00 (2H, dd, J=7Hz), 7.40
(2H, dd, J=7Hz) Example 9 3- (2-(4-(4-fluorobenzoyl)=1-
piperidinyl)ethyl]-2-methyl-4-one-3,
Preparation of 4,5,6,7,8-hexahydroquinazoline (Compound No. 300) Acetamidine Hydrochloride 16. Ig (170 mmol)
, 38.17 g (340 mmol) of potassium t-butoxy were added to ethanol 5007, and the mixture was stirred at room temperature. To this solution, 29 g (170 mmol) of ethyl 2-oxo-cycloheptanecarboxylate was added dropwise at room temperature, and after the dropwise addition was completed, the mixture was heated under reflux for 5 hours. After the reaction is complete, add 300ml of ethanol under reduced pressure! Distill, add 200ml of water, and add 3NHC.
After making the mixture acidic with 1, 300% of chloroform was added for extraction. The aqueous layer was further extracted with 300-chloroform,
The chloroform layers were combined and dried with magnesium sulfate. After removing magnesium sulfate, the chloroform layer was concentrated to yield the intermediate 2-methyl-4-one-3,4,5
, 18.5 g of 6,7,8-hexahydroquinazoline (
Yield: 66%).

A solution of 25.0 g (152 mmol) of this intermediate and 200 ml of dimethyl sulfoxide was dissolved in a suspension of 100 g (697 mmol) of 1-chloro-2-bromo-ethane and 6.1 g (153 mmol) of 60% sodium hydride. The mixture was added dropwise to the solution over 30 minutes under water cooling, and stirred for 1 hour. After heating up to room temperature, add 100 ml of water and 200 rnl of methylene chloride.
was 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/I), yielding intermediate 3-
7.5 g (yield 22%) of (2-(1-chloro)ethyl)-2-methyl-4-one-hexahydroquinazoline was obtained.

1.0 g (4.4 mmol) of this intermediate, 4-(4-fluorobenzoyl)-1-piperidine hydrobromide 1.
2g (4.4 mmol), potassium carbonate 1.22g (
8.8 mmol), 0.15 g of potassium iodide, and 50 d of methyl isobutyl ketone and post-treated in the same manner as in Example 8 to obtain 0.65 g (yield: 37.2%) of the target compound.

'! (-NMR spectrum (CDC1, solution,
ppm) 1.50-2.10 (8H, m), 2.10
~2.40 (3H, m), 2.40~2.88 (8H
, m), 2.90-3.48 (3H, m), 4.1
4 (2H, t, J=7Hz).

7, 16 (2H, dd, J=7Hz), 8.00 (
2H, dd, J=7Hz) Example 10 3-(2-(4-(4-fluorobenzoyl)-1-
piperidinyl)ethyl]-2-methyl-4-one-3,
Preparation of 4-dihydroquinapurine (Compound No. 304) Ethylacetimidate hydrochloride 89 (0.72 mmol) and potassium carbonate 0.1 g (0.72 mmol) were added to 10 methanol at room temperature for 30 minutes. Stirred. To this solution was added 0.1 g (0.72 mmol) of 2-amino acid benzoic acid, and the mixture was stirred at room temperature for 6 hours, then heated to 70 °C for 7 hours.
Time reacted. After the reaction, methanol was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol = 20/l) to obtain the intermediate 2-methyl-4-one-3,4 -0.06 g (yield 52%) of dihydroquinazoline was obtained.

The desired compound could be synthesized by chloroethylating this intermediate and reacting it with 4-(4-fluorobenzoyl)-l-piperazine hydrobromide using the method described in Example 9 (yield: 58%).

'H-NMR spectrum (1g CDC solution, p
pm) 1.60~2.00 (4H, m), 2.08~
2.44 (2H, m), 2.72 (3H, s).

2.72 (2H, t, J=7Hz), 2.88-3.
36 (3Fl, m), 4.24 (2H, t.

J=7Hz), 7.12(2f(,dd, J=7H2
), 7.30-7.78 (4H, m).

7.96 (2H, dd, J=7Hz), 8.22 (I
H, d, J=7Hz) Hereinafter, compound 302.
306, 308, 309° 310, and 312 were synthesized, and the spectral data are summarized in Table 3.

(Margin below this page) Example 11 Table 3 Fluorophenylthio)-1-piperidino)ethyl)-2,3-dihydro-7-
Methyl-5H-thiazolo(3,2,a)pyrimidine-5
Preparation of -one (Compound No. 202) 4-chloro-1-methylpiperidine hydrochloride 3.4 g (20 mmol), 4
- Fluorophenyl mercaptan 2, 56 g (20 mm
A mixture of 6.07 g (44 mmol) of potassium carbonate and DMF 2 (W) was stirred at 100°C for 4 hours.

The mixture was added to 100 g of ice water, adjusted to pH 12 with IN-NaOH, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.

By molecularly distilling the residue, 3.58 g of 4-(4-fluorophenylthio)-1-methylpiperidine was obtained as a pale yellow oil (b, I), 135-14
5°C/7mmHg).

Add 2.58 g (23.8 mmol) of ethyl chloroformate to a mixture of 3.54 g (15.8 mmol) of 4-(4-fluorophenylthio)-1-methylpiperidine and 30 mmol of toluene.
After a mixed solution of 3 ml of toluene and 3 ml of toluene was added dropwise at room temperature, the mixture was heated under reflux for 5 hours. After cooling, the mixture was added to 50 rnl of sodium bicarbonate solution and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. By separating and purifying the residue using silica gel column chromatography,
0.97 g of -ethoxycarbonyl-4-(4-fluorophenylthio)piperidine was obtained as a colorless oil.

A mixture of 0.97 g (3.4 mmol) of -ethoxycarbonyl-4-(4-fluorophenylthio)piperidine and a 47% aqueous HBr solution 5 was stirred at 130'C for 3 hours. After cooling, add I N-NaO to 100 g of ice water.
After adjusting the pH to 12 with H, the mixture was extracted twice with ethyl acetate.

The organic layer was washed with saturated brine, 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 0.66 g (3,0 mmol) of 4-(4-fluorophenylthio)piperidine
By reacting, 0.83 g of the target product was obtained (
yield 6%).

'H-NMR spectrum (CDC13 solution, p
pm) 1.53-2.15 (6H, m), 2.23
(3H, s), 2.32-2.78 (4H.

m), 2.83-3.06 (3H, m), 3.41
(2H, t, J=9Hz), 4.42 (2H, t,
J=9Hz), 6.98 (2H, t, J=9Hz)
, 7.41(2)1. dd, J=5.9Hz) 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)pyrimidin-5-one (Compound No. 2
04) Production of 3-hydroxy-8-methyl-8-azabicycloC3,
2,1) 10 g (71 mmol) of octane was dissolved in 20 ml of chloroform, and a mixed solution of water-cooled methanesulfonyl chloride 1004- and 20 mt' of chloroform was added dropwise over 1 hour. After further stirring at room temperature for 2 hours, 1
In addition to 50 mt' of 0% aqueous sodium carbonate solution, the organic layer was extracted twice with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to give 3-methanesulfonyloxy-8-methyl-8. -4.01 g of asabicyclo(3,2,1)octane were 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], 6-(2-bromoethyl)
-2,3-dihydro-7-methyl-5H-thiazolo(3
,2,a) Pyrimidin-5-one hydrobromide 1.1
g (3,1 mmol) and 0.63 g (2,7 mmol) of 3-(4-fluorophenylthio)-8-azabicyclo(3,2,1)octane to obtain the desired product as a pale yellow oil. .56g was obtained (yield 39%).

'H-NMR spectrum (CDCI3 solution, p
pm) 1.5-2.1 (8H, m), 2.27 (3H
, s), 2.3-2.7 (4H, m).

3.0-3.4 (3H, m), 3.43 (2H, t,
J=8Hz), 4.44 (2H, t.

J=8F(z), 6.99(2F(,t, J=9Hz
), 7.42 (2H, dd, J=5.9Hz) Example 13 4- (2-(4-(4-fluorobenzoyl)-1-
Production of piperidino)ethoxy)-2-methyl-1,2-dihydrophthalazin-1-one (compound number 400) 2-methylphthalazide 0.88 g (5 mmol), 2
-bromochloroethane 6.9 g (48 mmol),
Potassium carbonate 0.76g (5.5mmol) and DM
The mixture of F 10d was stirred at 80"C for 30 minutes. After cooling, it was added to 50 g of ice water and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Residue By separating and purifying with silica gel column chromatography, 4-(2-chloroethoxy)-2-methyl-1°2-dihydrophthalazin-1-one 0.91
g was obtained 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)
By reacting 1), 0.78 g of the target product was obtained as a pale yellow oil (yield 57%).

') f-NMR spectrum (CDCI3 solution,
ppm) 1.7-2.1 (4H, m), 2.34 (
IH, +n), 2.86-3.23 (6H, m).

3,74(3H,s), 4.46(2H,t, J
=9Hz), 7.13(2H,t, ,19Hz)
, 7.70-8.05 (5H, m), 8.40 (I
H, dd, J = 3.6 Hz) Example 14 2-(2-(4-(4-fluorophenylthio)-1-
Production of (compound number 404) 4-methoxy-1,2-cyhydrophthalazin-1-one (piperidino)ethyl) A mixed solution of 11.84 g (80 mmol) of phthalic anhydride and 80 ml of ethanol was cooled with water. A mixed solution of 6.68 g (88 mmol) of 2-hydroxyethylhydrazine and 20 g of ethanol was added dropwise, and the mixture was stirred for 1 hour. The precipitated crystals were filtered, washed with ethanol, and dried to give 2-(2-hydroxyethyl)phthalazide 10°5.
9g was obtained.

2-(2-hydroxyethyl)butalazide 10.59g
(51.4 mmol), potassium carbonate 7.83 g (5
7 mmol), DMF 77- and dimethyl sulfate 8.
A mixture of 08g (64mmol) was stirred at 120°C for 3 hours. After cooling, add 300g of ice water and dilute with methylene chloride.
Extracted twice. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and recrystallized from methylene chloride-hexane to give 2-(2-hydroxyethyl)-4-methoxy-1.
4.82 g of 2-dihydrophthalazin-1-one was obtained.

2-(2-hydroxyethyl)-4-methoxy1.2-
Dihydrophthalazin-1-one 4.82g (21.8m
mol), thionyl chloride5. l1g (43mmol
) and ethyl ether 100rd at room temperature.
．． Stirred for 5 hours. Hexane 50- was added to the reaction mixture and cooled on ice, and the precipitated crystals were filtered, washed with hexane, and dried to give 2-(2-chloroethyl)-4-methoxy-1,2-dihydrophthalazine-1- On 4, 2
1 g was obtained.

In the same manner as in Example 1, 2-(2-chloroethyl)-
0.57 g (2,4 mmol) of 4-methoxy-1,2-dihydrophthalazin-1-one and 0.5 g (2,4 mmol) of 4-(4-fluorophenylthio)piperidine
0.23g of the target product was obtained as a pale yellow oil (yield 23%).

H-NMR spectrum (CDC1, solution, I)
I) m) 1.48-2.33 (4H, m), 2.7
3-3.10 (7H, m), 3.96 (3H.

s), 4.26 (2, tj=7Hz), 6.97 (
2H, tj=9Hz), 7.41(2H, dd, J=
5.9Hz), 7.66-8.01 (3H, m),
8.38 (IH.

, dd, J=3. 6Hz) Example 15 Production of 2-(2-(4-(4-fluorobenzoyl)-1piperidino)ethyl)-4-methoxy-1,2-dihydrophthalazin-1-one (Compound No. 402) Example 2-(2-chloroethyl)-
0.4 g (1,7 mmo 1) of 4-methoxy-1,2-dihydrophthalazin-1-one and 0.48 g of 4-(4-fluorobenzoyl)piperidine hydrobromide
(1.7 mmol) to obtain 0.2 g of the target product as a pale yellow oil (yield 24%).

'H-NMR spectrum (CDC13 solution, I
) I) m) 1.70-2.42 (6H, m), 2.8
8 (2H, t, J=8Hz), 3.05-3.31 (
3H, m), 3.98 (3H, s), 4. ．． 30(
2H, t, J=8Hz).

7.12 (2H, t, J=9Hz), 7.70-8.
04 (5H, m), 8.40 (IH.

dd, J=3. 6Hz) Example 16 (A) (B) (C) (D) (One of X and Y represents N and the other represents CH) Anhydrous 2,
3-pyridinedicarboxylic acid (A) lOg (6,71m
A solution of 3.4 g (74 mmol) of methylhydrazine in which 201 n1 of ethanol was dissolved was added dropwise to the solution under water cooling.

The mixture was stirred for 3 hours under water cooling, and then left at room temperature overnight. The precipitated crystals were filtered to obtain 5.19 g of compound (B) (yield: 44%).

Compound (B) 3. OOg (16.9 mmol)
, 2-bromo l-chloroethane 12g (85mmol
) and potassium carbonate 2.1g (34mmol) in DM
E 30rlLl and reaction was carried out at 60°C for 2 hours. After cooling, brine was added and extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate and filtering off the desiccant,
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) 0.80g (3.34mmol), 4
-(4-fluorobenzoyl)-piperidine 0.96g
(3,34 mmol) Potassium carbonate 0.46 g (3
, 34 mmol) and potassium iodide 0.2 g (1,
2 mmol) was added to DMF 10-, and the reaction was carried out 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, the desiccant was filtered off, and then concentrated. The obtained crude product was purified by column chromatography (silica gel 60, chloroform/ethanol = 20/l) to obtain 0.45 g of compound (D) (yield 33%).

NMR (CDC13) δ: 1.7-2.1 (4H), 2
．． 1-2.5 (4H), 1.9-2.4 (3)1)
, 3.77+3.82 (S+S, 3H), 4.1
2 (q.

2H,J=5.8Hz), 7.15(t, 2H,J
=9H2), 7.72(dd.

IH, -J+=9.4Hz, b・4.7Hz), 7
．． 9-8.1 (2H), 8.33+8.73 (ddd
dd, IH, J, = 8.6H2J, = 1.8H2)
, 9.0-9゜2 (IH) Melting point niol Example 17 (E) (F) (G) (H) (One of A and B is N and the other is CH)
3.4-pyridinedicarboxylic acid (E) 5.00g (
29.9 mmol), methylhydrazine 1.38 g
(29.9 mmol) and DCC12.3 g (60 [
1111101) was added to 50 m of THF (!) under water cooling. The mixture was stirred for 1 hour under water cooling and overnight at room temperature, and the precipitate deposited was collected by filtration. The product was recrystallized with ethanol to obtain crude crystals 1.
2g was obtained. The obtained crude crystals were added to 20 mt' of 10% aqueous sodium hydroxide solution, and insoluble matter was 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 compound (F) 3. x7g
I got it.

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

NMR (CDC12) 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
), 7.0-7.4 (2H), 766-8.3 (3
H), 9.0 (d, IH, J5, 4Hz), 9.6
8 (IH) Melting point: 115-130°C Example 18 Tablets containing 10 μ of active ingredient are manufactured as follows.

Active Ingredients Corn Starch Microcrystalline Cellulose Polyvinylpyrrolidone (as 10% aqueous solution) Carboxymethylcellulose Calcium Magnesium Stearate Talc Per tablet 10 ■ 55 ■ 35 ■ 5 ■ 10 ■ 4 ■ 1 ■ Total 120 ■ Active ingredients, starch and crystalline cellulose 80 Pass through a mesh sieve and mix thoroughly. The obtained powder is mixed with a polyvinylpyrrolidone solution and granulated, and then passed through an 18-mesh sieve. The granules produced in this way are
Dry at 0°C and sieve again using an 18-mesh sieve. Calcium carboxymethyl cellulose and magnesium stearate and talc are added to the granules, previously passed through an 80 mesh sieve, and after mixing are produced in a tablet machine into tablets each weighing 120 square centimeters.

Example 19 Tablets containing 100 μ of active ingredient are manufactured as follows.

Active ingredients per tablet: 100 ■ Corn starch 50 ■ Crystalline cellulose 42 ■ Light silicic anhydride
7■Magnesium stearate
1■Total 200■ Pass the above ingredients through an 80 mesh sieve and mix thoroughly. The obtained powder is compression molded to produce tablets weighing 200 square meters.

Example 20 Capsules containing 50 μ of active ingredient are prepared as follows.

Active Ingredients Corn starch per capsule 50 ■ 40 ■ Lactose 5 ■ Magnesium stearate 5 ■ Total 10
0 Combine the above ingredients and pass through an 80 mesh sieve to mix thoroughly. Fill 100 square capsules of the obtained powder.

Example 21 A ready-to-dissolve injection in a vial containing 5 ml of active ingredient is produced as follows.

Active ingredient per vial: 5 ■ Mannitol 50 ■ When using, 1 portion of distilled water for injection
Dissolve with i and use.

Example 22 An ampoule injection containing 20 ml of active ingredient is prepared as follows.

Active ingredient per ampoule 20 ■ Distilled water for sodium chloride injection 18 ■ Adequate amount total 27 nl Example 23 An adhesive patch preparation containing 17.5 ■ of the active ingredient is produced as follows.

10 parts of ammonium polyacrylate are dissolved in 60 parts of water. Meanwhile, add 2 parts of glycerin diglycidyl ether to 10 parts of water.
Dissolve while heating. Furthermore, in the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water, and 1 part of the active ingredient were dissolved with stirring. Next, while stirring the aqueous solution of ammonium polyacrylate, an aqueous solution of glycerin diglycidyl ether and an aqueous solution containing active ingredients of polyethylene glycol were added and mixed to create a drug-containing hydrogel solution.
The active ingredient was applied to a flexible plastic film at an amount of 0.5 cm per square centimeter, the surface was covered with release paper, and the film was cut into 35 square centimeters to prepare a preparation.

Example 24 An adhesive patch containing 10 cm of active ingredient is prepared as follows.

100 parts of sodium polyacrylate, 100 parts of glycerin
A mixed aqueous sol solution containing 150 parts of water, 0.2 parts of triepoxypropyl isocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25 parts of propylene glycol, and 15 parts of the active ingredient was prepared.

Next, this sol solution was applied to a thickness of 100 μm on the nonwoven surface of a composite film consisting of a rayon nonwoven fabric and a polyethylene film to form an adhesive layer containing the agent fJ-. The content of release aids (isopropyl myristate and propylene glycol) contained in this layer was approximately 20% by weight. Thereafter, it was crosslinked at 25°C for 24 hours, a release film was attached to the adhesive interface, and this was further cut into 35 square centimeters to prepare a preparation.

〔Effect of the invention〕

Compound (I) of the present invention can be used in vitro and in vitro.
v.

Pharmacological tests conducted in 2015 confirmed that it has excellent anti-serotonin and anti-dopamine effects.

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

In the in vivo test, using mice, the antiserotonin effect was evaluated by the effect of the compound of the present invention on quipazine-induced head switch, and the antidopamine effect was
The effects of the compounds of the present invention on apomorphine-induced climbing behavior were evaluated, but both results were
It showed excellent anti-serotonin and anti-dopamine effects, in good agreement with the results of the itro test. Furthermore, when the antihypertensive effect of the compound of the present invention was tested in spontaneously hypertensive rats, it showed a stronger antihypertensive effect than the control ketanserin.

Furthermore, when the compound of the present invention was tested for toxicity, it was found that the compound had relatively low toxicity and could be used as a drug with a wide safety margin.

Test examples will be shown below to explain in detail the pharmacological activity of the compounds of the present invention.

Test Example 1 (Affinity with serotonin 2 receptor) ['H]
Ketanserin Binding Activity The affinity activity of the compounds of the present invention for serotonin 2 receptors was evaluated based on their ability to displace and bind [3H]ketanserin from the frontal cortex membrane fraction prepared from the brains of male Wistar rats.

After decapitating the rat and removing the brain, the frontal cortex was removed.

This frontal cortex was soaked in 40 volumes of 50mM Tris-HCl buffer (
The mixture was homogenized in pH 7.6) and then centrifuged.

The pellet was homogenized again in 100 volumes of the same buffer and used for binding studies. The binding test was conducted by the following method. That is, the test drug and inM [3H]ketanserin were mixed with 50 mM
37° in Tris-HCl buffer (pH 7,6)
Incubate for 10 minutes at C. After completion, the reaction solution was suction filtered through a glass fiber filter (Whatman GF/B) and washed three times with buffer.

Filter scintillation cocktail (AC3II,
After mixing, the filter was placed in a filter (Amarjam) and left to stand overnight, and the radioactivity retained on the filter was measured using a liquid scintillation counter. Nonspecific binding was measured in the presence of 1 μM methysergide, and the drug concentration that inhibited specific binding by 50% was determined from the graph. Closed. Ki was determined by the following formula.

The results of this test are shown in Table 4.

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

The rat was decapitated, the brain was removed, and the striatum was removed. The striatum was diluted with 40 volumes of 50mM )')suhydrochloric acid buffer (
The mixture was homogenized in pH 7.6) and centrifuged. The pellets were rehomogenized in 50 volumes of the same buffer and used for binding studies. The binding test was conducted by the following method. That is, striatum wet tissue weight 20 μl/rILl, 100 μl of test drug, and 0.5 nM [3H]spiperone were added at 50 μl/rILl.
) in Lis-HCl buffer (pH 7,6)
Incubate for 10 minutes at 7°C. After completion, the reaction solution was suction filtered through a glass fiber filter (Whatman GF/B) and washed three times with buffer.

Filter with scintillation cocktail (AC3II,
After mixing, the filter was placed in a filter (Amarjam) and left to stand overnight, and the radioactivity retained on the filter was measured using a liquid scintillation counter. Non-specific binding is 1 μM (+)
Measured in the presence of butacramol, and determined from the graph the drug concentration that inhibits specific binding by 50%, ICs. Closed. Ki
was calculated using the following formula.

IC6゜ The results of this test are shown in Table 4.

Test Example 3 (Antipsychotic effect) Using 10 or more 5-week-old ddY male mice per group,
Anti-serotonin effects (hereinafter referred to as anti-5-HT) and anti-dopamine effects (hereinafter referred to as anti-DA) were investigated using the following methods.

All test drug doses were 1/-, and the administered volume was 0.
．． The suspension was suspended in 0.5% carboxymethyl cellulose (CMC)/physiological saline to a concentration of 1 mN/10 g, and administered intraperitoneally.

■ Kipajin's Hevdotwitch (head twit
ch) (anti-5-HT effect) 30 minutes after intraperitoneal administration of the test drug, quipazine (3■/kg)
was administered intraperitoneally, and 10, 20, and 30 minutes later, each mouse was given a head-twitch for 2 minutes each time.
d twitch) was measured. The results were expressed as inhibition rate (%) relative to the control.

The results of this test are shown in Table 5.

■ Effect of apomorphine on climbing behavior (anti-DA effect) Intraperitoneal administration of the test drug 30 minute diameter apomorphine (3■/
kg) was administered subcutaneously, and the climbing (cljmbing) behavior time of the mice was measured for 20 minutes.

The results were expressed as inhibition rate (%) relative to the control.

The results of this test are shown in Table 5.

Test Example 4 (hypertensive effect) 20-25 week old male SHR (spontaneous hypertensive rats)
Three or more animals were used per group. The test drug was administered intraperitoneally, and 3
Blood pressure was measured non-invasively at 0 and 60 minutes later. Blood pressure was measured using a non-invasive blood pressure measuring device for rats (Muromachi Kikai MK-1).
000 type), the rats were placed in a heating box at 36°C for 10 minutes, and then the systolic blood pressure was measured from the tail vein pulse wave. The results were expressed as the 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) 1 group of dcty male mice (body weight 25-30 g)
Six animals were used. One day after administering the test drug intraperitoneally? The presence or absence of death was observed. 5096 Lethal dose LDso (mg
/kg) and the results are shown in Table 7.

Table 4 - ■ 5- Effects on HT2 and D2 receptors (margins below this page) > 1000 11.5 46.6 8.57 8.30 1.60 2.94 4.38 2.82 7.99 > 1000 > 1000 33.7 > ioo.

No. Table - ■ No. Table - ■ 1O98 24,8 37,2 1O93 51,5 56,3 (Margins below this page) Table -■ Table 7 acute toxicity Table 6 (Mean value ± S, E,.

n=3-6)

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ・・・・・・・・・・・・(I) [However, in the formula, m represents an integer from 1 to 3. , n is zero or 1~
2, X represents CH or N, Y represents CO or S, (Het) represents formulas (1) to (15) (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼; (2 )▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4)▲There are mathematical formulas, chemical formulas, tables, etc.▼; (5)▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; (7) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (8) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; (9) ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ (10) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; (11)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (12) ▲There are mathematical formulas, chemical formulas, tables, etc.▼; (13)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (14) ▲There are mathematical formulas, chemical formulas, tables, etc.▼; (15)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in formulas (1) to (15), R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or represents a lower alkoxy group, and R
^2 represents a lower alkoxycarbonyl group, R^3 represents a lower alkyl group, R^4 represents a hydrogen atom or a lower alkylcarbonyl group, R^5 represents a hydrogen atom, a lower alkyl group, or a lower 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, and R^1^0 represents a lower Indicates an alkyl group, R^1
^1 represents a lower alkyl group, R^1^2 represents a lower alkyl group, and R^1^3 represents a lower alkyl group); however, (Het )
is formula (4), when X is CH and Y is CO and n is zero and R^4 is a hydrogen atom, R^5 represents a lower alkoxy group] cyclic compound. 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ ・・・・・・・・・・・・(I) [However, in the formula, m represents an integer from 1 to 3, and n represents 0 or 1. ~
2, X represents CH or N, Y represents CO or S, (Het) represents formulas (1) to (15) (1) ▲ Numerical formulas, chemical formulas, tables, etc. ▼; (2 )▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4)▲There are mathematical formulas, chemical formulas, tables, etc.▼; (5)▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; (7) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (8) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; (9) ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ (10) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼; (11)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (12) ▲There are mathematical formulas, chemical formulas, tables, etc.▼; (13)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (14) ▲There are mathematical formulas, chemical formulas, tables, etc.▼; (15)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in formulas (1) to (15), R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or represents a lower alkoxy group, and R
^2 represents a lower alkoxycarbonyl group, R^3 represents a lower alkyl group, R^4 represents a hydrogen atom or a lower alkylcarbonyl group, R^5 represents a hydrogen atom, a lower alkyl group, or a lower 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, and R^1^0 represents a lower Indicates an alkyl group, R^1
^1 represents a lower alkyl group, R^1^2 represents a lower alkyl group, and R^1^3 represents a lower alkyl group); however, (Het )
is formula (4), when X is CH and Y is CO and n is zero and R^4 is a hydrogen atom, R^5 represents a lower alkoxy group] A pharmaceutical composition comprising, as an active ingredient, a compound selected from the group consisting of cyclic compounds, pharmaceutically acceptable acid addition salts thereof, or stereoisomers thereof.