WO1998031679A1

WO1998031679A1 - Thiophene compounds and medicinal use thereof

Info

Publication number: WO1998031679A1
Application number: PCT/JP1998/000077
Authority: WO
Inventors: Takanobu Kuroita; Yoshifumi Togo; Masakazu Fujio; Takashi Futamura
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.
Priority date: 1997-01-21
Filing date: 1998-01-09
Publication date: 1998-07-23
Also published as: AU5343498A; JP3185222B2

Abstract

Thiophene compounds represented by general formula (1), optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates of the same, wherein each symbol is as defined in the specification; and medicinal compositions containing as the active ingredient the compounds of general formula (1), optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates of the same together with pharmaceutically acceptable additives. Because of exerting selective and potent blocking effects on D4 receptors rather than D2 receptors, these compounds are useful as antipsychotic agents efficacious not only against positive symptoms typified by hallucination and delusion characteristic to the acute stage of schizophrenia but also negative symptoms such as emotional torpidity, abulia and autism. Moreover, they are applicable as useful antipsychotic agents which are excellent in oral absorbability, bioavailability and intracerebral transmigration properties while showing relieved side effects caused by the administration of the existing antipsychotic agents with a D2 receptor antagonism, such as extrapyramidal symptoms and disendocriasis. These compounds are also usable as remedies for alcohol dependence and drug abuse.

Description

Specification

Thiophane compounds and their pharmaceutical uses

Technical field

The invention Dopami emissions D ₄ (hereinafter, pursuant to the approximately normal for Dopami emissions receptor subtypes described that. After D _4.) Relates to a novel Chiofue emission compounds with affinity for receptors, these Chiofen compounds Dopamine receptor blockers containing are used in the medical field as central nervous drugs, especially antipsychotics, drugs for alcohol dependence, and drugs for drug abusers.

Background art

D ₄ about the central dosage having affinity for receptors, for example, patent applications as follows have been published. International Patent Application Publication WO 9 4Z1 0 1 6 2, WO 94

1 6 3 0 No., the WO 9 4/2 1 6 2 6 No., tricyclic heteroaromatic compounds having an affinity for the D ₄ receptor has been disclosed in International Patent Application Publication WO 9 4 Z 2 1 6 2 7 No., WO 9 4Z2 1 6 2 8 No., in WO 9 4Z2 4 1 0 5 items, and in-Dole derivatives having affinity for D ₄ receptor is disclosed in International Patent application Publication WO 9 4 / 2 0 4 5

No. 9, the WO 9 4/2 0 4 9 7 No., etc. Piropirijin derivatives having affinity for D ₄ receptor is disclosed in International Patent Application Publication WO 9 4/2 1 6 1 5 No., WO 9 4Z

The 2 2 8 3 No. 9, etc. Benzuimidazo Ichiru derivatives having affinity for D ₄ receptor is disclosed. Furthermore, International Patent Application Publication WO 9 4Z 1 0 1 4 5 No., the WO 9 4/2 0 4 7 1 No. and pyrazole derivatives Contact and quinolinone port emissions derivatives having affinity for each D ₄ receptor disclosed Have been. Furthermore, Japanese Patent Application Laid-Open No. 7-70135 discloses a D ₂ receptor blocking action, a serotonin 2 (5-HT ₂ ) receptor blocking action and a serotonin _1A (5-HT _1A ) receptor stimulating action. 4,5,6,7-Tetrahydrocheno [2,3-c] pyridine derivatives are known. JP Hei 8 _ 3

The 2 5 2 5 7 No., piperidines Rajin compounds having selectivity for the D ₄ receptor, Piperi Gin compound and 1, 2, 5, 6-tetrahydropyridine compound is disclosed. Japanese Patent Application Laid-Open No. Hei 9-310600 discloses a benzocerenbiperazine compound having an antipsychotic effect. Compounds are disclosed. GB 2 3 1 1 0 1 to 0 No., D ₄ receptor that having a affinity 4 _ (Benzochiofen one 2-I le) one 1- (4 one black port benzyl) one 1, 2, 3, Tetrahydropyridine derivatives such as 6-tetrahydropyridine are disclosed.

Antipsychotics to schizophrenia adaptive diseases, the most have a common pharmacological action of receptor blockade of dopamine which is one of the brain neurotransmitter, particularly potent D ₂ receptors blocking action Is shown. These drugs (typical antipsychotics) are effective for positive symptoms, mainly hallucinations and delusions, which are characteristic of the acute phase of schizophrenia, but they are not effective for emotional weakness, inactivity, autism, etc. It has been pointed out that it has almost no effect on the negative symptoms of cysteine. In addition, side effects such as extrapyramidal symptoms (eg, late-onset dyskinesia, acute dystonia, and akathisia) and endocrine abnormalities (eg, hyperprolactinemia) that occur during acute administration and long-term use are serious problems. I have.

Dopamine receptors have previously been identified by pharmacological techniques as being classified into two receptor subtypes based on their ligand-binding properties and their form of association with adenylate cyclase [Nature et al. Vol. 27, p. 93 (1977)]. That is, D, a receptor that activates adenylate cyclase via a promoting G protein to produce cyclic AMP, and a receptor type, and suppresses adenylate cyclase via an inhibitory G protein, resulting in cyclic cycling. AMP c but is suppresses D ₂ receptor type production, along with the revolutionary development in recent years in molecular biology, five different genes of Dopami emissions receptors have been black-learning, D, family Lee belonging Di, and D ₅ receptor, D ₂ family one belonging D _2, D _3, D ₄ receptor is it is a clearly ivy classified into [Trends' in 'Pharmacol logical' Saienshizu (T rendsin P Harma col. S ci.) Vol. 15, p. 264 (1994)]. The Haroperi Dole a typical antipsychotic exhibits a high affinity to D ₂ receptors than D ₄ receptor, the effective clozapine also less negative symptoms extrapyramidal side effects D ₂ receptors than D ₄ receptor (Nature), Vol. 350, pp. 6110 (1991); —Macrological * Sciences (Trendsin Pharmacol. Sci.), Vol. 15, p. 264 (1994)]. Moreover, also a reported [Torre lens that effective therapeutic plasma concentration of clozapine which correlates with the affinity constant for the D ₄ receptor. In Pharmacology logical Sciences (T rendsin P ha rma col. S c i. ) Vol.15, p.264 (1994)]. Further, results of the binding studies with post-mortem brains of schizophrenic patients, is also reported that D ₄ receptor was also increased 6-fold compared to normal individuals [Neichiya one (Na ture) 3 6 5 Volume 44 1 page (1 9 9 3)]. Therefore, it is highly possible that D ₄ receptors are involved in the action site of the pathogenesis of schizophrenia or therapeutic agents. Moreover, the difference is recognized between subtypes in the brain distribution of Dopami emissions receptor, D ₂ receptors for most often in the striatum, D ₄ receptors in the cerebral cortex frontal lobe which governs the emotional function It is clear that it is the most abundant.

Further, D ₄ receptor knockout mice created by gene recombination (micelackingdo am ine D ₄ receptors) Chikaraku, Anore call, cocaine, it is reported that susceptibility is enhanced to drugs, such as Metanfeta Mi emissions [cell (Cell), Vol. 90, p. 991 (1997)].

Disclosure of the invention

From these, selective D ₄ receptor antagonists can be expected as effective antipsychotics also less positive and negative symptoms extrapyramidal side effects. The present invention shows a selective and strong blocking action on D ₄ receptor, characteristic hallucinations in the acute phase of schizophrenia, not only positive symptoms centering on such delusions, apathy and inaction, self is also effective against negative symptoms, such as closing, also seen when administering a conventional antipsychotic drug with D ₂ receptors blocking action, extrapyramidal symptoms and endocrine abnormalities and time were the side effects is reduced Another object of the present invention is to provide a highly safe antipsychotic drug which has excellent oral absorbability, bioavailability, and localization in the brain. Further, the present invention by showing a selective and strong blocking action on D ₄ receptor, and to provide a alcoholic patients and drug abusers therapeutic agents. As a result of intensive studies, the present inventors have found that a novel thiophene compound represented by the following general formula (1), an optical isomer, a pharmaceutically acceptable salt thereof or a hydrate thereof is a D ₂ receptor. It began looking to have selective and strong blocking action on D ₄ receptor than. Therefore, the compound of the present invention exerts an effect not only on positive symptoms such as hallucinations and delusions that are characteristic in the acute phase of schizophrenia, but also on negative symptoms such as dullness, inactivity, and autism. , it is reduced conventional antipsychotics side effects such as extrapyramidal symptoms and endocrine abnormalities seen when administered has at D ₂ receptor antagonism, and oral absorption, bioavailability and foremost, excellent migration in the brain The present inventors have found that they can be useful antipsychotics and that they can be useful therapeutics for alcohol-dependent patients and drug abusers, and have completed the present invention.

That is, the present invention relates to the following.

(1) General formula (1)

[In the formula, A represents methylene, one C (= 0) one or one CH (OR ¹ )-(wherein, R ¹ represents hydrogen or alkyl.)

D is absent or represents a linear or branched alkylene chain having 1 to 8 carbon atoms,

n represents 0 or an integer of 1 to 3,

R ² represents hydrogen or alkyl,

R ³ represents hydrogen, halogen, alkyl, acyl, amino or nitro; R ⁴ represents hydrogen or alkyl;

The bond represented by Q—T is CH, CH ₂ —N, (CH ₂ ) ₂ —N, CH ₂ — C (R ⁵ ) (Wherein, R ⁵ represents hydrogen, hydroxy, alkyl or alkoxy.) Or CH 2 C,

E represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent. ]

Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

(2) The thiophene compound of the above (1), wherein R ⁴ is hydrogen in the general formula (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

(3) In the general formula (1), A is methylene, one C (= 0) one or

-CH (0H) indicates one,

D represents a linear or branched alkylene chain having 1 to 5 carbon atoms,

n indicates 1;

R ² represents hydrogen,

R ³ represents hydrogen or alkyl,

R ⁴ represents hydrogen,

The bond represented by Q—T represents CH ₂ —N or CH = C,

E is an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent, wherein the thiophene compound of the above (1), an optical isomer thereof, and a medicament thereof; Acceptable salts or hydrates thereof.

(4) 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-1-3-y Le) Pu mouth bread 1_ on,

3- (4- (4-chlorophenyl) piperazine-1-1-yl) 1-1-1 (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophene-3-yl) propa One-one-one-all,

1— (4-chlorophenyl) 1-41 (3— (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) propyl) piperazine, 1- (4-fluorophenyl) 1-4-1 (3- (4,5,6,7-tetrahydro--2-methylbenzo [b] thiophen-13-yl) propyl) pidazine,

4- (3- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propyl) 1- (3-trifluoromethylphenyl) piperazine,

4- (3- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) propyl) 1- (4-methylphenyl) piperazine,

1- (4-chlorophenyl) 1-4-1 (3- (2-ethyl-4,5,6,7-tetrahdrobenzo [b] thiophen-1-yl) propyl) piperazine,

1- (4—Chlorophenyl) 1—4— (3— (4,5,6,7-Tetrahydrobenzo [b] thiophene-3-yl) propyl) piperazine, and

4- (4-chlorophenol) 1-1 (3- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) propyl) 1,1,2,3 A thiophene compound of the above (1) selected from 6,6-tetrahydropyridine, an optical isomer, a pharmaceutically acceptable salt thereof or a hydrate thereof.

(5) A medicament comprising the thiophene compound of the above (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

(6) above (1) Chiofen compound, its optical isomers, D ₄ receptor blockers containing salt or hydrate thereof their pharmaceutically acceptable.

(7) A pharmaceutical composition comprising the thiophene compound of the above (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive. Specific examples of each group in the general formula (1) are as follows.

The linear or branched alkylene chain having 1 to 8 carbon atoms in D means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexmethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene Len, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene, getylmethylene, 1-ethylethylene, 2-ethylethyl Tylene, 1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, Examples thereof include 2-ethyltrimethylene and 3-ethyltrimethylene. A linear or branched alkylene chain having 2 to 5 carbon atoms is preferable, and ethylene, trimethylene or tetramethylene is particularly preferable.

n represents 0 or an integer of 1 to 3, and preferably n == l.

The alkyl of R ¹ represents an alkyl having 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, etc. Four alkyls are preferred.

As the alkyl for R ² , R ³ , R ⁴ and R ⁵ , the same as the alkyl for R ′ can be mentioned.

The term “acyl” in R ³ means alkenyl having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isoptyryl, etc., and preferably alkanol having 2 to 4 carbon atoms.

The alkoxy in R ⁵ represents alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxyquin, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, etc. Alkoxy having 1 to 4 carbon atoms is preferred.

Examples of the halogen in R ³ include fluorine, chlorine, and bromine.

Aryl in E means phenyl, naphthyl, 4-indanyl and so on. The aromatic heterocyclic group in E represents pyridyl, furyl, phenyl, pyrimidinyl and the like. The aryl and the aromatic heterocyclic group in E may have a substituent, and the substituent is a halogen such as fluorine, chlorine, or bromine; a haloalkyl having 1 to 4 carbon atoms such as trifluoromethyl; Alkyl having 1 to 4 carbon atoms, such as butyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl; methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy Examples thereof include alkoxy having 1 to 8 carbon atoms such as C, pentyloxy, hexyloxy, heptyloxy, and octyloxy; hydroxy; nitro; amino; methylamino; dimethylamino.

— As A—D—, A represents methylene, and D is preferably a straight-chain or branched alkylene chain having 1 to 5 carbon atoms. In particular, — A—D— is trimethylene. Certain cases are preferred. As R ² , hydrogen or alkyl is preferable, and hydrogen is particularly preferable. R ³ is preferably hydrogen or alkyl, and particularly preferably methyl. R ⁴ is preferably hydrogen or alkyl, and particularly preferably hydrogen. E is preferably aryl which may have a substituent. In particular, the aryl in E is preferably phenyl having 1 to 2 substituents such as naphthyl or halogen, methyl, trifluoromethyl, methoxy, etc., for example, 4-chlorophenyl, 4-fluorophenyl, 3_ Trifluoromethylphenyl, 4-methylphenyl and the like. As the aromatic heterocyclic group for E, phenyl, pyridyl or phenyl or pyridyl having 1 to 2 substituents such as halogen and methyl are preferable.

Expression

Factory

• The cyclic amino group represented by NT-E includes the following embodiments (a) to (e). Among these, a group of the formula (b) or (e) in which the bond represented by Q—T is CH ₂ —N or CH 2 C is preferred.

(a) (b) (c) R ⁴ R ⁴

• N NE

E

(d) (e)

Pharmaceutically acceptable salts of the compound of the general formula (1) include inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid) , Malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and ascorbic acid).

Since the compound of the general formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate, these hydrates (1Z10 hydrate, 12 water Hydrate, monohydrate, 3Z dihydrate, dihydrate, etc.) and solvates are also included in the present invention. When the compound of the general formula (1) has an asymmetric atom, at least two kinds of optical isomers exist. These optical isomers and their racemates are included in the present invention.

The compound of the general formula (1) and the compound of the present invention contained in the general formula (1) can be synthesized by a method represented by the following reaction formula. Each symbol in the reaction formulas has the same meaning as described above unless otherwise specified.

Method 1

(1-4) Bultan de la Sochete Cimiq de France (Bull. So Chim. Fr.) 122 A compound of the general formula (2) obtained according to the method described on page 52 (1955). Lewis acid (aluminum chloride, boron trifluoride, zinc chloride, iron chloride, salt) in a suitable solvent (such as nitrobenzene, methylene chloride, chloroform, dichloroethane or any mixture thereof) is used in a haloacyl halide (3). The compound of formula (4) can be obtained by reacting with tin oxide at room temperature or at the reflux temperature of the solvent for 1 to 24 hours under cooling. In a solvent that does not interfere with the reaction (such as methanol, ethanol, dimethylformamide, methylene chloride, chloroform, benzene, toluene, or a mixture thereof), potassium carbonate, sodium hydrogen carbonate, Triethylamine, pyridine, dimethylaminopyri A compound of the general formula (5) obtained according to the method described in Tetrahedron Letters, Vol. 37, p. 319 (1996), in the presence of a base such as gin. By reacting at room temperature to the reflux temperature of the solvent for 1 to 24 hours, the compound represented by the general formula (11-1) is obtained.

In addition, the compound of the general formula (1-1) is converted into a solvent that does not hinder the reaction (methanol, ethanol, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, getyl ether, or any mixed solvent thereof). Suitable reducing agent

(Sodium borohydride, borane, lithium aluminum hydride, etc.) and reacting for 1 to 24 hours under ice-cooling or heating, the general formula

The compound represented by (1-2) is obtained. In a solvent that does not hinder the reaction of this compound (112) (such as dimethylformamide, methylene chloride, chloroform, acetonitrile, benzene, toluene, dimethylsulfoxide, or a mixture of these in any proportion), a base ( By reacting with an alkyl halide (R'-C1, R'-Br, etc.) in the presence of sodium hydride, potassium carbonate, sodium methoxide, sodium ethoxide, etc., the general formula (1-3) ) Can be obtained.

Further, the compound represented by the general formula (1-2) is reacted with a solvent that does not hinder the reaction (dimethylformamide, methylene chloride, chloroform, acetonitrile, benzene, toluene, etc.) in the presence of sodium iodide, By reacting with silyl chloride at room temperature to the reflux temperature of the solvent for 1 to 8 hours, the compound represented by the general formula (1-4) can be obtained. Further, the compound of the general formula (1-4) can also be obtained by reacting the compound of the general formula (1-2) in trifluoroacetic acid with triethylsilane in the above reaction. Method 2

R ⁴ R ⁴

0 O

HN EtO-J! —ICHzJq-Y (CH ₂ ) qN, T- w

(5) (Y = CI or Br)

(q = l ~ 8) (7)

(6)

HO

Potassium carbonate, hydrogen carbonate, etc. in a solvent that does not hinder the reaction of the compound of general formula (5) (such as dimethylformamide, methylene chloride, chloroform, benzene, toluene, or a mixture of these in any proportion) Reaction with an ester halide of the general formula (6) using a base such as sodium, triethylamine, pyridin, or dimethylaminopyridine for 30 minutes to 24 hours under cooling, room temperature, or heating. As a result, a compound of the general formula (7) is obtained.

In a solvent (methanol, ethanol, acetone, dimethylformamide, acetonitrile, or a mixture of these in any proportion) which does not hinder the reaction of the compound of the general formula (7), lithium hydroxide, sodium hydroxide, etc. The compound of the general formula (8) is obtained by hydrolysis with an aqueous solution of In a suitable solvent (such as methylene chloride, chloroform, dichloroethane, acetonitrile, benzene, toluene, xylene, or a mixed solvent of any of these), the compound of the general formula (8) is reacted at a reflux temperature of thionyl chloride and the solvent. The reaction is carried out for up to 24 hours to obtain the corresponding acid chloride compound of the compound of the general formula (8). Combine this compound with compound (2) in a suitable solvent (nitrobenzene, methylene chloride, chloroform, dichloroethane or Mixed with any of these) in a Lewis acid (aluminum chloride, boron trifluoride, zinc chloride, iron chloride, tin chloride, etc.) at room temperature or at the reflux temperature of the solvent under cooling

By reacting for 1 to 24 hours, a compound of the general formula (111) is obtained. Method 3

R ⁴

0 0

HN Small ¹ T- + X (CH ₂ ) qY Y- (CH ₂ ) q- JL TE

(X = CI or Br)

(9)

(5) (Y = CI or Br)

(q = l ~ 8)

Bases (potassium carbonate, sodium bicarbonate, triethylamine) in a solvent (methylene chloride, chloroform, acetonitrile, benzene, toluene, water or a mixture of any ratio thereof) which does not hinder the reaction of the compound of the general formula (5) , Pyridine, dimethylaminopyridine, etc.) in the presence of a haloacyl halide of the general formula (3) to give a compound of the general formula (9). Lewis acid (aluminum chloride, boron trifluoride, zinc chloride, etc.) in a suitable solvent (such as nitrobenzene, methylene chloride, chloroform, dichloroethane or any mixture thereof) is used in a suitable solvent. By reacting with iron chloride, tin chloride, etc.) under cooling at room temperature or at the reflux temperature of the solvent for 1 to 24 hours, the compound of the general formula (10) can be obtained.

Solvents that do not interfere with the reaction of the compound of general formula (10) (eg, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, getyl ether, The reaction can also be performed by using a suitable reducing agent (borane, lithium aluminum hydride, etc.) in a mixture of the above and reacting under ice-cooling or heating for 1 to 24 hours. A compound represented by 1) is obtained.

Method 4

Solvent (Methanol, Ethanol, Ethyl Acetate, Acetic Acid, Aqueous Hydrochloric Acid, Acetonitrile, or a mixture of these in any proportion) which does not hinder the reaction of compound (1-5) in which R ³ is chlorine or bromine in general formula (1) ) In the presence of a catalyst such as palladium carbon, Raney nickel or platinum oxide, the compound of the general formula (16) wherein R ³ is hydrogen can be obtained.

The thiophene compound of the general formula (1) obtained by the above method is converted into a suitable solvent such as methanol, ethanol, isopropyl alcohol, isopropyl ether, chloroform, ethyl acetate, hexane, getyl ether or a mixture thereof. ) And added to inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) or organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, quenched acid) Acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or ascorbic acid) or a hydrate thereof, and the precipitated crystals are dissolved in a suitable solvent (methanol, Ethanol, isopropyl alcohol, isopropyl ether, black hole , Shioma acetate Echiru, hexane, by recrystallized from Jefferies chill ether, water or a mixed solvent thereof and the like), an inorganic acid or an organic acid of the compound of general formula (1) Or its hydrate. Also, oxalic acid can be added to oxalate for the purpose of crystallization of the compound.

The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the resulting product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column filled with an optically active carrier. Can be. Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These can also be obtained by using optically active starting compounds and the like. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

Chiofunin compounds of the present invention, an optical isomer, a pharmaceutically acceptable salt or hydrate thereof is D ₄ receptor blocker with a strong blocking action on D ₄ receptor, schizophrenia It is a useful antipsychotic drug that is effective not only for positive symptoms such as hallucinations and delusions that are characteristic of the acute phase, but also for negative symptoms such as dullness, inactivity, and autism. Also seen in case of administration of conventional antipsychotic drug with D ₂ receptors blocking action, side effects such as extrapyramidal symptoms and endocrine abnormalities are expected as antipsychotics which are alleviated. Therefore, the compound of the present invention can be used as a therapeutic drug for schizophrenia and the like. Further, the thiophene compound, its optical isomer, its pharmaceutically acceptable salt or hydrate thereof of the present invention can also be used as a therapeutic drug for alcohol-dependent patients and drug abusers. .

When the compound of the present invention is used as a medicine, the compound of the present invention is mixed with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier, diluent, solubilizing agent, etc.). Tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs, suspensions, solutions, injections, infusions or tablets obtained by formulating the obtained pharmaceutical composition according to a usual method It can be administered orally or parenterally in the form of a suppository or the like.

In this specification, parenteral means subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection Includes injection or infusion methods. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as an aqueous solution. Examples of acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil and fatty acid can be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. Suppositories for rectal administration consist of the drug and suitable nonirritating excipients, such as cocoa butter and polyethylene glycols, which are solid at normal temperatures, liquid at intestinal tract temperatures, and melt in the rectum However, it can be manufactured by mixing with a substance that releases a drug.

Examples of solid dosage forms for oral administration include those described above such as powders, granules, tablets, pills, and capsules. In such dosage forms, the active ingredient compound may comprise at least one additive, such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginate, chitins, chitosans , Pectins, tragacanth gums, gum arabic, gelatins, collagens, caseins, albumins, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also contain, as usual, further additives, such as inert diluents, lubricants such as magnesium stearate, parabens, sorbic acid or salts thereof. Examples include preservatives, antioxidants such as ascorbic acid, tocoprol, and cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents, and perfumes. Tablets and pills can additionally be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, Drops, elixirs, suspensions, solutions and the like, which may contain an inert diluent commonly used in the art, such as water.

Dosage will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, drug combination, the extent of the condition being treated by the patient at the time, and other factors. Determined in consideration of factors. The compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof can be safely used with low toxicity, and its daily dose depends on the condition and weight of the patient, the type of the compound, and the route of administration. For example, parenterally, subcutaneously, intravenously, intramuscularly, or rectally, about 0.01 to 5 Omg / person, preferably 0.01 to 2 Omg Z persons It is preferably administered at about 0.01 to 150 mg / person / day, preferably 0.1 to 100 mg / day.

Example

Hereinafter, the present invention will be described in more detail with reference to Raw Material Synthesis Examples, Examples, Formulation Formulation Examples, and Experimental Examples, but the present invention is not limited thereto.

Raw material synthesis example 1

4,5,6,7-tetrahydro-1-methylbenzo [b] 107 g of thiophene and 268 g of 3_-propionylc- mouth are dissolved in 1 L of methylene chloride and stirred. While cooling in an ice bath, 282 g of aluminum chloride was gradually added. The mixture was stirred at room temperature for 17 hours, and the reaction solution was poured into ice water. The reaction solution was stirred at room temperature for 2 hours to decompose excess propionyl chloride, and then extracted twice with chloroform. Subsequently, the black mouth form layer is washed with saturated aqueous sodium hydrogen carbonate and then with saturated saline. Then, it was dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was adsorbed on 300 g of silica gel and subjected to silica gel column chromatography (600 g of silica gel). From the effluent of hexane alone, 30 g of raw material (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophene) was recovered. Hexane: ethyl acetate = 20: 1 From the effluent, 106 g of 3- (3-chloropropionyl) -1,4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene was obtained.

Ή-NMR (CDC 1 a) (5: 3.87 (2 H, t, J = 6.59 Hz), 3.20 (2 H, t, J = 6.59 Hz) , 2.65-2.72 (4H, m), 2.57 (3H, s), 1.73-1.86 (4H, m)

Raw material synthesis example 2

In the same manner as in Raw Material Synthesis Example 1, 2-ethyl-4,5,6,7-tetrahydrobenzone [b] thiophene and 3-chloropropionyl chloride chloride, 3- (3-chlorofluoropropane) Propionyl) 1-2-ethyl-1,4,5,6,7-tetrahydrobenzo [b] thiophene is obtained.

Raw material synthesis example 3

In the same manner as in Raw Material Synthesis Example 1, 2-butyl-1,3-, 3-butylpropionyl chloride was obtained from 2-butyl-4,5,6,7-tetrahydrobenzo [b] thiophene and 3-cyclopropionyl chloride. 1,4,5,6,7-Tetrahydrobenzo [b] thiophene is obtained.

Raw material synthesis example 4

In the same manner as in Raw Material Synthesis Example 1, 2-promo 4,5,6,7-tetrahydrobenzo [b] thiophene and 3-chloropropionyl chloride dokapara, 2-bromo-13- (3 1,4-, 5,6,7-tetrahydrobenzo [b] thiophene is obtained.

Raw material synthesis example 5

In the same manner as in Raw Material Synthesis Example 1, 4,5,6,7-tetrahydro-1,4,2-dimethylbenzo [b] thiophene and 3-chloropropionyl chloride dokapara, 3- (3—clo Propionyl) 1,4,5,6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophene is obtained. Raw material synthesis example 6

CH ₂ one C1

In the same manner as in Raw Material Synthesis Example 1, 4, 5, 6, 7-tetrahydro-2-methylbenzo [b] 3- (chloroacetyl) —4, 5, 6, 7 —Tetrahydro 2-methylbenzo [b] thiophene was obtained. Ή-NMR (CD C 13) δ 4.45 (2 Η, s), 2.63-2.76 (4 H, m), 2.58 (3 H, s), 1. 7 3—1.90 (4 H, m) Example of raw material synthesis Ί

In the same manner as in Raw Material Synthesis Example 1, 4,5-, 6-, 7-tetrahydro-2-methylbenzo [b] thiophene and 4-chlorobutyryl chloride were converted to 3- (4-chlorobutyryl) 1-4 , 5,6,7-tetrahydro-2-methylbenzo [b] thiophene were obtained.

Ή-NMR (CD C 1 a) 5: 3.64 (2 H, t, J = 6.60 Hz), 2.92 (2 H, t, J = 6.60 Hz) , 2.62-2.75 (4H, m), 2.56 (3H, s), 2.17 (2H, tt, J = 6.60, 6.60H z), 1.69-1.88 (4 H, m) Raw material synthesis example 8

In the same manner as in Raw Material Synthesis Example 1, 3-, (3-chlorobutyryl) was obtained by using 4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene and 3-chlorobutyryl chloride. 1) 4, 5, 6, 7—Tetrahi Draw 2—Me

[B] Obtain thiophene.

Raw material synthesis example 9

In the same manner as in Raw Material Synthesis Example 1, 5, 6-dihydro-2-methyl-4-H-cyclopenta [b] thiophene and 3-chloropropionyl chloride were converted to 3— (3-chloropropionyl). _ 5,6-Dihydro-2-methyl-4H-cyclopenta

[B] Get a chief. Raw material synthesis example 10

In the same manner as in Raw Material Synthesis Example 1, 3, _ (3 — from 5,6,7,8-tetrahydro_2-methyl-4H-cyclohepta [b] thiophene and 3-chloropropionyl chloride. 1,5,6,7,8-Tetrahydroxy 2-methyl-4H-cyclohepta [b] thiophene is obtained.

Example 1

A mixed solution of 10 g of N- (4-chlorophenyl) piperazine hydrochloride and 18 g of potassium carbonate was suspended in 60 ml of (1: 1) toluene and stirred at room temperature. While dissolving 1 g of 3- (3-chloropropionyl) -1,4,5,6,7-tetrahydro-12-methylbenzo [b] thiophene in the above mixed solution 15 m1, The solution was added dropwise. After completion of the dropwise addition, the mixture was heated and stirred for 14 hours, the solvent was distilled off under reduced pressure, and water and toluene were added to the residue and stirred. The solution was extracted with toluene and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. 100 ml of isopropyl ether was added to the obtained residue, a small amount of product crystals were further added, and the crystals were collected by filtration. 1) 1) 1) (4,5,6,7-Tetrahydro 2 —methylbenzo [b] thiophene_3—yl) Propane-1 1 1 g (Pale yellow crystals) was obtained. Melting point 82 ° C

Example 2

Compound of Example 1 3 _ (4- (4-chlorophenyl) pirazin-1-yl) _1-1 (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene-3-yl) 15 g of propane-1-one was dissolved in 150 ml of methanol and 50 ml of chloroform, and 4 g of sodium borohydride was gradually added while stirring in an ice bath. The mixture was stirred at room temperature for 2.5 hours, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. 40 ml of isopropyl alcohol and 70 ml of isopropyl ether were added to the obtained residue, and the crystals were collected by filtration, and 3_ (4- (4-chlorophenyl) piperazine-1-yl) 1-1- (4,5,6,7-Tetrahydr-1-methylbenzo [b] thiophen-3-yl) Propan-1-ol 12 g (brown crystals) was obtained. Melting point 1 10 V

Example 3

To 300 ml of an acetonitrile solution of 30 g of sodium iodide was added 26 ml of chlorotrimethylsilane while stirring at room temperature. To this reaction mixture, the compound of Example 2 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5,6,7-tetrahydro-1-methylbenzene) Zo [b] thiophen-1-yl) Propane-11-ol (12 g) was added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was poured into ice water, and sodium sulfite and potassium carbonate were added with stirring. After the acetonitrile layer was separated, the aqueous layer was extracted with chloroform, combined with the acetonitrile layer, and dried over magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel gel column chromatography (60 g) to obtain 11 g of crude crystals from chloroform: methanol = 30: 1 effluent. This was dissolved in 150 ml of acetone, and 6 g of an isopropyl alcohol solution of hydrochloric acid (35% W / W) was added. The resulting crystals are collected by filtration and recrystallized with a mixed solvent of ethanol and water to give 1- (4-chlorophenyl) 14_ (3- (4,5,6,7-tetrahydro-1-methylbenzo [ b] 9 g of thiophen-3-yl) propyl) piperazine dihydrochloride. Melting point 2 15 ° C (decomposition)

Example 4

By using N- (4-monofluorophenyl) piperazine instead of N_ (4-chlorophenyl) piperazine hydrochloride in the same manner as in Example 1, 3- (4- (4-fluorophenyl) (Pirazine-1 1-yl) 1 1 1 (4,5,6,7-tetrahydro-1 2-methylbenzo [b] thiophene-3-yl) propane 1-1 I got it.

Ή-NMR (CDC 13) (5: 6.81-7.02 (4 H, m), 3.10 (4 H, t, J = 4.73 Hz), 2.9 6 (2 H, t, J = 6.0 2 H z)

2.86 (2H, t, J = 6.02Hz), 2.52-2.78 (8H, m)

2.55 (3H, s), 1.70—1.88 (4H, m)

Example 5

In the same manner as in Example 2, the compound of Example 4 was replaced with the compound of Example 4 3- (4- (4-fluorophenyl) pidazine-1 1-yl) 1 1- (4,5, By using 6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propane-1-one, 3- (4- (4-fluorophenyl) piperazine-1 1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propan-1-ol was obtained. Melting point 1 2 8 ° C

Example 6

In the same manner as in Example 3, the compound of Example 5 was replaced with the compound of Example 5 3- (4- (4-fluorophenyl) piperazine-1-yl) 1-1- (4,5, 6, 7 1- (4-Fluorophenyl) 1- (3-(4,5,6,7-tetrahydro) 2-tetrabenzoyl-2-methylbenzo [b] thiophen-1-yl) propane-1-ol 2-Methylbenzo [b] thiophene-3-yl) pulp) piperazine dihydrochloride was obtained. Melting point 205 ° C

Example 7

In the same manner as in Example 1, N- (3-chlorophenyl) pidazine hydrochloride was replaced with N- (3-trifluoromethylphenyl) pirazine, whereby 1- (4, 5, 6, 7-tetrahydro-1-methylbenzo [b] thiophen-1-yl) 1-3- (4- (3-trifluoromethylphenyl) piperazine-1-yl) Propane-1-got on.

Ή-NMR (CDC 1) δ: 7.33 (1Η, dd, J = 7.30, 7.35 Hz), 7.00-7.13 (3H, m), 3.2 2 (4 H, t, J = 5.01 Hz), 2.96 (2 H, t, J = 6.01 Hz), 2.84 (2 H, t, J = 6.01 Hz, 2.51-2.73 (8H, m), 2.55 (3H, s), 1.70-1.89 (4H, m)

Example 8

In the same manner as in Example 2, the compound of Example 7 was replaced with the compound of Example 1 (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-13-yl). — (4— (3—Trifluoromethylphenyl) pirazin-1-yl) propane-1-one gives 1— (4,5,6,7—tetrahydro-1--2-) Methylbenzo [b] thiophen-1-yl) -1- (4- (3-trifluoromethyl phenyl) pidazine-1-yl) propane-1-ol was obtained.

Ή-NMR (CF ₃ COOD) 6: 1.78-8.03 (4 H, m), 6.92-7.08 (1 H, m), 4.2 1-4.6 1 (1 0 H, m), 4.00—4.14 (2H, m), 2.67-2.75 (2H, m), 2.58-2.65

(2H, m), 2.45 (3H, s), 1.82-1.92 (4H, m)

Compound 11 of Example 8 (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-13-yl) in place of Compound of Example 2 in the same manner as in Example 3 By using 3- (4- (3-trifluoromethylphenyl) piperazine-1-1yl) propan-1-ol, 4- (3- (4,5,6,7- Tetrahydro-1-methylbenzo [b] thiophen-13-yl) propyl) -111 (3-trifluoromethylphenyl) pidazine dihydrochloride was obtained. Melting point 2 36 ° C Example 1 o

In the same manner as in Example 1, N_ (4-chlorophenyl) pidazine hydrochloride was used in place of N— (4-methylphenyl) pidazine to obtain 1 _ (4, 5, 6, 7— Tetrahydro-1-methylbenzo [b] thiophen-1-yl) -1-3- (4- (4-methylphenyl) pyrazine-1-yl) propane-1-one was obtained.

Ή-NMR (CDC 1 a) 5: 7.06 (2 H, d, J = 8.57 Hz), 6.82 (2 H, d, J = 8.57 Hz), 3.12 (4 H, t, J = 5.32 Hz), 2.95 (2 H, t, J = 6.00 Hz), 2.82 (2 H, t, J = 6.00 Hz), 2.52-2.74 (8H, m), 2.54 (3H, s), 2.26 (3H, s), 1. 6 8—1.88 (4 H, m)

Example 1 1

In the same manner as in Example 2, the compound of Example 10 was replaced with the compound of Example 10 in place of the compound of Example 1 (4,5,6,7-tetrahydro-1-2-methylbenzo [b] thiophen-13-yl-1) 3— (4- (4-methylphenyl) piperazine-1-11) Prono, .1 1 By using 1-one, 1- (4,5,6,7-tetrahydro-1-methyl-benzo [b] thiophen-13-yl) 1-3- (4- (4-methylphenyl) piperazine— 1-yl) Propane-1-ol dihydrochloride was obtained. Melting point 2 2 4 ° C Example 1 2

In the same manner as in Example 3, the compound of Example 11 was replaced with the compound of Example 11 (4, 5, 6, 7-tetrahydro-2-methylbenzo [b] thiophene-3-yl). By using 3- (4- (4-methylphenyl) piperazine-1-yl) propane-1-ol dihydrochloride, 4- (3- (4,5,6,7-tetrahydro-1-yl) —Methylbenzo [b] thiophene-3-yl) propyl) -11- (4-methylphenyl) pirazine dihydrochloride was obtained. Melting point 2 2 1 ° C

Example 13

In the same manner as in Example 1, by using N— (1-naphthyl) piperazine instead of N— (4-chlorophenyl) piperazine hydrochloride, 1- (4,5,6,7-tetrahydrazine) was obtained. 1-Methylbenzo [b] Thiophene-1-3-yl) 1- (4- (1-naphthyl) pirazin-1 1-yl) Propane 1-one is obtained. Example 14

Compound 11 of Example 13 (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-13-yl) in place of Compound of Example 1 in the same manner as in Example 2 By using one 3 _ (4- (1-naphthyl) pidazine-1-yl) propane-1-one, it is possible to obtain 1- (4,5,6,7-tetrahydro-1-2-methylbenzo [b] Thiophene-1-yl) 3- (4- (1-naphthyl) piperazine-1-yl) Propane-1-ol.

Example 15

In the same manner as in Example 3, the compound of Example 14 was replaced with the compound of Example 1 1- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-13-yl) 1 3— (4-(1 naphthyl) piperazine 1 1 -yl) Propane 1 by using 4-(3-(4, 5, 6, 7-tetrahydro 2- Methylbenzo [b] thiophene-3-yl) propyl) 1 1-(1 naphthyl) piperazine is obtained. Example 16

In the same manner as in Example 1, N- (3-pyridyl) piperazine hydrochloride was used in place of N- (3-pyridyl) piperazine to obtain 1- (4,5,6,7-tetrahydrazine). Dro-2-methylbenzo [b] thiophene-3-yl) 1-3- (4- (3-pyridyl) pyrazine-11-yl) Propane-1-one is obtained.

Example 17

In the same manner as in Example 2, the compound of Example 16 was replaced with the compound of Example 1 (4, 5, 6, 7-tetrahydro-2-methylbenzo [b] thiophen-13-yl). By using 3- (4- (3-pyridyl) piperazine-1-yl) propane-1-one, 1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene-1 3- (yl) -1- (4- (3-pyridyl) piperazine-1-yl) Propane-l-ol is obtained. Example 18

Compound 11 of Example 17 (4,5,6,7-tetrahydro-12-methylbenzo [b] thiophen-13-yl) in the same manner as in Example 3 and replacing the compound of Example 2 1 3— (4- (3-pyridyl) piperazine-1 1-yl) Propane-1 can be used to prepare 4 _ (3— (4,5,6,7-tetrahydro-2-methylpentazo) [B] Thiophane-1-yl) propyl) _1- (3-pyridyl) piperazine is obtained.

Example 19

In the same manner as in Example 1, the compound of Raw Material Synthesis Example 2 was replaced with the compound of Raw Material Synthesis Example 2 3- (3-chloropropionyl) -12-ethyl-1,4,5,6,7-tetrahyd. By using thiophene [b] thiophene, it is possible to obtain 3-(4-(4-black mouth phenol) piperazine 1 1-yl) 1 1-(2-ethyl 1, 4, 5, 6 , 7-tetrahydrobenzone [b] thiophene 13_yl) Propane 11-one is obtained. Example 20

In the same manner as in Example 2, the compound of Example 19 was replaced by the compound of Example 19 3- (4- (4-chlorophenyl) piperazine-111-yl) 1-1- (2-ethyl-1, 5,6,7—Tetrahidrobenzo [b] Thiophene-1 3-yl) Propane 1 1 1-one can be used to obtain 3 — (4- 1 (4-cloclophenyl) piperazine 1 1 1-yl) 1 1 _ (2-ethyl 4-, 5, 6, 7-tetrahydrobenzo [b] thiophen-3-yl) Propan-1-ol is obtained.

Example 2 1

In the same manner as in Example 3, the compound of Example 20 was replaced with the compound of Example 20. 3- (4- (4-chlorophenyl) pidazine-11-yl) 1-1- (2-) 1,4-, 5-, 6-, 7-tetrahydro-drobenzo [b] thiophen-1-yl) propane-1— By using ol, 1— (4-chlorophenyl) 1-41 ( 3— (2-ethyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-3-yl) propyl) piperazine is obtained. Example 22

In the same manner as in Example 1, the compound of Raw Material Synthesis Example 3 2-butyl-3- (3-chloropropionyl) -1,4,5,6,7-tetrahide was used in place of the compound of Raw Material Synthesis Example 1. 1- (2-butyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-3-yl) 1 3— (4 — (4-Chlorofanil) piperazine-1-yl) Propane-1-one is obtained.

Example 23

In the same manner as in Example 2, the compound of Example 22 was replaced with the compound of Example 22 (2-butyl-4,5,6,7-tetrahydrobenzene [b] thiophen-3-yl). 1) 3- (4- (4-chlorophenyl) pirazin-1-yl) propane-1-one can be used to produce 1- (2-butyl-4,5,6,7-tetrahydrobenzo). [B] Thiophene-1-yl) 3- (4- (4-chlorophenyl) piperazine-11-yl) propan-1-ol is obtained. Example 2 4

In the same manner as in Example 3, the compound of Example 23 was replaced with the compound of Example 23 1- (2-butyl-1,4,5,6,7-tetrahydrobenzo [b] thiophen-13- 1) 3- (4- (4-chlorophenyl) piperazine-1 1-yl) propane-1-ol can be used to obtain 4- (3- (2-butyl-4,5,6,7-tetra) Rahi drobenzo [b] thiophene 1- (yl) propyl) 1 1- (4-chlorophenyl) pidazine is obtained.

Example 2 5

In the same manner as in Example 1, the compound of Raw Material Synthesis Example 4 was replaced with the compound of Raw Material Synthesis Example 4 2-bromo-3- (3-chloropropionyl) -1,4,5,6,7-tetrahydro By using de lip benzo [b] thiophene, it is possible to obtain 1- (2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophen-13-yl) 1 3 — (4 4 phenyl) 1-pyrazine 1-yl) Propane 1-one. Example 26

In the same manner as in Example 2, the compound of Example 25 was replaced with the compound of Example 25 1- (2-bromo-4,5,6,7-tetrahydrobenzo [b] thiophene-13-y in place of the compound of Example 1. 1) 3- (4- (4-chlorophenyl) pirazin-1-yl) propane-1-one can be used to give 1- (2-bromo-1,4,5,6,7-tetrahydrobenzo [ b] Thiophane 3 -yl) 1-3-(4-(4-chlorophenyl) pyridine 1 -yl) Propane 1 -ol.

Example 2 7

In the same manner as in Example 3, the compound of Example 26 was replaced with the compound of Example 26 1- (2-bromo-1,4,5,6,7-tetrahydrobenzo [b] thiophen-13- The use of 3- (4- (4-chlorophenyl) piperazine-1-yl) propane-1-1ol gives 4- (3- (2-bromo-4,5,6,7-) Tetrahidrobenzo [b] thiophene-3-yl) propyl) 1-11 (4-chlorophenyl) pidazine is obtained. Example 2 8

In the same manner as in Example 1, the compound of the starting material synthesis example 5 was replaced with the compound of the starting material synthesis example 5 3 — (3-chloropropionyl) -14,5,6,7-tetrahydro-1,2,4- By using dimethylbenzo [b] thiophene, it is possible to obtain 3 — (4 — (4 — chloro phenyl) piperazine- 1-1 -yl) 1 1-(4, 5, 6, 7-tetrahydro- 1, 2-4 —Dimethylbenzo [b] thiophen-3-yl) propane-1-one. Example 2 9

In the same manner as in Example 2, the compound of Example 28 was replaced with the compound of Example 28 instead of the compound of Example 1. 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, By using 6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophen-13-yl) propan-1-one, 3- (4- (4-chlorophenyl) piperazine-1 1 —Yl) 1 1 — (4,5,6,7—tetrahydro-1,2,4-dimethylbenzo [b] thiophene 3 —yl) propane 1 1-ol is obtained. Example 30

In the same manner as in Example 3, the compound of Example 29 was replaced with the compound of Example 29. 3- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1- (4, By using 5,6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophen-1-yl) propan-1-ol, 1- (4-chlorophenyl) -14- (3— ( 4,5,6,7-tetrahydro-1,2,4-dimethylbenzo [b] thiophene

3-yl) propyl) to obtain pirazine.

Example 3 1

In the same manner as in Example 1, the compound of Raw Material Synthesis Example 6 was replaced with the compound of Raw Material Synthesis Example 6 3- (chloroacetyl) -1,4,5,6,7-tetrahydro-12-methylbenzo [b] thiophene Can be used to produce 2- (4- (4-chlorophenyl) piperazine-11-yl) _1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene-3-yl 1) I got 1-on.

Ή-NMR (CD C 1 a) <5: 7.18 (2 H, d, J = 9.24 Hz), 6.82 (2 H, d, J = 9.24 Hz) ), 3.61 (2H, s), 3.18— 3.27 (4H, m), 2.65—2.80 (8H, m), 2.56 (3H, s), 1.70-1.88 (4H , m)

Example 3 2

In the same manner as in Example 2, the compound of Example 31 was replaced with the compound of Example 31. 2- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, 6,7-tetrahydro 2-methylbenzo [b] thiophene-3-yl) ethane-1-one can be used to give 2- (4- (4-chlorophenyl) piperazine-1 1- 1- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-1-yl) ethanol was obtained.

Ή-NMR (CDC 1 a) (5: 7.21 (2 H, d, J = 9.24 Hz)), 6.83 (2H, d, J = 9.24 Hz) , 4.91 (1H, dd, J = 3.30, 10.56 Hz), 3.18-3.28 (4H, m), 2.52-2. 9 1 (10 H, m), 2.43 (3 H, s), 1.72—1.90 (4 H, m) Example 3 3

In the same manner as in Example 3, the compound of Example 32 was replaced with the compound of Example 32. 2- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1 1 (4, By using 5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) ethanol, it is possible to obtain 11- (4-chlorophenyl) 14- (2- (4,5,6,7-tetrahydro). Draw 2-methylbenzo [b] thiophene-3-yl) ethyl) piperazine to give the 5-hydrochloride 0.1-hydrate. Melting point 2 36 ° C

Example 3 4

In the same manner as in Example 1, the compound 3- (4-chlorobutyryl) -1,4,5,6,7-tetrahydro-12-methylbenzo was used in place of the compound of Raw Material Synthesis Example 1 instead of that of Raw Material Synthesis Example 7. [B] By using thiophene, it is possible to obtain 4 _ (4- (4-chlorophenyl) piperazine-11-yl) 1-11 (4,5,6,7-tetrahydro-2-methylbenzo [b] 1-one) Butane 1-on was obtained.

Ή-NMR (CDC 1) 5: 7.18 (2 H, d, J = 9.23 Hz), 6.82 (2 H, d, J = 9.23 Hz), 3 70 (2H, t, J = 15.18 Hz), 3.12-3.25 (4H, m), 2.58-2.92 (10H, m), 2.54 (3 H, s), 1.72-1.89 (4 H, m) Example 3 5

In the same manner as in Example 2, the compound of Example 34 was replaced with the compound of Example 34. 4- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4,5, By using 6,7-tetrahydro-2-methylbenzo [b] thiophene-3-yl) butan-1-one, it is possible to obtain 4- (4- (4-chlorophenyl) piperazine-1_yl 1- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophen-3-yl) butan-1-ol was obtained.

Ή-NMR (CDC 1) (5: 7.18 (2 H, d, J = 9.24 Hz), 6.82 (2 H, d, J = 9.24 Hz), 4.68—4.83 (1H, m), 3.13—3.23 (4H, m), 2.48—2.81 (10H, m), 2 . 3 7 (3H, s), 1.68—1.89 (6H, m)

Example 3 6

In the same manner as in Example 3, the compound of Example 35 was replaced with the compound of Example 35 instead of the compound of Example 4. 4- (4- (4-chlorophenyl) piperazine-1 1-yl) _ 1— (4, 5, 6, 7-tetrahydro-1--2-methylbenzo [b] thiophen-3-yl) butane-1 11 By using all, it is possible to use 1- (4-chlorophenyl) 1-4-1 (4- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-1--3-yl) butyl) Piperazine dihydrochloride was obtained. Melting point 198 ° C

Example 3 7

In the same manner as in Example 1, compound 3- (3-chlorobutyryl) -1,4,5,6,7-tetrahydro-2-methylbenzo [b By using thiophene, it is possible to obtain 3- (4- (4-chlorophenyl) piperazine-1-1-yl) -111- (4,5,6,7-tetrahydro-1--2-methylbenzo [b] thiophene One 3 — yl) butane one 1 — get on.

Example 3 8

In the same manner as in Example 2, the compound of Example 37 was replaced with the compound of Example 37 instead of the compound of Example 1. 3- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1— (4, 5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) butane-1-one can be used to give 3- (4- (4-chlorophenyl) piperazine-1 — Yl) 1 1 — (4, 5, 6, 7 — tetrahydro-1- 2 — methylbenzo [b] thiof Getting Oars,

In the same manner as in Example 3, the compound of Example 38 was replaced by the compound of Example 3 instead of the compound of Example 3. 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (4, By using 5,6-, 7-tetrahydro 2-methylbenzo [b] thiophen-3-yl) butan-1-ol, it is possible to obtain 1- (4-chlorophenyl) 1-4-1 (1-methyl-1-3- (4 , 5,6,7-Tetrahydro-1-methylbenzo [b] thiophene-3-yl) propyl) pidazine.

Example 40

Compound of Example 3 1 _ (4-chlorophenyl) 1-4 1 (3- (4,5,6,7-tetrahydro-12-methylbenzo [b] thiophen-13-yl) propyl) piperazine 2HCl 1 g of the salt was dissolved in a mixed solution (1: 1) of methanol and an aqueous solution of sodium hydroxide, and 0.2 g of Raney nickel was added. The mixture was heated to 40 ° C and subjected to catalytic reduction at normal pressure. . After stirring for 5 hours, the catalyst was removed by celite filtration, and the filtrate was concentrated. Water was added to the residue, extracted with chloroform, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. 1- 4- (3- (4,5,6,7-tetrahydrobenzo [b] thiophen-3-yl) propyl) piperazine is obtained.

Example 4 1

In the same manner as in Example 40, the compound of Example 6 was replaced with the compound of Example 6 1- (4-fluorophenyl) 1-141 (3— (4,5,6,7-tetrahydro-1 2 — Methylbenzo [b] thiophen-1-yl) propyl) piperazine dihydrochloride allows the use of 1- (4-fluorophenyl) -4-1 (3- (4,5,6,7-tetrahi Drobenzo [b] thiophen-1-yl) propyl) pidazine obtained Example 4 2

In the same manner as in Example 1, use 4- (4-chlorophenyl) 1-1,2,3,6-tetrahydropyridine instead of N- (4-chlorophenyl) piperazine hydrochloride. According to the formula, 3 — (4-(4 —Chlorophenyl) -1,2,3,6-tetrahydropyridine-1- 1-yl) 1 1 — (4,5,6,7 —tetrahydro-1- 2 —methyl Lebenzo [b] Thiophane-3-yl) Propane 1-one is obtained. Example 4 3

In the same manner as in Example 2, the compound of Example 4 was replaced with the compound of Example 4 2 in the same manner as in Example 2. Compound 3— (4- (4-chlorophenyl) 1-1,2,3,6—tetrahydropyridine1-1 — Yl) 1 1 1 (4, 5, 6, 7-tetrahydro 2-methylbenzo [b] thiophene 1 3 — yl) Propane 1 _ 1 —Chlorophenyl) 1,1,2,3,6 —Tetrahydropyridine_1 —1yl) 1 1 — (4,5,6,7—Tetrahydro 2 —Methylbenzo [b] thiophene 1-3 —yl) Get 1-ol propane.

Example 4 4

In the same manner as in Example 3, the compound of Example 4 was replaced with the compound of Example 4 3 in place of the compound of Example 2 3 — (4- (4-chlorophenyl) 1-1,2,3,6-tetrahydropyridine-1- 1 1) (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propane-1 1-ol gives 4- (4-chlorophenyl) 1 1 — (3 — (4,5,6,7-tetrahydro-1-2-methylbenzo [b] thiophen-3-yl) propyl) 1 1,2,3,6 —tetrahydropyri Get the gin.

Example 4 5

In the same manner as in Example 1, the compound of the starting material synthesis example 9 was replaced with the compound of the starting material synthesis example 9 3- (3-chloropropionyl) -1,5,6-dihydro-2-methyl-14H-cyclopentane [B] By using thiophene, 3- (4- (4-chlorophenyl) piperazine-11-yl) -11- (5,6-dihydro-12-methyl-4H-cyclopenta [b] Thiophene 3-yl) Propane 1-on is obtained.

Example 4 6

In the same manner as in Example 2, the compound of Example 45 was replaced with the compound of Example 45 instead of the compound of Example 1. 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (5, 6-Diethyl mouth 2-methyl-14 H-cyclopentene (b) thiophene-3-yl) Propane-one is used to give 3- (4- (4-chlorophenyl) piperazine 1 1-yl) 1 1- (5,6-dihydro 2-methyl-4H-cyclopentyl [b] thiophen-3-yl) Propane-1-ol is obtained.

In the same manner as in Example 3, the compound of Example 4 was replaced with the compound of Example 4 6 instead of the compound of Example 2 3 — (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1 — (5, 6-Dimethyl-l- 2-Methyl-l4H-cyclopentyl (b) thiophene-l-yl) Propane-l-ol can be used to obtain 1- (4-chlorophenyl) -l 4- (3— (5, 6-Dihydro-12-methyl-14H-cyclopenta [b] thiophen-13-yl) propyl) pidazine is obtained.

Example 4 8

In the same manner as in Example 1, the compound of Starting Material Synthesis Example 10 was replaced with the compound of Starting Material Synthesis Example 1 3 — (3—Clo-propionyl) -1, 5, 6, 7, 8 — Tetrahydro 1 2 —Methyl-4H-cycloheptane [b] By using thiophene, 3— (4— (4-chlorophenyl) piperazine-1 1) 1 1— (5,6,7, 8—Tetrahydro-2-methyl-4H-cyclohepta [b] thiophene-3-yl) Propane 1-one is obtained.

Example 4 9

4 7

In the same manner as in Example 2, the compound of Example 48 was replaced with the compound of Example 48 instead of the compound of Example 1. 3- (4- (4-chlorophenyl) piperazine-1 1-yl) 1 1- (5, 6,7,8-tetrahydro 2-methyl-14H-cyclohepta [b] thiophen-13-yl) By using propane-one, 3- (4-(4-chlorophenyl)) Piperazine-1-yl) _1-1 (5,6,7,8-tetrahydro-2-methyl-4H-cyclohepta [b] thiophen-1-yl) Propane-1-yl is obtained. Example 5 0

In the same manner as in Example 3, the compound of Example 49 was replaced with the compound of Example 49. 3- (4- (4-chlorophenyl) piperazine-11-yl) 1-1- (5, 6, 7, 8

—Tetrahydro-1-methyl-4-H-cycloheptane [b] thiophene-3-yl) propane-1- 1-ol allows the use of 1- (4-chlorophenyl) -1 4 -— (3— (5, 6,7,8-Tetrahydro-12-methyl-14H-cyclohepta [b] thiophen-13-yl) propyl) pidazine is obtained.

Formulation example 1 The compound of the present invention (0.5 part), lactose (25 parts), crystalline cellulose (35 parts) and corn starch (3 parts) were mixed well, and then kneaded well with a binder made from corn starch (2 parts). The kneaded material is sieved with 16 mesh, dried in an oven at 50 ° C, and sieved with 24 mesh. The kneaded powder thus obtained, 8 parts of corn starch, 11 parts of crystalline cellulose and 9 parts of talc are mixed well, and the mixture is compressed into tablets to obtain tablets containing 0.5 mg of active ingredient per tablet.

Formulation example 2

Dissolve 1.0 mg of the compound of the present invention and 9.0 mg of sodium chloride in water for injection, filter to remove pyrogens, transfer the filtrate to an ampoule under aseptic conditions, sterilize, and seal by melting to give the active ingredient. 1. Obtain an Omg-containing injection.

The excellent pharmacological activity of the compound of the general formula (1) is proved by the following series of tests.

³ H- spiperone binding; affinity D ₄ receptor: Experiment 1

D ₄ receptor expression cell membrane specimen and ³ H- spiperone was 2 7 ° C, 2 hours Inkyupeto in the presence of the test compound. Immediately after the completion of the reaction, the solution was suction-filtered with a Putman GFZB filter (trade name), and the radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding was determined in the presence of 10 / M haloperidol. The 50% inhibitory concentration (IC ₅ ) of the test compound was calculated by non-linear regression, and the inhibition constant (K i value) was determined. As a result, the i value of Y—36074 (the compound of Example 3) was 0.50 nM.

³ H- spiperone binding; affinity for D ₂ receptors: Experiment 2

The preparation and binding experiments of the crude synaptic membrane were carried out according to the method of I. Creese et al. [Jochi Bian 'Journal' Ob '' Pharmaco G. Vol. 46, p. 377 (1977)] went. A crude synaptic membrane was prepared from the cryopreserved rat striatum, and the membrane specimen was reacted with ³ H-spiperone at 37 ° C for 20 minutes in the presence of the test compound. Immediately after the completion of the reaction, the solution was suction-filtered with a Putman GF / B filter (trade name), and the radioactivity on the filter was measured with a liquid scintillation counter. Non-specific The specific binding was determined in the presence of 10 O ^ M (sat) -sulpiride. The 50% inhibitory concentration (IC ₅ ) of the test compound was calculated by non-linear regression, and the inhibition constant (K i value) was determined. As a result, the Ki value of Y-36074 was 170 nM.

As a result of Experimental Examples 1 and 2, the K i value of the compound of the present invention for the D ₄ receptor was 0.1 to 1 nM, but was 10 O nM or more for the D ₂ receptor. Thus, the onset bright compound is confirmed to have a strong affinity for D ₄ receptor than D ₂ receptors, the deviation was 1 or 0 0 or more times.

Experimental example 3: Experiment on antagonist action

Action attitude to D ₄ receptor test compound, ^[35 S] - Therefore discussed GTP § S binding assay method. The D ₄ receptor expressing cell membrane was reacted with guaiacolsulfonate Noshin diphosphate 1 0 mo 1 L to remove non-specific binding, was reacted for 1 0 minutes in the test compound and 3 7. Thereafter, the a-receptor agonist quinpirole added from 1 0_ ⁸ at a concentration of 1 0 one ⁴ m 0 1 ZL, radioisotope ³⁵ 3 § position in labeled guanosine triphosphate and 3 7 ° C in S The reaction was performed for 0 minutes. All reactions were 0.5 mmo1 / L dithiothreitol, 0.01% Lubrol PX, 1 mmo1 ZL disodium ethylenediamintetraacetate, 3 mmo1 ZL magnesium chloride and 100 mmo1 ZL The reaction was performed in HE PES-sodium hydroxide buffer (pH 8.0) containing sodium chloride. After completion of the reaction, the reaction solution was filtered through a cell harvester, a scintillator was added, the radiation dose was measured with a radiation measurement device (Topcount, Amersham), and [ ³⁵ S] —GTPaS by an agonist acting as a receptor was used. Whether the compound was an agonist or an antagonist was determined by the effect of the test compound on the increase in the amount of binding. The above experiments, Y- 3 6 0 7 4 are ^[35 S] - was found amount of bound GTP 7 S is en evening agonist since it was in a concentration-dependent manner.

Experimental Example 4: Evaluation of alcohol dependence in a withdrawal behavior symptom model

Using 5 to 8 rats / group, 5 ml of 20% ethanol was orally administered to rats at 8 o'clock, 13 o'clock, 18 o'clock and 24 o'clock four times a day for 7 days I do. The test compound is administered orally at 17 o'clock on day 4, at 5 o'clock on day 5 and at 7 o'clock on day 6 at 17 o'clock in total. You. Each animal is observed for differences in behavioral results of alcohol withdrawal for 8 to 12 hours after the last ethanol dose. The effect of the test compound on alcohol dependence can be evaluated by evaluating the severity in the state of withdrawal phenomena (inducing seizures, drinking water, etc.) and comparing it with the control group (the test compound non-administration group). Experimental example 5: Evaluation for morphine dependence in a withdrawal behavior symptom model

Morphine (10 mg / kg, subcutaneous) and test compound (5, 10, or 20 mg Zkg, oral) were co-administered for 5 days using 5-8 rats / group, and on day 5 One hour after administration of naloxone, naloxone (2.0 mgZkg, subcutaneous) is administered and morphine withdrawal symptoms are observed. The effects of the test compound on drug dependence can be evaluated by observing behavior such as shivering, diarrhea, and jibing, for 20 minutes, and comparing it with the control group (the group not administered the test compound).

Example 6: Toxicity test

When four 5-week-old female SD rats were orally administered Y-366071000 mg / kg, no deaths were observed. Repeated oral administration of Y-36674 to rats for 10 days showed no deaths at a dose of 100 mg / kg, and general condition, body weight, food consumption, and hematology. No abnormalities were found in any of the tests, blood chemistry tests, urinalysis, organ weights, and necropsy (histological examination). No toxicological changes were observed when dogs were repeatedly administered 3 O mgZkg for 10 days. <Experimental example 7: Evaluation of bioavailability in rats>

After intravenous administration of 5 mg / kg and oral administration of 30 mg / kg to SD male rats (5 animals per group), blood was collected over time, and the drug concentration in plasma was determined using a high-performance liquid chromatograph. It was measured. As a result of calculating the bioavailability (BA) by the following equation, the BA of Y-36674 was as good as 30% or more. AUC for oral administration Dose for intravenous administration

XX 100 (%) AUC after intravenous administration Oral dose AUC: Area under the plasma concentration-time curve Example 8: Measurement of brain translocation in rats

After intravenous administration of 5 mg Zkg to SD male rats (3 animals per group), decapitation was performed 30 minutes after blood injection, blood and brain were collected, and drug concentrations in plasma and brain were measured using high-performance liquid chromatography. It was measured. As a result, the ratio of the drug concentration in the brain / plasma of Y-36674 was more than twice, and the transferability to the brain was good.

From the results of Experimental Example 7, 8, bioavailability one (BA) and intracerebral transitivity of the present invention compounds are good, the present invention compound to be useful as an antipsychotic has been confirmed in the D ₄ receptor It is a D ₄ receptor blocker that has a selective strong blocking effect on the contrary. It is a useful antipsychotic that is effective against negative symptoms such as. Also seen when given throw a conventional antipsychotic drug with D ₂ receptor blocking action is expected as a highly safe antipsychotic side effects such as extrapyramidal symptoms and endocrine abnormality is alleviated. Also, other receptors of the present invention compounds _{(D., 5 - HT 1A,} 5 -HT 2, M, / M 2, a,) K i values for the relative K i values for the D ₄ receptor It shows a divergence of 100 times or more, and may be an antipsychotic drug with little influence by other central effects. The compound of the present invention can be used as a therapeutic drug for schizophrenia. In addition, the compounds of the present invention have excellent oral absorbability, bioavailability, and ability to enter the brain. Further, the compound of the present invention can be used as a therapeutic agent for alcohol-dependent patients and substance abusers. This application is based on patent application No. 8161 of 1997 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. General formula (1)

n represents 0 or an integer of 1 to 3,

R ² represents hydrogen or alkyl,

R ³ represents hydrogen, halogen, alkyl, acyl, amino or nitro; R represents hydrogen or alkyl;

The bond represented by Q—T is CH, CH ₂ —N, (CH ₂ ) ₂ —N, CH ₂ —C (R ⁵ ) (wherein, R ⁵ represents hydrogen, hydroxy, alkyl or alkoxy. ) Or CH2C

Or an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

2. The thiophene compound according to claim 1, wherein R ⁴ is hydrogen in the general formula (1), an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

3. —In the general formula (1), A is methylene, one C (-0) — or

One CH (0H) — D represents a linear or branched alkylene chain having 1 to 5 carbon atoms, n represents 1,

R ² represents hydrogen,

R ³ represents hydrogen or alkyl,

R ⁴ represents hydrogen,

The bond represented by Q—T indicates CH ₂ —N or CH = C,

2. The thiophene compound according to claim 1, wherein E is an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent, an optical isomer thereof, and a pharmaceutically acceptable salt thereof. Salts or hydrates thereof.

4.3- (4- (4-chlorophenyl) piperazine-11-yl) -11- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophene-3-yl ) Pu mouth bread 1-on,

3- (4- (4-chlorophenyl) piperazine-1-1-yl) 1-11 (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophene-3-yl) propane 1—all,

1— (4-chlorophenyl) -1- (3- (4,5,6,7-tetrahydro-1-methylbenzo [b] thiophene-3-yl) propyl) pidazine,

1- (4-fluorophenyl) 1-4-1 (3- (4,5,6,7-tetrahydro--2-methylbenzo [b] thiophen-13-yl) propyl) pidazine,

4- (3- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propyl) 1 1 1 (3-trifluoromethylphenyl) piperazine ,

4- (3- (4,5,6,7-tetrahydro-2-methylbenzo [b] thiophen-3-yl) propyl) 1 1- (4-methylphenyl) pidazine,

1-(4-chlorophenyl) 1-4-(3- (2-ethyl 4-, 5, 6, 7-tetrahidrobenzo [b] thiophen-3-yl) propyl) piperazine,

1 — (4—Chlorophenyl) 1 4 1 (3— (4,5,6,7—Tetrahydrobe Benzo [b] thiophene_3 —yl) propyl) pirazine, and

4- (4-chlorophenyl) 1 1 — (3— (4,5,6,7-tetrahydro-12-methylbenzo [b] thiophen-13-yl) propyl) 1-1,2,3,6 — The thiophene compound according to claim 1, selected from tetrahydropyridine, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

5. A medicament comprising the thiophene compound according to claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.

6. Chiofunin compound according to claim 1, wherein, the optical isomers, D ₄ receptor blockers containing salt or hydrate thereof their pharmaceutically acceptable.

7. A pharmaceutical composition comprising the thiophene compound according to claim 1, an optical isomer thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof and a pharmaceutically acceptable additive.