WO1998037893A1

WO1998037893A1 - Dopamine d4 receptor antagonist

Info

Publication number: WO1998037893A1
Application number: PCT/JP1998/000744
Authority: WO
Inventors: Yukihiro Ohno; Atsuyuki Kojima; Junko Wakabayashi; Rie Tagashira
Original assignee: Sumitomo Pharmaceuticals Co., Ltd.
Priority date: 1997-02-26
Filing date: 1998-02-23
Publication date: 1998-09-03
Also published as: AU6230698A

Abstract

An imide derivative represented by general formula (1) [wherein Z is represented by formula (2) (wherein B represents a carbonyl group or the like; for R?1, R2, and R3, R1 and R2¿ combine with each other to form an optionally substituted hydrocarbon ring with R3 representing a hydrogen atom, or alternatively R?1 and R3¿ may combine with each other to form an optionally substituted hydrocarbon ring with R2 representing a hydrogen atom; and n is 0 or 1), or a group represented by R4CO-NR5-(wherein R4 represents an optionally substituted phenyl group or the like; and R5 represents a hydrogen atom or a lower alkyl group); W represents an optionally substituted lower alkylene group or the like, G represents a nitrogen atom or a methine group; Ar represents an optionally substituted pyrimidyl group or the like; and Y represents a hydrogen atom or -(CH¿2?)m- (wherein m is 1, 2 or 3) with the other end being optionally bonded to the o-position of Ar] or a pharmaceutically acceptable salt thereof is an antagonist against a dopamine D4 receptor that does not cause an extrapyramidal syndrom associated with dopamine D2 receptor antagonism and is useful as a therapeutic agent for metal disorder, e.g., schizophrenia in a negative state or the like and L-DOPA mental disorder during treatment of Parkinson's disease.

Description

Description Dopamine D4 receptor antagonist Technical field

The present invention relates to dopamine D4 receptor antagonists containing imido derivatives and the like. The dopamine D 4 receptor antagonist has selective and strong affinity for dopamine D 4 receptor, and is useful as a therapeutic drug for psychiatric disorders such as schizophrenia and Parkinson's disease. Background art

Clozapine is a typical example of a compound having selective affinity for the dopamine D4 receptor. Clozapine is classified as an atypical antipsychotic, has few extrapyramidal side effects, is effective for typical antipsychotics, is effective against negative symptoms, and appears when treating Parkinson's disease To improve the mental disorder caused by L-D0PA »Yaguchi Rare (P. ^ eeman, International Clinical Psychopharmaco 1 ogy (1995), 10 Suppl. 3, 5). The clinical utility of clozapine is said to be due to its selective affinity for dopamine D4 receptor over dopamine D2 receptor (G. Taubes , Science, 265, 1034 (1994)).

It is known that various imide derivatives have an antidepressant action (for example, JP-A-58-126865, JP-A-61-238784, JP-A-59-76059, etc.) It is not known to have dopamine D 4 antagonism. Problems to be solved by the invention

An object of the present invention is to find a drug capable of treating psychiatric disorders such as schizophrenia and Parkinson's disease by exhibiting selective antagonism to dopamine D4 receptor and having few side effects. It is in. Means to solve the problem

As a result of intensive studies, the present inventors have found that imido derivatives and the like have selective and strong affinity for dopamine D4 receptor, and have completed the present invention.

That is, the present invention

[1] Equation 1:

Where 式 is Equation 2

(Wherein, Β represents a methylene group, a carbonyl group or a sulfonyl group. RR ² and R ³ represent a hydrocarbon ring which may be substituted by R ¹ and R ² together; ³ represents a hydrogen atom, or R ¹ and R ³ together represent an optionally substituted hydrocarbon ring, R ² represents a hydrogen atom, and η represents 0 or 1. Represents a group

R ⁴ CO-NR ^5-

(In the formula, R ⁴ represents an optionally substituted phenyl group or an optionally substituted hydrocarbon ring group. R ⁵ represents a hydrogen atom or a lower alkyl group.)

W represents an optionally substituted lower alkylene group, an optionally substituted lower alkenylene group or an optionally substituted lower alkynylene group.

G represents a nitrogen atom or a methine group. Ar is an optionally substituted phenyl group, an optionally substituted benzoyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group, an optionally substituted naphthyl group, an optionally substituted quinolyl group Represents an optionally substituted isoquinolyl group or an optionally substituted quinazolyl group.

Y represents a hydrogen atom, or — (CH ₂ ) _m _ (where m represents 1, 2 or 3; one of CH ₂ — in the formula is replaced by an oxygen atom or a sulfur atom; And may be bonded to the ortho position of Ar at the other end. ]

A dopamine D 4 receptor antagonist containing an imid derivative represented by or a pharmaceutically acceptable salt thereof,

[2] Z is formula 3:

(In the formula, a solid line with a broken line represents a single bond or a double bond. E represents a lower alkylene group or an oxygen atom which may be substituted. R ⁶ represents a hydrogen atom or a substituent. It is synonymous.)

Equation 4:

(Wherein, the meaning of E, R ⁶ , B and the solid line accompanied by a broken line is the same as defined above.)

(Wherein, ring F represents a saturated or unsaturated cyclohexane ring or benzene ring. R ⁶ and B have the same meanings as described above.), Or

Equation 6:

(In the formula, R ⁷ and R ⁸ independently represent a hydrogen atom or a substituent, or represent a saturated hydrocarbon ring which may be substituted together. B has the same meaning as described above.) A dopamine D4 receptor antagonist according to [1],

[3] The dopamine D4 receptor antagonist according to [1] or [2], wherein Ar is an optionally substituted phenyl group, an optionally substituted pyridyl group or an optionally substituted pyrimidyl group.

[4] Ar is a phenyl group substituted with one or more lower alkoxy groups, or a 2-pyridyl group or a 2-pyrimidyl group. [1] A compound according to any one of [1] to [3]. Monopamine D 4 receptor antagonist,

[5] The dopamine D 4 receptor antagonist according to any one of [1] to [4], wherein G is a nitrogen atom,

[6] (1 R, 2 S, 3 R, 4 S) — N— [4— [4— (pyrimidine-1-yl) piperazine-11-yl] butyl] — 2,3-bicyclo [2.2. 1] Heptane dicarboximid (tandospirone), (1R, 2S, 3R, 4S) —N— [4—1—4— (3 -Methoxypyridine-1-yl) piperazine-1_yl] butyl] —2,3-bisic [2.2.1] heptanedicarboximide, (1R, 2S) —N— [4 — [4— (Pyridine-1-2-yl) piperazine-1-yl] butyl] —1,2-Cyclohexanedicalpoxyimide or (1R, 2S) -N— [4_ [4 — (2-Methoxyphenyl) piperazine-1-yl] butyl] -1,2-cyclohexanedicarboximide or dopamine D 4 receptor containing pharmaceutically acceptable salt thereof Body antagonists,

[7] The dopamine D4 receptor antagonist according to any one of [1] to [6], which is a therapeutic agent for mental disorders,

[8] The dopamine D4 receptor antagonist according to any one of [1] to [6], which is a therapeutic agent for Parkinson's disease;

[9] a method of antagonizing dopamine D4 receptor by administering an imid derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof,

[10] A pharmaceutical composition for antagonizing dopamine D4 receptor, comprising an imido derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof, and

[11] A use of an imid derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof for producing a dopamine D4 receptor antagonist. Examples of the lower alkyl group include a linear or branched group having 4 or less carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

Examples of the lower alkylene group include linear or branched groups having 5 or less carbon atoms, and specific examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, and 3-methyl-tetramethylene. No.

Examples of the lower alkenylene group include a linear or branched group having 2 to 5 carbon atoms, and specific examples include ethenylene, probenylene, 2-butenylene and the like. Examples of the lower alkynylene group include a linear or branched group having 2 to 5 carbon atoms, and specific examples thereof include ethynylene, propynylene, and 2-pentynylene. Examples of the lower alkoxy group include a linear or branched group having 4 or less carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the halogen-substituted lower alkyl group include lower alkyl groups substituted with 1 to 5 halogen atoms, and specific examples include fluoromethyl, trifluoromethyl, 2-chloroethyl, 3-chloropropyl, and 3-chloropropyl. Bromo_2-fluorobutyl and the like.

Examples of the hydrocarbon ring in Z in Formula 1 include a hydrocarbon ring having 8 or less carbon atoms, and such a hydrocarbon ring may be bridged with a lower alkylene or an oxygen atom. Examples of the hydrocarbon ring having 8 or less carbon atoms include cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane, cycloalkenes such as cyclopentene, cyclohexene and cycloheptene, and benzene ring And the like. Examples of the hydrocarbon ring bridged by a lower alkylene group or an oxygen atom include a ring having 10 or less carbon atoms. Specifically, bicyclo [2.2. 1] heptane, bicyclo [2.2. Bicyclo [2.2.2] octane, bicyclo [2.2.1] octa-2-ene, 7-oxabicyclo [2.2.1] heptan, 7-oxabicyclo [2.2.1] hepta _2-phen And adamantane.

Y represents one (CH ₂ ) _m — (wherein, m represents 1, 2 or 3 and one —CH ₂ in the formula may be substituted with an oxygen atom or a sulfur atom.) In the expression, bonding to the ortho position of Ar means that Y is bonded to the ortho position of the bonding position of Ar with G. As one (CH ₂ ) _m —, for example, one CH ₂ —, One CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, 110, one S—, _CH ₂₀ —, one CH ₂ CH ₂₀ — and the like.

A preferred example of Ar in which Y is bonded to the ortho position is a phenyl group. Hydrocarbon ring, lower alkylene group, lower alkenylene group, lower alkynylene group, Examples of the substituent in the phenyl group, benzoyl group, pyridyl group, pyrimidyl group, naphthyl group, quinoyl group, isoquinoyl group and quinazolyl group include, for example, hydroxyl group, lower alkyl group, lower alkoxy group, halogen atom, halogen-substituted lower alkyl group. And an amino group. Preferably, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a halogen atom and the like are mentioned.

Preferred examples of W in Formula 1 include, for example, tetramethylene. Preferred examples of Ar in the formula 1 include 2-pyrimidyl, 2-pyridyl, 3-lower alkoxy-2-pyridyl, 2-lower alkoxyphenyl, 2,6-di-lower alkoxyphenyl and the like. . Preferred compounds include the following compounds.

(1 R, 2 S, 3 R, 4 S) — N— [4- [4- (pyridine-1-2-yl) pyrazine-1-yl] butyl] — 2,3-bicyclo [2.2. 1] Heptanedicarboximide

(1 R, 2 S, 3 R, 4 S) — N— [4— [4 -— (2-methoxyphenyl) pyrazine — 1-yl] butyl] — 2,3-bicyclo [2.2. 1 ] Heptanedicarboximide

(1R, 2S, 3R, 4S) -N- [4- [4- (2-naphthyl) piperazine—1 ^ (l] butyl] —2,3-bicyclo [2.2.1] heptane Dicarboximide

(1R, 2S) -N- [4- [4- (pyrimidine-1-yl) pyrazine-1-yl] butyl] 1-1,2-cyclohexandicarboximide

(1 R, 2 S) — N_ [4— [4_ (3-Methoxypyridine 1-2- ^ f1) piperazine-1 1-yl] butyl] -1,1,2-cyclohexanedicarboximide

(1 R, 2 S) — N— [4 -— [4- (4-fluorobenzyl) piperazine—1-yl] butyl) —1,2-cyclohexanedicarboximide

(1 S, 2 S, 3 R, 4 R) — N— [4— [4 -— (pyrimidine-1-2-yl) piperazine-1—yl] butyl] -2,3-bicyclo [2.2. 1] Heptanedicarboximide

(1 S, 2 S, 3 R, 4 R) 1 N— [4— [4— (3-methoxypyridine-1-yl) piperazine-1—yl] ptinole] — 2, 3-bicyclo [2.2.1] Heptanedicarboxy Imide

(IS, 2 S, 3 R, 4 R) 1 N— [4— [4— (Pyridine-1-yl) piperazine-11-yl] butyl] -1,2,3-bicyclo [2.2. 1 ] Heptanedicarboximide

(1 S, 2 S, 3 R, 4 R) — N— [4- (4- (2-methoxyphenyl) pidazine—1-yl] butyl) -1,2,3-bicyclo [2.2. 1 ] Heptanedicarboximide

(1 S, 2 S, 3 R, 4 R) — N— [4- [4- (2-naphthyl) piperazine-1-yl] butyl] — to 2,3-bicyclo [2.2. 1] Putandicarboxymid

(1 S, 2 S, 3 R, 4 R) — N— [4- (4- (4-fluorobenzoyl) piperazin-1-yl] butyl) -1,2,3-bicyclo [2.2. 1] Heptanedicarboximide (2R, 3S) -N- [4- [4- (pyrimidine-2-yl) piperazine-1-yl] butyl] —2,3-bicyclo [ 2.2.2] octanedicarboximide

(2 R, 3 S) 1 N— [4— [4— (3-Methoxypyridine-1 2 f) piperazine-11-yl] butyl] -2,3-bicyclo [2.2,2] octanedi Carboximid

(2 R, 3 S) 1 N— [4— [4— (Pyridine-1 2— ^）) pirazin-1 1-yl] butyl] -1,2,3-bicyclo [2.2.2] octanedi Carboximid

(2 R, 3 S) -N- [4- (4- (2-Methoxyphenyl) piperazine-l-yl] butyl] -l, 3-Bicyclo [2.2.2] octanedicarboxy Mid

(2 R, 3 S) 1 N_ [4— [4— (2-naphthyl) piperazine-1—yl] butyl] —2,3-bis [2.2.2] octanedicarboximide

(2 R, 3 S) —N— [4 -— [4- (4-fluorobenzoyl) piperazine-1-yl] butyl) —2,3-bicyclo [2.2.2] octanedicarboxy Imid

N- [4_ [4- (pyrimidine-1-yl) piperazine-111] butyl] -N-methylcyclohexanecarboxamide

N— [4 -— [4- (3-Methoxypyridine-1-yl) piperazine-1-yl] butyl] —N-methylcyclohexanecarboxamide

N- [4- [4- (Pyridine- 1 f) pirazazine- 1-yl] butyl] -N-methylcyclohexanecarboxamide N- [4- [4- (2-Methoxyphenyl) piperazine-1-yl] butyl] -1-N-methylcyclohexanecarboxamide

N- [4- [4- (2-naphthyl) piperazine-11-yl] butyl] —N-methylcyclohexanecarboxamide

N- [4- -4- (4-Fluorobenzoyl) piperazine-1-yl] butyl]-N-methylcyclohexanecarboxamide

N— [4— [4— (pyrimidine-1_yl) piperazine-1—yl] butyl] adamantantancarboxamide

N— [4 -— [4- (3-Methoxypyridine-1-yl) piperazine-1-yl] butyl] adamantane

N- [4- [4- (pyridine-1-yl) piperazine-1-yl] butyl] adamantancarboxamide

N- [4- [4- (2-methoxyphenyl) pidazine—1-yl] butyl] adamantanecarboxamide

N— [4— [4— (2-Naphthyl) pidazine-1-yl] butyl] adamantanecarboxamide

N- [4--[4-(4-Fluorobenzoyl) piperazine-11-yl] butyl] adamantanecarboxamide

(1 R, 2 S, 3 R, 4 S) one N— [4— [2, 3, 4, 4 a, 5, 6—hexahydro — 1 (H) — virazino [2, 1— c] _ l, 4-Benzoxazine-1-3-yl] butyl] -2,3-bicyclo [2.2.1] heptanedicarboximide

(1 S, 2 S, 3 R, 4 R) 1 N— [4— [2, 3, 4, 4 a, 5, 6—hexahydro-1 1 (H) — virazino [2, 1-c]- 1,4-benzoxazine-1-3-yl] butyl] —2,3-bicyclo [2.2.1] heptanedicarboximide

(2 R, 3 S) — N— [4-I [2, 3, 4, 4 a, 5, 6-Hexahydro-1 (H) — Virazino [2, 1—c] -1 1, 4-Venzoxazine 1 3 —Yl] butyl] -2,3-bi N— [4 -— [2,3,4,4a, 5,6-hexahydro-1 (H) —birazino [2,1—c] —1,4-benzoxazine-1-yl] ptinole] 1-N —Methylcyclohexane power Lupoxamide

N— [4 -— [2,3,4,4a, 5,6-hexahydro-1 (H) —birazino [2,1—c] —1,4_benzoxazine-1-yl] butyl] a Damantanecarboxamide (1 R, 2 S, 3 R, 4 S) —N— [4-1 [4-1 (pyrimidine-1 2_yl) piperazine — 1yl] — 2 (E) —butenyl] 1,2,3-Bicyclo [2.2.1] heptane dicarboximide.

(1 R, 2 S, 3R, 4 S) — N— [4— [4-— (3-methoxypyridine-1-yl) piperazine-11-yl] — 2 (E) —butenyl] -one 2,3-bicyclo [2.2.1] heptane dicarboximide

(1 R, 2 S, 3 R, 4 S) — N— [4— [4— (Pyridine-1 2— ^ f1) Piperazine-1 1-yl] _ 2 (E) —Butenyl] -1 2 , 3-Bicyclo [2.2.1] heptanedicarboximide

N— [4— [4— (pyrimidine—2-yl) pidazine—1-yl] -12 (E) —butenyl] —N—methylcyclohexanecarboxamide

N— [4-—4- (3-Methoxypyridine-1-yl) pidazine-1-yl] -12 (E) -butenyl] -1-N-methylcyclohexane

N— [4 -— [4- (pyridine-1-yl) piperazine-11-yl] —2 (E) -butenyl] —N-methylcyclohexanecarboxamide

N- [4- [4- (pyrimidine-2-yl) piperazine-1-yl] -1 2 (E) _butenyl] adamantanecarboxamide

N— [4-1-1 [4- (3-methoxypyridine-1-yl) piperazine-1 per] -2 (N— [4-—4- (pyridine-1-2-yl) piperazine-1 1-yl] -1 2 (E) —butenyl 8— [4— [4— (pyrimidine-1-yl) piperazine-1-1-inole] butyl] —8-azaspiro [4,5] decane-1 7,9 dione (Buspirone)

8— [4— [4— (3-Methoxypyridine-1-yl) piperazine-11-yl] butyl] -1-8-azaspiro [4,5] decane-1 7,9-dione

8— [4 -— [4- (Pyridine-1-2-yl) piperazine-11-isole] butyl] —8-azaspi [4,5] decane-1 7,9-dione

8- [4- [4- (2-Methoxyphenyl) piperazine-1-yl] butyl] _8-azaspiro [4,5] decane-1 7,9-dione

8— [4— [4— (2-naphthyl) piperazine—11-yl] butyl—1—8-azaspiro [4,5] decane—1,9,9 dione

8— [4— [4-1 (4-fluorobenzoyl) piperazine—1—yl] butyl] —8—aza spiro [4,5] decane—7,9—dione

(2 R, 3 S) -8- [4- [2,3,4,4a, 5,6-hexahydro-1 (H) -birazino [2,1-c] —1,4-benzoxazine 1-3-yl] butyl] _8-azaspiro [4,5] decane-1,9-dione

8- [4- [4- (Pyrimidine-1-2-yl) pirazin-1 1-yl] _2 (E) -butenyl] -8-azaspiro [4,5] decane-1 7,9-dione

8— [4— [4— (3-Methoxypyridine-1-yl) piperazine-1-yl] —2 (E) —butenyl] —8-azaspiro [4,5] decane-1,7,9 —Zeon

8- [4- [4- (pyridine-1-yl) pirazazine-1-yl] -12 (E) -butenyl] -1-azaspiro [4,5] decane-1,9-dione Pharmaceutical The above acceptable salts include acid addition salts with inorganic or organic acids, which are acceptable as pharmaceuticals. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. Examples of the organic acid include acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid and the like. The imid derivatives also include solvates such as hydrates. The compound of the present invention can be produced by a known method. For example, it can be produced by the method described in the following patent publication.

JP-A-58-126865, JP-A-58-213755, JP-A-59-29665, JP-A-59-76059, JP-A-59-190990, JP-A-60- 87262, JP-A-60-87284, JP-A-61-238784, JP-A-63-83067, JP-A-63-10786, JP-A-63-183576, JP-A-2-235865, JP-A-5-17440, and WO96 / 14297.

Specifically, for example, it can be produced by reacting in the presence of a base by the following production method.

Manufacturing method a:

H + ~ ► Z— W— NG— Ar

Production method b:

[Wherein, Z, W, G, Ar and Y are as defined above. X represents a halogen atom. When the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is used as an antipsychotic, it can be administered orally or parenterally. That is, it can be administered orally in the form of commonly used dosage forms such as tablets, capsules, sublingual tablets, syrups, suspensions and the like. Alternatively, liquid forms can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories. The above-mentioned appropriate dosage form is produced by mixing the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof with an acceptable usual carrier, excipient, binder, stabilizer and the like. can do. When used as an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added.

The dose and frequency of administration of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof will vary depending on the symptom-age, body weight, dosage form, etc. The dose of 1-500 mg, preferably 5-100 mg for oral administration, and 0.1-100 mg, preferably 0.3-50 mg for intravenous injection, in one or several divided doses Can be. Example

The present invention will be specifically described below with reference to examples and the like, but the present invention is not limited to these examples.

Example 1

Production of Compounds 1-7

Compound 1: (1 R, 2 S, 3 R, 4 S) — N— [4-—4- (pyrimidine-1-yl) piperazine-1—yl] butyl] — 2,3-bicyclo [2.2.1] Heptanedicarboximid (tandospirone)

_C produced according to the method described in JP-A-58-126865.

Melting point: 169 ° C (decomposition) (Quenic acid salt) Compound 2: (1 R, 2 S, 3 R, 4 S) — N— [4— [4— (3-Methoxypyridine 1-2-yl) [Razine-1-yl] butyl] —2,3-bicyclo [2.2.1] heptamide '

It was produced according to the methods described in JP-A-58-126865 and JP-A-61-238784.

Melting point: 196.5-198.5 ° C (decomposition) (Hydrochloride) Compound 3: (1 R, 2 S) -N-C4-E4-(pyridine-1-yl) piperazine-11-yl] butyl — 1,2-cyclohexanedicarboximide

It was produced according to the method described in JP-A-59-76059.

Melting point: 87-88 ° C. Compound 4: (1 R, 2 S) — N— [4— [4 -— (2-methoxyphenyl) pipera 1-yldibutyl Ί—1,2-cyclohexanedi Carboximid

It was produced according to the method described in JP-A-59-76059.

Melting point: 197-200 ° C (hydrochloride) Compound 5: (1 R, 2 S) —N— [4 -— [4- (2-naphthyl) piperazine-1-yl] butyl] -1-1,2-cyclohexanedicarboximide

It was produced according to the method described in JP-A-5-17440.

Melting point ··· 252- 253 ° C (hydrochloride) Compound 6: (1R, 2S, 3R, 4S) — N— [4— [4— (4-fluorobenzoyl) piperazine-1 —Yl] butyl] — 2,3-bicyclo [2.2.1] heptanedicarboxyimide

It was produced according to the method described in JP-A-5-17440.

Melting point: 253-254 ° C (hydrochloride) Compound 7: (1 R, 2 S) — N— [4— [2, 3, 4, 4 a, 5, 6—hexahydro — 1 (H) — virazino [2,1—c] —1,4-Benzoxazine-3-l] —1,2-cyclohexanedicarboximide

According to the method described in JP-A-60-87262, 2, 3, 4, 4a, 5, 6-hexa Hydro-1 (H) —Birazino [2,1-c] —1,4-benzoxazine (synthesized according to the method described in Indian J. Chein., ^, 462 (1975)), (1R, 2S) — It was prepared by heating N- (4-chlorobutyl) -1,2-cyclohexanedicarboximide, potassium carbonate, and potassium iodide under reflux in acetonitrile. Melting point: 181-183 ° C (hydrochloride)

Human dopamine D4 receptor binding activity.

1) Experimental method

The activity of the compound was determined using a D4 receptor membrane preparation prepared from CHO-K1 cells transfected with human D receptor cDNA according to the method described in Nature, 610-614 (1991), etc. The inhibition rate of the radioligand [¾] -spiperone against the binding reaction to the D4 receptor membrane standard by a predetermined concentration of the test compound was determined.

2) Result

Table 1 shows the binding activity of the compounds as Ki values. Example 3

Human dopamine D2 receptor binding activity.

1) Experimental method

The activity of the compound was determined using a D2 receptor membrane preparation prepared from CH0-K1 cells transfected with human D2 receptor cDNA according to the method described in Nature, 610-614 (1991). The inhibitory rate of the radioligand [¾] -spiperone to the binding reaction to the D2 receptor membrane standard by the test compound at a predetermined concentration was determined.

2) Result

Table 1 shows the binding activity of the compounds as Ki values. table 1 :

Compound No. 04 Binding activity (:) D 2 binding activity (Ki: nM)

1 7 2 4 6 0

2 1 3 2 7

3 5 5 1 1 0

4 1 1 5 9

5 0 6 8 2 9

6 1 1 3 1

7 3 8 4 6 Example 4

Human dopamine D4 receptor inhibitory activity

1) Experimental method

The activity of the compound was determined using a cell suspension of CHO-K1 cells transfected with human D4 receptor cDNA according to the method described in J. Neurochem., 65, 1157-1165 (1995). The inhibitory rate of dopamine (0.3 mM) in the presence of forskolin (10) against the cyclic-AMP (c-AMP) production inhibitory effect in the presence of forskolin (10) was determined.

2) Result

The inhibitory activity of compound 1 was IC ₅ . The value was 300 nM.

From the results of Examples 2-4 above, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof has a selective and strong affinity for dopamine D4 receptor. It has been shown to act as an antagonist at the d-pamine D4 receptor. Formulation Examples 1-3

Manufacture of coated tablets

Ground tandospirone citrate, lactose, corn starch and carmellose Calcium is put into a fluidized bed granulator, granulated by spraying an aqueous solution of polyvinyl alcohol (partially saponified), and granulated to produce granules.

Magnesium stearate is added to the granules, mixed, and tabletted to form tablets. The tablet is sprayed with a coating solution prepared from hydroxypropyl methylcellulose 2910, concentrated glycerin, yellow iron sesquioxide (only for 5 mg tablets), titanium oxide, carnaupa wax, and purified water. Manufacture coated tablets.

(Prescription) Unit mg

Formulation Examples 4 to 6

Manufacture of film-coated tablets

Pulverized product of tandospirone citrate, lactose, corn starch and low-substituted hydroxypropylcellulose are charged into a fluidized bed granulator, and granulated by spraying with an aqueous solution of povidone (K value 30). To produce granules.

Magnesium stearate is added to the granules, mixed, and tabletted to form tablets. This tablet was prepared from hydroxypropyl methylcellulose 2910, concentrated glycerin, yellow iron sesquioxide (only for 5 mg tablets), titanium oxide and purified water. Coating solution by spraying, to produce a film-coated tablets ₍

(Prescription) Unit mg

Formulation Example 7

Production of fine granules

A milled product of tandospirone citrate, lactose, and corn starch are mixed, and a corn starch aqueous solution is heated and gelatinized, added, kneaded, extruded, dried, and sized to produce fine granules. Formulation Example 8

Production of persistent granules

Pulverized product of tandospirone citrate, lactose, and corn starch are mixed, an aqueous solution of polyvinyl alcohol (partially saponified) is added, kneaded, extruded, sized with a marmalizer, and dried to produce granules. The obtained granules are put into a fluidized bed coating machine and sprayed with a coating liquid consisting of ethyl cellulose, hydroxypropyl methylcellulose 2910, methylene chloride and ethanol to obtain persistent granules. (Prescription) Unit mg

Industrial applicability

A dopamine D4 receptor antagonist containing a compound represented by the formula 1 or a pharmaceutically acceptable salt thereof, etc., selectively inhibits dopamine D4 receptor. It does not cause extrapyramidal tracts related to receptor antagonism, and is useful as a therapeutic drug for psychiatric disorders that is effective for schizophrenia symptoms such as negative symptoms and L-D0PA psychiatric disorders in treating Parkinson's disease.

Claims

1.Equation 1

Saguchi

Lord E D

[Where Z is equation 2

of

Enclosure

(Wherein B represents a methylene group, a carbonyl group or a sulfonyl group. RR ² and R ³ represent a hydrocarbon ring in which R ¹ and R ² may be substituted together; ³ represents a hydrogen atom, or R ¹ and R ³ together represent an optionally substituted hydrocarbon ring, R ² represents a hydrogen atom, and n represents 0 or 1. Represents a group

R ⁴ CO-NR ^5-

W represents a substituted or lower alkylene group, a substituted or unsubstituted lower alkenylene group or a substituted or unsubstituted lower alkynylene group.

G represents a nitrogen atom or a methine group.

Ar is an optionally substituted phenyl group, an optionally substituted benzoyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group, an optionally substituted naphthyl group, an optionally substituted quinolyl group , An optionally substituted isoquinolyl group or a substituted Represents a quinazolyl group which may be substituted.

Y represents a hydrogen atom or one (CH ₂ ) _m — (wherein m represents 1, 2 or 3 and one CH ₂ — in the formula is replaced by an oxygen atom or a sulfur atom And may be bonded to the ortho position of Ar at the other end. ]

A dopamine D 4 receptor antagonist comprising an imid derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

2. Z is equation 3:

(In the formula, a solid line with a broken line represents a single bond or a double bond. E represents an optionally substituted lower alkylene group or an oxygen atom. R ⁶ represents a hydrogen atom or a substituent. It is synonymous with the meaning of 1.)

Equation 4:

(Wherein, the meaning of E, R ⁶ , B and the solid line accompanied by a broken line is the same as described above.) Formula 5:

(In the formula, ring F represents a saturated or unsaturated cyclohexane ring or a benzene ring. R ⁶ and B are as defined above. ) Or

Equation 6:

(In the formula, R ⁷ and R ⁸ independently represent a hydrogen atom or a substituent, or represent a saturated hydrocarbon ring which may be substituted together. B has the same meaning as described above.)

The dopamine D4 receptor antagonist according to claim 1, which is a group represented by the formula:

3. The dopamine D 4 receptor antagonist according to claim 1, wherein Ar is an optionally substituted phenyl group, an optionally substituted pyridyl group, or an optionally substituted pyrimidyl group.

4. The dopamine D 4 according to any one of claims 1 to 3, wherein Ar is a phenyl group substituted with one or more lower alkoxy groups, or a 2-pyridyl group or a 2-pyrimidyl group. Receptor antagonist.

5. The dopamine D4 receptor antagonist according to any one of claims 1 to 4, wherein G is a nitrogen atom.

6. (1 R, 2 S, 3 R, 4 S) 1 N— [4— [4— (pyrimidine—2—yl) piperazine—1—yl] butyl] —1,2,3-bicyclo 2.2. 1] Heptanedicarboximidide (tandospirone), (1R, 2S, 3R, 4S) —N— [4— [4- (3-methoxypyridine-1--2-yl) pidazine 1-yl] butyl] -1,2,3-bicyclo mouth [2.2.1] heptane dicarboximide, (1R, 2S) —N— [4— [4— (pyridin-1-yl) [Piperazine-1-yl] butyl] —1,2-cyclohexanedicarboximid or (1R, 2S) —N— [4-—4- (2-methoxyphenyl) piperazine [1-yl] butyl] —a dopamine D 4 receptor antagonist containing 1,2-cyclohexanedicarboximide or a pharmaceutically acceptable salt thereof.

7. Dopamine D 4 according to any one of claims 1 to 6, which is a therapeutic agent for mental disorders. Receptor antagonist.

8. The doppan D4 receptor antagonist according to any one of claims 1 to 6, which is a therapeutic agent for Parkinson's disease.

9. Equation 1:

[Wherein, Z, W, G, Ar and Y have the same meanings as in claim 1]. ] The dopamine D4 receptor antagonistic method by administering the imid derivative represented by these, or its pharmacologically acceptable salt.

1 0. Equation 1:

[Wherein, Z, W, G, Ar and Y have the same meanings as in claim 1]. A pharmaceutical composition for antagonizing dopamine D 4 receptor, comprising an imid derivative represented by the formula: or a pharmaceutically acceptable salt thereof.

1 1. Formula 1 for producing dopamine D4 receptor antagonist:

[Wherein, Z, W, G, Ar and Y have the same meanings as in claim 1]. ] Use of the imid derivative represented by these, or its pharmacologically acceptable salt.