2-carbonylthiazole derivatives and use of the same

Details 2-carbonylthiazole derivatives and use of the same 2-carbonylthiazole derivatives and use of the same

1999-11-05

2000-12-26

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

5142368, 5142531, 514326, 544129, 544360, 546186, 546187, 546209, A61K 314535, A61K 31496, C07D41306, C07D21170, C07D40114

Patent

active

061660337

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a 2-carbonylthiazole derivative having antipsychotic action.


BACKGROUND ART

Antipsychotic drugs are used for the treatment of not only schizophrenia but also problematic behavior (such as aggressive behavior, mental excitation, poriomania and delirium) caused by cerebrovascular accidents and senile dementia. However, the conventional antipsychotic drugs, dopamine D.sub.2 receptor antagonists, have a serious problem in that they cause strong extrapyramidal disorders as their side effects.
On the other hand, the structure and properties of recently discovered dopamine D.sub.4 receptor are close to those of dopamine D.sub.2 receptor, and a great difference between them is their intracerebral distribution. Regarding the intracerebral distribution of dopamine D.sub.4 receptor, it is distributed in a high concentration in the cerebral cortex frontal lobe which is related to the onset of schizophrenia, but in a small amount in the striate body which is concerned in the expression of extrapyramidal disorders. In consequence, dopamine D.sub.4 receptor antagonists have a great possibility to be used as novel schizophrenia treating drugs which do not accompany extrapyramidal disorders as the side effects that are common in dopamine D.sub.2 receptor antagonists (Nature, 350, 610-614 (1991); Nature, 358, 109 (1992); Nature, 365, 393 (1993); Nature, 365, 441-445 (1993)).
Clozapine is one of such compounds. It has been reported that affinity of clozapine for dopamine D.sub.4 receptor is higher than its affinity for dopamine D.sub.2 receptor (Nature, 350, 610-614 (1991)). It has been reported also that, unlike the case of dopamine D.sub.2 receptor antagonists, clozapine is effective in drug-resistant schizophrenia and negative symptoms and causes less extrapyramidal disorders, according to its clinical investigation (Arch. Gen. Psych., 45, 789-796 (1988)). However, clozapine has a serious disadvantage in that it generates a hemotoxin as agranulocytosis which resulted in certain mortal cases (Summary and Clinical Data, Sandoz, Canada Inc. (1990)).
In consequence, such a dopamine D.sub.4 receptor antagonist having no side effects is highly useful as a drug for the treatment of diseases such as schizophrenia, having an extremely low possibility of causing extrapyramidal disorders.


DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a dopamine D.sub.4 receptor antagonistic compound which shows antipsychotic action without generating extrapyramidal disorders.
The inventors of the present invention have conducted intensive studies on 2-carbonylthiazole derivatives and found as a result of the efforts a novel 2-carbonylthiazole derivative which shows high affinity for dopamine D.sub.4 receptor, thereby accomplishing the present invention.
The following describes the present invention.
The present invention is a 2-carbonylthiazole derivative represented by formula (I): ##STR2## [wherein each of Ar.sup.1 and Ar.sup.2 represents a phenyl group, a phenyl group having one or two substituents selected from "a halogen atom, an alkyl group having 1 to 5 carbon atoms, a trifluoromethyl group, an alkoxy group having 1 to 5 carbon atoms and a hydroxyl group" or a thienyl group; R.sup.1 represents an alkoxy group having 1 to 5 carbon atoms, a hydroxyl group or an amino group represented by formula N(R.sup.3)R.sup.4 (wherein each of R.sup.3 and R.sup.4 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, or R.sup.3 and R.sup.4, together with the nitrogen atom to which they are bound, form a pyrrolidino, piperidino, morpholino or piperazino group, or a pyrrolidino, piperidino, morpholino or piperazino group having one to four substituents selected from "an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms and a hydroxyl group"); Y.sup.1 --Y.sup.2 represents CH--CO or C.dbd.C(R.sup.2) (wherein R.sup.2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms); and n is an integer of from 1 to 4] or a phar

REFERENCES:
patent: 4123529 (1978-10-01), Verge et al.
patent: 5071864 (1991-12-01), Rendenbach-Mueller et al.
patent: 5401762 (1995-03-01), Rendenbach-Mueller et al.

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