N-(3-pyrrolidinyl) benzamide derivative

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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Details

548529, 548557, C07D20706, A61K 3140

Patent

active

056864825

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP95/00818 filed Apr. 26, 1995 published as WO95/29891 Nov. 9, 1995.


TECHNICAL FIELD

This invention relates to N-(3-pyrrolidinyl)benzamide derivatives, or a pharmaceutically acceptable salt thereof, which have selective and high affinity for dopamine D.sub.3 (to be referred to as D.sub.3 hereinafter) receptor and/or dopamine D.sub.4 (to be referred to as D.sub.4 hereinafter) receptor and weak action upon dopamine D.sub.2 (to be referred to as D.sub.2 hereinafter) receptor. It also relates to D.sub.3 receptor and/or D.sub.4 receptor antagonists which contain N-(3-pyrrolidinyl)benzamide derivatives or a pharmaceutically acceptable salt thereof as their active ingredient.


BACKGROUND ART

Dopamine, i.e., 4-(2-aminoethyl)-1,2-benzenediol, takes markedly varied and important roles in the central nervous system and peripheral nervous system. In the conventional studies, dopamine receptor has been classified into D.sub.1 like receptor and D.sub.2 like receptor based on a pharmacological classification. The D.sub.2 like receptor is deeply related to mental functions and locomotive functions, and a number of drugs which act upon this type of receptor are used mainly as psychotropic agents for use in the treatment of schizophrenia, depression and other mental diseases/ Typical examples of such drugs include haloperidol, sulpiride and the like. However, though these drugs show excellent effects upon symptoms which are called positive symptoms of schizophrenia (e.g., psychomotor excitement, hallucination, delusion and the like), their effects are not sufficient for the patients of chronic schizomycosis mainly having negative symptoms such as lack of spontaneity, disappearance of interest, flattening of affect and the like. In addition, these drugs are accompanied by adverse side effects, though the degree varies. Typical examples of such side effects are so-called extrapyramidal symptoms in which diskinetic disorders are mainly generated, such as dystonia, Parkinson disease-like symptoms and akathisia which occur in a relatively acute manner with a relatively high frequency, and intractable tardive dyskinesia which is generated after prolonged administration.
In addition to the above, endocrine symptoms such as hyperprolactinemia, amenorrhea and the like are also developed.
It is considered in general that the psychotropic action, which is the main action of these drugs, is based on an action mediated by the D.sub.2 like receptor which is present in the frontal cortex and limbic system, the extrapyramidal symptoms as side effects are based on an action mediated by the D.sub.2 like receptor which is present in the striate body and the endocrine symptom-based side effects are based on an action mediated by the D.sub.2 like receptor which is present in the anterior lobe of hypophysis (Baldessarini, R. L., "Drugs and the treatment of psychiatric disorders" in Gilman, A. G. et al., eds. "The Pharmacological Basis of Therapeutics 8th Ed.", Pergamon Press, New York, 1990, pp. 383-435).
With the development of genetic engineering in recent years, new dopamine receptor subtypes have been discovered, and the dopamine receptor has been re-classified into five subtypes of D.sub.1 to D.sub.5 receptors having different constituting amino acid sequences. Thus, it was revealed that the D.sub.2 like receptor based on the conventional pharmacological classification is a subfamily which includes the D.sub.2 receptor and newly discovered D.sub.3 receptor and D.sub.4 receptor, and the D.sub.1 like receptor is a subfamily which includes the D.sub.1 receptor and 61-69 (1992)!.
It is also known that the D.sub.2, D.sub.3 and D.sub.4 receptors belonging to the D.sub.2 like receptor subfamily have characteristic differences in Res., 564, 203-219 (1991), Gehlert D. et al., Eur. J. Pharmacol., 211, 189-194 (1992) and Van Tol H. H. M. et al., Nature, 350, 610 (1991)!. The D.sub.2 receptor is distributed particularly frequently in the striate body which relates to the onset of extrapyramidal symptoms as a main s

REFERENCES:
patent: 3966957 (1976-06-01), Cale, Jr. et al.
patent: 4109005 (1978-08-01), Lunsford et al.

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