Imidazolone and oxazolone derivatives as dopamine antagonists

Details Imidazolone and oxazolone derivatives as dopamine antagonists Imidazolone and oxazolone derivatives as dopamine antagonists

1996-03-12

1997-12-16

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514212, 514318, 514320, 514374, 514397, 540603, 546193, 546196, 546210, 548229, 5483147, A61K 31415, A61K 31445, C07D40104, C07D41304

Patent

active

056985738

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GD94/01934 filed Sep. 6, 1994.
This invention relates to a particular glass of substituted oxazolone and imidazolone derivatives which are antagonists of dopamine receptor subtypes within the brain and are therefore of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia.
The "dopamine hypothesis" of schizophrenia predicts an increased activity of dopamine neurotransmission in the disease. The hypothesis is supported by early observations that drugs, such as amphetamine, with dopamine agonist or dopamine-releasing properties are capable of eliciting a psychosis indistinguishable from acute paranoid schizophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In the majority of cases, the symptoms of schizophrenia can be treated successfully with so-called "classical" neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D.sub.2 receptors. The fact that classical neuroleptic drugs have an action on dopamine receptors in the brain thus lends credence to the "dopamine hypothesis" of schizophrenia.
Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D.sub.1 receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D.sub.2 receptor subtype, and at least one form of the D.sub.3 receptor subtype, have also been discovered. More recently, the D.sub.4 (Van Tol et al., Nature (London), 1991, 350, 610) and D.sub.5 (Sunahara et al., Nature (London), 1991, 350, 614) receptor subtypes have been described.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms and neuroendocrine disturbances. These side-effects, which clearly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D.sub.2 receptor blockade in the striatal region of the brain. It is considered (Van Tol et al., supra) that compounds which can interact selectively with the dopamine D.sub.4 receptor subtype, whilst having a less-pronounced action at the D.sub.2 subtype, might be free from, or at any rate less prone to, the side-effects associated with classical neuroleptics, whilst at the same time maintaining a beneficial level of antipsychotic activity.
The compounds according to the present invention, being antagonists of dopamine receptor subtypes within the brain, are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. Moreover, the compounds according to the invention have a selective affinity for the dopamine D.sub.4 receptor subtype over other dopamine receptor subtypes, in particular the D.sub.2 subtype, and can therefore be expected to manifest fewer side-effects than those associated with classical neuroleptic drugs.
EP-A-0379990 describes a class of 4,5-disubstituted 2H-imidazol-2-ones which are stated to have affinity in vitro against D.sub.2, 5-HT.sub.2 and .alpha..sub.1 receptors, as well as showing activity in vivo on the central nervous system in various behavioural tests, and antihypertensive activity. The compounds described therein are accordingly alleged to be useful as antipsychotic, antidepressant and anxiolytic agents, as well as having utility in the treatment of hypertension and other cardiovascular complaints. Since their antipsychotic activity is presumably mediated by antagonism of D.sub.2 receptors, however, it seems reasonable to suppose that these compounds are subject to the drawbacks, in terms of their unpleasant side-effects, customarily associated with classical neuroleptic drugs.
The present invention accordingly provides a compound of formula I, or a salt thereof or a prodrug thereof: ##STR3## wherein X represents oxygen or N--R.sup.1 ; heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the imidazolone or ox

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Wyngaarden et al. "Cecil Textbook of Medicine" Sauder Co., p. 67, 1983.
Van Kammen "Gamma aminobutyric acid and the dopamine hypothesis of schezophrenia" Ind. Medicus 77:109461, 1977.
Shaywitz et al. "Selective brain dopamine depletion . . . " Ind. Medicus 76:104593, 1976.

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