Indole derivatives as dopamine D.sub.4 antagonists

Details Indole derivatives as dopamine D.sub.4 antagonists Indole derivatives as dopamine D.sub.4 antagonists

1995-09-13

1996-11-19

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546201, A61K 3140, C07D21114

Patent

active

055763367

DESCRIPTION:

BRIEF SUMMARY
This is the national stage application of PCT/GB94/00527 filed Mar. 16, 1994 and published as WO94/21627 Sep. 29, 1994.
This invention relates to a particular class of heteroaromatic compounds. More particularly, the invention is concerned with the use of substituted indole 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 in accordance with 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.
In GB-A-2083476 there is described inter alia a class of 3-[piperidin-1-ylmethyl]-1H-indole and 3-[1,2,3,6-tetrahydropyrid-1-ylmethyl]-1H-indole derivatives, substituted at the 4-position respectively of the piperidine or tetrahydropyridine moiety by an optionally substituted phenyl group. These compounds are stated to exhibit psychotropic activity and, in some cases, anti-depressant activity. There is, however, no suggestion in GB-A-2083476 that the compounds described therein might be antagonists of dopamine receptor subtypes within the brain, and thus be of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia, still less that in doing so they might be expected to manifest fewer side-effects than those exhibited by classical neuroleptic agents. Indeed, certain of the compounds described in GB-A-2083476 are explicitly stated to show dopamine agonist activity.
The generic disclosure of EP-A-0449186 en

REFERENCES:
patent: Re28973 (1976-09-01), Welstead, Jr.

Affiliated with

Also associated with

Rating

Indole derivatives as dopamine D.sub.4 antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Indole derivatives as dopamine D.sub.4 antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indole derivatives as dopamine D.sub.4 antagonists will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-541320