Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-09-12
1997-06-24
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 546148, 548455, C07D 4006, C07D40306, A61K 3147, A61K 31395
Patent
active
056417870
DESCRIPTION:
BRIEF SUMMARY
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 of use in 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 of use in 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 expected to manifest fewer side-effects than those associated with classical neuroleptic drugs.
The compound 3-(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-1H-indole is described in Recl. Trav. Chim. Pays-Bas, 1954, 73, 629, and is stated to have oxytocic activity. There is, however, no suggestion therein that this compound might be an antagonist 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 it might be expected to manifest fewer side-effects than those exhibited by classical neuroleptic agents.
The present invention accordingly provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof: ##STR2## wherein R.sup.1 represents hydrogen or C.sub.1-6 alkyl; aryl(C.sub.1-6)alkyl or halogen; a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, ---SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a or --CONR.sup.a R.sup.b ; and heterocyclic group;
REFERENCES:
patent: 3472854 (1969-10-01), Archer
patent: 5432177 (1995-07-01), Baker et al.
Wijngaarden, et al. "2-Phenylpyrroles as Conformationally Restricted Benzamide Analogues, A New Class of Potential Antipsychotics.", J. Med Chem. vol. 31, pp. 1934-1940 (1988).
Broughton Howard Barff
Kulagowski Janusz Jozef
Leeson Paul David
Mawer Ian Michael
Merck Sharp & Dohme Ltd.
North Robert J.
Springer David B.
Winokur Melvin
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