Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-10-18
1997-09-09
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514307, 514320, 514337, 514338, 514414, 544376, 546148, 546196, 5462841, 548454, C07D40506, C07D40106, A61K 31495
Patent
active
056657226
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB/00947 filed May 26, 1995.
This invention relates to a particular class of heteroaromatic compounds. More particularly, the invention is concerned with benzofuran 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 (movement disorders) and neuroendocrine (hormonal) 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; and WO-A-92/10571) 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. In particular, the compounds of use in this invention are extremely potent antagonists of the human dopamine D.sub.4 receptor subtype. 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 be expected to manifest fewer side-effects than those associated with classical neuroleptic drugs.
EP-A-0077607 describes a class of piperidine derivatives substituted in the 3-position by a substituted phenyl moiety and on the ring nitrogen atom by inter alia an optionally substituted benzofuryl or benzofuryl-alkyl group. Certain of these compounds are stated to be dopamine agonists, whilst others are alleged to be dopamine antagonists. There is, however, no disclosure in EP-A-0077607 of substitution at the 4-position of the piperidine ring, nor is there any suggestion that the compounds described therein might be potent antagonists of the human dopamine D.sub.4 receptor subtype, still less that they might have a selective affinity for the dopamine D.sub.4 receptor subtype over other dopamine receptor subtypes, and especially the D.sub.2 subtype.
The present invention provides a compound of formula I, or a salt or prodrug thereof: ##STR
REFERENCES:
Chemical Abstracts, Abstract 124908t, p. 104; col. L, vol. 120, No. 11, Mar. 14, 1994.
Chemical Abstracts, Abstract 71429c, p. 946; col. L, vol. 93, No. 7, Aug. 18, 1980.
Kulagowski Janusz Jozef
Leeson Paul David
Mawer Ian Michael
Dentz Bernard
Merck Sharp & Dohme Ltd.
North Robert J.
Winokur Melvin
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