Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-25
1999-08-17
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514318, 546193, 546194, 546208, 546209, 546211, A61K 31445, C07D40104
Patent
active
059394366
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a particular class of heterocyclic compounds which incorporate a substituted five-membered heteroaromatic nucleus containing at least two nitrogen atoms. More particularly, the invention concerns substituted pyrazole, imidazole, triazole and tetrazole derivatives which are ligands for dopamine receptor subtypes within the body, in particular the dopamine D.sub.4 receptor subtype. They are therefore of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, depression, anxiety, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea, and delusional disorders (cf. Catalano et al., Biol. Psychiatry, 1993, 34, 459).
Upper gastrointestinal tract motility is believed to be under the control of the dopamine system. The compounds according to the present invention may thus be of use in the prevention and/or treatment of gastrointestinal disorders, and the facilitation of gastric emptying.
Dependence-inducing agents such as cocaine and amphetamine have been shown to interact with the dopamine system. Compounds capable of counteracting this effect, including the compounds in accordance with the present invention, may accordingly be of value in the prevention or reduction of dependence on a dependence-inducing agent.
Dopamine is known to be a peripheral vasodilator; for example, it has been shown to exert a dilatory effect on the renal vascular bed. This implies that the compounds of the present invention may be beneficial in controlling vascular blood flow.
The localisation of dopamine receptor mRNA in rat heart and large vessels has been noted. This suggests a role for dopamine receptor ligands in controlling cardiovascular function, either by affecting cardiac and smooth muscle contractility or by modulating the secretion of vasoactive substances. The compounds according to the present invention may therefore be of assistance in the prevention and/or treatment of such conditions as hypertension and congestive heart failure.
By virtue of their activity as ligands for dopamine receptor subtypes within the body, the compounds in accordance with the present invention may also be of benefit in enhancing cognitive function, and in treating and/or preventing cognitive disorders including presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively).
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.
The compounds in accordance with the present invention, being ligands for dopamine receptor subtypes within the body, are accordingly of use in the treatment and/or prevention of disorders of the dopamine system.
The present invention accordingly provides a compound of formula I, or a salt thereof or a prodrug thereof: ##STR1## wherein
X represents nitrogen or C--R.sup.2 ;
Y.dbd.Z represents a moiety of formula N.dbd.C--R.sup.3, N.dbd.N or CH.dbd.N;
Q represents a substituted five-, six- or seven-membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the five-membered heteroaromatic ring containing the variables X, Y and Z via a carbon atom; and
one of R.sup.1, R.sup.2 and R.sup.3 represents C.sub.3-7 cycloalkyl or a group of formula (i), (ii) or (iii); and the other(s) of R.sup.1, R.sup.2 and R.sup.3, when present in the molecule, independently represent(s) hydrogen or C.sub.1-6 alkyl; the g
REFERENCES:
patent: 5227486 (1993-07-01), Merce-Vidal et al.
Cram and Hammond, "Organic Chemistry", McGraw-Hill Book Co., NY (1964) 2nd Ed. pp. 565-567.
Carling William Robert
Leeson Paul David
Moore Kevin William
Durette Philippe L.
Merck Sharp & Dohme Ltd.
Morris Patricia L.
Winokur Melvin
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