Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-20
1997-05-20
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514318, 514323, 546194, 546201, 546209, 546211, A61K 31445, C07D21128
Patent
active
056312695
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 93/02190 filed Oct. 22, 1993.
This invention relates to five-membered heteroaromatic compounds, and to beta-dicarbonyl precursors thereto, which are ligands for dopamine receptor subtypes within the body. More particularly, the invention is concerned with substituted isoxazole, isothiazole and pyrazole derivatives, and with substituted 1,3-dioxopropane precursors thereto. Being ligands for dopamine receptor subtypes within the body, the compounds according to the invention are therefore of use in the treatment and/or prevention of disorders of the dopamine system, including schizophrenia, depression, nausea, Parkinson's disease, tardive dyskinesias and extrapyramidal side-effects associated with treatment by conventional neuroleptic agents, neuroleptic malignant syndrome, and disorders of hypothalamic-pituitary function such as hyperprolactinaemia and amenorrhoea.
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.
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.
EP-A-0296721 and EP-A-0316718 describe inter alia substituted piperidine derivatives which are stated to be muscarinic agonists and hence potentially useful in the treatment of inter alia Alzheimer's disease.
In EP-A-0135781 and EP-A-0402644 there is described a class of indazole and related fused bicyclic heteroaromatic derivatives-which are alleged to have antipsychotic activity.
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.
In one aspect, therefore, the present invention provides a compound of formula I, or a salt thereof or a prodrug thereof: ##STR2## wherein the broken circle represents two non-adjacent double bonds in any position within the five-membered ring; oxygen, sulphur or N--R.sup.2 ; alkoxy; ##STR3## in which Z represents oxygen, sulphur or NH; R.sup.3, R.sup.4 and R.sup.5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --S.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, --C.sub.2 R.sup.a, or --CONR.sup.a R.sup.b ; heterocyclic group; and ##STR4## in which R.s
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Ferles, M. et al, Collect. Czech. Chem. Commun. 1990, 55(5), pp. 1228-1233.
Baker Raymond
Broughton Howard B.
Collins Ian J.
Leeson Paul D.
Rowley Michael
Appollina Mary A.
Dahlen Garth M.
Ivy C. Warren
Merck Sharp & Dohme Limited
Thompson John
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