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
1997-09-23
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514321, 514379, 514403, 546198, 546199, 546225, 548241, 5483591, A61K 31445, A61K 3141, C07D40104, C07D41304
Patent
active
056705220
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/02189 filed Oct. 22, 1993.
This invention relates to fused tricyclic 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 compounds containing an isoxazole, isothiazole or pyrazole ring fused to a dihydronaphthalene moiety, and with substituted 3,4-dihydro-1-hydroxy-2-oxomethyl-naphthalene 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.
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 ; ring which contains one nitrogen atom as the sole heteroatom and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom; 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 --CO.sub.2 NR.sup.a R.sup.b ; and heterocyclic group.
The five-membered heteroaromatic ring containing the moieties X and Y in formula I above may be a substituted isoxazole, isoth
REFERENCES:
patent: 3926988 (1975-12-01), Krapcho et al.
patent: 3932430 (1976-01-01), Habeck
patent: 3940418 (1976-02-01), Hamilton
patent: 3957816 (1976-05-01), Habeck
patent: 3959308 (1976-05-01), Coombs
patent: 4173634 (1979-11-01), Krapcho
AMA Abstract "Analysis of the D4/dopamine receptor gene variant in an Italian schizophrenia kindred" AMA Apr. 1994, p. 288 1994.
Lesson Paul David
Rowley Michael
Appollina Mary A.
Chang Ceila
Merck Sharp & Dohme Limited
Winokur Melvin
LandOfFree
Dopamine receptor subtype ligands does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Dopamine receptor subtype ligands, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Dopamine receptor subtype ligands will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1938784