Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-18
1998-06-09
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544122, 544123, 544295, 544296, 544238, 544316, 544330, 544331, 544332, 544333, 544334, 544335, 5142335, 5142358, 5142365, 514252, 514256, 514275, C07D40104, C07D40114, A61K 31505
Patent
active
057634483
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application filed under 35 USC .sctn.371 corresponding to international application PCT/GB94/00999, filed May 9, 1994.
This invention relates to a particular class of six-membered heteroaromatic compounds. More particularly, the invention is concerned with substituted pyrimidine derivatives which are ligands for dopamine receptor subtypes within the body and 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.
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: ##STR2## wherein Q represents a substituted five- or six-membered monocyclic heteroaliphatic ring which contains one nitrogen atom as the sole heteroatom and is linked to the pyrimidine ring via a carbon atom; alkoxy; --NR.sup.a R.sup.b ; and ##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, --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.
The monocyclic heteroaliphatic ring Q in the compounds of formula I above represents a substituted pyrrolidinyl or piperidinyl moiety linked through carbon. Examples of suitable rings include the moieties of formula Qa to Qe: ##STR4## wherein one of R.sup.6 and R.sup.7 represents hydrocarbon or a heterocyclic group, and the other of R.sup.6 and R.sup.7 represents hydrogen, hydrocarbon or a heterocyclic group.
A particular monocyclic heteroaliphatic ring represented
REFERENCES:
Strekowski et al, Chemical Abstracts, vol. 117, abstract 204550 (1992).
Abdelal et al, Chemical Abstracts, vol. 117, abstract 111558 (1992).
Beilstein Reg. No. 6212885: Petrenko et al. Bull. Acad. Sci, vol. 29, No. 7, pp. 1154-1158 (1980).
Carling William Robert
Collins Ian James
Leeson Paul David
Rowley Michael
Ford John M.
Merck Sharp & Dohme Limited
Winokur Melvin
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