Morpholine derivatives as dopamine receptor subtype ligands

Details Morpholine derivatives as dopamine receptor subtype ligands Morpholine derivatives as dopamine receptor subtype ligands

1996-05-20

1997-03-25

Ramsner, Robert W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

5142352, 544127, 544128, 544139, 544140, 544143, 544144, A61K 31535, C07D41306

Patent

active

056145187

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/02557 filed Nov. 21, 1994.
This invention relates to a particular class of morpholine 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 thereforel 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 Y represents an optionally substituted bicyclic heteroaromatic ring system containing one or two nitrogen atoms, the ring system comprising a six-membered aromatic or heteroaromatic ring fused to a five- or six-membered heteroaromatic ring; and or aryl(C.sub.1-6)alkoxymethyl group.
The bicyclic heteroaromatic ring system Y in formula I above comprises a phenyl or pyridyl moiety fused at any position to a pyrrolyl or pyridyl moiety; or a phenyl moiety fused at any position to a pyrazolyl, imidazolyl, pyrazinyl, pyrimidinyl or pyridazinyl moiety. Suitably, the ring system Y comprises a phenyl or pyridyl moiety fused at any position to a pyrrolyl, pyridyl or imidazolyl moiety. More particularly, Y may represent an optionally substituted 2- or 3-indolyl, 2- or 3-quinolyl, 3-indazolyl, 2-benzimidazolyl, or 2- or 3-pyrrolo[2,3-b]pyridyl ring system.
The aryl moiety of the substituent Z in formula I above is suitably an optionally substituted phenyl or naphthyl group.
As used herein, the expression "C.sub.1-6 alkyl", and derived expressions such as "C.sub.1-6 alkoxy", refers to straight-chained and branched groups containing from 1 to 6 carbon atoms. Typical examples of alkyl groups include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl g

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