Fused tricyclic heteroaromatic derivatives as dopamine receptor

Details Fused tricyclic heteroaromatic derivatives as dopamine receptor Fused tricyclic heteroaromatic derivatives as dopamine receptor

1996-03-12

2000-06-27

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544249, 544250, 544368, 544371, A61K 3142, A61K 31415, C07D23154, C07D26120

Patent

active

060807458

DESCRIPTION:

BRIEF SUMMARY
This invention relates to a particular class of fused tricyclic heteroaromatic compounds based on a substituted isoxazole or pyrazole moiety. These compounds 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: ##STR1## wherein the broken line represents a double bond whereby the heteroaromatic ring containing Q is aromatic; heteroaromatic ring; .dbd.N--NR.sup.5 --, --NR.sup.5 --N.dbd., .dbd.N--O--, --O--N.dbd. and .dbd.N--CR.sup.6 .dbd.N--; ethylene group; alkyl; and the other of R.sup.3 and R.sup.4 represents hydrogen, hydrocarbon or a heterocyclic group; and and R.sup.b independently represent hydrogen or C.sub.1-6 alkyl.
The compounds of the present invention are preferably prepared and utilised in the form of the free base or as a pharmaceutically acceptable salt thereof.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds o

REFERENCES:
patent: 4946844 (1990-08-01), Tomari et al.
patent: 5004745 (1991-04-01), Antoine et al.
Jones, J. H. et al. "Synthesis of 4-Substituted 2H-Naphth[1,2-b]-1,4-oxazines, a New Class of Dopamine Agonists" J. Med. Chem. 1984, 27, pp. 1607-1613.

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