Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-09-08
1997-09-09
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514322, 514339, 514403, 546150, 546199, 546256, 548207, A61K 31435, A61K 31415, C07D40106
Patent
active
056657323
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. 371 National Stage filing of PCT/BG94/000503 published as WC 94/21626 on Sep. 24, 1994.
This invention relates to a particular class of heteroaromatic compounds. More particularly, the invention is concerned with substituted indazole 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 disclosure of U.S. Pat. No. 3,678,059 generically encompasses inter alia a class of 3-[piperidin-1-ylalkyl]indazole derivatives substituted on the indazole nitrogen atom by an araliphatic or aromatic radical. These compounds are alleged therein to possess antidepressant and anti-inflammatory activity. There is, however, no suggestion in U.S. Pat. No. 3,678,059 that such compounds would be of benefit in the treatment and/or prevention of disorders of the dopamine system.
The generic disclosure of EP-A-0449186 encompasses inter alia a series of substituted piperidin-1-ylalkyl-indazole derivatives which are stated to be antipsychotic agents that act by selective antagonism of the sigma receptor. There is, however, no specific disclosure therein of a [4-substituted-piperidin-1-ylmethyl]-1H-indazole derivative. Moreover, there is no suggestion in EP-A-0449186 that the compounds described therein would be of benefit in the treatment and/or prevention of disorders of the dopamine system. Indeed, it is explicitly stated in EP-A-0449186 that the compounds described therein do not bind to the dopamine receptors or only have weak binding for the dopamine receptors.
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 or prodrug thereof: ##STR2## wher
REFERENCES:
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patent: 5432177 (1995-07-01), Baker et al.
Kochetkov, N.K., Dudykina, N.V., "Substituted Indazole-3-Carboxamides and 3-Aminomethylindazoles" J.Gen.Chem. USSR, 32, pp. 189-191, 1962.
Baker Raymond
Kulagowski Janusz Jozef
Leeson Paul David
Smith Adrian Leonard
Ivy C. Warren
Merck Sharp & Dohme Ltd.
North Robert J.
Smith Lyman H.
Winokur Melvin
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