Benzimidazole derivatives

Details Benzimidazole derivatives Benzimidazole derivatives

1995-09-12

1998-02-03

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514322, 514338, 514394, 546148, 546199, 5462734, 5483051, A61K 3147, C07D40106

Patent

active

057144982

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/6B/94/00528 filed Mar. 16, 1994.
This invention relates to a particular class of heteroaromatic compounds. More particularly, the invention is concerned with substituted benzimidazole 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.
JP-A-61-227565 and JP-A-64-52718 describe in generic terms various stated to be effective against certain cardiovascular complaints. There is, however, no suggestion in either of these publications that the compounds described therein might be of any assistance in solving the problem of providing compounds which are ligands for dopamine receptor subtypes within the body and thus effective in the treatment and/or prevention of disorders of the dopamine system.
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: ##STR1## wherein E represents --CH.sub.2 -- or --CH.sub.2 CH.sub.2 --; ##STR2## in which the broken line represents an optional chemical bond;
R.sup.1 represents hydrogen, or an optionally substituted C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, aryl(C.sub.1-6)alkyl, aryl(C.sub.1-6)alkoxy, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, C.sub.3-7 heterocycloalkyl(C.sub.1-6)alkyl, heteroaryl, heteroaryl(C.sub.1-6)alkyl, heteroaryl(C.sub.2-6)alkenyl or heteroaryl(C.sub.2-6)alkynyl group;
R.sup.2 represents aryl, aryl(C.sub.-6)alkyl, aryloxy(C.sub.1-6)alkyl, aryl(C.sub.1-6)alkyl, aryl(C.sub.1-6)alkoxy, aryl(C.sub.2-6)alkenyl, aryl(C.sub.2-6)alkynyl, heteroaryl or heteroaryl(C.sub.2-6)alkenyl, any of which groups may be optionally subs

REFERENCES:
Derwent Abstract, JP-A-61-227565, 10-9-86, "Novel Piperidine Derivatives . . . ", Assignee Eisai KK Japan.

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