4(5) substituted imidazoles and their preparation and use

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514397, 5483114, 5483435, C07D23354, A61K 31415

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active

054986230

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel 4(5)-substituted imidazole derivatives and their non-toxic salts, to their preparation, to pharmaceutical compositions containing them, and to their use.
The imidazole derivatives of this invention have the general formula: ##STR2## wherein Y is --CH.sub.2 -- or --CO-- or CH.sub.2 CH.sub.3 and pharmaceutically acceptable salts thereof, excluding 4-(5-chloro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and 4-(4-chloro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole.
The most preferable compounds according to the present invention are those wherein R.sub.1 is F, R.sub.2 is hydrogen or F, especially hydrogen. Also preferable are compounds, wherein R.sub.3 is hydrogen or CH.sub.2 CH.sub.3 and Y is --CH.sub.2 --. As specific examples of such preferred compounds are mentioned 4-(2-ethyl-5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole and 4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. These compounds are also valuable intermediates for the preparation of disubstituted indan-imidazole derivatives according to the invention.
The compounds of this invention are highly selective and long-acting antagonists of .alpha..sub.2 -adrenoceptors and they have good peroral bioavailability. The compounds are especially valuable in the treatment of cognitive disorders.
Valuable .alpha..sub.2 -adrenoceptor antagonists have been disclosed earlier e.g. in the European patent publications No. 183492, 247764 and 372954. PCT patent application No. 91/18886 discloses the use of some inden-imidazole derivatives, especially atipamezole, in the treatment of age-related memory impairment and other cognitive disorders. The compounds disclosed in these earlier patent applications, though some of them are very potent and selective .alpha..sub.2 -adrenoceptor antagonists, have usually a very short duration of action. This causes no problems when the compounds are used during clinical procedures. However, compounds with longer duration of action and good peroral bioavailability are necessary to obtain sufficient patient compliance. There are also indan-imidazole derivatives which have reported to have long duration of action e.g. those disclosed in EP 372954. However, such compounds are not so potent .alpha..sub.2 -adrenoceptor antagonists as the compounds of the present invention.
.alpha.-Adrenoceptors can be divided on a pharmacological basis into two subclasses, viz .alpha..sub.1 -and .alpha..sub.2 -adrenoceptors (see e.g. Starke & Docherty, J. Cardiovasc. Pharmacol., I, Suppl. 1, 514-523, 1981). It is well established that while .alpha..sub.1 -adrenoceptors are located postsynaptically, .alpha..sub.2 -adrenoceptors are situated both at presynaptic nerve terminals and postsynaptically e.g. in vascular smooth muscle, platelets, pancreatic .beta.-cells, fat cells and central nervous system.
The presynaptic .alpha..sub.2 -receptors modulate the release of noradrenalone by means of a negative feedback mechanism. Thus, if presynaptic .alpha..sub.2 -adrenoceptors are stimulated (under physiological conditions by noradrenaline) noradrenalone release in inhibited. Blockade of these receptors by an .alpha..sub.2 -antagonist, on the contrary, increases the release of noradrenaline, .alpha..sub.2 -Adrenoceptor antagonism at presynaptic .alpha..sub.2 -receptors can thus be expected to be of use in disease states which are believed to be connected with deficiency of noradrenaline available in the postsynaptic adrenoceptors. These diseases include e.g. endogeneous depression, age dependent memory impairment and other cognitive disorders, particularly Alzheimer's disease.
The best known pharmacodynamic effect mediated by postsynaptic .alpha..sub.2 -adrenoceptors is the contraction of vascular smooth muscle. Blockade of peripheral postsynaptic .alpha..sub.2 -adrenoceptors in blood vessels can thus be expected to dilate the vessel and lead to decrease in the blood pressure. .alpha..sub.2 -Blockers may thus be valuable as antihypertensive agents.
Glucose and lipid metabolism are also regulated by an inhibitory mechanism invol

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