Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-04-11
1998-07-07
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142375, 514330, 514399, 514450, 514459, 514456, 514519, 514546, 514603, 514619, 514646, 544165, 546220, 546225, 5483381, 549 28, 549 23, 549352, 560 48, 564 86, 564163, 564430, A01N 4340
Patent
active
057769516
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/01409 filed Jun. 29, 1994.
The present invention is concerned with diaryl compounds, processes for their preparation, compositions containing them and their use in medicine, particularly in the prophylaxis and treatment of atherosclerosis.
The deposition of cholesterol and cholesteryl esters in atherosclerotic lesions is one of the principal pathological processes of atherogenesis. The enzyme acyl coenzyme A: cholesterol acyltransferase (ACAT) catalyses the synthesis of cholesteryl esters and is thought to play an important role in the regulation of intracellular cholesterol metabolism. Inhibition of ACAT is therefore expected to reduce the content of cholesteryl esters within the lesion and to render the lesion less capable of provoking a thrombotic event. To achieve inhibition of lesion ACAT, a suitable compound would clearly need to be systemically bioavailable.
ACAT may also play a key role in the gastrointestinal absorption of cholesterol on the basis that (a) more than 90% of the cholesterol which appears in the lymph is esterified, (b) substantial ACAT activity has been observed in the intestinal mucosal cells of several animal species, (c) the site of greatest intestinal ACAT activity is the jejunum where the majority of cholesterol absorption occurs, (d) ACAT activity in the jejunum parallels increases in dietary cholesterol. A likely consequence of inhibiting cholesterol absorption in the gut will be a reduction in plasma cholesterol concentration. There is also evidence that a systemically-available ACAT inhibitor may lower plasma cholesterol by reducing the secretion of very low density lipoprotein by the liver. ACAT inhibitors are known to decrease the absorption of cholesterol from the gut and to lower the concentration of total plasma cholesterol in a range of animal models.
European Patent Specification 0370740 discloses diaryl compounds having non-systemic ACAT inhibitory activity.
A further class of aryl compounds has now been discovered which are bioavailable and exhibit ACAT inhibitory activity as demonstrated hereinafter in the ACAT inhibition assay in which representative compounds of the present invention have been shown to be active. The compounds of the invention may therefore be particularly useful for decreasing the steady state concentration of cholesterol and cholesterol ester in the arterial wall, thereby retarding and/or reversing the build-up of atherosclerotic lesions as well as being hypolipidaemic.
According to the present invention, therefore, there are provided compounds of formula (I) ##STR2## wherein: W is hydrogen, or a C.sub.1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from halo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl C.sub.1-4 haloalkoxy, and RC(O)-- (wherein R is selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, and C.sub.1-4 haloalkoxy); --C(O)NR.sup.2 --, or --OC(O)NR.sup.2 -- (wherein R.sup.1 and R.sup.2 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl); C.sub.1-4 alkylene, --(CH.sub.2).sub.n --O--(CH.sub.2).sub.p --, or --(CH.sub.2).sub.n --S(O).sub.q --(CH.sub.2).sub.p --, (wherein n and p are integers independently selected from 0, 1, 2, 3, and 4; providing that n+p is not greater than 4; and q is an integer selected from 0, 1, and 2), selected from halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; --, --(CH.sub.2).sub.r --S(O).sub.t --(CH.sub.2).sub.s --, --(CH.sub.2).sub.r --C(O)--(CH.sub.2).sub.s -- (wherein r and s are integers independently selected from 0, 1, 2, 3 and 4; providing that r+s is not greater than 4; and t is an integer selected from 0, 1, and 2), --OC(O)--, --C(O)O--, --S(O).sub.2 N(R.sup.3)--, --(R.sup.3)NS(O).sub.2 --, --C(O)N(R.sup.3)--, --(R.sup.3)NC(O)N(R.sup.4)--, or --(R.sup.3)NC(O)-- (wherein R.sup.3 and R.sup.4 are independently selected from hydrogen, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl); halo, or aryl, selected from halo, cyano, --CO.sub.2 R.sup.6
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Arrowsmith Richard James
Dann John Gordon
Franzmann Karl Witold
Hodgson Simon Teanby
Wates Peter John
Dahlen Garth M.
Glaxo Wellcome Inc.
Ivy C. Warren
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