Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-17
1999-12-14
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142355, 514318, 514343, 514349, 544131, 546194, 5462764, 546285, 546291, 546293, 546306, A61K 3144, C07D21375
Patent
active
060018607
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to new N-aryl and N-heteroarylurea derivatives, pharmaceutical compositions comprising such compounds, and the use of such compounds to inhibit intestinal absorption of cholesterol, lower serum cholesterol and reverse the development of atherosclerosis. The compounds are inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT).
Cholesterol that is consumed in the diet (dietary cholesterol) is absorbed as free cholesterol by the mucosal cells of the small intestine. It is then esterified by the enzyme ACAT, packaged into particles known as chylomicrons, and released into the bloodstream. Chylomicrons are particles into which dietary cholesterol is packaged and transported in the bloodstream. By inhibiting the action of ACAT, the compounds of this invention prevent intestinal absorption of dietary cholesterol and thus lower serum cholesterol levels. They are therefore useful in preventing atherosclerosis, heart attacks and strokes.
By inhibiting the action of ACAT, the compounds of the present invention also enable cholesterol to be removed from the walls of blood vessels. This activity renders such compounds useful in slowing or reversing the development of atherosclerosis as well as in preventing heart attacks and strokes.
Other inhibitors of ACAT are referred to in U.S. Pat. Nos. 4,994,465, 4,716,175 and 4,743,605 (a divisional of the '175 patent) and in the European Patent Applications having publication numbers 0 242 610, 0 245 687, 0 252 524, 0 293 880, 0 297 610, 0 335 374, 0 335 375, 0 386 487, 0 399 422, 0 415 123, 0 421 456 and 0 439 059. Additional ACAT inhibitors are described in PCT publications WO 9015048 and WO 91/04027. Certain ureas and thioureas as antiatherosclerosis agents are referred to in U.S. Pat. No. 4,623,662.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein Q is oxygen or sulfur R.sup.17 is --(CH.sub.2).sub.n --(CR.sup.19 R.sup.20).sub.z (CH.sub.2).sub.r --Ar XXXVIII halogenated (C.sub.1 -C.sub.12) alkyl, optionally substituted aryl-(C.sub.1 -C.sub.5) alkyl, (C.sub.3 -C.sub.8) cycloalkyl-(C.sub.1 -C.sub.5)alkyl and Ar; or R.sup.19 and R.sup.20 and the carbon to which they are attached form a (C.sub.5 -C.sub.7) cycloalkyl ring or a benzene-fused (C.sub.5 -C.sub.7) cyclo-alkyl or -heteroalkyl ring; with the proviso that R.sup.19 and R.sup.20 cannot both be hydrogen; ##STR3## wherein U is J, a direct bond --CH.dbd.CH--or --CH.sub.2 CH.sub.2 --; z, n and r are as defined above; x is an integer from 3 to 10 and w is 0 or an integer from 1 to x-1. group consisting of optionally halogenated (C.sub.1 -C.sub.6)alkyl, optionally halogenated (C.sub.1 -C.sub.6)alkoxy, optionally halogenated (C.sub.1 -C.sub.6)alkylthio, phenyl and halogen; wherein the alkyl groups in said alkyl, alkoxy and althylthio groups may be straight chained or if comprising three or more carbons may be branched, cyclic or a combination of cyclic and branched or straight chained moieties; optionally substituted (C.sub.3 -C.sub.8)cycloalkyl, aryl or optionally substituted aryl-(C.sub.1 -C.sub.4)alkyl with the proviso that R.sup.18 is hydrogen if any one of n, z or r in formula XXXVIII is not 0; ##STR4## wherein m is as defined above; n is 0 or 1. consisting of halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6) haloalkyl, optionally halogenated (C.sub.1 -C.sub.6) alkoxy, optionally halogenated (C.sub.1 -C.sub.6) alkylthio, (C.sup.5 -C.sup.7) cycloalkylthio, phenyl (C.sub.1 -C.sub.6)alkylthio, substituted phenylthio, heteroarylthio, heteroaryloxy, (C.sub.1 -C.sub.6)alkylsulfinyl, (C.sub.1 -C.sub.6) alkylsulfonyl, (C.sub.5 -C.sub.7) cycloalkylsulfinyl, (C.sub.5 -C.sub.7) cycloalkylsulfonyl, phenyl (C.sub.1 -C.sub.6) alkylsulfinyl, phenyl (C.sub.1 -C.sub.5) alkylsulfonyl, substituted phenylsulfinyl, substituted phenylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, and NR.sup.10 R.sup.11, wherein R.sup.10 and R.sup.11 are the same or different and are selected from the group consisting of hydrogen, (C.su
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patent: 3426031 (1969-02-01), Fischback
patent: 4623662 (1986-11-01), De Vries
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Teiji Kimura, et al., J. Med. Chem. 1993, vol. 36 pp. 1630-1640, "Structure--Activity Relationship of N-[2-(Dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-l-yl)propoxy]phen yl-N'-pentylurea and Analogues. Novel Potent Inbititors oc Acyl-CoA:Cholesterol O-Acyltransferase with Antiatherosclerotic Activity".
Teiji Kimura, et al, J. Med. Chem. 1993, vol. 36 pp. 1641-1653, "Structure-Activity Relationship of a Series of Phenylureas Linked to 4-Phenylimidazole. Novel Potent Inhibitors of Acyl-CoA:Cholesterol O-Acyltransferase with Antiatherosclerotic Activity. 2".
Benson Gregg C.
Olson A. Dean
Pfizer Inc.
Raymond Richard L.
Richardson Peter C.
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