Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-10-18
1996-10-15
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514243, 514248, 514256, 514258, 544183, 544235, 544322, 544328, 546156, 546157, A61K 3147, C07D21522
Patent
active
055654720
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to new 4-aryl-3-(heteroarylureido)-1,2-dihydro-2-oxo-quinoline derivatives, pharmaceutical compositions comprising such compounds, novel 3-(p-nitrobenzyloxycarbonylamino) quinoline intermediates used in the synthesis of 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. 4,716,175 and 4,743,605 (a divisional of the '175 patent), the European Patent Applications having publication numbers 0 242 610, 0 245 687, 0 252 524, and 0 354 994, and U.S. patent application Ser. No. 07/648,677, filed Jan. 31, 1991 and assigned in common with the present application.
Certain ureas and thioureas as antiatherosclerosis agents are referred to in U.S. Pat. No. 4,623,662 and in the European Patent Applications having publication numbers 0 335 374, 0 386 487, 0 370 740, 0 405 233 and 0 421 456.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein each m is independently selected from 0 to 4;
R.sup.2 is selected from hydrogen and (C.sub.1 -C.sub.6) alkyl; Each R.sup.3 and R.sup.4 is independently selected from halogen, (C.sub.1 -C.sub.6) alkyl optionally substituted with one or more halogen atoms, (C.sub.1 -C.sub.6) alkoxy optionally substituted with one or more halogen atoms, (C.sub.1 -C.sub.6) alkylthio optionally substituted with one or more halogen atoms; nitro, carboxyl optionally esterified with a (C.sub.1 -C.sub.6) alkyl group; hydroxyl, (C.sub.1 -C.sub.4) acyloxy and (C.sub.1 -C.sub.3) acyl;
X is sulfur or oxygen; and
Q is a group of the formula ##STR3##
wherein m is as defined above;
n is 0 or 1.
Each l is independently selected from 0 to 3;
Each R.sup.6 and R.sup.7 is independently selected from the group 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, (C.sub.1 -C.sub.6) alkylthio, (C.sub.5 -C.sub.7) cycloalkylthio, optionally substituted 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.6) 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.sub.1 -C.sub.6) alkyl, optionally substituted phenyl, (C.sub.1 -C.sub.6) acyl and optionally substituted aroyl, wherein said substituted phenyl and substituted aroyl groups are substituted with one or more substituents independently selected from the group consisting of (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkoxy, (C.sub.1 -C.sub.6) alkylthio, halogen and trifluoromethyl, or R.sup.10 and R.sup.11,
REFERENCES:
patent: 4623662 (1986-11-01), De Vries
patent: 4716175 (1987-12-01), Hoefle et al.
patent: 4743605 (1988-05-01), Hoefle et al.
Bekelnitzky Seymour G.
Ginsburg Paul H.
Gupta Yogendra N.
Pfizer Inc.
Richardson Peter C.
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