Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1993-03-23
1995-06-06
Kumar, Shailendra
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514467, 514507, 514596, 514622, 514824, 549449, 560 29, 564 48, 564 52, 564170, A61K 3117, C07C27530, C07C27510
Patent
active
054223733
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with a novel genus of diaryl compounds, with processes for their preparation, with medicaments containing them and with their use as therapeutic agents, particularly in the prophylaxis and treatment of atherosclerosis.
The enzyme acyl coenzyme A - cholesterol acyl transferase (ACAT) is known to be involved in the intestinal absorption of cholesterol and in the accumulation of cholesterol as cholesterol esters in the arterial wall. Thus compounds which inhibit ACAT have potent hypocholesterolaemic activity and significantly decrease arterial cholesterol deposition.
A group of clinically useful compounds known collectively as `fibrates` give rise to a modest decrease in LDL-cholesterol, a significant decrease in triglycerides and a marked elevation of HDL-cholesterol in the plasma. The increase in the level of HDL-cholesterol is particularly important since it facilitates the removal of free cholesterol from the arterial wall for return to the liver (`reverse cholesterol transport`).
It follows that a drug combining the hypochoiesterolaemic/anti-atherosclerotic properties of an ACAT inhibitor with hypolipidaemic/HDL-enhancing properties would be particularly useful in the prophylaxis and treatment of atherosclerosis, the enhanced HDL-cholesterol level induced giving rise to an increase in the capacity of the reverse cholesterol transport mechanism to remove the free cholesterol resulting from ACAT inhibition in the arterial wall. Such a drug would be especially beneficial to those patients having both high serum cholesterol and triglyceride levels who are at particular risk of contracting coronary heart disease.
On the basis of the foregoing, we have discovered a series of novel compounds having potential hypolipidaemic/hypocholesterolaemic activity.
According to the present invention, therefore, there is provided a compound of formula (I) ##STR1## wherein
Ar is a mono- or bicyclic aromatic group optionally containing one or two heteroatoms independently selected from nitrogen, oxygen and sulphur, said group being optionally substituted by one or more atoms or groups independently selected from halogen, nitro, amino, -NRR.sup.1 where R and R.sup.1 are independently selected from hydrogen, C.sub.1-8 alkyl and C.sub.1-8 alkanoyl, cyano, carboxyalkoxy, alkoxycarbonylalkoxy, C.sub.1-8 alkyl (including cycloalkyl and cycloalkylalkyl), C.sub.1-8 alkoxy (including cycloalkoxy and cycloalkylalkoxy), C.sub.8 thioalkyl, said alkyl, alkoxy and/or thioalkyl group(s) being optionally substituted by one or more halogen atoms, aryl, aryloxy, aralkyl and aralkyloxy, said aryl, aryloxy, aralkyl and/or aralkyloxy group(s) being optionally substituted by one or more atoms or groups independently selected from halogen, alkyl, alkoxy, alkanoyl, hydroxyalkyl, perfluoroalkyl, perfluoroalkoxy, carboxyalkoxy, alkoxycarbonylalkoxy, and C.sub.3-8 ether or polyether groups containing from one to three oxygen atoms;
D is --CH.sub.2 --, --NH--, or --O--;
E is --N< or --CH<;
F is --O--or ##STR2##
G is C.sub.3-12 straight, branched, or cyclic alkyl, or aralkyl, said aralkyl group being optionally substituted by one or more atoms or groups independently selected from halogen, amino, N-(C.sub.1-6 alkyl)amino, N,N-di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkyl and C.sub.1-6 alkoxy, or a C.sub.3-8 ether or polyether group containing one to three oxygen atoms;
J is a bond or C.sub.1-6 straight or branched alkylene;
X is a C.sub.2-8 straight, branched, or cyclic alkylene group optionally substituted by one or more halogen atoms or C.sub.1-4 alkoxy groups, wherein one or two of the linear carbon atom(s) is/are replaced by oxygen; and
Z is hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.2-5 alkanoyl, or carboxyl, said alkyl group being optionally substituted by one or more halogen atoms;
A "linear" carbon as referred to in the definition of X is a carbon located in the carbon chain or, in the case where X is an optionally substituted cyclic alkylene group, carbon chains linking the atom (oxygen or carbon according to
REFERENCES:
patent: 4387106 (1983-06-01), De Vries et al.
patent: 4397868 (1983-08-01), De Vries
patent: 4623662 (1986-11-01), De Vries
patent: 4857556 (1989-08-01), Yamada et al.
Brown Donald
Burroughs Wellcome Co.
Kumar Shailendra
Nielsen Lawrence A.
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