O-acyl-4-phenyl-cyclohexanols, their salts, medicaments containi

Details O-acyl-4-phenyl-cyclohexanols, their salts, medicaments containi O-acyl-4-phenyl-cyclohexanols, their salts, medicaments containi

1997-01-17

1998-03-10

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514530, 514531, 560 20, 560 43, 560 61, 560100, A61K 31135

Patent

active

057262055

DESCRIPTION:

BRIEF SUMMARY
This is the National Phase Application of PCT EP94/01276 field Apr. 25, 1994 now WO95/29148 published Nov. 2, 1995.
The present invention relates to O-acyl-4-phenyl-cycloalkanols, the salts thereof with physiologically acceptable organic and inorganic acids, processes for preparing these compounds and pharmaceutical compositions containing them and the use thereof.
The compounds according to the invention are inhibitors of cholesterol biosynthesis, more particularly inhibitors of the enzyme 2,3-epoxysqualene-lanosterol-cyclase, a key enzyme in cholesterol biosynthesis. The compounds according to the invention are suitable for the treatment and prophylaxis of hyperlipidaemia, hypercholesterolaemia and atherosclerosis. Other possible fields of application consist of the treatment of hyperproliferative skin and vascular disorders, tumours, gallstone problems and mycoses.
Compounds which intervene in cholesterol biosynthesis are of importance in the treatment of a number of syndromes. Particular examples are hypercholesterolaemias and hyperlipidaemias which are risk factors for the development of atherosclerotic vascular changes and their sequelae such as, for example, coronary heart disease, cerebral ischaemia, claudicatio intermittens and gangrene.
The significance of elevated serum cholesterol levels as a main risk factor in the occurrence of atherosclerotic vascular changes is generally recognised. Extensive clinical trials have led to the finding that the risk of coronary heart disease can be reduced by lowering serum majority of cholesterol is synthesised in the body and only a small proportion is taken in with food, the inhibition of biosynthesis constitutes a particularly attractive method of lowering elevated cholesterol levels.
Other possible fields of application for cholesterol biosynthesis inhibitors consist of the treatment of hyperproliferative skin and vascular disorders as well as tumoral diseases, the treatment and prophylaxis of gallstone problems and use in mycoses. This latter case involves intervention in the ergosterol biosynthesis in fungal organisms, which proceeds to a considerable extent in the same way as cholesterol biosynthesis in mammalian cells.
Cholesterol or ergosterol biosynthesis proceeds, starting from acetic acid, via a large number of reaction steps. This multi-step process presents a series of possible interventions, of which the following may be mentioned by way of example:
For inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, .beta.-lactones and .beta.-lactams with a potential antihypercholesterolaemic activity may be mentioned (see J. Antibiotics 4,983,597).
Inhibitors of the enzyme HMG-CoA-reductase are 3,5-dihydroxycarboxylic acids of the statin type and the .delta.-lactones, of which lovastatin, simvastatin and pravastatin are used in the treatment of hypercholesterolaemia.
Other possible uses for these compounds are fungal infections (U.S. Pat. No. 4,375,475, EP-A-0 113 881, U.S. Pat. No. 5,106,992), skin diseases (EP-A-0 369 263) and gallstone problems and tumoral diseases (U.S. Pat. the inhibition of the proliferation of smooth muscle cells using
Inhibitors of the enzyme squalene-synthetase include, for example, isoprenoid-(phosphinylmethyl)phosphonates which have been described as suitable for the treatment of hypercholesterolaemia, gallstone problems and tumoral diseases in EP-A-0 409 181 and in J. Med. Chemistry 34, 1912
Known inhibitors of the enzyme squalene-epoxidase are allylamines such as naftifin and terbinafin, which have been used in therapy as drugs to combat fungal diseases, as well as the allylamine NB-598 which has an antihypercholesterolaemic effect (J. Biol. Chemistry 265, 18075-18078, effect (U.S. Pat. No. 5,011,859). In addition, piperidines and azadecalins having a potential hypocholesterolaemic and/or antifungal activity have been described, the mechanism of activity of which has not been adequately explained and which constitute squalene epoxidase and/or 2,3-epoxysqualene-lanosterol-cyclase inhibitors (EP-A-0 4

REFERENCES:
patent: 5391571 (1995-02-01), Mewshaw
patent: 5455273 (1995-10-01), Maier
CA 103: 204217--Abstract of JP60097925 May 31, 1985 "Substituted phenyl cyclohexane derivative as liquid cryst".

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