3,3,5-trimethylcyclohexyl 2-methylpropionate derivatives, their

Details 3,3,5-trimethylcyclohexyl 2-methylpropionate derivatives, their 3,3,5-trimethylcyclohexyl 2-methylpropionate derivatives, their

1992-01-16

1994-05-10

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

560 52, 560 43, 560 57, 560 59, 560 61, 560 62, 514531, 514535, A01N 3710, C07C 6976

Patent

active

053107578

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel 3,3,5-trimethylcyclohexyl 2-methylpropionate derivatives, to their method of preparation and to the therapeutic compositions in which they are present.
Phenoxyisobutyric acids and their esters with lower alcohols have been known for a long time as hypolipidaemics and are used in therapeutics for correcting lipidaemic disorders. U.S. Pat. No. 3,907,792 describes fenofibrate, or isopropyl 4-(4-chlorobenzoyl)phenoxyisobutyrate, and is employed in therapeutics for the treatment of hypercholesterolaemia and hypertriglyceridaemia. Other analogues, such as bezafibrate, or 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropionic acid, described in U.S. Pat. No. 3,781,328, ciprofibrate, or 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionic acid, described in U.S. Pat. No. 3,948,973, or gemfibrozil, described in U.S. Pat. No. 3,674,836, are used as drugs and prescribed for lipidaemic disorders.
3,3,5-Trimethylcyclohexanol, on the other hand, is known for its pharmacological properties, especially vasodilating properties, and is used in cyclandelate as the mandelic acid ester. European patent application 157 151 in turn discloses 3,3,5-trimethylcyclohexyl 2-nicotinoylmandelate, which is another vasodilator. Other simple esters have been described in this same field of activity. Bisphenoxyacetic acid esters (German patent 2 326 061) and biphenyl-4-carboxylic acid esters (European patent 57 141) may be mentioned in particular.
The object of the present invention was to provide novel hypolipidaemic compounds which unexpectedly have a very much greater hypolipidaemic activity than the corresponding 2-methylpropionic acids or their esters, both on triglycerides and on cholesterol.
A further object of the invention is to provide a method of preparing said compounds.
The present invention relates to 3,3,5-trimethylcyclohexanol derivatives, characterized in that they have the general formula ##STR2## in which: n=0, 1, 2, 3, 4 or 5 and or one of the following substituents: --CH.sub.3 ; --OCH.sub.3 ; --F; --CF.sub.3 ; ethyl; propyl; hydroxypropyl; propionyl; acetylcyclopropyl; 2,2-dichlorocyclopropyl; a 4-benzoyl group in which the benzoyl ring can be substituted by one or more of the following moieties: Cl--, F--, Br--, CF.sub.3 --, CH.sub.3 -- and CH.sub.3 O--; a 4phenylacetyl group; a phenyl group; a 4-parachlorobenzoylaminoethyl group; or a 4-(3-phenoxypropyl) group in which the phenyl ring can be substituted by one or more moieties selected from Cl, Br, F, CF.sub.3, OCH.sub.3 and CH.sub.3.
The preferred compounds according to the invention are: 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropionate, 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methylpropionate, 2-(3-(2,5-dimethylphenoxy)propyl)-2-methylpropionate and 2-(4-(2-(4-chlorobenzamido)ethyl)phenoxy)-2-methylpropionate.
In terms of the present invention, 3,3,5-trimethylcyclohexanol includes not only a mixture of its CIS and TRANS isomers but also a mixture of these isolomers enriched in either CIS or TRANS, or else each of these isomers in the pure state. Of course, each of these CIS or TRANS forms is understood as meaning each optical isomer of (R) or (S) configuration, arising from the chirality of the carbon in the 3-position to the alcohol group, or else their racemic mixture.
The compounds according to the present invention possess valuable pharmacological properties as hypolipidaemics and prove to be useful in the treatment of lipidaemic or cholesterolaemic dysfunctions both in man and in animals.
The Applicant has in fact found that the 3,3,5-trimethylcyclohexyl esters of 2-substituted 2-methylpropionic acid have very much greater antihypertriglyceridaemic, hypocholesterolaemic and hypolipidaemic activities than the corresponding 2-methylpropionic acids or their simple alkyl esters. The advantage of the products according to the present invention is that they have activities which modulate the enzymatic systems involved in cholesterol synthesis, as a consequence of which they are of particular value in the treatment of

REFERENCES:
patent: 3931302 (1976-01-01), Allais et al.
patent: 4153724 (1979-05-01), Hamazaki et al.
Metz et al, "Hypolipemic Activity of Clofibrate-Related Compounds", Arzneim.-Forsch, 25(11), 1686-92, 1975, CA 84(13): 83991g. Abstract only.

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