Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-10-30
1997-03-25
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514316, 514317, 514323, 514326, 546186, 546187, 546191, 546201, 546210, 546232, 546233, 546246, 546247, C07D21126, C07D21134, A61K 31445
Patent
active
056145349
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. 371 National Stage filing of PCT/FR94/00584 published as WO 94/26713 on Nov. 24, 1994.
FIELD OF THE INVENTION
The present invention concerns .beta.,.beta.-dimethyl-4-piperidineethanamine derivatives, as novel industrial products, which are inhibitors to the biosynthesis of cholesterol, in particular of epoxysqualene cyclase, in mammals and fungi. The invention also concerns a method for their preparation and their therapeutic use as hypocholesterolemic, hypolipemic, antiatheromatic and antifungal agents.
PRIOR ART
Many studies have shown (i) that there is a link between a high cholesterol level and the associated cardiovascular risks, and (ii) the importance of normalising this cholesterol level.
A number of compounds which inhibit biosynthesis of cholesterol have thus been developed, for example HGM-CoA reductase inhibitors.
It is preferable to inhibit this biosynthesis in its final stage since the first precursors can be involved in the synthesis of other biologically important molecules.
Research has therefore been carried out with the aim of developing epoxysqualene cyclase and squalene epoxydase inhibitors; these enzymes catalyse the transformation of squalene, via 2,3-oxydosqualene, to lanosterol which is the first compound to be formed in the sterol family.
Similarly, the biosynthesis of endogenous ergosterol is necessary for the growth and reproduction of certain fungi. Compounds which inhibit this biosynthesis, and inhibit in particular the two enzymes described above, thus have very important antifungal properties.
Some epoxysqualene cyclase inhibitors which can be used as inhibitors for cholesterol biosynthesis are already known.
Examples are International application WO-A-89/08450 and U.S. Pat. No. 5,084,461, which describe decaline and azadecaline derivatives, and patent application EP-A-0 468 434, which describes ethers or thioethers of 4-hydroxypiperidine. Patent applications EP-A-0 468 457 and EP-A-0 420 116 describe derivatives of .beta.-methyl-4-piperidine ethanol and alkyl-4-piperidinol compounds for use as squalene epoxydase inhibitors and indicate their use as antiatheromatic and antifungal agents.
None of these prior art documents either describes or suggests (i) .beta.,.beta.-dimethyl-4-piperidineethanamine derivatives as products, and (ii) their use as inhibitors for the biosynthesis of cholesterol, and in particular as inhibitors of epoxysqualene cyclase.
OBJECT OF THE INVENTION
The present invention thus proposes .beta.,.beta.-dimethyl-4-piperidineethanamine derivatives which are inhibitors to the biosynthesis of cholesterol, and in particular inhibitors of epoxysqualene cyclase.
The present invention concerns compounds selected from the group consisting of .beta.,.beta.-dimethyl-4-piperidineethanamines with of the formula: ##STR2## wherein R.sub.1 and R.sub.2, which may be identical or different, each represent a hydrogen atom, a C.sub.1 -C.sub.4 alkyl group, a C.sub.2 -C.sub.5 acyl group or a phenylmethyl group, or form a piperidinyl group with the nitrogen atom to which they are bonded, by: C.sub.1 -C.sub.4 alkyl group, C.dbd.or C.tbd.C bonds, and which may be substituted by a phenyl group, para-chlorophenyl group, C.sub.8 -C.sub.11 alkyl group which may be substituted by an imidazolyl group, a linear or branched C.sub.1 -C.sub.4 alkyloxy group, substituted by a para-chlorophenyl group, or a linear or branched C.sub.2 -C.sub.4 alkyl group comprising at least one double bond and substituted by a phenyl group, following groups: a linear or branched C.sub.1 -C.sub.4 alkyl group, identical or different, each represent a hydrogen atom or a linear or branched C.sub.1 -C.sub.4 alkyl group, represents a linear or branched C.sub.1 -C.sub.6 alkyl group, and their addition salts.
The invention also concerns a method for the preparation of compounds of the formula I, as described below.
DETAILED DESCRIPTION OF THE INVENTION
Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, t.-butyl, 2-methylpropyl, 5-methylpentyl,
REFERENCES:
patent: 4248877 (1981-02-01), Rissi et al.
patent: 4473694 (1984-09-01), Lai
patent: 4569933 (1986-02-01), Cornu et al.
patent: 4879300 (1989-11-01), Giordani et al.
patent: 4939161 (1990-07-01), Lalinde et al.
patent: 5246945 (1993-09-01), Kikuchi et al.
Binet Jean
De Fornel Daniel
Samreth Soth
Fournier Industrie et Sante
Ivy C. Warren
Smith Lyman H.
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