Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-27
1996-12-03
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546139, 546146, 546149, C07D21702, C07D21704, C07D40506, A61K 3147
Patent
active
055808816
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR/01022 filed Oct. 18, 1993.
BACKGROUND OF THE INVENTION
The present invention relates to 1,2,3,5,6,7,8,8a-octahydro-5,5,8a-trimethyl-(8a.beta.)-6-isoquinolineamine derivatives, which inhibit the biosynthesis of cholesterol, and especially of epoxysqualene cyclase, in mammals and fungi, to their method of preparation and to their use in therapeutics as hypocholesterolemics, hypolipidemics, antiatheromatous agents and antifungal agents.
Various compounds which inhibit the different enzymes involved in the biosynthesis of cholesterol, and especially of squalene epoxidase and epoxysqualene cyclase, are already known.
Numerous studies have stressed the importance and advantage of these products in the normalization of the cholesterol level and in the antifungal sphere by virtue of their capacity to inhibit the biosynthesis of ergosterol.
For example, patent application EP-A-468434 describes 4-hydroxypiperidine ethers or thioethers which inhibit epoxysqualene cyclase.
Likewise, patent applications EP-A-468457 and EP-A-420116 describe .beta.-methyl-4-piperidineethanol derivatives and alkyl-4-piperidinol compounds as squalene epoxidase inhibitors, said derivatives and compounds being useful as antiatheromatous agents and antifungal agents.
These compounds also include decalin and azadecalin derivatives such as those described for example in international patent application WO-A-89/08450 and patent U.S. Pat. No. A-5084461, which are useful as hypocholesterolemics and antifungal agents.
None of these documents of the prior art either describes or suggests 1,2,3,5,6,7,8,8a-octahydro-5,5,8a-trimethyl-(8a.beta.)-6-isoquinolineamine derivatives useful as inhibitors of the biosynthesis of cholesterol, and especially of epoxysqualene cyclase.
SUMMARY OF THE INVENTION
The present invention therefore proposes 1,2,3,5,6,7,8,8a-octahydro-5,5,8a-trimethyl-(8a.beta.)-6-isoquinolineamine derivatives which inhibit the biosynthesis of cholesterol, and especially of epoxysqualene cyclase.
DESCRIPTION OF THE INVENTION
The present invention relates to the compounds selected from the group consisting of the 1,2,3,5,6,7,8,8a-octahydro-5,5,8a-trimethyl-(8a.beta.)-6-isoquinolineamine s of the formula ##STR2## in which R.sub.1 is: by: double or triple bonds and optionally substituted by one or two phenyl groups, or more hydroxyl groups, hydrogen atom or a C.sub.1 -C.sub.4 -alkyl group, R.sub.2 is a hydrogen atom or a C.sub.1 -C.sub.4 -alkyl group and R.sub.3 is a trifluoroacetyl group or an acetyl group, and
Addition salts are understood here as meaning the acid addition salts.
Acid addition salts are understood as meaning the salts obtained with organic acids such as, for example, 4-methylbenzenesulfonic, (E)-2-butenedioic, (Z)-2-butenedioic, ethanedioic and methanesulfonic acids, or with mineral acids such as, for example, hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids.
C.sub.1 -C.sub.12 -Alkyl group is understood here as meaning a linear or branched alkyl group containing from 1 to 12 carbon atoms.
The preferred alkyl groups are the n-propyl, methyl, 2-methylethyl, 2-methylpropyl and dodecyl groups.
The preferred C.sub.1 -C.sub.12 -alkyl groups containing one or more double or triple bonds are the 2-propen-1-yl, 6,6-dimethylhept-2-en-4-yn-1-yl, 3-methyl-2-buten-1-yl, 3-phenyl-2-propen-1-yl and 3,3-diphenyl-2-propen-1-yl groups.
The 2,3-dihydroxypropyl group is the preferred group among the linear or branched C.sub.3 -C.sub.4 -alkyl groups containing from 3 to 4 carbon atoms and substituted by one or more hydroxyl groups.
Cycloalkyl group is understood here as meaning a cyclic alkyl group containing from 3 to 6 carbon atoms; the preferred cycloalkyl group according to the invention is cyclopropane.
According to the invention, the following compounds are preferred: thyl-(6.beta.,8a.beta.)-6-isoquinolineamine ,8a.beta.)-6-isoquinolineamine (E)-2-butenedioate rimethyl-(6.beta.,8a.beta.)-6-isoquinolineamine 4-methylbenzenesulfonate nyl]propyl]-5,5,8a-trimethyl-(6.beta.,8a.beta.)-
REFERENCES:
patent: 4863932 (1989-09-01), Jinensky
patent: 5084461 (1992-01-01), Wannamaker et al.
Binet Jean
Boucher Thierry
De Fornel Daniel
Renaut Patrice
Samreth Soth
Davis Zinna Northington
Fournier Industrie et Sante
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