Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-07-27
2000-09-26
Seaman, D. Margaret
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514318, 546192, 546193, A61K 31445, C07D27704, C07D27718, C07D27738
Patent
active
061243183
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 4-substituted gem-diphenylalkyl-1,2,3,6-tetrahydropyridines with neurotrophic and neuroprotective activity, to a process for their preparation and to pharmaceutical compositions containing them.
EP-0 458 696 describes the use of a 1-(2-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine for the preparation of drugs intended for the treatment of cerebral and neuronal disorders.
It has now been found that certain gem-diphenylalkyl-1,2,3,6-tetrahydropyridines substituted by a phenyl or pyridyl group exert a neurotrophic action on the nervous system which is similar to the action of nerve growth factor (NGF), and can restore the function of damaged cells or cells exhibiting anomalies in their physiological functions.
According to one of its features, the present invention therefore relates to the gem-diphenylalkyl-1,2,3,6-tetrahydropyridines of formula (I): ##STR2## in which: Y is --CH-- or --N--; -C.sub.4)alkoxy group; monosubstituted or polysubstituted phenyl group;
Advantageous compounds according to the present invention are those of formula (I) in which Y is CH and R.sub.1 is CF.sub.3 and those of formula (I) in which Y is N and R.sub.1 is Cl.
Among these compounds, those of formula (I) in which, in addition, R.sub.2 and R.sub.3 are both hydrogens and n is 0 or 1 are particularly advantageous.
Particularly advantageous compounds are represented by formula (I'): ##STR3## in which R.sub.1 ' is CF.sub.3 and Y' is CH, or R.sub.1 ' is Cl and Y' is N, and n is zero or 1, Ph.sub.1 and Ph.sub.2 being as defined above.
In formulae (I) and (I'), Ph.sub.1 and Ph.sub.2 are preferably identical but they can also be different, implying the existence of a chiral carbon atom.
Advantageously Ph.sub.1 and Ph.sub.2 are each independently a phenyl group; a phenyl group monosubstituted in the 2-, 3- or 4-position by a fluorine or chlorine atom or by a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, cyano, methoxy, methylthio, methylsulfonyl, ethoxy, ethylthio, ethylsulfonyl, (C.sub.1 -C.sub.3)alkoxycarbonyl or di(C.sub.1 -C.sub.3)alkylaminocarbonyl group; a phenyl group disubstituted in the 2,4-, 3,4-, 3,5- or 2,6-positions by a fluorine or chlorine atom or by a methyl, ethyl, trifluoromethyl, cyano or methoxy group; or a phenyl group trisubstituted in the 3,4,5-, 2,4,5- or 2,4,6-positions by a chlorine or fluorine atom or by a methyl, ethyl, trifluoromethyl, cyano or methoxy group.
If Ph.sub.1 and Ph.sub.2 are different, one of the phenyl groups is preferably unsubstituted and the other is preferably monosubstituted in the 2-, 3- or 4-position as indicated above.
In the present description the term "(C.sub.1 -C.sub.3)alkyl" denotes methyl, ethyl, n-propyl and i-propyl groups.
The term "alkoxy" denotes a hydroxyl group substituted by a (C.sub.1 -C.sub.4)alkyl group.
The following compounds are particularly preferred: e; trahydropyridine; 1,2,3,6-tetrahydropyridine; etrahydropyridine; trahydropyridine; ne; dropyridine;
According to another of its features, the present invention relates to a process for preparing the compounds of formula (I), their salts or solvates and their quaternary amrnonium salts, characterized in that: ##STR4## in which Y and R.sub.1 are as defined above, is reacted with an acid of formula (III): ##STR5## in which n, R.sub.2, R.sub.3, Ph.sub.1 and Ph.sub.2 are as defined above, or one of its functional derivatives; ##STR6## is reduced; and (c) the resulting compound of formula (I) is isolated and optionally converted to one of its salts or solvates or one of its quaternary ammonium salts.
The reaction of step (a) can conveniently be carried out in an organic solvent at a temperature between -10.degree. C. and the reflux temperature of the reaction mixture; the reaction is preferably carried out at low temperature.
The reaction solvent used is preferably a halogenated solvent such as methylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform or the like, or an alcohol such as methanol or ethanol, bu
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Baroni Marco
Cardamone Rosanna
Fournier Jacqueline
Guzzi Umberto
Alexander Michael D.
DuPont Paul E.
Sanofi-Synthelabo
Seaman D. Margaret
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