Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-05-08
1999-07-27
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514326, 546187, 546209, A61K 31445, C07D41314, C07D41304
Patent
active
059290897
DESCRIPTION:
BRIEF SUMMARY
5-Phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one derivatives, their preparation and their application in therapeutics.
The subject of the present invention is compounds corresponding to the general formula (I) ##STR2## in which R.sub.1 represents a (C.sub.1 -C.sub.4)alkyl or (C.sub.3 -C.sub.7)cycloalkylmethyl group, X.sub.1 represents a hydrogen or halogen atom or a (C.sub.1 -C.sub.4)alkoxy group or else OR.sub.1 and X.sub.1 together represent a group of formula -OCH.sub.2 O-, -O(CH.sub.2).sub.2 -, -O(CH.sub.2).sub.3 -, -O(CH.sub.2).sub.2 O- or -O(CH.sub.2).sub.3 -, X.sub.2 represents a hydrogen atom or an amino group, X.sub.3 represents a hydrogen or halogen atom, and R.sub.2 represents either a hydrogen atom or an optionally substituted (C.sub.1 -C.sub.6) alkyl group or a phenyl (C.sub.1 -C.sub.4) alkyl group which is optionally substituted on the phenyl ring or a phenyl (C.sub.2 -C.sub.3) alkenyl group or a phenoxy (C.sub.2 -C.sub.4) alkyl group or a cyclo (C.sub.3 -C.sub.7) alkylmethyl group or a 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl group or a group of general formula -(CH.sub.2).sub.n CO-Z in which n represents a number from 1 to 6 and Z represents a piperidin-1-yl or 4- (dimethylamino)piperidin-1-yl group.
When R.sub.2 represents an optionally substituted alkyl group, such a group is preferably a 2-ethoxy-2-oxoethyl group, a 2-(dimethylamino)-2-oxoethyl group, a 2-hydroxy-2-phenylethyl group, a butyl group, a 4,4,4-trifluorobutyl group or a 4-trifluoro-3-hydroxybutyl group.
When R.sub.2 represents a phenyl (C.sub.1 14 C.sub.3) alkyl group which is optionally substituted on the phenyl ring, such a group is preferably a group optionally substituted on the phenyl ring by a halogen atom, by a trifluoromethyl group or by one or two methoxy groups.
When R.sub.2 represents a group of general formula -(CH.sub.2).sub.n CO-Z, such a group is preferably a 4-oxo-4-(piperidin-1-yl)butyl group, a
The compounds of the invention can exist in the form of free bases or of addition salts with acids. Moreover, some R.sub.2 substituents contain an asymmetric carbon atom; the compounds can therefore exist in the form of pure enantiomers or of mixtures of enantiomers.
In accordance with the invention, the compounds of general formula (I) can be prepared by a process illustrated in the following scheme. ##STR3##
An ester of general formula (II), in which R.sub.1, X.sub.1, X.sub.2 and X.sub.3 are as defined above and R.sub.3 represents a methyl or ethyl group, is reacted with hydrazine hydrate, in the absence of solvent or in a polar protic solvent, for example ethanol, in order to obtain a hydrazide of general formula (III), which is cyclized to the oxadiazole of general formula (IV), either by means of phosgene, in an aprotic solvent, for example dioxane, or by means of phenyl chloroformate, in an aprotic solvent, for example toluene. When, in the general formula (III), X.sub.2 represents an amino group, the latter reacts with phosgene and the product obtained is esterified with benzyl alcohol, the amino group thus being protected by a benzyloxycarbonyl group. The oxadiazole of general formula (IV) is then reacted with a piperidin-4-ol of general formula (V), in which R.sub.2 is as defined with respect to the general formula (I) but is other than a hydrogen atom or else represents a (1,1-dimethylethoxy)carbonyl protective group, in the presence of triphenylphosphine and ethyl azodicarboxylate, in an aprotic solvent, for example tetrahydrofuran, then, if it takes place, the nitrogen of the piperidine ring is deprotected by means of trifluoroacetic acid and, when R.sub.2 represents a hydrogen atom and if it is desired, the compound obtained is reacted with a derivative of general formula R.sub.2 -X, in which X represents a leaving or functionalizable group, for example a halogen atom, a methanesulphonate or 4-methylbenzenesulphonate group or a carbonyl functional group, and R.sub.2 is as defined with respect to the general formula (I) but is other than a hydrogen atom, in the presence of triethylamine,
REFERENCES:
patent: 5580885 (1996-12-01), King et al.
Chemical Abstract, vol. 121, No. 23, Abstract 280649k, 1994, p. 1035.
De Cruz Laurence
Galli Frederic
Jegham Samir
Lochead Alistair
Nedelec Alain
Morris Patricia L.
Synthelabo
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