Oxazolidinone derivatives, their preparation and therapeutical u

Details Oxazolidinone derivatives, their preparation and therapeutical u Oxazolidinone derivatives, their preparation and therapeutical u

1997-12-02

1998-12-01

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514373, 548212, 548231, A61K 31425, C01D41304

Patent

active

058439757

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/FR96/00292 filed May 28, 1996.
The present invention relates to isoindole derivatives, and more particularly to 5-(hydroxymethyl)oxazolidine-2-one derivatives which are substituted at the 3 position by an indazole, benzisoxazole or benzisothiazole ring system, to a process for their preparation and to their application in therapy.
The compounds of the invention correspond to the general formula (I) ##STR1## in which: X represents an oxygen atom, a sulphur atom or a group NR, R being a hydrogen atom or a linear or branched C.sub.1 -C.sub.4 alkyl chain, atom, or a benzyl group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a methoxyethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl or 4,4,4-trifluorobut-2-enyl group, or (ii) a group --CH.dbd.CH--R.sub.4 or --CH.sub.2 --CH.sub.2 --R.sub.4, in which R.sub.4 represents a hydrogen atom or a phenyl, 3,3,3-trifluoropropyl or 3,3,3-trifluoro-2-hydroxypropyl group.
The compounds of formula (I) comprise one or two asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These various forms and their mixtures, including the racemic mixtures, are part of the invention.
The compounds of formula (I) in which X is an oxygen atom and R.sub.2 represents a group --CH.dbd.CH--R.sub.4, with the exception of compounds in which R.sub.4 is a hydrogen atom, exist in the form of cis or trans isomers. These forms and their mixtures are part of the invention.
The compounds of formula (I) in which R.sub.2 represents a group OR.sub.3 in which R.sub.3 represents the 4,4,4-trifluorobut-2-enyl group exist in the form of cis or trans isomers. These forms and their mixtures are part of the invention.
Preferred compounds are those for which: hydrogen atom or a linear or branched C.sub.1 -C.sub.4 alkyl chain, alternatively a hydrogen atom, or a benzyl group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a methoxyethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl or 4,4,4-trifluorobut-2-enyl group, various forms, including racemic mixtures.
Other preferred compounds are those for which: hydrogen atom or a linear or branched C.sub.1 -C.sub.4 alkyl chain, --R.sub.4, in which R.sub.4 represents a hydrogen atom, or a phenyl, 3,3,3-trifluoropropyl or 3,3,3-trifluoro-2-hydroxypropyl group, various forms, including racemic mixtures.
The compounds of choice are those for which: atom, or a benzyl group which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a methoxyethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl or 4,4,4-trifluorobut-2-enyl group, or which R.sub.4 represents a hydrogen atom, or a phenyl, 3,3,3-trifluoropropyl or 3,3,3-trifluoro-2-hydroxypropyl group, various forms, including racemic mixtures.
Among the latter, mention may be made of compounds for which: which is optionally substituted with a halogen atom or with a nitro or methylenedioxy group, or represents a 4,4,4-trifluorobutoxy group or a 4,4,4-trifluoro-3-hydroxybutoxy group, various forms, including racemic mixtures, zolidin-2-one.
The compounds of formula (I) in which R.sub.1 is a methyl group and R.sub.2 is a group OR.sub.3 can be prepared according to the process represented in scheme 1. According to this process, the isoindole derivative of formula (II) is treated with one of the 4(R) or 4(S) isomers of 4-methoxymethyl-1,3-dioxolan-2-one of formula (IIIa) in the presence of potassium carbonate in order to obtain the 5(S) or 5(R) isomer of the compound of formula (Ia) according to the invention. It is then possible to debenzylate the compound (Ia) by catalytic hydrogenation under conditions which are conventional to the person skilled in the art, or with the aid of a Lewis acid such as aluminium chloride, in order to obtain the 5(S) or 5(R) isomer of the compound of formula (Ib) according to the invention. Subsequently, it is possible

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