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
1999-07-20
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548232, 549404, 549462, C07D41304, A61K 3142
Patent
active
059256621
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds derived from oxazolidin-2-one, a process for their preparation and their application in therapeutics.
The compounds of the invention correspond to the general formula (I) ##STR2## in which: n is equal to 0 or 1, atoms or a fluoroalkyl group comprising 1 to 4 carbon atoms,
In the context of the present invention: least one of the carbon atoms is substituted by one or more fluorine atoms. Usually, a fluoroalkyl group according to the invention comprises 3 fluorine atoms substituted onto the terminal carbon atom of the alkyl chain.
Preferred compounds of formula (I) are those for which (i) R.sub.1 represents a cyano, methyl or trifluoromethyl group and/or (ii) R.sub.3 represents a methyl group.
The compounds of formula (I) have at least two asymmetric carbon atoms, one in position 5 of the oxazolidine, the other in position 2 of the dihydrobenzofuran or of the dihydrobenzopyran (these positions are respectively indicated by 5 and 2 in the configurations). They can thus exist in the form of enantiomers or of diastereoisomers. The invention comprises these different forms as well as their mixtures, including their racemic mixtures.
The compounds of formula (I) can be prepared according to the process represented in Annex 1. The compounds of formula (I) in which R.sub.3 represents a methyl group can be prepared starting from a compound of formula (II) ##STR3## in which n and R.sub.1 are defined as in formula (I) and R is a hydrogen atom or an OR' group, in which R' represents a hydroxy protective group such as the phenylmethyl group (Bn).
According to this process, the nitro group of the compound of formula (II) is reduced and the compound of formula (III) ##STR4## prepared in this way is reacted with ethyl chloroformate and sodium bicarbonate to obtain a compound of formula (IV) ##STR5## where R, R.sub.1 and n have the meanings indicated above and Et is an ethyl group.
The compound of formula (IV) can then be reacted with 4-methoxymethyl-1,3-dioxolan-2-one to obtain either a compound of formula (I) in which R.sub.2 is a hydrogen atom and R.sub.3 is a methyl group, or a compound of formula (V) ##STR6## where R.sub.1, R' and n have the meanings indicated further above, which is deprotected to give a compound of formula (I) in which R.sub.2 represents a hydroxyl group, and optionally treated with thiocarbonyldiimidazole (TCDI), then with tributyltin hydride and .alpha.,.alpha.'-azodiisobutyronitrile (AIBN) to give a compound of formula (I) in which R.sub.2 represents a hydrogen atom.
The compounds of formula (I) where R.sub.3 represents a hydrogen atom can be prepared, starting from corresponding compounds of formula (I) where R.sub.3 represents a methyl group, by reaction with boron tribromide.
The compounds of formula (I) in which R.sub.2 represents a hydrogen atom and n is equal to 0, can likewise be prepared according to the process represented in Annex 2, by reduction of the corresponding benzofuran derivative of formula (IX) ##STR7## in which R.sub.1 is defined as previously. The reduction can be carried out, for example, by hydrogen in the presence of a catalyst such as palladium on carbon.
The compounds of formula (IX) can be prepared starting from (2-hydroxy-5-nitrophenyl)methyltriphenylphosphonium bromide (compound described in Chem. Ber. 1986, 119, 2169), which is reacted with an acid chloride of formula R.sub.1 (CH.sub.2).sub.2 COCl, where R.sub.1 has one of the meanings indicated in formula (I), to prepare a 5-nitrobenzofuran derivative of formula (VI) ##STR8## which is then treated to form a 5-aminobenzofuran derivative of formula (VII) ##STR9## which is then in turn treated to form 5-ethoxycarbonylaminobenzofuran of formula (VIII) ##STR10## which is then reacted with 4-methoxymethyl-1,3-dioxolan-2-one according to a procedure analogous to the procedure described previously. In the compounds of formula (VI), (VII) and (VIII), R.sub.1 has one of the meanings given for the formula (I).
The compounds of formula (II) in which R.sub.1 represents a cyano or triflu
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Berthon Danielle
Burnier Philippe
Jegham Samir
Puech Frederic
Berch Mark L.
Razgunas Ann
Synthelabo
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