Collect. Czech. Chem. Commun.
1997, 62, 498-509
https://doi.org/10.1135/cccc19970498
Chiral Forms of 4-(2',4'-Difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic Acid (Flobufen) and Its Metabolite.Synthesis and Basic Biological Properties
Miroslav Kuchařa, Marie Poppováa, Antonín Janderaa, Vladimíra Panajotovováa, Hana Zůnováa, Miloš Buděšínskýb, Hana Tomkováa, Alexandr Jegorovc and Jan Taimra
a Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3, Czech Republic
b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,166 10 Prague 6, Czech Republic
c Galena, a.s., 370 05 České Budějovice, Czech Republic
Abstract
4-(2',4'-Difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid (1, flobufen) is subjected to clinical testing in the treatment of rheumatoid arthritis. Owing to the occurrence of a centre of chirality, the compound exists in two enantiomers, and its major human metabolite, viz. 4-(2',4'-difluorobiphenyl-4-yl)-4-hydroxy-2-methylbutanoic acid isolated in the lactone form (2), possesses two chiral centres, making possible the existence of four stereoisomers. All of the optical isomers of the substances 1 and 2 were prepared. For flobufen (1), the racemate was separated into the stereoisomers by using the salts 3 with R-(+)- or S-(-)-1-phenylethylamine. The pairs of stereoisomers of 2, obtained by reduction of R-(+)-flobufen or the S-(-)-enantiomer, were separated by column chromatography. The physico-chemical parameters of the optical isomers were determined and some biological activities were evaluated in both in vitro and in vivo models.
Keywords: Flobufen; Human metabolite; Chiral forms; Synthesis; Antiinflammatory activity.
