Synthesis and Biological Activities of Optical Isomers of 2-(4-Chlorophenyl)-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-Oxide

Two enantiomers of 2-(4-chlorophenyl)-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxide ((±)-1 : Y-23684) were synthesized in high yields by asymmetric oxidation of the synthetic precursor (2) using modified Sharpless reagent. Among the oxidants tested, cumene hydroperoxide (CHP) gave the highest optical and chemical yields, while tert-butyl, tert-amyl, and 1, 1, 3, 3-tetramethylbutyl hydroperoxides did not show such high enantio-selectivities. The absolute configuration of (+)-1 enantiomer synthesized form 2, Ti(O-iso-Pr)4, (-)-diethyl tartarate, and CHP was determined to be S by X-ray crystallographic analysis. Both enantiomers, S-(+)-1 and R-(-)-1, and (±)-1 had approximately equivalent in vivo activities to antibicuculline test in mice and anticonflict test in rats, although S-(+)-1 showed about three times higher affinity to benzodiazepine receptor than R-(-)-1 in [3H]diazepam binding assay.