Synthesis and biological activities of optical isomers of 2-(4-chlorophenyl)-5,6-dihydro-(1)benzothiepino[5,4-c]pyridazin-3(2H)-o ne 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 from 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.
Nakao
T
T
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Obata
M
M
Yamaguchi
Y
Y
Marubayashi
N
N
Ikeda
K
K
Morimoto
Y
Y
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D001582:Benzothiepins / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D003220:Conflict, Psychological; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D013237:Stereoisomerism
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001582:Benzothiepins; D011724:Pyridazines; D011963:Receptors, GABA-A; C074367:Y 23684