Studies of the Synthesis of Condensed Pyridazine Derivatives. IV. Synthesis and Anxiolytic Activity of 2-Aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and Related Compound

A series of 2-aryl-5, 6-dihydro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-ones and related compounds were synthesized and evaluated for their ability to displace 3H-diazepam from rat brain membranes in vitro, and to prevent bicuculline induced convulsions in mice in vivo.Compounds with a 4'-methoxyphenyl (36) or 4'-chlorophenyl group (37, 39-42) as 2-aryl substituents showed prominent activities in both the in vitro and in vivo tests. Among them, 2-(4'-chlorophenyl)-5, 6-dihydro- (37) and 2-(4'-chlorophenyl)-5, 6-dihydro-10-fluoro-(1)benzothiepino[5, 4-c]pyridazin-3(2H)-one 7-oxides (41) showed activity twice as potent as diazepam in an anticonflict test (Vogel type, rats) while exhibiting less muscle relaxation (rotarod test, mice) and augmentation of γ-aminobutyric acid-induced chloride current (1cl) in isolated frog sensory neurones than diazepam. Compound 37 (Y-23684) was selected from this series as a candidate for further development. The structure-activity relationships are discussed.