Studies on the Synthesis of Condensed Pyridazine Derivatives. II. Synthesis and Anxiolytic Activities of 2-Aryl-4, 4a, 5, 6-tetrahydro-pyridazino [4, 3-c] quinolin-3 (2H)-ones, 2-Aryl-4a, 5-dihydro-2H-(1) benzothiopyrano [4, 3-c] pyridazin-3 (4H)-ones, and Related Compounds

Abstract

A series of 2-aryl-4, 4a, 5, 6-tetrahydropyridazino [4, 3-c] quinolin-3 (2H)-ones, 2-aryl-4a, 5-dihydro-2H-(1) benzothiopyrano [4, 3-c] pyridazin-3 (4H)-ones, and related compounds were synthesized and tested for their ability to displace [³H] diazepam from rat brain membranes in vitro, and to prevent bicuculline-induced convulsions in mice in vivo. Among them, 2-(4-chlorophenyl)-4a, 5-dihydro-2H-(1) benzothiopyrano [4, 3-c] pyridazin-3 (4H)-one (16b) showed remarkable activities both in vitro (K_i 48 nM) and in vivo (ED₅₀ 12.4 mg/kg, p.o.). The trans sulfoxide (19a) of 16b exhibited anxioselective pharmacological activities. Compound 19a was equipotent with diazepam in the anticonflict assay (Vogel type, rat, MED 10 mg/kg, p. o.) while exhibiting reduced muscle relaxation (rotarod test) and narcotic potentiation. The structure-activity relationships are discussed.