title: [Studies on the synthesis of condensed pyridazine derivatives. II. Synthesis and anxiolytic activities 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].
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]pyr idazin-3(4H)- one (16b) showed remarkable activities both in vitro (Ki 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.
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakao
authors.forename: M
authors.initials: M
authors.lastname: Kawakami
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.forename: M
authors.initials: M
authors.lastname: Obata
authors.forename: Y
authors.initials: Y
authors.lastname: Morimoto
authors.forename: S
authors.initials: S
authors.lastname: Takehara
authors.forename: T
authors.initials: T
authors.lastname: Tahara
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011724:Pyridazines