[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].
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.
Nakao
T
T
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Kawakami
M
M
Morita
K
K
Obata
M
M
Morimoto
Y
Y
Takehara
S
S
Tahara
T
T
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
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011724:Pyridazines