Synthetic studies on condensed-azole derivatives. IV. Synthesis and anti-asthmatic activities of omega-sulfamoylalkyloxyimidazo[1,2-b]pyridazines.
A series of novel (imidazo[1,2-b]pyridazin-6-yl)oxyalkylsulfonamides was synthesized and evaluated for the ability to inhibit platelet activating factor (PAF)-induced bronchoconstriction in guinea pigs. The compounds bearing a gem-dialkyl or a cycloalkylidene group at the 2 position of the sulfamoylpropyloxy group in the side chain were found to have potent activity. Among them, 3-(imidazo[1,2-b]pyridazin-6-yl)oxy-2,2-dimethylpropanesulfonam ide (6) showed excellent anti-asthmatic activity and the longest duration of action. The compounds bearing a methyl group at the 7 or 8 position of the imidazo[1,2-b]pyridazine ring were found to have enhanced activity. Among them, 3-(7-methylimidazo[1,2-b]pyridazin-6-yl)oxy-2,2- dimethylpropanesulfonamide (25) showed the most potent inhibitory effect, and its anti-asthmatic effect in an experimental model of allergic asthma was superior to that of theophylline. The structure-activity relationships in this series of compounds are discussed.
Kuwahara
M
M
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kawano
Y
Y
Shimazu
H
H
Ashida
Y
Y
Miyake
A
A
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D006168:Guinea Pigs; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits
D018927:Anti-Asthmatic Agents; D001393:Azoles; D007093:Imidazoles; D010972:Platelet Activating Factor; D011724:Pyridazines