Synthesis and antiallergic activity of novel azaazulene derivatives.
Various azaazulene derivatives were synthesized and their antiallergic activity was examined. The structure-activity relationship among various derivatives modified by introducing substituents at the 1-,2-, or 3-position of the azaazulene ring was investigated. The inhibitory activities on allergic histamine release of the compounds bearing a 5-tetrazolyl group at the 3-position were more potent than those of the corresponding compounds with other groups (CN, COOH, and CHO). The compounds substituted with amino, azide and carboxymethylamino groups at the 2-position showed strong inhibitory activity. The compounds with various phenylalkyl groups at the 1-position showed a greater activity than those with other substituents. Among the compounds with substituents at the 1-,2-, or 3-position of the azaazulene ring, 1-benzyl-7-isopropyl-3-(5-tetrazolyl)-1-azaazulen-2-one (18f) and 1-(4-fluorobenzyl)-7-isopropyl-3-(5-tetrazolyl)-1-azaazulen- 2-one (19c) had the most potent inhibitory activities on histamine release from mast cells and on passive cutaneous anaphylaxis (PCA) in rats after oral administration (ED50 = 0.56 and 0.58 mg/kg, respectively).
Nagahara
M
M
Central Research Institute, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan.
Nakano
J
J
Mimura
M
M
Nakamura
T
T
Uchida
K
K
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006636:Histamine Release / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013552:Swine
D001372:Aza Compounds; D006633:Histamine Antagonists; D010726:Phosphodiesterase Inhibitors