Synthesis and Antiallergic Activity of 11-(Aminoalkylidene)-6,11-dihydrodibenzoxepin Derivatives

Article abstract of DOI:10.1021/jm00089a020

A new series of 11-substituted 6,11-dihydrodibenzoxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents.These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agents.Most compounds synthesized exhibited potent inhibitory effects on 48-h homogolous passive cutaneous anaphylaxis (PCA) in rats and on IgG₁-mediated bronchoconstriction in guinea pigs.Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenzoxepin ring system exhibited inhibitory effects on specific <3H>pyrilamine binding to guinea pig cerebellum histamine H₁ receptors, whereas these demonstrated negligible effects on specific <3H>QNB binding to rat striatum muscarinic acetylcholine M₁ receptors.Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system.Among the compounds synthesized, (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenzoxepin-2-acetic acid hydrochloride (16) was selected for further evaluation.It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs.Furthermore, it had a K_i value of 16 +/- 0.35 nM for the histamine H₁ receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po.Compound 16 is now under clinical evaluation as KW-4679.