A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-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 agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous 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 dibenz[b,e]oxepin 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-dihydrodibenz [b,e]oxepin-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 Ki 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.