Amphoteric Drugs. II. Synthesis and Antiallergic Activity of [4-(5H-Dibenzo[a, d]cycloheptan-5-ylidene)piperidino]alkanoic Acid Derivatives and Related Compounds

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A simple method of transforming clalssical tricyclic antihistaminics into nonsedative antiallergic agents with equal potency in rats and guinea-pigs is described. A series of [4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)-piperidino]alkanoic acid derivatives (6a) and related compounds (6b-f) were synthesized and examined for antiallergic and antihistaminic activities and effects on the central nervous system (CNS) in comparison with the corresponding N-methyl derivatives (2a-f). N-Alkylcarboxylic acids (6a-f) showed stronger inhibitory effects on 48h homologous passive cutaneous anaphylaxis (PCA) in rats than 2a-f, and also were less effective in prolongation of the sleeping time on hexobarbital-induced anesthesia in mice in comparison with 2a-f. As a result of further modification, it was found that introduction of an oxygen atom into the central ring of the tricyclic system in amphoteric compounds enhanced their antiallergic and antihistaminic activities. 3-[4-(6H-Dibenz[b, e]oxepin-11-ylidene)piperidino]propionic acid (6c) exhibited strong inhibitory effects on 48h homologous PCA in rats (ED_<50>=0.067mg/kg, p.o.) and on histamine-induced bronchoconstriction in anesthetized guinea-pigs (ED_<50>=0.0085mg/kg, p.o.), and thus is a promising candidate as an antiallergic agent.
社団法人日本薬学会の論文
1994-11-15