AMPHOTERIC DRUGS .2. SYNTHESIS AND ANTIALLERGIC ACTIVITY OF ENZO[A,D]CYCLOHEPTEN-5-YLIDENE)PIPERIDINO]ALKANOIC ACID-DERIVATIVES AND RELATED-COMPOUNDS

A simple method of transforming classical tricyclic antihistaminics in to nonsedative antiallergic agents with equal potency in rats and guin ea-pigs is described. A series of enzo[a,d]cyclohepten-5-ylidene)piper idino]alkanoic acid derivatives (6a) and related compounds (6b-f) were synthesized and examined for antiallergic and antihistaminic activiti es 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 48 h homologous passive cutaneous anaphylaxis (PCA) in rats than 2a-f, and also were less effe ctive in prolongation of the sleeping time on hexobarbital-induced ane sthesia in mice in comparison with 2a-f. As a result of further modifi cation, it was found that introduction of an oxygen atom into the cent ral ring of the tricyclic system in amphoteric compounds enhanced thei r antiallergic and antihistaminic activities. -Dibenz[b,e]oxepin-11-yl idene)piperidino]propionic acid (6c) exhibited strong inhibitory effec ts on 48 h homologous PCA in rats (ED(50) = 0.067 mg/kg, p.o.) and on histamine-induced bronchoconstriction in anesthetized guinea-pigs (ED( 50) = 0.0085 mg/kg, p.o.), and thus is a promising candidate as an ant iallergic agent.