AMPHOTERIC DRUGS .1. SYNTHESIS AND ANTIALLERGIC ACTIVITY OF [4-(DIPHENYLMETHOXY)PIPERIDINO]ALKANOIC, [4-(DIPHENYLMETHYL)PIPERAZINYL]ALKANOIC AND [4-(DIPHENYLMETHYLENE)PIPERIDINO]ALKANOIC ACID DERIVATIVES

A simple method of transforming classical antihistaminics into nonseda tive antiallergic agents with strong effects in rat models is describe d. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylme thyl)piperazinyl]- (series B) and [4-(diphenylmethylene)piperidino]alk anoic acid derivatives (series C) were synthesized and examined for an tiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a-c). N-a lkylcarboxylic acids (5a-c) showed stronger inhibitory effects on comp ound 48/80-induced lethality in rats than the corresponding N-methyl d erivatives (1a-c). In particular, N-alkylcarboxylic acids (5a) in seri es A exhibited approximately 100-fold stronger inhibitory effects than la, and were the least effective in prolonging the sleeping time on h exobarbital-induced anesthesia in mice in all series. As II result of chemical modification in series A, it ws found that introduction of a methyl group at the para-position on one benzene ring in the (diphenyl methoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (4-Methylphenyl)phenylmethoxy]piperid ino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibit ed a stronger antiallergic effect (ED(50) = 0.17 mg/kg, p.o.) than ket otifen and terfenadine in the 48 h homologous passive cutaneous anaphy laxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30 mg/kg. Compound (+)-5l was thus proved to be a p romising candidate as a nonsedative antiallergic agent.