Amphoteric drugs. I. Synthesis and antiallergic activity of [4-(diphenylmethoxy)piperidino]-, [4-(diphenylmethyl)piperazinyl]- and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives.
A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]-(series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a--c). N-Alkylcarboxylic acids (5a--c) showed stronger inhibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a--c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activity. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED50 = 0.17 mg/kg, p.o.) than ketotifen and terfenadine in the 48 h homologous passive cutaneous anaphylaxis (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 promising candidate as a nonsedative antiallergic agent.
Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
N
N
Iwasaki
J
J
Sakaguchi
T
T
Ohashi
E
E
Takahara
N
N
Ogawa
S
S
Yasuda
E
E
Koshinaka
H
H
Kato
Y
Y
Ito
H
H
Sawanishi
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002493:Central Nervous System Diseases / Q000139:chemically induced; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D006967:Hypersensitivity / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D002264:Carboxylic Acids; D006634:Histamine H1 Antagonists; D010879:Piperazines; D010880:Piperidines