Synthesis of terfenadine.
The synthesis of alpha-[4-(1,1-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1- piperidinebutanol (terfenadine, RMI 9918, Triludan, Teldane, resp.) is described. A limited structure-activity analysis of the central nervous system-mediated side effects of this compound and related analogs is made relative to the antipsychotic agent, haloperidol. Modification of the piperidine 4-position substituents of haloperidol to give a 4-(alpha, alpha-diphenylmethanol) moiety has conveyed histamine H1 -antagonism to the anti-psychotic agent, haloperidol. Structural changes of this fluorobutyrophenone have progressively reduced and finally eliminated centrally-mediated side effects. The result of this exercise is terfenadine, a preferred antihistamine, potent and selective in antagonizing histamine H1-receptor-mediated responses but lacking the usual side effect profile of known histamine H1-receptor antagonists.
D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055598:Chemical Phenomena; D002621:Chemistry; D006634:Histamine H1 Antagonists; D007928:Lethal Dose 50; D051379:Mice; D016593:Terfenadine
D001559:Benzhydryl Compounds; D006634:Histamine H1 Antagonists; D016593:Terfenadine