Synthesis and Antihistaminic H1 Activity of 1,2,5(6)-Trisubstituted Benzimidazoles

Abstract

A number of benzimidazoles, having several substituents on the azoIe and benzene nudei and C-2 (methylamino, ethylenediamine, morpholine, piperazine and piperidine) were prepared.Regioselective synthesis was designed for the N'-alkyl substituted benzimidazoles (14-15).X-Ray structure analysis of (14) was also revealed.Compounds were evaluated for their in vitro HI-antihistaminic activity in the isolated guinea-pig ileum method.The compound (11) exhibits best activity.Classical HI--antihistaminic compounds have been usehl for the treatment of allergic diseases.Unfortunately, because of their depressive effects such as sedation and hypnosis on the central nervous system and peripheral side effects there is a limitation for the use of them.'During the last decade considerable efforts have been spent for discovering a new antihistaminic agent with minimum CNS effects while retaining a potent antihistaminic activity.It is getting more important day by day, because of the increasing ratio of the allergic disease particularly in developed ~ountries.~In previous ~t u d i e s ~, ~ we reported the synthesis and biological evaluation of 1,2,5(6)-aisubstituted benzimidazoles as an antimicrobial agents.Continuing our interest in this field, we found some papers concerning the synthesis and sbucture activity relationships of 2-(4-substituted l-piperazinyl)benzimidazoles, which have potent HI-antihistaminic Among the synthesized compounds, l-(2-ethoxyethyl)-2-(4-methyl-l-homopiperazinyl)benzimidazole (KB-2413) 0 was 39 times more potent than chlorpheniramine maleate in H~antihistaminic activity in vivo launched in Japan in 1994, for the treatment of allergic rhinitis and urticaria, named as Emedastine Drfumarate.'