Synthesis of 2-(4-substituted-1-piperazinyl)benzimidazoles as H1-antihistaminic agents

Abstract

A series of 2-(4-substituted-1-(homo)piperazinyl)benzimidazoles was prepared and tested for H1-antihistaminic activity in vitro and in vivo. Most of the compounds showed antihistaminic activity and some of the 1-[2-(substituted-oxy)ethyl] derivatives exhibited potent activity. In a structure-activity comparison it was found that the oxygen atom in the 2-(substituted-oxy)ethyl group at the 1-position of the benzimidazole nucleus played an important role for potent antihistaminic activity, especially in vivo. One of the most potent compounds, 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole (69), was 39 times more potent than chlorpheniramine maleate in H1-antihistaminic activity in vivo and was selected for clinical evaluation. The structure of compound 69 is of interest because it provides only a single aromatic unit linked through a chain to a basic nitrogen, while most H1-antihistaminic agents have structures that comprise a double-aromatic unit linked through a chain to a basic tertiary amino group.

Unusual synthesis of 1-(4-fluorobenzyl)-N-(1-(1-(4-fluorobenzyl)-6-isopropoxy-1H-benzo[d]imidazol-2-yl)piperidin-4-yl)-6-isopropoxy-1H-benzo[d]imidazol-2-amine

“…Treatment of compound 10 with 1/3 equivalents of triphosgene under basic conditions 9 resulted in formation of benzimidazolone 11, which was in turn converted to compound 12 by the action of POCl 3 . 10 Finally when compound 12 was reacted with two equivalents of compound 6 to obtain compound 3 according to literature reports on similar reactions, 3,4 compound 4 was the only product isolated while substantial amount of compound 12 was recovered. Although synthesis of compound 3 requires one equivalent each of compound 6 and compound 12, excess of compound 6 was used to trap the released HCl.…”

Synthesis and SAR Study of Novel Amidino 2-substituted Benzimidazoles as Potential Antibacterial Agents

“…[2] Even though Moraxella catharralis has not been identified as an important human pathogen, it is obvious that it has a significant financial impact on global health care systems. [3] Benzimidazoles displayed a variety of biological effects, such as antihelmintic, [4] antiviral, [5,6] anticancer, [7] anti-inflammatory [8] or antioxidant [9] activities. Consequently, benzimidazole core received attention as an important pharmacophore for the development of novel B antimicrobial agents in inhibiting synthesis of microbial nucleic acids and proteins and preventing the growth of various microorganisms ( Figure 1).…”

Synthesis of Benzimidazole Derivatives Containing Schiff Base Exhibiting Antimicrobial Activities

“…The different benzimidazole derivatives are associated with a wide range of biological activities such as anti-cancer [13] , anti-viral [21] , anti-bacterial [7,9,22] , anti-fungal [18] , anti-helmintic [23] , antiinflammatory [10] , anti-histaminic [15] , proton pump inhibitor [8] , anti-oxidant [2] , anti-hypertensive [14] and anti-coagulant [17] properties. Literature review shows that along with the benzimidazole derivatives, 2-substituted ones are found to be pharmacologically more important and hence syntheses of 2-substituted benzimidazoles are the reasonable area of research [4,19] .…”