title: 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.
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000633:toxicity; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000502:physiology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; D007202:Indicators and Reagents; D010879:Piperazines; D006632:Histamine