Synthesis and histamine H1-receptor antagonist activity of 4-(diphenylmethyl)-1-piperazine derivatives with a terminal heteroaryl or cycloalkyl amide fragment

Article abstract of DOI:10.1016/0223-5234(96)83975-4

New 4-(diphenylmethyl)-1-piperazine derivatives with a terminal heteroaryl or cycloalkyl amide fragment were synthesized and evaluated for their antihistaminic anticholinergic and antiallergic activities. Tested compounds were found to be moderate to potent in vitro (guinea-pig ileum) histamine H₁-receptor antagonists. Derivatives with a four methylene chain (1e-1h) were as potent in vivo (capillary permeability in rats) as cetirizine; the heteroaryl derivatives 1e and 1h were found to be the most active agents. These compounds displayed only weak in vitro (guinea-pig ileum) muscarinic M₃-receptor antagonist activity. Compounds 1e and 1g were about 100 times more potent than ketotifen in preventing the compound 48/80-induced histamine release from rat peritoneal mast cells. Derivatives 1e, 1f and 1h did not modify the spontaneous motor activity in rats at 100 mg/kg po. Compound 1e has been selected for further studies.