Synthesis and histamine H(1)-receptor antagonist activity of 4-(diphenylmethyl)-1-piperazine derivatives with a terminal heteroaryl or cycloalkyl amide fragment.
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 H(1)-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 M(3)-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.
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A
Orjales
J
J
Gil-Sánchez
L
L
Alonso-Cires
L
L
Labeaga
R
R
Mosquera
A
A
Berisa
M
M
Ucelay
A
A
Innerárity
R
R
Corcóstegui