YRIDYLALKYL)PIPERIDYLIDENE]BENZOCYCLOHEPTAPYRIDINE DERIVATIVES AS DUAL ANTAGONISTS OF PAF AND HISTAMINE

A series of [(3-pyridylalkyl)piperidylidene]- and (nicotinoylpiperidyl idene)benzocyclohept derivatives, Ia,b, were prepared and evaluated fo r PAF antagonist and H-1 antihistamine activity. PAF antagonist activi ty was investigated by the in vitro PAF-induced platelet aggregation a ssay (PPA) arid the in vivo PAF-induced hypotension test in rats (PH) and mortality test in mice (PM). For the evaluation of H-1 antihistami ne activity, the in vitro histamine-induced contraction of the guinea- pig ileum assay (HC) and the in vivo histamine-induced hypotension tes t (HH) in normotensive rats were used. The potential antiallergic acti vity of the compounds was evaluated using the active anaphylactic shoc k test in mice. These compounds are structurally related to loratadine (1) and were generated by replacement of the ethoxycarbonyl group of 1 with substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti- PAF and H-1 antihistamine activities have shown a high dependence on t he exact nature and position of the substituent in the pyridine ring. Optimum structure 19 (UR-12592) incorporating a (5-methyl-3-pyridyl)me thyl radical displayed an unique dual activity inhibiting both PAF-ind uced effects (PPA, IC50 = 3.7 mu M; PH, ID50 = 0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv). Furthermore, 19 was highly active in the passiv e cutaneous anaphylactic shock in rats (ID50 = 1.2 mg/kg po) and stron gly protected mice and rats from mortality induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv, respectively). Compound 19 showed itself to be devoid of CNS depressant effects, neither modifying spontaneous motor activity nor prolonging barbiturate-sleeping time in mice at a dose o f 100 mg/kg po, and is now under development.