N-HETEROARYL-2-PHENYL-3-(BENZYLOXY)PIPERIDINES - A NOVEL CLASS OF POTENT ORALLY-ACTIVE HUMAN NK1 ANTAGONISTS

The preparation of a series of N-heteroarylpiperidine ether-based huma n NK1 antagonists is described. Two of the compounds )-3-(((3,5-bis(tr ifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino)methyl]-1,2,4-tri azol (11) and 5-[((2S,3S)-3-(((3,5-bis(trifluoromethyl y)-2-phenylpipe ridino}methyl]-3-oxo-1,2,4-triazole (12)), in particular, are orally b ioavailable and exhibited significant improvements in potency, both in vitro and in vivo, over the lead (carboxamidomethyl)piperidine ether 1. Rat Liver microsome studies on a selected number of compounds from this series show the triazolone heterocycle to be considerably more st able than the others. Furthermore, both 11 and 12 have been profiled i n a number of assays that may be predictive of the clinical utility of substance P antagonists.