N-Heteroaryl-2-phenyl-3-(benzyloxy)piperidines:  A Novel Class of Potent Orally Active Human NK₁Antagonists

The preparation of a series of N-heteroarylpiperidine ether-based human NK1 antagonists is described. Two of the compounds (3-[{(2S,3S)-3-(((3,5-bis(trifluoromethyl)phenyl)methyl)oxy)- 2-phenylpiperidino)methyl]-1,2,4-triazol (11) and 5-[((2S,3S)-3-(((3,5-bis(trifluoromethyl phenyl)methyl)oxy)-2-phenylpiperidino}methyl]-3-oxo-1,2,4-triazole (12)), in particular, are orally bioavailable 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 stable than the others. Furthermore, both 11 and 12 have been profiled in a number of assays that may be predictive of the clinical utility of substance P antagonists.