N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: A novel class of potent orally active human NK1 antagonists

被引：64

作者：

Ladduwahetty, T ^{[1
]}

Baker, R ^{[1
]}

Cascieri, MA ^{[1
]}

Chambers, MS ^{[1
]}

Haworth, K ^{[1
]}

Keown, LE ^{[1
]}

MacIntyre, DE ^{[1
]}

Metzger, JM ^{[1
]}

Owen, S ^{[1
]}

Rycroft, W ^{[1
]}

Sadowski, S ^{[1
]}

Seward, EM ^{[1
]}

Shepheard, SL ^{[1
]}

Swain, CJ ^{[1
]}

Tattersall, FD ^{[1
]}

Watt, AP ^{[1
]}

Williamson, DW ^{[1
]}

Hargreaves, RJ ^{[1
]}

机构：

[1] MERCK & CO INC,MERCK SHARP & DOHME RES LABS,RAHWAY,NJ 07065

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1996年 / 39卷 / 15期

关键词：

D O I：

10.1021/jm9506534

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2907 / 2914

页数：8

共 33 条

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