4-Alkylpiperidines related to SR-48968: Potent antagonists of the neurokinin-2 (NK 2) receptor

A series of 4-alkylpiperidine derivatives related to the potent neurokinin-2 (NK 2) receptor antagonist SR-48968 ( 1) is described. Simple aliphatic derivatives were found to be poorly active, but appropriate placement of an alcohol functional group afforded compounds that were of similar activity to 1 Several representatives in this series, such as the 4-(1-hydroxy-1-ethylpropyl)piperidine ( 14), were found to exhibit oral activity in a model of labored abdominal breathing in guinea pigs. These results expand the latitude of substituents available in this region of this series of NK 2 receptor antagonists. A series of 4-alkylpiperidine derivatives related to the potent NK 2 receptor antagonist SR-48968 is described. The most interesting example in this series was the 4-(1-hydroxy-1-ethylpropyl)piperidine (R 1R 2C 2H 5), which exhibited good in vitro and oral activity.