SPIRO-SUBSTITUTED PIPERIDINES AS NEUROKININ RECEPTOR ANTAGONISTS - II- SYNTHESES AND NK2 RECEPTOR-ANTAGONISTIC ACTIVITIES OF N-[2-ARYL-4-(SPIRO-SUBSTITUTED PIPERIDIN-1'-YL)BUTYL]CARBOXAMIDES

In the course of our research on spiro-compounds as neurokinin recepto r antagonists, N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]ca rboxamides were designed, based on YM-35375 (3) as a lead compound, an d evaluated for NK2 receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK2 recept or with IC50 values at the level of 10(-9) M. Among these compounds, b enzoyl-N-methylamino)-3-(3,4-dichlorophenyl)butyl 4'-piperidine] 2-oxi de (58, YM-38336) showed 10 times more potent NK2 receptor binding aff inity than compound 3 (IC50 values of 8.9 and 84 nM, respectively). It showed more potent inhibitory activity (ID50 20 mu g/kg (i.v.)) again st [beta-Ala(8)]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID50 41 mu g/kg (i.v.)). This compound was also effec tive intraduodenally in the same model, exhibiting an ID50 value of 0. 41 mu g/kg.