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

抄録

In the course of our research on spiro-compounds as neurokinin receptor antagonists, N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides were designed, based on YM-35375 (3) as a lead compound, and evaluated for NK₂ receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK₂ receptor with IC₅₀ values at the level of 10^-9M. Among these compounds, (±)-1'-[4-(N-benzoyl-N-methylamino)-3-(3, 4-dichlorophenyl)butyl]spiro[benzo[c]thiophene-1(3H), 4'-piperidine] 2-oxide (58, YM-38336) showed 10 times more potent NK₂ receptor binding affinity than compound 3 (IC₅₀ values of 8.9 and 84nM, respectively). It showed more potent inhibitory activity (ID₅₀ 20μg/kg (i.v.)) against [β-Ala⁸]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID₅₀ 41μg/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID₅₀ value of 0.41μg/kg.