Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. III. Synthesis of (.+-.)-N-12-(3,4-Dichlorophenyl)-4-(spiro-substituted piperidin-1-yl)butyll-N-methylbenzamides and Evaluation of NK1-NK2 Dual Antagonistic Activities.

Abstract

To discover a novel NK₁-NK₂ dual antagonist, we have synthesized a series of spiro-substituted piperidines utilizing YM-35375 as a lead compound, and evaluated affinities for NK₁ and NK₂ receptors. In the N-methylbenzamide moiety, introduction of methoxy groups increased affinity for the NK₁ receptor without a significant loss of affinity for the NK₂ receptor. We also found that a conformation in which the phenyl groups of the N-methylbenzamide and 3, 4-dichlorophenyl moieties are close to each other through a cis-amide bond, may be favorable for showing high affinity for the NK₁ receptor and that a hydrogen bond-accepting group in the spiro-substituted piperidine moiety may be crucial for exhibiting high affinity for the NK₂ receptor. Among the compounds prepared, YM-44778 (31) showed high and well-balanced affinity for NK₁ and NK₂ receptors (IC₅₀ values of 18 and 16 nM, respectively). This compound also exhibited potent antagonistic activities against both NK₁ and NK₂ receptors (IC₅₀ values of 82 and 62 nM, respectively) in isolated tissues.