Preparation of substituted biaryl piperazinyl-pyridine analogs as capsaicin receptor modulators.

Abstract

Title compds. I [wherein Ar2 = (un)substituted Ph, 6-membered arom. heterocyclyl; X, Y, Z = independently CH and derivs., N, such that at least one of X, Y, and Z = N; D, K, J, F = independently N, CH and derivs.; R1 = 0-3 substituents selected from halo, CN, NO2, -Q-M-R5, etc.; Q = alkylene; each M = absent, O, CO, OCO, SO, etc.; R5 = H, haloalkyl, alk(en/yn)yl, etc.;R10 = Q-M-R5, or groups that taken together with one R1 to form a fused optionally substituted 5- to 7-membered carbocyclyl or heterocyclyl; R3 = H, halo, halo/alkyl, alkylene-NH2, pyrrolidinyl, morpholinyl, etc.; R4 = 0-2 substituents selected from halo/alkyl, oxo; and their pharmaceutically acceptable salts], useful for treating conditions related to capsaicin receptor activation, were prepd. I modulate, preferably inhibit binding of vanilloid ligand to VR1 activation capsaicin receptor VR1 (vanilloid receptor subtype 1), exhibit no detectable agonist activity in an in vitro assay of capsaicin receptor agonism, show IC50 of ≤1 μM in a capsaicin receptor calcium mobilization assay, and reduce calcium conductance of a cellular capsaicin receptor. Radiolabeled compds. I are used for detg. the presence or absence of capsaicin receptor in a sample in receptor localization studies. An 8-step synthesis is given for title compd. II (no data for the intermediates). [on SciFinder(R)]