Preparation of heterocycle amide derivatives as inhibitors for production of cytokines.

Abstract

The present invention relates to novel heterocycle amide derivs. such as 1H-pyrazole-4-carboxamide, 1H-pyrrole-3-carboxamide, and furan-2-carboxamide derivs. [I; R1a, R1b, R1c = H, halo, cyano, HO, NH2, alkylamino, each (un)substituted alkyl or alkoxy; n, m = an integer of 0-3; Het1 = thiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cycloalkyl, heterocyclyl, indolyl, etc.; Het2 = cycloalkyl, aryl, heterocyclyl, or heteroaryl; or Het1 and Het2 together form a ring; R2a, R2b, R3a, R3b, R3c = H, halo, cyano, HO, each (un)substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, etc.; i = an integer of 0-3; k = an integer of 0-2; X, Y, Z = each independently N or (un)substituted CH; A = C or (un)substituted CH; D = O, C(O), each (un)substituted NH or CH2, S, S(O), S(O)2 ] or pharmaceutically acceptable salts thereof. More specifically, the present invention provides a medicinal agent useful as a prophylactic or therapeutic agent contg. the amide I, a pharmacol. acceptable salt thereof or a solvate of the deriv. or the pharmacol. acceptable salt as an active ingredient, for diseases which rely on the prodn. of cytokines in T cells, particularly Interleukin 17 (IL-17), from T cells, in particular autoimmune disease and articular rheumatism. Thus, a soln. of 96 mg 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid in 4.0 mL toluene was stirred with 114 mg SOCl2 and a catalytic amt. of N,N-dimethylformamide at 80° for 1 h, followed by distg. off the excess SOCl2. The reaction product obtained was treated with 2.0 mL pyridine and then with a soln. of 100 mg N-[4-(5-amino-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-2,2,2-trifluoro-N-methylacetamide in 2.0 mL pyridine, stirred at 50° for 1 h, treated with 1.0 mL Et3N and water, followed by filtering off the pptd. solid and purifn. using silica gel chromatog. to give 141 mg 5-methyl-N-[5-methyl-6-[4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino]cyclohex-1-en-1-yl]pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (II; R = trifluoroacetyl). II (R = trifluoroacetyl) and II (R = 3,3-dimethylbutyl) in vitro inhibited the IL-23-stimulated prodn. of IL-17 in mouse spleen cells with IC50 of 4.91 and 368 nM, resp., and in vitro also inhibited hERG in HEK293 cells introduced with hERG by 35.9 and 79.5%, resp., at 1 μM. [on SciFinder(R)]