Preparation of pyrimidinecarboxylates for treating inflammatory conditions.

Abstract

The title compds. [I; R2 = R2a when R4 = R4a, and R2 = R2b when R4 = R4b; R2b, R4a = H, halo, C1-8 alkyl, etc.; R2a, R4b = II-V; R5 = CO2R7, C(O)R8, etc.; R6 = H, Me, PhCH2, F, CF3; R7 = H, C1-8 alkyl, etc.; R8 = (un)substituted C1-8 alkyl, C6-12 aryl, C7-12 aralkyl; R9 = H, C1-8 alkyl, etc.; R10, R11 = H, (un)substituted C1-8 alkyl, C6-12 aryl], useful as anti-inflammatory agents in general and, more specifically, for the prevention and/or treatment of immunoinflammatory and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, transplant rejection, sepsis, ARDS, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus, uveitis, chronic hepatitis, trauma, oxidative stress, cell death, irradn. damage, ischemia, reperfusion, cancer, and viral infection, were prepd. Thus, reaction of Et 2-hydrazino-4-trifluoromethylpyrimidine-5-carboxylate with citraconic anhydride in CHCl3 afforded 39% I [R2 = III (R9 = R11 = H; R10 = Me); R4 = CF3; R5 = H; R6 = CO2Et] which showed IC50 of 0.7 μM against activation of transcription factors NFκB and AP-1. [on SciFinder(R)]