Preparation of 2-(4-bromo or 4-iodo phenylamino)benzoic acid derivatives as MEK inhibitors.

Abstract

The title compds. (I) [wherein R1 = H, OH, alkyl, alkoxy, halo, CF3, or CN; R3-R5 = independently H, OH, halo, CF3, alkyl, alkoxy, NO2, CN, or (O or NH)m-(CH2)n-R9, where R9 = H, OH, CO2H, or NR10R11; m = 0 or 1; n = 0-4; R10 and R11 = H, alkyl, or taken together with the N to which they are attached form a 3-10 membered ring; Z = CO2R7, tetrazolyl, CONR6R7, CONHNR10R11, or CH2OR7; R6 and R7 = independently H, (cyclo)alkyl, alkenyl, alkynyl, acyl, (hetero)aryl, or taken together with the N to which they are attached form a 3-10 membered ring, etc.] were prepd. by std. or combinatorial synthetic methods involving the addn. of halobenzoic acids to haloanilines and optional redn. or amidation of the acid. Thus, treatment of 2-amino-5-iodotoluene in THF with LDA in THF/heptane/ethenylbenzene soln., followed by addn. of 2,4-difluorobenzoic acid in THF afforded II. Combination chemotherapy of I with a known mitotic agent caused dramatic increases of apoptosis of colon and lung carcinoma cells. For instance, 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 184352) in combination with paclitaxel resulted in 44% to 55% apoptosis, 6% to 18% increases over using either agent alone, of colon 26 carcinoma, HT-29 colon carcinoma, and A549 lung carcinoma cells. [on SciFinder(R)]