Starting with commercially available or nitropyrazole carbox

Starting with commercially available 4- or 5-nitropyrazole-3-carboxylic acid, anilides containing nitro, amino or methylsulfonamido were synthesized. Here, manipulation of the substituents on the pyrazole ring was conducted after the anilide formation (). The Benzamil synthesis of the nitro group was performed with PtO with NaBH as the hydrogen donor. If H was used, the chlorine on the phenyl group was replaced by hydrogen. Other heterocyclic cores were explored in parallel to the investigation of the pyrazoles (). Only 1,2,3-triazoles show any appreciable inhibitory activity and these compounds were investigated further (). They were prepared using the same methodology as for the pyrazoles, that is, dimerization followed by addition of an aniline. Having an anilide moiety in a drug may be problematic as anilines, present as minute impurities, or formed by hydrolysis in the stomach or in the intestines, are potentially mutagenic. We therefore prepared a series of benzoxazolyl-substituted pyrazoles, as a benzoxazole can be considered to be an anilide bioisoster. The compounds are readily prepared by condensing pyrazole-3-carboxylic acids and 2-aminophenols using polyphosphoric acids (). The yields were at best modest, but we did not spend time optimizing the reaction. In a selection of amides of pyrazole-3-carboxylic acid, unsubstituted on the pyrazole core, are shown. The comparison of the anilide (entry 1) with the benzylamide (entry 2) clearly shows that moving the phenyl away from the pyrazole skeleton essentially eliminates inhibitory activity. On the anilide portion fluoro and/or chloro substituents, particularly in the 2 and 4-position, are favorable (entries 3–6). Replacing fluoro or chloro with trifluoromethyl decreases activity, but not by much (entries 3 and 6 vs 7 and 8). The unsubstituted 2-pyridyl amide (entry 9) is significantly more potent than the 3- and 4-pyridyls (entries 10 and 11), and also here addition of halogen substituents increases activity (entries 12 and 13). Some 5-membered heterocyclic as well as some bicyclic heterocyclic amides also show good activity (entries 14–18). The lack of activity for -alkylated carboxanilides (entry 19) suggests that an amide NH is needed for activity. shows -(2-chloro-4-fluorophenyl)pyrazole-3-carboxamides with various substituents in the 4- and/or 5-positions. Compared to the unsubstituted compound (entry 1), alkyl substituents decrease activity (entries 2–6). A 4-phenyl substituent abolishes activity. Introduction of one halogen generally does not have much influence on the inhibitory activity whereas two halogens gave stronger inhibition (entries 8–15). One or two trifluoromethyl groups decrease the activity, which is restored by the addition of a chlorine (entries 16–19). Compounds with difluoromethyl substituents behaved similarly (entries 20 and 21). 4-Nitro, and particularly, 4-amino substitution gave decent activity, whereas the 5-substituted ones only showed low activity (entries 22–25). The sulfonamido-substituted compounds (entries 26–27) were practically inactive. In analogy with the pyrazole SAR, the activity of triazole-3-carboxanilides is increased by a fluoro or chloro substituents in the 2-, and particular in the 4-position, which was further increased by 2,3-dihalo substitution (entries 1-6, ). In contrast to the pyrazole series, the pyridyl and quinoline amides were not particularly active (cf. entries 7–9, with entries 11,12 and 16, ). Judging by the lack of activity for -alkylated carboxanilides, entry 18, , one would tend to believe that the amide NH is essential for activity. However, this notion is not correct as evident from the activity of the 2-(pyrazol-3-yl)benzoxazoles in . A chloro substituent, particularly in the 6-positon (entry 2) of the benzoxazole increases activity. As before, chloro substituents on the pyrazole core are beneficial for activity and compound (entry 7) was the most active of all tested compounds. Unfortunately, all benzoxazoles of suffered from very low metabolic stability ( a few minutes) and were deemed unsuitable for further development.