Preparation of amides of pyrazolamines and anilines as well as analogs as cytokine inhibitors for the treatment of inflammatory diseases.

Abstract

Title compds., such as I and II (four Markush structures are claimed), wherein X = C(O), C(S) or CH2; G = (un)substituted carbocyclyl or heterocyclyl; Ar = indazolyl, indolyl, pyrazolyl, alkyl, etc.; L = covalent bond or (un)substituted carbon chain; Q = H, (un)substituted amino, cycloalkyl, heterocyclyl, alkoxy or sulfonyl; with some limitations and exclusions, and stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, were prepd. as cytokine inhibitors. For instance, cyclization of p-tolylhydrazine hydrochloride with 4,4-dimethyl-3-oxopentanenitrile to the corresponding pyrazolamine (92% yield) followed by EDC-mediated coupling with indazole-3-carboxylic acid gave indazolopyrazole III (40% yield). I were found to have activity in the TNFa ELISA assay, with some compds. having IC50 < 10 μM. Therefore, I and their pharmaceutical compns. are useful in preventing or treating conditions mediated by cytokines, such as arthritis and inflammatory diseases. [on SciFinder(R)]