Preparation of pyrazolo-pyridinone derivatives for preventing and treating proinflammatory cytokine-mediated diseases such as p38-mediated inflammation and related conditions.

Abstract

The title compds. I [each of A1-A4 = CR6 or N, provided that no more than two of A1-A4 = N; X = O, S or NR4; R1 = H, alkyl, cycloalkyl, etc.; R2, R3 = H, halo, haloalkyl, etc.; R4 = H or (un)substituted alkyl optionally comprising 1-2 heteroatoms selected from N, O and S; R5 = R7, OR7, N(R7)2, etc.; R7 = H, alkyl, cycloalkyl, etc.], useful for the prophylaxis and treatment of pro-inflammatory cytokine mediated diseases, and in particular, p38 activity mediated inflammation and related conditions, were prepd. E.g., a multi-step synthesis of II, starting from Et (ethoxymethylene)cyanoacetate and 3-fluorophenylhydrazine hydrochloride, was given. Compds. I were found to inhibit the activity of various kinase enzymes, including, without limitation, p38 receptor kinase at doses less than 25 μM. The invention also comprises pharmaceutical compns. including one or more compds. I, uses of such compds. and compns. for treatment of inflammatory diseases including rheumatoid arthritis, psoriasis and other disorders, as well as intermediates and processes useful for the prepn. of compds. I. [on SciFinder(R)]