Preparation of 2-substituted 5-(4-fluorophenyl)-4-(4-pyridyl)pyrimidines and related compounds as drugs.

Abstract

Novel pyrimidines [I; R1, R2 = ZY, with a proviso; Z = bond, (un)substituted alk(en)yl, alkynyl, (un)substituted heterocyclyl, (un)substituted (hetero)aryl; etc; Y = H, halo, NO2, COR20, CNR5NR5R21, OR21, O2CR21, etc.; R5 = H, (un)substituted alk(en)yl, alkynyl, cycloalkyl, (hetero)aryl, etc.; R20 = (un)substituted alk(en)yl, alkynyl, aralkoxy, aralkylthio, aralkylsulfonyl, etc.; R21 = H, any of definitions for R20] and their pharmaceutically acceptable salts, effective for prophylaxis and treatment of diseases mediated by tumor necrosis factor α (TNF-α), IL-1β, IL-6 and/or IL-8 and other maladies, e.g., pain and diabetes, were prepd., e.g., by enamination of 2-(4-fluorophenyl)-1-(4-pyridinyl)ethanone (II) with (Me2N)2CHOMe and cyclocondensation of the resulting (dimethylamino)propenone with an amidine, guanidine or urea. I analogs, prodrugs , pharmaceutical compns., methods for prophylaxis and treatment of diseases or conditions involving inflammation, pain, diabetes, etc., and processes for making such compds. and their intermediates are also claimed. For example, heating a mixt. of II with (Me2N)2CHOMe at 110° for 1.5 h under Ar gave 3-(dimethylamino)-2-(4-fluorophenyl)-1-(4-pyridyl)-3-propen-1-one which was cyclocondensed with 4-pyridylamidine (prepd. in situ from pyridylamidine-HCl and Na) by refluxing in EtOH to give a title compd. I (R1 = R12 = 4-pyridinyl, R2 = H, R11 = 4-FC6H4). The latter in mice inhibited lipopolysaccharide-induced TNF-α release with IC50 ≤20 μM. [on SciFinder(R)]