New 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives are peroxisome proliferator activated receptor agonists, useful for treatment of e.g. diabetic dyslipidemia, obesity, atherosclerosis, psoriasis and acne

摘要

3,5-Dioxo-(2H,4H)-1,2,4-triazine derivatives are new. 3,5-Dioxo-(2H,4H)-1,2,4-triazine derivatives of formulae (I) and (II) and their addition salts with pharmaceutically acceptable bases, enantiomers having asymmetric carbons, and mixtures including racemic mixtures are new. R 1H, optionally branched 1-6C alkyl, optionally branched alkoxy, optionally branched alkenyl radical, 3C or 5-6C cycloalkyl, phenyl-1-2C alkyl, phenyl, thiophen-2-yl heterocycle, secondary 1-7C alkylamine, 5-6C cycloalkylamine or halo (where phenyl is optionally substituted by at least one of 1-4C alkyl, 1-4C alkoxy, nitrile, nitro, halo or trifluoromethyl); R 2H, optionally branched 1-7C alkyl, optionally branched alkenyl, 1-6C alkyl (substituted by trifluoromethyl, monofluoroethyl or polyfluoroethyl), 5-6C cycloalkyl, nitrile, benzodioxan-2-yl, phthalimido, pyridinyl, 2,2,2-trifluoroacetylamino, 1-4C alkoxy-carbonylvinyl, hydroxycarbonylvinyl, 1-4C alkoxycarbonyl, carboxylate, thiophen-2-carbonyl, indolyl, phenyloxy, benzyloxy, phenyl, benzhydryl, benzoyl (where the phenyl ring is optionally substituted by at least one of 1-4C alkyl, 1-4C alkoxy, nitro, halo or trifluoromethyl), phenylcarbamoyl (where the phenyl ring is optionally substituted by at least one of 1-2C alkyl or nitro), 1-4C alkoxy or 1-4C alkoxy-2-4C alkyl; linker : 2-6C alkyl, -(CH 2) n-C?=C- or -(CH 2) n-O-; n : 1 - 5; R 3phenyl-X-C(R 9)(R 10)-C(O)O-R 11 (where phenyl is substituted by R 4 - R 8 at positions 2 - 6 respectively); X : O or S; R 4 and R 8H, F or optionally branched 5-10C alkenyl; R 5 - R 7H or F; and R 9 - R 11H or optionally branched 1-5C alkyl. The linker is connected to the ortho-, meta- or para-positions of the aromatic of R 3. An independent claim is also included for preparation of (I) and (II). [Image] ACTIVITY : Antilipemic; Antidiabetic; Antiarteriosclerotic; Anorectic; Antipsoriatic; Antiseborrheic; Dermatological. MECHANISM OF ACTION : Peroxisome proliferator activated receptor (PPAR)-alpha agonist; PPAR-gamma receptor agonist. The efficacy of ethyl 2-(3-{5-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate (Ia) as agonist of peroxisome proliferators activated receptor was evaluated on human PPARalpha using reporter gene assay as described in J.M. Lehmann et al. (J. Biol. Chem 1995, 270:12953-12956). (Ia) showed an EC 50 value of 0.001 - 0.003 mu M.