Patent EP-1864979-A1 (EP)
Inventor: KALLUS CHRISTOPHER
IPC: A61K31/435
Filed: 2005-04-07
Abstract: Imidazolyl-acetic acid derivatives (I) are new. Imidazolylacetic acid derivatives of formula (I) and their stereoisomers, mixtures and/or salts are new. U = H, 1-6C alkyl, 3-6C cycloalkyl, F, OCF 3 or CF 3; X = (A 1) m-A 2; Y = CH[6-14C aryl] 2, A 3-(A 4) o-(A 5) p, lactam of formula (a), CR 16R 17(CR 18R 19) x-C(O)NR 12R 13 or CR 26R 27(CR 28R 29) x-SO 2NR 24R 25; Z = H, 1-6C alkyl, 1-6C hydroxyalkyl, 3-6C cycloalkyl(0-4C alkyl), (1-10C alkylene)-OC(O)OR 1 or (CH 2) n-(6-14C aryl) or (CH 2) n-Het (both optionally substituted by 1-3 R 1); A 1 = (CH 2) n or O(CH 2) n; m = 0 or 1; n = 1-3; x = 0-3; y = 1-5; A 2 = 4-15 membered heterocyclic ring containing at least one N and substituted by amino, (optionally further substituted by 1-3 1-3C alkyl, halo, CF 3 or OCF 3), 1-6C aminoalkyl or 3-8C aminocycloalkyl; either (a) A 3 = 3-8C cycloalkyl or 2-6C alkynylene (optionally substituted (os) by 1-3 OR 10 or R 1), A4 = N(R 2) 2, A 5 is absent and o = 0 or 1; or (b) A 3 = 3-8C cycloalkyl (os by 1-3 OR 10 or R 1), A 4 = NR 2, A 5 = C(O)R 3, C(O)NR 4R 5, SO 2R 6 or C(O)OR 7, o and p =1; (c) A 3 = 3-8 membered cyclic amine (os by 1-3 R 1), A 4 and A 5 are as in (b) with A 5 bonded to the N atom of A 3, o = 0 and p = 0 or 1; (d) A 3 = (CH 2) q(6-14C aryl) optionally ring-substituted by 1-3 R 1, A 4 and A 5 are as in (b), o = 0 or 1, p = 1 and q = 1-3; (e) A 3 = (CH 2) r-Het1, A 4 and A 5 are as in (b), o = 0 or 1, p = 1 and r = 1-3; or (f) A 3 = (CH 2) q(6-14C aryl) optionally ring-substituted by 1-3 R 1, A 4 = O, A 5 = 6-14C aryl (os by 1-3 R 1), o, p = 1 and q =1-3; Het1 = 4-15 membered heterocycle os by 1-3 oxo or R 1; R 1 = 6-14C aryl (os by 1-3 1-6C alkyl, 3-8C cycloalkyl(0-4C alkyl), CF 3, O, OCF 3 or halo), 4-15 membered heterocycle, 1-6C alkyl, 3-8C cycloalkyl(0-4C)alkyl, CF 3, OCF 3 or halo; R 2 = 6-14C aryl, 1-6C alkyl or 3-8C cycloalkyl (all os by 1-3 R 1), CF 3 or H; R 3, R 6-R 8 = 1-6C alkyl, 6-14C aryl, 4-15 membered heterocycle or 3-8C cycloalkyl (all os by 1-3 R 1) or H; R 4, R 5 = 1-6C alkyl, 2-10C alkenyl, 6-14C aryl, 4-15 membered heterocycle or 3-8C cycloalkyl (all os by 1-3 R 1) or H; or R 4+R 5 complete a 3-8 membered ring optionally including 1 or 2 additional O, S or N; R 12 = 1-6C alkyl or Q-(0-3C alkyl) (all os by 1-3 R 1) and R 13 = 6-14C aryl(0-3C alkyl) or Het(0-3C alkyl) (both os by 1-3 R 1); or R 12 = H, 1-6C alkyl, 0-3C alkyl(6-14C aryl) or 0-3C alkyl(Het) (all os by 1-3 R1) and R 13 = CHR 8R 9; Q = 3-6C cycloalkyl, 6-14C aryl or heterocycle; R 8, R 9 = 6-14C aryl or heterocycle (both os by 1-3 1-4C alkoxy or R 1); R 16-R 19 = H, 1-6C alkyl (os by 1 or 2 R 1), halo, OH, amino, 0-3C alkyl(6-14C aryl) or 0-3C alkyl-Het (all os by 1-3 R 1); or R 16+R 17 or R 18+R 19 = 3-6 membered ring; R 24, R 25 = H, 1-6C alkyl (os by 1-2 R 1), 0-3C alkyl(6-14C aryl or Het), os by 1-3 R 1, or 0-3C alkyl(3-6C cycloalkyl); or R 24+R 25 complete a 3-8 membered ring that may contain 1 or 2 additional O, S or N; R 26-R 29 = H, 1-6C alkyl (os by 1 or 2 R 1), halo, OH, amino, or (0-3C alkyl)-6-14C aryl or -Het (all os by 1-3 R 1); or R 26+R 27 or R 28+R 29 = 3-6 membered ring. An independent claim is also included for preparation of (I). [Image] [Image] ACTIVITY : Thrombolytic; Anticoagulant; Cardiant; Antianginal; Cerebroprotective; Antiarteriosclerotic; Antidiabetic; Cytostatic; Ophthalmological; Vulnerary. MECHANISM OF ACTION : TAFIa inhibitor (activated thrombin-activatable fibrinolysis inhibitor). 3-(6-Aminopyridin-3-yl)-2-(1-cyclohexyl-1H-imidazol-1-yl)propionic acid, when tested using Actichrome Plasma TAFI Activity kit, had IC 50 against TAFIa of 0.03 mu M.