Patent DE-10136435-A1 (DE)
Title: New carbamimidoyl phenyl derivative useful for treating e.g. thrombotic diseases e.g. deep leg vein thrombosis, ischemic incidents in patients with unstable angina and rheumatoid arthritis, are factor Xa inhibitors
Inventor: RIES UWE
IPC: C07C237/36
Filed: 2001-07-26
Abstract: Carbamimidoyl phenyl derivative or its salts are new.  Antithrombotic compounds of formula (I) or its salts are new.  m = 0-2; n = 0 or 1; A = X or bond; X = 1-3C alkylene, mono or disubstituted by 1-3C alkyl or monosubstituted by (CH2)p-Rf; p = 0-3; Rf = hydroxycarbonyl, 1-3C alkoxycarbonyl, E-carbonyl, 1-3C alkyl-E-carbonyl, di-(1-3C alkyl)-E-carbonyl, 3-7C cycloalkyl-E-carbonyl, N-(1-3C-alkoxy-carbonylmethyl)-N-(1-3C alkyl)-E-carbonyl, N-(D-methyl)-N-(1-3C alkyl)-E-carbonyl or 4-7 membered cycloalkylene-E1-carbonyl; R1 = E, 1-5C alkyl-E, 3-7C cycloalkyl-E or A-(1-3C) alkyl-E (all substituted at the N in E by A-carbonyl, A-sulfonyl, 1-3C alkyl, or 1-3C alkylcarbonyl (optionally substituted by D, E, 1-3C alkyl-E, or di-(1-3C alkyl)-E)), T, T1, 2,5-dihydropyrrol-1-yl-carbonyl, E-sulfonyl (optionally mono- or disubstituted by 1-3C alkyl, 3-7C cycloalkyl-carbonyl (in which the methylene group in the 3 or 4 position in a 5-7C cycloalkyl-carbonyl is substituted by NH (substituted by 1-3C alkyl, 1-3C alkylcarbonyl, A-carbonyl, or A-sulfonyl)), A-carbonyl, Q-carbonyl, or 1-3C alkyl optionally monosubstituted by E, 1-3C alkyl-E, di-(1-3C alkyl)-E, OH, A, or 4-7 membered cycloalkylene-E1; or terminally disubstituted by A or OH (in which A is substituted by amidino optionally substituted by one or two 1-3C alkyl, F, Cl, Br, trifluoromethyl, 1-3C alkyl, or 1-3C alkoxy);  T = di-(1-5C alkyl)-E or N-(3-7C cycloalkyl)-(1-5C) alkyl-E (in which the 1-5C alkyl moiety of both is substituted by OH, 1-3C alkoxy, E, 1-3C alkyl-E, or di-(1-3C alkyl)-E except at position 1);  T1 = 4-7 membered cycloalkylene-E1-carbonyl or cycloalkylene-E1-sulfonyl (both optionally substituted by 1-3C alkyl, E-1-3C alkyl, 1-3C alkyl-E-1-3C alkyl, di-(1-3C alkyl)-E-(1-3C) alkyl, E-carbonyl, 1-3C alkyl-E-carbonyl or di-(1-3C alkyl)-E-carbonyl); Q = 5-membered heteroaryl bound via a C or N containing E1 (optionally substituted by 1-4C alkyl or 1-4C alkyl-carbonyl), O, S, or 1 or 2 N; or 6-membered heteroaryl containing 1 or 2 N (both fused by a phenyl ring additionally substituted by F, Cl, Br, trifluoromethyl, 1-3C alkyl, or 1-3C alkoxy);  R2 = 1-3C alkyl (partly or wholly substituted by F, 2-3C alkenyl, 2-3C alkynyl, OH, 1-3C alkoxy, or trifluoromethoxy), H, F, Cl, or Br; R3 = H or 1-3C alkyl; R4 = R3 optionally substituted by D; D = carboxy, group convertible into carboxy, or a negatively charged group; Ar = phenyl or naphthyl (both substituted by R5 - R7), or T2; R5 = cyano, or amidino optionally substituted by one or two 1-3C alkyl, E-(1-3C)-alkyl, 1-3C alkyl-E-(1-3C)-alkyl, or di-(1-3C alkyl)-E-(1-3C) alkyl; R6 = H, F, Cl, Br, trifluoromethyl, 1-3C alkyl, OH, OH-(1-3C) alkyl, 1-3C alkoxy, 1-3C alkoxy-(1-3C) alkyl, carboxy, carboxy-(1-3C) alkyl, carboxy (1-3C) alkoxy, 1-4C alkoxy-carbonyloxy, 1-4C alkoxy-carbonyl-(1-3C) alkoxy, A-(1-3C) alkoxy, E, 1-3C alkyl-E, or di-(1-3C alkyl)-E; A = phenyl additionally substituted by F, Cl, Br, trifluoromethyl, 1-3C alkyl, or 1-3C alkoxy); R7 = H, F, Cl, Br, or 1-3C alkyl; T2 = thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl (all optionally substituted by 1-3C alkyl); E = amino substituted by a group which can be cleaved in vivo; E1 = imino substituted by a group which can be cleaved in vivo. Provided that when: (1) m is 0 and n is 1, then A is X; (2) m and n are 1, then A is a bond; (3) m is 0-1 and n is 0, then A is X; and (4) m is 2 and n is 0, then A is a bond. Independent claims are also included for:  (1) a salt of (I) (excluding the compounds in which Ar is phenyl or naphthyl substituted by R5-R7 and R5 is cyano);  (2) a pharmaceutical composition containing (I) (excluding the compounds in which Ar is phenyl or naphthyl substituted by R5-R7 and R5 is cyano, or its salt along with at least one inert carrier and/or diluent); and  (3) treatment of thrombus infection involving administering (I) (excluding the compounds in which Ar is phenyl or naphthyl substituted by R5-R7 and R5 is cyano, or its salt).