Patent DE-10310278-A1 (DE)
Title: New N-(benzazinyl)-(hetero)aralkylamine derivatives, are inhibitors of factor Xa and/or related serine proteases, useful e.g. as antithrombotic agents and intermediates
Inventor: RIES UWE
IPC: C07D417/06
Filed: 2003-03-10
Abstract: N-(Quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalizinyl or benzo-1,2,3-triazinyl)-(hetero)aralkylamine derivatives (I) are new. N-(Quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, phthalizinyl or benzo-1,2,3-triazinyl)-(hetero)aralkylamine derivatives of formula (I) (including tautomers, enantiomers, diastereomers and mixtures) and their prodrugs and salts are new. [Image] X, Z : N or CH; Y : CH, C(T) or C(NH2); R1(i) NH2, alkylamino, NH-Cy or NH-T-Ph (all optionally substituted (os) on N- by COPh or SO2Ph or by T or COT (both os by COOH, a group convertible into COOH in vivo, NH2, NHT or NT2)); (ii) dialkylamino or N-(Cy)-alkylamino (both os in the alkyl (but not in the 1-position) by OH, OT, NHT or NT2); (ii) 4-7 membered cycloalkyleneimino (os (but not adjacent to N) by OH, OT, NH2, NHT or NT2); (iii) 4-7 membered cycloalkyleneimino-carbonyl or -sulfonyl, which (a) is os by T, -T-NH2, -T-NHT, -T-NT2, CONH2, CONHT, N-(Cy)-alkylaminocarbonyl, N-(T-Ph)-alkylaminocarbonyl or CONT2 or (not adjacent to N) by OH, OCH2Ph, NH2, NHT or NT2,(b) optionally has CH2 in the 3-position of a 5-7 membered ring replaced by S, SO or SO2 or CH2 in the 4-position of a 6- or 7-membered ring replaced by O, S, NH, N(COMe), N(COEt), SO or SO2 and/or (c) optionally has CH2CH2 in a 5-7 membered ring replaced by NHCO; (iv) 2,5-dihydropyrrol-1-ylcarbonyl or 1,2,5,6-tetrahydro-pyridin-1-ylcarbonyl (both os by T, -T-NH2, -T-NHT, -T-NT2, CONH2, CONHT, N-(Cy)-alkylaminocarbonyl, N-(T-Ph)-alkylaminocarbonyl or CONT2); (v) SO2NH2 or CONH2 (both os by 1 or 2 of T, -T-Ph and/or Cy); (vi) alkylcarbonyl; (vii) -CO-Cy (optionally having CH2 in the 3- or 4-position of a 5-7 membered ring replaced by NH, N(T), N(COT), N(COPh) or N(SO2T)); (viii) -CO-Ph or -CO-Het; or (ix) T (os by NH2, NHT, NT2, OH, Ph or 4-7 membered cycloalkyleneimino); the phenyl substituents are os by F, Cl, Br, CF3, T or OT; R2>H, F, Cl, Br, T (os by one or more F), 2-3C alkenyl, 2-3C alkynyl, OH, OT or OCF3; R3>(i) H; (ii) 1-6C alkyl (os by OH, COOH, COOT, NH2, NHT, NT2, NHCOT, NHCOOT or NHCOO-T-Ph); (iii) methyl or ethyl, both substituted by (a) phenyl or Het (both os by OH, 1-4C alkoxy, OCH2Ph, -O-T-COOH, -O-T-COOT, -O-T-CONH2, -O-T-CONHT, -O-T-CONT2, COOH or COOT), (b) 1H-pyridonyl or 1-(T)-pyridonyl, (c) 4-7 membered cycloalkyleneimino or (d) 4-7C cycloalkyl, in which 1 or 2 non-adjacent CH2 group(s) is/are replaced by O, S, NH or N(T), and one CH2 adjacent to one NH or N(T) (if only one NH or N(T) is present) or to both NH or N(T) (if only two NH or N(T) are present) is optionally replaced by CO; or (iv) phenyl or Het (both os by OH, 1-4C alkoxy, OCH2Ph, -O-T-COOH, -O-T-COOT, -O-T-CONH2, -O-T-CONHT, -O-T-CONT2, COOH or COOT); Ar : phenyl substituted by R4>, R5> and R6>, or thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl (all os on C by R4> and R5>); R4>CN, amidino (os by 1 or 2 of OH, T, (1-8C) alkylcarbonyl, (1-8C) alkoxycarbonyl or benzoyl), -T-NH2, -T-NHT, -T-NT2 or -C(NH2)=N-CO-O-CH(R7>)-O-CO-R8>; R7>H or T; R8>T; R5>H, F, Cl, Br, CF3, T, OH, -T-OH, OT, OCH2Ph, -T-OT, NH2, NHT or NT2; R6>H, F, Cl, Br or T; T : 1-3C alkyl (including alkylene where appropriate); Cy : 3-7C cycloalkyl; Het : 5- or 6-membered heteroaryl (os by T, COOH, COOT or NHCOOT), where (i) 5-membered heteroaryl contains (a) one NH, N(T), N(T-Ph), O or S, (b) one NH, N(T), N(T-NH2), N(T-NHT) or NT-NT2) or N(T-Ph), O or S plus one further N or (b) one NH, N(T) or N(T-Ph) plus 2 or 2 further N, (ii) 6-membered heteroaryl contains 1-3 N, (iii) the groups as in (i) or (ii) are optionally fused to a benzene ring and (iv) Het is bonded via N- or C- of the heterocyclic part or via the fused benzene ring (if present); unless specified otherwise alkyl moieties have 1-5C; all methyl or ethyl groups are os by 1-3 F. An independent claim is included for the preparation of (I). ACTIVITY : Thrombolytic; Anticoagulant; Vasotropic; Cerebroprotective; Cytostatic; Antiinflammatory; Antirheumatic; Antiarthritic; Vulnerary. MECHANISM OF ACTION : Factor Xa inhibitor; Serine protease inhibitor. Thrombin inhibitor; Urokinase inhibitor; Factor VIIa inhibitor; Factor IX inhibitor; Factor XI inhibitor; Factor XII inhibitor. In a test, 4-hydroxy-3-((7-(pyrrolidin-1-yl-carbonyl)-quinolin-1-yl)-aminomethyl)-benzamidine (Ia) exhibited an IC50 value of less than 100 mu M for inhibition of Factor Xa.