Benzimidazoles

Abstract

Novel compounds of the formula I in which R 1 , R 1′ , L, E, G, M, Q, U, R 2 , m, p and q have the meanings indicated in Claim 1 and are, for example, inhibitors of tyrosine kinases, for example TIE-2, and can be employed, for example, for the treatment of tumours or other diseases.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       R 1 , R 1′ , R 2 , each, independently of one another, are selected from the group consisting of Hal, A, OH, OA, SA, SO 2 H, SO 2 A, SO 3 H, SO 3 A, CN, NO 2 , NH 2 , NHA, NAA′, NHCOA, CHO, C(═O)A, COOH, COOA, CONH 2 , CONHA and CONAA′, 
       L is selected from the group consisting of CH 2 , CH 2 CH 2 , O, S, SO, SO 2 , NH, NA, C═O or CHOH, 
       E, G, M, 
       Q and U each, independently of one another, are selected from the group consisting of a C atom and an N atom, 
       A, A′, each, independently of one another, are selected from unsubstituted or substituted alkyl having 1-10 C atoms, unsubstituted or substituted cycloalkyl having 3-10 C atoms, unsubstituted or substituted alkoxyalkyl having 2-12 C atoms, unsubstituted or substituted aryl having 6-14 C atoms, unsubstituted or substituted arylalkyl having 7-15 C atoms, unsubstituted or substituted, saturated, unsaturated or aromatic heterocyclyl having 2-7 C atoms and 1-3 hetero atoms selected from the group consisting of N, O and S, or unsubstituted or substituted, saturated, unsaturated or aromatic heterocyclylalkyl having 3-10 C atoms and 1-3 hetero atoms selected from the group consisting of N, O and S, 
       Hal is selected from the group consisting of F, Cl, and I, and 
     
     m, p, q each, independently of one another, are 0, 1, 2, 3 or 4, 
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       2 . The compound according to  claim 1 , wherein
 R 1  is selected from the group consisting of A, Hal, CN, COOH, COOA, SO 2 A, C(═O)A, NH 2 , NHA and NO 2 , and   m is 1, 2 or 3,   
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       3 . The compound according to  claim 1  wherein
 R 1  is selected from the group consisting of methyl, ethyl, CF 3 , OCF 3 , F, Cl, Br, CN, COOH, COOCH 3 , COOCH 2 CH 3 , SO 2 CH 3 , NH 2 , NHCH 3 , NHCH 2 CH 3 , NO 2 , and thiophen-2-ylcarbonyl, and   m is 1, 2 or 3,   
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       4 . The compound according to  claim 1   R 1′  is Hal or A,   p is 0 or 1,   
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       5 . The compound according to  claim 1  wherein
 L is selected from the group consisting of O, S and CH 2 ,   
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       6 . The compound according to  claim 1  wherein
 R 2  is selected from the group consisting of A, COOA, CONHA and CONH 2 , and   q is 0, 1 or 2,   
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       7 . The compound according to  claim 1  wherein
 R 1  is selected from the group consisting of Hal, alkyl, CN, COOH, COOalkyl, SO 2 alkyl, NH 2 , NHalkyl, C(═O)alkyl, C(═O)heterocyclyl and NO 2 ,   m is 1, 2 or 3, preferably 1 or 2,   R 1′  is Hal or A, preferably Hal or alkyl,   p is 0 or 1,   L is selected from the group consisting of O, S and CH 2 ,   R 2  is selected from the group consisting of A, COOalkyl, CONHalkyl and CONH 2 , and   q is 0, 1 or 2,   
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       8 . The compound according to  claim 1  wherein
 the group   
     
       
         
         
             
             
         
       
       in formula I is selected from the group consisting of 
     
     
       
         
         
             
             
         
       
     
     wherein L, R 2  and q have the meanings indicated in  claim 1 , 
     and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
   
   
       9 . The compound according to  claim 1 , selected from the group consisting of 
     (5-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl)[4-(pyridin-4-yloxy)phenyl]amine; 
     [4-(pyridin-4-yloxy)phenyl](6-trifluoromethyl-1H-benzimidazol-2-yl)-amine; 
     (6-methyl-1H-benzimidazol-2-yl)[4-(pyridin-4-yloxy)phenyl]amine; 
     (5-chloro-4-methyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]-amine; 
     (4-bromo-6-trifluoromethyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]amine; 
     (4-bromo-6-trifluoromethyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]amine; 
     (5,6-dimethyl-1H-benzimidazol-2-yl)[4-(pyridin-4-yloxy)phenyl]amine; 
     (5-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]amine; 
     (5,6-dichloro-1H-benzimidazol-2-yl)[4-(pyridin-4-yloxy)phenyl]amine; 
     (5,6-dichloro-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]amine; 
     (5-chloro-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]amine; 
     (5-chloro-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]amine; 
     (4-methyl-1H-benzimidazol-2-yl)[4-(pyridin-3-yloxy)phenyl]amine; 
     (4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]amine; 
     (4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl)[4-(pyridin-3-yloxy)phenyl]amine; 
     (4,5-dimethyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]amine; 
     (5-chloro-6-methyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]-amine; 
     (5-chloro-6-methyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]-amine; 
     (4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)-phenyl]amine; 
     (4,6-bistrifluoromethyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)-phenyl]amine; 
     [4-(pyridin-3-yloxy)phenyl] (6-trifluoromethyl-1H-benzimidazol-2-yl)-amine; 
     (6-methyl-1H-benzimidazol-2-yl)[4-(pyridin-3-yloxy)phenyl]amine; 
     (4,5-dimethyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]amine; 
     (5-chloro-4-methyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]-amine; 
     (4-methyl-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]amine; 
     (5,6-dimethyl-1H-benzimidazol-2-yl) [4-(pyridin-3-yloxy)phenyl]amine; 
     (4-bromo-6-trifluoromethyl-1H-benzimidazol-2-yl)[4-(2,6-dimethyl-pyrimidin-4-yloxy)phenyl]amine; 
     N-methyl-4-[4-(bromotrifluoromethyl-1H-benzimidazol-2-ylamino)-phenoxy]pyridine-2-carboxamide; 
     2-[4-(pyridin-4-yloxy)phenylamino]-3H-benzimidazole-5-carbonitrile; 
     [4-(2-amino-6-methylpyrimidin-4-yloxy)phenyl](4-bromo-6-trifluoro-methyl-1H-benzimidazol-2-yl)amine; 
     (4-chloro-6-trifluoromethyl-1H-benzimidazol-2-yl) [4-(2,6-dimethyl-pyrimidin-4-yloxy)phenyl]amine; 
     [4-(2-amino-6-methylpyrimidin-4-yloxy)phenyl] (4-chloro-6-trifluoro-methyl-1H-benzimidazol-2-yl)amine; 
     (6-nitro-1H-benzimidazol-2-yl) [4-(pyridin-4-yloxy)phenyl]amine; 
     methyl 2-[4-(pyridin-4-yloxy)phenylamino]-3H-benzimidazole-5-carboxylate; 
     2-[4-(pyridin-4-yloxy)phenylamino]-3H-benzimidazole-5-carboxylic acid; 
     methyl 7-methanesulfonyl-2-[4-(pyridin-4-yloxy)phenylamino]-3H-benzimidazole-5-carboxylate; 
     (4-fluoro-6-trifluoromethyl-1H-benzimidazol-2-yl)[4-(pyridin-4-yloxy)phenyl]amine; 
     [4-(2,6-dimethylpyrimidin-4-yloxy)phenyl](4-fluoro-6-trifluoromethyl-1H-benzimidazol-2-yl)amine; 
     [4-(2-amino-6-methylpyrimidin-4-yloxy)phenyl](4-fluoro-6-trifluoro-methyl-1H-benzimidazol-2-yl)amine; 
     N-methyl-4-{4-[6-(1-thiophen-2-ylmethanoyl)-1H-benzimidazol-2-yl-amino]phenoxy}pyridine-2-carboxamide; and 
     N 2 -[4-(pyridin-4-yloxy)phenyl]-3H-benzimidazole-2,5-diamine;
 and pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. 
 
   
   
       10 . A process for the preparation of compounds of the formula I and pharmaceutically usable derivatives, solvates and stereoisomers thereof, comprising reacting 
     a compound of the formula II 
     
       
         
         
             
             
         
       
     
     wherein R 1  and m have the meanings indicated in  claim 1 , is reacted with a compound of the formula III 
     
       
         
         
             
             
         
       
     
     in which R 1′ , L, E, G, M, Q, U, R 2  and q have the meanings indicated in  claim 1 , 
     and optionally converting the compound of formula I into a salt. 
   
   
       11 . A pharmaceutical composition comprising at least one compound according to  claim 1  pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants. 
   
   
       12 . A method of treatment of diseases comprising inhibiting, regulating or modulating kinase signal transduction comprising administering to a patient in need thereof, a pharmaceutical composition according to  claim 11 . 
   
   
       13 . The method according to  claim 12 , wherein said kinases are selected from the group consisting of tyrosine kinases and Raf kinases. 
   
   
       14 . The method according to  claim 13 , where wherein said tyrosine kinases are TIE-2. 
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . The method according to  claim 12  wherein said disease comprises a solid tumour. 
   
   
       18 . The method according to  claim 17  wherein said solid tumour originates from the group consisting brain tumour, tumour of the urogenital tract, tumour of the lymphatic system, stomach tumour, laryngeal tumour and lung tumour. 
   
   
       19 . The method according to  claim 17 , wherein said solid tumour originates from the group consisting of monocytic leukaemia, lung adenocarcinoma, small cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma. 
   
   
       20 . The method according to  claim 12  wherein angiogenesis is implicated in said disease. 
   
   
       21 . The method according to  claim 20 , wherein said disease is an ocular disease. 
   
   
       22 . The method according to  claim 12  wherein said disease is selected from the group consisting of retinal vascularisation, diabetic retinopathy, age-induced macular degeneration and/or inflammatory diseases. 
   
   
       23 . The method according to  claim 22 , wherein said inflammatory disease originates from the group consisting of rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reaction. 
   
   
       24 . The method according to  claim 12  wherein said disease involves bone pathologies, where the bone pathology originates from the group consisting of osteosarcoma, osteoarthritis and rickets. 
   
   
       25 . The pharmaceutical composition according to  claim 11  comprising at least one additional active ingredient. 
   
   
       26 . A kit comprising separate packs of
 (a) an effective amount of a compound according to  claim 1  and/or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios,   and   (b) an effective amount of an additional active ingredient.   
   
   
       27 . The method according to  claim 12  wherein said pharmaceutical composition is administered in combination with a compound from the group consisting of 1) oestrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor. 
   
   
       28 . The method according to  claim 12  wherein said pharmaceutical composition is administered in combination with radiotherapy and a compound from the group consisting of 1) oestrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl-protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor. 
   
   
       29 . The method according to  claim 12  wherein said pharmaceutical composition is administered in combination with a growth-factor receptor inhibitor. 
   
   
       30 . The method according to  claim 12  wherein said diseases are caused, medicated and/or propagated by Raf kinases. 
   
   
       31 . The method according to  claim 30 , wherein said Raf kinase is selected from the group consisting of A-Raf, B-Raf and Raf-1. 
   
   
       32 . The method according to  claim 12  wherein said diseases are selected from the group consisting of hyperproliferative and non-hyperproliferative diseases. 
   
   
       33 . The method according to  claim 12  wherein said disease is cancerous. 
   
   
       34 . The method according to  claim 12  wherein said disease is non-cancerous. 
   
   
       35 . The method according to  claim 34  wherein said non-cancerous diseases are selected from the group consisting of psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases. 
   
   
       36 . The method according to  claim 33  wherein said cancerous diseases are selected from the group consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer, colorectal cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, gynaecological cancer, thyroid cancer, lymphoma, chronic leukaemia and acute leukaemia.