Chromenone derivatives

Abstract

Novel compounds of the formula I in which R 1 , R 2 , R 3 and Het are as defined herein, which are inhibitors of tyrosine kinases and/or Raf kinases and can be employed for the treatment of tumours, for neuroprotection and for protection of the stress proteins of the skin.

1 - 56 . (canceled) 
     
     
         57 . A method of treating a disease in which the inhibition, regulation and/or modulation of kinase signal transduction plays a role, or a method of treating a disease and/or dysfunction related to an oxidative stress condition,
 comprising administering to a patient in need thereof an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound or said salt thereof and a pharmaceutically acceptable carrier   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —OH or —OA, 
 R 2  is H, —OH, —OA, phenoxy, —O—CO-A, —OSO 3 H, —OSO 3 A, —OSO 2 A or Hal, 
 R 3  is H, 
 R 1  and R 2  together are alternatively methylenedioxy or ethylenedioxy, 
 Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by Hal and/or A, and 
 A is unbranched or branched alkyl having 1-6 carbon atoms, where 1-5H atoms may be replaced by F. 
 
     
     
         58 . A method according to  claim 57 , wherein the kinase whose transduction is affected is a tyrosine kinase or Raf kinase. 
     
     
         59 . A method according to  claim 57 , wherein a tyrosine kinase is inhibited. 
     
     
         60 . A method according to  claim 59 , wherein the disease treated is a solid tumour. 
     
     
         61 . A method according to  claim 60 , wherein the solid tumour is brain tumour, tumour of the urogenital tract, tumour of the lymphatic system, stomach tumour, laryngeal tumour or lung tumour. 
     
     
         62 . A method according to  claim 60 , wherein the solid tumour is monocytic leukaemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma or breast carcinoma. 
     
     
         63 . A method according to  claim 60 , wherein the disease treated is affected by angiogenesis. 
     
     
         64 . A method according to  claim 63 , wherein the disease treated is an ocular disease. 
     
     
         65 . A method according to  claim 59 , wherein the disease treated is retinal vascularisation, diabetic retinopathy, age-related macular degeneration or an inflammatory disease. 
     
     
         66 . A method according to  claim 65 , wherein the inflammatory disease is rheumatoid arthritis, psoriasis, contact dermatitis or delayed hypersensitivity reaction. 
     
     
         67 . A method according to  claim 59 , wherein the disease treated is osteoarthritis or rickets. 
     
     
         68 . A method according to  claim 59 , further comprising administering 1) an oestrogen receptor modulator, 2) an androgen receptor modulator, 3) a retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor or 10) an angiogenesis inhibitor. 
     
     
         69 . A method according to  claim 59 , further comprising administering radiotherapy. 
     
     
         70 . A method according to  claim 57 , wherein the disease is treated, mediated and/or propagated by Raf kinase. 
     
     
         71 . A method according to  claim 70 , wherein the Raf kinase is A-Raf, B-Raf or Raf-1. 
     
     
         72 . A method according to  claim 70 , wherein the disease treated is a hyperproliferative disease. 
     
     
         73 . A method according to  claim 70 , wherein the disease treated is cancerous. 
     
     
         74 . A method according to  claim 70 , wherein the disease treated is non-cancerous. 
     
     
         75 . A method according to  claim 70 , wherein the non-cancerous disease is psoriasis, arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, an immunological disease, an autoimmune disease or an immunodeficiency disease. 
     
     
         76 . A method according to  claim 70 , wherein the disease is 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, gynecological cancer, thyroid cancer, lymphoma, chronic leukaemia or acute leukaemia. 
     
     
         77 . A method according to  claim 57 , which is for treating a disease and/or dysfunction related to an oxidative stress condition. 
     
     
         78 . A method according to  claim 77 , wherein the disease and/or dysfunction is memory loss or a neurodegenerative disease. 
     
     
         79 . A method of protecting the stress proteins of the skin, comprising administering to a patient in need thereof a compound according to formula I or a pharmaceutically or cosmetically acceptable salt thereof or a pharmaceutical or cosmetic composition comprising said compound or said salt thereof and a pharmaceutically or cosmetically acceptable carrier 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —OH or —OA, 
 R 2  is H, —OH, —OA, phenoxy, —O—CO-A, —OSO 3 H, —OSO 3 A, —OSO 2 A or Hal, 
 R 3  is H, 
 R 1  and R 2  together are alternatively methylenedioxy or ethylenedioxy, 
 Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by Hal and/or A, and 
 A is unbranched or branched alkyl having 1-6 carbon atoms, where 1-5H atoms may be replaced by F. 
 
     
     
         80 . A method according to  claim 79 , wherein a topical composition is applied to the skin. 
     
     
         81 . A method according to  claim 70 , wherein the disease treated is a non-hyperproliferative disease. 
     
     
         82 . A food supplement comprising a food carrier and a compound of formula I or a salt thereof 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —OH or —OA, 
 R 2  is H, —OH, —OA, phenoxy, —O—CO-A, —OSO 3 H, —OSO 3 A, —OSO 2 A or Hal, 
 R 3  is H, 
 R 1  and R 2  together are alternatively methylenedioxy or ethylenedioxy, 
 Het is chromen-2-onyl, benzothiazolyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, furyl, pyrrolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl or isoquinolyl, each of which is unsubstituted or mono- or disubstituted by Hal and/or A, and 
 A is unbranched or branched alkyl having 1-6 carbon atoms, where 1-5H atoms may be replaced by F.