Methods of treating diseases using quinazoline derivatives and pharmaceutical compositions containing them

Abstract

A compound of general formula I wherein: R a is a benzyl, 1-phenylethyl, or 3-chloro-4-fluorophenyl group; R b is a dimethylamino, N-methyl-N-ethylamino, diethylamino, N-methyl-N-isopropylamino, N-methyl-N-cyclopropylamino, N-methyl-N-(2-methoxyethyl)amino, N-ethyl-N-(2-methoxyethyl)amino, bis(2-methoxyethyl)amino, morpholino, N-methyl-N-(tetrahydrofuran-3-yl)amino, N-methyl-N-(tetrahydrofuran-2-ylmethyl)amino, N-methyl-N-(tetrahydrofuran-3-ylmethyl)amino, N-methyl-N-(tetrahydropyran-4-yl)amino, or N-methyl-N-(tetrahydropyran-4-ylmethyl)amino group; and R c is a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy, tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group, or a tautomer, stereoisomer, or salt thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in the treatment of diseases, especially tumoral diseases and diseases of the lungs and airways, and the preparation thereof.

1 . A method of treating benign or malignant tumors, diseases of the airways and lungs, and diseases of the gastrointestinal tract, bile duct, and gall bladder in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R a  is a 3-chloro-4-fluorophenyl group; 
 R b  is a dimethylamino group; and 
 R c  is a tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group, 
 or a stereoisomer or physiologically acceptable salt thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein:
 R c  is a tetrahydrofuran-3-yloxy,   or a steroisomer or physiologically acceptable salt thereof.   
     
     
         3 . The method according to  claim 1 , wherein the compound is:
 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-(tetrahydrofuran-3-yl)oxy)quinazoline or physiologically acceptable salt thereof.   
     
     
         4 . The method according to  claim 1 , wherein the compound is a physiologically acceptable salt comprising the combination of the compound 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-(tetrahydrofuran-3-yl)oxy)quinazoline with an organic or inorganic acid. 
     
     
         5 . The method according to  claim 4 , wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. 
     
     
         6 . The method according to  claim 5 , wherein the acid is maleic acid. 
     
     
         7 . The method according to  claim 1 , wherein the compound is:
 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-(tetrahydrofuran-3-yl)oxy)quinazoline or physiologically acceptable salt thereof.   
     
     
         8 . The method according to  claim 1 , wherein the benign or malignant tumors diseases is chosen from diseases involving tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis). 
     
     
         9 . The method according to  claim 5 , wherein the benign or malignant tumors diseases is chosen from diseases involving tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis). 
     
     
         10 . The method according to  claim 9 , wherein the benign or malignant tumors diseases is chosen from diseases involving tumours of epithelial and neuroepithelial origin. 
     
     
         11 . The method according to  claim 1 , wherein the diseases of the airways and lungs is chosen from chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-antitrypsin deficiency, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways. 
     
     
         12 . The method according to  claim 1 , wherein the diseases of the gastrointestinal tract, bile duct, and gall bladder is chosen from cholecystitis, Crohn's disease, ulcerative colitis, ulcers in the gastrointestinal tract, Ménétrier's disease, secreting adenomas and protein loss syndrome. 
     
     
         13 . The method according to  claim 1 , wherein the disease is psoriasis.