Quinazoline derivatives and pharmaceutical compositions containing them

Abstract

A compound of general formula I wherein: Ra is a benzyl, 1-phenylethyl, or 3-chloro-4-fluorophenyl group; Rb 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 Rc 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.

We claim: 
     
       1. A compound of 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, 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 stereoisomer or physiologically acceptable salt thereof. 
 
     
     
       2. The compound of  claim 1 , wherein Rb is a dimethylamino or a stereoisomer or physiologically acceptable salt thereof. 
     
     
       3. The compound of formula I according to  claim 1 , wherein:
 R a  is a 1-phenylethyl or 3-chloro-4-fluorophenyl group;   R b  is a dimethylamino, N-methyl-N-ethylamino, 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, tetradrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy, or tetrahydropyran-4-ylmethoxy group,   or a stereoisomer or physiologically acceptable salt thereof.   
     
     
       4. The compounds of  claim 3 , wherein
 R b  is a dimethylamino,   or a stereoisomer or physiologically acceptable salt thereof.   
     
     
       5. The compounds of  claim 3 , wherein
 R a  is a 3-chloro-4-fluorohenyl group and   R b  is a dimethylamino group,   or a stereoisomer or physiologically acceptable salt thereof.   
     
     
       6. The compound of formula I according to  claim 1 , wherein:
 R a  is a 3-chloro-4-fluorophenyl group;   R b  is a dimethylaminno 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 steroisomer or physiologically acceptable salt thereof.   
     
     
       7. The compound of claim 1, wherein:
 R c  is a tetrahydrofuran-3-yloxy,   or a steroisomer or physiologically acceptable salt thereof.   
     
     
       8. 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. 
     
     
       9. A physiologically acceptable salt comprising the combination of the compound according to claim 8 with an organic or inorganic acid. 
     
     
       10. The salt according to claim 9 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. 
     
     
       11. The salt according to claim 10, wherein the acid is maleic acid. 
     
     
       12. 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.