Bicyclic heterocylces, pharmaceutical compositions containing these compounds, their use and processes for preparing them

Abstract

The present invention relates to bicyclic heterocycles of general formula wherein R a , R b , R c , R d , R e and X are defined as in claim 1 , the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids, which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases and benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract, and the preparation thereof.

1 . A bicyclic heterocycle of formula  
       
         
           
           
               
               
           
         
         wherein  
         R a  denotes a hydrogen atom or a C 1-4 -alkyl group,  
         R b  denotes a phenyl, benzyl or 1-phenylethyl group, wherein the phenyl nucleus in each case is substituted by the groups R 1  to R 3 , while 
 R 1  and R 2 , which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine or iodine atom,  
 a C 1-4 -alkyl, hydroxy, C 1-4 -alkoxy, C 2-3 -alkenyl or C 2-3 -alkynyl group,  
 an aryl, aryloxy, arylmethyl or arylmethoxy group,  
 a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group,  
 a methyl or methoxy group substituted by 1 to 3 fluorine atoms or  
 cyano, nitro or amino group, and  
 R 3  denotes a hydrogen, fluorine, chlorine or bromine atom,  
 a methyl or trifluoromethyl group,  
 
         R c  denotes a hydrogen atom or a fluorine, chlorine or bromine atom,  
         a hydroxy or C 1-4 -alkyloxy group,  
         a methoxy group substituted by 1 to 3 fluorine atoms,  
         an ethyloxy group substituted by 1 to 5 fluorine atoms,  
         a C 2-4 -alkyloxy group which is substituted by a group R 4 , while 
 R 4  denotes a hydroxy, C 1-3 -alkyloxy, C 3-6 -cycloalkyloxy, C 3-6 -cycloalkyl-C 1-3 -alkyloxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)amino, bis-(2-C 1-3 -alkyloxy-ethyl)-amino, bis-(3-C 1-3 -alkyloxy-propyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4-(C 1-3 -alkyl)-piperazin-1-yl, homopiperazin-1-yl or 4-(C 1-3 -alkyl)-homopiperazin-1-yl group,  
 
         a C 3-7 -cycloalkyloxy or C 3-7 -cycloalkyl-C 1-4 -alkyloxy group,  
         a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group,  
         a tetrahydrofuranyl-C 1-4 -alkyloxy or tetrahydropyranyl-C 1-4 -alkyloxy group,  
         a pyrrolidin-3-yloxy, piperidin-3-yloxy or piperidin-4-yloxy group,  
         a 1-(C 1-3 -alkyl)-pyrrolidin-3-yloxy, 1-(C 1-3 -alkyl)-piperidin-3-yloxy or 1-(C 1-3 -alkyl)piperidin-4-yloxy group,  
         a C 1-4 -alkoxy group which is substituted by a pyrrolidinyl, piperidinyl or homopiperidinyl group substituted in the 1 position by the group R 5 , where 
 R 5  denotes a hydrogen atom or a C 1-3 -alkyl group,  
 or a C 1-4 -alkoxy group which is substituted by a morpholinyl or homomorpholinyl group substituted in the 4 position by the group R 5 , where R 5  is as hereinbefore defined,  
 
         R e  and R d , which may be identical or different, in each case denote a hydrogen atom or a C 1-3 -alkyl group and  
         X denotes a methyne group substituted by a cyano group or a nitrogen atom,  
         while by the aryl groups mentioned in the definition of the above groups is meant in each case a phenyl group which is mono- or disubstituted by R 6 , while the substituents may be identical or different and 
 R 6  denotes a hydrogen atom, a fluorine, chlorine, bromine or iodine atom or a C 1-3 -alkyl, hydroxy, C 1-3 -alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group,  
 
         by the heteroaryl groups mentioned in the definition of the above groups is meant a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, while the above-mentioned heteroaryl groups are mono- or disubstituted in each case by the group R 6 , while the substituents may be identical or different and R 6  is as hereinbefore defined, and  
         unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched,  
         a tautomer or a stereoisomer thereof, or a mixture of such thereof, or a salt thereof.  
       
     
     
         2 . The bicyclic heterocycle of formula I according to  claim 1 , wherein 
 R a  denotes a hydrogen atom,    R b  denotes a phenyl group substituted by the groups R 1  to R 3 , while 
 R 1  denotes a hydrogen, fluorine, chlorine or bromine atom,  
 a methyl, trifluoromethyl or ethynyl group,  
 a phenyloxy or phenylmethoxy group, while the phenyl moiety of the above-mentioned groups is optionally substituted by a fluorine or chlorine atom, or  
 a pyridinyloxy or pyridinylmethoxy group, while the pyridinyl moiety of the above-mentioned groups is optionally substituted by a methyl or trifluoromethyl group,  
 R 2  denotes a hydrogen, fluorine or chlorine atom and  
 R 3  denotes a hydrogen atom,  
   R c  denotes a hydrogen atom,    a C 1-3 -alkyloxy group,    a C 4-6 -cycloalkyloxy or C 3-6 -cycloalkyl-C 1-2 -alkyloxy group,    a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C 1-2 -alkyloxy or tetrahydropyranyl-C 1-2 -alkyloxy group,    an ethyloxy group which is substituted in the 2 position by a group R 4 , where 
 R 4  denotes a hydroxy, C 1-3 -alkyloxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)amino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, piperazin-1-yl, 4-(C 1-3 -alkyl)-piperazin-1-yl, homopiperazin-1-yl or 4-(C 1-3 -alkyl)-homopiperazin-1-yl group,  
   a propyloxy group which is substituted by a group R 4  in the 3 position, while R 4  is as hereinbefore defined, or    a butyloxy group which is substituted by a group R 4  in the 4 position, while R 4  is as hereinbefore defined,    R e  and R d , which may be identical or different, in each case denote a hydrogen atom or a methyl group and    X denotes a nitrogen atom,    while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched,    a tautomer or a stereoisomer thereof, or a mixture of such thereof, or a salt thereof.    
     
     
         3 . The bicyclic heterocycle of formula I according to  claim 1 , wherein 
 R a  denotes a hydrogen atom,    R b  denotes a 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluoro-phenyl group,    R c  denotes a hydrogen atom,    a methoxy, ethyloxy, 2-(methoxy)ethyloxy, 3-(morpholin-4-yl)propyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclopentylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuran-2-yl methoxy, tetrahydrofuran-3-yl methoxy or tetrahydropyran-4-ylmethoxy group,    R e  and R d  in each case denote a hydrogen atom and    X denotes a nitrogen atom,    a tautomer or a stereoisomer thereof, a mixture of such thereof, or a salt thereof.    
     
     
         4 . The bicyclic heterocycle of formula I according to  claim 1 , wherein 
 R a  denotes a hydrogen atom,    R b  denotes a 3-chloro-4-fluoro-phenyl group,    R c  denotes a tetrahydrofuran-3-yloxy group,    R e  and R d  in each case denote a hydrogen atom and    X denotes a nitrogen atom,    a tautomer or a stereoisomer thereof, or a mixture of such thereof or a salt thereof.    
     
     
         5 . The following compound of formula I according to  claim 1:   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline    or a salt thereof.    
     
     
         6 . The physiologically acceptable salt of a compound according to  claim 1  with an inorganic or organic acid, or a mixture thereof, or a base.  
     
     
         7 . A pharmaceutical composition comprising a compound according to  claim 1  or a physiologically acceptable salt thereof and one or more inert carriers and/or diluents.  
     
     
         8 . A method for treating in a warm-blooded animal which comprises administering to said animal a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         9 . A method for preventing or treating diseases of the airways and lungs in a warm-blooded animal which comprises administering to said animal a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         10 . A method for treating diseases of the gastrointestinal tract or bile duct or gall bladder in a warm-blooded animal which comprises administering to said animal a therapeutically effective amount of a compound according to  claim 1.