Bicyclic heterocycles, 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 , X and n 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 inhibiting effect on the signal transduction mediated by tyrosine kinases, their use in treating diseases, particularly tumoral diseases, as well as benign prostatic hyperplasia (BPH), diseases of the lungs and respiratory tract and the preparation thereof.

1 . A compound of general formula 
       
         
           
           
               
               
           
         
       
       wherein
 R a  denotes a hydrogen atom or a C 1-3 -alkyl group, 
 R b  denotes a phenyl or 1-phenylethyl group, wherein the phenyl nucleus is substituted in each case 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, 
 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 pyridyloxy or pyridinylmethoxy group, while the pyridinyl moiety of the above-mentioned groups is optionally substituted by a methyl or trifluoromethyl group, 
 a methyl or methoxy group substituted by 1 to 3 fluorine atoms or 
 a cyano, nitro or amino group, and 
 R 3  denotes a hydrogen, fluorine, chlorine or bromine atom or 
 a methyl or trifluoromethyl group, 
 
 R c  denotes a (2-hydroxyethyl)amino group wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups, 
 an N-(2-hydroxyethyl)-N-(C 1-3 -alkyl)-amino group wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups, or 
 a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups, R d  denotes a hydrogen atom, 
 a hydroxy group, 
 a C 1-3 -alkyloxy group, 
 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, 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, 2-oxa-5-aza-bicyclo-[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo-[3.2.1]oct-3-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, while the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl- and morpholinyl groups may each be substituted by one or two C 1-3 -alkyl groups, 
 
 a C 3-7 -cycloalkyloxy or C 3-7 -cycloalkyl-C 1-3 -alkyloxy group, 
 a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group, or 
 a tetrahydrofuranyl-C 1-3 -alkyloxy or tetrahydropyranyl-C 1-3 -alkyloxy group, 
 X denotes a methyne group substituted by a cyano group or a nitrogen atom and 
 n denotes the number 2, 3 or 4, 
 while, unless otherwise stated, the above-mentioned alkyl groups may be straight-chain or branched, 
 the tautomers, the stereoisomers, the mixtures thereof and the salts thereof. 
 
     
     
         2 . A compound according to  claim 1 , wherein
 R a  denotes a hydrogen atom,   R b  denotes a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or a 3-ethynylphenyl group,   R c  denotes a (2-hydroxypropyl)amino or N-(2-hydroxypropyl)-N-(C 1-3 -alkyl)-amino group,   an N-(2-hydroxybutyl)amino or N-(2-hydroxybutyl)-N-(C 1-3 -alkyl)-amino group,   a (2-hydroxy-2-methyl-propyl)amino or N-(2-hydroxy-2-methyl-propyl)-N-(C 1-3 -alkyl)-amino group,   an N-(2-hydroxy-2-ethyl-butyl)amino or N-(2-hydroxy-2-ethyl-butyl)-N-(C 1-3 -alkyl)-amino group, or   a 2-oxo-5-methyl-oxazolidin-3-yl, 2-oxo-5-ethyl-oxazolidin-3-yl, 2-oxo-5,5-dimethyl-oxazolidin-3-yl or 2-oxo-5,5-diethyl-oxazolidin-3-yl group,   R d  denotes a hydrogen atom,   a methoxy, ethyloxy or 2-methoxyethyloxy group,   a cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group,   a cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy group,   a tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group, or   a tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,   X denotes a nitrogen atom, and   n denotes the number 2 or 3,   the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.   
     
     
         3 . A compound according to  claim 1 , wherein
 R a  denotes a hydrogen atom,   R b  denotes a 3-chloro-4-fluoro-phenyl group or 3-ethynylphenyl group,   R c  denotes a (2-hydroxypropyl)amino group,   an N-(2-hydroxypropyl)-N-methyl-amino or N-(2-hydroxypropyl)-N-ethyl-amino group,   a (2-hydroxy-2-methyl-propyl)amino group,   an N-(2-hydroxy-2-methyl-propyl)-N-methyl-amino or N-(2-hydroxy-2-methyl-propyl)-N-ethyl-amino group, or   a 2-oxo-5-methyl-oxazolidin-3-yl or 2-oxo-5,5-dimethyl-oxazolidin-3-yl group,   R d  denotes a methoxy, ethyloxy or 2-methoxyethyloxy group,   X denotes a nitrogen atom, and   n denotes the number 2,   the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.   
     
     
         4 . A compound according to  claim 1  selected from the group consisting of:
 a) (S)-4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2-oxo-5-methyl-oxazolidin-3-yl) ethyloxy]-7-methoxy-quinazoline   (b) (S)-4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[(2-hydroxypropyl) amino]ethyloxy }-7-methoxy-quinazoline   (c) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-[(2-hydroxy-2-methyl-propyl) amino]ethyloxy]-7-methoxy-quinazoline   (d) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2-oxo-5,5-dimethyl-oxazolidin-3-yl) ethyloxy]-7-methoxy-quinazoline,   and the salts thereof.   
     
     
         5 . Physiologically acceptable salts of the compounds according to  claim 1  with inorganic to or organic acids. 
     
     
         6 . Pharmaceutical compositions containing a compound according to  claim 1  or a physiologically acceptable salt thereof optionally together with one or more inert carriers and/or diluents. 
     
     
         7 . A method of treating a disease selected from the list consisting of benign or malignant tumours, diseases of the airways and lungs and diseases of the gastro-intestinal tract, bile duct and gall bladder which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         8 . The method of  claim 7  wherein the disease is a disease of the airways and lungs. 
     
     
         9 . A method of preventing diseases of the airways and lungs which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         10 . A process for preparing a compound of general formula I according to  claim 1  comprising the step of reacting a compound of general formula II 
       
         
           
           
               
               
           
         
       
       wherein
 R a , R b , R d  and X are defined as in  claim 1 , 
 with a compound of general formula III
   Z 1 -(CH 2 ) n -R c   (III), 
 
 
       wherein
 R c  and n are defined as in  claim 1  and Z 1  denotes a leaving group or hydroxy group, and optionally converting a compound of general formula I thus obtained wherein R c  denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups by hydrolysis into a compound of general formula I wherein R e  denotes a (2-hydroxy-ethyl) amino group optionally substituted at the carbon skeleton of the (2-hydroxyethyl)-moiety, 
 optionally converting a compound of general formula I wherein R c  denotes a (2-hydroxyethyl) amino group, wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups, into a compound wherein R c  denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups, 
 optionally converting a compound of general formula I thus obtained which contains an amino, alkylamino or imino group by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I, 
 optionally cleaving any protective group used during the reactions described above, 
 optionally resolving a compound of general formula I thus obtained into its stereoisomers and 
 optionally converting a compound of general formula I thus obtained into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof. 
 
     
     
         11 . A process for preparing a compound of general formula I according to  claim 1  wherein X denotes a nitrogen atom comprising the steps of:
 a) reacting a compound of general formula IV   
       
         
           
           
               
               
           
         
       
       wherein R c , R d  and n are defined as in  claim 1 , with a halogenating agent to form an intermediate compound of general formula (V), 
       
         
           
           
               
               
           
         
       
       wherein R c , R d  and n are defined as in  claim 1  and Z 2  denotes a halogen atom such as a chlorine or bromine atom, and
 b) reacting the product (V) with a compound of general formula
   R a -NH-R b   (VI), 
 
 
       wherein R a  and R b  are defined as in  claim 1 , and
 optionally converting a compound of general formula I thus obtained wherein R c  denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups by hydrolysis into a compound of general formula I wherein R e  denotes a (2-hydroxy-ethyl) amino group optionally substituted at the carbon skeleton of the (2-hydroxyethyl)-moiety, 
 optionally converting a compound of general formula I wherein R c  denotes a (2-hydroxy-ethyl) amino group, wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is 
 optionally substituted by one or two C 1-3 -alkyl groups, into a compound wherein R c  denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups, 
 optionally converting a compound of general formula I thus obtained which contains an amino, alkylamino or imino group by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I, 
 optionally cleaving any protective group used during the reactions described above, 
 optionally resolving a compound of general formula I thus obtained into its stereoisomers and 
 optionally converting a compound of general formula I thus obtained into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof. 
 
     
     
         12 . A process for making a compound of general formula I according to  claim 1  comprising the steps of reacting a compound of general formula VII 
       
         
           
           
               
               
           
         
         wherein R a , R b , R d , X and n are defined as in  claim 1  and Z 3  denotes a leaving group, 
         with a compound of general formula VIII
   H-R c   (VIII), 
 
       
       wherein R c  is defined as in  claim 1  and
 optionally converting a compound of general formula I thus obtained wherein R c  denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups by hydrolysis into a compound of general formula I wherein R c  denotes a (2-hydroxy-ethyl) amino group optionally substituted at the carbon skeleton of the (2-hydroxyethyl)-moiety, 
 optionally converting a compound of general formula I wherein R e  denotes a (2-hydroxyethyl)amino group, wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups, into a compound wherein R c  denotes a 2-oxo-oxazolidin-3-yl group optionally substituted by one or two C 1-3 -alkyl groups, 
 optionally converting a compound of general formula I thus obtained which contains an amino, alkylamino or imino group by alkylation or reductive alkylation into a corresponding alkyl compound of general formula I, 
 optionally cleaving any protective group used during the reactions described above, 
 optionally resolving a compound of general formula I thus obtained into its stereoisomers and 
 optionally converting a compound of general formula I thus obtained into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof. 
 
     
     
         13 . A process for preparing quinazoline derivatives of general formula IX 
       
         
           
           
               
               
           
         
       
       wherein R a , R b , R d  and n are defined as in  claim 1  and R e  and R f  independently of one another denote hydrogen atoms or C 1-3 -alkyl groups,
 said process comprising the steps reacting a compound of general formula I wherein R a , R b , R d  and n are defined as in  claim 1  , X denotes a nitrogen atom and R e  denotes a (2-hydroxyethyl)amino group wherein the carbon skeleton of the (2-hydroxyethyl)-moiety is optionally substituted by one or two C 1-3 -alkyl groups, with a reactive acetic acid derivative.