Use of 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-quinolonecarboxylic acid and -naphthyridonecarboxylic acid derivatives for the therapy of Helicobacter pylori infections and associated gastroduodenal disorders

Abstract

The invention relates to the use of quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in position 7 by a 1-aninomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl radical, and of their salts for the therapy of Helicobacter pylori infections and associated gastroduodenal disorders.

1 . Use of compounds of the formula (I)  
       T—Q (I),  in which    Q represents a radical of the formulae                          in which 
 R 1  represents alkyl having 1 to 4 carbon atoms which is optionally mono- to trisubstituted by halogen or hydroxyl, alkenyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms which is optionally substituted by 1 or 2 fluorine atoms, bicyclo[1.1.1 ]pent-1-yl, 1,1-dimethylpropargyl, 3-oxetanyl, methoxy, amino, methylamino, dimethylamino, phenyl which is optionally mono- or disubstituted by halogen, amino or hydroxyl, isoxazolyl, thiadiazolyl,  
 R 2  represents hydroxyl, alkoxy having 1 to 4 carbon atoms which is optionally substituted by hydroxyl, methoxy, amino, dimethylamino or ethoxycarbonyl, benzyloxy, allyloxy, propargyloxy or (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy, acetoxymethyloxy, pivaloyloxymethyloxy, 5-indanyloxy, phthalidinyloxy, 3-acetoxy-2-oxo-butyloxy, nitromethyl or dialkoxycarbonylmethyl having 1 to 2 carbon atoms in each alkyl moiety,  
 R 3  represents hydrogen, amino, hydroxyl, methyl or halogen,  
 R 9  represents hydrogen or optionally methoxy-, hydroxyl- or halogen-substituted alkyl having 1 to 3 carbon atoms,  
 R 11  represents hydrogen, CH 3  or CH 2 F,  
 A represents N or C—R 7  in which 
 R 7  represents hydrogen, halogen, CF 3 , OCH 3 , OCHF 2 , CH 3 , CN, CH═CH 2  or C—CH or else together with R 1  may form a bridge of the structure —*O—CH 2 —CH—CH 3 , —*S—CH 2 —CH 2 —, —*S—CH 2 —CH—CH 3 , —*CH 2 —CH 2 —CH—CH 3  or —*O—CH 2 —N—R 8  where the atom marked with is attached to the carbon atom of A and in which 
 R 8  represents hydrogen, methyl or formyl,  
 
 
 B represents N, C—H, C—F, C—Cl, C—NO 2 , C—NH 2 ,  
 D represents N or C—R 10  in which 
 R 10  represents hydrogen, halogen, CF 3 , OCH 3 , OCHF 2  or CH 3  or else together with R 9  may form a bridge of the structure —O—CH 2 —, —*NH—CH 2 —, —N(CH 3 )—CH 2 —, —*N(C 2 H 5 )—CH 2 —, —N(c—C 3 H 5 )—CH 2 — or —*S—CH 2 — where the atom marked with * is attached to the carbon atom of D,  
 
 Y represents hydrogen or together with R 2  may form a bridge of the structure —*S—NH— where the atom marked with * represents Y, and  
   T represents a radical of the formula                          in which    R 4  represents H, CH 3 , C 2 H 5 , optionally amino-substituted acyl having 1 to 5 carbon atoms, alkoxycarbonyl, aminocarbonyl, alkylthio-thiocarbonyl and dialkoxyphosphoryl having 1 to 4 carbon atoms in the alkyl moiety,    R 5  represents H, CH 3 , C 2 H 5  and    R 6  represents H, CH 3 ,    and their pharmaceutically useful hydrates and acid addition salts and the alkali metal, alkaline earth metal, silver and guanidinium salts of the parent carboxylic acids for the therapy of  Helicobacter pylori  infections and associated gastroduodenal disorders.    
     
     
         2 . Use of compounds of the formula (I) according to    claim 1    in which 
 Q represents a radical of the formula  
                     in which    R 1  represents alkyl having 1 to 4 carbon atoms which is optionally mono- to trisubstituted by fluorine, represents vinyl, optionally fluorine-substituted cyclopropyl, bicyclo[1.1.1]pent-1-yl, 1,1-dimethylpropargyl, 3-oxetanyl, methylamino, phenyl which is optionally mono- or disubstituted by fluorine, amino or hydroxyl, thiadiazolyl,    R 2  represents hydroxyl, optionally ethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms, benzyloxy, allyloxy, propargyloxy,    R 3  represents hydrogen, amino, hydroxyl, methyl or fluorine,    A represents N or C—R 7  in which 
 R 7  represents hydrogen, halogen, CF 3 , OCH 3 , OCHF 2 , CH 3 , CN, CH═CH 2  or C═CH or else together with R 1  may form a bridge of the structure —*O—CH 2 —CH—CH 3  or —*O—CH 2 —N—R 8  where the atom marked with is attached to the carbon atom of A and in which 
 R 8  is hydrogen or methyl,  
 
   B represents N, C—H, C—F, C—Cl, C—NH 2 ,    Y represents hydrogen or together with R 2  may form a bridge of the structure —*S—NH— where the atom marked with represents Y, and    
 T represents a radical of the formula  
                     in which    R 4  represents H, CH 3 , C 2 H 5 , optionally amino-substituted acyl having 1 to 5 carbon atoms, alkoxycarbonyl, aminocarbonyl, alkylthio-thiocarbonyl and dialkoxyphosphoryl having 1 to 4 carbon atoms in the alkyl moiety,    R 5  represents H, CH 3 , C 2 H 5  and    R 6  represents H,    and their pharmaceutically useful hydrates and acid addition salts and the alkali metal, alkaline earth metal, silver and guanidinium salts of the parent carboxylic acids for the therapy of Helicobacter pylori infections and associated gastroduodenal disorders.    
 
     
     
         3 . Use of compounds of the formula (I) according to    claim 1    in which 
 Q represents a radical of the formula  
                     
 in which  
 R 1  represents alkyl having 1 to 4 carbon atoms which is optionally mono- or disubstituted by fluorine, optionally fluorine-substituted cyclopropyl, phenyl which is optionally mono- or disubstituted by fluorine,  
 R 2  represents hydroxyl, optionally ethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms, benzyloxy, allyloxy, propargyloxy,  
 R 3  represents hydrogen, amino, hydroxyl, methyl or fluorine,  
 A represents N or C—R 7  in which 
 R 7  represents hydrogen, chlorine, fluorine, OCH 3 , OCHF 2 , CH 3  or CN or else together with R 1  may form a bridge of the structure —*O—CH 2 —CH—CH 3 , or —*O—CH 2 —N—CH 3  where the atom marked with * is attached to the carbon atom of A,  
 
 B represents N, C—H, C—F,  
 Y represents hydrogen or together with R 2  may form a bridge of the structure —*S—NH— where the atom marked with represents Y, and  
 T represents a radical of the formula  
                     in which    R 4  represents H, CH 3 , C 2 H 5 , optionally amino-substituted acyl having 1 to 4 carbon atoms or alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety,    R 5  represents H and    R 6  represents H,    and their pharmaceutically useful hydrates and acid addition salts and the alkali metal, alkaline earth metal, silver and guanidinium salts of the parent carboxylic acids for the therapy of Helicobacter pylori infections and associated gastroduodenal disorders.    
 
     
     
         4 . Use of diastereomerically pure and enantiomerically pure compounds according to    claims 1    to    3    for the therapy of Helicobacter pylori infections and associated gastroduodenal disorders.  
     
     
         5 . Use of (+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-carboxylic acid for the therapy of  Helicobacter pylori  infections and associated gastroduodenal disorders.  
     
     
         6 . Diastereomerically pure and enantiomerically pure compounds from the group consisting of 
 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid,    7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.    
     
     
         7 . (+)-7-[(1S,5R)-1-Aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid.  
     
     
         8 . Compounds from the group consisting of 
 (1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo[3.3.0]octane,    (1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane,    (1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane hydrochloride.    
     
     
         9 . Use of (+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-carboxylic acid for preparing medicaments.  
     
     
         10 . Medicaments comprising (+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylic acid.