Substituted piperidines

Abstract

The invention relates to novel substituted piperidines, to processes for preparation thereof, to the use thereof for treatment and/or prophylaxis of diseases and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially of cardiovascular disorders and tumour disorders.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         in which 
         A is an oxygen atom or —NR 4 —,
 where 
 R 4  is hydrogen or C 1 -C 3 -alkyl, 
 or 
 R 2  and R 4  together with the nitrogen atom to which they are bonded form a 4- to 6-membered heterocycle,
 in which the heterocycle may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkylamino, 
 
 
         R 1  is phenyl,
 where phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, monofluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -alkoxycarbonyl, 
 
         R 2  is C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, hydroxyl, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino and phenyl,
 in which phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen and trifluoromethyl, 
 
 
         and
 where C 1 -C 6 -alkyl may be substituted by one substituent selected from the group consisting of hydroxyl, trifluoromethyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylsulphonyl, C 3 -C 6 -cycloalkyl and phenyl,
 in which cycloalkyl and phenyl may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy, 
 
 
         R 3  is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, 5- or 6-membered heteroaryl, C 3 -C 7 -cycloalkyloxy, C 3 -C 7 -cycloalkylamino, 4- to 7-membered heterocyclylamino, phenylamino or 5- or 6-membered heteroarylamino,
 where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by one substituent selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 3 -C 7 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, 
 and 
 where cycloalkyl, heterocyclyl, phenyl, heteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylamino, phenylamino and heteroarylamino may be substituted by 1 to 3 substituents selected independently from the group consisting of halogen, cyano, oxo, hydroxyl, amino, mono fluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylaminocarbonyl and cyclopropyl, 
 in which alkyl may be substituted by one hydroxyl substituent, 
 
         or one of its salts, its solvates or the solvates of its salts. 
       
     
     
         2 . A compound according to  claim 1 , wherein
 A is an oxygen atom,   R 1  is phenyl,
 where phenyl is substituted by 1 to 2 substituents selected independently from the group consisting of fluorine, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethoxy and ethyl, 
   R 2  is methyl, ethyl or isopropyl,
 where ethyl may be substituted by one substituent selected from the group consisting of hydroxyl, methoxy and ethoxy, 
   R 3  is 1-oxidothiomorpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 3-hydroxyazetidin-1-yl, 3-hydroxypyrrolidin-1-yl or 4-hydroxypiperidin-1-yl,   or one of its salts, its solvates or the solvates of its salts.   
     
     
         3 . A compound according to  claim 1 , wherein
 A is an oxygen atom,   R 1  is phenyl,
 where phenyl is substituted by one substituent in the para position to the site of attachment to the piperidine ring, selected from the group consisting of trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl and trifluoromethoxy, 
   R 2  is ethyl,   where ethyl may be substituted by one methoxy substituent,   R 3  is 1-oxidothiomorpholin-4-yl or 1,1-dioxidothiomorpholin-4-yl,   or one of its salts, its solvates or the solvates of its salts.   
     
     
         4 . A compound according to  claim 1 , wherein the —R 1  and 1,2,4-oxadiazol-5-yl substituents are in cis-positions to one another. 
     
     
         5 . A process for preparing a compound of the formula (I) or one of its salts, its solvates or the solvates of its salts according to  claim 1 , wherein either
 a compound of the formula   
       
         
           
           
               
               
           
         
         in which 
         R 1  and R 3  are each as defined in  claim 1   
         is reacted with a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A and R 2  are each as defined in  claim 1   
         or 
         a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         R 1  and R 3  are each as defined in  claim 1 , 
         is reacted with a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A and R 2  are each as defined in  claim 1   
         or 
         a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A, R 1  and R 2  are each as defined in  claim 1   
         is reacted with 0.8 to 1.1 equivalents of meta-chloroperbenzoic acid to give a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A, R 1  and R 2  are each as defined in  claim 1   
         or 
         a compound of the formula (Ia) is reacted with 2.0 to 3.0 equivalents of meta-chloroperbenzoic acid to give a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A, R 1  and R 2  are each as defined in  claim 1   
         or 
         a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         A, R 1  and R 2  are each as defined in  claim 1   
         is reacted with a compound of the formula 
       
       
         
           
           
               
               
           
         
         in which 
         R 3  is as defined in  claim 1  and 
         X 1  is halogen, preferably bromine or chlorine, or hydroxyl or 4-nitrophenoxy, 
         or 
         a compound of the formula (XV) is reacted in the first stage with 4-nitrophenyl chloroformate and in the second stage with a compound of the formula
   R 3 —H  (XVI)
 
 
         in which 
         R 3  defined in  claim 1 . 
       
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 1  in combination with an inert, non-toxic, pharmaceutically acceptable excipient. 
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  in combination with a further active ingredient. 
     
     
         12 . (canceled) 
     
     
         13 . A method for the treatment and/or prophylaxis of a thromboembolic disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a compound according to  claim 1 . 
     
     
         14 . A method for the prevention of blood coagulation in vitro, comprising adding to blood ex vivo an anticoagulatory amount of a compound according to  claim 1 . 
     
     
         15 . A method for the treatment and/or prophylaxis of a cardiovascular disorder comprising administering to a human or animal in need thereof an effective amount of a compound according to  claim 1 . 
     
     
         16 . A method for the treatment and/or prophylaxis of a tumour disorder comprising administering to a human or animal in need thereof an effective amount of a compound according to  claim 1 . 
     
     
         17 . A method for the treatment and/or prophylaxis of a thromboembolic disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a pharmaceutical composition according to  claim 10 . 
     
     
         18 . A method for the treatment and/or prophylaxis of a cardiovascular disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a pharmaceutical composition according to  claim 10 . 
     
     
         19 . A method for the treatment and/or prophylaxis of a tumour disorder comprising administering to a human or animal in need thereof an anticoagulatory amount of a pharmaceutical composition according to  claim 10 .