Isotopically substituted proton pump inhibitors

Abstract

The invention relates to compounds of formula 1 and formula 10 and to compositions comprising these compounds and methods of treating gastrointestinal disorders by administering these compounds.

1 . A compound of the formula 1 
     
       
         
         
             
             
         
       
     
     in which
 R1 is difluoromethoxy, 
 R2 is methoxy, 
 R3 is methoxy 
 or a salt, solvate, hydrate, solvate of a salt, hydrate of a salt or enantiomer thereof, 
 
     wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom. 
   
   
       2 . A compound of formula 1 according to  claim 1 , wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom. 
   
   
       3 . A compound of formula 1 according to  claim 1 , wherein R1 is deuteriodifluoromethoxy. 
   
   
       4 . A compound of formula 1 according to  claim 1 , wherein at least one or both of R2 and R3 is trideuteriomethoxy. 
   
   
       5 . A compound of formula 1 according to  claim 1 , wherein at least one or both of R2 and R3 is dideuteriomethoxy. 
   
   
       6 . A compound of formula 1 according to  claim 1 , wherein R1 is difluoromethoxy, R2 is methoxy and R3 is dideuteriomethoxy or trideuteriomethoxy. 
   
   
       7 . A compound of formula 1 according to  claim 1 , wherein R1 is difluoromethoxy and wherein R2 and R3 are trideuteriomethoxy. 
   
   
       8 . A compound of formula 1 according to  claim 1 , wherein the salt is the magnesium salt or the sodium salt. 
   
   
       9 . A compound of formula 1 according to  claim 8 , wherein the sodium salt is the sodium monohydrate salt or sodium sesquihydrate salt. 
   
   
       10 . A compound of formula 1 according to  claim 8 , wherein the magnesium salt is the magnesium dihydrate salt or the magnesium trihydrate salt. 
   
   
       11 . A compound of formula 1 according to  claim 1 , selected from the group consisting of 5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[3-monodeuteriomethoxy-4-methoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-dideuteriomethoxy-4-methoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(monodeuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(dideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-trideuteriomethoxy-4-methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, and the salts, solvates, hydrates, solvates of the salts, hydrates of the salts and enantiomers thereof. 
   
   
       12 . A compound of formula 1 according to  claim 1 , wherein the compound is (R/S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof. 
   
   
       13 . A compound of formula 1 according to  claim 12 , wherein the compound is S(−)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl-1H-benzimidazole or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof. 
   
   
       14 . A compound of formula 2 
     
       
         
         
             
             
         
       
     
     in which
 R1 is difluoromethoxy, 
 R2 and R3 are methoxy 
 or a salt, solvate, enantiomer or solvate of a salt thereof, 
 
     wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom. 
   
   
       15 . A process for preparing a compound of formula 1 as claimed in  claim 1  comprising the step of oxidizing a compound of formula 2 
     
       
         
         
             
             
         
       
     
     in which
 R1 is difluoromethoxy, 
 R2 and R3 are methoxy 
 or a salt, solvate, enantiomer or solvate of a salt thereof, 
 
     wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom. 
   
   
       16 . A process for preparing a compound of formula 2 as claimed in  claim 14  comprising the steps of:
 quaternizing a compound of formula 3   
     
       
         
         
             
             
         
       
     
     in which
 X is a halogen, 
 R2 and R3 are methoxy 
 
     wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom; and
 subsequently reacting the obtained quaternized compound of formula 3 with a compound of formula 4 
 
     
       
         
         
             
             
         
       
     
     in which
 R1 is difluoromethoxy or deuteriodifluoromethoxy. 
 
   
   
       17 . A compound of formula 3 
     
       
         
         
             
             
         
       
     
     in which
 X is a halogen, 
 R2 and R3 are methoxy 
 
     wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom. 
   
   
       18 .- 49 . (canceled)