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 .- 17 . (canceled) 
   
   
       18 . A compound of formula 10 
     
       
         
         
             
             
         
       
     
     in which
 R10 is hydrogen, difluoromethoxy or 1-4C-alkoxy, 
 R20 is 1-4C-alkyl or 1-4C-alkoxy, 
 R30 is 1-4C-alkyl, 1-4C-alkoxy, 2,2,2-trifluoroethoxy or 2-8C-alkoxyalkoxy, 
 R40 is hydrogen or 1-4C-alkyl, 
 Z is C—H, 
 or a salt, hydrate, hydrate of a salt or enantiomer thereof, wherein at least one hydrogen atom of R10, R20, R30, R40 or any combination of R10, R20, R30 and R40 is replaced by a deuterium atom. 
 
   
   
       19 . A compound of formula 10 according to  claim 18 , wherein at least one of the hydrogen atoms of R30 is replaced by a deuterium atom and R30 is a 1-2C alkoxy group or a 2-5C-alkoxyalkoxy group. 
   
   
       20 . A compound of formula 10 according to  claim 18 , wherein R20 is a 1-4C alkyl group and R30 is a 2-8C-alkoxyalkoxy group, and wherein at least one of the hydrogen atoms of R20, R30 or R20 and R30 is replaced by a deuterium atom. 
   
   
       21 . A compound of formula 10 according to  claim 18 , wherein R10 is a 1-4C alkoxy group, R20 and R40 are a 1-4C alkyl group and R30 is a 1-4C-alkoxy group, and wherein at least one of the hydrogen atoms of R10, R30, R40 or any combination of R10, R30 and R40 is replaced by a deuterium atom. 
   
   
       22 . A compound of formula 10 according to  claim 18 , wherein R10 is hydrogen, methoxy or difluoromethoxy, R20 is methyl or methoxy, R30 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R40 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R30 is replaced by a deuterium atom. 
   
   
       23 . A compound of formula 10 according to  claim 18 , wherein R20 is methyl, R30 is methoxypropoxy, wherein at least one of the hydrogen atoms of R20, R30 or R20 and R30 is replaced by a deuterium atom. 
   
   
       24 . A compound of formula 10 according to  claim 18 , wherein R10 is methoxy, R20 and R40 are methyl and R30 is methoxy, wherein at least one of the hydrogen atoms of R10, R30, R40 or any combination of R10, R30 and R40 is replaced by a deuterium atom. 
   
   
       25 . A compound of formula 10 according to  claim 18 , wherein R10 is methoxy, R20 is methyl, R30 is methoxy, R40 is methyl or wherein R10 is hydrogen, R20 is methyl, R30 is 2,2,2-trifluoroethoxy or methoxypropoxy, R40 is hydrogen or wherein R10 is difluoromethoxy, R20 is methoxy, R30 is methoxy, R40 is hydrogen and wherein at least one of the hydrogen atoms of R30 is replaced by a deuterium atom. 
   
   
       26 . A compound of formula 10 according to  claim 18 , wherein R10 is methoxy, R20 is methyl, R30 is methoxy, R40 is methyl or wherein R10 is hydrogen, R20 is methyl, R30 is 2,2,2-trifluoroethoxy or methoxypropoxy, R40 is hydrogen, or wherein R10 is difluoromethoxy, R20 is methoxy, R30 is methoxy, R40 is hydrogen and wherein at least two of the hydrogen atoms of R30 are replaced by a deuterium atom. 
   
   
       27 . A compound of formula 10 according to  claim 18 , wherein R20 is a 1-4C alkyl group and R30 is a 2-8C-alkoxyalkoxy group, wherein all hydrogen atoms of R20, R30 or R20 and R30 are replaced by deuterium atoms. 
   
   
       28 . A compound of formula 10 according to  claim 18 , wherein R10 is a 1-4C alkoxy group, R20 and R40 are a 1-4C alkyl group and R30 is a 1-4C-alkoxy group, wherein all hydrogen atoms of R10, R30, R40 or any combination of R10, R30 and R40 are replaced by deuterium atoms. 
   
   
       29 . A compound of formula 10 according to  claim 18 , wherein all hydrogen atoms of R30 are replaced by deuterium atoms and wherein R30 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy. 
   
   
       30 . A compound of formula 10 according to  claim 18 , wherein R20 is methyl, R30 is methoxypropoxy, wherein all hydrogen, atoms of R20, R30 or R20 and R30 are replaced by deuterium atoms. 
   
   
       31 . A compound of formula 10 according to  claim 18 , wherein R10 is methoxy, R20 and R40 are methyl and R30 is methoxy, wherein all hydrogen atoms of R10, R30, R40 or any combination of R10, R30 and R40 are replaced by deuterium atoms. 
   
   
       32 . A compound of formula 10 according to  claim 18 , wherein R10 is hydrogen, methoxy or difluoromethoxy, R20 is methyl or methoxy, R30 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R40 is hydrogen or methyl and wherein all hydrogen atoms of R30 are replaced by deuterium atoms. 
   
   
       33 . A compound of formula 10 according to  claim 18 , wherein R30 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy and wherein all hydrogen atoms of R30 are replaced by deuterium atoms. 
   
   
       34 . A compound of formula 10 according to  claim 18 , wherein R10 is hydrogen, methoxy or difluoromethoxy, R20 is methyl or methoxy, R30 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R40 is hydrogen or methyl and wherein all hydrogen atoms of R30 are replaced by deuterium atoms. 
   
   
       35 . A compound of formula 10 according to  claim 18 , wherein R10 is methoxy, R20 is methyl, R30 is methoxy, R40 is methyl or wherein R10 is hydrogen, R20 is methyl, R30 is 2,2,2-trifluoroethoxy or methoxypropoxy, R40 is hydrogen, or wherein R10 is difluoromethoxy, R20 is methoxy, R30 is methoxy, R40 is hydrogen and wherein all hydrogen atoms of R30 are replaced by deuterium atoms. 
   
   
       36 . A compound of formula 10 according to  claim 18 , selected from the group consisting of 5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-methoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-methoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 2-[3-methyl-4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-trideuteriomethoxy-4-methoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3-dideuteriomethoxy-4-methoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(dideuteriomethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, 2-{[4-(3-trideuteriomethoxyhexadeuteriopropoxy)-3-methylpyridin-2-yl]methylsulphinyl}-1H-benzimidazole, 2-{[4-(3-trideuteriomethoxyhexadeuteriopropoxy)-3-trideuteriomethylpyridin-2-yl]methylsulphinyl}-1H-benzimidazole, and the salts, hydrates, hydrates of the salts and enantiomers thereof. 
   
   
       37 . The compound of formula 10 according to  claim 18 , selected from the group consisting of (R/S)-5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, (R/S)-2-[3-methyl-4-(1,1-dideuterio-2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, (R/S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole, (R/S)-2-{[4-(3-trideuteriomethoxyhexadeuteriopropoxy)-3-methylpyridin-2-yl]methylsulphinyl}-1H-benzimidazole and pharmaceutically acceptable salts thereof. 
   
   
       38 . A compound of formula 10 according to  claim 37 , wherein the compound is S(−)-5-Methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole or a pharmaceutically acceptable salt, solvate, or solvate of the salt thereof. 
   
   
       39 . A compound of formula 20 
     
       
         
         
             
             
         
       
     
     in which
 R10 is hydrogen, difluoromethoxy or 1-4C-alkoxy, 
 R20 is 1-4C-alkyl or 1-4C-alkoxy, 
 R30 is 1-4C-alkyl, 1-4C-alkoxy, 2,2,2-trifluoroethoxy or 2-8C-alkoxyalkoxy, 
 R40 is hydrogen or 1-4C-alkyl, 
 Z is C—H, 
 or a salt or enantiomer thereof, 
 wherein at least one of hydrogen atom of R10, R20, R30, R40 or any combination of R10, R20, R30 and R40 is replaced by a deuterium atom. 
 
   
   
       40 . (canceled) 
   
   
       41 . (canceled) 
   
   
       42 . (canceled) 
   
   
       43 . A compound selected from the group consisting of
 a. (R/S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   b. (S)(−)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   c. 5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   d. Sodium (S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}hydrate,   e. Sodium (R/S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}hydrate,   f. Magnesium (S)-bis-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}hydrate,   g. Magnesium (R/S)-bis-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}hydrate,   j. 5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   k. 5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   l. 5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   m. 5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   n. 5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylthio]-1H-benzimidazole   o. rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   p. rac-5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   q. rac-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteromethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole.   r. rac-5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   s. rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   t. rac-5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt mono hydrate,   u. rac-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt mono hydrate,   v. rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt mono hydrate,   w. rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt sesqui hydrate,   x. (S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   y. (R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   z. (R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt trihydrate,   aa. Bis-[(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole]magnesium salt trihydrate,   bb. rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt mono hydrate,   cc. Bis-[rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole]magnesium salt di hydrate,   dd. (S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt,   ee. (R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt,   ff. Bis-[(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole]magnesium salt tri hydrate,   ii. 5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1H-benzimidazole,   jj. 5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   kk. 5-Methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole,   ll. rac-5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   mm. rac-5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   nn. rac-5-Methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,   oo. (S)-5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt, and   pp. Bis-[(S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole]magnesium salt.   
   
   
       44 .- 45 . (canceled) 
   
   
       46 . A pharmaceutical composition comprising a compound of formula 10 according to  claim 18  or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or enantiomer thereof, together with one or more pharmaceutically acceptable excipients. 
   
   
       47 . The pharmaceutical composition according to  claim 46 , wherein a single dose comprises from about 2 to about 60 mg of the compound of general formula 10. 
   
   
       48 . (canceled) 
   
   
       49 . A method of treating a gastrointestinal disorder in a patient comprising administering to a patient in need thereof a compound of formula 10 according to  claim 18 , or a pharmaceutically acceptable salt, hydrate, hydrate of a salt or enantiomer thereof.