Prodrugs of proton pump inhibitors

Abstract

Prodrugs of proton pump inhibitors of Formulas 1 through 4, where the symbols are as defined in the specification, and the R group includes at least one acidic group or its pharmaceutically acceptable salt, have improved aqueous solubility and bioavailability.

1 . A compound of Formula 1, Formula 2, Formula 3 or of Formula 4  
       
         
           
           
               
               
           
         
       
       or isomers of the compounds of Formulas 2 and 3 where the OCH 3 , and HF 2 CO groups, respectively are linked to the 6 position of the benzimidazole ring, and 
 wherein R represents the groups selected from Formulas (ii) and (iv);  
 the dashed line represents the bond connecting the R group with the SO 2  group;  
                     
 R 1  and R 2  independently are H, a straight chained or branch-chained di- or trisubstituted alkyl group of 1 to 12 carbons including 1 or two R 5  groups, or a straight chained or branch-chained saturated hydrocarbon skeleton having no more than 12 carbons including 1 or two R 5  groups and optionally further including one to three X groups where X is independently selected from the group consisting of —O—, —S—, —NR 6 —, —NHCO—, —CONH—, —CONHCO—, —COO—, —OCO— and a disubstituted phenyl group which can optionally be substituted with one or two halogen atoms or with one or two R 3  groups; or the R 5  group is directly attached without an intervening R 1  or R 2  group to the heteroaromatic ring;  
 R 3  and R 4  independently are H, alkyl of 1 to 3 carbons, fluoroalkyl of 1 to 3 carbons, O-alkyl of 1 to 3 carbons, O-fluoroalkyl of 1 to 3 carbons, S-alkyl of 1 to 3 carbons, S-fluoroalkyl of 1 to 3 carbons;  
 R 5  is independently H, COOH or a tetrazole moiety;  
 R6 is H or alkyl of 1 to 3 carbons;  
 with the provisos that  
 at least one the R 1  and R 2  groups is not H, and  
 at least one R 5  is not H and no more than two R 5  groups are COOH or tetrazole whereby the compound includes at least one but no more than two COOH or tetrazole groups  
 
     
     
         2 . A compound in accordance with  claim 1  which has the structure in accordance with Formula 1.  
     
     
         3 . A compound in accordance with  claim 1  which has the structure in accordance with Formula 2.  
     
     
         4 . A compound in accordance with  claim 1  which has the structure in accordance with Formula 3.  
     
     
         5 . A compound in accordance with  claim 1  which has the structure in accordance with Formula 4.  
     
     
         6 . A compound in accordance with  claim 1  where R 5  is independently selected from H and COOH, or a pharmaceutically acceptable salt of said compound.  
     
     
         7 . A compound in accordance with  claim 1  where the formula includes at least one X group.  
     
     
         8 . A compound in accordance with  claim 1  where at least one X is O.  
     
     
         9 . A compound in accordance with  claim 1  where at least one X is CONH.  
     
     
         10 . A compound in accordance with  claim 1  having two R 5  groups which represent COOH, or a pharmaceutically acceptable salt of said compound.  
     
     
         11 . A compound in accordance with  claim 1  where R represents formula (ii).  
     
     
         11 . (canceled)  
     
     
         12 . A compound in accordance with  claim 1  where R represents formula (iv).  
     
     
         13 - 17 . (canceled)  
     
     
         18 . A compound in accordance with  claim 1  that includes only one COOH group, or its pharmaceutically acceptable salt.  
     
     
         19 . A compound in accordance with  claim 1  that includes only two COOH groups, or its pharmaceutically acceptable salt.  
     
     
         20 . A compound in accordance with claim where R 2 , R 3  and R 4  are hydrogen and R 1  is OCH 2 COOH, or it pharmaceutically acceptable salt.  
     
     
         21 - 28 . (canceled)  
     
     
         29 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound in accordance with  claim 1 .  
     
     
         30 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound in accordance with  claim 11 .  
     
     
         31 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound in accordance with  claim 12 .  
     
     
         32 . (canceled)  
     
     
         33 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound in accordance with  claim 1 , and a proton pump inhibitor drug selected from the groups consisting of the formulas (w), (x) (y) and (z)