Prodrugs of NH-Acidic Compounds

Abstract

The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.

What is claimed is: 
     
         1 . A compound of formula XXXVIII or XXXIX, and the geometric isomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts and solvates thereof: 
       
         
           
           
               
               
           
         
         wherein   represents a single or double bond; 
         X is —S— or —O; 
         R 1  is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 , —(C(R A )(R B ))—OPO 3 MY, —(C(R A )(R B ))—OP(O)(OR 20 )(OR 21 ), —[C(R A )(R B )O] z —R 20 , —[C(R A )(R B )O] z —C(O)OR 20 , —[C(R A )(R B )O] z —C(O)R 20 , —[C(R A )(R B )O] z —C(O)NR 20 R 21 , —[C(R A )(R B )O] z —OPO 3 MY, —[C(R A )(R B )O] z —P(O) 2 (OR 20 )M and —[C(R A )(R B )O] z —P(O)(OR 20 )(OR 21 );
 wherein z is 2 or 3; 
 wherein each R A  and R B  is independently selected from hydrogen, halogen, aliphatic, 
 
         substituted aliphatic, aryl or substituted aryl;
 each R 20  and R 21  is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; 
 Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation; 
 
         Each R 3 , and R 4  is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; 
         Each R 10  and R 11  is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10  and R 11  together with the atoms to which they are attached may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; 
         X 11  is —N— or —C(R 10 )—; 
         X 12  is —C(O)— or —C(S)—; 
         X 13  is —O, —S, —N(R 10 )(R 11 ), or —OR 10 ; and, 
         m and q are independently selected from 0, 1, and 2. 
       
     
     
         2 . A compound of  claim 1 , selected from TABLE XXXVIII, or a pharmaceutically acceptable salt thereof: 
       
         
           
                 
                 
                 
               
                   TABLE XXXVIII 
                 
                     
                 
                     
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   12 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   14 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         3 . A compound of  claim 1 , wherein X 11  is —N—, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound of  claim 1 , wherein X 11  is —C(R 10 )— or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound of  claim 1 , wherein X 12  is —C(O), or a pharmaceutically acceptable salt thereof.