US2014323554A1PendingUtilityA1

Nucleotide and oligonucleotide prodrugs

Assignee: SPRING BANK PHARMACEUTICALS INCPriority: Dec 13, 2005Filed: Feb 21, 2014Published: Oct 30, 2014
Est. expiryDec 13, 2025(expired)· nominal 20-yr term from priority
A61P 31/20A61P 31/00A61P 43/00A61P 31/14A61K 31/7084C07H 19/20C07H 21/04A61K 31/7076C07J 43/003C07J 17/00
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Claims

Abstract

The present invention discloses compounds of formula (I): which exhibit antiviral properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of anti-HBV treatment. The invention also relates to methods of treating a HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Claims

exact text as granted — not AI-modified
What is claimed: 
     
         1 . A pronucleotide of formula (I): 
       
         
           
           
               
               
           
         
         or the racemates, enantiomers, diastereomers, geometric isomers, tautomers thereof, 
         wherein 
         X=absent, O, NH, NR, S; 
         X 1 =absent, O, NH; 
         A=absent, aryl, aralkyl; 
         n=0, 1, 2, 3, 4, 5; 
         R=alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, heterocylic, O-alkyl, O-heteroaryl, steroidal; 
         R 1 , R 2  are independently, H, OH, O-alkyl, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, aralkyl, heterocyclic, O-aryl, O-heteroarylaryl, heterocyclic; 
         R 3  is selected from hydrogen, alkyl, substituted alkyl, C(O)-alkyl, C(O)O-alkyl, C(O)-aryl, C(O)O-aryl, C(O)NH-alkyl, and C(O)NH-aryl; 
         Y, Z are indendently, O and S; 
         B 1 , B 2  are independently adenine, guanine, thymine, cytosine, uracil or modified nucleosides; 
         m=1 to 40. 
       
     
     
         2 . A pronucleotide according to  claim 1 , represented by the formula (II): 
       
         
           
           
               
               
           
         
         wherein m is 1, 2 or 3; and R, X, X 1 , A, n, R 1 , R 2 , R 3 , B 1  and B 2  are as previously defined in  claim 1 . 
       
     
     
         3 . A pronucleotide according to  claim 1 , represented by the formula (III): 
       
         
           
           
               
               
           
         
         wherein R, X, X 1 , A, n, R 3 , B 1  and B 2  are as previously defined in  claim 1 . 
       
     
     
         4 . A pronucleotide according to  claim 1 , represented by the formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 4  is selected from hydrogen, hydrogen, C(O)-alkyl, C(O)O-alkyl, C(O)-aryl, C(O)O-aryl, C(O)NH-alkyl, and C(O)NH-aryl; and R, R 3 , X, X 1 , A and n are as previously defined in  claim 1 . 
       
     
     
         5 . A compound of  claim 4  having the Formula A1, selected from compounds 1-8 of Table 1: 
       
         
           
           
               
               
           
         
         wherein R, X 1 , R 3  and R 4  is delineated for each example in Table 1. 
       
       
         
           
                 
                 
                 
                 
                 
               
                   TABLE 1 
                 
                     
                 
                   Compound 
                     
                     
                     
                     
                 
                   No. 
                   R 
                   X 1   
                   R 3   
                   R 4   
                 
                     
                 
                   1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   absent 
                   H 
                   H 
                 
                     
                 
                   2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   H 
                 
                     
                 
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   absent 
                   H 
                   H 
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   H 
                 
                     
                 
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   C(O)Ph 
                   H 
                 
                     
                 
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   C(O)Ph 
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   absent 
                   H 
                   H 
                 
                     
                 
                   8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   H 
                 
                     
                 
             
                
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . A pronucleotide according to  claim 1 , represented by the formula (V): 
       
         
           
           
               
               
           
         
         wherein R, R 3 , R 4 , X, X 1 , A and n are as previously defined in  claim 1 . 
       
     
     
         7 . A compound of  claim 6  having the Formula B1, selected from compounds 9-16 of Table 2: 
       
         
           
           
               
               
           
         
         wherein R, X 1 , R 3  and R 4  is delineated for each example in Table 2. 
       
       
         
           
                 
                 
                 
                 
                 
               
                   TABLE 2 
                 
                     
                 
                   Compound 
                     
                     
                     
                     
                 
                   No. 
                   R 
                   X 1   
                   R 3   
                   R 4   
                 
                     
                 
                     
                 
                 
                 
                 
                 
                 
               
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   absent 
                   H 
                   H 
                 
                     
                 
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   H 
                 
                     
                 
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   absent 
                   H 
                   H 
                 
                     
                 
                   12 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   H 
                 
                     
                 
                   13 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   C(O)Ph 
                   H 
                 
                     
                 
                   14 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   C(O)Ph 
                 
                     
                 
                   15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   absent 
                   H 
                   H 
                 
                     
                 
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   O 
                   H 
                   H 
                 
                     
                 
             
                
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         8 . A pronucleotide according to  claim 1 , represented by the formula (VI): 
       
         
           
           
               
               
           
         
         wherein R, R 3 , X, X 1 , A and n are as previously defined in  claim 1 . 
       
     
     
         9 . A method for treating HBV in a subject in need of such treatment comprising, administering to said subject a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         10 . A method for treating HBV in a subject in need of such treatment comprising, administering to said subject a therapeutically effective amount of a compound according to  claim 1 , in combination with other agents. 
     
     
         11 . A method for treating HBV in a subject infected with resistant strains of HBV in need of such treatment comprising, administering to said subject a therapeutically effective amount of a compound according to  claim 1 , alone or in combination with other agents. 
     
     
         12 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in combination with a pharmaceutically acceptable carrier or excipient. 
     
     
         13 . A method for treating HBV in a subject in need of such treatment comprising, administering to said subject a therapeutically effective amount of a pharmaceutical composition of  claim 7 .

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