Modulation of hepatitis b virus cccdna transcription

Abstract

The present invention provides small molecule inhibitors of hepatitis B virus (HBV) covalently closed circular (ccc) DNA, which are useful as therapeutics in the management of chronic HBV. The compounds of the invention achieve epigenetic modification of the cccDNA, histone modification and histone deacetylase activity inhibition, thus modulating HBV cccDNA. The present invention further provides methods for modulating HBV cccDNA, for treating or preventing HBV in a subject, and for modulating cccDNA transcription of hepatitis B in a subject.

What is claimed: 
     
         1 . A method of modulating cccDNA transcription of hepatitis B in a subject comprising administering to said subject an inhibitor of histone deacetylase activity. 
     
     
         2 . The method according to  claim 1  wherein said inhibitor of histone deacetylase activity is an inhibitor of class I histone deacetylase activity. 
     
     
         3 . The method according to  claim 1  wherein said inhibitor of histone deacetylase activity is Trichostatin A, suberoyl bis hydroxamic acid, dimethylamino hydroxy-benzamide, Apicidin or an analog thereof, or a compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 ) n — or —C(═O)—; 
 R 2  is —C(═O)—, 3,5-triazolyl, or —C(Z)N(R 4 )—; 
 R 4  is hydrogen, alkyl, aryl, aralkyl, dialkylaminoalkyl, or carboxyalkyl; 
 R 3  is —CH(R 5 )—, or R 2  is nitrogen and R 3  is —CH— and R 2  and R 3  together form piperidinyl; 
 R 5  is hydrogen, —CH 3 , or an alpha amino acid R group; 
 R 6  is —(CH 2 ) m C(X)Y, —(CH 2 ) 2 CH 3 , or —(CH 2 ) q -phenyl-(CH 2 ) m C(═O)NHOH; 
 X is ═O, H 2 , ═N—NH 2 , or ═N—NH—C(═O)NH 2 ; 
 Y is NHOH or —CH 2 CH 3 ; 
 Z is H 2  or O; 
 R 7  is hydrogen or alkoxy; 
 R 8  is alkyl or carboxyalkyl; 
 n is 0-2; 
 m is 0-6; and, 
 q is 0-3; 
 
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         4 . The method according to  claim 1  wherein said inhibitor of histone deacetylase activity is Apicidin, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 )—, 
 and, 
 R 2  is —C(Z)N(R 4 )—. 
 
     
     
         5 . The method according to  claim 3  wherein said inhibitor of histone deacetylase activity is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 1  further comprising administering to said subject a therapeutically effective amount of a further agent that modulates hepatitis B virus. 
     
     
         7 . A method of treating hepatitis B in a subject comprising administering to said subject an inhibitor of histone deacetylase activity. 
     
     
         8 . The method according to  claim 7  wherein said inhibitor of histone deacetylase activity is an inhibitor of class I histone deacetylase activity. 
     
     
         9 . The method according to  claim 7  wherein said inhibitor of histone deacetylase activity is Trichostatin A, suberoyl bis hydroxamic acid, dimethylamino hydroxy-benzamide, Apicidin or an analog thereof, or a compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 ) n — or —C(═O)—; 
 R 2  is —C(═O)—, 3,5-triazolyl, or —C(Z)N(R 4 )—; 
 R 4  is hydrogen, alkyl, aryl, aralkyl, dialkylaminoalkyl, or carboxyalkyl; 
 R 3  is —CH(R 5 )—, or R 2  is nitrogen and R 3  is —CH— and R 2  and R 3  together form piperidinyl; 
 R 5  is hydrogen, —CH 3 , or an alpha amino acid R group; 
 R 6  is —(CH 2 ) m C(X)Y, —(CH 2 ) 2 CH 3 , or —(CH 2 ) q -phenyl-(CH 2 ) m C(═O)NHOH; 
 X is ═O, H 2 , ═N—NH 2 , or ═N—NH—C(═O)NH 2 ; 
 Y is NHOH or —CH 2 CH 3 ; 
 Z is H 2  or O; 
 R 7  is hydrogen or alkoxy; 
 R 8  is alkyl or carboxyalkyl; 
 n is 0-2; 
 m is 0-6; and, 
 q is 0-3; 
 
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         10 . The method according to  claim 7  wherein said inhibitor of histone deacetylase activity is Apicidin, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 )—, 
 and, 
 R 2  is —C(Z)N(R 4 )—. 
 
     
     
         11 . The method according to  claim 10  wherein said inhibitor of histone deacetylase activity is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 7  further comprising administering to said subject a therapeutically effective amount of a further agent that modulates hepatitis B virus. 
     
     
         13 . A method of modulating hepatitis B virus covalently closed circular DNA comprising contacting a hepatitis B virus with an inhibitor of histone deacetylase activity. 
     
     
         14 . The method according to  claim 13  wherein said inhibitor of histone deacetylase activity is an inhibitor of class I histone deacetylase activity. 
     
     
         15 . The method according to  claim 13  wherein said inhibitor of histone deacetylase activity is Trichostatin A, suberoyl bis hydroxamic acid, dimethylamino hydroxy-benzamide, Apicidin or an analog thereof, or a compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 ) n — or —C(═O)—; 
 R 2  is —C(═O)—, 3,5-triazolyl, or —C(Z)N(R 4 )—; 
 R 4  is hydrogen, alkyl, aryl, aralkyl, dialkylaminoalkyl, or carboxyalkyl; 
 R 3  is —CH(R 5 )—, or R 2  is nitrogen and R 3  is —CH— and R 2  and R 3  together form piperidinyl; 
 R 5  is hydrogen, —CH 3 , or an alpha amino acid R group; 
 R 6  is —(CH 2 ) m C(X)Y, —(CH 2 ) 2 CH 3 , or —(CH 2 ) q -phenyl-(CH 2 ) m C(═O)NHOH; 
 X is ═O, H 2 , ═N—NH 2 , or ═N—NH—C(═O)NH 2 ; 
 Y is NHOH or —CH 2 CH 3 ; 
 Z is H 2  or O; 
 R 7  is hydrogen or alkoxy; 
 R 8  is alkyl or carboxyalkyl; 
 n is 0-2; 
 m is 0-6; and, 
 q is 0-3; 
 
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         16 . The method according to  claim 13  wherein said inhibitor of histone deacetylase activity is Apicidin, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 )—, 
 and, 
 R 2  is —C(Z)N(R 4 )—. 
 
     
     
         17 . The method according to  claim 13  wherein said inhibitor of histone deacetylase activity is 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method according to  claim 13  further comprising contacting the hepatitis B virus with a further agent that modulates hepatitis B virus. 
     
     
         19 . A compound according to formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 ) n — or —C(═O)—; 
 R 2  is —C(═O)— or —C(Z)N(R 4 )—; 
 R 4  is hydrogen, alkyl, aryl, aralkyl, dialkylaminoalkyl, or carboxyalkyl; 
 R 3  is —CH(R 5 )—; 
 R 5  is hydrogen, —CH 3 , or an alpha amino acid R group; 
 R 6  is —(CH 2 ) in C(X)Y, —(CH 2 ) 2 CH 3 , or —(CH 2 ) q -phenyl-(CH 2 ) m C(═O)NHOH; 
 X is ═O, H 2 , ═N—NH 2 , or ═N—NH—C(═O)NH 2 ; 
 Y is NHOH or —CH 2 CH 3 ; 
 Z is H 2  or O; 
 R 7  is hydrogen or alkoxy; 
 R 8  is alkyl or carboxyalkyl; 
 n is 0-2; 
 m is 0-6; and, 
 q is 0-3; 
 
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound according to  claim 19  wherein said compound is 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is —(CH 2 )—, 
 and, 
 R 2  is —C(Z)N(R 4 )—. 
 
     
     
         21 . The compound according to  claim 19  wherein said compound is