D-amino acid compounds for liver disease

Abstract

Provided herein are compounds, compositions and methods for the treatment of liver disease and conditions, including HCV infections. In certain embodiments, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-viral agents.

1 . A compound according to formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, stereoisomeric form, tautomeric form or polymorphic form thereof, wherein:
 Base is a nucleobase; 
 W is S or O; 
 X is a D-amino acid residue, or an ester thereof; 
 Y is hydrogen, —OR 1 , —SW, or —NR 1 R 2 ; 
 R b1  is —CH 3 , —H, azido, cyano, or halogen; 
 R b2  is —OH, —Cl, —F, —H, azido, cyano, amino, or alkoxyl; 
 R c  is —H or —OH, or, in the alternative, Y and R c  join to form a six-membered heterocyclic ring wherein Y and R c  together represent a single divalent —O—; 
 
         R d  is —H, —F, azido, or allenyl; or, in the alternative, R b2  and R d  join to form alkylene or substituted alkylene; 
         R e  is —H or alkyl; 
         each R 1  is independently alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, substituted alkyl or hydantoinylalkyl; and 
         each R 2  is independently hydrogen or alkyl. 
       
     
     
         2 . The compound of  claim 1  wherein each R 1  is independently alkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylcarbonylthioalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, alkylcarbonylalkoxy(arylalkyl), (alkoxycarbonyl)(alkoxycarbonylamino)alkyl, cycloalkylcarbonylalkoxyl, alkoxycarbonylaminoalkylcarbonylthioalkyl, hydroxylalkylcarbonylthioalkyl, aminoalkylcarbonylalkoxycarbonylthioalkyl, or hydantoinylalkyl. 
     
     
         3 . The compound of  claim 1  according to formula (II): 
       
         
           
           
               
               
           
         
         wherein each Y is independently —OR 1 , —SR 1 , or —NR 1 R 2 ; 
         each R 10  is independently alkyl, arylalkyl, heteroarylalkyl, cycloalkyl or a side chain of a naturally occurring amino acid other than hydrogen; and 
         each R 11  is independently alkyl or —H. 
       
     
     
         4 . The compound of  claim 1  wherein R e  and R d  are H. 
     
     
         5 - 10 . (canceled) 
     
     
         11 . The compound of  claim 1  wherein W is O, and R b2  is Cl, F or OH. 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1  wherein Y is 
       
         
           
           
               
               
           
         
         and R 3  is alkyl, alkoxycarbonylaminoalkyl, hydroxylalkyl, or aminoalkylcarbonylalkoxyl. 
       
     
     
         14 . The compound  claim 1  wherein:
 each Base is independently 
 
       
         
           
           
               
               
           
         
         or a tautomer thereof; 
         each R 4  is independently hydrogen, hydroxyl, hydroxylamine, alkylamino, halogen, sulfanyl, amino or alkoxyl; 
         each R 5  is independently hydrogen, halogen or methyl; and 
         each R 6  is independently hydrogen, amino, or halo. 
       
     
     
         15 . The compound of  claim 14  wherein R 4  is alkylamino. 
     
     
         16 . The compound of  claim 1  according to any of the following formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1  according to any of the following formulas: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The R P  compound of  claim 1 . 
     
     
         19 . The S P  compound of  claim 1 . 
     
     
         20 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient, carrier or diluent. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the composition is an oral formulation. 
     
     
         22 . A method for the treatment of a host infected with a hepatitis C virus, comprising the administration of an effective treatment amount of a compound of  claim 1 . 
     
     
         23 . The method of  claim 22 , wherein the host is a human. 
     
     
         24 . The method of  claim 22 , wherein the administration directs a substantial amount of the compound, or pharmaceutically acceptable salt or stereoisomer thereof, to a liver of the host. 
     
     
         25 . The method of  claim 22 , wherein the compound or composition is administered in combination or alternation with a second anti-viral agent selected from the group consisting of an interferon, a nucleotide analogue, a polymerase inhibitor, an NS3 protease inhibitor, an NS5A inhibitor, an entry inhibitor, a non-nucleoside polymerase inhibitor, a cyclosporine immune inhibitor, an NS4A antagonist, an NS4B-RNA binding inhibitor, a locked nucleic acid mRNA inhibitor, a cyclophilin inhibitor, and combinations thereof. 
     
     
         26 . The method of  claim 25 , wherein the second anti-viral agent is selected from the group consisting of telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, ribavirin, and combinations thereof. 
     
     
         27 . The method of  claim 25 , wherein the second anti-viral agent is selected from the group consisting of telaprevir, bocepravir, interferon alfacon-1, interferon alfa-2b, pegylated interferon alpha 2a, pegylated interferon alpha 2b, and combinations thereof, and further wherein the administration is not in combination or alternation with ribavirin. 
     
     
         28 . A method of treating a liver disease or condition comprising administering to a host in need thereof a compound comprising a D-amino acid linked to a therapeutic moiety.