Acyclic Nucleoside Phosphonate Diesters

Abstract

The present disclosure relates, inter alia, to compositions and methods for treating viral diseases and cancer. There are disclosed lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, preparation thereof, and methods of using the compounds to treat viral diseases and cancer.

What is claimed is: 
     
         1 . A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein:
 B Nuc(a)  is a naturally occurring purine, a naturally occurring pyrimidine, or 2,6-diaminopurine; 
 L a  is a substituted glyceryl moiety having the formula —CH 2 CH(OR 1 )—CH 2 (OR 2 ), wherein R 1  and R 2  are independently selected from an unsubstituted C 13-29  alkyl, an unsubstituted C 13-29  heteroalkyl, a substituted or unsubstituted aryl-C 1-6  alkyl, a substituted or unsubstituted heteroaryl-C 1-6  alky and a substituted or unsubstituted heterocycloalkyl-C 1-6  alkyl; 
 R a  is selected from the group consisting of a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl-C 1-6  alkyl, a substituted or unsubstituted heteroaryl-C 1-6  alkyl and a substituted or unsubstituted heterocycloalkyl-C 1-6  alkyl; 
 X a  is hydrogen, an unsubstituted C 1-6  alkyl, a halogen substituted C 1-6  alkyl, a hydroxy substituted C 1-6  alkyl or an unsubstituted C 1-6  alkoxy; and 
 wherein the substituent is selected from —OH, —NH 2 , —SH, —CN, —CF 3 , —NO 2 , oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl. 
 
       
     
     
         2 . The compound of  claim 1 , wherein X a  is hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein X a  is methyl. 
     
     
         4 . The compound of  claim 1 , wherein X a  is methoxy. 
     
     
         5 . The compound of  claim 1 , wherein X a  is a fluoro substituted C 1-6  alkyl. 
     
     
         6 . The compound of  claim 5 , wherein X a  is a CH 2 F. 
     
     
         7 . The compound of  claim 1 , wherein X a  is a CH 2 OH. 
     
     
         8 . The compound of  claim 1 , wherein L a  is a substituted glyceryl moiety, wherein the glyceryl moiety is substituted with an unsubstituted C 13-29  alkyl. 
     
     
         9 . The compound of  claim 8 , wherein L a  has the structure —(CH 2 )—CH(OR a1 )—(CH 2 )—O(CH 2 ) 11-21 —CH 3 , wherein R a1  is a substituted or unsubstituted aryl-C 1-6  alkyl, a substituted or unsubstituted heteroaryl-C 1-6  alkyl or a substituted or unsubstituted heterocycloalkyl-C 1-6  alkyl. 
     
     
         10 . The compound of  claim 9 , wherein L a  has the structure 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein R a  is a substituted or unsubstituted aryl. 
     
     
         12 . The compound of  claim 11 , wherein the substituted or unsubstituted aryl is a substituted or unsubstituted phenyl. 
     
     
         13 . The compound of  claim 11  wherein the substituted or unsubstituted aryl is a substituted or unsubstituted naphthyl. 
     
     
         14 . The compound of  claim 1 , wherein R a  is a substituted or unsubstituted aryl-C 1-6  alkyl. 
     
     
         15 . The compound of  claim 14 , wherein the substituted or unsubstituted aryl-C 1-6  alkyl is a substituted or unsubstituted benzyl. 
     
     
         16 . The compound of  claim 1 , wherein R a  is a substituted or unsubstituted heterocycloalkyl-C 1-6  alkyl. 
     
     
         17 . The compound of  claim 16 , wherein the substituted or unsubstituted heterocycloalkyl-C 1-6  alkyl is a substituted or unsubstituted galactosyl. 
     
     
         18 . The compound of  claim 1 , wherein B Nuc(a)  is a naturally occurring purine. 
     
     
         19 . The compound of  claim 1 , wherein B Nuc(a)  is a naturally occurring pyrimidine. 
     
     
         20 . The compound of  claim 1 , wherein B Nuc(a)  is 2,6-diaminopurine. 
     
     
         21 . The compound of  claim 1 , wherein B Nuc(a)  is guanine, adenine, cytosine, thymine, or uracil. 
     
     
         22 . The compound of  claim 1 , wherein B Nuc(a)  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein X a  is an unsubstituted C 1-6  alkyl, a halogen substituted C 1-6  alkyl, a hydroxy substituted C 1-6  alkyl or an unsubstituted C 1-6  alkoxy. 
       
     
     
         26 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the foregoing. 
       
     
     
         27 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt. 
       
     
     
         28 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt. 
       
     
     
         29 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the pharmaceutical composition is a topical formulation. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the pharmaceutical composition is in the form of a cream, a gel or an ointment. 
     
     
         32 . A method for treating human papilloma virus in a subject in need thereof, comprising administering a compound of  claim 1 , optionally in a pharmaceutically acceptable carrier. 
     
     
         33 . The method of  claim 32 , wherein the human papilloma virus is type 52 or 58. 
     
     
         34 . The method of  claim 32 , wherein the human papilloma virus is type 11, type 16 or type 18. 
     
     
         35 . A method for treating cancer of the cervix in a subject in need thereof, comprising administering a compound of  claim 1 , optionally in a pharmaceutically acceptable carrier. 
     
     
         36 . A method for treating cervical intraepithelial neoplasia (CIN), anal intraepithelial neoplasia (AIN), and vulvar intraepithelial neoplasia (VIN) in a subject in need thereof, comprising administering a compound of  claim 1 , optionally in a pharmaceutically acceptable carrier.