Vitamin b6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates

Abstract

Provided herein are compounds, compositions, and methods of using them to treat infections, neoplastic disease, inflammatory disease, and pain. Such compounds are nucleotides, acyclonucleotides, and ANP phosphonates conjugated with forms and/or moieties of Vitamin B6 for delivery past the cell membrane and into the cell.

What is claimed is: 
     
         1 . A method of ameliorating or treating a viral disease, a neoplastic disease, an inflammatory disease, a parasitic disease, or a disease caused by a bacterial or a fungal infection, the method comprising administering to a subject suffering from the disease a therapeutically effective amount of one or more compounds having the following structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is substituent derived by removal of the hydrogen from the 5′-O-hydroxyl of a nucleoside or removal of an equivalent hydrogen from an acyclonucleoside; 
         X, Y, and Z are independently O, S, or NH; 
         L is alkyl, alkenyl or alkynyl; 
         R 2  and R 3  are independently selected from the group consisting of H, phenyl, alkyl, aryl, heteroaryl, and a vitamin B 6  moiety having one of the structures 
       
       
         
           
           
               
               
           
         
         wherein at least one of R 2  and R 3  is a vitamin B 6  moiety; and 
         R 12  is a vitamin B 6  moiety having the following structure: 
       
       
         
           
           
               
               
           
         
       
       and
 a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein B is a modified or unmodified nucleic acid base; 
         E is O, CH 2 , NH, or S; 
         and 
         R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently selected from the group consisting of H, OH, F, NH 2 , N 3 , alkyl, alkenyl, and alkynyl. 
       
     
     
         3 . The method of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein B is a modified or unmodified nucleic base; 
         E is O or CH 2 ; and 
         R 10  and R 11  are independently selected from the group consisting of H, OH, F, NH 2 , N 3 , alkyl, alkenyl, and alkynyl. 
       
     
     
         4 . The method of  claim 1 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein R 1  is selected from the group consisting of: cytarabine, fludarabine, gemcitabine, clofarabine, cladribine, vidaza, dacogen, pentostatin, aristeromycin, acyclovir, ganciclovir, pencyclovir, adefovir, cidofovir, tenofovir, zidovudine, lamivudine, and cladribine. 
     
     
         6 . The method of  claim 1 , where the viral disease is caused by virus selected from the group consisting of Alphaviridae, Arbovirus, Astrovirus, Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Hepadnaviridae, Herpesviridae, Alphaherpesvirinae, Betaherpesvirinae, Gammaherpesvirinae, Norwalk Virus, Astroviridae, Caliciviridae, Orthomyxoviridae, Paramyxoviridae, Paramyxoviruses, Rubulavims, Morbillivirus, Papovaviridae, Parvoviridae, Picornaviridae, Aphthoviridae, Cardioviridae, Enteroviridae, Coxsackie virus, Polio Virus, Rhinoviridae, Phycodnaviridae, Poxviridae, Reoviridae, Rotavirus, Retroviridae, A-Type Retrovirus, Immunodeficiency Virus, Leukemia Virus, Avian Sarcoma Virus, Rhabdovirus, Rubiviridae, and Togaviridae. 
     
     
         7 . The method of  claim 1 , wherein the viral disease is a hepatitis C viral infection or a HIV viral infection. 
     
     
         8 . The method of  claim 1 , where the neoplastic disease is cancer. 
     
     
         9 . The method of  claim 1 , where the neoplastic disease is leukemia. 
     
     
         10 . The method of  claim 1 , where the inflammatory disease is Multiple Sclerosis. 
     
     
         11 . The method of  claim 1 , where the parasitic disease is Chaga's disease.