β-2′- or 3′-halonucleosides
View Patent ↗The present invention includes compounds and compositions of β-halonucleosides, as well as methods to treat HIV, HBV or abnormal cellular proliferation comprising administering said compounds or compositions.
1. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β-D or β-L-3′-halonucleoside of the formula (II):
or its pharmaceutically acceptable salt, optionally in combination with a pharmaceutically acceptable carrier, wherein
X is S;
Y is fluoro, chloro, bromo or iodo;
R 1 is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;
Y 1 is OH, OR 2 , NH 2 , NHR 2 , NR 2 R 3 , SH, SR 2 or halogen;
X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OH, OR 4 , NH 2 , NHR 2 , NR 4 R 5 , SH or SR 4 ; and
R 2 , R 3 , R 4 and R 5 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.
2. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β-D or β-L-3′-halonucleoside of the formula (II):
or its pharmaceutically acceptable salt, in combination or alternation with one or more other effective anti-HIV agent, optionally in combination with a pharmaceutically acceptable carrier, wherein
X is S;
Y is fluoro, chloro, bromo or iodo;
R 1 is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;
Y 1 is OH, OR 2 , NH 2 , NHR 2 , NR 2 R 3 , SH, SR 2 or halogen;
X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OH, OR 4 , NH 2 , NHR 2 , NR 4 R 5 , SH or SR 4 ; and
R 2 , R 3 , R 4 and R 5 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.
3. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β-D or β-L-3′-halonucleoside of the formula (II):
or its pharmaceutically acceptable salt, optionally in combination with a pharmaceutically acceptable carrier, wherein
X is O or S;
Y is fluoro, chloro, bromo or iodo;
R 1 is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;
Y 1 is OH, OR 2 , SH, SR 2 or halogen;
X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OH, OR 4 , NH 2 , NHR 2 , NR 4 R 5 , SH or SR 4 ; and
R 2 , R 3 , R 4 and R 5 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.
4. The method of claim 3 wherein X is O.
5. The method of claim 3 wherein X is S.
6. The method of claim 3 wherein Y is F.
7. A method for the treatment of an HIV infection in a host, comprising administering an effective treatment amount of a β-D or β-L-3′-halonucleoside of the formula (II):
or its pharmaceutically acceptable salt, in combination or alternation with one or more other effective anti-HIV agent, optionally in combination with a pharmaceutically acceptable carrier, wherein
X is O or S;
Y is fluoro, chloro, bromo or iodo;
R 1 is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;
Y 1 is OH, OR 2 , SH, SR 2 or halogen;
X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen OH, OR 4 , NH 2 , NHR 2 , NR 4 R 5 , SH or SR 4 ; and
R 2 , R 3 , R 4 and R 5 are independently H, straight chained, branched or cyclic alkyl dialkylaminoalkylene, dimethylaminomethylene, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.
8. The method of claim 7 , wherein X is O.
9. The method of claim 7 , wherein X is S.
10. The method of claim 7 , wherein Y is F.
11. The method of any one of claims 3 , 4 - 6 , 7 or 8 - 10 , wherein the host is a human.
12. A method for the treatment of an HBV infection in a host, comprising administering an effective treatment amount of a β-D or β-L-3′-halonucleoside of the formula (II):
or its pharmaceutically acceptable salt, optionally in combination with a pharmaceutically acceptable carrier, wherein
X is O, S, SO 2 ;
Y is fluoro, chloro, bromo or iodo;
R 1 is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative;
Y 1 is OH, OR 2 , NH 2 , NHR 2 , NR 2 R 3 , SH, SR 2 or halogen;
X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OH, OR 4 , NH 2 , NHR 2 , NR 4 R 5 , SH or SR 4 ; and
R 2 , R 3 , R 4 and R 5 are indepcndently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene), CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.
13. A method for the treatment of an HBV infection in a host, comprising administering an effective treatment amount of a β-D or β-L-3′-halonucleoside of the formula (II):
or its pharmaceutically acceptable salt, in combination or alternation with one or more other effective anti-HBV agents optionally in combination with a pharmaceutically acceptable carrier, wherein
X is O, S, SO 2 or CH 2 ;
Y is fluoro, chloro, bromo or iodo;
R 1 is hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO aryloxyalkyl, CO-substituted aryl, aryl, alkylsufonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di or triphosphate or a phosphate derivative
Y 1 is OH, OR 2 , NH 2 , NHR 2 , NR 2 R 3 , SH, SR 2 or halogen;
X 1 and X 2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OH, OR 4 , NH 2 , NHR 2 , NR 4 R 5 , SH or SR 4 ; and
R 2 , R 3 , R 4 and R 5 are independently H, straight chained, branched or cyclic alkyl, dialkylaminoalkylene, dimethylaminomethylene, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate.
14. The meihod of claim 12 or 13 , wherein the host is a human.
15. The method of claim 12 or 13 , wherein Y is F.
16. The method of any of claims 3 , 7 , 1 or 2 wherein R 1 is hydrogen.
17. The method of any of claims 3 , 7 , 1 or 2 wherein Y 1 is OH.
18. The method of any of claims 1 or 2 wherein Y 1 is NH 2 .
19. The method of any of claims 1 or 2 wherein Y 1 is NHR 2 .
20. The method of any of claims 3 , 7 , 1 or 2 wherein Y 1 is Cl.
21. The method of any of claims 3 , 7 , 1 or 2 wherein X 1 and X 2 are independently H.
22. The method of any of claims 3 , 7 , 1 or 2 wherein X 1 and X 2 are independently OH.
23. The method of any of claims 3 , 7 , 1 or 2 wherein X 1 and X 2 are independently NH 2 .
24. The method of any of claims 3 , 7 , 1 or 2 wherein R 2 , R 3 , R 4 and R 5 are independently H.
25. The method of any of claims 3 , 7 , 1 or 2 wherein R 2 , R 3 , R 4 and R 5 are independently alkyl.
26. The method of any of claims 3 , 7 , 1 or 2 wherein R 2 , R 3 , R 4 and R 5 are independently amino acid residue.
27. The method of any of claims 3 , 7 , 1 or 2 wherein R 2 , R 3 , R 4 and R 5 are independently mono-phosphate.
28. The method of any of claims 3 , 7 , 1 or 2 wherein R 2 , R 3 , R 4 and R 5 are independently di-phosphate.
29. The method of any of claims 3 , 7 , 1 or 2 wherein R 2 , R 3 , R 4 and R 5 are independently tri-phosphate.
30. The method of claim 13 , wherein the other effective anti-HBV agent is selected from the group consisting of (−)-enantiomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), L-FMAU, interferon, β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), famciclovir, penciclovir, BMS-200475, bis porn PMEA; lobucavir, ganciclovir, and ribavarin.
31. The method of claim 7 or 2 , wherein the other effective anti-HIV agent is selected from the group consisting of a protease inhibitor, cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), the (−)-enantiomer of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), carbovir, acyclovir, foscarnet, interferon, AZT, DDI, DDC, D4T, CS-87 (3′-azido-2′,3′-dideoxy-uridine), and β-D-dioxolane nucleosides, and MKC-442 (6-benzyl-1-(ethoxymethyl)-5-isopropyl uracil.
32. The method of one of claims 1 or 2 wherein Y is F.
33. The method of one of claims 1 or 2 wherein X 1 and X 2 are each H and Y 1 is NH 2 .
34. The method of one of claims 3 , 7 , 1 or 2 wherein R 1 is CO-alkyl.
35. The method of one of claims 3 , 7 , 1 or 2 wherein wherein X 2 is NH 2 .
36. The method of one of claims 3 , 7 , 1 or 2 wherein X 2 is F.
37. The method of claim 3 , wherein the 3′-halonucleoside is a β-D nucleoside.
38. The method of claim 7 wherein the 3′-halonucleoside is a β-D nucleoside.
39. The method of claim 1 wherein the 3′-halonucleoside is a β-D nucleoside.
40. The method of claim 2 wherein the 3′-halonucleoside is a β-D nucleoside.
41. The method of claim 3 , wherein the 3′-halonucleoside is a β-L nucleoside.
42. The method of claim 7 wherein the 3′-halonucleoside is a β-L nucleoside.
43. The method of claim 1 wherein the 3′-halonucleoside is a β-L nucleoside.
44. The method of claim 2 wherein the 3′-halonucleoside is a β-L nucleoside.