5′-modified bicyclic nucleic acid analogs

• US 7,750,131 B2
• Filed: 03/19/2009
• Issued: 07/06/2010
• Est. Priority Date: 05/11/2006
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Bhat, Balkrishen, Seth, Punit P., Swayze, Eric E.
• Primary Examiner(s): Lewis; Patrick T
• Application Number:
  US12/407,643
• Publication Number:
  US 20090192302A1
• Time in Patent Office: 474 Days
• Field of Search: None
• US Class Current: 536/22.1
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

The present invention provides 5′-modified bicyclic nucleoside analogs and oligomeric compounds comprising at least one of these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 5′-carbon. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including for example enhanced nuclease resistance.

Claims

1. An oligomeric compound having the formula:

G-[T-L]_j-[R-L]_q-R-[L-T]_r-E

wherein;

each T is a monomer of formula II;

2. The oligomeric compound of claim 1 wherein each Z is a substituted C₁-C₆ alkyl.

3. The oligomeric compound of claim 2 wherein each Z is substituted methyl.

4. The compound of claim 3 wherein each of said substituent groups is, independently, F, NJ₁J₂, N₃, CN, OJ₁, SJ₁, O—

C(═

O)NJ₁J₂, N(H)C(═

NH)NJ₁J₂ or N(H)C(═

O)N(H)J₂.

5. The oligomeric compound of claim 4 wherein each J₁ and J₂ is, independently H or C₁-C₆ alkyl.

6. The oligomeric compound of claim 1 wherein each Z is methyl, ethyl or methoxymethyl.

7. The oligomeric compound of claim 6 wherein each Z is methyl.

8. The oligomeric compound of claim 1 wherein each Z is vinyl.

9. The oligomeric compound of claim 1 wherein each Z is substituted acyl.

10. The oligomeric compound of claim 9 wherein each Z is C(═

O)NJ₁J₂.

11. The oligomeric compound of claim 1 wherein each monomer having formula II has the configuration:

12. The oligomeric compound of claim 1 wherein each monomer having formula II has the configuration:

13. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate internucleoside linking group.

14. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.

15. The oligomeric compound of claim 1 wherein j is 0.

16. The oligomeric compound of claim 1 wherein r is 0.

17. The oligomeric compound of claim 1 wherein j and r are each other than 0.

18. The oligomeric compound of claim 1 wherein j and r are each 2.

19. The oligomeric compound of claim 18 wherein q is from about 9 to about 13.

20. The oligomeric compound of claim 1 wherein j and r are each 5.

21. The oligomeric compound of claim 20 wherein q is about 10.

22. An oligomeric compound comprising at least one monomer having formula I:

23. The oligomeric compound of claim 22 wherein each of said modified nucleosides comprises at least a 2′

-F modified sugar moiety, a 2′

-OCH₃ modified sugar moiety, a 2′

-O—

(CH₂)₂—

OCH₃ modified sugar moiety, a 2′

-O—

CH₂-4′

bicyclic modified sugar moiety or a 4′

-S modified sugar moiety.

24. The oligomeric compound of claim 22 wherein each Z is a substituted C₁-C₆ alkyl.

25. The oligomeric compound of claim 24 wherein each Z is substituted methyl.

26. The compound of claim 25 wherein each of said substituent groups is, independently, F, NJ₁J₂, N₃, CN, OJ₁, SJ₁, O—

C(═

O)NJ₁J₂, N(H)C(═

NH)NJ₁J₂ or N(H)C(═

O)N(H)J₂.

27. The oligomeric compound of claim 26 wherein each J₁ and J₂ is, independently H or C₁-C₆ alkyl.

28. The oligomeric compound of claim 22 wherein each Z is methyl, ethyl or methoxymethyl.

29. The oligomeric compound of claim 28 wherein each Z is methyl.

30. The oligomeric compound of claim 22 wherein each Z is vinyl.

31. The oligomeric compound of claim 22 wherein each Z is substituted acyl.

32. The oligomeric compound of claim 31 wherein each Z is C(═

O)NJ₁J₂.

33. The oligomeric compound of claim 22 wherein one T₃ is H, a hydroxyl protecting group or a linked conjugate group.

34. The oligomeric compound of claim 22 wherein one T₄ is H, a hydroxyl protecting group or a linked conjugate group.

35. The oligomeric compound of claim 22 wherein at least one T₃ an internucleoside linking group attached to the oligomeric compound.

36. The oligomeric compound of claim 22 wherein at least one T₄ an internucleoside linking group attached to the oligomeric compound.

37. The oligomeric compound of claim 22 wherein each monomer having formula I has the configuration:

38. The oligomeric compound of claim 22 wherein each monomer having formula I has the configuration:

39. The oligomeric compound of claim 22 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate internucleoside linking group.

40. The oligomeric compound of claim 22 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.