6-modified bicyclic nucleic acid analogs

• US 7,399,845 B2
• Filed: 01/27/2007
• Issued: 07/15/2008
• Est. Priority Date: 01/27/2006
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Seth, Punit P., Swayze, Eric E.
• Primary Examiner(s): Lewis; Patrick T.
• Application Number:
  US11/627,964
• Publication Number:
  US 20070249049A1
• Time in Patent Office: 535 Days
• Field of Search: None
• US Class Current: 536/22.1
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
• 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides 6-modified bicyclic nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 6-position. These bicyclicnucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.

Claims

1. A bicyclic nucleoside having the formula:

2. The compound of claim 1 wherein Z is C₁-C₆ alkyl or substituted C₁-C₆ alkyl.

3. The compound of claim 2 wherein Z is methyl.

4. The compound of claim 2 wherein Z is substituted C₁-C₆alkyl.

5. The compound of claim 4 wherein said substituent group is C₁-C₆ alkoxy.

6. The compound of claim 4 wherein Z is CH₃OCH₂—

.

7. The compound of any one of claims 1-6 wherein the compound has the formula:

8. The compound of any one of claims 1-6 wherein the compound has the formula:

9. The compound of claim 1 wherein at least one of T₁ and T₂ is a hydroxyl protecting group.

10. The compound of claim 9 wherein each of said hydroxyl protecting groups is, independently, selected from benzyl, benzoyl, 2,6-dichlorobenzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl mesylate, tosylate, dimethoxytrityl (DMT), 9-phenylxanthine-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl (MOX).

11. The compound of claim 9 wherein T₁ is selected from acetyl, benzyl, t-butyl-dimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl.

12. The compound of claim 11 wherein said T₁ is 4,4′

-dimethoxytrityl.

13. The compound of claim 1 wherein T₂ is a reactive phosphorus group.

14. The compound of claim 13 wherein said reactive phosphorus group is diisopropylcyanoethoxy phosphoramidite or H-phosphonate.

15. The compound of claim 1 wherein T₁ is 4,4′

-dimethoxytrityl and T₂ is diisopropylcyanoethoxy phosphoramidite.

16. An oligomeric compound having at least one monomer of formula:

17. The oligomeric compound of claim 16 wherein each of the substituted groups, is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, hydroxyl, OJ₁, NJ₁J₂, SJ₁, N₃, OC(═

X)J₁, OC(═

X)NJ₁J₂, NJ₃C(═

X)NJ₁J₂ and CN, wherein each J₁, J₂ and J₃ is, independently, H or C₁-C₆ alkyl, and X is O, S or NJ₁.

18. The oligomeric compound of claim 16 wherein each Z is, independently, C₁-C₆ alkyl or substituted C₁-C₆ alkyl.

19. The oligomeric compound of claim 18 wherein at least one Z is methyl.

20. The oligomeric compound of claim 18 wherein at least one Z is substituted C₁-C₆ alkyl.

21. The oligomeric compound of claim 20 wherein each of said substituent groups is C₁-C₆ alkoxy.

22. The oligomeric compound of claim 20 wherein at least one Z is CH₃OCH₂—

.

23. The oligomeric compound of claim 16 wherein each Z is methyl or CH₃OCH₂—

.

24. The oligomeric compound of claim 16 wherein at least one of said monomer of formula I, II, III has the formula:

25. The oligomeric compound of any one of claims 16-23 wherein each of said monomer of formula I, II, or III has the formula:

26. The oligomeric compound of claim 16 wherein at least one of said monomer of formula I, II, or III has the formula:

27. The oligomeric compound of any one of claims 16-23 wherein each of said monomer of formula I, II, or III has the formula:

28. The oligomeric compound of claim 16 wherein T₃ is H or a hydroxyl protecting group.

29. The oligomeric compound of claim 16 wherein T₃ is an internucleoside linking group attached to a nucleoside, a nucleotide or a monomeric subunit.

30. The oligomeric compound of claim 16 wherein T₃ is an internucleoside linking group attached to an oligonucleoside or an oligonucleotide.

31. The oligomeric compound of claim 16 wherein T₃ is an internucleoside linking group attached to an oligomeric compound.

32. The oligomeric compound of claim 16 wherein T₄ is H or a hydroxyl protecting group.

33. The oligomeric compound of claim 16 wherein T₄ is an internucleoside linking group attached to a nucleoside, a nucleotide or a monomeric subunit.

34. The oligomeric compound of claim 16 wherein T₄ is an internucleoside linking group attached to an oligonucleoside or an oligonucleotide.

35. The oligomeric compound of claim 16 wherein T₄ is an internucleoside linking group attached to an oligomeric compound.

36. The oligomeric compound of claim 16 wherein at least one of T₃ and T₄ comprises an internucleoside linking group selected from phosphodiester or phosphorothioate.

37. The oligomeric compound of claim 16 comprising at least one region of at least two contiguous monomers of said formula.

38. The oligomeric compound of claim 37 comprising at least two regions of at least two contiguous monomers of said formula.

39. The oligomeric compound of claim 38 comprising a gapped oligomeric compound.

40. The oligomeric compound of claim 38 further comprising at least one region of from about 8 to about 14 contiguous β

-D-2′

-deoxyribofuranosyl nucleosides.

41. The oligomeric compound of claim 40 further comprising at least one region of from about 9 to about 12 contiguous β

-D-2′

-deoxyribofuranosyl nucleosides.

42. The oligomeric compound of claim 37 comprising one region of from 2 to three contiguous monomers of said formula, an optional second region of 1 or 2 contiguous monomers of said formula and a third region of from 8 to 14 β

-D-2′

-deoxyribofuranosyl nucleosides wherein said third region is located between said first and said second regions.

43. The oligomeric compound of claim 42 comprising from 8 to 10 β

-D-2′

-deoxyribofuranosyl nucleosides.

44. The oligomeric compound of claim 16 comprising from about 8 to about 40 nucleosides and/or modified nucleosides or mimetics in length.

45. The oligomeric compound of claim 16 comprising from about 8 to about 20 nucleosides and/or modified nucleosides or mimetics in length.

46. The oligomeric compound of claim 16 comprising from about 10 to about 16 nucleosides and/or modified nucleosides or mimetics in length.

47. The oligomeric compound of claim 16 comprising from about 10 to about 14 nucleosides and/or modified nucleosides or mimetics in length.

48. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 16.

49. The method of claim 48, wherein the animal is a human.