5'-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS

• US 20070287831A1
• Filed: 05/10/2007
• Published: 12/13/2007
• Est. Priority Date: 05/11/2006
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Swayze, Eric, Seth, Punit
• Granted Patent: US 7,547,684 B2
• Time in Patent Office: Days
• US Class Current: 536/22.100
• 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. A bicyclic nucleoside having the formula:

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

3. The compound of claim 2 wherein Z is substituted methylene.

4. The compound of claim 3 wherein each of the 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 compound of claim 4 wherein each J₁ and J₂ is, independently H or C₁-C₆ alkyl.

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

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

8. The compound of claim 1 wherein Z is ethylenyl.

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

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

O)NJ₁J₂.

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

12. The compound of claim 11 wherein each of said hydroxyl protecting groups is, independently, selected from acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4′

-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, 9-phenylxanthine-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl (MOX).

13. The compound of claim 11 wherein T₁ is acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or 4,4′

-dimethoxytrityl.

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

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

16. The compound of claim 15 wherein T₂ is diisopropylcyanoethoxy phosphoramidite and T₁ is 4,4′

-dimethoxytrityl.

17. The compound of claim 1 wherein the Z group is in the (R)-configuration:

18. The compound of claim 1 wherein the Z group is in the (S)-configuration:

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

20. The oligomeric compound of claim 19 wherein Z is substituted C₁-C₆ alkyl.

21. The oligomeric compound of claim 20 wherein Z is substituted methylene.

22. The compound of claim 21 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.

23. The oligomeric compound of claim 22 wherein each J₁ and J₂ is, independently H or C₁-C₆ alkyl.

24. The oligomeric compound of claim 19 wherein Z is methyl, ethyl or methoxymethyl.

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

26. The oligomeric compound of claim 19 wherein Z is ethylenyl.

27. The oligomeric compound of claim 19 wherein Z is substituted acyl.

28. The oligomeric compound of claim 27 wherein Z is C(═

O)NJ₁J₂.

29. The oligomeric compound of claim 19 wherein T₃ is H or a hydroxyl protecting group.

30. The oligomeric compound of claim 19 wherein T₄ is H or a hydroxyl protecting group.

31. The oligomeric compound of claim 19 wherein T₃ is an internucleoside linking group attached to a nucleoside, a nucleotide or a monomeric subunit.

32. The oligomeric compound of claim 19 wherein T₄ is an internucleoside linking group attached to a nucleoside, a nucleotide or a monomeric subunit.

33. The oligomeric compound of claim 19 wherein T₃ is an internucleoside linking group attached to an oligonucleoside or an oligonucleotide.

34. The oligomeric compound of claim 19 wherein T₄ is an internucleoside linking group attached to an oligonucleoside or an oligonucleotide.

35. The oligomeric compound of claim 19 wherein T₃ is an internucleoside linking group attached to an oligomeric compound.

36. The oligomeric compound of claim 19 wherein T₄ is an internucleoside linking group attached to an oligomeric compound.

37. The oligomeric compound of claim 19 wherein the Z group of at least one monomer of said formula is in the (R)-configuration:

38. The oligomeric compound of claim 19 wherein the Z group of at least one monomer of said formula is in the (S)-configuration:

39. The oligomeric compound of claim 19 wherein at least one of T₃ and T₄ comprises an internucleoside linking group selected from phosphodiester or phosphorothioate.

40. The oligomeric compound of claim 19 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate.

41. The oligomeric compound of claim 19 comprising at least one region of at least two contiguous monomers of said formula.

42. The oligomeric compound of claim 41 comprising at least two regions of at least two contiguous monomers of said formula.

43. The oligomeric compound of claim 42 comprising a gapped oligomeric compound.

44. The oligomeric compound of claim 19 comprising from about 8 to about 40 nuclesides and/or modified nucleosides or mimetics in length.

45. The oligomeric compound of claim 19 comprising from about 8 to about 20 nuclesides and/or modified nucleosides or mimetics in length.

46. The oligomeric compound of claim 19 comprising from about 10 to about 16 nuclesides and/or modified nucleosides or mimetics in length.

47. The oligomeric compound of claim 19 comprising from about 10 to about 14 nuclesides 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 19.