Bicyclic cyclohexitol nucleic acid analogs

• US 8,530,640 B2
• Filed: 02/06/2009
• Issued: 09/10/2013
• Est. Priority Date: 02/07/2008
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Seth, Punit P., Migawa, Michael T., Swayze, Eric E., Song, Quanlai, Han, Mingming, Ross, Bruce S.
• Primary Examiner(s): Bland, Layla
• Assistant Examiner(s): CRAIGO, BAHAR ALAWI
• Application Number:
  US12/866,708
• Publication Number:
  US 20110077390A1
• Time in Patent Office: 1,677 Days
• Field of Search: None
• US Class Current: 536/26.7
• 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 disclosure provides bicyclic cyclohexitol nucleoside analogs of formula I and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are expected to be useful for enhancing properties of oligomeric compounds including for example nuclease resistance.

Claims

1. A bicyclic nucleoside analog having formula I:

2. The bicyclic nucleoside analog of claim 1, wherein Z is O.

3. The bicyclic nucleoside analog of claim 1, wherein q₁ and q₂ are each H.

4. The bicyclic nucleoside analog of claim 1, wherein at least one of q₁ and q₂ is other than H.

5. The bicyclic nucleoside analog of claim 1, wherein at least one of q₁ and q₂ is methyl.

6. The bicyclic nucleoside analog of claim 1 wherein Bx is uracil, 5 thiazolo-uracil, 2-thio-uracil, 5-propynyl-uracil, thymine, 2′

-thio-thymine, cytosine, 5-methylcytosine, 5-thiazolo-cytosine, 5-propynyl-cytosine, adenine, guanine, 2,6-diamino purine, 1H-pyrimido[5,4-][1,4benzoxazin-2(3H)-one), 1H-pyrimido [5,4-b][1,4]benzothiazin-2(3H)-one, 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H) -one, 2H-pyrimido[4,5-b]indol-2-one or H-pyrido[3′

,2′

;

4,5]pyrrolo[2,3-d]pyrimidin-2-one.

7. The bicyclic nucleoside analog of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, 2,6-diaminopurine, adenine or guanine.

8. The bicyclic nucleoside analog of claim 1 wherein T₁ is 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-methoxytrityl, 4,4′

-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl-diphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl or substituted pixyl.

9. The bicyclic nucleoside analog of claim 1, wherein T₁ is acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or dimethoxytrityl.

10. The bicyclic nucleoside analog of claim 1, wherein T₁ is 4,4′

-dimethoxytrityl.

11. The bicyclic nucleoside analog of claim 1, wherein T₂ is diisopropylcyanoethoxy phosphoramidite or H-phosphonate.

12. The bicyclic nucleoside analog of claim 1, wherein T₂ is diiso-propylcyanoethoxy phosphoramidite.

13. The bicyclic nucleoside analog of claim 1, wherein T₁ is 4,4′

-dimethoxytrityl and T₂ is diisopropylcyanoethoxy phosphoramidite.

14. The bicyclic nucleoside analog of claim 1, wherein Q consists of from 2 to 4 of said linked biradical groups.

15. The bicyclic nucleoside analog of claim 1, wherein Q consists of 2 or 3 of said linked biradical groups.

16. The bicyclic nucleoside analog of claim 1, wherein Q comprises 1 of said biradical groups.

17. The bicyclic nucleoside analog of claim 1, having the configuration:

18. The bicyclic nucleoside analog of claim 1, wherein Q is —

O—

[C(R₁)(R₂)]_n—

wherein n is 1 or 2.

19. The bicyclic nucleoside analog of claim 1, having formula II:

20. The bicyclic nucleoside analog of claim 19, wherein Z is O.

21. The bicyclic nucleoside analog of claim 20, wherein q₁ and q₂ are each H.

22. The bicyclic nucleoside analog of claim 21, wherein R₁ and R₂ are each H.

23. The bicyclic nucleoside analog of claim 22, wherein n is 1.

24. The bicyclic nucleoside analog of claim 22, wherein n is 2.

41. The bicyclic nucleoside analog of claim 1 having the formula:

25. An oligomeric compound comprising at least one bicyclic nucleoside analog having formula III:

26. The oligomeric compound of claim 25, wherein each Z is O.

27. The oligomeric compound of claim 25, wherein each q₁ and q₂ is H.

28. The oligomeric compound of claim 25, wherein at least one of q₁ or q₂ is other than H for each of said bicyclic nucleoside analogs having formula III.

29. The oligomeric compound of claim 25, wherein at least one of q₁ or q₂ is methyl for each of said bicyclic nucleoside analogs having formula III.

30. The oligomeric compound of claim 25, wherein Q comprises from 2 to 4 of said linked biradical groups for each of said bicyclic nucleoside analogs having formula III.

31. The oligomeric compound of claim 25, wherein Q comprises from 2 or 3 of said linked biradical groups for each of said bicyclic nucleoside analogs having formula III.

32. The oligomeric compound of claim 25, wherein Q comprises 1 of said biradical groups for each of said bicyclic nucleoside analogs having formula III.

33. The oligomeric compound of claim 25, wherein each of said bicyclic nucleoside analogs has the configuration:

34. The oligomeric compound of claim 25, wherein Q is —

O—

[C(R₁)(R₂)]_n— and

n is 1 or 2, for each of said bicyclic nucleoside analogs having formula III.

35. The oligomeric compound of claim 25, wherein each bicyclic nucleoside analog has formula IV:

36. The oligomeric compound of claim 35, wherein each Z is O.

37. The oligomeric compound of claim 35, wherein each q₁ and q₂ is H.

38. The oligomeric compound of claim 35, wherein each R₁ and R₂ is H.

39. The oligomeric compound of claim 35, wherein each n is 1.

40. The oligomeric compound of claim 35, wherein each n is 2.

42. The oligomeric compound of claim 35, having the formula: