Bis-modified bicyclic nucleic acid analogs

• US 7,666,854 B2
• Filed: 12/09/2008
• Issued: 02/23/2010
• Est. Priority Date: 05/11/2006
• 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:
  US12/331,226
• Publication Number:
  US 20090156792A1
• Time in Patent Office: 441 Days
• Field of Search: None
• US Class Current: 514/44.00R
• CPC Class Codes: C07H 13/04 having the esterifying carboxyl radicals attached to acyclic carbon atoms
• CPC Class Codes: C07H 15/18 Acyclic radicals, substituted by carbocyclic rings
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• 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: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: C07H 7/02 Acyclic radicals
• CPC Class Codes: C07H 9/04 Cyclic acetals

Abstract

The present disclosure describes bis-modified bicyclic nucleosides and oligomeric compounds that can be prepared comprising at least one of these bis-modified bicyclic nucleosides. More particularly, the bis-modified bicyclic nucleosides have at least one substituent group at the 5′-methylene and on the bridge methylene and can be chiral. These bis-modified bicyclic nucleosides are expected to be useful for enhancing one or more property of oligomeric compounds including for example enhancing nuclease resistance.

Claims

1. A bicyclic nucleoside having Formula I:

2. The bicyclic nucleoside of claim 1 wherein Z₁ and Z₂ are each, independently, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl or substituted C₂-C₆ alkynyl.

3. The bicyclic nucleoside of claim 2 wherein Z₁ and Z₂ are each CH₃.

4. The bicyclic nucleoside of claim 1 wherein one of Z₁ and Z₂ is H.

5. The bicyclic nucleoside of claim 4 wherein the other one of Z₁ and Z₂ is substituted C₁-C₆ alkyl.

6. The bicyclic nucleoside of claim 5 wherein the other one of Z₁ and Z₂ is CH₂F, CHF₂ or CF₃.

7. The bicyclic nucleoside of claim 4 wherein the other one of Z₁ and Z₂ is C₁-C₆ alkyl.

8. The bicyclic nucleoside of claim 7 wherein the other one of Z₁ and Z₂ is CH₃.

9. The bicyclic nucleoside of claim 1 wherein Q₁ and Q₂ are each, independently, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl, thiol or substituted thiol.

10. The bicyclic nucleoside of claim 9 wherein Q₁ and Q₂ are each CH₃.

11. The bicyclic nucleoside of claim 1 wherein one of Q₁ and Q₂ is H.

12. The bicyclic nucleoside of claim 11 wherein the other one of Q₁ and Q₂ is substituted C₁-C₆ alkyl.

13. The bicyclic nucleoside of claim 12 wherein the other one of Q₁ and Q₂ is CH₂F, CHF₂ or CF₃.

14. The bicyclic nucleoside of claim 11 wherein the other one of Q₁ and Q₂ is C₁-C₆ alkyl.

15. The bicyclic nucleoside of claim 14 wherein the other one of Q₁ and Q₂ is CH₃.

16. The bicyclic nucleoside of claim 1 wherein Q₁ and Q₂ together are methylene (═

CH₂).

17. The bicyclic nucleoside of claim 16 wherein one of Z₁ and Z₂ is CH₃ and the other one of Z₁ and Z₂ is H.

18. The bicyclic nucleoside of claim 1 having Formula II:

19. The bicyclic nucleoside of claim 18 wherein Z₂ and Q₂ are each H.

20. The bicyclic nucleoside of claim 19 wherein Z₁ and Q₁ are each CH₃.

21. The bicyclic nucleoside of claim 18 wherein Z₂ and Q₁ are each H.

22. The bicyclic nucleoside of claim 21 wherein Z₁ and Q₂ are each CH₃.

23. The bicyclic nucleoside of claim 18 wherein Z₁ and Q₂ are each H.

24. The bicyclic nucleoside of claim 23 wherein Z₂ and Q₁ are each CH₃.

25. The bicyclic nucleoside of claim 18 wherein Z₁ and Q₁ are each H.

26. The bicyclic nucleoside of claim 25 wherein Z₂ and Q₂ are each CH₃.

27. The bicyclic nucleoside 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-diaminopurine, 1H-pyrimido[5,4-b][1,4-benzoxazin-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.

28. The bicyclic nucleoside of claim 27 wherein Bx is uracil, thymine, cytosine, 5-methyl-cytosine, 2,6-diaminopurine, adenine or guanine.

29. The bicyclic nucleoside of claim 1 wherein T₁ is selected from acetyl, benzyl, t-butyl-dimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl.

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

-dimethoxytrityl.

31. The bicyclic nucleoside of claim 1 wherein T₂ is a reactive phosphorus group selected from diisopropylcyanoethoxy phosphoramidite or H-phosphonate.

32. The bicyclic nucleoside claim 31 wherein T₁ is 4,4′

-dimethoxytrityl and T₂ is diisopropyl-cyanoethoxy phosphoramidite.

33. An oligomeric compound having at least one bicyclic nucleoside of Formula III:

34. The oligomeric compound of claim 33 wherein Z₁ and Z₂ are each, independently, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl or substituted C₂-C₆ alkynyl for essentially each bicyclic nucleoside having Formula III.

35. The oligomeric compound of claim 34 wherein Z₁ and Z₂ are each CH₃ for essentially each bicyclic nucleoside having Formula III.

36. The oligomeric compound of claim 33 wherein one of Z₁ and Z₂ is H for essentially each bicyclic nucleoside having Formula III.

37. The oligomeric compound of claim 36 wherein the other one of Z₁ and Z₂ is substituted C₁-C₆ alkyl for essentially each bicyclic nucleoside having Formula III.

38. The oligomeric compound of claim 37 wherein the other one of Z₁ and Z₂ is CH₂F, CHF₂ or CF₃ for essentially each bicyclic nucleoside having Formula III.

39. The oligomeric compound of claim 36 wherein the other one of Z₁ and Z₂ is C₁-C₆ alkyl for essentially each bicyclic nucleoside having Formula III.

40. The oligomeric compound of claim 39 wherein the other one of Z₁ and Z₂ is CH₃ for essentially each bicyclic nucleoside having Formula III.

41. The oligomeric compound of claim 33 wherein Q₁ and Q₂ are each, independently, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂-C₆ alkynyl, thiol or substituted thiol for essentially each bicyclic nucleoside having Formula III.

42. The oligomeric compound of claim 41 wherein Q₁ and Q₂ are each CH₃ for essentially each bicyclic nucleoside having Formula III.

43. The oligomeric compound of claim 33 wherein one of Q₁ and Q₂ is H for essentially each bicyclic nucleoside having Formula III.

44. The oligomeric compound of claim 43 wherein the other one of Q₁ and Q₂ is substituted C₁-C₆ alkyl for essentially each bicyclic nucleoside having Formula III.

45. The oligomeric compound of claim 44 wherein the other one of Q₁ and Q₂ is CH₂F, CHF₂ or CF₃ for essentially each bicyclic nucleoside having Formula III.

46. The oligomeric compound of claim 43 wherein the other one of Q₁ and Q₂ is C₁-C₆ alkyl for essentially each bicyclic nucleoside having Formula III.

47. The oligomeric compound of claim 46 wherein the other one of Q₁ and Q₂ is CH₃ for essentially each bicyclic nucleoside having Formula III.

48. The oligomeric compound of claim 33 wherein Q₁ and Q₂ together are methylene (═

CH₂) for essentially each bicyclic nucleoside having Formula III.

49. The oligomeric compound of claim 48 wherein one of Z₁ and Z₂ is CH₃ and the other one of Z₁ and Z₂ is H for essentially each bicyclic nucleoside having Formula III.

50. The oligomeric compound of claim 33 having Formula IV:

51. The oligomeric compound of claim 50 wherein Z₂ and Q₂ are each H for essentially each bicyclic nucleoside having Formula IV.

52. The oligomeric compound of claim 51 wherein Z₁ and Q₁ are each CH₃ for essentially each bicyclic nucleoside having Formula IV.

53. The oligomeric compound of claim 50 wherein Z₂ and Q₁ are each H for essentially each bicyclic nucleoside having Formula IV.

54. The oligomeric compound of claim 53 wherein Z₁ and Q₂ are each CH₃ for essentially each bicyclic nucleoside having Formula IV.

55. The oligomeric compound of claim 50 wherein Z₁ and Q₂ are each H for essentially each bicyclic nucleoside having Formula IV.

56. The oligomeric compound of claim 55 wherein Z₂ and Q₁ are each CH₃ for essentially each bicyclic nucleoside having Formula IV.

57. The oligomeric compound of claim 50 wherein Z₁ and Q₁ are each H for essentially each bicyclic nucleoside having Formula IV.

58. The oligomeric compound of claim 57 wherein Z₂ and Q₂ are each CH₃ for essentially each bicyclic nucleoside having Formula IV.

59. The oligomeric compound of claim 33 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-diaminopurine, 1H-pyrimido[5,4-b][1,4-benzoxazin-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 for essentially each bicyclic nucleoside having Formula IV.

60. The oligomeric compound of claim 59 wherein Bx is uracil, thymine, cytosine, 5-methyl-cytosine, 2,6-diaminopurine, adenine or guanine for essentially each bicyclic nucleoside having Formula IV.

61. The oligomeric compound of claim 33 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate.

62. The oligomeric compound of claim 33 wherein each internucleoside linking group is a phosphorothioate.

63. The oligomeric compound of claim 33 comprising at least two regions wherein each region independently comprises at least two contiguous bicyclic nucleosides having Formula III and wherein the two regions are separated by a plurality of monomeric subunits.

64. The oligomeric compound of claim 63 wherein said plurality of monomeric subunits comprise a plurality of β

-D-2′

-deoxyribofuranosyl nucleosides.

65. The oligomeric compound of claim 33 comprising from about 8 to about 40 monomeric subunits.

66. The oligomeric compound of claim 33 comprising from about 8 to about 20 monomeric subunits.

67. The oligomeric compound of claim 33 comprising from about 10 to about 16 monomeric subunits.

68. The oligomeric compound of claim 33 comprising from about 10 to about 14 monomeric subunits.