Substituted alpha-L-bicyclic nucleosides

• US 8,501,805 B2
• Filed: 09/23/2009
• Issued: 08/06/2013
• Est. Priority Date: 09/24/2008
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Seth, Punit P., Swayze, Eric E.
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US13/063,921
• Publication Number:
  US 20110166205A1
• Time in Patent Office: 1,413 Days
• Field of Search: 514/470, 549/220, 549/463
• US Class Current: 514/470
• 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 disclosure describes substituted α-L-bicyclic nucleoside analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, substituted α-L-bicyclic nucleoside analogs are provided, having one or more chiral substituents, that are useful for enhancing properties of oligomeric compounds including binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Claims

1. A bicyclic nucleoside having Formula I:

2. The bicyclic nucleoside of claim 1 wherein at least one of q₁, q₂, q₃, q₄, q₅ and q₆ is C₁-C₆ alkyl or substituted C₁-C₆ alkyl.

3. The bicyclic nucleoside of claim 1 wherein at least one of q₁, q₂, q₃, q₄, q₅ and q₆ is substituted C₁-C₆ alkyl having at least one substituent group selected from fluoro and OCH₃.

4. The bicyclic nucleoside of claim 1 wherein at least one of q₁, q₂, q₃, q₄, q₅ and q₆ is methyl.

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

6. The bicyclic nucleoside of claim 1 having Formula III:

7. The bicyclic nucleoside of claim 1 having Formula IV:

8. The bicyclic nucleoside of claim 1 having Formula IX:

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

-dimethoxytrityl and T₂ is diisopropylcyanoethoxy phosphoramidite.

10. An oligomeric compound comprising at least one bicyclic nucleoside having Formula V:

11. The oligomeric compound of claim 10 wherein at least one of q₁, q₂, q₃, q₄, q₅ and q₆ is C₁-C₆ alkyl or substituted C₁-C₆ alkyl for at least one of said bicyclic nucleoside of Formula V.

12. The oligomeric compound of claim 11 wherein each substituted C₁-C₆ alkyl comprises at least one substituent group selected from fluoro and OCH₃.

13. The oligomeric compound of claim 10 wherein at least one of q₁, q₂, q₃, q₄, q₅ and q₆ is methyl for at least one of said bicyclic nucleoside of Formula V.

14. The oligomeric compound of claim 10 wherein at least one of said bicyclic nucleoside has Formula VI:

15. The oligomeric compound of claim 10 wherein at least one of said bicyclic nucleoside has Formula VII:

16. The oligomeric compound of claim 10 wherein at least one of said bicyclic nucleoside has Formula VIII:

17. The oligomeric compound of claim 10 wherein at least one of said bicyclic nucleoside has Formula X:

18. The oligomeric compound of claim 10 wherein each internucleoside linking group is, independently, selected from phosphodiester or phosphorothioate.

19. The oligomeric compound of claim 10 wherein each internucleoside linking group is a phosphorothioate.

20. The oligomeric compound of claim 10 comprising at least one region of at least two contiguous bicyclic nucleosides having Formula V.

21. The oligomeric compound of claim 20 further comprising at least one region of from 8 to 14 contiguous β

-D-2′

-deoxyribofuranosyl nucleosides.

22. The oligomeric compound of claim 20 further comprising at least one region of from 9 to 12 contiguous β

-D-2′

-deoxyribofuranosyl nucleosides.

23. The oligomeric compound of claim 10 comprising one region of from 2 to three contiguous bicyclic nucleosides having Formula V, an optional second region of 1 or 2 contiguous bicyclic nucleosides having Formula V 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.

24. The oligomeric compound of claim 10 comprising from 8 to 40 monomer subunits.

25. The oligomeric compound of claim 10 wherein q₁, q₂, q₃, q₄, q₅ and q₆ are uniformly modified for each of said at least one bicyclic nucleoside having Formula V.

26. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 10 wherein said oligomeric compound is complementary to a target RNA.

27. The method of claim 26 wherein said cells are in a human.

28. The method of claim 26 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA.

29. The method of claim 28 wherein said target RNA is mRNA.

30. The method of claim 28 wherein said target RNA is human mRNA.

31. The method of claim 26 wherein said target RNA is cleaved thereby inhibiting its function.

32. The method of claim 26 further comprising detecting the levels of target RNA.