6-modified bicyclic nucleic acid analogs

• US 7,741,457 B2
• Filed: 05/29/2008
• Issued: 06/22/2010
• 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:
  US12/129,154
• Publication Number:
  US 20090012281A1
• Time in Patent Office: 754 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. An oligomeric compound having at least one monomer of formula:

2. The oligomeric compound of claim 1 wherein each of said modified sugar moieties is, independently, selected from a 2′

-F modified sugar moiety, a 2′

-OCH₃ modified sugar moiety, a 2′

-O—

(CH₂)₂—

OCH₃ modified sugar moiety, a 2′

-O—

CH₂-4′

bicyclic modified sugar moiety or a 4′

-S modified sugar moiety.

3. The oligomeric compound of claim 1 wherein each Z is, independently, C₁-C₆ alkyl or substituted C₁-C₆ alkyl.

4. The oligomeric compound of claim 3 wherein each Z is methyl.

5. The oligomeric compound of claim 3 wherein each Z is substituted C₁-C₆ alkyl.

6. The oligomeric compound of claim 5 wherein each of said substituent groups is C₁-C₆ alkoxy.

7. The oligomeric compound of claim 6 wherein each Z is CH₃OCH₂—

.

8. The oligomeric compound of claim 1 wherein the Z group of each monomer of said formula has the configuration represented by formula:

9. The oligomeric compound of claim 1 wherein the Z group of each monomer of said formula has the configuration represented by formula:

10. The oligomeric compound of claim 1 wherein each internucleoside linking group is selected from phosphodiester or phosphorothioate.

11. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate.

12. An oligomeric compound having the formula:

[T-L]_j-[R-L]₁-R-[L-T]_r

wherein;

each T is a monomer of formula I;

13. The oligomeric compound of claim 12 wherein each Z is, independently, C₁-C₆ alkyl or substituted C₁-C₆ alkyl.

14. The oligomeric compound of claim 13 wherein each Z is methyl.

15. The oligomeric compound of claim 13 wherein each Z is substituted C₁-C₆ alkyl.

16. The oligomeric compound of claim 15 wherein each of said substituent groups is C₁-C₆ alkoxy.

17. The oligomeric compound of claim 16 wherein each Z is CH₃OCH₂—

.

18. The oligomeric compound of claim 12 wherein the Z group of each monomer of said formula has the configuration represented by formula:

19. The oligomeric compound of claim 12 wherein the Z group of each monomer of said formula has the configuration represented by formula:

20. The oligomeric compound of claim 12 wherein each internucleoside linking group is selected from phosphodiester or phosphorothioate.

21. The oligomeric compound of claim 12 wherein each internucleoside linking group is a phosphorothioate.

22. The oligomeric compound of claim 12 wherein j is 0.

23. The oligomeric compound of claim 12 wherein r is 0.

24. The oligomeric compound of claim 12 wherein j and r are each other than 0.