Compounds and methods for synthesis of bicyclic nucleic acid analogs

• US 7,569,686 B1
• Filed: 05/10/2007
• Issued: 08/04/2009
• Est. Priority Date: 01/27/2006
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Vasquez, Guillermo, Bhat, Balkrishen, Allerson, Charles, Xia, Jie, Seth, Punit P., Swayze, Eric E., Prakash, Thazha P., Migawa, Michael T.
• Primary Examiner(s): Lewis; Patrick T
• Application Number:
  US11/747,042
• Time in Patent Office: 817 Days
• Field of Search: None
• US Class Current: 536/25.3
• 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

Abstract

The present invention provides compounds and methods of using them for preparing bicyclic nucleosides. The bicyclic nucleosides are useful for preparing chemically modified oligomeric compounds. Oligomeric compounds comprising these bicyclic nucleosides have enhanced properties such as increased nuclease resistance.

Claims

1. A compound having formula I:

2. The compound of claim 1 wherein said optionally substituted polycyclylic aromatic or heteroaromatic radical comprises from 2 to about 5 fused rings.

3. The compound of claim 2 wherein Q comprises two fused rings.

4. The compound of claim 2 wherein Q comprises at least one heteroaromatic ring.

5. The compound of claim 3 wherein Q includes only carbon and hydrogen atoms.

6. The compound of claim 5 wherein Q is 2-naphthalenyl.

7. The compound of claim 1 wherein Q is pyrenyl, purinyl, acridinyl, xanthenyl, fluorenyl, phenanthrenyl, anthracenyl, quinolinyl, isoquinolinyl, naphthalenyl, perylenyl, phenanthridinyl, phenazinyl, anthraquinonyl, azulenyl or dibenzofuranyl.

8. The compound of claim 1 wherein R₁ and R₂ are each H.

9. The compound of claim 1 wherein R₁ and R₂ are each, independently, a hydroxyl protecting group.

10. The compound of claim 1 wherein one of R₁ and R₂ is H and the other of R₁ and R₂ is a hydroxyl protecting group.

11. The compound of claim 1 wherein R₃ and R₄ are each, independently, C₁-C₆ alkyl.

12. The compound of claim 11 wherein R₃ and R₄ are each methyl.

13. The compound of claim 1 wherein:

R₁ is a hydroxyl protecting group;

R₂ is H; and

R₃ and R₄ are each methyl.

14. The compound of claim 13 wherein Q is 2-napthalenyl.

15. The compound of claim 1 having the configuration:

16. The compound of claim 15 having the formula:

17. The compound of claim 1 having the configuration:

18. The compound of claim 17 having the formula:

19. A method of preparing a bicyclic nucleoside comprising a bridge between the 4′

and 2′

ring carbons using the compound of claim 1.

20. The method of claim 19 wherein said bridge comprises from 2 to 3 bivalent subunits.

21. The method of claim 20 wherein said bivalent subunits are each, independently, selected from —

CR₅R₆—

, —

C(═

O)—

, —

NR₅, and —

O—

, wherein each R₅ and R₆ is, independently, H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, a substituted heteroatom (O, S or N) or a protecting group.

22. The method of claim 21 wherein said bivalent subunits form a bridge having the formula:

—

CH₂—

O—

, —

(CH₂)₂—

O—

, —

CH₂—

O—

N(R₅)—

, —

CH₂—

N(R₅)—

O—

, CH₂—

N(R₅)—

CH₂—

, —

CH(R₅)—

O—

, —

CH₂—

N(R₅)—

N(R₅)—

or —

C(═

O)—

N(R₅)—

CH₂—

.

23. The method of claim 19 wherein said compound has the configuration:

24. The method of claim 23 wherein said compound has the formula:

25. The method of claim 19 wherein said compound has the configuration:

26. The method of claim 25 wherein said compound has the formula: