5′-modified bicyclic nucleic acid analogs
View Patent ↗The present invention provides 5′-modified bicyclic nucleoside analogs and oligomeric compounds comprising at least one of these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 5′-carbon. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including for example enhanced nuclease resistance.
1. An oligomeric compound having the formula:
G-[T-L] j -[R-L] q -R-[L-T] r -E
wherein:
each T is a monomer of formula II:
wherein independently for each monomer having formula II:
Bx is a heterocyclic base moiety;
Z is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkynyl or substituted acyl;
each R is a β-D-2′-deoxyribonucleoside;
each L is an internucleoside linking group;
G and E are each, independently, H, a hydroxyl protecting group or a linked conjugate group;
wherein each substituted group is mono or poly substituted with substituent groups independently selected from halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , COOJ 1 , CN, O—C(═O)—NJ 1 J 2 , N(H)C(═NH)NR 1 R 2 or N(H)C(═X)N(H)J 2 wherein X is O or S;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, C 1 -C 6 aminoalkyl, substituted C 1 -C 6 aminoalkyl or a protecting group;
q is from 7 to about 15;
j is 0 or from 1 to about 5;
r is 0 or from 1 to about 5;
the sum of j and r is at least 1; and
the sum of j, q and r is from 7 to 39.
2. The oligomeric compound of claim 1 wherein each Z is a substituted C 1 -C 6 alkyl.
3. The oligomeric compound of claim 2 wherein each Z is substituted methyl.
4. The compound of claim 3 wherein each of said substituent groups is, independently, F, NJ 1 J 2 , N 3 , CN, OJ 1 , SJ 1 , O—C(═O)NJ 1 J 2 , N(H)C(═NH)NJ 1 J 2 or N(H)C(═O)N(H)J 2 .
5. The oligomeric compound of claim 4 wherein each J 1 and J 2 is, independently H or C 1 -C 6 alkyl.
6. The oligomeric compound of claim 1 wherein each Z is methyl, ethyl or methoxymethyl.
7. The oligomeric compound of claim 6 wherein each Z is methyl.
8. The oligomeric compound of claim 1 wherein each Z is vinyl.
9. The oligomeric compound of claim 1 wherein each Z is substituted acyl.
10. The oligomeric compound of claim 9 wherein each Z is C(═O)NJ 1 J 2 .
11. The oligomeric compound of claim 1 wherein each monomer having formula II has the configuration:
12. The oligomeric compound of claim 1 wherein each monomer having formula II has the configuration:
13. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate internucleoside linking group.
14. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.
15. The oligomeric compound of claim 1 wherein j is 0.
16. The oligomeric compound of claim 1 wherein r is 0.
17. The oligomeric compound of claim 1 wherein j and r are each other than 0.
18. The oligomeric compound of claim 1 wherein j and r are each 2.
19. The oligomeric compound of claim 18 wherein q is from about 9 to about 13.
20. The oligomeric compound of claim 1 wherein j and r are each 5.
21. The oligomeric compound of claim 20 wherein q is about 10.
22. An oligomeric compound comprising at least one monomer having formula I:
wherein independently for each monomer having formula I:
Bx is a heterocyclic base moiety;
one of T 3 and T 4 is an internucleoside linking group attaching the monomer having formula I to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside linking group attaching the monomer having formula I to the oligomeric compound;
Z is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkynyl or substituted acyl;
wherein each substituted group is mono or poly substituted with substituent groups independently selected from halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , COOJ 1 , CN, O—C(═O)—NJ 1 J 2 , N(H)C(═NH)NR 1 R 2 or N(H)C(═X)N(H)J 2 wherein X is O or S;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, C 1 -C 6 aminoalkyl, substituted C 1 -C 6 aminoalkyl or a protecting group;
said oligomeric compound comprising at least one monomeric subunit that is other than a monomer having formula I, selected from a β-D-ribonucleoside, a β-D-2′-deoxyribonucleoside and a modified nucleoside wherein said modified nucleoside comprises at least a sugar substituent group, a 4′-S group or a bicyclic modified sugar; and
wherein said oligomeric compound comprises from 8 to 40 nucleosides and/or modified nucleosides or mimetics in length.
23. The oligomeric compound of claim 22 wherein each of said modified nucleosides comprises at least a 2′-F modified sugar moiety, a 2′-OCH 3 modified sugar moiety, a 2′-O—(CH 2 ) 2 —OCH 3 modified sugar moiety, a 2′-O—CH 2 -4′ bicyclic modified sugar moiety or a 4′-S modified sugar moiety.
24. The oligomeric compound of claim 22 wherein each Z is a substituted C 1 -C 6 alkyl.
25. The oligomeric compound of claim 24 wherein each Z is substituted methyl.
26. The compound of claim 25 wherein each of said substituent groups is, independently, F, NJ 1 J 2 , N 3 , CN, OJ 1 , SJ 1 , O—C(═O)NJ 1 J 2 , N(H)C(═NH)NJ 1 J 2 or N(H)C(═O)N(H)J 2 .
27. The oligomeric compound of claim 26 wherein each J 1 and J 2 is, independently H or C 1 -C 6 alkyl.
28. The oligomeric compound of claim 22 wherein each Z is methyl, ethyl or methoxymethyl.
29. The oligomeric compound of claim 28 wherein each Z is methyl.
30. The oligomeric compound of claim 22 wherein each Z is vinyl.
31. The oligomeric compound of claim 22 wherein each Z is substituted acyl.
32. The oligomeric compound of claim 31 wherein each Z is C(═O)NJ 1 J 2 .
33. The oligomeric compound of claim 22 wherein one T 3 is H, a hydroxyl protecting group or a linked conjugate group.
34. The oligomeric compound of claim 22 wherein one T 4 is H, a hydroxyl protecting group or a linked conjugate group.
35. The oligomeric compound of claim 22 wherein at least one T 3 an internucleoside linking group attached to the oligomeric compound.
36. The oligomeric compound of claim 22 wherein at least one T 4 an internucleoside linking group attached to the oligomeric compound.
37. The oligomeric compound of claim 22 wherein each monomer having formula I has the configuration:
38. The oligomeric compound of claim 22 wherein each monomer having formula I has the configuration:
39. The oligomeric compound of claim 22 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate internucleoside linking group.
40. The oligomeric compound of claim 22 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.