6-modified bicyclic nucleic acid analogs
View Patent ↗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.
1. An oligomeric compound comprising at least one monomer having Formula IX:
wherein independently for each of said monomers having Formula IX:
Bx is a heterocyclic base moiety;
T 3 and T 4 are each, independently, an internucleoside linking group linking the monomer to the oligomeric compound or one of T 3 and T 4 is an internucleoside linking group linking the monomer to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group or a linked conjugate group;
Z is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from fluoro, OJ 1 , NJ 1 J 2 , SJ 1 and CN, wherein each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl or a protecting group; and
wherein said oligomeric compound comprises from about 8 to about 40 nucleosides and/or modified nucleosides or mimetics in length.
2. The oligomeric compound of claim 1 wherein each Z is methyl.
3. The oligomeric compound of claim 1 wherein each Z is CH 2 OCH 3 .
4. The oligomeric compound of claim 1 wherein each Z is CH 2 F, CHF 2 or CF 3 .
5. The oligomeric compound of claim 1 including at least one modified nucleoside wherein each modified nucleoside independently comprises a modified sugar moiety selected from a 4′-S modified sugar, a bicyclic modified sugar or a substituted sugar.
6. The oligomeric compound of claim 5 wherein each modified nucleoside comprises a modified sugar moiety independently selected from a 2′-F, 2′-OCH 3 , 2′-O—(CH 2 ) 2 —OCH 3 or a 2′-O—CH 2 -4′ modified sugar moiety.
7. The oligomeric compound of claim 1 comprising from about 8 to about 20 nucleosides and/or modified nucleosides or mimetics in length.
8. The oligomeric compound of claim 1 wherein essentially each internucleoside linkage is a phosphorothioate internucleoside linkage.
9. The oligomeric compound of claim 1 wherein essentially each internucleoside linkage is a phosphodiester internucleoside linkage.
10. An oligomeric compound having the formula:
G-[T-L] j -[R-L] q -R-[L-T] r -E III
wherein:
each R is a β-D-2′-deoxyribonucleoside;
each L is, independently, a phosphodiester or phosphorothioate internucleoside linking group;
G and E are each, independently, H, a hydroxyl protecting group or a linked conjugate group;
each T is a monomer of the Formula VIII:
wherein independently for each monomer having Formula VIII:
Bx is a heterocyclic base moiety;
Z is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from fluoro, OJ 1 , NJ 1 J 2 , SJ 1 and CN, wherein each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl or a protecting group;
q is from 8 to about 14;
j is 0 or from 1 to 5;
r is 0 or from 1 to 5; and
the sum of j and r is at least 1.
11. The oligomeric compound of claim 10 wherein each Z is methyl.
12. The oligomeric compound of claim 10 wherein each Z is CH 2 OCH 3 .
13. The oligomeric compound of claim 10 wherein each Z is CH 2 F, CHF 2 or CF 3 .
14. The oligomeric compound of claim 10 wherein j is 0.
15. The oligomeric compound of claim 10 wherein r is 0.
16. The oligomeric compound of claim 10 wherein j and r are each other than 0.
17. The oligomeric compound of claim 10 wherein j and r are each 2, q is 9 and G and H are each H.
18. The oligomeric compound of claim 10 wherein each L is a phosphodiester internucleoside linkage.
19. The oligomeric compound of claim 10 wherein each L is a phosphorothioate internucleoside linkage.