Bis-modified bicyclic nucleic acid analogs
View Patent ↗The present disclosure describes bis-modified bicyclic nucleosides and oligomeric compounds that can be prepared comprising at least one of these bis-modified bicyclic nucleosides. More particularly, the bis-modified bicyclic nucleosides have at least one substituent group at the 5′-methylene and on the bridge methylene and can be chiral. These bis-modified bicyclic nucleosides are expected to be useful for enhancing one or more property of oligomeric compounds including for example enhancing 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 V:
wherein independently for each monomer having Formula V:
Bx is a heterocyclic base moiety;
one of Z 1 and Z 2 is 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 or substituted C 2 -C 6 alkynyl and the other one of Z 1 and Z 2 is 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 or substituted C 2 -C 6 alkynyl;
one of Q 1 and Q 2 is 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, thiol or substituted thiol and the other one of Q 1 and Q 2 is 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, thiol or substituted thiol;
or Q 1 and Q 2 together are methylene (═CH 2 );
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, a linked conjugate group or a 5′ or 3′-terminal group;
wherein each substituted group is mono or poly substituted with substituent groups independently selected from halogen, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , COOJ 1 , CN, O—C(═O)NJ 1 J 2 , N(H)C(═NH)NJ 1 J 2 , N(H)C(═O)N(H)J 2 or N(H)C(═S)N(H)J 2 ;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 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; and
the sum of j and r is at least 1.
2. The oligomeric compound of claim 1 wherein for each monomer having Formula V, Z 1 or Z 2 is H and the other of Z 1 and Z 2 is 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 or substituted C 2 -C 6 alkynyl.
3. The oligomeric compound of claim 2 wherein the other of Z 1 and Z 2 is CH 2 F, CHF 2 or CF 3 .
4. The oligomeric compound of claim 2 wherein the other of Z 1 and Z 2 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.
5. The oligomeric compound of claim 2 wherein the other of Z 1 and Z 2 is CH 3 .
6. The oligomeric compound of claim 1 wherein for each monomer having Formula V, Q 1 and Q 2 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl wherein at least one of Q 1 and Q 2 is other than H.
7. The oligomeric compound of claim 1 wherein for each monomer having Formula V, one of Q 1 and Q 2 is H and the other of Q 1 and Q 2 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.
8. The oligomeric compound of claim 7 wherein the other of Q 1 and Q 2 is CH 3 .
9. The oligomeric compound of claim 1 wherein for each monomer having Formula V, one of Q 1 and Q 2 is H and the other of Q 1 and Q 2 is CH 2 F, CHF 2 or CF 3 .
10. The oligomeric compound of claim 1 wherein for each monomer having Formula V, Q 1 and Q 2 are each CH 3 .
11. The oligomeric compound of claim 1 wherein for each monomer having Formula V, Q 1 and Q 2 together are methylene (═CH 2 ).
12. The oligomeric compound of claim 1 wherein for each monomer having Formula V, one of Q 1 and Q 2 is H, the other of Q 1 and Q 2 is CH 3 , one of Z 1 or Z 2 is H and the other of Z 1 and Z 2 is CH 3 .
13. The oligomeric compound of claim 1 wherein for each monomer having Formula V, Bx is uracil, thymine, cytosine, 5-methylcytosine, 2,6-diaminopurine, adenine or guanine.
14. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate.
15. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate.
16. The oligomeric compound of claim 1 wherein for each monomer having Formula V, Z 2 and Q 2 are each H.
17. The oligomeric compound of claim 16 wherein Z 1 and Q 1 are each CH 3 for each monomer having Formula V.
18. The oligomeric compound of claim 1 wherein Z 2 and Q 1 are each H for each monomer having Formula V.
19. The oligomeric compound of claim 18 wherein Z 1 and Q 2 are each CH 3 for each monomer having Formula V.
20. The oligomeric compound of claim 1 wherein Z 1 and Q 2 are each H for each monomer having Formula V.
21. The oligomeric compound of claim 20 wherein Z 2 and Q 1 are each CH 3 for each monomer having Formula V.
22. The oligomeric compound of claim 1 wherein Z 1 and Q 1 are each H for each monomer having Formula V.
23. The oligomeric compound of claim 22 wherein Z 2 and Q 2 are each CH 3 for each monomer having Formula V.
24. The oligomeric compound of claim 1 comprising from about 8 to about 20 monomeric subunits.
25. The oligomeric compound of claim 1 comprising from about 10 to about 16 monomeric subunits.
26. The oligomeric compound of claim 1 comprising from about 10 to about 14 monomeric subunits.