Substituted 2′-amino and 2′-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom
View Patent ↗Provided herein are 2′-amino and 2′-thio bicyclic nucleosides and oligomenc compounds prepared therefrom. The novel bicyclic nucleosides provided herein are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as nuclease resistance.
1. A bicyclic nucleoside having Formula I:
wherein:
Bx is a heterocyclic base moiety;
one of T 1 and T 2 is H or a hydroxyl protecting group and the other of T 1 and T 2 is H, a hydroxyl protecting group or a reactive phosphorus group;
Q 1 and Q 2 are each 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 or substituted C 2 -C 6 alkynyl;
G 1 and G 2 are each 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 or substituted C 2 -C 6 alkynyl;
Z is S or NR;
R is H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl or substituted acyl;
each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , CN, C(═O)OJ 1 , C(═O)NJ 1 J 2 , C(═O)J 1 , O—C(═O)NJ 1 J 2 , N(H)C(═O)NJ 1 J 2 and N(H)C(═S)NJ 1 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; and
wherein at least one of Q 1 , Q 2 , G 1 and G 2 is other than H.
2. The bicyclic nucleoside of claim 1 wherein Bx is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
3. The bicyclic nucleoside of claim 1 wherein T 1 is 4,4′-dimethoxytrityl and T 2 is diisopropylcyanoethoxy phosphoramidite.
4. The bicyclic nucleoside of claim 1 wherein Q 1 and Q 2 are each H.
5. The bicyclic nucleoside of claim 1 wherein 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.
6. The bicyclic nucleoside of claim 1 wherein one of Q 1 and Q 2 is CH 3 .
7. The bicyclic nucleoside of claim 1 wherein G 1 and G 2 are each H.
8. The bicyclic nucleoside of claim 1 wherein one of G 1 and G 2 is H and the other of G 1 and G 2 is C 1 -C 6 alkyl or substituted C 1 -C 6 alky.
9. The bicyclic nucleoside of claim 1 wherein at least one of G 1 and G 2 is CH 3 .
10. The bicycle nucleoside of claim 1 wherein Z is NR wherein R is H or C 1 -C 6 alkyl.
11. The bicyclic nucleoside of claim 10 wherein R is CH 3 .
12. The bicyclic nucleoside of claim 1 wherein Z is S.
13. The bicyclic nucleoside of claim 1 having Formula Ia:
14. The bicyclic nucleoside of claim 13 wherein three of Q 1 , Q 2 , G 1 and G 2 are H and the other one of Q 1 , Q 2 , G 1 and G 2 is CH 3 .
15. The bicyclic nucleoside of claim 13 wherein two of Q 1 , Q 2 , G 1 and G 2 are H and the remaining two of Q 1 , Q 2 , G 1 and G 2 are CH 3 wherein the two that are CH 3 are selected from Q 1 and G 1 , Q 1 and G 2 , Q 2 and G 1 , and Q 2 and G 2 .
16. An oligomeric compound comprising at least one bicyclic nucleoside of Formula II:
wherein independently for each bicyclic nucleoside of Formula II:
Bx is a heterocyclic base moiety;
one of T 3 and T 4 is an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound;
Q 1 and Q 2 are each 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 or substituted C 2 -C 6 alkynyl;
G 1 and G 2 are each 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 or substituted C 2 -C 6 alkynyl;
Z is S or NR;
R is H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl or substituted acyl;
each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , CN, C(═O)OJ 1 , C(═O)NJ 1 J 2 , C(═O)J 1 , O—C(═O)NJ 1 J 2 , N(H)C(═O)NJ 1 J 2 and N(H)C(═S)NJ 1 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; and
wherein at least one of Q 1 , Q 2 , G 1 and G 2 is other than H.
17. The oligomeric compound of claim 16 wherein Bx is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine for each bicyclic nucleoside of Formula II.
18. The oligomeric compound of claim 16 wherein at least one of T 3 and T 4 is a 5′ or 3′-terminal group.
19. The oligomeric compound of claim 16 wherein Q 1 and Q 2 are each H for each bicyclic nucleoside of Formula II.
20. The oligomeric compound of claim 16 wherein 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 for each bicyclic nucleoside of Formula II.
21. The oligomeric compound of claim 20 wherein one of Q 1 and Q 2 is CH 3 for each bicyclic nucleoside of Formula II.
22. The oligomeric compound of claim 16 wherein G 1 and G 2 are each H for each bicyclic nucleoside of Formula II.
23. The oligomeric compound of claim 16 wherein one of G 1 and G 2 is H and the other of G 1 and G 2 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl for each bicyclic nucleoside of Formula II.
24. The oligomeric compound of claim 23 wherein one of G 1 and G 2 is CH 3 for each bicyclic nucleoside of Formula II.
25. The oligomeric compound of claim 16 wherein Z is NR and wherein R is H or C 1 -C 6 alkyl for each bicyclic nucleoside of Formula II.
26. The oligomeric compound of claim 25 wherein R is CH 3 for each bicycle nucleoside of Formula II.
27. The oligomeric compound of claim 16 wherein each bicyclic nucleoside has Formula IIa:
28. The oligomeric compound of claim 27 wherein three of Q 1 , Q 2 , G 1 and G 2 are H and the other one of Q 1 , Q 2 , G 1 and G 2 is CH 3 for each bicyclic nucleoside of Formula IIa.
29. The oligomeric compound of claim 27 wherein two of Q 1 , Q 2 , G 1 and G 2 are H and the remaining two of Q 1 , Q 2 , G 1 and G 2 are CH 3 wherein the two that are CH 3 are selected from Q 1 and G 1 , Q 1 and G 2 , Q 2 and G 1 , Q 2 and G 2 for each bicyclic nucleoside of Formula IIa.
30. The oligomeric compound of claim 16 comprising at least two regions wherein each region independently comprises from 1 to about 5 contiguous bicyclic nucleosides of Formula II and wherein the two regions are separated by an internal region comprising at least one monomer subunit different from bicycle nucleosides having Formula II and independently selected from nucleosides and modified nucleosides.
31. The oligomeric compound of claim 30 comprising a gapped oligomeric compound wherein one region of contiguous bicyclic nucleosides of Formula II is located at the 5′-end and a second region of contiguous bicyclic nucleosides of Formula II is located at the 3′-end, wherein the two regions are separated by an internal region comprising from about 6 to about 18 monomer subunits different from bicycle nucleosides having Formula II and independently selected from nucleosides and modified nucleosides.
32. The oligomeric compound of claim 16 wherein each inter-nucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
33. The oligomeric compound of claim 16 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.
34. A method comprising contacting a cell with an oligomeric compound of claim 16 wherein said oligomeric compound is complementary to a target RNA.
35. The method of claim 34 wherein said cell is in an animal.
36. The method of claim 34 wherein said cell is in a human.