Carbocyclic alpha-L-bicyclic nucleic acid analogs
View Patent ↗The present invention provides novel carbocyclic α-L-bicyclic nucleosides and oligomeric compounds comprising at least one of these carbocyclic α-L-bicyclic nucleosides. The carbocyclic α-L-bicyclic nucleosides are useful for enhancing one or more properties of the oligomeric compounds they are incorporated into including 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 is 4′-C(q 1 )(q 2 )-C(q 3 )(q 4 )-2′,4′-C(q 1 )=C(q 3 )-2′,4′-C[═C(q 1 )(q 2 )]-C(q 3 )(q 4 )-2′ or 4′-C(q 1 )(q 2 )-C[═C(q 3 )(q 4 )]-2′;
q 1 , q 2 , q 3 and q 4 are each, independently, H, 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, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, OJ 1 , SJ 1 , SOJ 1 , SO 2 J 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(═NH)NJ 1 J 2 , N(H)C(═O)NJ 1 J 2 or N(H)C(═S)NJ 1 J 2 ;
wherein 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 ; and
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.
2. The bicyclic nucleoside of claim 1 wherein Q is 4′-C(q 1 )(q 2 )-C(q 3 )(q 4 )-2′,4′-C[═C(q 1 )(q 2 )]-C(q 3 )(q 4 )-2′ or 4′-C(q 1 )(q 2 )-C[═C(q 3 )(q 4 )]-2′.
3. The bicyclic nucleoside of claim 2 wherein q 1 , q 2 , q 3 and q 4 are each H.
4. The bicyclic nucleoside of claim 2 wherein three of q 1 , q 2 , q 3 and q 4 are H and the other one of q 1 , q 2 , q 3 and q 4 is other than H.
5. The bicyclic nucleoside of claim 2 wherein two of q 1 , q 2 , q 3 and q 4 are H and the other two of q 1 , q 2 , q 3 and q 4 are other than H.
6. The bicyclic nucleoside of claim 2 wherein at least one of q 1 , q 2 , q 3 and q 4 is F, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy.
7. The bicyclic nucleoside of claim 6 wherein at least one of q 1 , q 2 , q 3 and q 4 is CH 3 .
8. The bicyclic nucleoside of claim 6 wherein at least two of q 1 , q 2 , q 3 and q 4 are F.
9. The bicyclic nucleoside of claim 2 wherein three of q 1 , q 2 , q 3 and q 4 are H and the other one of q 1 , q 2 , q 3 and q 4 is CH 2 F, CHF 2 , CF 3 , CH 2 OH, C(═O)OJ 1 or C(═O)NJ 1 J 2 wherein 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.
10. The bicyclic nucleoside of claim 1 wherein Q is 4′-C(q 1 )=C(q 3 )-2′.
11. The bicyclic nucleoside of claim 10 wherein q 1 and q 3 are each H.
12. The bicyclic nucleoside of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methyl-cytosine, 2,6-diaminopurine, adenine or guanine.
13. The bicyclic nucleoside of claim 1 wherein T 1 is 4,4′-dimethoxytrityl.
14. The bicyclic nucleoside of claim 13 wherein T 2 is a reactive phosphorus group selected from diisopropylcyanoethoxy phosphoramidite or H-phosphonate.
15. An oligomeric compound comprising at least one bicyclic nucleoside having Formula III:
wherein independently for each of said at least one bicyclic nucleoside having Formula III:
Bx is a heterocyclic base moiety;
T 3 and T 4 are each, independently, an internucleoside linking group linking the bicyclic nucleoside having Formula III to the oligomeric compound or one of T 3 and T 4 is an internucleoside linking group linking the bicyclic nucleoside having Formula III to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group, a linked conjugate group or a 5′ or 3′-terminal group;
Bx is a heterocyclic base moiety;
Q is 4′-C(q 1 )(q 2 )-C(q 3 )(q 4 )-2′,4′-C(q 1 )=C(q 3 )-2′,4′-C[═C(q 1 )(q 2 )]-C(q 3 )(q 4 )-2′ or 4′-C(q 1 )(q 2 )-C[═C(q 3 )(q 4 )]-2′;
q 1 , q 2 , q 3 and q 4 are each, independently, H, 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, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, OJ 1 , SJ 1 , SOJ 1 , SO 2 J 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(═NH)NJ 1 J 2 , N(H)C(═O)NJ 1 J 2 or N(H)C(═S)NJ 1 ;
wherein 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 ; and
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.
16. The oligomeric compound of claim 15 wherein Q is 4′-C(q 1 )(q 2 )-C(q 3 )(q 4 )-2′,4′-C[═C(q 1 )(q 2 )]-C(q 3 )(q 4 )-2′ or 4′-C(q 1 )(q 2 )-C[═C(q 3 )(q 4 )]-2 for essentially each bicyclic nucleoside having Formula III.
17. The oligomeric compound of claim 16 wherein q 1 , q 2 , q 3 and q 4 are each H for essentially each bicyclic nucleoside having Formula III.
18. The oligomeric compound of claim 16 wherein three of q 1 , q 2 , q 3 and q 4 are H and the other one of q 1 , q 2 , q 3 and q 4 is other than H for essentially each bicyclic nucleoside having Formula III.
19. The oligomeric compound of claim 16 wherein two of q 1 , q 2 , q 3 and q 4 are H and the other two of q 1 , q 2 , q 3 and q 4 are other than H for essentially each bicyclic nucleoside having Formula III.
20. The oligomeric compound of claim 16 wherein at least one of q 1 , q 2 , q 3 and q 4 is F, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy for essentially each bicyclic nucleoside having Formula III.
21. The oligomeric compound of claim 20 wherein at least one of q 1 , q 2 , q 3 and q 4 is CH 3 for essentially each bicyclic nucleoside having Formula III.
22. The oligomeric compound of claim 20 wherein at least two of q 1 , q 2 , q 3 and q 4 are F for essentially each bicyclic nucleoside having Formula III.
23. The oligomeric compound of claim 16 wherein three of q 1 , q 2 , q 3 and q 4 are H and the other one of q 1 , q 2 , q 3 and q 4 is CH 2 F, CHF 2 , CF 3 , CH 2 OH, C(═O)OJ 1 or C(═O)NJ 1 J 2 wherein 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 for essentially each bicyclic nucleoside having Formula III.
24. The oligomeric compound of claim 15 wherein Q is 4′-C(q 1 )=C(q 3 )-2 for essentially each bicyclic nucleoside having Formula III.
25. The oligomeric compound of claim 24 wherein each q 1 and each q 3 is H.
26. The oligomeric compound of claim 15 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate.
27. The oligomeric compound of claim 15 wherein each internucleoside linking group is a phosphorothioate.
28. The oligomeric compound of claim 15 comprising at least two regions wherein each region independently comprises from 1 to about 5 contiguous bicyclic nucleosides having Formula III and wherein the two regions are separated by an internal region comprising at least one monomer subunit other than a bicyclic nucleoside having Formula III.
29. The oligomeric compound of claim 15 comprising from about 8 to about 40 monomeric subunits.
30. The oligomeric compound of claim 15 comprising from about 8 to about 20 monomeric subunits.
31. The oligomeric compound of claim 15 comprising from about 10 to about 16 monomeric subunits.
32. The oligomeric compound of claim 15 comprising from about 10 to about 14 monomeric subunits.