Tetrahydropyran nucleic acid analogs
View Patent ↗The present disclosure describes tetrahydropyran nucleoside analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, tetrahydropyran nucleoside analogs are provided, having one or more chiral substituents, that are useful for enhancing properties of oligomeric compounds including nuclease resistance and binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
1. A gapped oligomeric compound comprising at least two regions of from 1 to about 5 contiguous tetrahydropyran nucleoside analogs of Formula XIII wherein one of said at least two regions of contiguous tetrahydropyran nucleoside analogs of Formula XIII is located at the 5′-end and the other of said at least two regions of contiguous tetrahydropyran nucleoside analogs of Formula XIII is located at the 3′-end and wherein the two regions are separated by an internal region comprising from about 6 to about 14 monomer subunits wherein each monomer subunit is, independently, a nucleoside or a modified nucleoside;
wherein independently for each of said tetrahydropyran nucleoside analogs of Formula XIII:
Bx is a heterocyclic base moiety;
T 3 and T 4 are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the oligomeric compound or one of T 3 and T 4 is an internucleoside linking group linking the tetrahydropyran nucleoside analog 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;
q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 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;
R 3 and R 4 are each independently, H, hydroxyl, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 , OC(═X)J 1 , OC(═X)NJ 1 J 2 , NJ 3 C(═X)NJ 1 J 2 and CN, wherein X is O, S or NJ 1 and each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl; and
wherein said gapped oligomeric compound comprises at least two contiguous tetrahydropyran nucleoside analogs of Formula XIII that are linked by a phosphorothioate internucleoside linking group.
2. An oligomeric compound comprising at least two tetrahydropyran nucleoside analogs of the formula:
wherein independently for each of said tetrahydropyran nucleoside having said formula:
Bx is a heterocyclic base moiety;
T 3 and T 4 are each, independently, an internucleoside linking group linking the tetrahydropyran nucleoside analog to the oligomeric compound or one of T 3 and T 4 is an internucleoside linking group linking the tetrahydropyran nucleoside analog 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;
wherein said oligomeric compound comprises from about 8 to about 40 monomer subunits; and
wherein at least two of the tetrahydropyran nucleoside analogs of said formula are linked by a phosphorothioate internucleoside linking group.
3. The gapped oligomeric compound of claim 1 wherein one of R 3 and R 4 is H and the other of R 3 and R 4 is H, OCH 3 or F for each tetrahydropyran nucleoside analog of Formula XIII.
4. The gapped oligomeric compound of claim 1 comprising at least one β-D-2′-deoxyribonucleoside.
5. The gapped oligomeric compound of claim 4 wherein at least one β-D-2′-deoxyribonucleoside is linked to a tetrahydropyran nucleoside analog of Formula XIII by a phosphorothioate internucleoside linking group.
6. The oligomeric compound of claim 2 comprising at least one region of from 2 to about 5 contiguous tetrahydropyran nucleoside analogs of said formula.
7. The oligomeric compound of claim 6 further comprising at least one additional region of from 1 to about 5 contiguous monomer subunits other than β-D-ribonucleosides and β-D-2′-deoxyribonucleosides wherein the additional region is separated from the at least one region by at least one β-D-2′-deoxyribonucleoside.
8. The oligomeric compound of claim 6 further comprising at least one additional region of from 1 to about 5 contiguous tetrahydropyran nucleoside analogs of said formula wherein the at least one region of from 2 to about 5 contiguous tetrahydropyran nucleoside analogs of said formula is separated from the additional region of from 1 to about 5 contiguous tetrahydropyran nucleoside analogs of said formula by at least one nucleoside or modified nucleoside.
9. The oligomeric compound of claim 2 comprising at least two regions of from 1 to about 5 contiguous tetrahydropyran nucleoside analogs of said formula that are separated by at least one nucleoside or modified nucleoside.
10. The oligomeric compound of claim 9 comprising a gapped oligomeric compound wherein one of said at least two regions of contiguous tetrahydropyran nucleoside analogs of said formula is located at the 5′-end and the other of said at least two regions of contiguous tetrahydropyran nucleoside analogs of said formula is located at the 3′-end and wherein the two regions are separated by an internal region comprising from about 6 to about 14 monomer subunits wherein each monomer subunit is, independently, a nucleoside or a modified nucleoside.
11. The gapped oligomeric compound of claim 1 wherein each monomer subunit is a β-D-2′-deoxyribonucleoside.
12. The gapped oligomeric compound of claim 1 wherein at least one internucleoside linking group is a phosphodiester internucleoside linking group.
13. The gapped oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.
14. The gapped oligomeric compound of claim 1 wherein each q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is H.
15. The gapped oligomeric compound of claim 1 wherein at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 or q 7 is other than H.
16. The gapped oligomeric compound of claim 1 wherein at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 or q 7 is methyl.
17. The gapped oligomeric compound of claim 1 wherein each tetrahydropyran nucleoside analog of Formula XIII has the configuration of Formula XIV:
18. The gapped oligomeric compound of claim 1 wherein at least one tetrahydropyran nucleoside analog has Formula XV:
wherein:
Bx is a heterocyclic base moiety; and
R 5 is H, OCH 3 or F.
19. The gapped oligomeric compound of claim 18 wherein each tetrahydropyran nucleoside analog has Formula XV.
20. The gapped oligomeric compound of claim 19 wherein each R 5 is H.
21. The gapped oligomeric compound of claim 19 wherein each R 5 is OCH 3 .
22. The gapped oligomeric compound of claim 19 wherein each R 5 is F.
23. The oligomeric compound of claim 2 comprising from about 10 to about 21 monomer subunits.
24. The oligomeric compound of claim 2 comprising from about 12 to about 17 monomer subunits.
25. The oligomeric compound of claim 2 comprising from about 13 to about 16 monomer subunits.
26. The oligomeric compound of claim 2 comprising at least one β-D-2′-deoxyribonucleoside.
27. The oligomeric compound of claim 2 wherein at least one β-D-2′-deoxyribonucleoside is linked to a tetrahydropyran nucleoside analog of said formula by a phosphorothioate internucleoside linking group.
28. The oligomeric compound of claim 10 wherein each monomer subunit is a β-D-2′-deoxyribonucleoside.
29. The oligomeric compound of claim 2 wherein at least one internucleoside linking group is a phosphodiester internucleoside linking group.
30. The oligomeric compound of claim 2 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.