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, novel tetrahydropyran nucleoside analogs are provided having at least one chiral substituent that are expected to be useful for enhancing one or more properties of oligomeric compounds such as nuclease resistance and/or binding affinity. In certain embodiments, the oligomeric compounds are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
1. A tetrahydropyran nucleoside analog 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 selected from a phosphoramidite, an H-phosphonate, a phosphate triester or a phosphorus containing chiral auxiliary;
Q is CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , or CH 2 C(═O)N(H)CH 3 ;
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 , g 2 , g 3 , g 4 , g 5 , and g 6 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 or substituted C 2 -C 6 alkynyl;
wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , NJ 1 J 2 , ═NJ 1 , SJ 1 , N 3 , CN, OC(═L)J 1 , OC(═L)NJ 1 J 2 and NJ 3 C(═L)NJ 1 J 2 , wherein each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl, and L is O, S or NJ 1 .
2. The tetrahydropyran nucleoside analog of claim 1 wherein g 1 , g 2 , g 3 , g 4 , g 5 , and g 6 are each H.
3. The tetrahydropyran nucleoside analog of claim 1 wherein q 1 and q 2 are each H.
4. The tetrahydropyran nucleoside analog of claim 1 wherein q 1 is methyl and q 2 is H or q 2 is methyl and q 1 is H.
5. The tetrahydropyran nucleoside analog of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
6. The tetrahydropyran nucleoside analog of claim 1 wherein T 1 is selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl.
7. The tetrahydropyran nucleoside analog of claim 1 wherein T 1 is 4,4′-dimethoxytrityl and T 2 is diisopropylcyanoethoxy phosphoramidite.
8. The tetrahydropyran nucleoside analog of claim 1 wherein Q is CH 2 CH 2 F or CH 2 C(═O)N(H)CH 3 .
9. An oligomeric compound comprising at least one tetrahydropyran nucleoside analog of Formula II:
wherein independently for each of said at least one tetrahydropyran nucleoside analog of Formula II:
Bx is a heterocyclic base moiety capable of hydrogen bonding to a complementary 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 intemucleoside 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 or a 5′ or 3′-terminal group;
Q is CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , or CH 2 C(═O)N(H)CH 3 ;
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 , g 2 , g 3 , g 4 , g 5 , and g 6 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 or substituted C 2 -C 6 alkynyl; and
wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , NJ 1 J 2 , ═NJ 1 , SJ 1 , N 3 , CN, OC(═L)J 1 , OC(═L)NJ 1 J 2 and NJ 3 C(═L)NJ 1 J 2 , wherein each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl, and L is O, S or NJ 1 .
10. The oligomeric compound of claim 9 wherein each g 1 , g 2 , g 3 , g 4 , g 5 , and g 6 is H for each of said at least one tetrahydropyran nucleoside analog of Formula II.
11. The oligomeric compound of claim 9 wherein q 1 and q 2 are each H for each of said at least one tetrahydropyran nucleoside analog of Formula II.
12. The oligomeric compound of claim 9 wherein q 1 is methyl and q 2 is H, or q 2 is methyl and q 1 is H for each of said at least one tetrahydropyran nucleoside analog of Formula II.
13. The oligomeric compound of claim 9 wherein Q is CH 2 CH 2 F or CH 2 C(═O)N(H)CH 3 for each of said at least one tetrahydropyran nucleoside analog of Formula II.
14. The oligomeric compound of claim 9 comprising at least one region having at least 2 contiguous tetrahydropyran nucleoside analogs of Formula II.
15. The oligomeric compound of claim 9 comprising at least two regions wherein each region independently comprises from 1 to about 5 contiguous tetrahydropyran nucleoside analogs of Formula II and wherein the two regions are separated by an internal region comprising at least one monomer subunit wherein each monomer subunit in the internal region is, independently, a nucleoside or a modified nucleoside.
16. The oligomeric compound of claim 15 comprising a gapped oligomeric compound wherein one of said at least two regions of contiguous tetrahydropyran nucleoside analogs of Formula II is located at the 5′-end and the other of said at least two regions of contiguous tetrahydropyran nucleoside analogs of Formula II is located at the 3′-end and wherein the two regions are separated by an internal region comprising from about 6 to about 18 monomer subunits wherein each monomer subunit is, independently, a nucleoside or a modified nucleoside.
17. The oligomeric compound of or claim 16 wherein said internal region comprises from about 8 to about 14 contiguous β-D-2′-deoxyribofuranosyl nucleosides.
18. The oligomeric compound of claim 16 wherein said internal region comprises from about 9 to about 12 contiguous β-D-2′-deoxyribofuranosyl nucleosides.
19. The oligomeric compound of claim 9 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
20. The oligomeric compound of claim 9 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.
21. The oligomeric compound of any one of claim 9 comprising from about 8 to about 40 linked monomer subunits.
22. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 9 .