Provided herein are bicyeMc nucleosides comprising a substituted amino group in the bridge, oligomeric compounds having at least one of these bicyclic nucleosides and methods of using the oligomeric compounds. The bicyclic nucleosides comprising a substituted amino group in the bridge are useful for
Provided herein are bicyeMc nucleosides comprising a substituted amino group in the bridge, oligomeric compounds having at least one of these bicyclic nucleosides and methods of using the oligomeric compounds. The bicyclic nucleosides comprising a substituted amino group in the bridge are useful for enhancing properties of oligomeric compounds including nuclease resistance, in certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
대표청구항▼
1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;R is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted
1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;R is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;q1 and q2 are each independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl, C1-C6 alkoxyl, substituted C1-C6 alkoxyl, acyl, substituted acyl, C1-C6 aminoalkyl or substituted C1-C6 aminoalkyl;q3 and q4 are each independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl, C1-C6 alkoxyl, substituted C1-C6 alkoxyl, acyl, substituted acyl, C1-C6 aminoalkyl or substituted C1-C6 aminoalkyl;wherein each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ1, SJ1, NJ1J2, N3, COOJ1, CN, O—C(═O)NJ1J2, N(H)C(═NH)NJ1J2 or N(H)C(═X)N(H)J2 wherein X is O or S; andeach J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group. 2. The bicyclic nucleoside of claim 1 wherein R is C1-C6 alkyl or substituted C1-C6 alkyl. 3. The bicyclic nucleoside of claim 2 wherein R is methyl, —(CH2)2OCH3 or —(CH2)2F. 4. The bicyclic nucleoside of claim 1 having Formula I and further having the configuration of Formula Ia: 5. The bicyclic nucleoside of claim 1 having Formula I and further having the configuration of Formula Ib: 6. The bicyclic nucleoside of claim 1 wherein one of q1, q2, q3 and q4 is CH3 and the other three of q1, q2, q3 and q4 are independently H. 7. The bicyclic nucleoside of claim 1 wherein one of q1 and q2 is CH3 and one of q3 and q4 is CH3 and the other two of q1, q2, q3 and q4 are independently H. 8. The bicyclic nucleoside of claim 1 wherein T1 is H or 4,4′-dimethoxy-trityl and T2 is H, diisopropylcyanoethoxy phosphoramidite or H-phosphonate. 9. The bicyclic nucleoside of claim 1 wherein T1 is 4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 10. The bicyclic nucleoside claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, 5-thiazolo-uracil, 5-thiazolo-cytosine, adenine, guanine, 2,6-diaminopurine, or other substituted or unsubstituted purine or pyrimidine. 11. An oligomeric compound comprising at least one bicyclic nucleoside having Formula II: wherein independently for each of said at least one bicyclic nucleoside having Formula II: Bx is a heterocyclic base moiety;T3 and T4 are each, independently, an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound or one of T3 and T4 is an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound and the other of T3 and T4 is H, a hydroxyl protecting group, a linked conjugate group or a 5′ or 3′-terminal group;R is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;q1 and q2 are each independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl, C1-C6 alkoxyl, substituted C1-C6 alkoxyl, acyl, substituted acyl, C1-C6 aminoalkyl or substituted C1-C6 aminoalkyl;q3 and q4 are each independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl, C1-C6 alkoxyl, substituted C1-C6 alkoxyl, acyl, substituted acyl, C1-C6 aminoalkyl or substituted C1-C6 aminoalkyl;wherein each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ1, SJ1, NJ1J2, N3, COOJ1, CN, O—C(═O)NJ1J2, N(H)C(═NH)NJ1J2 or N(H)C(═X)N(H)J2 wherein X is O or S; andeach J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group. 12. The oligomeric compound of claim 11 wherein for each bicyclic nucleoside having Formula II R is C1-C6 alkyl or substituted C1-C6 alkyl. 13. The oligomeric compound of claim 11 wherein for each bicyclic nucleoside having Formula II R is methyl, —(CH2)2OCH3 or —(CH2)2F. 14. The oligomeric compound of claim 11 wherein each bicyclic nucleoside having Formula II has the configuration of Formula IIa: 15. The oligomeric compound of claim 11 wherein each bicyclic nucleoside having Formula II has the configuration of Formula IIb: 16. The oligomeric compound of claim 11 wherein independently for each bicyclic nucleoside having Formula II one of q1, q2, q3 and q4 is CH3 and the other three of q1, q2, q3 and q4 are independently H. 17. The oligomeric compound of claim 11 wherein independently for each bicyclic nucleoside having Formula II one of q1 and q2 is CH3 and one of q3 and q4 is CH3 and the other two of q1, q2, q3 and q4 are independently H. 18. The oligomeric compound of claim 11 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate. 19. The oligomeric compound of claim 11 comprising at least one region of at least two contiguous bicyclic nucleosides having Formula II located at either the 3′ or the 5′-end of the oligomeric compound. 20. The oligomeric compound of claim 11 comprising gapped oligomeric compound having at least two regions, each region comprising from 1 to about 5 contiguous bicyclic nucleosides having Formula II, wherein one of said regions of bicyclic nucleosides having Formula II is located externally at the 5′-end and the other of said regions is located externally at the 3′-end and wherein the two external regions are separated by an internal region comprising from about 6 to about 14 monomeric subunits independently selected from nucleosides and modified nucleosides. 21. The oligomeric compound of claim 11 comprising from about 8 to about 40 monomers in length. 22. The oligomeric compound of claim 11 comprising from about 12 to about 16 monomers in length. 23. A method of inhibiting gene expression comprising contacting a cell with an oligomeric compound comprising at least one bicyclic nucleoside of claim 11 and wherein said oligomeric compound comprises from about 8 to about 40 monomeric subunits and is complementary to a target RNA. 24. The method of claim 23 wherein said cell is in an animal. 25. The method of claim 23 wherein said cell is in a human. 26. The method of claim 23 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA. 27. The method of claim 23 wherein said target RNA is mRNA. 28. The method of claim 23 wherein said target RNA is human mRNA. 29. The method of claim 23 wherein said target RNA is cleaved thereby inhibiting its function. 30. The method of claim 23 further comprising detecting the levels of target RNA.
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