6-disubstituted or unsaturated bicyclic nucleic acid analogs
AssigneeIsis Pharmaceuticals, Inc.
InventorsPunit P. Seth, Eric E. Swayze
Life of this patent
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Abstract
The present disclosure describes 6-disubstituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, the 6-disubstituted bicyclic nucleosides each comprise a 2′-O—C(Ri)(R2)-4′ or 2′-O—C=(R3)(R.4)-4′ bridge wherein each R is, independently a substituent group and Ri and R2 include H. The 6-disubstituted bicyclic nucleosides are useful for enhancing properties of oligomeric compounds including nuclease resistance. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
Claims44
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;
- q1 and q2 are each, independently, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C1-C12 alkoxy, substituted C1-C12 alkoxy, OJ1, SJ1, SOJ1, SO2J1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═NH)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;
- or q1 and q2 together are ═C(q3)(q4);
- q3 and q4 are each, independently, H, halogen, C1-C12 alkyl or substituted C1-C12 alkyl;
- each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;
- and
- each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group.
An oligomeric compound comprising at least one bicyclic nucleoside having Formula III:
- wherein independently for each bicyclic nucleoside having Formula III:
- Bx is a heterocyclic base moiety;
- 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, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound;
- q1 and q2 are each, independently, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C1-C12 alkoxy, substituted C1-C12 alkoxy, OJ1, SJ1, SOJ1, SO2J1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═NH)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;
- or q1 and q2 together are ═C(q3)(q4);
- q3 and q4 are each, independently, H, halogen, C1-C12 alkyl or substituted C1-C12 alkyl;
- each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;
- each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group;
- and
- wherein said oligomeric compound comprises from 8 to about 40 linked nucleosides.
Dependencies are inferred from the claim text.