Bis-modified bicyclic nucleic acid analogs
AssigneeIsis Pharmaceuticals, Inc.
InventorsPunit P. Seth, Eric E. Swayze
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Abstract
The present disclosure describes bis-modified bicyclic nucleosides and oligomeric compounds that can be prepared comprising at least one of these bis-modified bicyclic nucleosides. More particularly, the bis-modified bicyclic nucleosides have at least one substituent group at the 5′-methylene and on the bridge methylene and can be chiral. These bis-modified bicyclic nucleosides are expected to be useful for enhancing one or more property of oligomeric compounds including for example enhancing nuclease resistance.
Claims68
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;
- one of Z1 and Z2 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl and the other one of Z1 and Z2 is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;
- one of Q1 and Q2 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, thiol or substituted thiol and the other one of Q1 and Q2 is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, thiol or substituted thiol;
- or Q1 and Q2 together are methylene (═CH2);
- each substituted group is 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, N(H)C(═O)N(H)J2 or N(H)C(═S)N(H)J2;
- 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 having at least one bicyclic nucleoside of Formula III:
- wherein independently for each bicyclic nucleoside having Formula III:
- Bx is a heterocyclic base moiety;
- T3 and T4 are each, independently, an internucleoside linking group linking the bicyclic nucleoside of Formula III to the oligomeric compound or one of T3 and T4 is an internucleoside linking group linking the bicyclic nucleoside of Formula III 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;
- one of Z1 and Z2 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl and the other one of Z1 and Z2 is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;
- one of Q1 and Q2 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, thiol or substituted thiol and the other one of Q1 and Q2 is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, thiol or substituted thiol;
- or Q1 and Q2 together are methylene (═CH2);
- each substituted group is 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, N(H)C(═O)N(H)J2 or N(H)C(═S)N(H)J2;
- and
- each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group.
Dependencies are inferred from the claim text.