Bicyclic abasic nucleic acid analogs and oligomeric compounds prepared therefrom
AssigneeShanghai Argo Biopharmaceutical Co., Ltd.
InventorsDongxu SHU, Pengcheng Patrick SHAO
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Abstract
The present invention relates to bicyclic abasic nucleic acid analogs and oligomeric compounds prepared therefrom, and more particularly, to a bicyclic abasic nucleic acid analog, and a bicyclic abasic nucleic acid analog monomeric compound that can be used for being incorporated into one or two termini of an oligomeric compound. The oligomeric compound is delivered in vivo to cells requiring specific targeting, and in addition to liver-related tissues, the oligomeric compound can also be delivered to extrahepatic tissues such as ophthalmic and CNS target cells.
Claims52
A compound, having a structure represented by formula (I) or a stereoisomer thereof:
- wherein A1 and A2 are each independently selected from O, S, SO, SO2, NR2, and CR3R4;
- R2, R3, and R4 are each independently selected from hydrogen, halogen, sulfonyl, sulfinyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, and substituted or unsubstituted 5- to 12-membered heterocyclyl;
- one of T1 and T2 is a protecting group, Z, L, or —Z-L, wherein Z represents a targeting group or a lipophilic group, the lipophilic group being optionally linked to one of A1 or A2 via a linker, and L represents a carrier spacer or a carrier moiety linked via a spacer;
- the other of T1 and T2 is an active phosphorus group or a protecting group;
- and T1 and T2 are not protecting groups simultaneously;
- each R1 is independently selected from halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, and substituted or unsubstituted 5- to 12-membered heterocyclyl;
- n is an integer of 0-6;
- wherein formula (I) does not comprise the following structure:
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An oligomeric compound, comprising at least one 5′-terminal and/or 3′-terminal monomer represented by formula (III) or a stereoisomer thereof:
- wherein A1 and A2 are each independently selected from O, S, SO, SO2, NR2, and CR3R4;
- R2, R3, and R4 are each independently selected from hydrogen, halogen, sulfonyl, sulfinyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, and substituted or unsubstituted 5- to 12-membered heterocyclyl;
- one of T3 and T4 is H, a protecting group, a lipophilic group, or optionally a covalent bond;
- the lipophilic group is optionally linked to one of A1 or A2 via a linker;
- and the other of T3 and T4 is an internucleoside linking group that links the monomer of formula (III) or the stereoisomer thereof to the oligomeric compound;
- each R1 is independently selected from halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C5-C12 aryl, substituted or unsubstituted 5- to 12-membered heteroaryl, and substituted or unsubstituted 5- to 12-membered heterocyclyl;
- n is an integer of 0-6;
- the oligomeric compound optionally further comprises a targeting group.
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The oligomeric compound according to claim 29, wherein:
- (i) the other of T3 and T4 is:
- (a) an internucleoside linking group that links the monomer to the 5′-end and/or the 3′-end of the oligomeric compound, and the internucleoside linking group is selected from a phosphorus-containing linking group and a phosphorus-free linking group;
- (b) a protecting group, a lipophilic group, or optionally a covalent bond;
- the lipophilic group is optionally linked to one of A1 or A2 via a linker;
- and
- the other of T3 and T4 is an internucleoside linking group that links the monomer according to any one of claims 29-52 to the 5′-end of the oligomeric compound,
- (c) one of T3 and T4 is H, a protecting group, a lipophilic group, or optionally a covalent bond;
- the lipophilic group is optionally linked to one of A1 or A2 via a linker;
- and the other of T3 and T4 is an internucleoside linking group that links the monomer according to any one of claims 29-52 to the 3′-end of the oligomeric compound;
- or
- (d) one of T3 and T4 is H, a protecting group a lipophilic group, or optionally a covalent bond;
- the lipophilic group is optionally linked to one of A1 or A2 via a linker;
- and the other of T3 and T4 is an internucleoside linking group that independently links one identical or different monomer according to any one of claims 29-52 to the 5′-end and the 3′-end of the oligomeric compound;
- (ii) each R1 is independently selected from halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl;
- and/or
- (ii) n is 0.
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Dependencies are inferred from the claim text.