Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom
AssigneeIonis Pharmaceuticals, Inc.
InventorsPunit P. Seth, Eric E. Swayze
Life of this patent
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Abstract
The present invention provides novel bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom. Incorporation of one or more of the bicyclic carbocyclic nucleosides into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in modulation of normal function of the target RNA. In certain embodiments, bicyclic carbocyclic nucleosides are provided as monomers for use as antivirals.
Claims28
A bicyclic carbocyclic nucleoside having Formula I:
- wherein:
- Bx is an optionally protected heterocyclic base moiety;
- T1 is a protected hydroxyl;
- T2 is a reactive phosphorus group capable of forming an internucleoside linkage selected from diisopropylcyanoethoxy phosphoramidite and H-phosphonate;
- Q is halogen or O—[C(A1)(A2)]n-[(C═O)m—X]j—Z wherein Q is other than a protected hydroxyl group;
- A1 and A2 are each, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;
- X is O, S or N(E1);
- Z is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or N(E2)(E3);
- E1, E2 and E3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;
- n is from 1 to about 6;
- m is 0 or 1;
- j is 0 or 1 provided that when j is 1 then Z is other than halogen or N(E2)(E3);
- L1 and L2 are each H or one of L1 and L2 is H and the other of L1 and L2 is C1-C6 alkyl or substituted C1-C6 alkyl;
- R1, R2, R3, R4, R5 and R6 are each H or one of R1, R2, R3, R4, R5 and R6 is F, CH3 or OCH3 and the remaining of R1, R2, R3, R4, R5 and R6 are each H;
- each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, OC(=G)J1, OC(=G)N(J1)(J2) and C(=G)N(J1)(J2);
- G is O, S or NJ3;
- and
- each J1, J2 and J3 is, independently, H or C1-C6 alkyl.
An oligomeric compound comprising at least one bicyclic carbocyclic nucleoside having Formula II:
- wherein independently for each bicyclic carbocyclic nucleoside of Formula II
- Bx is an optionally protected heterocyclic base moiety;
- one of T3 and T4 is an internucleoside linking group attaching the bicyclic nucleoside to the remainder of one of the 5′ or 3′ end of the oligomeric compound and the other of T3 and T4 is hydroxyl, a protected hydroxyl, a 5′ or 3′ terminal group or an internucleoside linking group attaching the bicyclic nucleoside to the remainder of the other of the 5′ or 3′ end of the oligomeric compound;
- Q is halogen or O—[C(A1)(A2)]n-[(C═O)m—X]j—Z wherein Q is other than a protected hydroxyl group;
- A1 and A2 are each, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;
- X is O, S or N(E1);
- Z is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or N(E2)(E3);
- E1, E2 and E3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;
- n is from 1 to about 6;
- m is 0 or 1;
- j is 0 or 1 provided that when j is 1 then Z is other than halogen or N(E2)(E3);
- L1 and L2 are each H or one of L1 and L2 is H and the other of L1 and L2 is C1-C6 alkyl, or substituted C1-C6 alkyl;
- R1, R2, R3, R4, R5 and R6 are each H or one of R1, R2, R3, R4, R5 and R6 is F, CH3 or OCH3 and the remaining of R1, R2, R3, R4, R5 and R6 are each H;
- each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, OC(=G)J1, OC(=G)N(J1)(J2) and C(=G)N(J1)(J2);
- G is O, S or NJ3;
- each J1, J2 and J3 is, independently, H or C1-C6 alkyl;
- and
- wherein said oligomeric compound comprises from 8 to 40 monomeric subunits linked by internucleoside linking groups and wherein at least some of the heterocyclic base moieties are capable of hybridizing to a nucleic acid molecule.
Dependencies are inferred from the claim text.