Tricyclic nucleic acid analogs
View Patent ↗The present disclosure provides tricyclic nucleosides and oligomeric compounds prepared therefrom. The tricyclic nucleosides each have a tricyclic ribosyl sugar moiety wherein a bridge between the 2′ and 4′ ribosyl ring carbon atoms further comprises a fused carbocyclic or heterocyclic ring. The tricyclic nucleosides are expected to be useful for enhancing properties of oligomeric compounds including for example binding affinity and nuclease resistance.
1. A tricyclic nucleoside having Formula I:
wherein:
Bx is a heterocyclic base moiety;
Q is CH 2 —CH 2 , CH═CH, O, S, or NR 1 ;
R 1 is H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl or a protecting group;
one of q 1 and q 2 is hydroxyl or a protected hydroxyl and the other of q 1 and q 2 is H;
one of q 3 and q 4 is hydroxyl, a protected hydroxyl or a reactive phosphorus group selected from a phosphoramidite, H-phosphonate and phosphate triester and the other of q 3 and q 4 is H;
wherein each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , CN, C(═O)OJ 1 , C(═O)NJ 1 J 2 , C(═O)J 1 , O—C(═O)NJ 1 J 2 , N(H)C(═O)—NJ 1 J 2 , N(H)C(═S)NJ 1 J 2 and a protecting group;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 aminoalkyl or a protecting group;
n is 1 or 2; and
m is 0 when Q is CH 2 —CH 2 or CH═CH and m is 1 when Q is O, S, or NR 1 .
2. The compound of claim 1 wherein Bx is a pyrimidine, substituted pyrimidine, purine or substituted purine.
3. The tricyclic nucleoside of claim 1 wherein n is 1.
4. The tricyclic nucleoside of claim 1 wherein Q is CH═CH or CH 2 —CH 2 .
5. The tricyclic nucleoside of claim 1 wherein Q is O, S or NR 1 wherein R 1 is H, C 1 -C 3 alkyl or substituted C 1 -C 3 alkyl.
6. The tricyclic nucleoside of claim 5 wherein R 1 is methyl.
7. The tricyclic nucleoside of claim 1 having the configuration of one of formulas Ia or Ib:
8. The tricyclic nucleoside of claim 7 wherein the tricyclic nucleoside has Formula Ia and q 1 and q 4 are each H or the tricyclic nucleoside has formula Ib and either q 1 and q 3 or q 2 and q 3 are each H.
9. The tricyclic nucleoside of claim 1 wherein one of q 1 and q 2 is a 4,4′-dimethoxytrityl protected hydroxyl group and one of q 3 and q 4 is diisopropylcyanoethoxy phosphoramidite.
10. An oligomeric compound comprising at least one tricyclic nucleoside having Formula II:
wherein independently for each tricyclic nucleoside having Formula II:
Bx is a heterocyclic base moiety;
Q is CH 2 —CH 2 , CH═CH, O , S, or NR 1 ;
R 1 is H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl or a protecting group;
wherein each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , CN, C(═O)OJ 1 , C(═O)NJ 1 J 2 , C(═O)J 1 , O—C(═O)NJ 1 J 2 , N(H)C(═O)—NJ 1 J 2 , N(H)C(═S)NJ 1 J 2 and a protecting group;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 aminoalkyl or a protecting group;
one of q 5 and q 6 is an internucleoside linking group linking the tricyclic nucleoside to the oligomeric compound, an optionally protected hydroxyl group or an oligomeric compound terminal group and the other of q 5 and q 6 is H;
one of q 7 and q 8 is an internucleoside linking group linking the tricyclic nucleoside to the oligomeric compound, an optionally protected hydroxyl group or an oligomeric compound terminal group and the other of q 7 and q 8 is H;
wherein at least one of q 5 , q 6 , q 7 and q 8 is an internucleoside linking group linking the tricyclic nucleoside to the oligomeric compound;
n is 1 or 2; and
m is 0 when Q is CH 2 —CH 2 or CH═CH and m is 1 when Q is O, S, or NR 1 .
11. The oligomeric compound of claim 10 wherein each Bx is, independently, uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine for each tricyclic nucleoside having Formula II.
12. The oligomeric compound of claim 10 wherein n is 1 for each tricyclic nucleoside having Formula II.
13. The oligomeric compound of claim 10 wherein each Q is CH═CH.
14. The oligomeric compound of claim 10 wherein each Q is CH 2 —CH 2 .
15. The oligomeric compound of claim 10 wherein each Q is O, S or NR 1 wherein R 1 is H, C 1 -C 3 alkyl or substituted C 1 -C 3 alkyl.
16. The tricyclic nucleoside of claim 10 wherein each R 1 is methyl.
17. The oligomeric compound of claim 10 wherein each tricyclic nucleoside has the configuration of one of formulas IIa or IIb:
18. The oligomeric compound of claim 17 wherein each tricyclic nucleoside has formula IIa and each q 5 and q 8 is H or each tricyclic nucleoside has Formula IIb and either each q 5 and q 7 or each q 6 and q 7 is H.
19. The oligomeric compound of claim 10 wherein each internucleoside linking group between adjacent monomeric subunits is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
20. The oligomeric compound of claim 10 wherein essentially each internucleoside linking group between adjacent monomeric subunits is a phosphorothioate internucleoside linking group.
21. The oligomeric compound of claim 10 comprising at least two contiguous tricyclic nucleosides having Formula II.