Bicyclic nucleosides and oligomeric compounds prepared therefrom
View Patent ↗The present invention provides novel 3′,5′-linked bicyclic nucleosides and oligomeric compounds prepared therefrom. The bicyclic nucleosides provided herein are useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as nuclease resistance.
1. A bicyclic nucleoside having Formula I:
wherein:
Bx is a heterocyclic base moiety;
T 1 is H or a hydroxyl protecting group;
T 2 is a phosphoramidite, H-phosphonate or phosphate triester;
Q is CH═CH, CE 1 E 2 -CE 3 E 4 , CH 2 OCH 2 , CH 2 SCH 2 or CH 2 N(G)CH 2 ;
E 1 , E 2 , E 3 and E 4 are each, independently, H, hydroxyl, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, amino or substituted amino;
G 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 t 1 and t 2 is H and the other of t 1 and t 2 is absent;
n is 0 or 1;
q 1 and q 2 are each independently, H, hydroxyl, halogen or O-A-[(C═O) m —X] j —Z;
A is 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 or substituted C 2 -C 6 alkynyl;
X is O, S or N(R 1 );
Z is H, halogen, 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, N(R 2 )(R 3 ) or a protecting group;
R 1 , R 2 and R 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
m is 0 or 1;
j is 0 or 1;
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 and N(H)C(═S)NJ 1 J 2 ;
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;
when j is 1 then Z is other than halogen or N(R 2 )(R 3 ); and
when n is 0 and Q is CH═CH or when n is 0 or 1 and Q is-CE 1 E 2 -CE 3 E 4 then at least one of E 1 E 2 E 3 E 4 , q 1 and q 2 is other than H.
2. The bicyclic nucleoside of claim 1 wherein n is 1.
3. The bicyclic nucleoside of claim 1 wherein n is 0.
4. The bicyclic nucleoside of claim 1 wherein Q is CE 1 E 2 -CE 3 E 4 .
5. The bicyclic nucleoside of claim 4 wherein at least one of E 1 , E 2 , E 3 and E 4 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.
6. The bicyclic nucleoside of claim 4 wherein E 1 , E 2 , E 3 and E 4 are each H.
7. The bicyclic nucleoside of claim 1 wherein Q is CH═CH, CH 2 OCH 2 , CH 2 SCH 2 or CH 2 N(G)CH 2 wherein G is H or CH 3 .
8. The bicyclic nucleoside of claim 1 wherein q 1 and q 2 are each independently H.
9. The bicyclic nucleoside of claim 1 wherein one of q 1 and q 2 is H and the other of q 1 and q 2 is hydroxyl, protected hydroxyl, fluoro, or substituted or unsubstituted O—C 1 -C 6 alkyl.
10. The bicyclic nucleoside of claim 1 wherein T 1 is 4,4′-dimethoxy -trityl and T 2 is diisopropylaminocyanoethoxy phosphoramidite.
11. The bicyclic nucleoside of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
12. The bicyclic nucleoside of claim 1 having Formula Ia, Ib, Ic or Id:
13. The bicyclic nucleoside of claim 1 wherein t 1 is H.
14. The bicyclic nucleoside of claim 1 wherein t 2 is H.
15. An oligomeric compound comprising at least one bicyclic nucleoside having Formula II:
wherein independently for each bicyclic nucleoside of Formula II:
Bx is a heterocyclic base moiety;
one of T 3 and T 4 is an internucleoside linking group attaching the bicyclic nucleoside of Formula II to the oligomeric compound and the other of T 3 and T 4 is hydroxyl, a protected hydroxyl, a terminal group or an internucleoside linking group attaching the bicyclic nucleoside of Formula II to the oligomeric compound;
Q is CH═CH, CE 1 E 2 -CE 3 E 4 , CH 2 OCH 2 , CH 2 SCH 2 or CH 2 N(G)CH 2 ;
E 1 , E 2 , E 3 and E 4 are each, independently, H, hydroxyl, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, amino or substituted amino;
G 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 t 1 and t 2 is H and the other of t 1 and t 2 is absent;
n is 0 or 1;
q 1 and q 2 are each independently, H, hydroxyl, halogen or O-A-[(C═O) m —X] j —Z;
A is 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 or substituted C 2 -C 6 alkynyl;
X is O,S or N(R 1 );
Z is H, halogen, 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, N(R 2 )(R 3 ) or a protecting group;
R 1 , R 2 and R 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
m is 0 or 1;
j is 0 or 1;
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 and N(H)C(═S)NJ 1 J 2 ;
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;
when j is 1 then Z is other than halogen or N(R 2 )(R 3 );
when n is 0 and Q is CH═CH or CE 1 E 2 -CE 3 E 4 then at least one of E 1 E 2 E 3 , E 4 , q 1 and q 2 is other than H and when n is 1 and Q is CE 1 E 2 -CE 3 E 4 then t 1 is H; and
wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and at least some of the heterocyclic base moieties are capable of hybridizing to a nucleic acid molecule.
16. The oligomeric compound of claim 15 wherein each n is 1.
17. The oligomeric compound of claim 15 wherein each n is 0.
18. The oligomeric compound of claim 15 wherein each Q is CE 1 E 2 -CE 3 E 4 .
19. The oligomeric compound of claim 15 wherein at least one of E 1 , E 2 , E 3 and E 4 is C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl for each bicyclic nucleoside of Formula II.
20. The oligomeric compound of claim 15 wherein E 1 , E 2 , E 3 and E 4 are each H for each bicyclic nucleoside of Formula II.
21. The oligomeric compound of claim 15 wherein Q is CH═CH, CH 2 OCH 2 , CH 2 SCH 2 or CH 2 N(G)CH 2 wherein G is H or CH 3 for each bicyclic nucleoside of Formula II.
22. The oligomeric compound of claim 15 wherein q 1 and q 2 are each H for each bicyclic nucleoside of Formula II.
23. The oligomeric compound of claim 15 wherein one of q 1 and q 2 is H and the other of q 1 and q 2 is hydroxyl, protected hydroxyl, fluoro, or substituted or unsubstituted O—C 1 -C 6 alkyl for each bicyclic nucleoside of Formula II.
24. The oligomeric compound of claim 15 wherein each Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
25. The oligomeric compound of claim 15 wherein each bicyclic nucleoside has Formula IIa, Formula IIb, Formula IIc or Formula IId:
26. The oligomeric compound of claim 15 wherein each t 1 is H.
27. The oligomeric compound of claim 15 wherein each t 2 is H.
28. The oligomeric compound of claim 15 comprising at least one region of from 2 to 5 contiguous bicyclic nucleosides of said formula.
29. The oligomeric compound of claim 15 comprising from about 12 to about 20 monomer subunits in length.