Modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom
The present invention provides modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides and analogs thereof that are useful for incorporation at the terminus of an oligomeric compound. Such oligomeric compounds can also be included in a double stranded composition. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
1. An oligomeric compound comprising at the 5′-position a moiety having Formula IIc:
wherein:
Bx 1 is a heterocyclic base moiety;
T 1 is an optionally protected phosphorus moiety having the formula:
T 2 is an internucleoside linking group linking the compound of Formula IIc to the oligomeric compound;
A has one of the formulas:
R a and R c are each, independently, OH, SH, protected hydroxyl, protected thiol, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, protected amino or substituted amino;
R b is O or S;
Q 1 and Q 2 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or substituted C 1 -C 6 alkoxy;
M 3 is OC(R 15 )(R 16 );
R 15 and R 16 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
J 4 , J 5 , J 6 and J 7 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
or J 4 forms a bridge with J 5 or J 7 wherein said bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR 19 , C(R 20 )(R 21 ), C(R 20 )═C(R 21 ), C[═C(R 20 )(R 21 )] and C(═O) and the other two of J 5 , J 6 and J 7 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
R 19 , R 20 and R 21 are each, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
G is H, OH, halogen or O—[C(R 8 )(R 9 )] n —[(C═O) m —X 1 ] i —Z;
R 8 and R 9 are each, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
X 1 is O, S or N(E 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 or N(E 2 )(E 3 );
E 1 , E 2 and E 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
n is from 1 to about 6;
m is 0 or 1;
j is 0 or 1;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), ═NJ 1 , Sh 1 , N 3 , CN, OC(═X)J 1 , OC(═X)N(J 1 )(J 2 ) and C(═X)N(J 1 )(J 2 );
X is O, S or NJ 3 ; and
J 1 , J 2 and J 3 are each, independently, H or C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein each of J 4 , J 5 , J 6 , J 7 , R 15 and R 16 is H.
3. The compound of claim 1 , wherein T 1 -A is
4. The compound of claim 1 , wherein exactly one of J 7 and G is F and the other of J 7 and G is H.
5. The compound of claim 1 , wherein G is OMe and J 7 is H.
6. The compound of claim 1 , wherein G is O(CH 2 ) 2 OCH 3 and J 7 is H.
7. The compound of claim 1 , wherein Q 1 and Q 2 are each, independently, H or C 1 -C 6 alkyl.
8. The compound of claim 1 , wherein Q 1 and Q 2 are each H.
9. The compound of claim 1 , wherein R a and R c are each, independently, OH, OCH 3 , OCH 2 CH 3 , or OCH(CH 3 ) 2 .
10. The compound of claim 9 , wherein R b is O.
11. An oligomeric compound comprising at the 5′-position a moiety having formula IIc:
wherein:
Bx is a heterocyclic base moiety;
T 1 is an optionally protected phosphorus moiety having the formula:
T 2 is an internucleoside linking group linking the compound of Formula IIc to the oligomeric compound;
A has one of the formulas:
R a and R c are each, independently, OH, SH, protected hydroxyl, protected thiol, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, protected amino or substituted amino;
R b is O or S;
Q 1 and Q 2 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or substituted C 1 -C 6 alkoxy;
M 3 is C(R 15 )═C(R 17 );
R 15 and R 17 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
J 4 , J 5 , J 6 and J 7 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
or J 4 forms a bridge with J 5 or J 7 wherein said bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR 19 , C(R 20 )(R 21 ), C(R 20 )═C(R 21 ), C[═C(R 20 )(R 21 )] and C(═O) and the other two of J 5 , J 6 and J 7 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
each R 19 Rao and R 21 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
G is H, OH, halogen or O—[C(R 8 )(R 9 )] n —[(C═O) m —X 1 ] j —Z;
each R 8 and R 9 is, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
X 1 is O, S or N(E 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 or N(E 2 )(E 3 );
E 1 , E 2 and E 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
n is from 1 to about 6;
m is 0 or 1;
j is 0 or 1;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), ═NJ 1 , SJ 1 , N 3 , CN, OC(═X)J 1 , OC(=X)N(J 1 )(J 2 ) and C(═X)N(J 1 )(J 2 );
X is O, S or NJ 3 ; and
J 1 , J 2 and J 3 are each, independently, H or C 1 -C 6 alkyl.
12. The compound of claim 11 , wherein each of J 4 , J 5 , J 6 , J 7 , R 15 and R 17 is H.
13. The compound of claim 11 , wherein each of J 4 , J 5 , J 6 , J 7 , R 15 and R 17 is H; exactly one of J 7 and G is H, and the other of J 7 and G is a sugar substituent group selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and substituted C 1 -C 6 alkoxy; wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), ═NJ 1 , SJ 1 , N 3 , CN, OC(═X)J 1 , OC(═X)N(J 1 )(J 2 ) and C(═X)N(J 1 )(J 2 );
X is O, S or NJ 3 ; and
J 1 , J 2 and J 3 are each, independently, H or C 1 -C 6 alkyl.
14. The compound of claim 13 , wherein exactly one of J 7 and G is H and the other is F.
15. The compound of claim 13 , wherein exactly one of J 7 and G is H and the other is OMe or O(CH 2 ) 2 OCH 3 .
16. The compound of claim 11 , wherein T 1 -A is
17. The compound of claim 11 , wherein Q 1 and Q 2 are each, independently, H or C 1 -C 6 alkyl.
18. The compound of claim 11 , wherein Q 1 and Q 2 are each H.
19. The compound of claim 11 , wherein R a and R c are each, independently, OH, OCH 3 , OCH 2 CH 3 , or OCH(CH 3 ) 2 .
20. The compound of claim 19 , wherein R b is O.