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. A compound having Formula I f :
wherein:
T 1 is a phosphorus moiety having the formula:
R a and R c are each, independently, 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;
M 1 is H, OH or OR 1 ;
M 2 is OH, OR 1 or N(R 1 )(R 2 );
each R 1 and R 2 is, independently, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
r is 0 or 1;
A has one of the formulas:
Q 1 and Q 2 are each, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
Q 3 is O, S, N(R 5 ) or C(R 6 )(R 7 );
each R 5 , R 6 and R 7 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
Bx 1 is a heterocyclic base moiety;
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 2 )J 1 , OC(═X 2 )N(J 1 )(J 2 ) and C(═X 2 )N(J 1 )(J 2 );
X 2 is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl; and
when j is 1 then Z is other than halogen or N(E 2 )(E 3 ).
2. The compound of claim 1 wherein Q 3 is C(R 6 )(R 7 ).
3. The compound of claim 2 wherein R 6 and R 7 are each, independently, H or C 1 -C 6 alkyl.
4. The compound of claim 2 wherein R 6 and R 7 are each H.
5. The compound of claim 1 wherein Q 3 is O, S or N(R 5 ) wherein R 5 is H or C 1 -C 6 alkyl.
6. The compound of claim 1 wherein Q 1 and Q 2 are each, independently, H or C 1 -C 6 alkyl.
7. The compound of claim 1 wherein Q 1 and Q 2 are each H.
8. The compound of claim 1 wherein G is halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 10 )(R 11 ), O(CH 2 ) 2 —ON(R 10 )(R 11 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 12 )—(CH 2 ) 2 —N(R 10 )(R 11 ) or O(CH 2 ) 2 —N(R 12 )—C(═NR 13 )[N(R 10 )(R 11 )] wherein R 10 , R 11 , R 12 and R 13 are each, independently, H or C 1 -C 6 alkyl.
9. The compound of claim 1 wherein said heterocyclic base moiety is a pyrimidine, substituted pyrimidine, purine or substituted purine.
10. The compound of claim 9 wherein said heterocyclic base moiety is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
11. An oligomeric compound comprising a 5′-terminal compound having Formula II f :
wherein:
T 1 is an optionally protected phosphorus moiety having the formula:
R a and R c are each, independently, OH, SH, 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;
R b is O or S;
T 2 is an internucleoside linking group linking the compound of Formula IIc to the remainder of the oligomeric compound;
A has one of the formulas:
Q 1 and Q 2 are each, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
Q 3 is O, S, N(R 5 ) or C(R 6 )(R 7 );
each R 5 , R 6 and R 7 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
Bx 1 is a heterocyclic base moiety;
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 2 )J 1 , OC(═X 2 )N(J 1 )(J 2 ) and C(═X 2 )N(J 1 )(J 2 );
X 2 is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl;
when j is 1 then Z is other than halogen or N(E 2 )(E 3 ); and
wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is hybridizable to at least a portion of a target nucleic acid.
12. The oligomeric compound of claim 11 wherein Q 3 is C(R 6 )(R 7 ).
13. The oligomeric compound of claim 12 wherein R 6 and R 7 are each, independently, H or C 1 -C 6 alkyl.
14. The oligomeric compound of claim 12 wherein R 6 and R 7 are each H.
15. The oligomeric compound of claim 11 wherein Q 3 is O, S or N(R 5 ) wherein R 5 is H or C 1 -C 6 alkyl.
16. The oligomeric compound of claim 11 wherein Q 1 and Q 2 are each, independently, H or C 1 -C 6 alkyl.
17. The oligomeric compound of claim 11 wherein Q 1 and Q 2 are each H.
18. The oligomeric compound of claim 11 wherein R b is O and R a and R c are each, independently, OCH 3 , OCH 2 CH 3 or OCH(CH 3 ) 2 .
19. The oligomeric compound of claim 11 wherein R b is O and R a and R c are each OH or OCH 3 .
20. The oligomeric compound of claim 11 wherein G is halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 10 )(R 11 ), O(CH 2 ) 2 —ON(R 10 )(R 11 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 12 )—(CH 2 ) 2 —N(R 10 )(R 11 ) or O(CH 2 ) 2 —N(R 12 )—C(═NR 13 )[N(R 10 )(R 11 )] wherein R 10 , R 11 , R 12 and R 13 are each, independently, H or C 1 -C 6 alkyl.
21. The oligomeric compound of claim 11 said heterocyclic base moiety is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
22. The oligomeric compound of claim 11 wherein said 5′-terminal compound has one of the formulas:
wherein:
Bx 1 is uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine;
T 2 is a phosphorothioate internucleoside linking group linking said 5′-terminal compound having one of said formulas to the remainder of the oligomeric compound; and
G is halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 or OCH 2 —N(H)—C(═NH)NH 2 .
23. The oligomeric compound of claim 11 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
24. A double stranded composition comprising:
a first oligomeric compound and a second oligomeric compound wherein the first oligomeric compound is complementary to the second oligomeric compound and the second oligomeric compound is complementary to a nucleic acid target;
at least one of the first and second oligomeric compounds is an oligomeric compound according to claim 11 ; and
wherein said composition optionally comprises one or more 5′ and or 3′ terminal groups.