5′ and 2′ BIS-substituted nucleosides and oligomeric compounds prepared therefrom
View Patent ↗The present invention provides modified nucleosides and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides having at least one 5′-substituent and a 2′-O-substituent, oligomeric compounds comprising at least one of these modified nucleosides and methods of using the oligomeric compounds. 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 one monomer of Formula IV:
wherein:
Bx is a heterocyclic base moiety;
T 7 is a phosphorus moiety having the formula:
wherein:
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; and
R b is O or S;
T 8 is an internucleoside linking group linking the monomer of Formula IV to the oligomeric compound;
Q 1 , Q 2 , Q 3 and Q 4 are each, independently, 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 or substituted C 2 -C 6 alkynyl;
G 1 is O—[C(R 2 )(R 3 )] n —[(C═O) m —X] j —Z or halogen;
each R 2 and R 3 is, independently, H or halogen;
X is O, S or N(E 1 );
Z 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 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(=L)J 1 , OC(=L)N(J 1 )(J 2 ) and C(=L)N(J 1 )(J 2 );
L is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl;
provided that when j is 1 then Z is other than N(E 2 )(E 3 );
provided that when Q 1 , Q 2 , Q 3 and Q 4 are each H then G 1 is other than H or OH; and
wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is complementary to at least a portion of a nucleic acid target.
2. The oligomeric compound of claim 1 wherein Bx is uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl, or guaninyl.
3. The oligomeric compound of claim 1 wherein G 1 is 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 4 )(R 5 ), O(CH 2 ) 2 —ON(R 4 )(R 5 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 4 )(R 5 ), OCH 2 C(═O)—N(R 4 )(R 5 ), OCH 2 C(═O)—N(R 6 )—(CH 2 ) 2 —N(R 4 )(R 5 ) or O(CH 2 ) 2 —N(R 6 )—C(═NR 7 )[N(R 4 )(R 5 )] wherein R 4 , R 5 , R 6 and R 7 are each, independently, H or C 1 -C 6 alkyl.
4. The oligomeric compound of claim 1 wherein G 1 is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 .
5. The oligomeric compound of claim 1 wherein Q 1 , Q 2 , Q 3 and Q 4 are each H.
6. The oligomeric compound of claim 1 wherein one of Q 1 , Q 2 , Q 3 and Q 4 is F or C 1 -C 6 alkyl and the other three of Q 1 , Q 2 , Q 3 and Q 4 are each H.
7. The oligomeric compound of claim 1 wherein two of Q 1 , Q 2 , Q 3 and Q 4 are F.
8. The oligomeric compound of claim 7 wherein Q 3 and Q 4 are each F and Q 1 and Q 2 are each H.
9. The oligomeric compound of claim 1 wherein Q 1 is CH 3 and Q 2 , Q 3 and Q 4 are each H or Q 2 is CH 3 and Q 1 , Q 3 and Q 4 are each H.
10. The oligomeric compound of claim 1 wherein each monomer of Formula IV has the configuration:
11. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
12. The oligomeric compound of claim 1 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.
13. 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 1 ; and
wherein said composition optionally comprises one or more 5′ or 3′ terminal groups.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an oligomeric compound comprising one monomer of Formula IV:
wherein:
Bx is a heterocyclic base moiety;
T 7 is a phosphorus moiety having the formula:
wherein:
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; and
R b is O or S;
T 8 is an internucleoside linking group linking the monomer of Formula IV to the oligomeric compound;
Q 1 , Q 2 , Q 3 and Q 4 are each, independently, 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 or substituted C 2 -C 6 alkynyl;
G 1 is O—[C(R 2 )(R 3 )] n —[(C═O) m —X] j —Z or halogen;
each R 2 and R 3 is, independently, H or halogen;
X is O, S or N(E 1 );
Z 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 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(=L)J 1 , OC(=L)N(J 1 )(J 2 ) and C(=L)N(J 1 )(J 2 );
L is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl;
provided that when j is 1 then Z is other than N(E 2 )(E 3 );
provided that when Q 1 , Q 2 , Q 3 and Q 4 are each H then G 1 is other than H or OH; and
wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is complementary to at least a portion of a nucleic acid target.
15. The pharmaceutical composition of claim 14 wherein Bx is uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl, or guaninyl.
16. The pharmaceutical composition of claim 14 wherein G 1 is 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 4 )(R 5 ), O(CH 2 ) 2 —ON(R 4 )(R 5 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 4 )(R 5 ), OCH 2 C(═O)—N(R 4 )(R 5 ), OCH 2 C(═O)—N(R 6 )—(CH 2 ) 2 —N(R 4 )(R 5 ) or O(CH 2 ) 2 —N(R 6 )—C(═NR 7 )[N(R 4 )(R 5 )] wherein R 4 , R 5 , R 6 and R 7 are each, independently, H or C 1 -C 6 alkyl.
17. The pharmaceutical composition of claim 14 wherein G 1 is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 .
18. The pharmaceutical composition of claim 14 wherein: a) Q 1 , Q 2 , Q 3 and Q 4 are each H, b) wherein one of Q 1 , Q 2 , Q 3 and Q 4 is F or C 1 -C 6 alkyl and the other three of Q 1 , Q 2 , Q 3 and Q 4 are each H, or c) wherein two of Q 1 , Q 2 , Q 3 and Q 4 are F.
19. The pharmaceutical composition of claim 14 wherein Q 3 and Q 4 are each F and Q 1 and Q 2 are each H.
20. The pharmaceutical composition of claim 14 wherein Q 1 is CH 3 and Q 2 , Q 3 and Q 4 are each H or Q 2 is CH 3 and Q 1 , Q 3 and Q 4 are each H.
21. The pharmaceutical composition of claim 14 wherein each monomer of Formula IV has the configuration:
22. The pharmaceutical composition of claim 14 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphoro-thioate internucleoside linking group.
23. The pharmaceutical composition of claim 14 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.