5′-cyclo-phosphonate modified nucleotides
Described are 5′-cyclo-phosphonate modified nucleotides, and oligonucleotides, such as interference (RNAi) agents, containing 5′-cyclo-phosphonate modified nucleotides. The RNAi agents having either double-stranded or single-stranded oligonucleotides described herein comprising 5′cyclo-phosphonate modified nucleotides are useful in modulating gene expression as well as therapeutic, diagnostic, target validation, and genomic discovery applications. The RNAi agents and single-stranded antisense oligonucleotides comprising 5′-cyclo-phosphonate modified nucleotides are useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.
1. A pharmaceutically acceptable salt of a compound having the structure of Formula I-b:
wherein D is O or S,
X is a 9-purinyl or 1-pyrimidinyl base;
Y 1 , Y 2 , Y 3 , and Y 4 are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
Z is H, OH, OCH 3 , O—(CH 2 ) 2 —OCH 3 or halogen;
G 1 , G 2 , G 3 and G 4 are each H;
J is O or S;
K and L are each independently OH, OR 16 , SR 16 , or NR 16 , wherein R 16 is selected from H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, or
wherein R 14 is H or C 1 -C 4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C 1 -C 4 alkyl), amino, hydroxyl, oxo or —NH—C═(NH)NH 2 , and R 15 is selected from H, or C 1 -C 18 alkyl;
Q is O, S, N(R 30 ), or C(R 31 )(R 32 ), wherein R 30 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R 31 and R 32 are each, independently, H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; and
A comprises a substituent derived from a phosphate or phosphorothioate moiety of an RNAi agent,
and wherein the pharmaceutically acceptable salt is a sodium salt.
2. The pharmaceutically acceptable salt of claim 1 , wherein Q is O.
3. The pharmaceutically acceptable salt of claim 1 , wherein the RNAi agent is double-stranded.
4. The pharmaceutically acceptable salt of claim 1 , wherein X is 1-uracilyl, 1-thyminyl, 1-cytosinyl, 5-methyl-1-cytosinyl, 9-adeninyl, 9-guaninyl, or 9-inosinyl.
5. The pharmaceutically acceptable salt of claim 3 , wherein Z is F or OCH 3 .
6. The pharmaceutically acceptable salt of claim 1 , wherein K is OH and L is OH.
7. A pharmaceutically acceptable salt of a compound having Formula III-b:
wherein X is a 9-purinyl or 1-pyrimidinyl base;
Z is H, OH, OCH 3 , O—(CH 2 ) 2 —OCH 3 or halogen;
J and J′ are each independently O or S; and
comprises a substituent derived from an RNAi agent, and wherein the pharmaceutically acceptable salt is a sodium salt.
8. The pharmaceutically acceptable salt of claim 7 , wherein X is 1-uracilyl, 1-thyminyl, 1-cytosinyl, 5-methyl-1-cytosinyl, 9-adeninyl, 9-guaninyl, or 9-inosinyl.
9. The pharmaceutically acceptable salt of claim 7 , wherein Z is F or OCH 3 .
10. A pharmaceutically acceptable salt of a compound having a formula selected from the group consisting of:
wherein X″ comprises a substituent derived from a phosphate or phosphorothioate moiety of an RNAi agent; J is O or S; and Z is H, —OH, F, OCH 3 , —O—(CH 2 ) 2 —OCH 3 or halogen, and wherein the pharmaceutically acceptable salt is a sodium salt.
11. The pharmaceutically acceptable salt of claim 10 , wherein Z is F or OCH 3 .
12. A composition comprising the pharmaceutically acceptable salt of claim 10 and a pharmaceutically acceptable excipient.
13. The composition of claim 12 , wherein the pharmaceutically acceptable excipient is saline solution.
14. The composition of claim 12 , wherein the pharmaceutically acceptable excipient is water for injection.
15. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutic amount of the composition of claim 12 to a subject in need of treatment thereof.
16. A method of inhibiting expression of a target nucleic acid in a subject in need thereof, the method comprising administering to the subject a therapeutic amount of a composition of claim 12 .