Conjugated antisense compounds and their use

Patent metadata

Field	Value
Publication number	US-10570169-B2
Application number	US-201515311436-A
Country	US
Kind code	B2
Filing date	May 21, 2015
Priority date	May 22, 2014
Publication date	Feb 25, 2020
Grant date	Feb 25, 2020

Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the gomeric compounds are conjugated to N-Acetylgalactosamine or to N-Acetylgalactosamine analogues.

First claim

What is claimed:

1. A compound comprising an oligomer and a conjugate group having Formula II:

wherein:
R 1 is selected from CH 2 NJ 1 J 2 and CH 2 SJ 3 ;
R 2 is N(H)C(═O) Q 2 ;
Q 2 is methyl;
Y is O;
L is a connecting group comprising a linear alkylene group optionally including one or more groups independently selected from O, S, NJ 7 , C(═O), a phosphorus linking group and a cleavable bond or L is a single bond between Y and T 1 ;
J 1 , J 2 , J 3 and J 7 are each, independently, H or a substituent group;
T 1 is said oligomer; and
each substituent group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heterocyclic and heteroaryl wherein each substituent group can include a linear or branched alkylene group optionally including one or more groups independently selected from O, S, NH and C(═O), and wherein each substituent group may be further substituted with one or more groups independently selected from C 1 -C 6 alkyl, halogen and C 1 -C 6 alkoxy wherein each cyclic group is mono or polycyclic.

2. The compound of claim 1 wherein R 1 is selected from CH 2 NJ1J2 and CH 2 SJ 3 wherein J 1 , J 2 and J 3 are each independently selected from H and CH 3 .

3. The compound of claim 2 wherein J 1 , J 2 and J 3 are each H.

4. The compound of claim 1 wherein L optionally comprises one or more amides and wherein L attaches to T 1 through a group selected from among:

5. The compound of claim 1 wherein L comprises a phosphorus linking group, NH 2 , or N(CH 3 ) 2 .

6. The compound of claim 1 having the configuration:

7. The compound of claim 1 , wherein the oligomer comprises at least one modified nucleoside comprising a modified base and or a modified sugar.

8. The compound of claim 7 having at least one modified nucleoside comprising a modified sugar selected from a bicyclic nucleoside and a 2′-modified nucleoside.

9. The compound of claim 8 , 4′-C(CH 3 )H-O-2′ or 4′-CH 2 —O-2′bridged bicyclic nucleoside.

10. The compound of claim 8 , comprising at least one 2′-O(CH 2 ) 2 OCH 3 substituted 2′-modified nucleoside.

11. The compound of claim 1 , wherein the conjugate group is attached to the 5′-terminal nucleoside of the oligomer.

12. The compound of claim 1 , wherein the conjugate group is attached to the 3′-terminal nucleoside of the oligomer.

13. The compound of claim 1 , wherein the oligomer has a sugar motif comprising:
a 5′-region consisting of 2-8 linked 5′-region nucleosides, wherein at least two 5′-region nucleosides are modified nucleosides and wherein the 3′-most 5′-region nucleoside is a modified nucleoside;
a 3′-region consisting of 2-8 linked 3′-region nucleosides, wherein at least two 3′-region nucleosides are modified nucleosides and wherein the 5′-most 3′-region nucleoside is a modified nucleoside; and
a central region between the 5′-region and the 3′-region consisting of 5-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside.

14. The compound of claim 1 , wherein the oligomer comprises at least one modified internucleoside linkage.

15. The compound of claim 1 , wherein each internucleoside linkage of the oligomer is independently a phosphodiester or a phosphorothioate internucleoside linkage.

16. The compound of claim 1 , wherein the oligomer has a nucleobase sequence comprising an at least 14 or 16 nucleobase portion complementary to an equal length portion of a target nucleic acid.

17. A pharmaceutical composition comprising a compound or oligomer according to claim 1 and a pharmaceutically acceptable carrier or diluent.

18. The compound of claim 1 comprising an oligomer and three conjugate groups having Formula II attached to said oligomer through a single connecting group.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Seth Punit P
• Prakash Thazha P
• Migawa Michael T
• Swayze Eric E

Classifications

• C07H19/16

  Purine radicals · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title