Functionally-modified oligonucleotides and subunits thereof

• US 10,344,281 B2
• Filed: 09/11/2017
• Issued: 07/09/2019
• Est. Priority Date: 11/18/2011
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Hanson, Gunnar J., Weller, Dwight D., Cai, Bao Zhong, Zhou, Ming
• Primary Examiner(s): Vajda, Kristin A
• Application Number:
  US15/700,718
• Publication Number:
  US 20180223278A1
• Time in Patent Office: 666 Days
• Field of Search: 544110
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07F 9/65846 the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/113 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 Class Codes: C12N 15/1131 against viruses
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/314 Phosphoramidates
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2310/3513 Protein; Peptide
• CPC Class Codes: C12N 2310/353 linked to the nucleic acid via an atom other than carbon

Abstract

Functionally-modified oligonucleotide analogues comprising modified intersubunit linkages and/or modified 3′ and/or 5′-end groups are provided. The disclosed compounds are useful for the treatment of diseases where inhibition of protein expression or correction of aberrant mRNA splice products produces beneficial therapeutic effects.

Claims

1. A compound having the structure of Formula (I):

2. The compound of claim 1, wherein Z⁵ is -(L¹¹)-(R¹⁵);

each Y is independently O, NH, or NR¹⁰;

each W is O;

each R¹ is independently hydrogen or alkyl;

each R² is independently C₁-C₁₂ alkyl; and

each X is independently selected from X1, X2, X3, X4, X5, X6, X7, or X8.

3. The compound of claim 1, wherein R¹³ is an optionally substituted triphenylmethyl group.

4. The compound of claim 2, wherein G⁵ is

5. The compound of claim 4, wherein each W is O and each Y is O.

6. The compound of claim 5, wherein at least one X is selected from:

7. The compound of claim 5, wherein at least one X is selected from -L1-heterocyclyl, and wherein L1 is selected from:

8. The compound of claim 5, wherein at least one X is selected from:

9. The compound of claim 5, wherein at least one X is selected from —

N(R¹)-alkylene-CNH—

NH₂, —

N(R¹)-alkylene-N(R¹)₂, —

N(R¹)-alkylene-N(R²)₃, —

N(R¹)-alkylene-heterocyclyl, —

N(R¹)-alkylene-N(O)(R²)₂, and —

N(R¹)-alkylene-NH—

CNH—

NH₂.

10. The compound of claim 5, wherein at least one X is selected from —

O-alkylene-aryl, —

N(R¹)-aryl, —

N(R¹)-alkylene-aryl, —

N(R¹)-alkylene-N(R¹)-aryl, —

N(R¹)-alkylene-N(R¹)CO-aryl, —

N(R¹)-alkylene-N(R¹)SO₂-aryl, and —

N(R¹)-alkylene-N(R¹)CH₂-aryl.

11. The compound of claim 5, wherein at least one X is selected from —

O-alkylene-heteroaryl, —

N(R¹)-alkylene-heteroaryl, —

N(R¹)-alkylene-N(R¹)-heteroaryl, —

N(R¹)-alkylene-N(R¹)CO-heteroaryl, —

N(R¹)-alkylene-N(R¹)SO₂-heteroaryl, and —

N(R¹)-alkylene-N(R¹)CH₂-heteroaryl.

12. The compound of claim 5, wherein at least one X is selected from -L1-heteroaryl, -L1-alkylene-heteroaryl, -L1-arylene-heteroaryl, -L1-CO-alkylene-heteroaryl, -L1-CO-alkenylene-heteroaryl, -L1-CO-arylene-heteroaryl, -L1-CONH-alkylene-heteroaryl, -L1-CONH-arylene-heteroaryl, -L1-SO₂-alkylene-heteroaryl, -L1-SO₂-arylene-heteroaryl.

13. The compound of claim 5, wherein at least one X is -L1-CO-alkyl.

14. The compound of claim 5, wherein at least one X is X8.

15. The compound of claim 5, wherein Z⁵ is -(L¹¹)-(R¹⁵) wherein R¹⁵ is selected from —

C(═

O)OCH₂CH₂OH, —

C(═

O)OCH₂CH₂OCH₂CH₂OH, or —

C(═

O)OCH₂CH₂OCH₂CH₂OCH₂CH₂OH.

16. The compound of claim 15, wherein Z⁵ is