Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups

• US 10,202,602 B2
• Filed: 08/25/2016
• Issued: 02/12/2019
• Est. Priority Date: 05/28/2010
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Hanson, Gunnar J., Rudolph, Alexander Charles, Cai, Bao Zhong, Zhou, Ming, Weller, Dwight D.
• Primary Examiner(s): Kosack, Joseph R
• Application Number:
  US15/247,584
• Publication Number:
  US 20170198287A1
• Time in Patent Office: 901 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• 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: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 295/108 to an acyclic saturated chain
• CPC Class Codes: C07F 9/222 Amides of phosphoric acids
• CPC Class Codes: C07F 9/26 containing P-halide groups
• CPC Class Codes: C07F 9/572 Five-membered rings
• CPC Class Codes: C07F 9/59 Hydrogenated pyridine rings
• CPC Class Codes: C07F 9/6544 Six-membered rings
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• 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 2310/3233 : Morpholino-type ring
• CPC Class Codes: C12N 2310/3513 : Protein; Peptide
• CPC Class Codes: Y02P 20/55 : Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Oligonucleotide analogs 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. An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages of type (A), (B), or combinations thereof, wherein each morpholino ring structure supports a base-pairing moiety, such that the oligomer compound can bind in a sequence-specific manner to a target nucleic acid, and wherein the oligomer comprises a 3′

terminus, a 5′

terminus and has the following structure (XVII);

2. The oligomer of claim 1, wherein R²⁰ is C₇-C₃₀ arylcarbonyl.

3. The oligomer of claim 1, wherein R²⁰ is C₇-C₃₀ aralkylcarbonyl.

4. The oligomer of claim 1, wherein R²⁰ is C₆-C₃₀ aryl.

5. The oligomer of claim 1, wherein R²⁰ is C₁-C₃₀ alkyl.

6. The oligomer of claim 1, wherein R²⁰ is C₃-C₃₀ alkylcarbonyl.

7. The oligomer of claim 1, wherein R²⁰ is —

C(═

O)(CH₂)_pSH or —

C(═

O)(CH₂)_pSSHet, wherein p is an integer from 3 to 6 and Het is a heteroaryl.

8. The oligomer of claim 1, wherein R²⁰ is C₃-C₈ cycloalkylcarbonyl.

9. The oligomer of claim 1, wherein R²⁰ is —

C(═

O)(CH₂)_nCO₂H, where n is 3 to 6.

10. The oligomer of claim 1, wherein R²⁰ is guanidinyl.

11. The oligomer of claim 1, wherein R¹⁹ is —

C(═

O)OR²¹.

12. The oligomer of claim 1, wherein R²⁰ is —

P(═

O)(R²²)₂.

13. The oligomer of claim 1, wherein R¹⁸ is trimethylglycine.

14. The oligomer of claim 1, wherein R¹⁸ is a cell-penetrating peptide and R¹⁹ is R²⁰.

15. The oligomer of claim 1, wherein R¹⁹ is a cell-penetrating peptide and R¹⁸ is R²⁰.

16. The oligomer of claim 1, wherein L¹ has the following structure (XXIX):

17. The oligomer of claim 1, wherein R²⁹ has the following structure (XXX):

18. The oligomer of claim 1, wherein R¹⁹ has the following structure:

19. The oligomer of claim 1, wherein R²⁰ has one of the following structures:

20. A composition comprising the oligomer of claim 1 and a pharmaceutically acceptable vehicle.

21. A method of treating a viral infection, a neuromuscular disease, a bacterial infection, inflammation or polycystic kidney disease in a subject, the method comprising administering a therapeutically effective amount of an oligomer of claim 1 to a subject in need thereof.