Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups

• US 8,779,128 B2
• Filed: 05/27/2011
• Issued: 07/15/2014
• Est. Priority Date: 05/28/2010
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Hanson, Gunnar J., Cai, Bao Zhong, Zhou, Ming, Weller, Dwight D., Rudolph, Charles
• Primary Examiner(s): KOSACK, JOSEPH R
• Application Number:
  US13/118,298
• Publication Number:
  US 20120065169A1
• Time in Patent Office: 1,145 Days
• Field of Search: 514/85, 514/90, 544/78, 544/82, 544/121
• US Class Current: 544/78
• 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 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. An oligomer comprising a backbone, the backbone comprising a sequence of morpholino ring structures joined by intersubunit linkages, the intersubunit linkages joining a 3′

-end of one morpholino ring structure to a 5′

-end of an adjacent morpholino ring structure, wherein each morpholino ring structure is bound to a base-pairing moiety, such that the oligomer can bind in a sequence-specific manner to a target nucleic acid, wherein the intersubunit linkages have the following general structure (I);

2. The oligomer of claim 1, wherein at least one of the morpholino ring structures has the following structure (i):

3. The oligomer of claim 1, wherein at least one of the intersubunit linkages is linkage (A).

4. The oligomer of claim 1, wherein X is —

N(CH₃)₂ at each occurrence of linkage (A).

5. The oligomer of claim 1, wherein W and Y are each O at each occurrence.

6. The oligomer of claim 1, wherein at least one linkage (B) has the following structure (IV):

7. The oligomer of claim 6, wherein Z has one of the following structures (III), (V), (VI), (VII) or (VIII):

8. The oligomer of claim 7, wherein Z has structure (V).

9. The oligomer of claim 7, wherein at least one R¹² has the following structure (IX):

10. The oligomer of claim 7, wherein at least one R¹² is —

NH₂, —

N(CH₃)₂ or —

N⁺(CH₃)₃.

11. The oligomer of claim 7, wherein at least one R¹² is pyrrolidinyl, piperidinyl or mopholinyl.

12. The oligomer of claim 7, wherein at least one R¹² is oxo, trifluoromethyl, guanidynyl or nitrile.

13. The oligomer of claim 7, wherein R¹¹ is ethyl, isopropyl, piperidinyl, pyrimidinyl, cholate, deoxycholate or —

C(═

O)(CH₂)_nCO₂H, where n is 1 to 6.

14. The oligomer of claim 6, wherein Z represents a crown ether.

15. The oligomer of claim 14, wherein Z has one of the following structures (X) or (XI):

16. The oligomer of claim 1, wherein at least one linkage (B) has the following structure (XII):

17. The oligomer of claim 16, wherein the at least one linkage (B) has the following structure (XIII):

18. The oligomer of claim 1, wherein R⁸ is C₂-C₁₂ alkyl and R⁹ is C₁-C₁₂ alkyl for at least one occurrence of linkage (B).

19. The oligomer of claim 1, wherein R⁹ is C₁-C₁₂ aralkyl or aryl for at least one occurrence of linkage (B).

20. The oligomer of claim 19, wherein R⁹ has one of the following structures (XIV), (XV) or (XVI):

21. The oligomer of claim 1, wherein at least one linkage (B) has one of the following structures:

22. The oligomer of claim 1, wherein at least 5% of the intersubunit linkages are linkage (B).

23. The oligomer of claim 1, wherein 10% to 50% of the intersubunit linkages are linkages (B).

24. The oligomer of claim 1, wherein each linkage (B) has the same structure at each occurrence.

25. The oligomer of claim 1, wherein each Y and each W are O.

26. The oligomer of claim 1, wherein the oligomer has the following structure (XVII):

27. The oligomer of claim 26, wherein at least one of R^{18 or R19} is R²⁰.

28. The oligomer of claim 26, wherein R²⁰ is trityl, methoxytrityl, benzhydryl, p-chlorobenzhydryl, triphenylacetyl, triphenylpropyl, diphenylactyl, chlorodiphenylacetyl, hydroxydiphenylacetyl, triphenylphosphoryl, diphenylphosphoryl, geranyl, farnesyl, prenyl, lauroyl, trimethoxybenzoyl, triphenylpropionyl, trimethylglycine, 1-hydroxy-2,2-diphenyl acetyl, 9-fluorene-carboxyl, 5-carboxyfluorescein, —

COCH₂CH₂SSPy, —

COCH₂SH, 4-carbazolylbenzoyl, 4-indazolylonebenzoyl, methylsuccinimidyl- cyclohexoyl, triethyleneglycoloyl, succinicacetyl, piperidin-4-yl, tritylpiperidin-4-yl, boc- piperidin-4-yl, hexyn-6-yl, piperazin-1-yl or guanidinyl.

29. The oligomer of claim 26, wherein R^°

is trityl or triphenylacetyl.

30. The oligomer of claim 26, wherein R¹⁹ is piperizinyl or

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

31. 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);