Oligonucleotide analogues having modified intersubunit linkages and/or terminal groups

• US 9,469,664 B2
• Filed: 06/06/2014
• Issued: 10/18/2016
• 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:
  US14/298,655
• Publication Number:
  US 20150073140A1
• Time in Patent Office: 865 Days
• US Class Current: 1/1
• 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. A morpholino subunit, wherein the morpholino subunit has the following structure (XXXI)

2. The morpholino subunit of claim 1, wherein Z is chloro.

3. The morpholino subunit of claim 1, wherein PG is trityl or methoxy trityl.

4. The morpholino subunit of claim 1, wherein R⁸ and R⁹, together with the atom to which they are attached, join to form a 5-18 membered mono or bicyclic heterocycle, and the morpholino subunit has the following structure (IV′

);

5. The morpholino subunit of claim 4, wherein the 5-18 membered mono or bicyclic heterocycle has one of the following structures (III), (V), (VI), (VII) or (VIII):

6. The morpholino subunit of claim 5, wherein the 5-18 membered mono or bicyclic heterocycle has structure (V).

7. The morpholino subunit of claim 5, wherein at least one R¹² has the following structure (IX):

8. The morpholino subunit of claim 5, wherein at least one R¹² is —

NH₂, —

N(CH₃)₂ or —

N⁺(CH₃)₃.

9. The morpholino subunit of claim 5, wherein at least one R¹² is pyrrolidinyl, piperidinyl or morpholinyl.

10. The morpholino subunit of claim 5, wherein at least one R¹² is oxo, trifluoromethyl guanidynyl or nitrile.

11. The morpholino subunit of claim 5, wherein R¹¹ is ethyl, isopropyl, piperidinyl, pyrimidinyl, cholate, deoxycholate or —

C(═

O)(CH₂)—

CO₂H, where n is 1 to 6.

12. The morpholino subunit of claim 4, wherein the 5-18 membered mono or bicyclic heterocycle is a crown ether.

13. The morpholino subunit of claim 12, wherein the crown ether has one of the following structures (X) or (XI):

14. The morpholino subunit of claim 1, wherein R⁸, R⁹ or R³, together with the atom to which they are attached, join with R¹⁰ to form a 5-7 membered heterocycle, and the morpholino subunit has the following structure (XII′

);

15. The morpholino subunit of claim 14, wherein the morpholino subunit has the following structure (XIII′

);

16. The morpholino subunit of claim 1, wherein the morpholino subunit has one of the following structures:

17. The morpholino subunit of claim 16, wherein the morpholino subunit has the following structure:

18. The morpholino subunit of claim 1, wherein B is selected from adenine (A), guanine (G), cytosine (C), thymine (T), uracil (U), hypoxanthine, and 5-methyl cytosine.