LINKAGE MODIFIED OLIGOMERIC COMPOUNDS

• US 20170044526A1
• Filed: 04/28/2015
• Published: 02/16/2017
• Est. Priority Date: 04/28/2014
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Wan, W. Brad, Migawa, Michael T., Oestergaard, Michael, Swayze, Eric E., Seth, Punit P.
• Granted Patent: US 9,926,556 B2
• Time in Patent Office: Days
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/167 with ribosyl as the saccharide radical
• 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: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/312 Phosphonates
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• 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 2310/3527 Other alkyl chain

Abstract

The present invention provides oligomeric compounds comprising at least one neutral methoxypropyl phosphonate modified internucleoside linkage. Such oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Such oligomeric compounds have enhanced stability to exposure to base during synthesis. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

Claims

1. An oligomeric compound comprising a gapped oligomeric compound comprising a contiguous sequence of from 12 to 24 monomer subunits linked by internucleoside linking groups having a gap region of from 6 to 14 contiguous β

-D-2′

-deoxyribonucleosides located between a 5′

-region and a 3′

-region wherein the 5′ and

3′

-regions each, independently, have from 2 to 8 contiguous monomer subunits selected from RNA-like modified nucleosides that each adopt a 3′

-endo conformational geometry independently selected from bicyclic nucleosides comprising a bicyclic furanosyl sugar moiety, modified nucleosides comprising a furanosyl sugar moiety having at least one substituent group and modified nucleosides comprising a sugar surrogate group; and

wherein at least one of the internucleoside linking groups has Formula I;

5. The oligomeric compound of claim 1 wherein the gap region has 10 contiguous monomer subunits and the 5′

and 3′

-regions each, independently, have 2, 3 or 5 contiguous monomer subunits.

14. The oligomeric compound of claim 1 comprising 2 internucleoside linking groups of Formula I.

15. The oligomeric compound of claim 1 wherein internucleoside linking groups of Formula I are contiguous.

16. The oligomeric compound of claim 1 comprising 1 internucleoside linking group of Formula I.

24. The oligomeric compound of claim 1 wherein at least one internucleoside linking group of Formula I is located in the gap region between monomer subunits 1 and 2, 2 and 3, 3 and 4 or 4 and 5 counting from the first monomer subunit at the 5′

end of the gap region.

27. The oligomeric compound of claim 1 having two internucleoside linking groups of Formula I located in the gap region between monomer subunits 1 and 3, 2 and 4 or 3 and 5 counting from the first monomer subunit at the 5′

end of the gap region.

41. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester, a phosphorothioate or an internucleoside linking group of Formula I.

42. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphorothioate or an internucleoside linking group of Formula I.

43. The oligomeric compound of claim 1 wherein each monomer subunit comprises an optionally protected heterocyclic base moiety independently selected from thymine, cytosine, 5-methylcytosine, adenine and guanine.

44. The oligomeric compound of claim 1 wherein each X is O.

45. The oligomeric compound of claim 1 wherein each X is S.

46. The oligomeric compound of claim 1 wherein the chirality of each internucleoside linking group having Formula I is either R_P or S_P.

50. The oligomeric compound of claim 1 wherein each modified nucleoside in the 5′

and 3′

-regions is, independently, selected from a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety having a 4′

-CH₂—

O-2′

or 4′

-CH[(S)—

(CH₃)]—

O-2′

bridging group and a modified nucleoside comprising a ribofuranosyl sugar moiety having a 2′

-O(CH₂)₂—

OCH₃ substituent group.

52. The oligomeric compound of claim 1 wherein the modified nucleosides in the 5′

and 3′

-regions comprise at least 2 different types of sugar moieties.

57. The oligomeric compound of claim 1 further comprising one 5′

or 3′

-conjugate group comprising a cell targeting moiety and a conjugate linker wherein the conjugate linker has the formula;

—

C(═

O)—

(CH₂)₃—

C(═

O)N(H)—

(CH₂)₆—

O—

.

59. The oligomeric compound of claim 57 wherein the cell targeting moiety and the conjugate linker have the formula:

62. The oligomeric compound of claim 57 wherein the conjugate group further includes a cleavable moiety having the formula:

64. The oligomeric compound of claim 62 wherein X is O.

65. The oligomeric compound of claim 62 wherein X is S.

67. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA.

2-4. -4. (canceled)

6-13. -13. (canceled)

17-23. -23. (canceled)

25-26. -26. (canceled)

28-40. -40. (canceled)

47-49. -49. (canceled)

51. (canceled)

53-56. -56. (canceled)

58. (canceled)

60-61. -61. (canceled)

63. (canceled)

66. (canceled)

68-73. -73. (canceled)