Modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom

• US 9,321,799 B2
• Filed: 02/20/2015
• Issued: 04/26/2016
• Est. Priority Date: 04/28/2010
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: Ionis Pharmaceuticals, Inc.
• Inventors: Prakash, Thazha P., Seth, Punit P., Swayze, Eric E.
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US14/627,960
• Publication Number:
  US 20150159163A1
• Time in Patent Office: 431 Days
• Field of Search: 536/4.1, 536/23.1, 536/24.5
• US Class Current: 1/1
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/067 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/167 with ribosyl as the saccharide radical
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• 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 15/113 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 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/318 where the PO2 is completely replaced, e.g. MMI or formacetal
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: C12N 2310/346 : having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2320/30 : Special therapeutic applications
• CPC Class Codes: C12N 2320/51 : modulating the chemical stability, e.g. nuclease-resistance

Abstract

The present invention provides modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides and analogs thereof that are useful for incorporation at the terminus of an oligomeric compound. Such oligomeric compounds can also be included in a double stranded composition. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Claims

1. A compound having Formula I_f:

2. The compound of claim 1 wherein Q₃ is C(R₆)(R₇).

3. The compound of claim 2 wherein R₆ and R₇ are each, independently, H or C₁-C₆ alkyl.

4. The compound of claim 2 wherein R₆ and R₇ are each H.

5. The compound of claim 1 wherein Q₃ is O, S or N(R₅) wherein R₅ is H or C₁-C₆ alkyl.

6. The compound of claim 1 wherein Q₁ and Q₂ are each, independently, H or C₁-C₆ alkyl.

7. The compound of claim 1 wherein Q₁ and Q₂ are each H.

8. The compound of claim 1 wherein G is halogen, OCH₃, OCH₂F, OCHF₂, OCF₃, OCH₂CH₃, O(CH₂)₂F, OCH₂CHF₂, OCH₂CF₃, OCH₂—

CH═

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

SCH₃, O(CH₂)₂—

OCF₃, O(CH₂)₃—

N(R₁₀)(R₁₁), O(CH₂)₂—

ON(R₁₀)(R₁₁), O(CH₂)₂—

O(CH₂)₂—

N(R₁₀)(R₁₁), OCH₂C(═

O)—

N(R₁₀)(R₁₁), OCH₂C(═

O)—

N(R₁₂)—

(CH₂)₂—

N(R₁₀)(R₁₁) or O(CH₂)₂—

N(R₁₂)—

C(═

NR₁₃)[N(R₁₀)(R₁₁)] wherein R₁₀, R₁₁, R₁₂ and R₁₃ are each, independently, H or C₁-C₆ alkyl.

9. The compound of claim 1 wherein said heterocyclic base moiety is a pyrimidine, substituted pyrimidine, purine or substituted purine.

10. The compound of claim 9 wherein said heterocyclic base moiety is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.

11. An oligomeric compound comprising a 5′

-terminal compound having Formula II_f;

12. The oligomeric compound of claim 11 wherein Q₃ is C(R₆)(R₇).

13. The oligomeric compound of claim 12 wherein R₆ and R₇ are each, independently, H or C₁-C₆ alkyl.

14. The oligomeric compound of claim 12 wherein R₆ and R₇ are each H.

15. The oligomeric compound of claim 11 wherein Q₃ is O, S or N(R₅) wherein R₅ is H or C₁-C₆ alkyl.

16. The oligomeric compound of claim 11 wherein Q₁ and Q₂ are each, independently, H or C₁-C₆ alkyl.

17. The oligomeric compound of claim 11 wherein Q₁ and Q₂ are each H.

18. The oligomeric compound of claim 11 wherein R_b is O and R_a and R_c are each, independently, OCH₃, OCH₂CH₃ or OCH(CH₃)₂.

19. The oligomeric compound of claim 11 wherein R_b is O and R_a and R_c are each OH or OCH₃.

20. The oligomeric compound of claim 11 wherein G is halogen, OCH₃, OCH₂F, OCHF₂, OCF₃, OCH₂CH₃, O(CH₂)₂F, OCH₂CHF₂, OCH₂CF₃, OCH₂—

CH═

CH₂, O(CH₂)₂—

OCH₃, O(CH₂)₂—

SCH₃, O(CH₂)₂—

OCF₃, O(CH₂)₃—

N(R₁₀)(R₁₁), O(CH₂)₂—

ON(R₁₀)(R₁₁), O(CH₂)₂—

O(CH₂)₂—

N(R₁₀)(R₁₁), OCH₂C(═

O)—

N(R₁₀)(R₁₁), OCH₂C(═

O)—

N(R₁₂)—

(CH₂)₂—

N(R₁₀)(R₁₁) or O(CH₂)₂—

N(R₁₂)—

C(═

NR₁₃)[N(R₁₀)(R₁₁)] wherein R₁₀, R₁₁, R₁₂ and R₁₃ are each, independently, H or C₁-C₆ alkyl.

21. The oligomeric compound of claim 11 said heterocyclic base moiety is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.

22. The oligomeric compound of claim 11 wherein said 5′

-terminal compound has one of the formulas;

23. The oligomeric compound of claim 11 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.

24. A double stranded composition comprising:

a first oligomeric compound and a second oligomeric compound wherein the first oligomeric compound is complementary to the second oligomeric compound and the second oligomeric compound is complementary to a nucleic acid target;

at least one of the first and second oligomeric compounds is an oligomeric compound according to claim 11; and

wherein said composition optionally comprises one or more 5′ and

or 3′

terminal groups.