Nucleic acid prodrugs and methods of use thereof

• US 9,744,183 B2
• Filed: 07/06/2010
• Issued: 08/29/2017
• Est. Priority Date: 07/06/2009
• Status: Active Grant

• Current Assignee: Wave Life Sciences Pte. Ltd.
• Original Assignee: WAVE Life Sciences Ltd.
• Inventors: Verdine, Gregory L., ., Meena, Iwamoto, Naoki
• Primary Examiner(s): Jarrell, Noble
• Application Number:
  US13/381,323
• Publication Number:
  US 20120316224A1
• Time in Patent Office: 2,611 Days
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• 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

Abstract

Described herein are nucleic acid prodrugs and nucleic acid prodrugs comprising chiral phosphorous moieties. Also described herein are methods of making and using nucleic acid prodrugs and nucleic acid prodrugs comprising chiral phosphorous moieties.

Claims

1. An oligonucleotide composition comprising a plurality of oligonucleotides of the following structure:

2. The composition of claim 1 wherein the diastereomeric purity is determined by ³¹P NMR spectroscopy or reverse-phase HPLC.

3. The composition of claim 1 wherein each X-phosphonate moiety has an R_P configuration.

4. The composition of claim 1 wherein each X-phosphonate moiety has an S_P configuration.

5. The composition of claim 1, wherein at least 90% of the X moieties of the oligonucleotide are independently selected from —

OCH₂CH₂S—

S(O)₂R₁₀, —

OCH₂CH₂S—

SCH₂CH₂OH, —

OCH₂CH₂CO₂H,

6. The composition of claim 1, wherein each instance of X is independently selected from —

OCH₂CH₂S—

S(O)₂R₁₀, —

OCH₂CH₂S—

SCH₂CH₂OH, —

OCH₂CH₂CO₂H,

7. The composition of claim 1, wherein R₁₀ is methyl.

8. The composition of claim 1, wherein R₁₁ is methyl.

9. The composition of claim 1, wherein R₁₂ is methyl.

10. The composition of claim 1, wherein n is an integer of 15 to about 200.

11. The composition of claim 1, wherein n is an integer of 20 to about 200.

12. The composition of claim 1, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

13. The composition of claim 1, wherein Y¹ is O.

14. The composition of claim 13, wherein:

R¹ is —

OH, hydrogen, alkyl, alkenyl, alkynyl, alkyl-Y¹—

, alkenyl-Y¹—

, alkynyl-Y¹—

, aryl-Y¹—

, heteroaryl-Y¹—

, or —

OR^a;

each instance of R² is independently hydrogen, —

OH, halogen, alkyl, alkenyl, alkynyl, alkyl-Y¹—

, alkenyl-Y¹—

, alkynyl-Y¹—

, aryl-Y¹—

, heteroaryl-Y¹—

, or —

OR^b, wherein R^b is a blocking group; and

R³ is hydrogen or a blocking group.

15. The composition of claim 14, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

16. The composition of claim 1, wherein each instance of R^d is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or acyl.

17. The composition of claim 16, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

18. The composition of claim 1, wherein Y² is O or S.

19. The composition of claim 18, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

20. A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 1 and a pharmaceutically acceptable excipient.

21. The composition of claim 1, wherein:

R¹ is —

OH or —

OR^a;

each instance of R² is independently hydrogen, —

OH, halogen, or —

OR^b; and

R³ is hydrogen or a blocking group;

each instance of Ba is independently adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

22. A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 15 and a pharmaceutically acceptable excipient.

23. A pharmaceutical composition comprising a therapeutically effective amount of a composition of claim 21 and a pharmaceutically acceptable excipient.