Nucleic acid prodrugs and methods of use thereof

• US 10,307,434 B2
• Filed: 05/27/2016
• Issued: 06/04/2019
• 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 E
• Application Number:
  US15/167,669
• Publication Number:
  US 20160347784A1
• Time in Patent Office: 1,103 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 composition is stereodefined in that each X-phosphonate moiety is more than 98% diastereomerically pure within the composition as determined by ³¹P NMR spectroscopy or reverse-phase HPLC.

3. The composition of claim 1, wherein at least one instance of X is selected from

4. The composition of claim 1, wherein at least 25% of the X moieties are independently selected from

5. The composition of claim 1, wherein each X moiety is independently selected from

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

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

8. The composition of claim 1, wherein R¹ is —

OH.

9. The composition of claim 1, wherein each instance of R² is independently hydrogen, halogen, or —

OR^b.

10. The composition of claim 8, wherein each instance of R² is independently hydrogen, halogen, or —

OR^b.

11. The composition of claim 8, wherein at least one R² is hydrogen.

12. The composition of claim 8, wherein at least one R² is halogen.

13. The composition of claim 8, wherein at least one R² is —

OR^b.

14. The composition of claim 12, wherein R^b is methyl.

15. The composition of claim 1, wherein R³ is hydrogen.

16. The composition of claim 10, wherein R³ is hydrogen.

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

18. The composition of claim 8, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

19. The composition of claim 10, wherein each instance of Ba is independently a blocked or unblocked adenine, cytosine, guanine, thymine, uracil or 5-methylcytosine.

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