Methods for the synthesis of functionalized nucleic acids

• US 10,280,192 B2
• Filed: 03/30/2018
• Issued: 05/07/2019
• Est. Priority Date: 07/19/2011
• Status: Active Grant

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: WAVE Life Sciences Ltd.
• Inventors: Verdine, Gregory L., Meena, Iwamoto, Naoki, Butler, David Charles Donnell
• Primary Examiner(s): Crane, Lawrence E
• Application Number:
  US15/941,494
• Publication Number:
  US 20180222936A1
• Time in Patent Office: 403 Days
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: C07C 309/66 Methanesulfonates
• CPC Class Codes: C07D 295/108 to an acyclic saturated chain
• CPC Class Codes: C07H 13/04 having the esterifying carboxyl radicals attached to acyclic carbon atoms
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

The present application, among other things, provides technologies, e.g., reagents, methods, etc. for preparing oligonucleotides comprising phosphorothiotriesters linkages. In some embodiments, provided methods comprise reacting an H-phosphonate of structure Ia or Ib with a silylating reagent to provide a silyloxyphosphonate, and reacting the silyloxyphosphonate with a thiosulfonate reagent of structure IIa or IIb to provide an oligonucleotide of structure IIIa or IIIb. In some embodiments, provided methods comprise reacting an H-phosphonate of structure Ic with a silylating reagent to provide a silyloxyphosphonate, reacting the silyloxyphosphonate with a bis(thiosulfonate) reagent of structure IVc to provide a phosphorothiotriester comprising a thiosulfonate group of structure Vc, and then reacting the phosphorothiotriester comprising a thiosulfonate group of structure Vc with a nucleophile of structure VIc to provide an oligonucleotide of structure IIIc. In some embodiments, the present application provides a thiosulfonate reagent of structure IIa:

Claims

1. A thiosulfonate compound of structure IIa:

2. The thiosulfonate compound of claim 1, wherein R¹ is selected from -alkenylenyl-S—

and -alkylenyl-S—

.

3. The thiosulfonate compound of claim 1, wherein R² is —

S-alkylenyl-heterocyclo.

4. The thiosulfonate compound of claim 1, wherein R¹ is selected from:

5. The thiosulfonate compound of claim 1, wherein R² is selected from:

6. The thiosulfonate compound of claim 1, wherein X is alkyl.

7. The thiosulfonate compound of claim 6, wherein X is methyl.

8. A compound selected from

9. The compound of claim 8, wherein the compound is

10. The compound of claim 8, wherein the compound is

11. The compound of claim 8, wherein the compound is