Methods for the synthesis of functionalized nucleic acids

Patent metadata

Field	Value
Publication number	US-10280192-B2
Application number	US-201815941494-A
Country	US
Kind code	B2
Filing date	Mar 30, 2018
Priority date	Jul 19, 2011
Publication date	May 7, 2019
Grant date	May 7, 2019

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:

First claim

What is claimed is:

1. A thiosulfonate compound of structure IIa:

wherein,
X is alkyl, cycloalkyl, or heteroaryl;
R is —R 1 -R 2 ;
R 1 is selected from alkenylenyl-S—, -alkylenyl-S—, -alkylenyl-aryl-alkylenyl-S—, -alkylenyl-aryl-CO—S— and alkylenyl-aryl-alkylenyl-CO—S—; and
R 2 is selected from —S-alkylenyl-heterocyclo, —S-alkenylenyl-heterocyclo, —S-aminoalkyl, and —S-alkylenyl-N(alkyl) 4 .

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

3. The thiosulfonate compound of claim 1 , wherein R 2 is —S-alkylenyl-heterocyclo.

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

5. The thiosulfonate compound of claim 1 , wherein R 2 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

wherein MTS is CH 3 —S(O) 2 —S—.

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

wherein MTS is CH 3 —S(O) 2 —S—.

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

wherein MTS is CH 3 —S(O) 2 —S—.

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

wherein MTS is CH 3 —S(O) 2 —S—.

Assignees

• Wave Life Sciences Ltd

Inventors

• Verdine Gregory L
• Meena
• Iwamoto Naoki
• Butler David Charles Donnell

Classifications

• A61K31/66

  Phosphorus compounds · CPC title

• C07D295/108

  to an acyclic saturated chain · CPC title

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title

• C07C309/66

  Methanesulfonates · CPC title

• C07H21/04 Primary

  with deoxyribosyl as saccharide radical · CPC title