LNA-G Process
AssigneeRoche Innovation Center Copenhagen A/S
InventorsDennis Jul Hansen, Joerg Hoernschemeyer, Jacob Ravn, Christoph Rosenbohm
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Abstract
Recent advancements in LNA oligonucleotides include the use of amine linkers to link an LNA antisense oligonucleotide to a conjugate group. For example please see WO2014/118267. The present invention originates from the identification of a problem when de-protecting LNA oligonucleotides which comprise an aliphatic amine group and DMF protected LNA G nucleoside, which results in the production of a +28 Da impurity. This problem is solved by using acyl protection groups on the exocyclic nitrogen of the LNA-G residue, rather than the standard DMF protection group.
Claims26
A method of preparing a LNA oligonucleotide comprising the steps of:
- a) Incorporating at least one LNA-G monomer comprising an acyl protected exocyclic nitrogen into an oligonucleotide
- b) Incorporating at least one optionally protected aliphatic amine group into the oligonucleotide
- c) deprotecting the acyl protected exocyclic nitrogen of the at least one LNA-G monomer by removal of the acyl protection group.
- wherein steps a) and b) can occur in either order.
An LNA oligonucleotide which comprises at least one LNA-G monomer comprising an acyl protected exocyclic nitrogen and at least one optionally protected aliphatic amine group, wherein said LNA oligonucleotide is attached to a solid support.
A pharmaceutical composition comprising an LNA oligomer conjugate which comprises an LNA-G monomer and an aliphatic amine linker positioned between the 5′ nucleotide of LNA oligomer and a conjugate moiety, and a pharmaceutically acceptable diluent, carrier or adjuvant, wherein said composition is essentially free of +28 adduct.
Use of an LNA-G monomer comprising an acyl protected exocyclic nitrogen for use in the synthesis of an aliphatic amine containing LNA oligonucleotide.
Use of an LNA-G monomer comprising an acyl protected exocyclic nitrogen for use in the synthesis of an aliphatic amine containing LNA oligonucleotide conjugate.
Dependencies are inferred from the claim text.