Trialkyne linking agents and methods of use

Patent metadata

Field	Value
Publication number	US-12065458-B2
Application number	US-201916970130-A
Country	US
Kind code	B2
Filing date	Feb 15, 2019
Priority date	Feb 17, 2018
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

Abstract

Described are improved linking agents that are useful for facilitating the attachment of targeting groups, pharmacokinetic (PK) enhancers or modifiers, or other delivery agents to oligonucleotides. The described linking agents may exhibit improved reaction yields, stability, and biological activity, particularly when used in connection with oligonucleotide-based compounds, such as RNA interference (RNAi) agents.

First claim

The invention claimed is:

1. A compound of Formula III,

or a pharmaceutically acceptable salt thereof,
wherein,
L 1 , L 2 , and L 3 are each linkers of the formula:

L 4 is selected from the group consisting of:

wherein indicates the point of attachment;
R 4 is H or optionally substituted alkyl;
X is O or S; and
RNA comprises or consists of an RNAi agent.

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein X is O.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein X is S.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein L 1 , L 2 , and L 3 are each

5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein L 1 , L 2 , and L 3 are each

6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:

Compound

No.
Structure

1-O-III

1-S-III

2-O-III

2-S-III

3-O-III

3-S-III

4-O-III

4-S-III

5-O-III

5-S-III

6-O-III

6-S-III

7-O-III

7-S-III

8-O-III

8-S-III

9-O-III

9-S-III

10-O-III

10-S-III

11-O-III

Assignees

• Arrowhead Pharmaceuticals Inc

Inventors

• Li Zhen
• Altenhofer Erich
• Carlson Jeffrey
• Fowler-Watters Matthew
• Chen Bo

Classifications

• C12N2310/351

  Conjugate · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07C235/34

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title