Lipids for lipid nanoparticle delivery of active agents

Patent metadata

Field	Value
Publication number	US-12151996-B2
Application number	US-202217862071-A
Country	US
Kind code	B2
Filing date	Jul 11, 2022
Priority date	Jan 11, 2019
Publication date	Nov 26, 2024
Grant date	Nov 26, 2024

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , G 1 , G 2 , and G 3 are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.

First claim

The invention claimed is:

1. A method for inducing expression of a protein in a mammal, comprising administering to the mammal a lipid nanoparticle comprising:
i) a compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
R 1 is optionally substituted C 1 -C 24 alkyl or optionally substituted C 2 -C 24 alkenyl;
R 2 and R 3 are each independently optionally substituted C 1 -C 36 alkyl;
R 4 and R 5 are each independently optionally substituted C 1 -C 6 alkyl, or R 4 and R 5 join, along with the nitrogen atom to which they are attached, to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;
L 1 , L 2 , and L 3 are each independently optionally substituted C 1 -C 18 alkylene;
G 1 is a direct bond, —(CH 2 ) n O(C═O)—, —(CH 2 ) n (C═O)O—, or —(C═O)—;
G 2 and G 3 are each independently —(C═O)O— or —O(C═O)—; and
n is an integer greater than 0; and
ii) an mRNA encoding the protein.

2. The method of claim 1 , wherein expression of the protein induces a pharmacological effect in the mammal.

3. The method of claim 2 , wherein the pharmacological effect is increased production of red blood cells.

4. The method of claim 2 , wherein the pharmacological effect is protection against infection.

5. The method of claim 1 , wherein the mRNA encodes a protein of an infectious agent.

6. The method of claim 5 , wherein the infectious agent is a virus.

7. The method of claim 1 , wherein the mRNA encodes an antibody.

8. The method of claim 1 , wherein the mammal is a non-human primate.

9. The method of claim 1 , wherein the mammal is a human.

10. The method of claim 1 , wherein the compound has the following structure (IA):

11. The method of claim 1 , wherein the compound has the following structure (IB):

12. The method of claim 1 , wherein R 1 is optionally substituted C 6 -C 18 alkyl or optionally substituted C 14 -C 18 alkenyl.

13. The method of claim 1 , wherein G 1 is a direct bond.

14. The method of claim 1 , wherein G 1 is —(CH 2 ) n (C═O)O— and n is greater than 1.

15. The method of claim 1 , wherein L 1 is unsubstituted C 1 -C 6 alkylene.

16. The method of claim 1 , wherein R 2 and R 3 are both unsubstituted C 8 -C 24 alkyl.

17. The method of claim 1 , wherein R 2 and R 3 each independently have one of the following structures:

wherein:
R 6 and R 7 are each independently unsubstituted C 2 -C 12 alkyl.

18. The method of claim 1 , wherein R 2 and R 3 each independently have one of the following structures:

19. The method of claim 1 , wherein L 2 and L 3 are each independently unsubstituted C 4 -C 10 alkylene.

20. The method of claim 1 , wherein R 4 and R 5 are both methyl, ethyl or n-butyl.

21. The method of claim 1 , wherein R 4 and R 5 join, along with the nitrogen atom to which they are attached, to form a heterocyclyl ring having the following structure:

22. The method of claim 1 , wherein the compound has one of the following structures:

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao

Classifications

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61K9/5123

  Organic compounds, e.g. fats, sugars · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• C07D295/15

  to an acyclic saturated chain · CPC title