Lipids for lipid nanoparticle delivery of active agents

Patent metadata

Field	Value
Publication number	US-11453639-B2
Application number	US-202016740253-A
Country	US
Kind code	B2
Filing date	Jan 10, 2020
Priority date	Jan 11, 2019
Publication date	Sep 27, 2022
Grant date	Sep 27, 2022

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 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.

2. The compound of claim 1 , having the following structure (IA):

3. The compound of claim 1 , having the following structure (IB):

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

5. The compound of claim 1 , wherein G 1 is a direct bond, —(CH 2 ) n O(C═O)—, or —(CH 2 ) n (C═O)O—.

6. The compound of claim 5 , wherein G 1 is a direct bond.

7. The compound of claim 5 , wherein G 1 is —(CH 2 ) n (C═O)O— and n is greater than 1.

8. The compound of claim 1 , wherein L 1 is unsubstituted C 1 -C 6 alkylene.

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

10. The compound of claim 1 , wherein R 2 and R 3 are optionally substituted branched C 1 -C 36 alkyl.

11. The compound 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.

12. The compound of claim 11 , wherein R 2 and R 3 each independently have one of the following structures:

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

14. The compound of claim 1 , wherein R 4 and R 5 are each independently unsubstituted C 1 -C 6 alkyl.

15. The compound of claim 14 , wherein R 4 and R 5 are both methyl, ethyl or n-butyl.

16. The compound of claim 1 , wherein R 4 and R 5 join, along with the nitrogen atom to which they are attached, to form an optionally substituted heterocyclyl ring.

17. The compound of claim 16 , wherein the optionally substituted heterocyclyl ring has the following structure:

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

19. A composition comprising the compound of claim 1 and a therapeutic agent.

20. A method for delivering a therapeutic agent to a patient in need thereof, the method comprising administering the composition of claim 19 the patient.

21. A lipid nanoparticle comprising the compound of claim 1 .

22. The composition of claim 19 , wherein the therapeutic agent comprises messenger RNA.

23. The lipid nanoparticle of claim 21 , further comprising messenger RNA.

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