Cationic lipids for use in lipid nanoparticles

Patent metadata

Field	Value
Publication number	US-11976019-B2
Application number	US-202117378083-A
Country	US
Kind code	B2
Filing date	Jul 16, 2021
Priority date	Jul 16, 2020
Publication date	May 7, 2024
Grant date	May 7, 2024

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein a, b, c, d, G 1 , G 2 , L 1 , L 2 , R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 and X are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, nanoparticles comprising the compounds and methods for their use and preparation are also provided.

First claim

The invention claimed is:

1. A compound having a structure of Formula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
G 1 and G 2 are each independently C 1 -C 6 alkylene;
L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—;
R 1a and R 1b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 1a is H or C 1 -C 12 alkyl, and R 1b together with the carbon atom to which it is bound is taken together with an adjacent R 1b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 2a and R 2b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 2a is H or C 1 -C 12 alkyl, and R 2b together with the carbon atom to which it is bound is taken together with an adjacent R 2b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 3a and R 3b are, at each occurrence, independently either (a): H or C 1 -C 12 alkyl; or (b) R 3a is H or C 1 -C 12 alkyl, and R 3b together with the carbon atom to which it is bound is taken together with an adjacent R 3b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 4a and R 4b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 4a is H or C 1 -C 12 alkyl, and R 4b together with the carbon atom to which it is bound is taken together with an adjacent R 4b and the carbon atom to which it is bound to form a carbon-carbon double bond;
R 5 and R 6 are each independently H or methyl;
R 7 is —O(C═O)R 10 , —(C═O)OR 10 , —NR 9 (C═O)R 10 or —(C═O)NR 9 R 10 ;
R 8 is OH, —N(R 11 )(C═O)R 12 , —(C═O)NR 11 R 12 , —NR 11 R 12 , —(C═O)OR 12 or —O(C═O)R 12 ;
R 9 is H or C 1 -C 15 alkyl;
R 10 is C 1 -C 15 alkyl;
R 11 is H or C 1 -C 6 alkyl;
R 12 is C 1 -C 6 alkyl;
X is —(C═O)— or a direct bond; and
a, b, c and d are each independently an integer from 1 to 24;
wherein each methyl, alkyl and alkylene is independently optionally substituted.

2. The compound of claim 1 , having one of the following structures (IA) or (IB):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3. The compound of claim 1 , wherein G 1 is C 2 -C 3 alkylene or C 4 -C 6 alkylene.

4. The compound of claim 1 , wherein G 2 is C 2 -C 3 alkylene or C 3 -C 4 alkylene.

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

6. The compound of any one of claim 1 , wherein R 7 is —O(C═O)R 10 or —(C═O)OR 10 .

7. The compound of claim 6 , wherein R 10 is linear C 6 -C 10 alkyl.

8. The compound of claim 6 , wherein R 10 is methyl.

9. The compound of claim 6 , wherein R 10 is branched C 10 -C 15 alkyl.

10. The compound of any one of claim 1 , wherein R 7 is —NR 9 (C═O) or —(C═O)NR 9 R 10 .

11. The compound of claim 10 , wherein R 9 is H.

12. The compound of claim 10 , wherein R 9 and R 10 are each independently C 6 -C 10 alkyl.

13. The compound of claim 1 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are, at each occurrence, independently H or C 1 -C 12 alkyl.

14. The compound of claim 13 , wherein at least one of R 1b and R 4b is C 1 -C 8 alkyl.

15. The compound of claim 1 , wherein

or both, independently has one of the following structures:

16. The compound of claim 1 , wherein a, b, c and d are each independently an integer from 2 to 12.

17. The compound of claim 1 , wherein R 8 is —N(R 11 )(C═O)R 12 .

18. The compound of claim 1 , wherein R 8 is —(C═O)N 11 R 12 .

19. The compound of claim 1 , wherein R 8 is —NR 11 R 12 .

20. The compound of claim 1 , wherein R 8 is —(C═O)OR 12 .

21. The compound of claim 20 , wherein R 8 is —O(C═O)R 12 .

22. The compound of claim 1 , wherein R 8 has one of the following structures:

23. The compound of claim 1 , having one of the following structures:

24. A lipid nanoparticle comprising the compound of claim 1 and an mRNA encoding a protein.

25. A pharmaceutical composition comprising the lipid nanoparticle of claim 24 and a pharmaceutically acceptable diluent or excipient.

26. A method for expressing a protein in a patient in need thereof, the method comprising administering the lipid nanoparticle of claim 24 to the patient, wherein the protein encoded by the mRNA is expressed in the patient.

27. A method for vaccinating a patient in need thereof against a viral pathogen, the method comprising administering the lipid nanoparticle of claim 24 to the patient, wherein the protein is a viral antigen.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Gatenyo Julia
• Du Xinyao

Classifications

• A61P31/12

  Antivirals · CPC title

• C07C219/06 Primary

  having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton · CPC title

• A61K9/5123

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

• A61K39/12

  Viral antigens · CPC title

• A61K2039/55555

  Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers · CPC title