Lipids for use in lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-12129223-B2
Application number	US-202218066954-A
Country	US
Kind code	B2
Filing date	Dec 15, 2022
Priority date	Dec 16, 2021
Publication date	Oct 29, 2024
Grant date	Oct 29, 2024

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 3 , L 1 , L 2 , 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 or stereoisomer thereof, wherein:
L 1 is —NR a C(═O)R 1 or —C(═O)NR b R c ;
L 2 is —NR d C(═O)R 2 or —C(═O)NR e R f ;
G 1 and G 2 are each independently C 3 -C 12 alkylene or C 3 -C 12 alkenylene;
G 3 is C 1 -C 24 alkylene or C 2 -C 24 alkenylene;
R a , R b , R d and R e are each independently H, C 1 -C 16 alkyl or C 2 -C 16 alkenyl;
R c and R f are each independently C 1 -C 16 alkyl or C 2 -C 16 alkenyl;
R 1 and R 2 are each independently C 6 -C 24 alkyl or C 6 -C 24 alkenyl;
R 3 is H, —OH, CN, —C(═O)N(R 4 )R 5 ; —N(R 4 )C(═O)R 5 ; —N(R 4 )C(═O)OR 5 ; —C(═O)OR 6 , —OC(═O)R 6 , —OR 7 , heteroaryl or aryl;
R 4 and R 5 are each independently is H, C 1 -C 12 alkyl, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl, or R 4 and R 5 , together with the nitrogen or carbon atom to which they are bound, form a 5 to 7-membered heterocyclic ring;
R 6 is H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl or aralkyl;
R 7 is C 1 -C 12 alkyl optionally substituted with hydroxyl or alkoxy; and
wherein each alkyl, alkenyl, alkylene, alkenylene, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, aryl and aralkyl is independently substituted or unsubstituted unless otherwise specified.

2. The compound of claim 1 , wherein at least one alkyl, alkenyl, alkylene, alkenylene, C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl, aryl or aralkyl is substituted with one or more fluorine and/or one or more oxo and/or one or more NH 2 and/or one or more alkylaminyl.

3. The compound of claim 1 , wherein G 3 is C 1 -C 12 alkylene.

4. The compound of claim 1 , wherein G 1 , G 2 and/or G 3 is substituted with one or more fluorine atoms.

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

wherein y and z are each independently integers ranging from 4 to 12.

6. The compound of claim 1 , wherein:
L 1 is —C(═O)NR b R c , and L 2 is —C(═O)NR e R f or
L 1 is —NR a C(═O)R 1 , and L 2 is —NR d C(═O)R 2 .

7. The compound of claim 6 , having one of the following structures (IB) or (IC):

wherein y and z are each independently an integer ranging from 4 to 10.

8. The compound of claim 1 , wherein R 1 and R 2 are each, independently, linear or branched C 6 -C 24 alkyl.

9. The compound of claim 8 , wherein R 1 and R 2 each, independently, have the following structure:

wherein:
R 7a and R 7b are, at each occurrence, independently either: (a) H or C 1 -C 12 alkyl, or (b) R 7a is H or C 1 -C 12 alkyl, and R 7b together with the carbon atom to which it is bound is taken together with an adjacent R 7b and the carbon atom to which it is bound to form a carbon-carbon double bond; and
a is an integer from 2 to 12,
wherein R 7a , R 7b and a are each selected such that R 1 and R 2 are each independently linear or branched and independently comprise from 6 to 20 carbon atoms.

10. The compound of claim 1 , wherein R 1 or R 2 , or both, independently has one of the following structures:

11. The compound of claim 1 , wherein R b , R c , R e and R f are each independently C 3 -C 12 alkyl.

12. The compound of claim 1 , wherein R a and R d are each independently C 1 -C 12 alkyl or C 2 -C 12 alkenyl and R 1 and R 2 are each independently C 6 -C 18 alkyl or C 6 -C 18 alkenyl.

13. The compound of claim 1 , wherein R 3 is H.

14. The compound of claim 1 , wherein R 3 is —OH.

15. The compound of claim 1 , wherein R 3 is —C(═O)OR 6 .

16. The compound of claim 1 , wherein R 3 is —C(═O)N(R 4 )R 5 .

17. The compound of claim 1 , wherein R 3 is —N(R 4 )C(═O)R 5 .

18. The compound of claim 1 , wherein R 3 is aryl or heteroaryl.

19. The compound of claim 1 , wherein R 3 has one of the following structures:

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

21. A lipid nanoparticle comprising the compound of claim 1 and a therapeutic agent.

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

23. The lipid nanoparticle of claim 21 , wherein the therapeutic agent comprises a nucleic acid.

24. The lipid nanoparticle of claim 23 , wherein the nucleic acid is selected from antisense and messenger RNA.

25. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the lipid nanoparticle of claim 21 , and administering the lipid nanoparticle to the patient.

26. A pharmaceutical composition comprising the lipid nanoparticle of claim 21 and a pharmaceutically acceptable diluent or excipient.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao
• Ansell Steven M
• Tan Jason Samuel
• Blagojevic Polina
• Arns Stephen Paul
• Gatenyo Julia

Classifications

• C07D233/64

  with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title

• A61K31/7105

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title

• A61K9/5123

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

• C07C2601/04

  with a four-membered ring · CPC title