Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids

Patent metadata

Field	Value
Publication number	US-11820728-B2
Application number	US-201816608610-A
Country	US
Kind code	B2
Filing date	Apr 27, 2018
Priority date	Apr 28, 2017
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

Compounds are provided having one of the following structures (I) or (II): or (I) (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R3a, R3b, L1, L2, G1a, G1b, G2a, G2b and G3 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 —O(C═O)R 1 , —(C═O)OR 1 , —C(═O)R 1 , —OR 1 , —S(O) x R 1 , —S—SR 1 , —C(═O)SR 1 , —SC(═O)R 1 , —NR a C(═O)R 1 , —C(═O)NR b R c , —NR a C(═O)NR b R c , —OC(═O)NR b R c or —NR a C(═O)OR 1 ;
L 2 is —O(C═O)R 2 , —(C═O)OR 2 , —C(═O)R 2 , —OR 2 , —S(O) x R 2 , —S—SR 2 , —C(═O)SR 2 , —SC(═O)R 2 , —NR d C(═O)R 2 , —C(═O)NR e R f , —NR d C(═O)NR e R f , —OC(═O)NR e R f ; —NR d C(═O)OR 2 or a direct bond to R 2 ;
G 1a and G 2a are each independently C 2 -C 12 alkylene or C 2 -C 12 alkenylene;
G 3 is C 1 -C 24 alkylene, C 2 -C 24 alkenylene, C 3 -C 8 cycloalkylene or C 3 -C 8 cycloalkenylene;
R a , R b , R d and R e are each independently H, C 1 -C 12 alkyl or C 2 -C 12 alkenyl;
R c and R f are each independently C 1 -C 12 alkyl or C 2 -C 12 alkenyl;
R 1 and R 2 are each independently branched C 6 -C 24 alkyl or branched C 6 -C 24 alkenyl;
R 3a is —C(═O)N(R 4a )R 5a ;
R 4a is C 1 -C 12 alkyl;
R 5a is H, C 1 -C 8 alkyl or C 2 -C 8 alkenyl; and
x is 0, 1 or 2, and

wherein each alkyl, alkenyl, alkylene, alkenylene, cycloalkylene and cycloalkenylene, is independently substituted or unsubstituted.

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

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

wherein y1 and z1 are each independently integers ranging from 2 to 12.

4. The compound of claim 1 , wherein L 1 is —O(C═O)R 1 , —(C═O)OR 1 or —C(═O)NR b R c , and L 2 is —O(C═O)R 2 , —(C═O)OR 2 or —C(═O)NR e R f ; or wherein L 1 and L 2 are each independently —O(C═O)R 1 or —(C═O)OR 1 .

5. The compound of claim 4 , having one of the following structures (IB), (IC), (ID) or (IE):

6. The compound of claim 4 , having one of the following structures (IF), (IG), (IH) or (IJ):

7. The compound of claim 3 , wherein y1 and z1 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, 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 H or C 1 -C 12 alkyl; 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 branched and independently comprise from 6 to 20 carbon atoms.

10. The compound of claim 9 , wherein a is an integer from 8 to 12.

11. The compound of claim 9 , wherein R 7a is H at each occurrence.

12. The compound of claim 9 , wherein at least one occurrence of R 7b is C 1 -C 8 alkyl.

13. The compound of claim 12 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

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

15. The compound of claim 1 , wherein R 4a is ethyl, propyl, n-butyl, n-hexyl, n-octyl or n-nonyl.

16. The compound of claim 1 , wherein R 5a is H, methyl, ethyl, propyl, n-butyl, n-hexyl or n-octyl.

17. The compound of claim 1 , wherein R 4a and R 5a are independently optionally substituted with one or more substituents selected from the group consisting of —OR g , —NR g C(═O)R h , —C(═O)NR g R h , —C(═O)R h , —OC(═O)R h , —C(═O)OR h and —OR i OH, wherein:
R g is, at each occurrence independently H or C 1 -C 6 alkyl;
R h is at each occurrence independently C 1 -C 6 alkyl; and
R i is, at each occurrence independently C 1 -C 6 alkylene.

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

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

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

21. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 20 , and administering the composition to the patient.

22. A lipid nanoparticle comprising a compound of claim 1 .

23. A pharmaceutical composition comprising the lipid nanoparticle of claim 22 and a pharmaceutically acceptable diluent or excipient.

24. The compound of claim 1 , wherein each alkyl, alkenyl, alkylene, alkenylene, cycloalkylene and cycloalkenylene, is unsubstituted.

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

26. A lipid nanoparticle comprising a compound of claim 19 .

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao
• Ansell Steven M

Classifications

• C07C237/08 Primary

  having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title

• A61K9/5123

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

• C07C237/06

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

• C07C233/36 Primary

  having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton · CPC title