Lipids for use in lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-11639329-B2
Application number	US-201816638733-A
Country	US
Kind code	B2
Filing date	Aug 16, 2018
Priority date	Aug 16, 2017
Publication date	May 2, 2023
Grant date	May 2, 2023

Abstract

Compounds are provided having the following structure: [Formula should be inserted here] 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 —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 1 and G 2 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 1 -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 3 is —N(R 4 )R 5 ;
R 4 is C 1 -C 12 alkyl;
R 5 is substituted C 1 -C 12 alkyl, wherein R 5 is 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; and

x is 0, 1 or 2, and

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

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

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

wherein y and z 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 .

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):

wherein y and z are each independently integers ranging from 2-12.

7. The compound of claim 3 , 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, 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 at least one occurrence of R 7b is C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

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

12. The compound of claim 1 , wherein R 4 is substituted or unsubstituted: methyl, ethyl, propyl, n-butyl, n-hexyl, n-octyl or n-nonyl.

13. The compound of claim 12 , wherein R 4 is unsubstituted.

14. The compound of any one of claim 12 , wherein R 4 is 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.

15. The compound of claim 1 , wherein R 5 is substituted: methyl, ethyl, propyl, n-butyl, n-hexyl, n-octyl or n-nonyl.

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

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

18. A composition comprising the compound of claim 1 and a nucleic acid.

19. The composition of claim 18 , wherein the nucleic acid is selected from antisense and messenger RNA.

20. A method for administering a nucleic acid to a patient in need thereof, the method comprising preparing or providing the composition of claim 18 , and administering the composition to the patient.

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

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

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

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao

Classifications

• A61K47/54

  the modifying agent being an organic compound · CPC title

• A61K9/5123

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

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K47/6929

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title