Lipids for use in lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-11524932-B2
Application number	US-201816638731-A
Country	US
Kind code	B2
Filing date	Aug 17, 2018
Priority date	Aug 17, 2017
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

Abstract

Compounds are provided having the following structure (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein X, Y, L1, L2, L3, G1, G2 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, prodrug or stereoisomer thereof, wherein:
X is N, and Y is absent; or X is CR, and Y is NR;
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 ;
L 3 is —O(C═O)R 3 or —(C═O)OR 3 ;
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 8 alkylene, C 2 -C 8 alkenylene, C 1 -C 8 heteroalkylene or C 2 -C 8 heteroalkenylene when X is CR, and Y is NR; and G 3 is unsubstituted C 1 -C 8 heteroalkylene or unsubstituted C 2 -C 8 heteroalkenylene when X is N, and Y is absent;
R a , R b , R d and R e are each independently H or 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;
each R is independently H or unsubstituted C 1 -C 12 alkyl;
R 1 , R 2 and R 3 are each independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; and
x is 0, 1 or 2.

2. The compound of claim 1 , wherein G 3 is C 1 -C 8 alkylene.

3. The compound of claim 1 , wherein G 3 is unsubstituted C 1 -C 8 heteroalkylene.

4. The compound of claim 3 , wherein G 3 is C 1 -C 8 aminylalkylene.

5. The compound of claim 1 , wherein X is N and Y is absent.

6. The compound of claim 1 , wherein X is CR and Y is NR.

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

8. 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 .

9. The compound of claim 8 , wherein L 1 is —(C═O)OR 1 and L 2 is —(C═O)OR 2 .

10. The compound of claim 1 , wherein L 3 is —(C═O)OR 3 .

11. The compound of claim 1 , wherein G 1 and G 2 are each independently C 4 -C 10 alkylene.

12. The compound of claim 1 , wherein R 1 , R 2 and R 3 are each, independently, branched C 6 -C 24 alkyl.

13. The compound of claim 12 , wherein R 1 , R 2 and R 3 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.

14. The compound of claim 13 , wherein a is an integer from 8 to 12.

15. The compound of claim 13 , 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.

16. The compound of claim 1 , wherein X is CR, Y is NR and R 3 is C 1 -C 12 alkyl.

17. The compound of claim 1 , wherein R 1 , R 2 and R 3 independently have one of the following structures:

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

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

20. The composition of claim 19 , wherein the therapeutic agent comprises a nucleic acid.

21. The composition of claim 20 , wherein the nucleic acid is selected from antisense and messenger RNA.

22. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 19 , and administering the composition to the patient.

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

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

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao

Classifications

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• A61K47/543

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

• A61K9/5123

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