Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids
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.
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 .