Lipids and lipid nanoparticle formulations for delivery of nucleic acids
Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , a, b, c, d and e 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:
or a pharmaceutically acceptable salt thereof, wherein:
X is OH or Cl;
each R is independently a saturated or unsaturated C 1 -C 24 alkyl or saturated or unsaturated cycloalkyl;
m is 0 or 1; and
each n is independently an integer from 5 to 24.
2. The compound of claim 1 , wherein X is OH.
3. The compound of claim 1 , wherein X is Cl.
4. The compound of claim 1 , wherein each n is the same.
5. The compound of claim 1 , wherein each n is 5.
6. The compound of claim 1 , wherein each R is the same.
7. The compound of claim 1 , wherein each R is independently a saturated or unsaturated C 1 -C 24 alkyl.
8. The compound of claim 7 , wherein each R is the same.
9. The compound of claim 1 , wherein each R is independently a saturated C 1 -C 24 alkyl.
10. The compound of claim 9 , wherein each R is the same.
11. The compound of claim 1 , wherein each R is independently a saturated C 16 -C 24 alkyl.
12. The compound of claim 1 , wherein each R is independently a saturated C 16 alkyl, saturated C 17 alkyl or saturated C 20 alkyl.
13. The compound of claim 1 , wherein each R independently has one of the following structures:
14. The compound of claim 1 , wherein m is 1.
15. The compound of claim 1 , having one of the following structures:
16. The compound of claim 1 , having one of the following structures:
17. A method for preparing the compound of claim 1 , the method comprising the following transformation:
wherein:
each R is independently a saturated or unsaturated C 1 -C 24 alkyl or saturated or unsaturated cycloalkyl;
m is 0 or 1; and
each n is independently an integer from 5 to 24.
18. The method of claim 17 , further comprising the following transformation:
19. The method of claim 17 , further comprising the following transformation: