Ionizable cationic lipid for RNA delivery
What is described is a compound wherein R 1 and R 2 are the same or different, each a linear or branched alkyl consisting of 1 to 20 carbons, or a linear or branched alkenyl or alkynyl consisting of 2 to 20 carbons; L 1 and L 2 are the same or different, each a bond, a linear alkylene of 1-18 carbons, or a linear alkenylene consisting of 2 to 18 carbons; L 3 is a bond or a linear or branched alkylene consisting of 1 to 6 carbons; L 4 is a bond or a methylene; X is S or O, R 3 is a linear or branched alkylene consisting of 1 to 6 carbons, and R 4 and R 5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof.
1. A compound of formula 1
wherein
R 1 and R 2 are the same or different, each a linear or branched alkyl consisting of 1 to 20 carbons, or a linear or branched alkenyl or alkynyl consisting of 2 to 20 carbons;
L 1 and L 2 are the same or different, each a bond, a linear alkylene of 1-18 carbons, or a linear alkenylene consisting of 2 to 18 carbons;
L 3 is a bond or a linear or branched alkylene consisting of 1 to 6 carbons;
L 4 is a bond or a methylene;
X is S or O,
R 3 is a linear or branched alkylene consisting of 1 to 6 carbons, and
R 4 and R 5 are the same or different, each a hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein L 3 is a bond.
3. The compound of claim 2 , wherein X is S.
4. The compound of claim 2 , wherein X is O.
5. The compound of claim 2 , wherein each of R 4 and R 5 is a linear alkyl.
6. The compound of claim 2 , wherein each of R 1 and R 2 is a linear alkyl or alkenyl.
7. The compound of claim 2 , wherein one or both of L 1 and L 2 is a linear alkylene.
8. The compound of claim 2 , wherein each of L 1 and L 2 is a bond.
9. The compound of claim 8 , wherein L 4 is a bond.
10. A method of making the compound of claim 9 , comprising steps of (i) reacting pyrrolidine-3, 4-dicarboxylic acid with a BOC 2 O protecting group; (ii) reacting the product of step (i) with R—OH, wherein R is alkyl or alkenyl; (iii) removing the protecting group from the product of step (ii) with trifluoroacetic acid; (iv) reacting the product of step (iii) with triphosgene; and (v) reacting the product of step (iv) with 2-(dimethylamino)ethane-1-thiol.
11. The compound of claim 8 , wherein L 4 is a methylene.
12. A method of synthesis of the compound of claim 11 , comprising steps of (i) reacting piperidine-3, 5-dicarboxylic acid with a BOC 2 O protecting group; (ii) reacting the product of step (i) with R—OH, wherein R is alkyl or alkenyl; (iii) removing the protecting group from the product of step (ii) with trifluoroacetic acid; (iv) reacting the product of step (iii) with triphosgene; and (v) reacting the product of step (iv) with 2-(dimethylamino)ethane-1-thiol.
13. The compound of claim 1 , wherein L 3 is an alkylene.
14. The compound of claim 13 , wherein X is S.
15. The compound of claim 13 , wherein X is O.
16. The compound of claim 13 , wherein each of R 4 and R 5 is a linear alkyl.
17. The compound of claim 13 , wherein each of R 1 and R 2 is a linear alkyl or alkenyl.
18. The compound of claim 13 , wherein each of L 1 and L 2 is a linear alkylene.
19. The compound of claim 13 , wherein L 4 is a bond.
20. The compound of claim 13 , wherein L 4 is a methylene.