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 with 1-9 carbons, or an alkenyl or alkynyl with 2 to 11 carbons; L 1 and L 2 are the same or different, each a linear alkyl having 3 to 18 carbons; X 1 and X 3 are —CO—O—; X 3 is S or O; L 3 is a lower alkyl; R 3 is a lower alkyl; and R 4 and R 5 are the same or different, each a lower alkyl; or a pharmaceutically acceptable salt thereof.
1. A compound of formula I
wherein
R 1 is a branched alkyl of 3, 4, 5, 6, 7, 8, or 9 carbons,
R 2 is a linear or branched alkyl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons, an alkenyl or alkynyl of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbons, or cholesteryl,
L 1 and L 2 are the same or different, each a linear alkylene or alkenylene of 3 or 4 carbons,
X 1 is —CO—O— whereby -L 2 -CO—O—R 2 is formed,
X 2 is S or O,
X 3 is —CO—O— whereby -L 1 -CO—O—R 1 is formed,
L 3 is a bond, or a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons,
R 3 is a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons, and
R 4 and R 5 are the same or different, each hydrogen or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein L 1 and L 2 are the same.
3. The compound of claim 2 , wherein L 1 and L 2 are propylene.
4. The compound of claim 1 , wherein R 1 and R 2 are the same.
5. The compound of claim 1 , wherein L 3 is a bond.
6. A compound of formula 2
wherein
R 1 is branched alkyl of 3, 4, 5, 6, 7, 8, or 9 carbons,
R 2 is a linear or branched alkyl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons, an alkenyl or alkynyl of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbons, or cholesteryl,
L 1 and L 2 are the same or different, each a linear alkylene or alkenylene of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons,
X 1 is —CO—O— whereby -L 2 -CO—O—R 2 is formed,
X 2 is S or O,
X 3 is-CO—O— whereby -L 1 -CO—O—R 1 is formed,
L 3 is a bond, or a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons,
R 3 is a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons, and
R 4 and R 5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , wherein L 3 is methylene.
8. The compound of claim 6 , wherein R 4 and R 5 are independently methyl or ethyl.
9. The compound of claim 6 , wherein R 3 is ethylene or propylene.
10. The compound of claim 6 , wherein X 2 is S.
11. The compound of claim 6 , wherein R 1 and R 2 are the same.
12. The compound of claim 11 , wherein R 2 is an alkyl of 1, 2, or 3 carbons.
13. The compound of claim 11 , wherein R 2 is an alkenyl of 9, 10, or 11 carbons.
14. The compound of claim 6 , wherein L 1 and L 2 are the same.
15. The compound of claim 14 , wherein L 1 and L 2 are an alkylene of 3, 4, 5, 6, or 7 carbons.
16. The compound of claim 14 , wherein L 1 and L 2 are an alkenylene of 13, 14, or 15 carbons.
17. The compound of claim 6 , wherein X 2 is 0.
18. The compound of claim 6 , wherein L 3 is a bond.
19. A compound of formula I
wherein
R 1 and R 2 are the same or different, each a linear or branched alkyl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons, an alkenyl or alkynyl of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbons, or cholesteryl,
L 1 and L 2 are propylene,
X 1 is —CO—O— whereby -L 2 -CO—O—R 2 is formed,
X 2 is S or O,
X 3 is −CO—O— whereby -L 1 -CO—O—R 1 is formed,
L 3 is a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons,
R 3 is a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons, and
R 4 and R 5 are the same or different, each hydrogen or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;
or a pharmaceutically acceptable salt thereof.
20. A compound of formula 2
wherein
R 1 and R 2 are the same, each an alkyl of 1, 2, or 3 carbons,
L 1 and L 2 are the same or different, each a linear alkylene or alkenylene of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 carbons,
X 1 is —CO—O— whereby -L 2 -CO—O—R 2 is formed,
X 2 is S or O,
X 3 is —CO—O— whereby -L 1 -CO—O—R 1 is formed,
L 3 is a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons,
R 3 is a linear or branched alkylene of 1, 2, 3, 4, 5 or 6 carbons, and
R 4 and R 5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;
or a pharmaceutically acceptable salt thereof.