Ionizable cationic lipid for RNA delivery
What is described is a compound of formula (1) 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 carbon atoms; L 1 and L 2 are the same or different, each a linear alkyl having 5 to 18 carbon atoms, or form a heterocycle with N; X 1 is a bond, or is —CO—O— whereby L 2 -CO—O—R 2 is formed; X 2 is S or O; L 3 is a bond or a lower alkyl, or form a heterocycle with N; 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
wherein
R 1 and R 2 are the same or different, each a linear or branched alkyl consisting of 1 to 9 carbons, an alkenyl or alkynyl consisting of 2 to 11 carbons, or cholesteryl,
L 1 and L 2 are the same or different, each a linear alkylene or alkenylene consisting of 5 to 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,
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 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 the X 2 is S.
3. The compound of claim 1 , wherein the R 3 is ethylene.
4. The compound of claim 1 , wherein the R 3 is n-propylene or isobutylene.
5. The compound of claim 1 , wherein the R 4 and R 5 are separately methyl, ethyl, or isopropyl.
6. The compound of claim 1 , wherein L 1 and L 2 are the same.
7. The compound of claim 1 , wherein L 1 and L 2 differ.
8. The compound of claim 1 , wherein L 1 or L 2 consists of a linear alkylene having seven carbons.
9. The compound of claim 1 , wherein L 1 or L 2 consists of a linear alkylene having nine carbons.
10. The compound of claim 1 , wherein R 1 and R 2 are the same.
11. The compound of claim 1 , wherein R 1 and R 2 differ.
12. The compound of claim 10 , wherein R 1 and R 2 each consists of an alkenyl.
13. The compound of claim 10 , wherein R 1 and R 2 each consists of an alkyl.
14. The compound of claim 12 , wherein the alkenyl consists of a single double bond.
15. The compound of claim 10 , wherein R 1 or R 2 consists of nine carbons.
16. The compound of claim 10 , wherein R 1 or R 2 consists of eleven carbons.
17. The compound of claim 10 , wherein R 1 or R 2 consists of seven carbons.
18. The compound of claim 1 , wherein L 3 is a bond, R 3 is ethylene, X 2 is S, and R 4 and R 5 are each methyl.
19. The compound of claim 1 , wherein L 3 is a bond, R 3 is n-propylene, X 2 is S, R 4 and R 5 are each methyl.
20. The compound of claim 1 , wherein L 3 is a bond, R 3 is ethylene, X 2 is S, and R 4 and R 5 are each ethyl.
21. The compound of claim 1 , selected from the group consisting of the compounds of formula ATX-001 to ATX-028, and ATX-031
22. A compound of formula I
wherein
R 1 and R 2 are the same or different, each a linear or branched alkyl consisting of 1 to 9 carbons, an alkenyl or alkynyl consisting of 2 to 11 carbons, or cholesteryl,
L 1 and L 2 are the same or different, each a linear alkylene or alkenylene consisting 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,
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 hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons;
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 22 consisting of the compound of formula ATX-029