Asymmetric ionizable cationic lipid for RNA delivery
What is described is a compound of formula I wherein R 1 consists of a linear or branched alkyl consisting of 1-18 carbons, an alkenyl or alkynyl consisting of 2 to 12 carbons, or a cholesteryl; R 2 consists of a linear or branched alkyl or an alkenyl consisting of 1 to 18 carbons; L 1 consists of a linear alkyl consisting of 5 to 9 carbons or, when R 1 consists of a cholesteryl then L 1 consists of a linear alkylene or alkenyl consisting of 3 to 4 carbons; X 1 consists of —O—(CO)— or —(CO)—O—; X 2 consists of S or O; L 2 consists of a bond or a linear alkylene of 1 to 6 carbons; R 3 consists of a linear or branched alkylene with 1 to 6 carbons; and R 4 and R 5 are the same or different, each consisting of a linear or branched alkyl of 1 to 6 carbons; or a pharmaceutically acceptable salt thereof.
1. A compound of formula I
wherein
R 1 consists of a linear or branched alkyl consisting of 1 to 20 carbons, an alkenyl or alkynyl consisting of 2 to 12 carbons, or a cholesteryl;
R 2 consists of a linear or branched alkyl consisting of 1 to 20 carbons or an alkenyl consisting of 2 to 20 carbons;
L 1 consists of a linear alkyl consisting of 3 to 9 carbons or, when R 1 consists of a cholesteryl then L 1 consists of a linear alkylene or alkenyl consisting of 3 to 4 carbons;
X 1 consists of —O—(CO)— or —(CO)—O—;
X 2 consists of S or O;
L 2 consists of a bond or a linear alkylene of 1 to 6 carbons;
R 3 consists of a linear or branched alkylene with 1 to 6 carbons; and
R 4 and R 5 are the same or different, each consisting of a linear or branched alkyl of 1 to 6 carbons;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein X 1 consists of —O—(CO)—.
3. The compound of claim 1 , wherein X 2 consists of S.
4. The compound of claim 1 , wherein R 3 consists of ethylene.
5. The compound of claim 1 , wherein R 3 consists of n-propylene or isopropylene.
6. The compound of claim 1 , wherein R 4 and R 5 each consist of methyl, ethyl, or isopropyl.
7. The compound of claim 1 , wherein L 2 consists of a bond.
8. The compound of claim 1 , wherein L 2 consists of a methylene.
9. The compound of claim 1 , wherein R 1 and R 2 each consist of branched alkyl.
10. The compound of claim 1 , wherein R 2 consists of an alkyl.
11. The compound of claim 1 , wherein R 1 and R 2 each consist of 19 or 20 carbon atoms.
12. The compound of claim 1 , wherein R 1 or R 2 each consist of 13 or 14 carbon atoms.
13. The compound of claim 1 , wherein L 2 consists of a methylene, R 3 consists of ethylene, X 1 consists of —O—(CO)—, X 2 consists of S, and R 4 and R 5 each consist of methyl.
14. The compound of claim 1 , wherein L 2 consists of a bond, R 3 consists of ethylene, X 1 consists of —O—(CO)—, X 2 consists of S, and R 4 and R 5 each consist of methyl.
15. The compound of claim 1 , wherein L 2 consists of a bond, R 3 consists of n-propylene, X 1 consists of —O—(CO)—, X 2 consists of S, and R 4 and R 5 each consist of methyl.
16. The compound of claim 1 , wherein L 2 consists of a bond, R 3 consists of isopropylene, X 1 consists of —O—(CO)—, X 2 consists of S, and R 4 and R 5 each consist of methyl.
17. The compound of claim 1 , selected from the group consisting of the compounds of formula ATX-A-1 to ATX-A-22