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
24. A compound of formula 1:
wherein:
R 1 and R 2 are different and are each a linear or branched alkyl consisting of 1 to 9 carbons, an alkenyl consisting of 2 to 11 carbons, alkynyl consisting of 2 to 11 carbons, or cholesteryl,
L 1 and L 2 are the same or different, and are 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, and are each hydrogen or a linear or branched alkyl consisting of 1 to 6 carbons;
or a pharmaceutically acceptable salt thereof.
25. The compound of claim 24 , wherein the alkenyl of R 1 and R 2 each consists of a single double bond.
26. A compound of formula 1:
wherein:
R 1 and R 2 are the same and are each a linear or branched alkyl consisting of 1 to 9 carbons, an 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.
27. The compound of claim 26 , wherein the X 2 is S.
28. The compound of claim 26 , wherein the R 3 is ethylene.
29. The compound of claim 26 , wherein the R 3 is n-propylene or isobutylene.
30. The compound of claim 26 , wherein the R 4 and R 5 are separately methyl, ethyl, or isopropyl.
31. The compound of claim 26 , wherein L 1 and L 2 are the same.
32. The compound of claim 26 , wherein L 1 and L 2 differ.
33. The compound of claim 26 , wherein L 1 or L 2 consists of a linear alkylene having seven carbons.
34. The compound of claim 26 , wherein L 1 or L 2 consists of a linear alkylene having nine carbons.
35. The compound of claim 26 , wherein R 1 and R 2 each consists of an alkyl.
36. The compound of claim 26 , wherein R 1 and R 2 each consists of nine carbons.
37. The compound of claim 26 , wherein R 1 and R 2 each consists of eleven carbons.
38. The compound of claim 26 , wherein R 1 and R 2 each consists of seven carbons.