Tricine and citric acid lipids
Disclosed are cationic lipids which are compounds of Formula (A). Cationic lipids provided herein can be useful for delivery and expression of mRNA and encoded protein, e.g., as a component of liposomal delivery vehicle, and accordingly can be useful for treating various diseases, disorders and conditions, such as those associated with deficiency of one or more proteins.
1 . A cationic lipid having a structure according to Formula (A):
or a pharmaceutically acceptable salt thereof, wherein
each n is independently 0 or 1;
X 1A is O or NR 1A ,
R 1A is H or C 1 -C 6 alkyl;
X 1B is a covalent bond, C(O), CH 2 CO 2 , or CH 2 C(O);
one of X 2A and X 2B is O and the other is a covalent bond;
one of X 3A and X 3B is O and the other is a covalent bond;
one of X 4A and X 4B is O and the other is a covalent bond;
R 1 is L 1 -B 1 ; unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
R 2 is L 2 -B 2 ; unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
R 3 is L 3 -B 3 ; unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
R 4 is L 4 -B 4 ; unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
L 1 , L 2 , L 3 , and L 4 are each independently unsubstituted C 1 -C 30 alkylene, C 2 -C 30 alkenylene, or C 2 -C 30 alkynylene;
each R 5 is independently unsubstituted C 6 -C 14 alkyl;
each of B 1 , B 2 , B 3 , and B 4 is independently NH 2 , guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl,
and
wherein the cationic lipid comprises at least one of B 1 , B 2 , B 3 , and B 4 .
2 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein the cationic lipid has a structure according to Formula (I),
wherein
each of R 2 , R 3 , and R 4 is independently unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ; and
L 1 is unsubstituted C 1 -C 10 alkylene.
3 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein the cationic lipid has a structure according to Formula (II),
wherein
each of R 2 , R 3 , and R 4 is independently unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ; and L 1 is unsubstituted C 1 -C 10 alkylene.
4 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein the cationic lipid has a structure according to Formula (AI),
wherein
L 1 is unsubstituted C 1 -C 10 alkylene; and
each of R 6A and R 6B is independently H or C 1 -C 6 alkyl.
5 . The cationic lipid or pharmaceutically acceptable salt of claim 4 , wherein both of R 6A and R 6B are methyl.
6 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein the cationic lipid has a structure according to one of the following formulas:
wherein R 1A is H;
and wherein
each of R 2 , R 3 , and R 4 is independently unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ; and
L 1 is unsubstituted C 1 -C 10 alkylene.
7 . The cationic lipid or pharmaceutically acceptable salt of claim 6 , wherein the cationic lipid has a structure according to one of the following formulas:
8 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein
L 1 is unsubstituted C 1 -C 10 alkylene;
each of R 2 , R 3 , and R 4 is independently unsubstituted linear C 6 -C 22 alkyl, unsubstituted linear C 6 -C 22 alkenyl, unsubstituted linear C 6 -C 22 alkynyl, unsubstituted branched C 6 -C 22 alkyl, unsubstituted branched C 6 -C 22 alkenyl, or unsubstituted branched C 6 -C 22 alkynyl; and/or
R 1 is unsubstituted linear C 6 -C 22 alkyl, unsubstituted linear C 6 -C 22 alkenyl, or unsubstituted linear C 6 -C 22 alkynyl.
9 . The cationic lipid or pharmaceutically acceptable salt of claim 8 , wherein each of L 1 , L 2 , L 3 , and L 4 is independently (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 , or (CH 2 ) 5 .
10 . The cationic lipid or pharmaceutically acceptable salt of claim 8 , wherein each of B 1 , B 2 , B 3 , and B 4 is independently:
11 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein each of R 2 , R 3 , and R 4 is independently
12 . The cationic lipid or pharmaceutically acceptable salt of claim 1 , wherein the cationic lipid has a structure according to one of the following formulas:
wherein R 1 is unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
wherein R 1 is unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
wherein R 1 is unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 ;
or
wherein R 1 is unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 .
13 . The cationic lipid or pharmaceutically acceptable salt of claim 12 , wherein
R 1 is unsubstituted linear C 6 -C 22 alkyl, unsubstituted linear C 6 -C 22 alkenyl, unsubstituted linear C 6 -C 22 alkynyl, unsubstituted branched C 6 -C 22 alkyl, unsubstituted branched C 6 -C 22 alkenyl, or unsubstituted branched C 6 -C 22 alkynyl; and/or
each of L 2 , L 3 , and L 4 is unsubstituted C 1 -C 10 alkylene.
14 . A cationic lipid that is any one of Compounds 1-264, Ia-Ih, IIb1-IIb4, IIc1-IIc4, IIIa-IIId, and Va-Vd, or a pharmaceutically acceptable salt thereof.
15 . A cationic lipid selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
16 . A cationic lipid having a structure according to Formula (IIa),
or a pharmaceutically acceptable salt thereof,
wherein
R 1A is H or C(O)—R 7 ,
L 1 is unsubstituted C 1 -C 10 alkylene,
B 1 is NH 2 , guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl
each of R 2 , R 3 , R 4 , and R 7 is independently unsubstituted linear or branched C 6 -C 30 alkyl, C 6 -C 30 alkenyl, or C 6 -C 30 alkynyl; or linear C 6 -C 12 alkyl, C 6 -C 12 alkenyl, or C 6 -C 12 alkynyl substituted with —O(CO)R 5 or —C(O)OR 5 , and
each R 5 is independently unsubstituted C 6 -C 14 alkyl.
17 . The cationic lipid or pharmaceutically acceptable salt of claim 16 , wherein the cationic lipid has a structure according to Formula (IId):
18 . A cationic lipid having a structure according to Formula (A):
or a pharmaceutically acceptable salt thereof, wherein
each n is independently 0 or 1;
X 1A is O or NR 1A ,
R 1A is H or C 1 -C 6 alkyl;
X 1B is a covalent bond, C(O), CH 2 CO 2 , or CH 2 C(O);
one of X 2A and X 2B is O and the other is a covalent bond;
one of X 3A and X 3B is O and the other is a covalent bond;
one of X 4A and X 4B is O and the other is a covalent bond;
R 1 is L 1 B 1 ;
L 1 is C 1 -C 30 alkylene, C 2 -C 30 alkenylene, or C 2 -C 30 alkynylene;
B 1 is NH 2 , guanidine, amidine, a mono- or dialkylamine, 5- to 6-membered nitrogen-containing heterocycloalkyl, or 5- to 6-membered nitrogen-containing heteroaryl,
and
each of R 2 , R 3 , and R 4 is independently:
19 . The cationic lipid or pharmaceutically acceptable salt of claim 18 , wherein L 1 is unsubstituted C 1 -C 10 alkylene.
20 . The cationic lipid or pharmaceutically acceptable salt of claim 18 , wherein B 1 is