Lipids and lipid compositions for the delivery of active agents
This invention provides for a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R A , R B , R 2 and R 4 are defined herein. The compounds of formula (I) and pharmaceutically acceptable salts thereof are cationic lipids useful in the delivery of biologically active agents to cells and tissues.
1. A compound of formula (II) or a pharmaceutically acceptable salt thereof:
wherein
R 1 is selected from
R 2 and R 3 are each, independently, C 12-22 alkyl, C 12-22 alkenyl,
and
R 4 is selected from hydrogen, halo and C 1-4 alkyl.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from:
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from:
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl 4-(dimethylamino)butanoate;
((2-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-(((3-(dimethylamino)propanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-(((1-methylpiperidine-4-carbonyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-((((3-(dimethylamino)propoxy)carbonyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
3-(dimethylamino)propyl 4-methyl-2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl carbonate;
4-methyl-2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl 4-(dimethylamino)butanoate;
(9Z,9′Z,12Z,12′Z)-((2-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(butane-4,1-diyl) bis(octadeca-9,12-dienoate);
4-(dimethylamino)butyl 4-methyl-2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl carbonate;
((2-(((1-ethylpiperidine-4-carbonyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-(((1-isopropylpiperidine-4-carbonyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-((2-(1-methylpiperidin-4-yl)acetoxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
((2-(((4-(pyrrolidin-1-yl)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(octane-8,1-diyl) bis(decanoate);
2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl (3-(dimethylamino)propyl) carbonate;
(9Z,9′Z,12Z,12′Z)-((2-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(ethane-2,1-diyl) bis(octadeca-9,12-dienoate);
2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl 3-(dimethylamino)propanoate;
2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl (3-(diethylamino)propyl) carbonate;
((2-(((4-(diethylamino)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(pentane-5,1-diyl) bis(4,4-bis(octyloxy)butanoate);
8-(4-((5-((4,4-bis(octyloxy)butanoyl)oxy)pentyl)oxy)-3-(((4-(dimethylamino)butanoyl)oxy)methyl)phenoxy)octyl decanoate;
8-(4-((5-((4,4-bis(octyloxy)butanoyl)oxy)pentyl)oxy)-2-(((4-(dimethylamino)butanoyl)oxy)methyl)phenoxy)octyl decanoate;
((2-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(propane-3,1-diyl) bis(4,4-bis(octyloxy)butanoate);
((2-(((4-(dimethylamino)butanoyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(pentane-5,1-diyl) bis(4,4-bis(octyloxy)butanoate); and
((2-(((1,4-dimethylpiperidine-4-carbonyl)oxy)methyl)-1,4-phenylene)bis(oxy))bis(pentane-5,1-diyl) bis(4,4-bis(octyloxy)butanoate).
5. A lipid composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
6. The lipid composition according to claim 5 , further comprising a biologically active agent.
7. The lipid composition according to claim 6 , wherein the biologically active agent is a DNA, siRNA or mRNA.
8. The lipid composition according to claim 5 , further comprising a helper lipid.
9. The lipid composition according to claim 8 , further comprising a neutral lipid.
10. The lipid composition according to claim 9 , further comprising a stealth lipid.
11. The lipid composition according to claim 10 , wherein the helper lipid is cholesterol, the neutral lipid is DSPC, and the stealth lipid is S010, S024, S027, S031, or S033.
12. The lipid composition according to claim 5 , wherein the lipid composition is in the form of a lipid nanoparticle.
13. The lipid composition according to claim 6 , wherein the biologically active agent is a mRNA.
14. A compound 2,5-bis((9Z,12Z)-octadeca-9,12-dien-1-yloxy)benzyl 4(dimethylamino)butanoate or a pharmaceutically acceptable salt thereof.
15. A lipid composition comprising a compound according to claim 14 .
16. The lipid composition according to claim 15 , further comprising a biologically active agent.
17. The lipid composition according to claim 16 , wherein the biologically active agent is a DNA, siRNA or mRNA.
18. The lipid composition according to claim 16 , wherein the biologically active agent is a mRNA.
19. The lipid composition according to claim 15 , further comprising a helper lipid.
20. The lipid composition according to claim 19 , further comprising a neutral lipid.
21. The lipid composition according to claim 20 , further comprising a stealth lipid.
22. The lipid composition according to claim 21 , wherein the helper lipid is cholesterol, the neutral lipid is DSPC, and the stealth lipid is S010, S024, S027, S031, or S033.
23. The lipid composition according to claim 15 , wherein the lipid composition is in the form of a lipid nanoparticle.