Lipids and lipid compositions for the delivery of active agents

1. A method for the treatment of a disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a lipid composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

L is C 1-6 alkylene, *—C 1-4 alkylene-L2-, or *—C 1-4 alkylene-L2-C 1-4 alkylene-, wherein the * denotes attachment of the moiety to the NR 1 R 2 group;

L2, attached in either direction, is —C(O)O—;

R 1 and R 2 are each independently optionally substituted C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or two substituents each independently selected from the group consisting of: OH, C 1-3 alkoxyl, COOH, and COO—C 1-4 alkyl,

R 3 and R 4 are each independently —Z 1 —R b —Z 2 —R a , wherein Z 1 , attached in either direction, is each independently —O— or —C(O)O—;

Z 2 , attached in either direction, is —C(O)O—;

R a is C 2-22 alkyl, C 2-22 alkenyl, or C 2-22 alkynyl;

each R b is independently C 1-20 alkylene, C 2-20 alkenylene, or C 2-20 alkynylene;

provided that —Z 1 —R b —Z 2 —R a has at least 12 carbon atoms and no more than 30 carbon atoms;

X is CR 6 ; and

R 6 is H, halo, C 1-6 alkyl, or R 4 ;

and

an mRNA agent.

2. The method of claim 1 , comprising administering a lipid composition comprising:

a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

L is C 1-6 alkylene, *—C 1-4 alkylene-L2-, or *—C 1-4 alkylene-L2-C 1-4 alkylene-, wherein in the * denotes attachment of the moiety to the NR 1 R 2 group;

L2, attached in either direction, is —C(O)O—;

R 1 and R 2 are each independently optionally substituted C 1-6 alkyl, ; wherein said C 1-6 alkyl is optionally substituted with one or two substituents each independently selected from the group consisting of: OH, C 1-3 alkoxy, COOH, and COO—C 1-4 alkyl,

R 3 and R 4 are each independently —Z 1 —R b —Z 2 —R a , wherein Z 1 , attached in either direction, is each independently —O— or —C(O)O—;

Z 2 , attached in either direction, is —C(O)O—;

R a is C 2-22 alkyl, C 2-22 alkenyl, or C 2-22 alkynyl;

each R b is independently C 1-20 alkylene, C 2-20 alkenylene, or C 2-20 alkynylene;

provided that —Z 1 —R b —Z 2 —R a has at least 12 carbon atoms and no more than 30 carbon atoms;

X is CR 6 ; and

R 6 is H, halo, C 1-6 alkyl, or R 4 ;

an mRNA;

and

a pharmaceutically acceptable carrier or excipient.

3. A method for the treatment of a disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a lipid composition comprising:

a compound of formula:

(9Z, 9′Z, 12Z, 12′Z)-((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4,1-diyl)bis(octadeca-9, 12-dienoate),

or a pharmaceutically acceptable salt thereof;

and

an mRNA agent.

4. The method of claim 3 , comprising administering a lipid composition comprising:

a compound of formula:

(9Z, 9′Z, 12Z, 12′Z)-((5-((dimethylamino)methyl)-1, 3-phenylene)bis(oxy))bis(butane-4,1-diyl) bis(octadeca-9, 12-dienoate)

or a pharmaceutically acceptable salt thereof;

an mRNA;

and

a pharmaceutically acceptable carrier or excipient.

5. A method for the treatment of a disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a lipid composition comprising:

a compound of formula:

((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate),

or a pharmaceutically acceptable salt thereof;

and

an mRNA agent.

6. The method of claim 5 , comprising administering a lipid composition comprising:

a compound of formula:

((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate),

or a pharmaceutically acceptable salt thereof;

an mRNA;

and

a pharmaceutically acceptable carrier or excipient.

7. The method of claim 1 , wherein the composition comprises one or more of a helper lipid, a neutral lipid, and a stealth lipid.

8. The method of claim 7 , wherein the helper lipid is cholesterol, the neutral lipid is DSPC, and the stealth lipid is PEG-DMG, S010, or S011.

9. The method of claim 3 , wherein the composition comprises one or more of a helper lipid, a neutral lipid, and a stealth lipid.

10. The method of claim 9 , wherein the helper lipid is cholesterol, the neutral lipid is DSPC, and the stealth lipid is PEG-DMG, S010, or S011.

11. The method of claim 5 , wherein the composition comprises one or more of a helper lipid, a neutral lipid, and a stealth lipid.

12. The method of claim 11 , wherein the helper lipid is cholesterol, the neutral lipid is DSPC, and the stealth lipid is PEG-DMG, S010, or S011.

13. The method of claim 1 , wherein the composition is in a form of a lipid nanoparticle.

14. The method of claim 3 , wherein the composition is in a form of a lipid nanoparticle.

15. The method of claim 5 , wherein the composition is in a form of a lipid nanoparticle.

16. The method of claim 8 , wherein the stealth lipid is PEG-DMG.

17. The method of claim 10 , wherein the stealth lipid is PEG-DMG.

18. The method of claim 12 , wherein the stealth lipid is PEG-DMG.

19. The method of claim 8 , wherein the lipid composition has a molar ratio of about 40/about 38/about 10/about 2 of the compound of formula (I)/cholesterol/DSPC/PEG-DMG, S010, or S011, respectively.

20. The method of claim 10 , wherein the lipid composition has a molar ratio of about 40/about 38/about 10/about 2 of the compound of (9Z, 9′Z, 12Z, 12′Z)-((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(butane-4,1-diyl) bis(octadeca-9, 12-dienoate)/cholesterol/DSPC/PEG-DMG, S010, or S011, respectively.

21. The method of claim 12 , wherein the lipid composition has a molar ratio of about 40/about 38/about 10/about 2 of a compound of ((5-((dimethylamino)methyl)-1,3-phenylene)bis(oxy))bis(octane-8,1-diyl)bis(decanoate)/cholesterol/DSPC/PEG-DMG, S010, or S011, respectively.