Lipids and lipid compositions for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-10125092-B2
Application number	US-201515505282-A
Country	US
Kind code	B2
Filing date	Sep 4, 2015
Priority date	Sep 5, 2014
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Beckwith Rohan Eric John
• Brito Luis
• Dechristopher Brian Addison
• Gamber Gabriel Grant
• Geall Andrew
• Zabawa Thomas
• Novartis Ag

Inventors

• Beckwith Rohan Eric John
• Brito Luis
• Dechristopher Brian Addison
• Gamber Gabriel Grant
• Geall Andrew
• Zabawa Thomas

Classifications

• A61K9/1272

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K9/5123

  Organic compounds, e.g. fats, sugars · CPC title

• C07D295/15

  to an acyclic saturated chain · CPC title

• A61K31/711

  Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title