Lipids and lipid nanoparticle formulations for delivery of nucleic acids

• US 10,723,692 B2
• Filed: 09/14/2018
• Issued: 07/28/2020
• Est. Priority Date: 06/25/2014
• Status: Active Grant

• Current Assignee: Acuitas Therapeutics, Inc.
• Original Assignee: Acuitas Therapeutics, Inc.
• Inventors: Ansell, Steven M., Du, Xinyao
• Primary Examiner(s): Puttlitz, Karl J
• Application Number:
  US16/132,287
• Publication Number:
  US 20190270697A1
• Time in Patent Office: 683 Days
• Field of Search: None
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 219/06 having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 219/08 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 219/10 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
• CPC Class Codes: C07C 227/16 by reactions not involving the amino or carboxyl groups
• CPC Class Codes: C07C 229/16 to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
• CPC Class Codes: C07C 229/24 having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
• CPC Class Codes: C07C 235/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C08G 65/33306 acyclic
• CPC Class Codes: C12Y 304/21022 Coagulation factor IXa (3.4.21.22)

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R⁵, R⁶, R⁷, R⁸, R⁹, L¹, L², a, b, c, d and e are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.

Claims

1. A compound having the following structure (II):

2. The compound of claim 1, wherein R¹⁰ and R¹¹ are each straight, saturated alkyl chains containing 12 carbon atoms.

3. The compound of claim 1, wherein R¹⁰ and R¹¹ are each straight, saturated alkyl chains containing 14 carbon atoms.

4. The compound of claim 1, wherein R¹⁰ and R¹¹ are each straight, saturated alkyl chains containing 16 carbon atoms.

5. The compound of claim 1, wherein z ranges from 30 to 60.

6. The compound of claim 1, wherein z is 45.

7. The compound of claim 1, wherein z is selected such that an average molecular weight of structure (II) is about 2500 g/mol.

8. The compound of claim 1, having the following structure:

9. The compound of claim 8, wherein n is 45.

10. The compound of claim 1, having the following structure:

11. The compound of claim 1, having the following structure:

12. The compound of claim 11, wherein n is 45.

13. The compound of claim 1, having the following structure:

14. The compound of claim 1, having the following structure:

15. The compound of claim 14, wherein n is 45.

16. The compound of claim 1, having the following structure:

17. A lipid nanoparticle comprising the compound of claim 1.

18. The lipid nanoparticle of claim 17, wherein R¹⁰ and R¹¹ are each straight, saturated alkyl chains containing 12 carbon atoms.

19. The lipid nanoparticle of claim 17, wherein R¹⁰ and R¹¹ are each straight, saturated alkyl chains containing 14 carbon atoms.

20. The lipid nanoparticle of claim 17, wherein R¹⁰ and R¹¹ are each straight, saturated alkyl chains containing 16 carbon atoms.

21. The lipid nanoparticle of claim 17, wherein z ranges from 30 to 60.

22. The lipid nanoparticle of claim 17, wherein z is 45.

23. The lipid nanoparticle of claim 17, wherein z is selected such that an average molecular weight of structure (II) is about 2500 g/mol.

24. The lipid nanoparticle of claim 17, wherein the compound has the following structure:

25. The lipid nanoparticle of claim 24, wherein n is 45.

26. The lipid nanoparticle of claim 17, wherein the compound has the following structure:

27. The lipid nanoparticle of claim 17, wherein the compound has the following structure:

28. The lipid nanoparticle of claim 27, wherein n is 45.

29. The lipid nanoparticle of claim 17, wherein the compound has the following structure:

30. The lipid nanoparticle of claim 17, wherein the compound has the following structure:

31. The lipid nanoparticle of claim 30, wherein n is 45.

32. The lipid nanoparticle of claim 17, wherein the compound has the following structure:

33. The lipid nanoparticle of claim 17, wherein the average molecular weight of the PEG portion,

34. The compound of claim 1, wherein the average molecular weight of the PEG portion,