NOVEL LIPIDS AND LIPID NANOPARTICLE FORMULATIONS FOR DELIVERY OF NUCLEIC ACIDS

• US 20150376115A1
• Filed: 06/05/2015
• Published: 12/31/2015
• 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
• Granted Patent: US 9,738,593 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 a structure of Formula I:

2. The compound of claim 1, wherein one of L¹ or L² is —

O(C═

O)—

.

3. The compound of claim 1, wherein one of L¹ or L² is —

(C═

O)O—

.

4. The compound of claim 1, wherein one of L¹ or L² is a carbon-carbon double bond.

5. The compound of claim 1, wherein the compound has one of the following structures (Ia), (Ib) or (Ic):

6. The compound of claim 1, wherein a, b, c and d are each independently an integer from 2 to 12.

7. The compound of claim 1, wherein a, b, c and d are each independently an integer from 5 to 9.

8. The compound of claim 1, wherein at least one of R^1a, R^2a, R^3a and R^4a is H.

9. The compound of claim 1, wherein R^1a, R^2a, R^3a and R^4a are H at each occurrence.

10. The compound of claim 1, wherein at least one of R^1a, R^2a, R^3a and R^4a is C₁-C₈ alkyl.

11. The compound of claim 10, wherein C₁-C₈ alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

12. The compound of claim 1, wherein at least one of R^1b, R^2b, R^3b and R^4b is H.

13. The compound of claim 1, wherein R^1b, R^2b, R^3b and R^4b are H at each occurrence.

14. The compound of claim 1, wherein R^1b together with the carbon atom to which it is bound is taken together with an adjacent R^1b and the carbon atom to which it is bound to form a carbon-carbon double bond.

15. The compound of claim 1, wherein R^4b together with the carbon atom to which it is bound is taken together with an adjacent R^4b and the carbon atom to which it is bound to form a carbon-carbon double bond.

16. The compound of claim 1, wherein one of R⁵ or R⁶ is methyl.

17. The compound of claim 1, wherein each of R⁵ and R⁶ is methyl.

18. The compound of claim 1, wherein one of R⁵ or R⁶ is cycloalkyl.

19. The compound of claim 1, wherein each of R⁵ and R⁶ is cycloalkyl.

20. The compound of claim 18, wherein the cycloalkyl is unsubstituted.

21. The compound of claim 18, wherein the cycloalkyl is substituted.

22. The compound of claim 18, wherein the cycloalkyl is substituted with C₁-C₆alkyl.

23. The compound of claim 22, wherein C₁-C₆alkyl is tert-butyl.

24. The compound of claim 18, wherein cycloalkyl is cyclohexyl.

25. The compound of claim 1, wherein at least one R⁷ is H.

26. The compound of claim 25, wherein each R⁷ is H.

27. The compound of claim 1, wherein at least one R⁷ is C₁-C₆ alkyl.

28. The compound of claim 1, wherein e is 2.

29. The compound of claim 1, wherein at least one of R⁸ or R⁹ is methyl.

30. The compound of claim 1, wherein each of R⁸ and R⁹ is methyl.

31. The compound of claim 1, wherein the compound has one of the following structures:

32. A composition comprising the compound of claim 1 and a therapeutic agent.

47. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 32, and administering the composition to the patient.

33-46. -46. (canceled)

48. A pegylated lipid having the following structure (II):

52. A composition comprising the pegylated lipid of claim 48 and a cationic lipid.

49-51. -51. (canceled)

53. (canceled)