Lipids and lipid nanoparticle formulations for delivery of nucleic acids

Patent metadata

Field	Value
Publication number	US-9738593-B2
Application number	US-201514732218-A
Country	US
Kind code	B2
Filing date	Jun 5, 2015
Priority date	Jun 25, 2014
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

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 , R 5 , R 6 , R 7 , R 8 , R 9 , L 1 , L 2 , 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.

First claim

The invention claimed is:

1. A compound having a structure of Formula I:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—;
R 1a and R 1b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 1a is H or C 1 -C 12 alkyl, and 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;
R 2a and R 2b are, at each occurrence, H;
R 3a and R 3b are, at each occurrence, H;
R 4a and R 4b are, at each occurrence, independently either (a) H or C 1 -C 12 alkyl, or (b) R 4a is H or C 1 -C 12 alkyl, and 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;
R 5 and R 6 are each independently methyl or cycloalkyl;
R 7 is, at each occurrence, independently H or C 1 -C 12 alkyl;
R 8 and R 9 are each independently unsubstituted C 1 -C 12 alkyl; or R 8 and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring comprising one nitrogen atom;
a and d are each independently an integer from 0 to 24;
b and c are each independently an integer from 4 to 12; and
e is 1 or 2,
provided that:
R 1a and R 1b are not isopropyl when a is 6 or n-butyl when a is 8.

2. The compound of claim 1 , wherein one of L 1 or L 2 is —O(C═O)—.

3. The compound of claim 1 , wherein one of L 1 or L 2 is —(C═O)O—.

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

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

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

7. The compound of claim 1 , wherein at least one of R 1a and R 4a is H.

8. The compound of claim 1 , wherein R 1a and R 4a are H at each occurrence.

9. The compound of claim 1 , wherein at least one of R 1a and R 4a is C 1 -C 8 alkyl.

10. The compound of claim 9 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

11. The compound of claim 1 , wherein at least one of R 1b and R 4b is H.

12. The compound of claim 1 , wherein R 1b and R 4b are H at each occurrence.

13. 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.

14. 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.

15. The compound of claim 1 , wherein one of R 5 or R 6 is methyl.

16. The compound of claim 1 , wherein each of R 5 and R 6 is methyl.

17. The compound of claim 1 , wherein one of R 5 or R 6 is cycloalkyl.

18. The compound of claim 1 , wherein each of R 5 and R 6 is cycloalkyl.

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

20. The compound of claim 17 , wherein the cycloalkyl is substituted.

21. The compound of claim 17 , wherein the cycloalkyl is substituted with C 1 -C 6 alkyl.

22. The compound of claim 21 , wherein C 1 -C 6 alkyl is tert-butyl.

23. The compound of claim 17 , wherein cycloalkyl is cyclohexyl.

24. The compound of claim 1 , wherein at least one R 7 is H.

25. The compound of claim 24 , wherein each R 7 is H.

26. The compound of claims 1 , wherein at least one R 7 is C 1 -C 6 alkyl.

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

28. The compound of claim 1 , wherein at least one of R 8 or R 9 is methyl.

29. The compound of claim 1 , wherein each of R 8 and R 9 is methyl.

30. A compound having one of the following structures:

31. A composition comprising the compound of claim 1 and a nucleic acid.

32. A method for administering a nucleic acid to a patient in need thereof, the method comprising preparing or providing the composition of claim 31 , and administering the composition to the patient.

33. The composition of claim 31 , further comprising one or more excipient selected from the group consisting of neutral lipids, steroids and polymer conjugated lipids.

34. The composition of claim 33 , wherein the composition comprises one or more neutral lipids selected from the group consisting of DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

35. The composition of claim 34 , wherein the neutral lipid is DSPC.

36. The composition of claim 33 , having a molar ratio of the compound to the neutral lipid of from about 2:1 to about 8:1.

37. The composition of claim 33 , wherein the steroid is cholesterol.

38. The composition of claim 37 , having a molar ratio of the compound to cholesterol of from about 2:1 to 1:1.

39. The composition of claim 33 , wherein the polymer conjugated lipid is a pegylated lipid.

40. The composition of claim 39 , having a molar ratio of the compound to the pegylated lipid of from about 100:1 to about 25:1.

41. The composition of claim 39 , wherein the pegylated lipid is PEG-DMG.

42. The composition of claim 39 , wherein the pegylated lipid has the following structure (II):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 10 and R 11 are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and
z has a mean value ranging from 30 to 60.

43. The composition of claim 42 , wherein R 10 and R 11 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.

44. The composition of claim 42 , wherein the average z is about 45.

45. The composition of claim 42 , wherein the pegylated lipid has one of the following structures:

wherein n has a mea

Assignees

• Acuitas Therapeutics Inc

Inventors

• Ansell Steven M
• Du Xinyao

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07C227/16

  by reactions not involving the amino or carboxyl groups · CPC title

• C07D295/13

  to an acyclic saturated chain · CPC title

• A61K38/4846

  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 title

• C07C219/10

  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 title