Lipids and lipid nanoparticle formulations for delivery of nucleic acids

• US 10,221,127 B2
• Filed: 06/29/2016
• Issued: 03/05/2019
• Est. Priority Date: 06/29/2015
• Status: Active Grant

• Current Assignee: Acuitas Therapeutics, Inc.
• Original Assignee: Acuitas Therapeutics, Inc.
• Inventors: Du, Xinyao, Ansell, Steven M.
• Primary Examiner(s): Epps-Smith, Janet L
• Application Number:
  US15/196,582
• Publication Number:
  US 20160376224A1
• Time in Patent Office: 979 Days
• Field of Search: 514 44, 435458, 435375, 435455, 424450
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• 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 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: C07C 211/09 Diamines
• CPC Class Codes: C07C 233/36 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/38 having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
• CPC Class Codes: C07C 235/10 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218

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, G¹, G², G³, a, b, c and d 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 IA or IB:

2. The compound of claim 1, wherein:

L¹ and L² are each independently —

O(C═

O)—

or —

(C═

O)O—

.

3. The compound of claim 1, having a structure of formula (IA).

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

O(C═

O)—

.

5. The compound of claim 4, wherein each of L¹ and L² are —

O(C═

O)—

.

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

(C═

O)O—

.

7. The compound of claim 6, wherein each of L¹ and L² is —

(C═

O)O—

.

8. The compound of claim 1, wherein for at least one occurrence of R^1a and R^1b, R^1a is H or C₁-C₁₂ 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.

9. The compound of claim 1, wherein for at least one occurrence of R^4a and R^4b, R^4a is H or C₁-C₁₂ 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.

10. The compound of claim 1, wherein for at least one occurrence of R^2a and R^2b, R^2a is H or C₁-C₁₂ alkyl, and R^2b together with the carbon atom to which it is bound is taken together with an adjacent R^2b and the carbon atom to which it is bound to form a carbon-carbon double bond.

11. The compound of claim 1, wherein for at least one occurrence of R^3a and R^3b, R^3a is H or C₁-C₁₂ alkyl, and R^3b together with the carbon atom to which it is bound is taken together with an adjacent R^3b and the carbon atom to which it is bound to form a carbon-carbon double bond.

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

13. The compound of claim 12, wherein a, b, c and d are each independently an integer from 5 to 9.

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

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

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

17. The compound of claim 16, wherein C₁-C₈ alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

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

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

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

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

22. The compound of claim 1, wherein R⁷ is C₆-C₉ alkyl.

23. The compound of claim 1, wherein R⁷ is substituted with —

(C═

O)OR^b, —

O(C═

O)R^b, —

C(═

O)R^b, —

OR^b, —

S(O)_xR^b, —

S—

SR^b, —

C(═

O)SR^b, —

SC(═

O)R^b, —

NR^aR^b, —

NR^aC(═

O)R^b, —

C(═

O)NR^aR^b, —

NR^aC(═

O)NR^aR^b, —

OC(═

O)NR^aR^b, —

NR^aC(═

O)OR^b, —

NR^aS(O)_xNR^aR^b, —

NR^aS(O)_xR^b or —

S(O)_xNR^aR^b, wherein;

R^a is H or C₁-C₁₂ alkyl;

R^b is C₁-C₁₅ alkyl; and

x is 0, 1 or 2.

24. The compound of claim 23, wherein R⁷ is substituted with —

(C═

O)OR^b or —

O(C═

O)R^b.

25. The compound of claim 23, wherein R^b is branched C₁-C₁₅ alkyl.

26. The compound of claim 25, wherein R^b has one of the following structures:

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

28. The compound of claim 27, wherein each of R⁸ and R⁹ is methyl.

29. The compound of claim 1, wherein R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring.

30. The compound of claim 29, wherein the heterocyclic ring is pyrrolidinyl.

31. The compound of claim 29, wherein the heterocyclic ring is piperazinyl.

32. The compound of claim 1, wherein G³ is C₂-C₄ alkylene.

33. The compound of claim 1, wherein G³ is C₃ alkylene.

34. The compound of claim 1, having one of the following structures:

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

36. The composition of claim 35, further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.

37. The composition of claim 36, wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

38. The composition of claim 37, wherein the neutral lipid is DSPC.

39. The composition of claim 36, wherein the steroid is cholesterol.

40. The composition of claim 39, wherein the molar ratio of the compound to cholesterol ranges from about 2:

1 to 1;

1.

41. The composition of claim 36, wherein the polymer conjugated lipid is a pegylated lipid.

42. The composition of claim 41, wherein the molar ratio of the compound to the pegylated lipid ranges from about 100:

1 to about 25;

1.

43. The composition of claim 41, wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.

44. The composition of claim 41, wherein the pegylated lipid has the following structure (II):

45. The composition of claim 44, wherein R¹⁰ and R¹¹ are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.

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

47. The composition of claim 35, wherein the molar ratio of the compound to the neutral lipid ranges from about 2:

1 to about 8;

1.

48. The composition of claim 35, wherein the therapeutic agent comprises a nucleic acid.

49. The composition of claim 48, wherein the nucleic acid is selected from antisense and messenger RNA.

50. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 35 and administering the composition to the patient.

51. The compound of claim 1, having a structure of formula (IB).