NOVEL LIPIDS AND COMPOSITIONS FOR THE DELIVERY OF THERAPEUTICS

• US 20120095075A1
• Filed: 08/16/2011
• Published: 04/19/2012
• Est. Priority Date: 11/10/2008
• Status: Abandoned Application

• Current Assignee: Arbutus Biopharma Corporation
• Original Assignee: Alnylam Pharmaceuticals Incorporated
• Inventors: MANOHARAN, Muthiah, Rajeev, Kallanthottathil G., Butler, David, Jayaprakash, Narayanannair K., Jayaraman, Muthusamy, Eltepu, Laxman
• Application Number:
  US13/211,150
• Publication Number:
  US 20120095075A1
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• 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 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07C 229/08 the nitrogen atom of the amino group being further bound to hydrogen atoms
• CPC Class Codes: C07C 229/30 the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07C 237/16 the carbon skeleton being acyclic and unsaturated
• CPC Class Codes: C07C 251/38 to carbon atoms of a saturated carbon skeleton
• CPC Class Codes: C07C 251/78 to carbon atoms of an unsaturated carbon skeleton
• CPC Class Codes: C07C 271/12 : to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 271/20 : to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 323/25 : the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07D 203/10 : Radicals substituted by singly bound oxygen atoms
• CPC Class Codes: C07D 317/28 : Radicals substituted by nitrogen atoms nitro radicals C07D317/16
• CPC Class Codes: C07D 317/44 : ortho- or peri-condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 317/46 : condensed with one six-membered ring
• CPC Class Codes: C07D 317/72 : spiro-condensed with carbocyclic rings
• CPC Class Codes: C07D 319/06 : not condensed with other rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/056 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 491/113 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C12N 15/111 : General methods applicable to biologically active non-coding nucleic acids
• 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
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2310/3515 : Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure:

Claims

1. A cationic lipid having the formula:

2. The cationic lipid of claim 1, wherein R₁ and R₂ are each independently unsubstituted C₁₀-C₃₀ alkyl or unsubstituted C₁₀-C₃₀ alkenyl.

3. The cationic lipid of claim 1, wherein R₁ and R₂ are each independently unsubstituted C₁₀-C₃₀ alkenyl.

4. The cationic lipid of claim 1, wherein R₁ and R₂ are

5. The cationic lipid of claim 1, wherein R₁ and R₂ are each independently unsubstituted C₁₀-C₃₀ alkyl.

6. The cationic lipid of claim 1, wherein R₁ and R₂ comprise the same number of unsaturation sites.

7. The cationic lipid of claim 1, wherein R₃ is a C₁-C₁₀ alkyl.

8. The cationic lipid of claim 1, wherein R₃ is a heterocycle.

9. The cationic lipid of claim 1, wherein X and Y are O.

10. The cationic lipid of claim 4, wherein X and Y are O.

11. The cationic lipid of claim 1, wherein A₂ is —

CH₂—

.

12. The cationic lipid of claim 9, wherein A₂ is —

CH₂—

.

13. The cationic lipid of claim 10, wherein A₂ is —

CH₂—

.

14. The cationic lipid of claim 1, wherein Z′

is N(Q).

15. The cationic lipid of claim 9, wherein Z′

is N(Q).

16. The cationic lipid of claim 13, wherein Z′

is N(Q).

17. The cationic lipid of claim 1, wherein Z′

is alkyl.

18. The cationic lipid of claim 1, wherein R₃ is alkylamine.

19. The cationic lipid of claim 9, wherein R₃ is alkylamine.

20. The cationic lipid of claim 13, wherein R₃ is alkylamine.

21. The cationic lipid of claim 1, wherein Q is alkyl.

22. The cationic lipid of claim 14, wherein Q is alkyl.

23. The cationic lipid of claim 15, wherein Q is alkyl.

24. The cationic lipid of claim 16, wherein Q is alkyl.

43. A lipid particle comprising a compound of claim 9.

44. A lipid particle comprising a compound of claim 14.

46. The lipid particle of claim 43, wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

47. The lipid particle of claim 44, wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

49. The lipid particle of claim 43, further comprises a nucleic acid.

50. The lipid particle of claim 44, further comprises a nucleic acid.

52. The lipid particle of claim 49, wherein the nucleic acid is an siRNA.

53. The lipid particle of claim 50, wherein the nucleic acid is an siRNA.

25. A cationic lipid of the formula

26. The cationic lipid of claim 25, wherein R₁ and R₂ are independently unsubstituted C₁₀-C₃₀ alkyl or unsubstituted C₁₀-C₃₀ alkenyl.

27. The cationic lipid of claim 25, wherein R₁ and R₂ are independently unsubstituted C₁₀-C₃₀ alkyl.

28. The cationic lipid of claim 25, R₁ and R₂ are independently unsubstituted C₁₀-C₃₀ alkenyl.

29. The cationic lipid of claim 25, wherein R₁ and R₂ are

30. The cationic lipid of claim 25, wherein X and Y are methyl.

31. The cationic lipid of claim 26, wherein X and Y are methyl.

32. The cationic lipid of claim 27, wherein X and Y are methyl.

33. The cationic lipid of claim 28, wherein X and Y are methyl.

34. The cationic lipid of claim 29, wherein X and Y are methyl.

35. The cationic lipid of claim 25, X and Y together are —

(CH₂)_n—

where n is 4 to 6.

36. The cationic lipid of claim 26, X and Y together are —

(CH₂)_n—

where n is 4 to 6.

37. The cationic lipid of claim 27, X and Y together are —

(CH₂)_n—

where n is 4 to 6.

38. The cationic lipid of claim 28, X and Y together are —

(CH₂)_n—

where n is 4 to 6.

39. The cationic lipid of claim 29, X and Y together are —

(CH₂)_n—

where n is 4 to 6.

40. The cationic lipid of claim 25, wherein the compound is

41. The cationic lipid of claim 40, wherein X and Y are methyl.

42. The cationic lipid of claim 40, wherein X and Y together are —

(CH₂)_n—

where n is 4 to 6.

45. A lipid particle comprising a compound of claim 25.

48. The lipid particle of claim 45, wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

51. The lipid particle of claim 45, further comprises a nucleic acid.

54. The lipid particle of claim 51, wherein the nucleic acid is an siRNA.