Di-aliphatic substituted pegylated lipids

• US 9,701,623 B2
• Filed: 09/27/2012
• Issued: 07/11/2017
• Est. Priority Date: 09/27/2011
• Status: Active Grant

• Current Assignee: Alnylam Pharmaceuticals Incorporated, Takeda Pharmaceutical Company Limited
• Original Assignee: Alnylam Pharmaceuticals Incorporated, Takeda Pharmaceutical Company Limited
• Inventors: Manoharan, Muthiah, Rajeev, Kallanthottathil G., Jayaraman, Muthusamy, Nair, Jayaprakash K., Matsumoto, Satoru
• Primary Examiner(s): Davis, Brian J
• Application Number:
  US14/346,924
• Publication Number:
  US 20150203446A1
• Time in Patent Office: 1,748 Days
• Field of Search: None
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 235/74 of a saturated carbon skeleton
• CPC Class Codes: C07C 237/06 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 43/04 Saturated ethers
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

The disclosure relates to di-aliphatic substituted PEGylated lipids and to methods of their preparation. The disclosure also relates to lipid conjugates containing di-aliphatic substituted PEGylated lipids, and to the use of di-aliphatic substituted PEGylated-lipid conjugates in drug delivery.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein R¹ and R² are independently C₁₀ to C₂₀ alkyl or C₁₀ to C₂₀ alkenyl.

3. The compound of claim 1, wherein L¹ is a bond or —

(CR⁵R⁵′

)_i—

.

4. The compound of claim 1, wherein Z¹ is —

O—

, —

N(H)—

, —

N(CH₃)—

, —

OC(O)—

, —

C(O)O—

, —

OC(O)N(CH₃)—

, —

N(H)C(O)O—

, —

N(CH₃)C(O)O—

, —

N(H)C(O)N(H)—

, —

N(H)C(O)N(CH₃)—

, —

N(CH₃)C(O)N(CH₃)—

, —

N(CH₃)C(O)N(H)—

, —

N(H)C(O)—

, —

N(CH₃)C(O)—

, —

C(O)N(H)—

, —

C(O)N(CH₃)—

, —

O—

N═

C(H)—

, —

O—

N═

C(CH₃)—

, —

O—

N(H)—

, —

O—

N(CH₃)—

or heteroaryl.

5. The compound of claim 1, wherein Z¹ is —

N(R^c)—

, —

N(R^c)C(O)O—

, —

N(R^c)C(O)N(R^c)—

, —

N(R^c)C(O)—

, or —

N═

C(R^a)—

, and the leftmost nitrogen atom in Z¹ is attached to the tertiary carbon atom of formula (I), or

Z¹ is a nitrogen-containing heteroaryl or heterocyclyl, wherein the nitrogen atom of the heteroaryl or heterocyclyl is bound to L¹ or if L¹ is a bond, then to the central tertiary carbon atom.

6. The compound of claim 1, wherein c is 1 and L² is —

(CR^aR^b)_p.

7. The compound of claim 1, wherein c is 1 and Z² is —

O—

, —

C(O)O—

, —

C(O)N(R^c)—

, or heteroaryl.

8. The compound of claim 1, wherein each A is, independently, L⁴ and each L⁴ is, independently —

OCH₂CH₂—

, —

CH₂CH₂O—

, —

OCH₂CH₂CH₂—

, —

OCH(CH₃)CH₂CH₂—

, —

OCH₂CH₂—

CH(CH₃)—

, —

OCH(CH₃)CH₂—

or —

OCH₂CH(CH₃)—

.

9. The compound of claim 1, wherein R³ is alkoxy.

10. The compound of claim 9, wherein R³ is methoxy.

11. The compound of claim 1, wherein b is from about 30 to about 60.

12. The compound of claim 1, wherein c is 0.

13. The compound of claim 1, wherein c is 1.

14. The compound of claim 1, wherein

R¹ and R² are each, independently C₁₂ to C₂₀ alkyl or C₁₂ to C₂₀ alkenyl;

L is -L¹-Z¹-L³- or -L¹-Z¹-(L²-Z²)-L³-;

L¹ is a bond or —

(CR⁵R^5′

)_i—

;

Z¹ is —

O—

, —

N(R^c)—

, —

OC(O)—

, —

C(O)O—

, —

N(R^c)C(O)O—

, —

N(R^c)C(O)N(R^c)—

, —

N(R^c)C(O)—

, —

C(O)N(R^c)—

, —

O—

N═

C(R^a)—

, —

O—

N(R^c)—

, heteroaryl, or heterocyclyl;

L² is —

(CR^aR^b)_p;

Z² is —

O—

, —

C(O)O—

, —

C(O)N(R^c)—

, or heteroaryl;

L³ is —

(CR^aR^b)_i—

;

each A is, independently, -L⁴-;

each L⁴ is, independently, —

OCH₂CH₂—

, —

CH₂CH₂O—

, —

OCH(CH₃)CH₂ or —

OCH₂CH(CH₃)—

;

R³ is —

OR^c;

each occurrence of R^a is, independently, H or alkyl;

each occurrence of R^b is, independently, H or alkyl; and

R^c is H or alkyl.

15. The compound of claim 1, wherein

R¹ and R² are each, independently C₁₂ to C₂₀ alkyl or C₁₂ to C₂₀ alkenyl;

and

Z¹ is —

N(R^c)—

, —

N(R^c)C(O)O—

, —

N(R^c)C(O)N(R^c)—

, —

N(R^c)C(O)—

, or —

N═

C(R^a)—

, wherein the leftmost nitrogen atom in Z¹ is bound to L¹ or if L¹ is a bond, then to the central tertiary carbon atom of formula (I)), or

Z¹ is a nitrogen-containing heteroaryl or heterocyclyl, wherein the nitrogen atom of the heteroaryl or heterocyclyl is bound to L¹ or if L¹ is a bond, then to the central tertiary carbon atom of formula (I).

20. A lipid particle comprising a compound of formula (I) claim 1, a cationic lipid, a neutral lipid, and a sterol.

21. The lipid particle of claim 20, wherein the cationic lipid is present in a mole percentage of about 20% and about 60%;

the neutral lipid is present in a mole percentage of about 5% to about 25%;

the sterol is present in a mole percentage of about 25% to about 55%; and

the compound according to formula (I) is present in a mole percentage of about 0.5% to about 15%.

22. The lipid particle of claim 20, further comprising an active agent selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

23. A pharmaceutical composition comprising a lipid particle of claim 20 and a pharmaceutically acceptable carrier.

24. A method of modulating the expression of a target gene in a cell comprising providing a lipid particle of claim 22 to the cell.

25. The compound of claim 1, wherein b ranges from about 10 to about 500.

26. The compound of claim 1, wherein b ranges from about 10 to about 250.

27. The compound of claim 1, wherein b ranges from about 25 to about 100.

28. The compound of claim 1, wherein b ranges from about 40 to about 50.

39. The compound of claim 1, wherein R³ is —

R^c, or —

OR^c, and R^c is alkyl, acyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl.

40. The compound of claim 1, wherein Z¹ is —

S—

, —

N(R^c)—

, —

OC(O)—

, —

C(O)O—

, —

OC(O)O—

, —

N(R^c)C(O)O—

, —

N(R^c)C(O)N(R^c)—

, —

N(R^c)C(O)—

, —

C(O)N(R^c)—

, —

N═

C(R^a)—

, —

C(R^a)═

N—

, —

O—

N═

C(R^a)—

, —

O—

N(R^c)—

;

heteroaryl, or heterocyclyl.

16. A compound of formula (II):

29. The compound of claim 16, wherein b ranges from about 10 to about 500.

30. The compound of claim 16, wherein b ranges from about 10 to about 250.

31. The compound of claim 16, wherein b ranges from about 25 to about 100.

32. The compound of claim 16, wherein b ranges from about 30 to about 60.

33. The compound of claim 16, wherein b ranges from about 40 to about 50.

17. A compound of formula (III):

34. The compound of claim 17, wherein b ranges from about 10 to about 500.

35. The compound of claim 17, wherein b ranges from about 10 to about 250.

36. The compound of claim 17, wherein b ranges from about 25 to about 100.

37. The compound of claim 17, wherein b ranges from about 30 to about 60.

38. The compound of claim 17, wherein b ranges from about 40 to about 50.

18. The compound selected from:

19. The compound of claim 18, wherein n is from about 30 to about 60.