Lipids and lipid nanoparticle formulations for delivery of nucleic acids

Patent metadata

Field	Value
Publication number	US-10221127-B2
Application number	US-201615196582-A
Country	US
Kind code	B2
Filing date	Jun 29, 2016
Priority date	Jun 29, 2015
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

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 , G 1 , G 2 , G 3 , 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.

First claim

The invention claimed is:

1. A compound having a structure of Formula IA or IB:

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
L 1 and L 2 are each independently —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, —SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, —NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O—;
G 3 is C 1 -C 6 alkylene;
R a is H or C 1 -C 12 alkyl;
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, independently either: (a) H or C 1 -C 12 alkyl; or (b) R 2a is H or C 1 -C 12 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;
R 3a and R 3b are, at each occurrence, independently either (a): H or C 1 -C 12 alkyl; or (b) R 3a is H or C 1 -C 12 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;
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 H or methyl;
R 7 is C 6 -C 16 alkyl;
R 8 and R 9 are each independently 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;
a, b, c and d are each independently an integer from 1 to 24; and
x is 0, 1 or 2.

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

5. The compound of claim 4 , wherein each of L 1 and L 2 are —O(C═O)—.

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

7. The compound of claim 6 , wherein each of L 1 and L 2 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 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.

9. The compound of claim 1 , wherein for at least one occurrence of R 4a and R 4b , 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.

10. The compound of claim 1 , wherein for at least one occurrence of R 2a and R 2b , R 2a is H or C 1 -C 12 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 C 1 -C 12 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 C 1 -C 8 alkyl.

17. The compound of claim 16 , wherein C 1 -C 8 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 R 5 or R 6 is methyl.

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

22. The compound of claim 1 , wherein R 7 is C 6 -C 9 alkyl.

23. The compound of claim 1 , wherein R 7 is substituted with —(C═O)OR b , —O(C═O)R b , —C(═O)R b , —OR b , —S(O) x R b , —S—SR b , —C(═O)SR b , —SC(═O)R b , —NR a R b , —NR a C(═O)R b , —C(═O)NR a R b , —NR a C(═O)NR a R b , —OC(═O)NR a R b , —NR a C(═O)OR b , —NR a S(O) x NR a R b , —NR a S(O) x R b or —S(O) x NR a R b , wherein: R a is H or C 1 -C 12 alkyl; R b is C 1 -C 15 alkyl; and x is 0, 1 or 2.

24. The compound of claim 23 , wherein R 7 is substituted with —(C═O)OR b or —O(C═O)R b .

25. The compound of claim 23 , wherein R b is branched C 1 -C 15 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 R 8 or R 9 is methyl.

28. The compound of claim 27 , wherein each of R 8 and R 9 is methyl.

29. The compound of claim 1 , wherein R 8 and R 9 , 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 G 3 is C 2 -C 4 alkylene.

33. The compound of claim 1 , wherein G 3 is C 3 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 o

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao
• Ansell Steven M

Classifications

• C07C233/36 Primary

  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 title

• A61K9/5123

  Organic compounds, e.g. fats, sugars · CPC title

• C07D295/13 Primary

  to an acyclic saturated chain · CPC title

• C07C235/10

  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 title

• C12N15/113

  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 title