Lipids for use in lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-12065396-B2
Application number	US-201816638726-A
Country	US
Kind code	B2
Filing date	Aug 17, 2018
Priority date	Aug 17, 2017
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

Abstract

Compounds are provided having the following structure (I) 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 , 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 I:

or a pharmaceutically acceptable salt, tautomer 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 1 is C 1 -C 2 alkylene, —(C═O)—, —O(C═O)—, —SC(═O)—, —NR a C(═O)— or a direct bond;
G 2 is a direct bond;
G 3 is C 1 -C 6 alkylene;
R a is, at each occurrence, independently 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 1 -C 2 alkyl;
R 8 is OH;
a and d are each independently an integer from 1 to 24;
b and c are each independently an integer from 2 to 12; 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—; and
G 1 is —(C═O)— or a direct bond.

3. The compound of claim 1 , having the following structure (IB):

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

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

6. The compound of claim 1 , wherein

or both, independently has one of the following structures:

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

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

9. 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.

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

11. The compound of claim 1 , wherein G 3 is C 2 -C 5 alkylene.

12. The compound of claim 1 , wherein the compound has one of the following structures:

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

14. The composition of claim 13 , wherein the therapeutic agent comprises a nucleic acid.

15. The composition of claim 14 , wherein the nucleic acid is selected from antisense and messenger RNA.

16. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 13 , and administering the composition to the patient.

17. A lipid nanoparticle comprising a compound of claim 1 .

18. A pharmaceutical composition comprising the lipid nanoparticle of claim 17 and a pharmaceutically acceptable diluent or excipient.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao

Classifications

• C12N2310/11

  Antisense · 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

• C07C237/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• 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

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title