Lipids for use in lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-2025084029-A1
Application number	US-202418661116-A
Country	US
Kind code	A1
Filing date	May 10, 2024
Priority date	Aug 16, 2017
Publication date	Mar 13, 2025
Grant date	—

Abstract

Compounds are provided having the following structure:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R3, L1, L2, G1, G2 and G3 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

1 . A compound having the following structure (I):

or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein:
L 1 is —O(C═O)R 1 or —(C═O)OR 1 ;
L 2 is —O(C═O)R 2 or —(C═O)OR 2 ;
G 1 and G 2 are each independently C 4 -C 10 alkylene;
G 3 is C 2 or C 3 alkylene,
R 1 and R 2 are each independently branched C 6 -C 24 alkyl or branched C 6 -C 24 alkenyl;
R 3 is —N(R 4 )R 5 ;
R 4 is C 1 -C 12 alkyl; and
R 5 is substituted C 1 -C 12 alkyl; and

wherein each alkyl, alkenyl and alkylene is unsubstituted unless otherwise specified.

2 - 6 . (canceled)

7 . The compound of claim 1 , having one of the following structures (IB) or (IC):

8 - 10 . (canceled)

11 . The compound of claim 1 , wherein R 1 and R 2 are each, independently, branched C 6 -C 24 alkyl.

12 . The compound of claim 11 , wherein R 1 and R 2 each, independently have the following structure:

wherein:
R 7a and R 7b are, at each occurrence, independently H or C 1 -C 12 alkyl; and
a is an integer from 2 to 12,
wherein R 7a , R 7b and a are each selected such that R 1 and R 2 are each independently branched and independently comprise from 6 to 20 carbon atoms.

13 . The compound of claim 12 , wherein a is an integer from 8 to 12.

14 - 17 . (canceled)

18 . The compound of claim 1 , wherein R 1 or R 2 , or both, independently has one of the following structures:

19 - 21 . (canceled)

22 . The compound of claim 1 , wherein R 4 is substituted or unsubstituted: methyl, ethyl, propyl, n-butyl, n-hexyl, n-octyl or n-nonyl.

23 - 24 . (canceled)

25 . The compound of claim 1 , wherein R 5 is substituted: methyl, ethyl, propyl, n-butyl, n-hexyl, n-octyl or n-nonyl.

26 . The compound of claim 25 , wherein R 5 is substituted ethyl or substituted propyl.

27 . The compound of claim 25 , wherein R 4 is methyl.

28 . The compound of claim 25 , wherein R 5 is substituted with hydroxyl.

29 . The compound of claim 25 , wherein R 5 is substituted with one or more substituents selected from the group consisting of —OR g , —NR g C(═O)R h ,
—C(═O)NR g R h , —C(═O)R h , —OC(═O)R h , —C(═O)OR h and —OR i OH, wherein:
R g is, at each occurrence independently H or C 1 -C 6 alkyl;
R h is at each occurrence independently C 1 -C 6 alkyl; and
R i is, at each occurrence independently C 1 -C 6 alkylene.

30 . The compound of claim 1 , wherein R 3 has one of the following structures:

31 . A compound having one of the following structures:

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

33 - 47 . (canceled)

48 . A lipid nanoparticle comprising the compound of claim 1 .

49 . A pharmaceutical composition comprising the lipid nanoparticle of claim 48 and a pharmaceutically acceptable diluent or excipient.

50 . A method for inducing expression of a protein in a subject, comprising administering to the subject the lipid nanoparticle of claim 48 , wherein the lipid nanoparticle comprises an mRNA encoding the protein.

51 . A lipid nanoparticle comprising a compound having the following structure (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
L 1 is —O(C═O)R 1 , —(C═O)OR 1 , —C(═O)R 1 , —OR 1 , —S(O) x R 1 , —S—SR 1 , —C(═O)SR 1 , —SC(═O)R 1 , —NR a C(═O)R 1 , —C(═O)NR b R c , —NR a C(═O)NR b R c , —OC(═O)NR b R c or —NR a C(═O)OR 1 ;
L 2 is —O(C═O)R 2 , —(C═O)OR 2 , —C(═O)R 2 , —OR 2 , —S(O) x R 2 , —S—SR 2 , —C(═O)SR 2 , —SC(═O)R 2 , —NR d C(═O)R 2 , —C(═O)NR e R f , —NR d C(═O)NR e R f , —OC(═O)NR e R f ;

—NR d C(═O)OR 2 or a direct bond to R 2 ;
G 1 and G 2 are each independently C 2 -C 12 alkylene or C 2 -C 12 alkenylene;
G 3 is C 1 -C 24 alkylene, C 2 -C 24 alkenylene, C 3 -C 8 cycloalkylene or C 3 -C 8 cycloalkenylene;
R a , R b , R d and R e are each independently H or C 1 -C 12 alkyl or C 1 -C 12 alkenyl;
R c and R f are each independently C 1 -C 12 alkyl or C 2 -C 12 alkenyl;
R 1 and R 2 are each independently branched C 6 -C 24 alkyl or branched C 6 -C 24 alkenyl;
R 3 is —N(R 4 )R 5 ;
R 4 is C 1 -C 12 alkyl;
R 5 is substituted C 1 -C 12 alkyl; and
x is 0, 1 or 2, and
wherein each alkyl, alkenyl, alkylene, alkenylene, cycloalkylene, cycloalkenylene, aryl and aralkyl is independently substituted or unsubstituted unless otherwise specified.

52 . The lipid nanoparticle of claim 51 , further comprising an mRNA encoding a protein.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao

Classifications

• A61K31/23

  of acids having a carboxyl group bound to a chain of seven or more carbon atoms · CPC title

• 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

• C07C219/06

  having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton · CPC title

• A61K9/5123

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