Cationic lipids for use in lipid nanoparticles

Patent metadata

Field	Value
Publication number	US-2022106257-A1
Application number	US-202117378083-A
Country	US
Kind code	A1
Filing date	Jul 16, 2021
Priority date	Jul 16, 2020
Publication date	Apr 7, 2022
Grant date	—

Abstract

Compounds are provided having the following structure:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein a, b, c, d, G 1 , G 2 , L 1 , L 2 , R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 and X are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, nanoparticles comprising the compounds and methods for their use and preparation are also provided.

First claim

1 . A compound having a structure of Formula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
G 1 and G 2 are each independently C 1 -C 6 alkylene;
L 1 and L 2 are each independently —O(C═O)— or —(C═O)O—;
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 —O(C═O)R 10 , —(C═O)OR 10 , —NR 9 (C═O)R 10 or —(C═O)NR 9 R 10 ;
R 8 is OH, —N(R 11 )(C═O)R 12 , —(C═O)NR 11 R 12 , —NR 11 R 12 , —(C═O)OR′ 2 or —O(C═O)R′ 2 ;
R 9 is H or C 1 -C 15 alkyl;
R 10 is C 1 -C 15 alkyl;
R 11 is H or C 1 -C 6 alkyl;
R 12 is C 1 -C 6 alkyl;
X is —(C═O)— or a direct bond; and
a, b, c and d are each independently an integer from 1 to 24;

wherein each methyl, alkyl and alkylene is independently optionally substituted.

2 . The compound of claim 1 , having one of the following structures (IA) or (TB):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

3 . The compound of claim 1 , wherein G 1 is C 2 -C 3 alkylene or C 4 -C 6 alkylene.

4 - 5 . (canceled)

6 . The compound of claim 1 , wherein G 2 is C 2 -C 3 alkylene or C 3 -C 4 alkylene.

7 . The compound of claim 1 , wherein X is —(C═O)—.

8 . The compound of claim 1 , wherein X is a direct bond.

9 . The compound of claim 1 , wherein R 7 is —O(C═O)R 10 or —(C═O)OR 10 .

10 . (canceled)

11 . The compound of claim 9 , wherein R 10 is linear C 6 -C 10 alkyl.

12 . The compound of claim 9 , wherein R 10 is methyl.

13 . (canceled)

14 . The compound of claim 9 , wherein R 10 is branched C 10 -C 15 alkyl.

15 . The compound of claim 1 , wherein R 7 is —NR 9 (C═O) or —(C═O)NR 9 R 10 .

16 . The compound of claim 15 , wherein R 9 is H.

17 . The compound of claim 15 , wherein R 9 and R 10 are each independently C 6 -C 10 alkyl.

18 - 21 . (canceled)

22 . The compound of claim 1 , wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b are, at each occurrence, independently H or C 1 -C 12 alkyl.

23 - 24 . (canceled)

25 . The compound of claim 22 , wherein at least one of R 1b and R 4b is C 1 -C 8 alkyl.

26 . (canceled)

27 . The compound of claim 1 , wherein

or both, independently has one of the following structures:

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

29 - 32 . (canceled)

33 . The compound of claim 1 , wherein R 8 is —N(R 11 )(C═O)R 12 .

34 . The compound of claim 1 , wherein R 8 is —(C═O)NR 11 R 12 .

35 . The compound of claim 1 , wherein R 8 is NR 11 R 12 .

36 - 39 . (canceled)

40 . The compound of claim 1 , wherein R 8 is —(C═O)OR 12 .

41 . The compound of claim 40 , wherein R 8 is —O(C═O)R 12 .

42 . The compound of claim 1 , wherein R 8 has one of the following structures:

43 . The compound of claim 1 , having one of the following structures:

44 . A lipid nanoparticle comprising the compound of claim 1 and a therapeutic agent.

45 - 58 . (canceled)

59 . A pharmaceutical composition comprising the lipid nanoparticle of claim 44 and a pharmaceutically acceptable diluent or excipient.

60 . A method for treating or preventing a disease in a patient in need thereof, the method comprising administering the lipid nanoparticle of claim 44 to the patient.

61 . A method for vaccinating a patient in need thereof against a viral pathogen, the method comprising administering the lipid nanoparticle of claim 44 to the patient, wherein the therapeutic agent is a viral antigen or a nucleic acid capable of transcribing a viral antigen.

Assignees

• Acuitas Therapeutics Inc

Inventors

• Gatenyo Julia
• Du Xinyao

Classifications

• A61P31/12

  Antivirals · CPC title

• C07C219/06 Primary

  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

• C07C237/06

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

• C07C233/36

  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

• C07C229/24 Primary

  having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid · CPC title