Lipids for use in lipid nanoparticle formulations

Patent metadata

Field	Value
Publication number	US-2021122703-A1
Application number	US-201816638731-A
Country	US
Kind code	A1
Filing date	Aug 17, 2018
Priority date	Aug 17, 2017
Publication date	Apr 29, 2021
Grant date	—

Abstract

Compounds are provided having the following structure (I) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein X, Y, L 1 , L 2 , L 3 , G 1 , G 2 and G 3 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:
X is N, and Y is absent; or X is CR, and Y is NR;
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 ;
L 3 is —O(C═O)R 3 or —(C═O)OR 3 ;
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 1 -C 24 heteroalkylene or C 2 -C 24 heteroalkenylene when X is CR, and Y is NR; and G 3 is C 1 -C 24 heteroalkylene or C 2 -C 24 heteroalkenylene when X is N, and Y is absent;
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;
each R is independently H or C 1 -C 12 alkyl;
R 1 , R 2 and R 3 are each independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; and
x is 0, 1 or 2, and

wherein each alkyl, alkenyl, alkylene, alkenylene, heteroalkylene and heteroalkenylene is independently substituted or unsubstituted unless otherwise specified.

2 . The compound of claim 1 , wherein G 3 is C 1 -C 12 alkylene.

3 . The compound of claim 1 , wherein G 3 is C 1 -C 12 heteroalkylene.

4 . The compound of claim 3 , wherein G 3 is C 1 -C 12 aminylalkylene.

5 . The compound of any one of claim 3 or 4 , wherein X is N and Y is absent.

6 . The compound of any one of claims 1 - 4 , wherein X is CR and Y is NR.

7 . The compound of claim 6 , wherein R is H.

8 . The compound of any one of claims 1 - 7 , having one of the following structures (IA), (IB), (IC) or (ID):

9 . The compound of any one of claims 1 - 8 , wherein L 1 is —O(C═O)R 1 , —(C═O)OR 1 or —C(═O)NR b R c , and L 2 is —O(C═O)R 2 , —(C═O)OR 2 or —C(═O)NR e R f .

10 . The compound of claim 9 , wherein L 1 is —(C═O)OR 1 and L 2 is —(C═O)OR 2 .

11 . The compound of any one of claims 1 - 10 , wherein L 3 is —(C═O)OR 3 .

12 . The compound of any one of claims 1 - 11 , wherein G 1 and G 2 are each independently C 2 -C 12 alkylene.

13 . The compound of any one of claims 1 - 11 , wherein G 1 and G 2 are each independently C 4 -C 10 alkylene.

14 . The compound of any one of claim 1 - 13 , wherein R 1 , R 2 and R 3 are each, independently, branched C 6 -C 24 alkyl.

15 . The compound of claim 14 , wherein R 1 , R 2 and R 3 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.

16 . The compound of claim 15 , wherein a is an integer from 8 to 12.

17 . The compound of any one of claim 15 or 16 , wherein at least one occurrence of R 7a is H.

18 . The compound of any one of claim 15 or 16 , wherein R 7a is H at each occurrence.

19 . The compound of any one of claims 15 - 18 , wherein at least one occurrence of R 7b is C 1 -C 8 alkyl.

20 . The compound of claim 19 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

21 . The compound of any one of claim 1 - 13 , wherein X is CR, Y is NR and R 3 is C 1 -C 12 alkyl.

22 . The compound of any one of claims 1 - 17 , wherein R 1 , R 2 and R 3 independently have one of the following structures:

23 . The compound of any one of claim 1 - 13 , wherein R 1 and R 2 and R 3 are each, independently, branched C 6 -C 24 alkyl and R is C 1 -C 24 alkyl or C 2 -C 24 alkenyl.

24 . The compound of any one of claims 1 - 9 , wherein R b , R c , R e and R f are each independently C 3 C 12 alkyl.

25 . The compound of any one of claims 1 - 9 , wherein R b , R c , R e and R f are n-hexyl.

26 . The compound of any one of claims 1 - 9 , wherein R b , R c , R e and R f are n-octyl.

27 . A compound selected from a compound in Table 1.

28 . A composition comprising the compound of any one of claims 1 - 27 and a therapeutic agent.

29 . The composition of claim 28 , further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.

30 . The composition of claim 29 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

31 . The composition of claim 29 , wherein the neutral lipid is DSPC.

32 . The composition of any one of claims 28 - 31 , wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:1.

33 . The composition of any one of claims 29 - 32 , wherein the steroid is cholesterol.

34 . The composition of claim 33 , wherein the molar ratio of the compound to cholesterol ranges from 5:1 to 1:1.

35 . The composition of any one of claims 29 - 34 , wherein the polymer conjugated lipid is pegylated lipid.

36 . The composition of claim 35 , wherein the molar ratio of the compound to pegylated lipid ranges from about 100:1 to about 20:1.

37 . The composition of anyone of claim 35 or 36 , wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.

38 . The composition of any one of claim 35 or 36 , wherein the pegylated lipid has the following structure (II):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 8 and R 9 are each independently a straight or branched, alkyl, alkenyl or alkynyl from 10 to 30 carbon atoms, wherein the alkyl, alkenyl or alkynyl is optionally interrupted by one or more ester bonds; and
w has a mean value ranging from 30 to 60.

39 . The composition of claim 38 , wherein R 8 and R 9 are each independently straight alkyl chain containing from 12 to 16 carbon atoms.

40 . The composition of any one of claim 38 or 39 , wherein the average w is about 49.

41 . The composition of any one of claims 28 - 40 , wherein the therapeutic agent comprises a nucleic acid.

42 . The composition of claim 41 , wher

Assignees

• Acuitas Therapeutics Inc

Inventors

• Du Xinyao

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07C229/24

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

• A61K47/543

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K9/5123

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