Negatively charged peg-lipid conjugates

Patent metadata

Field	Value
Publication number	US-12357705-B2
Application number	US-201917291908-A
Country	US
Kind code	B2
Filing date	Nov 8, 2019
Priority date	Nov 9, 2018
Publication date	Jul 15, 2025
Grant date	Jul 15, 2025

Abstract

The invention provides PEG-conjugated lipids of formula (I): A-B-C (I) wherein A, B, and C have any of the values defined in the specification, as well as compositions comprising the PEG-conjugated lipids of formula (I), nucleic acid lipid nanoparticles comprising the PEG-conjugated lipids of formula (I), and methods of using the PEG-conjugated lipids of formula (I), the compositions, and the nucleic acid nanoparticles.

First claim

What is claimed is:

1. A compound of formula (I):
A-B-C  (I)

wherein:
A is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, or (C 2 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy is substituted with one or more anionic precursor groups, and wherein any (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, and (C 2 -C 6 )alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxyl, (C 1 -C 3 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylthio, and(C 2 -C 3 )alkanoyloxy;
each anionic precursor group is capable of forming an anion at physiological pH;
A is linked to B directly or via a linker moiety selected from the group consisting of —C(O)NR b —, —NR b —, —C(O)—, —NR b C(O)O—, —NR b C(O)NR b —, —S—S—, —O—, —(O)CCH 2 CH 2 C(O)—, and —NHC(O)CH 2 CH 2 C(O)NH—;
B is a polyethylene glycol chain having a molecular weight of from about 550 daltons to about 10,000 daltons;
C is -L-R a
L is selected from the group consisting of a direct bond, —C(O)O—, —C(O)NR b —, —NR b —, —C(O)—, —NR b C(O)O—, —NR b C(O)NR b —, —S—S—, —O—, —(O)CCH 2 CH 2 C(O)—, and —NHC(O)CH 2 CH 2 C(O)NH—;
R a is a branched (C 10 -C 50 )alkyl or branched (C 10 -C 50 )alkenyl wherein one or more carbon atoms of the branched (C 10 -C 50 )alkyl or branched (C 10 -C 50 )alkenyl have been replaced with —O—; and
each R b is independently H or (C 1 -C 6 )alkyl.

2. The compound of claim 1 , wherein A is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl, wherein any (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl is substituted with one or more anionic precursor groups, and wherein any (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxyl, (C 1 -C 3 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylthio, and (C 2 -C 3 )alkanoyloxy.

3. The compound of claim 1 , wherein A is (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl, wherein any (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl is substituted with one or more anionic precursor groups, and wherein any (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 6 )alkenyl, and (C 2 -C 6 )alkynyl is not further substituted with one or more additional groups.

4. The compound of claim 1 , wherein A is (C 1 -C 6 )alkyl that is substituted with one or more anionic precursor groups, and is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxyl, (C 1 -C 3 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylthio, and(C 2 -C 3 )alkanoyloxy.

5. The compound of claim 1 , wherein each anionic precursor group is —CO 2 H.

6. The compound of claim 1 , wherein B is a polyethylene glycol chain having an average molecular weight range of about 2,000 daltons.

7. The compound of claim 1 , wherein A is linked to B via the linker moiety.

8. The compound of claim 1 , wherein L is —NR b —.

9. The compound of claim 1 , wherein C has the following structure:

wherein:
R 1 and R 2 are each independently (C 10 -C 20 )alkyl or (C 10 -C 20 )alkenyl;
M is a direct bond or a divalent (C 1 -C 5 )alkyl;
L is selected from the group consisting of a direct bond, —C(O)O—, —C(O)NR b —, —NR b —, —C(O)—, —NR b C(O)—, —NR b C(O)NR b —, —S—S—, —O—, —(O)CCH 2 CH 2 C(O)—, and —NHC(O)CH 2 CH 2 C(O)NH—; and
each R b is independently H or (C 1 -C 6 )alkyl.

10. The compound of claim 1 , wherein A is substituted with one anionic precursor group.

11. The compound of claim 1 , wherein A is substituted with three anionic precursor groups.

12. The compound of claim 1 , wherein each anionic precursor group is selected from the group consisting of —CO 2 H, —O—P(═O)(OH) 2 , —OS(═O) 2 (OH), —O—S(═O)(OH), and —B(OH) 2 .

13. The compound of claim 1 , wherein A is linked to B directly.

14. The compound of claim 1 , wherein L is —C(O)NR b —, —NR b —, —C(O)—, —NR b C(O)O—, —NR b C(O)NR b —, —S—S—, —O—, —(O)CCH 2 CH 2 C(O)—, or —NHC(O)CH 2 CH 2 C(O)NH—.

15. The compound of claim 1 , wherein R a is a branched (C 10 -C 50 )alkyl or branched (C 10 -C 50 )alkenyl, wherein two carbon atoms of the branched (C 10 -C 50 )alkyl or branched (C 10 -C 50 )alkenyl have been replaced with —O—.

16. The compound of claim 1 , wherein each R b is independently H.

17. The compound of claim 1 , wherein L is —NR b C(O)O—.

18. The compound of claim 9 , wherein M is a direct bond.

19. The compound of claim 9 , wherein at least one of R 1 or R 2 is lauryl (C12), myristyl (C14), palmityl (C16), stearyl (C18), or icosyl (C20).

20. The compound of claim 9 , wherein each R 1 and R 2 are the same.

Assignees

• Arbutus Biopharma Corp

Inventors

• Heyes James
• Lam Kieu Mong
• Wood Mark

Classifications

• A61K31/7105

  Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links · CPC title

• A61K9/1617

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

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/543

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

• A61K48/0041

  the non-active part being polymeric · CPC title