Granted Patent B2

US 12,667,627 · App. 18/493,428 · Granted Jun 30, 2026

Inventors: Steven M. Ansell (Vancouver, CA); Xinyao Du (Richmond, CA)

Assignee: Acuitas Therapeutics, Inc.

A61K48/0033A61K9/127A61K47/18C07C219/06C07C229/12C07C229/16C07C233/18C07C255/24C12N9/0069C12Y113/12007

Abstract

Claims (52)

1 . A compound having one of the following structures (IC) or (ID):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

one of L 1 and L 2 is —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—, and the other of L 1 and L 2 is —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— or a direct bond;

R a is H or C 1 -C 12 alkyl;

R 1 and R 2 are each independently branched C 6 -C 24 alkyl or branched C 6 -C 24 alkenyl;

R 3 is H, OR 5 , CN, —C(═O)OR 4 , —OC(═O)R 4 or —NR 5 C(═O)R 4 ;

R 4 is C 1 -C 12 alkyl;

R 5 is H or C 1 -C 6 alkyl;

A is a 3 to 8-membered cycloalkyl or cycloalkylene ring;

R 6 is, at each occurrence, independently H, OH or C 1 -C 24 alkyl;

n is 3, 4, 5 or 6;

y and z are each independently an integer ranging from 4 to 9; 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—.

3 . The compound of claim 1 , having one of the following structures (IG), (IH), (II) or (IJ):

4 . The compound of claim 1 , wherein R 1 or R 2 , or both, is branched C 6 -C 24 alkenyl.

5 . The compound of claim 1 , wherein R 1 or R 2 , or both, is branched C 6 -C 24 alkyl.

6 . The compound of claim 5 , 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 each independently comprise from 6 to 20 carbon atoms, and R 1 and R 2 are branched.

7 . The compound of claim 6 , wherein a is an integer from 8 to 12.

8 . The compound of claim 6 , wherein at least one occurrence of R 7a is H.

9 . The compound of claim 6 , wherein R 7a is H at each occurrence.

10 . The compound of claim 6 , wherein at least one occurrence of R 7b is C 1 -C 8 alkyl.

11 . The compound of claim 10 , wherein C 1 -C 8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

12 . The compound of claim 5 , wherein R 1 or R 2 , or both, has one of the following structures:

13 . The compound of claim 1 , wherein R 3 is OH.

14 . The compound of claim 1 , wherein R 3 is CN.

15 . The compound of claim 1 , wherein R 3 is —C(═O)OR 4 , —OC(═O)R 4 or —NHC(═O)R 4 .

16 . The compound of claim 15 , wherein R 4 is methyl or ethyl.

17 . A compound having one of the following structures:

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

19 . The composition of claim 18 , further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.

20 . The composition of claim 19 , wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

21 . The composition of claim 20 , wherein the neutral lipid is DSPC.

22 . The composition of claim 18 , wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:1.

23 . The composition of claim 19 , wherein the steroid is cholesterol.

24 . The composition of claim 23 , wherein the molar ratio of the compound to cholesterol ranges from 5:1 to 1:1.

25 . The composition of claim 19 , wherein the polymer conjugated lipid is pegylated lipid.

26 . The composition of claim 25 , wherein the molar ratio of the compound to pegylated lipid ranges from about 100:1 to about 20:1.

27 . The composition of claim 25 , wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.

28 . The composition of claim 25 , 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, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and

w has a mean value ranging from 30 to 60.

29 . The composition of claim 28 , wherein R 8 and R 9 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.

30 . The composition of claim 28 , wherein the average w is about 49.

31 . The composition of claim 18 , wherein the therapeutic agent comprises a nucleic acid.

32 . The composition of claim 31 , wherein the nucleic acid is selected from antisense and messenger RNA.

33 . A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 18 , and administering the composition to the patient.

Continuity (7)

References Cited (400)