# US 2019/0314524 A1 · Novel lipids and lipid nanoparticle formulations for delivery of nucleic acids

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- Number: US 2019/0314524 A1
- Document ID: US20190314524A1
- Status: Published application
- Kind: A1
- Application number: 16/184,782
- Filed: 2018-11-08
- Published: 2019-10-17
- Earliest claimed: 2015-10-28
- Assignees: Acuitas Therapeutics, Inc.
- Applicants: Acuitas Therapeutics, Inc.
- Inventors: Steven M. Ansell; Xinyao Du
- Web page: https://patentgrep.com/patent/US20190314524A1

## CPC

- A61K 48/0033: {the non-active part being non-polymeric}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- C07C 219/06: 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
- C07C 229/12: to carbon atoms of acyclic carbon skeletons
- C07C 229/16: to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
- C07C 233/18: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
- C07C 255/24: containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
- C12N 9/0069: {acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)}
- C12Y 113/12007: Photinus-luciferin 4-monooxygenase (ATP-hydrolysing) (1.13.12.7), i.e. firefly-luciferase
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, 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.

## Claims

### Claim 1

A compound having the following structure (IF):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
G1 and G2 are each independently unsubstituted C1-C12 alkylene or C1-C12 alkenylene;
G3 is C1-C24 alkylene, C1-C24 alkenylene, C3-C8 cycloalkylene; or C3-C8 cycloalkenylene;
R1 and R2 are each independently branched C6-C24 alkyl;
R3 is H, OR5, CN, —C(═O)OR4, —OC(═O)R4 or —NR5C(═O)R4;
R4 is C1-C12 alkyl; and
R5 is H or C1-C6 alkyl.

### Claim at position 2

2-5. (canceled)

### Claim 6 (depends on 1)

The compound of claim 1, having one of the following structures (IH) or (IJ):
wherein:
A is a 3 to 8-membered cycloalkyl or cycloalkylene ring;
R6 is H, OH or C1-C24 alkyl;
y and z are each independently integers ranging from 1 to 12;
and n is an integer ranging from 1 to 15.

### Claim 7 (depends on 6)

The compound of claim 6, wherein n is an integer ranging from 2 to 12.

### Claim 8 (depends on 7)

The compound of claim 7, wherein n is 3, 4, 5 or 6.

### Claim 9 (depends on 6)

The compound of claim 6, wherein y and z are each independently an integer ranging from 2 to 10.

### Claim 10 (depends on 6)

The compound of claim 6, wherein y and z are each independently an integer ranging from 4 to 9.

### Claim at position 8

11-12. (canceled)

### Claim 13 (depends on 1)

The compound of claim 1, wherein R1 and R2 each, independently have the following structure:
wherein:
R7a and R7b are, at each occurrence, independently H or C1-C12 alkyl; and
a is an integer from 2 to 12,
wherein R7a, R7b and a are each selected such that R1 and R2 are each independently a branched alkyl comprising from 6 to 20 carbon atoms.

### Claim 14 (depends on 13)

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

### Claim 15 (depends on 13)

The compound of claim 13, wherein at least one occurrence of R7a is H.

### Claim 16 (depends on 13)

The compound of claim 13, wherein R7a is H at each occurrence.

### Claim 17 (depends on 13)

The compound of claim 13, wherein at least one occurrence of R7b is C1-C8 alkyl.

### Claim 18 (depends on 17)

The compound of claim 17, wherein C1-C8 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-hexyl or n-octyl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R1 or R2, or both, has one of the following structures:

### Claim 20 (depends on 1)

The compound of claim 1, wherein R3 is OH.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R3 is CN.

### Claim 22 (depends on 1)

The compound of claim 1, wherein R3 is —C(═O)OR4, —OC(═O)R4 or —NHC(═O)R4.

### Claim 23 (depends on 22)

The compound of claim 22, wherein R4 is methyl or ethyl.

### Claim 24 (depends on 1)

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

### Claim 25 (depends on 1)

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

### Claim 26 (depends on 25)

The composition of claim 25, further comprising one or more excipient selected from neutral lipids, steroids and polymer conjugated lipids.

### Claim 27 (depends on 26)

The composition of claim 26, wherein the composition comprises one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

### Claim 28 (depends on 27)

The composition of claim 27, wherein the neutral lipid is DSPC.

### Claim 29 (depends on 25)

The composition of claim 25, wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:1.

### Claim 30 (depends on 26)

The composition of claim 26, wherein the steroid is cholesterol.

### Claim 31 (depends on 30)

The composition of claim 30, wherein the molar ratio of the compound to cholesterol ranges from 5:1 to 1:1.

### Claim 32 (depends on 26)

The composition of claim 26, wherein the polymer conjugated lipid is pegylated lipid.

### Claim 33 (depends on 32)

The composition of claim 32, wherein the molar ratio of the compound to pegylated lipid ranges from about 100:1 to about 20:1.

### Claim 34 (depends on 32)

The composition of claim 32, wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.

### Claim 35 (depends on 32)

The composition of claim 32, wherein the pegylated lipid has the following structure (II):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R8 and R9 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.

### Claim 36 (depends on 35)

The composition of claim 35, wherein R8 and R9 are each independently straight, saturated alkyl chains containing from 12 to 16 carbon atoms.

### Claim 37 (depends on 35)

The composition of claim 35, wherein the average w is about 49.

### Claim 38 (depends on 25)

The composition of claim 25, wherein the therapeutic agent comprises a nucleic acid.

### Claim 39 (depends on 38)

The composition of claim 38, wherein the nucleic acid is selected from antisense and messenger RNA.

### Claim 40 (depends on 25)

A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the composition of claim 25, and administering the composition to the patient.