# US 10,307,378 B2 · Diester and triester based low molecular weight, biodegradeable cationic lipids for oligonucleotide delivery

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- Number: US 10,307,378 B2
- Document ID: US10307378B2
- Status: Granted
- Kind: B2
- Application number: 15/827,162
- Filed: 2017-11-30
- Published: 2018-07-12
- Granted: 2019-06-04
- Earliest claimed: 2012-04-19
- Assignees: Sirna Therapeutics, Inc.
- Applicants: Sirna Therapeutics, Inc.
- Inventors: Steven L. Colletti; Matthew G. Stanton
- Web page: https://patentgrep.com/patent/US10307378B2

## CPC

- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- C07C 229/12: to carbon atoms of acyclic carbon skeletons
- C07C 229/28: the carbon skeleton being saturated and containing rings
- C07C 229/30: the carbon skeleton being acyclic and unsaturated
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C07C 2601/02: with a three-membered ring
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N 2320/51: modulating the chemical stability, e.g. nuclease-resistance
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The instant invention provides for novel cationic lipids of Formula A that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver. The present invention employs low molecular weight cationic lipids with one short lipid chain coupled with inclusion of hydrolysable functionality in the lipid chains to enhance the efficiency and tolerability of in vivo delivery of siRNA.

## Claims

### Claim 1

A cationic lipid of Formula A:
wherein:
R1 and R2 are each independently selected from the group consisting of H, (C1-C6)alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three R′;
or R1 and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three R′;
R3 is selected from the group consisting of (C4-C20)alkyl and (C4-C20)alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R4 is selected from the group consisting of (C1-C16)alkyl and (C2-C16)alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R5 is selected from the group consisting of (C4-C8)alkyl and (C4-C8)alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R6 is (C1-C2)alkyl optionally substituted with one to three R′;
Q1 and Q2 are each, independently, selected from the group consisting of a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S—, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, C(S)(NR″)—, —N(R″)C(O)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″)2O—, —C(O)(CR″2)C(O)O— and —OC(O)(CR″2)C(O)—), with the proviso that when either Q1 or Q2 is a bond then the other is not a bond;
X is selected from the group consisting of —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S—, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, C(S)(NR″)—, —N(R″)C(O)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″)2O—, —C(O)(CR″2)C(O)O— and —OC(O)(CR″2)C(O)—),
each occurrence of R′ is independently selected from the group consisting of halogen, R″, OR″, SR″, CN, CO2R″ or CON(R″)2;
each occurrence of R″ is independently selected from the group consisting of H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with halogen and OH; and
n is 1, 2, 3, 4 or 5;
or a pharmaceutically acceptable salt or stereoisomer thereof;
with the proviso that at least one of R3-Q1-R4 or R5-Q2-R6 is

### Claim 2 (depends on 1)

A cationic lipid of Formula A according to claim 1,
wherein:
R1 and R2 are each methyl;
n is 3;
R3 is selected from the group consisting of (C4-C20)alkyl and (C4-C20)alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R4 is selected from the group consisting of (C1-C16)alkyl and (C2-C16)alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R5 is selected from the group consisting of (C4-C8)alkyl and (C4-C8)alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R6 is (C1-C2)alkyl optionally substituted with one to three R′;
Q1 and Q2 are each, independently, a bond or —C(O)O—, with the proviso that when either Q1 or Q2 is a bond then the other is not a bond; and
X is —C(O)O—;
or a pharmaceutically acceptable salt or stereoisomer thereof;
with the proviso that at least one of R3-Q1-R4 or R5-Q2-R6 is

### Claim 3 (depends on 1)

A lipid nanoparticle comprising a cationic lipid of claim 1.

### Claim 4 (depends on 3)

The lipid nanoparticle of claim 3, wherein the lipid nanoparticle further comprises an oligonucleotide.

### Claim 5 (depends on 4)

The lipid nanoparticle of claim 4, wherein the oligonucleotide is an siRNA or miRNA.

### Claim 6 (depends on 5)

The lipid nanoparticle of claim 5, wherein the oligonucleotide is an siRNA.

### Claim 7 (depends on 3)

The lipid nanoparticle of claim 3, wherein the lipid nanoparticle further comprises cholesterol and PEG-DMG.

### Claim 8 (depends on 3)

The lipid nanoparticle of claim 3, wherein the lipid nanoparticle further comprises cholesterol, PEG-DMG and DSPC.

### Claim 9 (depends on 3)

The lipid nanoparticle of claim 3, wherein the lipid nanoparticle further comprises cholesterol, PEG-C-DMA and DSPC.