Low molecular weight cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-10576155-B2
Application number	US-201715591818-A
Country	US
Kind code	B2
Filing date	May 10, 2017
Priority date	Sep 20, 2010
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

Abstract

The instant invention provides for novel catiome lipids 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 to enhance the efficiency and tolerability of in vivo delivery of siRNA.

First claim

What is claimed is:

1. A cationic lipid of Formula A:

wherein:
R 1 and R 2 are independently selected from (C 1 -C 6 )alkyl, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to form a pyrrolidine ring;
R 3 is H;
n is 0, 1, 2, 3, 4 or 5;
L 1 is selected from straight chain C 12 -C 24 alkenyl;
or alkyl selected from the following structure;

and
L 2 is selected from C 3 -C 9 alkyl and C 3 -C 9 alkenyl;
or any pharmaceutically acceptable salt or stereoisomer thereof.

2. A cationic lipid which is selected from:
(12Z, 15Z)-N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine (Compound 31);
N,N-dimethyl-3-{7-[(1S,2R)-2-octylcyclopropyl]heptyl}dodecan-1-amine (Compound 40)
or any pharmaceutically acceptable salt or stereoisomer thereof.

3. A lipid nanoparticle comprising a cationic lipid of claim 1 .

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

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

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

7. A cationic lipid which is:
N,N-dimethyl-3-{7-[(1S,2R)-2-octylcyclopropyl]heptyl}dodecan-1-amine (Compound 40); or any pharmaceutically acceptable salt or stereoisomer thereof.

8. A lipid nanoparticle comprising cationic lipid N,N-dimethyl-3-{7-[(1S,2R)-2-octylcyclopropyl]heptyl}dodecan-1-amine (Compound 40), cholesterol, DSPC and PEG-DMG.

Assignees

• Sirna Therapeutics Inc
• Sirna Thereapeutics Inc

Inventors

• Stanton Matthew G
• Budzik Brian W
• Beutner Gregory L
• Liao Hongbiao

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D207/06

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title

• C07C211/21

  Monoamines · CPC title

• C07C211/04

  Mono-, di- or tri-methylamine · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title