Low molecular weight cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-9643916-B2
Application number	US-201615077447-A
Country	US
Kind code	B2
Filing date	Mar 22, 2016
Priority date	Jun 4, 2010
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

The instant invention provides for novel cationic 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 H, (C 1 -C 6 )alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three substituents selected from R′, or R 1 and R 2 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 substituents selected from R′;
R′ is independently selected from halogen, R″, OR″, SR″, CN, CO 2 R″ or CON(R″) 2 ;
R″ is independently selected from H and (C 1 -C 6 )alkyl, wherein said alkyl is optionally substituted with halogen and OH;
L 1 is selected from

 and
L 2 is selected from C 3 -C 13 alkyl and C 3 -C 13 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R′;
or any pharmaceutically acceptable salt or stereoisomer thereof.

2. A cationic lipid according to claim 1 ,
wherein:
R 1 and R 2 are each methyl;
L 1 is selected from

 and
L 2 is selected from C 3 -C 13 alkyl and C 3 -C 13 alkenyl;
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 comprises oligonucleotides.

5. The lipid nanoparticle of claim 4 , wherein the oligonucleotide are siRNA or miRNA.

6. The lipid nanoparticle of claim 4 wherein the oligonucleotide are siRNA.

Assignees

• Sirna Therapeutics Inc

Inventors

• Budzik Brian W
• Colletti Steven L
• Davis Jennifer R
• Hills Ivory D
• Seifried Darla Danile
• Stanton Matthew G

Classifications

• C07C217/44

  the carbon skeleton being saturated and containing rings · CPC title

• C07D317/28

  Radicals substituted by nitrogen atoms (nitro radicals C07D317/16) · CPC title

• C07D205/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D207/08

  with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms · CPC title

• C07D295/084

  with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings · CPC title