Low molecular weight cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-2017015998-A1
Application number	US-201615281823-A
Country	US
Kind code	A1
Filing date	Sep 30, 2016
Priority date	Sep 30, 2010
Publication date	Jan 19, 2017
Grant date	—

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 3 is selected from H and (C 1 -C 6 )alkyl, said alkyl optionally substituted with one to three substituents selected from R′;
R′ is independently selected from halogen, R″, OR″, SR″, CN, CO 2 R″ and 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;
n is 0, 1, 2, 3, 4 or 5; and
one of L 1 and L 2 is

one of L 1 and L 2 is C 24 alkyl and C 3 -C 24 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 . The cationic lipid of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of H, methyl, ethyl and propyl.

3 . The cationic lipid of claim 2 , wherein R 1 and R 2 each are methyl.

4 . The cationic lipid of claim 3 , wherein R 3 is H or methyl.

5 . The cationic lipid of claim 4 , wherein R 3 is H.

6 . The cationic lipid of claim 1 , wherein 11 is 0, 1 or 2.

7 . The cationic lipid of claim 6 , wherein n is 0 or 1.

8 . The cationic lipid of claim 7 , wherein n is 0.

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

10 . The lipid nanoparticle of claim 9 , wherein the lipid nanoparticle further comprises an oligonucleotide.

11 . The lipid nanoparticle of claim 10 , wherein the oligonucleotide is an siRNA or miRNA.

12 . The lipid nanoparticle of claim 11 , wherein the oligonucleotide is an siRNA.

13 . The lipid nanoparticle of claim 9 , wherein the lipid nanoparticle further comprises cholesterol and PEG-DMG.

14 . The lipid nanoparticle of claim 9 , wherein the lipid nanoparticle further comprises cholesterol, PEG-DMG and DSPC.

15 . The lipid nanoparticle of claim 9 , wherein the lipid nanoparticle further comprises cholesterol, PEG-C-DMA and DSPC.

Assignees

• Sirna Therapeutics Inc

Inventors

• Bawiec Iii John A
• Deng Zhengwu J

Classifications

• A61K9/5123 Primary

  Organic compounds, e.g. fats, sugars · CPC title

• C12N15/113 Primary

  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)} · CPC title

• C07C217/08 Primary

  the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title