Diether based biodegradable cationic lipids for siRNA delivery

Patent metadata

Field	Value
Publication number	US-9604908-B2
Application number	US-201615269197-A
Country	US
Kind code	B2
Filing date	Sep 19, 2016
Priority date	Mar 27, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

Disclosed herein are 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. The cationic lipids can demonstrate 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.

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 1 ; 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 5 is independently selected from (C 4 -C 8 )alkylene or (C 4 -C 8 )alkenylene, said alkylene or alkenylene optionally substituted with one to three substituents selected from R′;
R 6 is (C 1 -C 2 )alkyl, said alkyl optionally substituted with one to three substituents selected from R′;
Q 2 is 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)(R″)—, —(R″)C(O)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″) 2 O—, —C(O)(CR″ 2 )C(O)O—, or —OC(O)(CR″ 2 )C(O)—, with the proviso that when either Q 1 or Q 2 is a bond then the other is not a bond;
each occurrence of 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;
n is 0, 1, 2, 3, 4 or 5; and
-R 3 -Q 1 -R 4 is selected from the group consisting of

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A cationic lipid of claim 1 , wherein:
R 1 and R 2 are each methyl;
n is 0;
R 5 is independently selected from (C 4 -C 8 )alkylene and (C 4 -C 8 )alkenylene, said alkylene or alkenylene optionally substituted with one to three substituents selected from R′;
R 6 is (C 1 -C 2 )alkyl, said alkyl optionally substituted with one to three substituents selected from R′;
Q 2 is a bond or —C(O)O—;
or a 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 particle comprises oligonucleotides.

5. The lipid nanoparticle of claim 4 , wherein the oligonucleotides are siRNA.

6. A lipid nanoparticle comprising a cationic lipid of claim 1 cholesterol, DSPC and PEG-DMG.

Assignees

• Sirna Therapeutics Inc
• Sima Therapeutics Inc

Inventors

• Stanton Matthew G
• Budzik Brian W
• Colletti Steven L

Classifications

• A61K47/183 Primary

  Amino acids, e.g. glycine, EDTA or aspartame · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/146

  with organic macromolecular compounds · CPC title

• C07C2101/02

  Chemistry & Metallurgy · mapped topic

• C07C217/40 Primary

  having at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the same carbon atom of the carbon skeleton, e.g. amino-ketals, ortho esters · CPC title