Diester and triester based low molecular weight, biodegradeable cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-10307378-B2
Application number	US-201715827162-A
Country	US
Kind code	B2
Filing date	Nov 30, 2017
Priority date	Apr 19, 2012
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

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.

First claim

What is claimed is:

1. A cationic lipid of Formula A:

wherein:
R 1 and R 2 are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three 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 R′;
R 3 is selected from the group consisting of (C 4 -C 20 )alkyl and (C 4 -C 20 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 4 is selected from the group consisting of (C 1 -C 16 )alkyl and (C 2 -C 16 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 5 is selected from the group consisting of (C 4 -C 8 )alkyl and (C 4 -C 8 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 6 is (C 1 -C 2 )alkyl optionally substituted with one to three R′;
Q 1 and Q 2 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″) 2 O—, —C(O)(CR″ 2 )C(O)O— and —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;
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″) 2 O—, —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, CO 2 R″ or CON(R″) 2 ;
each occurrence of R″ is independently selected from the group consisting of H and (C 1 -C 6 )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 R 3 -Q 1 -R 4 or R 5 -Q 2 -R 6 is

2. A cationic lipid of Formula A according to claim 1 ,
wherein:
R 1 and R 2 are each methyl;
n is 3;
R 3 is selected from the group consisting of (C 4 -C 20 )alkyl and (C 4 -C 20 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 4 is selected from the group consisting of (C 1 -C 16 )alkyl and (C 2 -C 16 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 5 is selected from the group consisting of (C 4 -C 8 )alkyl and (C 4 -C 8 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 6 is (C 1 -C 2 )alkyl optionally substituted with one to three R′;
Q 1 and Q 2 are each, independently, a bond or —C(O)O—, with the proviso that when either Q 1 or Q 2 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 R 3 -Q 1 -R 4 or R 5 -Q 2 -R 6 is

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

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

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

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

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

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

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

Assignees

• Sirna Therapeutics Inc

Inventors

• Colletti Steven L
• Stanton Matthew G

Classifications

• C12N2320/32

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

• C07C229/12 Primary

  to carbon atoms of acyclic carbon skeletons · CPC title

• A61K9/51

  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)} · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N15/111

  General methods applicable to biologically active non-coding nucleic acids · CPC title