Cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-9670487-B2
Application number	US-201113574315-A
Country	US
Kind code	B2
Filing date	Jan 19, 2011
Priority date	Jan 22, 2010
Publication date	Jun 6, 2017
Grant date	Jun 6, 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 is susceptible to hydrolytic instability that may translate into reduced liver residence times and reduced hepatocellular toxicity. The present invention employs acetals and ketals to provide a low pH sensitive chemical handle for degradation.

First claim

What is claimed is:

1. A cationic lipid of Formula A:

wherein:
n is 0, 1 or 2;
R 1 and R 2 are independently selected from H and (C 1 -C 4 )alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from R′, or R 1 and R 2 can be taken together with the nitrogen to which they are attached to faun a monocyclic heterocycle which is optionally substituted with one or more substituents selected from R′;
R 3 is selected from H and (C 1 -C 4 )alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from R′, or R 3 can be taken together with R 1 to form a monocyclic heterocycle which is optionally substituted with one or more substituents selected from R′, or R 3 can be taken together with R 4 to form cyclopropyl or cyclobutyl;
R 4 is selected from H and (C 1 -C 4 )alkyl, said alkyl is optionally substituted with one or more substituents selected from R′;
R 5 is selected from H and (C 1 -C 4 )alkyl, or R 5 can be taken together with R 1 to form a monocyclic heterocycle which is optionally substituted with one or more substituents selected from R′;
R′ is independently selected from halogen, R″ and OR″;
R″ is selected from H and (C 1 -C 4 )alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;
L 1 is a C 6 -C 18 alkyl or a C 6 -C 18 alkenyl; and
L 2 is a C 4 -C 22 alkenyl;
or any pharmaceutically acceptable salt or stereoisomer thereof.

2. The cationic lipid of claim 1 , wherein L 2 is C 18 alkenyl.

3. The cationic lipid of claim 2 , wherein L 2 is

4. A cationic lipid of Formula A according to claim 1 , wherein:
L 1 and L 2 are

and
all other variables are as defined in claim 1 ;
or any pharmaceutically acceptable salt or stereoisomer thereof.

5. A cationic lipid according to claim 1 which is selected from:
N,N-dimethyl-2,2-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
N,N-dimethyl-2,2-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine;
2,2-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
(2R)-2-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}pyrrolidine;
(2R)-2-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}-1-methylpyrrolidine;
2-[(2R)-2-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}pyrrolidin-1-yl]ethanol;
(2S)-1,1-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine;
2-methyl-1,1-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine;
4,4-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]piperidine; and
3,3-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]pyrrolidine;
N,N-dimethyl-3,3-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine;
1-{3,3-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propyl}pyrrolidine;
3,3-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine;
N,N-dimethyl-2,2-bis[(9Z)-octadec-9-en-1-yloxy]ethanamine;
1-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}cyclopropanamine;
N,N-dimethyl-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-(octyloxy)ethanamine;
2-(decyloxy)-N,N-dimethyl-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
2-[(8Z)-dodec-8-en-1-yloxy]-N,N-dimethyl-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
1-{2-[(8Z)-dodec-8-en-1-yloxy]-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethyl}pyrrolidine;
1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-(octyloxy)ethyl}pyrrolidine;
[(2S)-1-{2-(decyloxy)-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethyl}pyrrolidin-2-yl]methanol;
1-{2-(decyloxy)-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethyl}piperidin-4-ol;
N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-1-amine;
2-(heptyloxy)-N,N-dimethyl-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
N,N-dimethyl-2-(nonyloxy)-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
1-{3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propyl}pyrrolidine;
2-(hexyloxy)-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-(octyloxy)ethanamine;
2-(decyloxy)-2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethanamine;
2-(decyloxy)-2-[(9Z)-octadec-9-en-1-yloxy]ethanamine;
2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-(tetradecyloxy)ethanamine;
[(2R)-1-{2,2-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethyl}pyrrolidin-2-yl]methanol;
[(2S)-1-{2,2-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]ethyl}pyrrolidin-2-yl]methanol;
(3R,5S)-5-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}pyrrolidin-3-ol;
(2S)-2-amino-3,3-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-ol;
4-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}piperidine;
3-{bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}piperidine;
3-amino-1,1-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-ol; and
1-methyl-4,4-bis[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]piperidine
or any pharmaceutically acceptable salt or stereoisomer thereof.

6. A lipid nanoparticle comprising a cationic lipid according to claim 1 .

7. The lipid nanoparticle according to claim 6 further comprises an siRNA or miRNA.

Assignees

• Colletti Steven L
• Deng Zhengwu James
• Stanton Matthew G
• Wang Weimin
• Hills Ivory
• Sirna Therapeutics Inc

Inventors

• Colletti Steven L
• Deng Zhengwu James
• Stanton Matthew G
• Wang Weimin
• Hills Ivory

Classifications

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title

• C12N2330/30

  chemically synthesised · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• C07D211/22

  by oxygen atoms · CPC title