Cationic lipids for oligonucleotide delivery
View Patent ↗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.
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.