Low molecular weight cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-11413348-B2
Application number	US-202016741100-A
Country	US
Kind code	B2
Filing date	Jan 13, 2020
Priority date	Sep 20, 2010
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

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 each methyl;
R 3 is H;
n is 0;
L 1 is an alkyl selected from the following structures:

and
L 2 is C 3 -C 9 alkyl or C 3 -C 9 alkenyl;
or any pharmaceutically acceptable salt or stereoisomer thereof.

2. The cationic lipid of claim 1 ,
wherein:
R 1 and R 2 are each methyl;
R 3 is H;
n is 0;
and
L 2 is C 3 -C 9 alkyl;

or any pharmaceutically acceptable salt or stereoisomer thereof.

3. The cationic lipid of claim 1 , wherein the cationic lipid is selected from:
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]heptadecan-8-amine (Compound 33);
1-[(1S,2R)-2-hexylcyclopropyl]-N,N-dimethylnonadecan-10-amine (Compound 34);
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]nonadecan-10-amine (Compound 35);
N,N-dimethyl-21-[(1S,2R)-2-octylcyclopropyl]henicosan-10-amine (Compound 36);
N,N-dimethyl-1-[(1 S,2 S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl} cyclopropyl]nonadecan-10-amine (Compound 37);
N,N-dimethyl-1-[(1 S,2R)-2-octylcyclopropyl]hexadecan-8-amine (Compound 38);
N,N-dimethyH-[(1R,2S)-2-undecyl cyclopropyl]tetradecan-5-amine (Compound 39);
1-[(1R,2S)-2-heptylcyclopropyl]-N,N-dimethyloctadecan-9-amine (Compound 41);
1-[(1 S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine (Compound 42);
N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]pentadecan-8-amine (Compound 43);
or any pharmaceutically acceptable salt or stereoisomer thereof.

4. A lipid nanoparticle comprising a cationic lipid of Formula A:

wherein:
R 1 and R 2 are independently methyl;
R 3 is H;
n is 0;
L 1 is C 4 -C 24 alkenyl or an alkyl selected from the following structures:

and
L 2 is C 3 -C 9 alkyl or C 3 -C 9 alkenyl,
or any pharmaceutically acceptable salt or stereoisomer thereof.

5. The lipid nanoparticle of claim 4 , wherein the lipid nanoparticle further comprises cholesterol, DSPC and PEG-DMG.

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

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

8. A cationic lipid selected from the group consisting of:
(20Z,23Z)—N,N-dimethylnonacosa-20,23-dien-10-amine (Compound 1);
(17Z,20Z)—N,N-dimemylhexacosa-17,20-dien-9-amine (Compound 2);
(16Z, 19Z)—N,N˜dimethylpentacosa-16,19-dien-8-amine (Compound 3);
(13Z,16Z)—N,N-dimethyldocosa-13,16-dien-5-amine (Compound 4);
(12Z,15Z)—N,N-dimethylhenicosa-12,15-dien-4-amine (Compound 5);
(14Z,17Z)—N,N-dimethyltricosa-14,17-dien-6-amine (Compound 6);
(15Z,18Z)—N,N-dimethyltetracosa-15,18-dien-7-amine (Compound 7);
(18Z,21Z)—N,N-dimethylheptacosa-18,21-dien-10-amine (Compound 8);
(15Z,18Z)—N,Ndimethylheptacosa-15,18-dien-5-amine (Compound 9);
(14Z,17Z)—N,N-dimethyltricosa-14,17-dien-4-amine (Compound 10);
(19Z,22Z)—N,N-dimethyloctacosa-19,22-dien-9-amine (Compound 11);
(18Z,21 Z)—N,N-dimethylheptacosa-18,21-dien-8-amine (Compound 12);
(17Z,20Z)—N,N-dimethylhexacosa-17,20-dien-7-amine (Compound 13);
(16Z;19Z)—N,N-dimethylpentacosa-16,19-dien-6-amine (Compound 14);
(22Z,25Z)—N,N-dimethylhentriaconta-22,25-dien-10-amine (Compound 15);
(21Z,24Z)—N,N-dimethyltriaconta-21,24-dien-9-amine (Compound 16);
(18Z)—N,N-dimetylheptacos-18-en-10-amine (Compound 17);
(17Z)—N,N-dimethylhexacos-17-en-9-amine (Compound 18);
(19Z,22Z)—N J N-dimethyloctacosa-19,22-dien-7-amine (Compound 19);
N,N-dimethylheptacosan-10-amine (Compound 20);
(20Z,23Z)—N-ethyl-N-methylnonacosa-20,23-dien-10-amine (Compound 21);
1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1-yl] pyrrolidine (Compound 22);
(20Z)—N,N-dimethylheptacos-20-en-10-amine (Compound 23);
(15Z)—N,N-dimethylheptacos-15-en-10-amine (Compound 24);
(14Z)—N,N-dimethylnonacos-14-en-10-amine (Compound 25);
(17Z)—N,N-dimethylnonacos-17-en-10-amine (Compound 26);
(24Z)—N,N-dimethyltritriacont-24-en-10-amine (Compound 27);
(20Z)—N,N-dimethylnonacos-20-en-10-amine (Compound 28);
(22Z)—N,N-dimethylhentriacont-22-en-10-amine (Compound 29);
(16Z)—N,N-dimethylpentacos-16-en-8-amine (Compound 30);
(11E,20Z,23Z)—N,N-dimethylnonacosa-11,20,23-trien-10-amine (Compound 44)
or any pharmaceutically acceptable salt or stereoisomer thereof.

9. The lipid nanoparticle of claim 4 , wherein L 1 is C 4 -C 24 alkenyl.

10. The lipid nanoparticle of claim 4 , wherein L 1 is C 12 -C 24 alkenyl.

11. The lipid nanoparticle of claim 10 , wherein Li a linear C 12 -C 24 alkenyl.

12. The lipid nanoparticle of claim 11 , wherein L 2 is C 3 -C 9 alkyl.

13. The lipid nanoparticle of claim 4 , wherein Li is selected from the group consisting of:

14. The lipid nanoparticle of claim 13 , wherein L 2 is C 3 -C 9 alkyl.

15. The lipid nanoparticle of claim 4 , wherein the lipid nanoparticle further comprises cholesterol, DSPC, and a PEG lipid.

16. The lipid nanoparticle of claim 15 , wherein the PEG lipid is PEG-C-DMA or PEG-DMG.

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

18. The lipid nanoparticle of claim 17 , wherein the lipid nanoparticle further comprises cholesterol, DSPC, and a PEG lipid.

19. The lipid nanoparticle of claim 18 , wherein the PEG lipid is PEG-C-DMA or PEG-DMG.

20. A lipid nanoparticle comprising a cationic lipid of claim 8 .

21. The lipid nanoparticle of claim 20 , wherein the lipid nanoparticle further comprises cholesterol, DSPC, and a PEG lipid.

22. The lipid nanoparticle of claim 21 , wherein the PEG lipid is PEG-C-DMA or PEG-DMG.

23. A lipid nanoparticle comprising N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl] heptadecan-8-amine (Compound 33).

24. The lipid nanoparticle of claim 23 , wherein the lipid nanoparticle further comprises cholesterol, DSPC, and a PEG lipid.

25. The lipid nanoparticle of claim 24 , wherein the PEG lipid is PEG-C-DMA or PEG-DMG.

Assignees

• Sirna Therapeutics Inc
• Sirna Therepeutics Inc

Inventors

• Stanton Matthew G
• Budzik Brian W
• Beutner Gregory L
• Liao Hongbiao

Classifications

• C07C211/21

  Monoamines · CPC title

• C07C211/16

  of a saturated carbon skeleton containing rings other than six-membered aromatic rings · CPC title

• C07C211/17 Primary

  containing only non-condensed rings · CPC title

• C12N15/88

  using microencapsulation, e.g. using {amphiphile} liposome vesicle · CPC title

• C07C211/25

  of an unsaturated carbon skeleton containing rings other than six-membered aromatic rings · CPC title