Low molecular weight cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-9458087-B2
Application number	US-201514681641-A
Country	US
Kind code	B2
Filing date	Apr 8, 2015
Priority date	Sep 30, 2010
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

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 lipid nanoparticle comprising a cationic lipid according 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′, 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 3 is selected from H and (C 1 -C 6 )alkyl, said alkyl optionally substituted with one to three substituents selected from R′;
R′ is independently selected from halogen, R″, OR″, SR″, CN, CO 2 R″ and 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
L 1 is selected from C 3 -C 24 alkyl and C 3 -C 24 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R;
L 2 is C 12 -C 24 alkenyl, which is optionally substituted;
or any pharmaceutically acceptable salt or stereoisomer thereof.

2. The lipid nanoparticle of claim 1 , wherein:
R 1 and R 2 are each methyl;
R 3 is H;
n is 0;
L 1 is selected from C 3 -C 9 alkyl and C 3 -C 9 alkenyl;
L 2 is C 12 -C 24 alkenyl;
or any pharmaceutically acceptable salt of stereoisomer thereof.

3. The lipid nanoparticle of claim 1 , wherein R 1 and R 2 are independently H, methyl, ethyl or propyl.

4. The lipid nanoparticle of claim 3 , wherein R 1 and R 2 are methyl.

5. The lipid nanoparticle of claim 1 , wherein R 3 is H or methyl.

6. The lipid nanoparticle of claim 5 , wherein R 3 is H.

7. The lipid nanoparticle of claim 1 , wherein n is 0, 1 or 2.

8. The lipid nanoparticle of claim 7 , wherein n is 0 or 1.

9. The lipid nanoparticle of claim 8 , wherein n is 0.

10. The lipid nanoparticle of claim 1 , wherein L 1 is C 3 -C 24 alkyl.

11. The lipid nanoparticle of claim 10 , wherein L 1 is C6, C8, C10, C11 or C16 alkyl.

12. The lipid nanoparticle of claim 11 , wherein L 1 is C8 alkyl.

13. The lipid nanoparticle of claim 1 , wherein L 2 is C 19 alkenyl.

14. The lipid nanoparticle of claim 13 , wherein L 2 is

15. The lipid nanoparticle according to claim 1 , wherein the lipid nanoparticle further comprises an oligonucleotide.

16. The lipid nanoparticle according to claim 15 , wherein the oligonucleotide is siRNA or miRNA.

17. The lipid nanoparticle according to claim 16 , wherein the oligonucleotide is siRNA.

18. The lipid nanoparticle according to claim 1 , wherein the lipid nanoparticle further comprises cholesterol and PEG-DMG.

19. The lipid nanoparticle according to claim 1 , wherein the lipid nanoparticle further comprises cholesterol, PEG-DMG and DSPC.

20. The lipid nanoparticle according to claim 1 , wherein the lipid nanoparticle further comprises cholesterol, PEG-C-DMA and DSPC.

Assignees

• Sirna Therapeutics Inc

Inventors

• Bawiec Iii John A
• Deng Zhengwu J

Classifications

• Y10S977/783

  Organic host/matrix, e.g. lipid · CPC title

• C12N15/88

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

• Y10S977/916

  Gene therapy · CPC title

• C07C217/08 Primary

  the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom · CPC title

• A61K9/5123 Primary

  Organic compounds, e.g. fats, sugars · CPC title