Cationic lipid having improved intracellular kinetics

Patent metadata

Field	Value
Publication number	US-9708628-B2
Application number	US-201414280016-A
Country	US
Kind code	B2
Filing date	May 16, 2014
Priority date	Nov 18, 2011
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention relates to a compound represented by the formula (1)

wherein X a and X b are each independently X 1 or X 2 ;

s is 1 or 2,

R 4 is an alkyl group having 1-6 carbon atoms,

n a and n b are each independently 0 or 1,

R 1a and R 1b are each independently an alkylene group having 1-6 carbon atoms,

R 2a and R 2b are each independently an alkylene group having 1-6 carbon atoms,

Y a and Y b are each independently an ester bond, an amide bond, a carbamate bond, an ether bond or a urea bond, and

R 3a and R 3b are each independently a sterol residue, a liposoluble vitamin residue or an aliphatic hydrocarbon group having 12-22 carbon atoms,

and use thereof.

First claim

The invention claimed is:

1. A compound represented by the formula (1)

wherein X a and X b are each independently X 1 or X 2 ;

s is 1 or 2,
R 4 is an alkyl group having 1-6 carbon atoms,
n a and n b are each 1,
R 1a and R 1b are each independently an alkylene group having 1-6 carbon atoms,
R 2a and R 2b are each independently an alkylene group having 1-6 carbon atoms,
Y a and Y b are each independently —CO—O— or —CO—NH—, and
R 3a and R 3b are each independently a sterol residue, a liposoluble vitamin residue or an aliphatic hydrocarbon group having 12-22 carbon atoms,
wherein the sterol residue is a cholesteryl group, cholestaryl group, stigmasteryl group, β-sitosteryl group, or a lanosteryl group,
wherein the liposoluble vitamin residue is a group obtained by replacing a hydroxyl group or carboxyl group in the liposoluble vitamin with a bond, —O—CO—CH 2 —CH 2 — or —O—CO—CH 2 —CH 2 —CH 2 —, and
wherein the liposoluble vitamin is retinoic acid, retinol, ergosterol, 7-dehydrocholesterol, calciferol, cholecalciferol, dihydroergocalciferol, dihydrotachysterol, tocopherol, or tocotrienol.

2. The compound of claim 1 , wherein X a and X b are each independently X 1 .

3. The compound of claim 1 , wherein X a and X b are each independently X 2 .

4. The compound of claim 1 , wherein R 3a and R 3b are each independently a liposoluble vitamin residue or an aliphatic hydrocarbon group having 12-22 carbon atoms.

5. The compound of claim 1 , wherein R 3a and R 3b are each independently a liposoluble vitamin residue.

6. The compound of claim 1 , wherein R 3a and R 3b are each independently an aliphatic hydrocarbon group having 12-22 carbon atoms.

7. A lipid membrane structure comprising the compound of claim 1 as a membrane-constituting lipid.

8. An agent for introducing a nucleic acid, comprising the compound of claim 1 or a lipid membrane structure comprising the compound as a membrane-constituting lipid.

9. A method of introducing a nucleic acid into a cell, comprising encapsulating the nucleic acid with the lipid membrane structure of claim 7 and contacting the cell with the encapsulated nucleic acid.

10. A method of introducing a nucleic acid into a cell, comprising encapsulating the nucleic acid with the lipid membrane structure of claim 7 , and administering the encapsulated nucleic acid to a living organism to deliver the nucleic acid to the cell.

11. The compound of claim 2 , wherein R 3a and R 3b are each independently a liposoluble vitamin residue.

12. The compound of claim 2 , wherein R 3a and R 3b are each independently an aliphatic hydrocarbon group having 12-22 carbon atoms.

13. The compound of claim 3 , wherein R 3a and R 3b are each independently a liposoluble vitamin residue.

14. The compound of claim 3 , wherein R 3a and R 3b are each independently an aliphatic hydrocarbon group having 12-22 carbon atoms.

15. A lipid membrane structure comprising the compound of claim 2 as a membrane-constituting lipid.

16. A lipid membrane structure comprising the compound of claim 3 as a membrane-constituting lipid.

17. A method of introducing a nucleic acid into a cell, comprising encapsulating the nucleic acid with the lipid membrane structure of claim 15 and contacting the cell with the encapsulated nucleic acid.

18. A method of introducing a nucleic acid into a cell, comprising encapsulating the nucleic acid with the lipid membrane structure of claim 15 , and administering the encapsulated nucleic acid to a living organism to deliver the nucleic acid to the cell.

19. A method of introducing a nucleic acid into a cell, comprising encapsulating the nucleic acid with the lipid membrane structure of claim 16 and contacting the cell with the encapsulated nucleic acid.

20. A method of introducing a nucleic acid into a cell, comprising encapsulating the nucleic acid with the lipid membrane structure of claim 16 , and administering the encapsulated nucleic acid to a living organism to deliver the nucleic acid to the cell.

Assignees

• Nof Corp
• Nat Univ Corp Hokkaido Univ

Inventors

• Tange Kota
• Arai Masaya
• Kubo Kazuhiro
• Akita Hidetaka
• Harashima Hideyoshi
• Hatakeyama Hiroto
• Ishiba Ryohei
• Ukawa Masami
• Tanaka Hiroki

Classifications

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/1272

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• C07C323/25

  the carbon skeleton being acyclic and saturated · CPC title

• A61K47/20

  containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids · CPC title