Cationic lipid

Patent metadata

Field	Value
Publication number	US-9408914-B2
Application number	US-201113643342-A
Country	US
Kind code	B2
Filing date	Apr 28, 2011
Priority date	Apr 28, 2010
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

The present invention provides a cationic lipid, which allow nucleic acids to be easily introduced into cells, represented by formula (I)
(wherein: R 1 and R 2 are, the same or different, alkenyl, etc, and
X 1 and X 2 are hydrogen atoms, or are combined together to form a single bond or alkylene, and
X 3 is absent or is alkyl, etc,
Y is absent or anion,
a and b are, the same or different, 0 to 3, and
L 3 is a single bond, etc,
R 3 is alkyl, etc,
L 1 and L 2 are —O—, —CO—O— or —O—CO—),
a composition comprising the cationic lipid and a nucleic acid, and
a method for introducing a nucleic acid into a cell by using the composition comprising the cationic lipid and the nucleic acid, and the like.

First claim

The invention claimed is:

1. A cationic lipid represented by formula (I):

wherein:
R 1 and R 2 are, the same or different, each linear or branched alkyl, alkenyl or alkynyl having 12 to 24 carbon atoms, or R 1 and R 2 are combined together to form dialkylmethylene, dialkenylmethylene, dialkynylmethylene or alkylalkenylmethylene,
X 1 and X 2 are combined together to form a single bond or alkylene,
X 3 is absent or is alkyl having 1 to 6 carbon atoms, or alkenyl having 3 to 6 carbon atoms,
when X 3 is absent,
Y is absent, a and b are, the same or different, 0 to 3, and are not 0 at the same time, L 3 is a single bond, R 3 is alkyl having 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, L 1 and L 2 are, the same or different, —O—, —CO—O— or —O—CO—, or
Y is absent, a and b are, the same or different, 0 to 3, L 3 is —CO— or —CO—O—, R 3 is pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl or morpholinyl, and L 1 and L 2 are, the same or different, —O—, —CO—O— or —O—CO—; and

when X 3 is alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms,
Y is a pharmaceutically acceptable anion, a and b are, the same or different, 0 to 3, L 3 is a single bond, R 3 is alkyl having 1 to 6 carbon atoms, alkenyl having 3 to 6 carbon atoms, pyrrolidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, L 1 and L 2 are, the same or different, —O—, —CO—O— or —O—CO—.

2. The cationic lipid according to claim 1 , wherein L 1 and L 2 are —O— or —O—CO—, and R 1 and R 2 are dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadec-9,12-dienyl, (9Z,12Z,15Z)-octadec-9,12,15-trienyl, (Z)-icos-11-enyl, (11Z,14Z)-icos-11,14-dienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl or 3,7,11,15-tetramethylhexadec-2-enyl.

3. The cationic lipid according to claim 1 , wherein L 1 and L 2 are —CO—O—, and R 1 and R 2 are tridecyl, pentadecyl, heptadecyl, nonadecyl, heneicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadec-5-enyl, (Z)-heptadec-8-enyl, (E)-heptadec-8-enyl, (Z)-heptadec-10-enyl, (8Z,11Z)-heptadec-8,11-dienyl, (8Z,11Z,14Z)-octadec-8,11,14-trienyl, (Z)-nonadec-10-enyl, (10Z,13Z)-nonadec-10,13-dienyl, (11Z,14Z)-icos-11,14-dienyl, 2,6,10-trimethylundec-1,5,9-trienyl or 2,6,10,14-tetramethylpentadec-1-enyl.

4. The cationic lipid according to any one of claims 1 to 3 , wherein a and b are both 0 or 1.

5. The cationic lipid according to any one of claim 1 or 2 , wherein L 3 is a single bond, R 3 is methyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, and L 1 and L 2 are —O—.

6. The cationic lipid according to any one of claims 1 to 3 , wherein L 3 is —CO— or —CO—O—, R 3 is pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl or morpholinyl, and L 1 and L 2 are identically —CO—O— or —O—CO—.

7. The cationic lipid as set forth above in any one of claims 1 to 3 , wherein X 1 and X 2 are combined together to form a single bond or alkylene, and R 3 is a hydrogen atom, methyl, or alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, hydroxy or carbamoyl.

8. The cationic lipid according to claim 6 , wherein X 1 and X 2 are combined together to form a single bond or alkylene, and R 3 is alkyl having 1 to 6 carbon atoms or alkenyl having 3 to 6 carbon atoms substituted with 1 to 3 substituent(s), which is(are), the same or different, amino, hydroxy or carbamoyl.

9. The cationic lipid according to any one of claims 1 to 3 , wherein X 3 is absent or is methyl.

10. A composition that comprises the cationic lipid according to any one of claims 1 to 3 , and a nucleic acid.

11. A composition comprising a complex particle of the cationic lipid according to any one of claims 1 to 3 and a nucleic acid, or a complex particle of a nucleic acid and a combination of the cationic lipid and a neutral lipid and/or a polymer.

12. A composition comprising a lipid particle constituted of a complex particle of the cationic lipid according to any one of claims 1 to 3 and a nucleic acid, or a complex particle of a nucleic acid and a combination of the cationic lipid and a neutral lipid and/or a polymer, and a lipid membrane that encapsulates the complex particle.

13. The composition according to claim 11 , wherein the nucleic acid is a nucleic acid having an activity of suppressing the expression of the target gene by utilizing RNA interference (RNAi).

14. The composition according to claim 13 , wherein the target gene is a gene associated with tumor or inflammation.

15. A method for introducing a nucleic acid into a cell with the composition according to claim 11 .

16. The method according to claim 15 , wherein the cell is a cell at a tumor or inflammation site of a mammal.

17. The method according to claim 15 , wherein the cell is a cell in the liver, lungs, kidneys or spleen of a mammal.

18. The method according to claim 16 , wherein the method of the introduction into a cell is a method of introduction into a cell by intravenous administration.

19. A method for treating cancer or inflammatory disease, the method including administering the composition according to claim 14 to a mammal.

20. The method according to claim 19 , wherein the method of administration is int

Assignees

• Kuboyama Takeshi
• Era Tomohiro
• Naoi Tomoyuki
• Kyowa Hakko Kirin Co Ltd

Inventors

• Kuboyama Takeshi
• Era Tomohiro
• Naoi Tomoyuki

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D207/08

  with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C07C217/28 Primary

  having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines · CPC title