Cationic lipid

Patent metadata

Field	Value
Publication number	US-9920028-B2
Application number	US-201615200356-A
Country	US
Kind code	B2
Filing date	Jul 1, 2016
Priority date	Apr 28, 2010
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

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 hydrogen atoms,
X 3 and Y are absent,
a and b are 0, 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, and L 1 and L 2 are —O—, or
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— or

a and b are, the same or different, 0 to 3, L 3 is —CO— or

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— or

2. The cationic lipid according to claim 1 , wherein L 1 and L 2 are —O—, 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

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 a hydrogen atom, 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

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

7. The cationic lipid according to any one of claims 1 to 3 , wherein 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 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. A composition comprising the cationic lipid according to any one of claims 1 to 8 , and a nucleic acid.

10. A composition comprising a complex particle of the cationic lipid according to any one of claims 1 to 8 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.

11. A composition comprising a lipid particle constituted of a complex particle of the cationic lipid according to any one of claims 1 to 8 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.

12. The composition according to claim 10 , wherein the nucleic acid is a nucleic acid having an activity of suppressing the expression of a target gene by utilizing RNA interference (RNAi).

13. The composition according to claim 12 , wherein the target gene is a gene associated with tumor or inflammation.

Assignees

• Kyowa Hakko Kirin Co Ltd

Inventors

• Kuboyama Takeshi
• Era Tomohiro
• Naoi Tomoyuki

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D211/58

  attached in position 4 · CPC title

• C07D207/08

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