Cationic lipid

Abstract

The present invention provides technology with which an active ingredient such as a nucleic acid can be introduced into various cells with excellent efficiency, specifically a cationic lipid for producing lipid particles containing an active ingredient or a composition containing an active ingredient. One aspect of the present invention provides a compound represented by formula (I) or a salt thereof. In formula (I): W is -NR1R2 or -N+R11R12R13(Z-); R1 and R2 are each independently a hydrogen atom or an optionally substituted C1-5 alkyl group; R11, R12, and R13 are each independently an optionally substituted C1-5 alkyl group; Z- is an anion; X is an optionally substituted C2-6 alkylene group; RA and RB are each independently an optionally substituted C1-17 alkyl group, an optionally substituted C3-17 alkenyl group, an optionally substituted C15-17 alkadienyl group, or a structure represented by -R3-Y1-CH(R4)(Y2-R5); RC is a structure represented by -R3-Y1-CH(R4)(Y2-R5); Y1 and Y2 are each independently -CO-O- or -O-CO-; R3 is an optionally substituted C1-3 alkylene group; R4 is a hydrogen atom, an optionally substituted C1-12 alkyl group, an optionally substituted C3-18 alkenyl group, or an optionally substituted C15-18 alkadienyl group; R5 is an optionally substituted C1-12 alkyl group, an optionally substituted C3-18 alkenyl group, or an optionally substituted C15-18 alkadienyl group; and, if any of RA, RB, and RC is a structure represented by -R3-Y1-CH(R4)(Y2-R5), then each of R3, R4,

Description

Cationic lipid

[0001] The present invention relates to a cationic lipid that enables introduction of nucleic acid as an active ingredient into a variety of cells, tissues or organs. Further, the present invention relates to lipid particles containing the cationic lipid, and a composition containing the lipid particles and nucleic acid.

[0002] [Background of the Invention] In recent years, research and development of nucleic acid pharmaceuticals containing nucleic acid as an active ingredient have been actively carried out. For example, many studies have been conducted on nucleic acid pharmaceuticals having an action of degrading target mRNA or suppressing its function, including nucleic acids such as siRNA, miRNA, miRNA mimic or antisense nucleic acid. Also, research has been conducted on nucleic acid pharmaceuticals for expressing a target protein intracellularly, including mRNA encoding the target protein. In relation to these research and developments, a technique for introducing nucleic acid into cells, tissues or organs with high efficiency has been developed as a drug delivery system (DDS) technique.

[0003] As the above DDS technique, a technique is conventionally known in which nucleic acid and lipid are mixed to form a complex, and then the nucleic acid is taken up into cells through the complex. As the lipid used for forming the complex, cationic lipid, hydrophilic polymer lipid, helper lipid and the like have been conventionally known. As the above cationic lipid, for example, compounds described in the following prior art documents are known.

[0004] Patent Document 1 describes a compound represented by the following formula or a salt thereof.

[0005] In the formula, R １ are each independently selected from the group consisting of optionally substituted C ８ - C ２４ alkyl and optionally substituted C ８ - C ２４ alkenyl; R ２ and R ３ are each independently selected from the group consisting of hydrogen, optionally substituted C １ - C ８ alkyl, optionally substituted arylalkyl, etc.; Y １ and Y２ Each of these is independently a hydrogen atom, or a C atom that may be substituted. １ ~C ６ Selected from the group consisting of alkyl groups, optionally substituted arylalkyl groups, etc.; Y ３ If present, these are, independently, hydrogen and possibly substituted C. １ ~C ８ The set is defined as being selected from the group consisting of alkyl groups, optionally substituted arylalkyl groups, etc.; m is an integer from 1 to 4, n is an integer from 0 to 3, p is 0 or 1, and the sum of m, n and p is 4; k is an integer from 1 to 5; and q is 0 or 1.

[0006] Patent Document 2 describes a compound represented by the following formula or a salt thereof.

[0007] In the formula, W is equal to -NR １ R ２ or formula -N ＋ R ３ R ４ R ５ (Z － ) indicates R １ and R ２ Each is independently C １－４ R represents an alkyl group or a hydrogen atom. ３ , R ４ and R ５ Each is independently C １－４ It indicates an alkyl group, Z － represents an anion, and X may be substituted C. １－６ It shows an alkylene group, Y Ａ , Y Ｂ and Y Ｃ Each of these represents a methine group which may be independently substituted, L Ａ , L Ｂ and L Ｃ Each of these represents a methylene group or bond that may be independently substituted, R Ａ１ , R Ａ２ , R Ｂ１ , R Ｂ２ , R Ｃ１ and R Ｃ２ Each of these can be substituted independently.４－１０ This indicates an alkyl group.

[0008] Patent Document 3 describes a compound represented by the following formula or a salt thereof.

[0009] In the formula, n is an integer between 2 and 5, and R is a linear C １－５ Alkyl alkyl groups, linear C ７－１１ Alkenyl group or linear carbon １１ The alkadienyl group is shown, and the wavy lines independently indicate cis or trans bonds.

[0010] Patent Document 4 describes a compound represented by the following formula or a salt thereof.

[0011] In the formula, n1 represents an integer from 2 to 6, n2 represents an integer from 0 to 2, n3 represents an integer from 0 to 2, L represents -C(O)O- or -NHC(O)O-, and Ra represents linear C ５－１３ Alkyl alkyl groups, linear C １３－１７ Alkenyl group or linear carbon １７ It exhibits an alkadienyl group, and Rb is a linear C ２－９ It represents an alkyl group, where Rc is a hydrogen atom or a linear C ２－９ It represents an alkyl group, where Rd is a hydrogen atom or a linear C ２－９ It represents an alkyl group, and Re is a linear C ２－９ It represents an alkyl group, and Rf is a linear C ２－９ This indicates an alkyl group.

[0012] Patent Document 5 describes a compound represented by the following formula or a salt thereof.

[0013] In the formula, W is -NR １ R ２ or -N ＋ R １１ R １２ R １３ (Z － ) represents R １ and R ２ Each of these is independently H or C, which may be substituted. １～５ R represents an alkyl group. １１ , R １２ and R１３ each independently represents an optionally substituted C １～５ alkyl group, Z － represents an anion, X represents an optionally substituted C ２～６ alkylene group, R Ａ and R Ｂ each independently represents an optionally substituted C １～１７ alkyl group, an optionally substituted C ３～１７ alkenyl group, an optionally substituted C １５～１７ alkadienyl group, or -R ３ -C(O)O-R ４ or -R ３ -OC(O)-R ４ represents, R Ｃ is -R ３ -C(O)O-R ４ or -R ３ -OC(O)-R ４ represents, R ３ is an optionally substituted C １～１６ alkylene group, an optionally substituted C ４～１６ alkenylene group or an optionally substituted C ７～１６ alkadienylene group represents, R ４ is H, an optionally substituted C １～１８ alkyl group, an optionally substituted C ３～１８ alkenyl group or an optionally substituted C １５～１８ alkadienyl group.

[0014] WO2003 / 102150 pamphlet WO2016 / 021683 pamphlet WO2019 / 131839 pamphlet WO2020 / 032184 pamphlet WO2023 / 085299 pamphlet

[0015] Cationic lipids that enable the introduction of active ingredients into cells with high efficiency, for example, cationic lipids that can interact with nucleic acids as negatively charged active ingredients, are expected to contribute to the creation of pharmaceuticals having excellent therapeutic effects in terms of drug efficacy expression, safety (low toxicity), etc. In addition, cationic lipids that enable the introduction of nucleic acids into various cells are expected to enable the creation of nucleic acid pharmaceuticals for various diseases occurring in various tissues. The inventions of cationic lipids described in Patent Documents 3, 4, and 5 can achieve certain effects in introducing nucleic acids into cells with excellent efficiency and introducing nucleic acids into various cells, but there is still room for further improvement in terms of, for example, improvement of the introduction efficiency into cells in vivo (delivery efficiency), that is, improvement of drug efficacy expression, for use as nucleic acid pharmaceuticals.

[0016] An object of the present invention is to provide a technique that enables the introduction of active ingredients such as nucleic acids into various cells with excellent efficiency, and particularly a cationic lipid for producing lipid particles and compositions containing the active ingredient.

[0017] As a result of intensive studies by the present inventors to solve the above problems, a compound represented by the following formula (I), that is, in at least one of the three side chains, three ester bonds (R Ａ 、R Ｂ Or R Ｃ Two ester bonds included in the definition of, and one ester bond shown in the structural formula of the corresponding side chain), it has been found that the above problems can be solved by using a cationic lipid or a salt thereof, and the present invention has been completed.

[0018] That is, the present invention relates to at least the following inventions. [1] Formula (I): [In formula (I), W is -NR １ R ２ Or -N ＋ R １１ R １２ R １３ (Z － ), R １ And R ２Each of these is independently a hydrogen atom or a substituted C １～５ It is an alkyl group, R １１ , R １２ and R １３ Each of these can be independently substituted. １～５ It is an alkyl group, Z － C is an anion, and X may be substituted. ２～６ It is an alkylene group, R Ａ and R Ｂ Each of these can be independently substituted. １～１７ Alkyl alkyl groups, optionally substituted C ３～１７ Alkenyl group, may be substituted C １５～１７ Alkadienyl group, or -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ This is a structure represented by R Ｃ is, -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ It is a structure represented by Y １ and Y ２ These are independently -CO-O- or -O-CO-, and R ３ C may be substituted. １～３ It is an alkylene group, R ４ C is a hydrogen atom, which may be substituted. １～１２ Alkyl alkyl groups, optionally substituted C ３～１８ Alkenyl group, or possibly substituted C １５～１８ It is an alkadienyl group, R ５ C may be substituted. １～１２ Alkyl alkyl groups, optionally substituted C ３～１８ Alkenyl group, or possibly substituted C １５－１８ It is an alkadienyl group, R Ａ , R Ｂ and R Ｃ All of them are -R ３ -Y １ -CH(R)４ ) (Y ２ -R ５ If the structure is represented by ), R Ａ , R Ｂ and R Ｃ R in the structure in ３ , R ４ and R ５ Each of these may be the same or different. [2] A compound represented by or a salt thereof. [1] Lipid particles containing the compound or salt thereof described in [1]. [3] A nucleic acid introduction composition containing nucleic acid and the lipid particles described in [2]. [4] The composition according to [3], wherein the nucleic acid is DNA or RNA.

[0019] In this specification, the compound represented by formula (I) may be referred to as "compound (I)". Also, "the compound represented by formula (I) or its salt" may be referred to as "the compound of the present invention". "Lipid particles containing the compound represented by formula (I) or its salt (the compound of the present invention)" may be referred to as "the lipid particles of the present invention". "A composition for introducing nucleic acids containing nucleic acids and the lipid particles of the present invention" may be referred to as "the composition of the present invention".

[0020] The present invention makes it possible to introduce active ingredients such as nucleic acids into various cells, tissues, or organs (which may include cancer cells or cancerous tissue) with excellent efficiency. Therefore, the present invention makes it possible to introduce active ingredients such as nucleic acids into various cells, tissues, or organs, and to obtain pharmaceuticals or research reagents with high efficiency in expressing the effects (pharmacological efficacy, etc.) of said active ingredients.

[0021] The compound of the present invention is a compound represented by the following formula (I) (compound (I)) or a salt thereof.

[0022]

[0023] In equation (I), W is -NR １ R ２ or -N ＋ R １１ R １２ R １３ (Z － ) and R １ and R ２Each of these is independently a hydrogen atom or a substituted C １～５ It is an alkyl group, R １１ , R １２ and R １３ Each of these can be independently substituted. １～５ It is an alkyl group, Z ― C is an anion, and X may be substituted. ２～６ It is an alkylene group, R Ａ and R Ｂ Each of these can be independently substituted. １～１７ Alkyl alkyl groups, optionally substituted C ３～１７ Alkenyl group, may be substituted C １５～１７ Alkadienyl group, or -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ This is a structure represented by R Ｃ is, -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ It is a structure represented by Y １ and Y ２ These are independently -CO-O- or -O-CO-, and R ３ C may be substituted. １～３ It is an alkylene group, R ４ C is a hydrogen atom, which may be substituted. １～１２ Alkyl alkyl groups, optionally substituted C ３～１８ Alkenyl group, or possibly substituted C １５～１８ It is an alkadienyl group, R ５ C may be substituted. １～１２ Alkyl alkyl groups, optionally substituted C ３～１８ Alkenyl group, or possibly substituted C １５－１８ It is an alkadienyl group, R Ａ , R Ｂ and R Ｃ All of them are -R ３ -Y １ -CH(R)４ ) (Y ２ -R ５ If the structure is represented by ), R Ａ , R Ｂ and R Ｃ R in the structure in ３ , R ４ and R ５ These may be the same or different.

[0024] "C １～５ Alkyl(R) １ , R ２ , R １１ , R １２ and R １３ C refers to an alkyl group having 1 to 5 carbon atoms, which may be linear or branched. In the case of a branched chain, the number of bonds in the branched chain (how many carbon atoms it is bonded to) and the bond position (which carbon atom it is bonded to) are arbitrary. １～５ Specific examples of alkyl groups include the following: [C １ ]methyl; [C ２ ]ethyl; [C ３ ]propyl, 1-methylethyl (also known as isopropyl); [C ４ ]Butyl, 1-methylpropyl (also known as sec-butyl), 2-methylpropyl (also known as isobutyl), 1,1-dimethylethyl (also known as tert-butyl); [C ５ Pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl (also known as isopentyl), 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl (also known as neopentyl).

[0025] R １ , R ２ , R １１ , R １２ and R １３ C which may be replaced １～５ "alkyl group" is preferably "a C group which may be substituted". １～４ "alkyl group", more preferably "a C which may be substituted" １～３ It is an alkyl group.

[0026] Z －W is -N ＋ R １１ R １２ R １３ In this case, any anion that can electrically bond is not particularly limited, but pharmacologically acceptable anions are preferred. － Preferred examples include halide ions (fluoride ions, chloride ions, bromide ions, and iodide ions); anions of inorganic acids such as nitrate ions, sulfate ions, and phosphate ions; anions of organic acids such as formate ions, acetate ions, trifluoroacetate ions, phthalate ions, fumarate ions, oxalate ions, tartrate ions, maleate ions, citrate ions, succinate ions, malate ions, methanesulfonate ions, benzenesulfonate ions, and p-toluenesulfonate ions; or aspartate ions.

[0027] "C ２～６ The alkylene group (X) refers to a divalent group derived from an alkyl group having 2 to 6 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of bonds in the branched chain are arbitrary. ２～６ Specific examples of alkylene groups include the following: [C ２ ] Ethylene, methylmethylene; [C ３ ]Propylene, 1-methylethylene, 2-methylethylene, ethylmethylene; [C ４ ]Butylene, 1-methylpropylene, 2-methylpropylene, 3-methylpropylene, 1-ethylethylene, 2-ethylethylene, 1,2-dimethylethylene, propylmethylene; [C ５ ] Pentylene, 1-methylbutylene, 2-methylbutylene, 3-methylbutylene, 4-methylbutylene, 1-ethylpropylene, 2-ethylpropylene, 3-ethylpropylene, 1,1-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, 2,2-dimethylpropylene, 2,3-dimethylpropylene, 1-propylethylene, 2-propylethylene, butylmethylene; [C ６Hexylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, 4-methylpentylene, 5-methylpentylene, 1-ethylbutylene, 2-ethylbutylene, 3-ethylbutylene, 4-ethylbutylene, 1,1-dimethylbutylene, 1,2-dimethylbutylene, 1,3-dimethylbutylene, 1,4-dimethylbutylene, 2,2-dimethylbutylene, 2,3-dimethylbutylene, 2,4-dimethylbutylene, 3,3-dimethylbutylene, 3,4-dimethylbutylene , 1-propylpropylene, 2-propylpropylene, 3-propylpropylene, 1-methyl-1-ethylpropylene, 1-methyl-2-ethylpropylene, 1-ethyl-2-methylpropylene, 1-methyl-3-ethylpropylene, 1-ethyl-3-methylpropylene, 2-methyl-2-ethylpropylene, 2-methyl-3-ethylpropylene, 2-ethyl-3-methylpropylene, 3-methyl-3-ethylpropylene, 1-butylethylene, 2-butylethylene, pentylmethylene.

[0028] X's "C may be substituted" ２～６ The alkylene group is preferably a C that may be substituted. ２～５ "alkylene group", more preferably "may be substituted C ２～４ This is an alkylene group.

[0029] "C １～１７ Alkyl(R) Ａ and R Ｂ ) refers to an alkyl group having 1 to 17 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of bonds in the branched chain are arbitrary. １～１７ A specific example of an alkyl group is the aforementioned C １～５ In addition to specific examples of alkyl groups, the following can be cited, but C can be used in the present invention. １～１７ Alkyl alkyl groups are not limited to these: [C ６] Hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl (also known as isohexyl), 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl; [C ７ ]heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylbutyl; [C ８ ] Octyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 5-methylpentyl, 6-methylpentyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 1-propylpentyl, 2-propylpentyl; [C ９ ] Nonyl, 1-methyloctyl, 2-methyloctyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 7-methyloctyl, 1-ethylheptyl, 2-ethylheptyl, 3-ethylheptyl, 4-ethylheptyl, 5-ethylheptyl, 1-butylhexyl, 2-butylhexyl, 3-butylhexyl, 1-butylpentyl; [C １０ Decyl, 1-methylnonyl, 2-methylnonyl, 3-methylnonyl, 4-methylnonyl, 5-methylnonyl, 6-methylnonyl, 7-methylnonyl, 8-methylnonyl, 1-ethyloctyl, 2-ethyloctyl, 3-ethyloctyl, 4-ethyloctyl, 5-ethyloctyl, 6-ethyloctyl, 1-propylheptyl, 2-propylheptyl, 3-propylheptyl, 1-butylhexyl, 2-butylhexyl; [C １１Undecyl, 1-methyldecyl, 2-methyldecyl, 3-methyldecyl, 4-methyldecyl, 5-methyldecyl, 6-methyldecyl, 7-methyldecyl, 8-methyldecyl, 9-methyldecyl, 1-ethylnonyl, 2-ethylnonyl, 3-ethylnonyl, 4-ethylnonyl, 5-ethylnonyl, 6-ethylnonyl, 7-ethylnonyl, 1-propyloctyl, 2-propyloctyl, 3-propyloctyl, 4-propyloctyl, 5-propyloctyl, 1-butylheptyl, 2-butylheptyl, 3-butylheptyl, 1-pentylhexyl; [C １２ ] Dodecyl, 1-methylundecyl, 2-methylundecyl, 3-methylundecyl, 4-methylundecyl, 5-methylundecyl, 6-methylundecyl, 7-methylundecyl, 8-methylundecyl, 9-methylundecyl, 10-methylundecyl, 1-ethyldecyl, 2-ethyldecyl, 3-ethyldecyl, 4-ethyldecyl, 5-ethyldecyl, 6-ethyldecyl, 7-ethyldecyl, 8-ethyldecyl, 1-propylnonyl, 2-propylnonyl, 3-propylnonyl, 4-propylnonyl, 5-propylnonyl, 6-propylnonyl, 1-butyloctyl, 2-butyloctyl, 3-butyloctyl, 4-butyloctyl, 1-pentylheptyl, 2-pentylheptyl; [C １３ Tridecyl, 1-methyldodecyl, 2-methyldodecyl, 3-methyldodecyl, 4-methyldodecyl, 5-methyldodecyl, 6-methyldodecyl, 7-methyldodecyl, 8-methyldodecyl, 9-methyldodecyl, 10-methyldodecyl, 11-methyldodecyl, 1-ethylundecyl, 2-ethylundecyl, 3-ethylundecyl, 4-ethylundecyl, 5-ethylundecyl, 6-ethylundecyl, 7-ethylundecyl , 8-ethylundecyl, 9-ethylundecyl, 1-propyldecyl, 2-propyldecyl, 3-propyldecyl, 4-propyldecyl, 5-propyldecyl, 6-propyldecyl, 7-propyldecyl, 1-butylnonyl, 2-butylnonyl, 3-butylnonyl, 4-butylnonyl, 5-butylnonyl, 1-pentyloctyl, 2-pentyloctyl, 3-pentyloctyl, 1-hexylpentyl, 3,4-dipropylheptyl; [C １４Tetradecyl, 1-methyltridecyl, 2-methyltridecyl, 3-methyltridecyl, 4-methyltridecyl, 5-methyltridecyl, 6-methyltridecyl, 7-methyltridecyl, 8-methyltridecyl, 9-methyltridecyl, 10-methyltridecyl, 11-methyltridecyl, 12-methyltridecyl, 1-ethyldodecyl, 2-ethyldodecyl, 3-ethyldodecyl, 4-ethyldodecyl, 5-ethyldodecyl, 6-ethyldodecyl, 7-ethyldodecyl, 8-ethyldodecyl, 9-ethyl Dodecyl, 10-ethyldodecyl, 1-propylundecyl, 2-propylundecyl, 3-propylundecyl, 4-propylundecyl, 5-propylundecyl, 6-propylundecyl, 7-propylundecyl, 8-propylundecyl, 1-butyldecyl, 2-butyldecyl, 3-butyldecyl, 4-butyldecyl, 5-butyldecyl, 6-butyldecyl, 1-pentylnonyl, 2-pentylnonyl, 3-pentylnonyl, 4-pentylnonyl, 1-hexyloctyl, 2-hexyloctyl; [C １５Pentadecyl, 1-methyltetradecyl, 2-methyltetradecyl, 3-methyltetradecyl, 4-methyltetradecyl, 5-methyltetradecyl, 6-methyltetradecyl, 7-methyltetradecyl, 8-methyltetradecyl, 9-methyltetradecyl, 10-methyltetradecyl, 11-methyltetradecyl, 12-methyltetradecyl, 13-methyltetradecyl, 1-ethyltridecyl, 2-ethyltridecyl, 3-ethyltridecyl, 4-ethyltridecyl, 5-ethyltridecyl, 6-ethyltridecyl, 7-ethyltridecyl, 8-ethyltridecyl, 9-ethyltridecyl, 10-ethyltridecyl 11-Ethyltridecyl, 1-Propyldodecyl, 2-Propyldodecyl, 3-Propyldodecyl, 4-Propyldodecyl, 5-Propyldodecyl, 6-Propyldodecyl, 7-Propyldodecyl, 8-Propyldodecyl, 9-Propyldodecyl, 1-Butylundecyl, 2-Butylundecyl, 3-Butylundecyl, 4-Butylundecyl, 5-Butylundecyl, 6-Butylundecyl, 7-Butylundecyl, 1-Pentyldecyl, 2-Pentyldecyl, 3-Pentyldecyl, 4-Pentyldecyl, 5-Pentyldecyl, 1-Hexylnonyl, 2-Hexylnonyl, 3-Hexylnonyl, 1-Heptyloctyl; [C １６] Hexadecyl, 1-methylpentadecyl, 2-methylpentadecyl, 3-methylpentadecyl, 4-methylpentadecyl, 5-methylpentadecyl, 6-methylpentadecyl, 7-methylpentadecyl, 8-methylpentadecyl, 9-methylpentadecyl, 10-methylpentadecyl, 11-methylpentadecyl, 12-methylpentadecyl, 13-methylpentadecyl, 14-methylpentadecyl, 1-ethyltetradecyl, 2-ethyltetradecyl, 3-ethyltetradecyl, 4-ethyltetradecyl, 5-ethyltetradecyl, 6-ethyltetradecyl, 7-ethyltetradecyl, 8-ethyltetradecyl, 9-ethyltetradecyl, 10-ethyltetradecyl, 11-ethyltetradecyl, 12-ethyltetradecyl, 1-propyltridecyl Cyl, 2-propyltridecyl, 3-propyltridecyl, 4-propyltridecyl, 5-propyltridecyl, 6-propyltridecyl, 7-propyltridecyl, 8-propyltridecyl, 9-propyltridecyl, 10-propyltridecyl, 1-butyldodecyl, 2-butyldodecyl, 3-butyldodecyl, 4-butyldodecyl, 5-butyldodecyl, 6-butyldodecyl, 7-butyldodecyl, 8-butyldodecyl, 1-pentylundecyl, 2-pentylundecyl, 3-pentylundecyl, 4-pentylundecyl, 5-pentylundecyl, 6-pentylundecyl, 1-hexyldecyl, 2-hexyldecyl, 3-hexyldecyl, 4-hexyldecyl, 1-heptylnonyl, 2-heptylnonyl, 3,4-dibutyloctyl; [C １７Heptadecyl, 1-methylhexadecyl, 2-methylhexadecyl, 3-methylhexadecyl, 4-methylhexadecyl, 5-methylhexadecyl, 6-methylhexadecyl, 7-methylhexadecyl, 8-methylhexadecyl, 9-methylhexadecyl, 10-methylhexadecyl, 11-methylhexadecyl, 12-methylhexadecyl, 13-methylhexadecyl, 14-methylhexadecyl, 15-methylhexadecyl 1-ethylpentadecyl, 2-ethylpentadecyl, 3-ethylpentadecyl, 4-ethylpentadecyl, 5-ethylpentadecyl, 6-ethylpentadecyl, 7-ethylpentadecyl, 8-ethylpentadecyl, 9-ethylpentadecyl, 10-ethylpentadecyl, 11-ethylpentadecyl, 12-ethylpentadecyl, 13-ethylpentadecyl, 1-propyltetradecyl, 2-propyltetradecyl, 3-propyltetradecyl, 4-propyltetradecyl, 5-propyltetradecyl, 6-propyltetradecyl, 7-propyltetradecyl, 8-propyltetradecyl, 9-propyltetradecyl, 10-propyltetradecyl, 11-propyltetradecyl, 1-butyltridecyl, 2-butyltridecyl, 3-butyltridecyl, 4-butyltridecyl, 5-butyltridecyl, 6-butyltridecyl, 7-butyltridecyl, 8-butyl Tridecyl, 9-butyltridecyl, 1-pentyldodecyl, 2-pentyldodecyl, 3-pentyldodecyl, 4-pentyldodecyl, 5-pentyldodecyl, 6-pentyldodecyl, 7-pentyldodecyl, 1-hexylundecyl, 2-hexylundecyl, 3-hexylundecyl, 4-hexylundecyl, 5-hexylundecyl, 1-heptyldecyl, 2-heptyldecyl, 3-heptyldecyl, 1-octylonyl.

[0030] R Ａ and R Ｂ C which may be replaced １～１７ The alkyl group is preferably a substituted C5-17 alkyl group, and more preferably a substituted C7-16 alkyl group.

[0031] "C １～３ Alkylene group (R ３) refers to an alkylene group having 1 to 3 carbon atoms, which can be linear or branched. １～３ A specific example of an alkylene group is the aforementioned C ２～６ Among specific examples of alkylene groups, [C ２ ] ~ [C ３ In addition to the items of [C １ Examples of methylene groups corresponding to ] include ].

[0032] "C １～１２ Alkyl(R) ４ , R ５ ) refers to an alkyl group having 1 to 12 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of bonds in the branched chain are arbitrary. １～１２ A specific example of an alkyl group is the aforementioned C １～３ Alkyl and C １～１７ Among specific examples of alkyl groups, [C １ ] ~ [C １２ Examples include the following.

[0033] R ４ and R ５ C which may be replaced １～１２ The alkyl group is preferably a substituted C3-10 alkyl group, and more preferably a substituted C4-8 alkyl group.

[0034] "C ３～１７ Alkenyl group (R Ａ and R Ｂ ) refers to an alkenyl group having 3 to 17 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of the branched bonds are arbitrary, and the position of the carbon-carbon double bond is also arbitrary. ３～１７ Specific examples of alkenyl groups include the following, but C can be used in the present invention. ３～１７ Alkenyl groups are not limited to these examples: [C ３ ] 1-propenyl, 2-propenyl; [C ４ ] 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl; [C ５] 1-Pentenyl, 2-Pentenyl, 3-Pentenyl, 4-Pentenyl, 1-Methyl-1-Butenyl, 2-Methyl-1-Butenyl, 3-Methyl-1-Butenyl, 1-Methyl-2-Butenyl, 2-Methyl-2-Butenyl, 3-Methyl-2-Butenyl, 1-Methyl-3-Butenyl, 2-Methyl-3-Butenyl, 3-Methyl-3-Butenyl, 1-Ethyl-1-Propenyl, 2-Ethyl-1-Propenyl, 1-Ethyl-2-Propenyl, 2-Ethyl-3-Propenyl; [C ６ ] 1-Hexenyl, 2-Hexenyl, 3-Hexenyl, 4-Hexenyl, 5-Hexenyl, 1-Methyl-1-Pentenyl, 1-Methyl-2-Pentenyl, 1-Methyl-3-Pentenyl, 1-Methyl-4-Pentenyl, 2-Methyl-1-Pentenyl, 2-Methyl-2-Pentenyl, 2-Methyl-3-Pentenyl, 2-Methyl-4-Pentenyl, 3-Methyl-1-Pentenyl, 3-Methyl-2-Pentenyl, 3-Methyl-3-Pentenyl, 3-Methyl-4-Pentenyl, 4-Methyl-1-Pentenyl L, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 3-ethyl-1-butenyl, 3-ethyl-2-butenyl, 3-ethyl-3-butenyl, 1-propyl-1-propenyl, 2-propyl-1-propenyl, 1-propyl-2-propenyl, 2-propyl-2-propenyl; [C ７ ] 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl; [C ８ ] 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl; [C ９ ] 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl; [C １０ ] 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl (C １０ ); [C １１] 1-Undecenyl, 2-Undecenyl, 3-Undecenyl, 4-Undecenyl, 5-Undecenyl, 6-Undecenyl, 7-Undecenyl, 8-Undecenyl, 9-Undecenyl, 10-Undecenyl; [C １２ ] 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl; [C １３ ] 1-Tridecenyl, 2-Tridecenyl, 3-Tridecenyl, 4-Tridecenyl, 5-Tridecenyl, 6-Tridecenyl, 7-Tridecenyl, 8-Tridecenyl, 9-Tridecenyl, 10-Tridecenyl, 11-Tridecenyl, 12-Tridecenyl; [C １４ ] 1-tetradecenyl, 2-tetradecenyl, 3-tetradecenyl, 4-tetradecenyl, 5-tetradecenyl, 6-tetradecenyl, 7-tetradecenyl, 8-tetradecenyl, 9-tetradecenyl, 10-tetradecenyl, 11-tetradecenyl, 12-tetradecenyl, 13-tetradecenyl; [C １５ ] 1-pentadecenyl, 2-pentadecenyl, 3-pentadecenyl, 4-pentadecenyl, 5-pentadecenyl, 6-pentadecenyl, 7-pentadecenyl, 8-pentadecenyl, 9-pentadecenyl, 10-pentadecenyl, 11-pentadecenyl, 12-pentadecenyl, 13-pentadecenyl, 14-pentadecenyl; [C １６ ]; 1-Hexadecenyl, 2-Hexadecenyl, 3-Hexadecenyl, 4-Hexadecenyl, 5-Hexadecenyl, 6-Hexadecenyl, 7-Hexadecenyl, 8-Hexadecenyl, 9-Hexadecenyl, 10-Hexadecenyl, 11-Hexadecenyl, 12-Hexadecenyl, 13-Hexadecenyl, 14-Hexadecenyl, 15-Hexadecenyl; [C １７1-heptadecenyl, 2-heptadecenyl, 3-heptadecenyl, 4-heptadecenyl, 5-heptadecenyl, 6-heptadecenyl, 7-heptadecenyl, 8-heptadecenyl, 9-heptadecenyl, 10-heptadecenyl, 11-heptadecenyl, 12-heptadecenyl, 13-heptadecenyl, 14-heptadecenyl, 15-heptadecenyl, 16-heptadecenyl. C ３～１７ Since the alkenyl group contains one carbon-carbon double bond, it can take on either a cis or trans structure, and either structure is acceptable.

[0035] "C １５～１７ Alkadienyl group (R Ａ and R Ｂ ) refers to an alkadienyl group having 15 to 17 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of the bonds in the branched chain are arbitrary, and the positions of the two carbon-carbon double bonds are also arbitrary. １５～１７ Specific examples of alkadienyl groups include the following, but C can be used in the present invention. １５～１７ Alkadienyl groups are not limited to these examples: [C １５] 1,3-pentadecadienyl, 1,4-pentadecadienyl, 1,5-pentadecadienyl, 1,6-pentadecadienyl, 1,7-pentadecadienyl, 1,8-pentadecadienyl, 1,9-pentadecadienyl, 1,10-pentadecadienyl, 1,11-pentadecadienyl, 1,12-pentadecadienyl, 1,13-pentadecadienyl, 1,14-pentadecadienyl, 2,4-pentadecadienyl, 2,5-pentadecadienyl, 2,6-pentadecadienyl, 2,7-pentadecadienyl, 2,8-pentadecadienyl, 2,9- Pentadecadienyl, 2,10-pentadecadienyl, 2,11-pentadecadienyl, 2,12-pentadecadienyl, 2,13-pentadecadienyl, 2,14-pentadecadienyl, 3,5-pentadecadienyl, 3,6-pentadecadienyl, 3,7-pentadecadienyl, 3,8-pentadecadienyl, 3,9-pentadecadienyl, 3,10-pentadecadienyl, 3,11-pentadecadienyl, 3,12-pentadecadienyl, 3,13-pentadecadienyl, 3,14-pentadecadienyl, 4,6-pentadecadienyl, 4,7-pentadecadienyl pentadecadienyl, 4,8-pentadecadienyl, 4,9-pentadecadienyl, 4,10-pentadecadienyl, 4,11-pentadecadienyl, 4,12-pentadecadienyl, 4,13-pentadecadienyl, 4,14-pentadecadienyl, 5,7-pentadecadienyl, 5,8-pentadecadienyl, 5,9-pentadecadienyl, 5,10-pentadecadienyl, 5,11-pentadecadienyl, 5,12-pentadecadienyl, 5,13-pentadecadienyl, 5,14-pentadecadienyl, 6,8-pentadecadienyl, 6,9-pentadecadienyl Tadecadienyl, 6,10-pentadecadienyl, 6,11-pentadecadienyl, 6,12-pentadecadienyl, 6,13-pentadecadienyl, 6,14-pentadecadienyl, 7,9-pentadecadienyl, 7,10-pentadecadienyl, 7,11-pentadecadienyl, 7,12-pentadecadienyl, 7,13-pentadecadienyl, 7,14-pentadecadienyl, 8,10-pentadecadienyl, 8,11-pentadecadienyl, 8,12-pentadecadienyl, 8,13-pentadecadienyl, 8,14-pentadecadienyl, 9,11-pentadecadienyl, 9,12-pentadecadienyl, 9,13-pentadecadienyl, 9,14-pentadecadienyl, 10,12-pentadecadienyl, 10,13-pentadecadienyl, 10,14-pentadecadienyl, 11,13-pentadecadienyl, 11,14-pentadecadienyl, 12,14-pentadecadienyl; [C, １６] 1,3-Hexadecadienyl, 1,4-Hexadecadienyl, 1,5-Hexadecadienyl, 1,6-Hexadecadienyl, 1,7-Hexadecadienyl, 1,8-Hexadecadienyl, 1,9-Hexadecadienyl, 1,10-Hexadecadienyl, 1,11-Hexadecadienyl, 1,12-Hexadecadienyl, 1,13-Hexadecadienyl, 1,14-Hexadecadienyl, 1,15-Hexadecadienyl, 2,4-Hexadecadienyl, 2,5-Hexadecadienyl, 2,6-Hexadecadienyl, 2,7-Hexadecadienyl, 2,8 -Hexadecadienyl, 2,9-Hexadecadienyl, 2,10-Hexadecadienyl, 2,11-Hexadecadienyl, 2,12-Hexadecadienyl, 2,13-Hexadecadienyl, 2,14-Hexadecadienyl, 2,15-Hexadecadienyl, 3,5-Hexadecadienyl, 3,6-Hexadecadienyl, 3,7-Hexadecadienyl, 3,8-Hexadecadienyl, 3,9-Hexadecadienyl, 3,10-Hexadecadienyl, 3,11-Hexadecadienyl, 3,12-Hexadecadienyl, 3,13-Hexadecadienyl, 3,14 -Hexadecadienyl, 3,15-Hexadecadienyl, 4,6-Hexadecadienyl, 4,7-Hexadecadienyl, 4,8-Hexadecadienyl, 4,9-Hexadecadienyl, 4,10-Hexadecadienyl, 4,11-Hexadecadienyl, 4,12-Hexadecadienyl, 4,13-Hexadecadienyl, 4,14-Hexadecadienyl, 4,15-Hexadecadienyl, 5,7-Hexadecadienyl, 5,8-Hexadecadienyl, 5,9-Hexadecadienyl, 5,10-Hexadecadienyl, 5,11-Hexadecadienyl, 5,12- Hexadecadienyl, 5,13-Hexadecadienyl, 5,14-Hexadecadienyl, 5,15-Hexadecadienyl, 6,8-Hexadecadienyl, 6,9-Hexadecadienyl, 6,10-Hexadecadienyl, 6,11-Hexadecadienyl, 6,12-Hexadecadienyl, 6,13-Hexadecadienyl, 6,14-Hexadecadienyl, 6,15-Hexadecadienyl, 7,9-Hexadecadienyl, 7,10-Hexadecadienyl, 7,11-Hexadecadienyl, 7,12-Hexadecadienyl, 7,13-Hexadecadienyl, 7,14-Hexadecadienyl, 7,15-Hexadecadienyl, 8,10-Hexadecadienyl, 8,11-Hexadecadienyl, 8,12-Hexadecadienyl, 8,13-Hexadecadienyl, 8,14-Hexadecadienyl, 8,15-Hexadecadienyl, 9,11-Hexadecadienyl, 9,12-Hexadecadienyl, 9,13-Hexadecadienyl, 9,14-Hexadecadienyl, 9,15-Hexadecadienyl Xadecadienyl, 10,12-Hexadecadienyl, 10,13-Hexadecadienyl, 10,14-Hexadecadienyl, 10,15-Hexadecadienyl, 11,13-Hexadecadienyl, 11,14-Hexadecadienyl, 11,15-Hexadecadienyl, 12,14-Hexadecadienyl, 12,15-Hexadecadienyl, 13,15-Hexadecadienyl, 13,16-Hexadecadienyl; [C, １７] 1,3-heptadecadienyl, 1,4-heptadecadienyl, 1,5-heptadecadienyl, 1,6-heptadecadienyl, 1,7-heptadecadienyl, 1,8-heptadecadienyl, 1,9-heptadecadienyl, 1,10-heptadecadienyl, 1,11-heptadecadienyl, 1,12-heptadecadienyl, 1,13-heptadecadienyl, 1,14-heptadecadienyl, 1,15-heptadecadienyl, 1,16-heptadecadienyl, 2,4-heptadecadienyl, 2,5-heptadecadienyl, 2,6-heptadecadienyl, 2,7 -heptadecadienyl, 2,8-heptadecadienyl, 2,9-heptadecadienyl, 2,10-heptadecadienyl, 2,11-heptadecadienyl, 2,12-heptadecadienyl, 2,13-heptadecadienyl, 2,14-heptadecadienyl, 2,15-heptadecadienyl, 2,16-heptadecadienyl, 3,5-heptadecadienyl, 3,6-heptadecadienyl, 3,7-heptadecadienyl, 3,8-heptadecadienyl, 3,9-heptadecadienyl, 3,10-heptadecadienyl, 3,11-heptadecadienyl, 3,12- Heptadecadienyl, 3,13-heptadecadienyl, 3,14-heptadecadienyl, 3,15-heptadecadienyl, 3,16-heptadecadienyl, 4,6-heptadecadienyl, 4,7-heptadecadienyl, 4,8-heptadecadienyl, 4,9-heptadecadienyl, 4,10-heptadecadienyl, 4,11-heptadecadienyl, 4,12-heptadecadienyl, 4,13-heptadecadienyl, 4,14-heptadecadienyl, 4,15-heptadecadienyl, 4,16-heptadecadienyl, 5,7-heptadecadienyl, 5,8- Heptadecadienyl, 5,9-heptadecadienyl, 5,10-heptadecadienyl, 5,11-heptadecadienyl, 5,12-heptadecadienyl, 5,13-heptadecadienyl, 5,14-heptadecadienyl, 5,15-heptadecadienyl, 5,16-heptadecadienyl, 6,8-heptadecadienyl, 6,9-heptadecadienyl, 6,10-heptadecadienyl, 6,11-heptadecadienyl, 6,12-heptadecadienyl, 6,13-heptadecadienyl, 6,14-heptadecadienyl, 6,15-heptadecadienyl, 6,16-heptadecadienyl, 7,9-heptadecadienyl, 7,10-heptadecadienyl, 7,11-heptadecadienyl, 7,12-heptadecadienyl, 7,13-heptadecadienyl, 7,14-heptadecadienyl, 7,15-heptadecadienyl, 7,16-heptadecadienyl, 8,10-heptadecadienyl Dienyl, 8,11-heptadecadienyl, 8,12-heptadecadienyl, 8,13-heptadecadienyl, 8,14-heptadecadienyl, 8,15-heptadecadienyl, 8,16-heptadecadienyl, 9,11-heptadecadienyl, 9,12-heptadecadienyl, 9,13-heptadecadienyl, 9, 14-heptadecadienyl, 9,15-heptadecadienyl, 9,16-heptadecadienyl, 10,12-heptadecadienyl, 10,13-heptadecadienyl, 10,14-heptadecadienyl, 10,15-heptadecadienyl, 10,16-heptadecadienyl, 11,13-heptadecadienyl, 11, 14-heptadecadienyl, 11,15-heptadecadienyl, 11,16-heptadecadienyl, 12,14-heptadecadienyl, 12,15-heptadecadienyl, 12,16-heptadecadienyl, 13,15-heptadecadienyl, 13,16-heptadecadienyl, 14,16-heptadecadienyl (C, １７ ). C １５～１７ Since the alkadienyl group contains two carbon-carbon double bonds, it can independently assume a cis or trans structure in each of them, and either structure is acceptable.

[0036] "C ３～１８ Alkenyl group (R ４ , R ５ ) refers to an alkenyl group having 3 to 18 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of the branched bonds are arbitrary, and the position of the carbon-carbon double bond is also arbitrary. ３～１８ A specific example of an alkenyl group is the aforementioned "C ３～１７ Alkenyl group (R Ａ and R Ｂ In addition to the above specific examples, the following can be cited, but C can be used in the present invention. ３～１８ Alkenyl groups are not limited to these: [C１８ 1-Octadecenyl, 2-Octadecenyl, 3-Octadecenyl, 4-Octadecenyl, 5-Octadecenyl, 6-Octadecenyl, 7-Octadecenyl, 8-Octadecenyl, 9-Octadecenyl, 10-Octadecenyl, 11-Octadecenyl, 12-Octadecenyl, 13-Octadecenyl, 14-Octadecenyl, 15-Octadecenyl, 16-Octadecenyl, 17-Octadecenyl. C ３～１８ Since the alkenyl group contains one carbon-carbon double bond, it can take on either a cis or trans structure, and either structure is acceptable.

[0037] R ４ and R ５ C which may be replaced ３～１８ The "alkenyl group" is preferably "a C which may be substituted". ５～１８ "alkenyl group", more preferably "may be substituted C ７～１８ This is an "alkenyl group".

[0038] "C １５～１８ Alkadienyl group (R ４ , R ５ ) refers to an alkadienyl group having 15 to 18 carbon atoms, which may be linear or branched. In the case of a branched chain, the number and position of bonds in the branched chain are arbitrary, and the position of the carbon-carbon double bond is also arbitrary. １５～１８ A specific example of an alkadienyl group is the aforementioned "C １５～１７ Alkadienyl group (R Ａ and R Ｂ In addition to the specific examples included in ), the following can be cited, but C can be used in the present invention. １５～１８ Alkadienyl groups are not limited to these examples: [C １８] 1,3-octadecadienyl, 1,4-octadecadienyl, 1,5-octadecadienyl, 1,6-octadecadienyl, 1,7-octadecadienyl, 1,8-octadecadienyl, 1,9-octadecadienyl, 1,10-octadecadienyl, 1,11-octadecadienyl, 1,12-octadecadienyl, 1,13-octadecadienyl, 1,14-octadecadienyl, 1,15-octadecadienyl, 1,16-octadecadienyl, 1,17-octadecadienyl, 2,4-octadecadienyl, 2,5-octadecadienyl, 2, 6-octadecadienyl, 2,7-octadecadienyl, 2,8-octadecadienyl, 2,9-octadecadienyl, 2,10-octadecadienyl, 2,11-octadecadienyl, 2,12-octadecadienyl, 2,13-octadecadienyl, 2,14-octadecadienyl, 2,15-octadecadienyl, 2,16-octadecadienyl, 2,17-octadecadienyl, 3,5-octadecadienyl, 3,6-octadecadienyl, 3,7-octadecadienyl, 3,8-octadecadienyl, 3,9-octadecadienyl, 3,10- Octadecadienyl, 3,11-octadecadienyl, 3,12-octadecadienyl, 3,13-octadecadienyl, 3,14-octadecadienyl, 3,15-octadecadienyl, 3,16-octadecadienyl, 3,17-octadecadienyl, 4,6-octadecadienyl, 4,7-octadecadienyl, 4,8-octadecadienyl, 4,9-octadecadienyl, 4,10-octadecadienyl, 4,11-octadecadienyl, 4,12-octadecadienyl, 4,13-octadecadienyl, 4,14-octadecadienyl, 4,1 5-octadecadienyl, 4,16-octadecadienyl, 4,17-octadecadienyl, 5,7-octadecadienyl, 5,8-octadecadienyl, 5,9-octadecadienyl, 5,10-octadecadienyl, 5,11-octadecadienyl, 5,12-octadecadienyl, 5,13-octadecadienyl, 5,14-octadecadienyl, 5,15-octadecadienyl, 5,16-octadecadienyl, 5,17-octadecadienyl, 6,8-octadecadienyl, 6,9-octadecadienyl, 6,10-octadecadienyl, 6,11-octadecadienyl, 6,12-octadecadienyl, 6,13-octadecadienyl, 6,14-octadecadienyl, 6,15-octadecadienyl, 6,16-octadecadienyl, 6,17-octadecadienyl, 7,9-octadecadienyl, 7,10-octadecadienyl, 7,11-octadecadienyl, 7,12-octadecadienyl, 7,13-octadecadienyl, 7,14-octadecadienyl, 7,15-octadecadienyl Tadecadienyl, 7,16-octadecadienyl, 7,17-octadecadienyl, 8,10-octadecadienyl, 8,11-octadecadienyl, 8,12-octadecadienyl, 8,13-octadecadienyl, 8,14-octadecadienyl, 8,15-octadecadienyl, 8,16-octadecadienyl, 8,17-octadecadienyl, 9,11-octadecadienyl, 9,12-octadecadienyl, 9,13-octadecadienyl Nyl, 9,14-octadecadienyl, 9,15-octadecadienyl, 9,16-octadecadienyl, 9,17-octadecadienyl, 10,12-octadecadienyl, 10,13-octadecadienyl, 10,14-octadecadienyl, 10,15-octadecadienyl, 10,16-octadecadienyl, 10,17-octadecadienyl, 11,13-octadecadienyl, 11,14-octadecadienyl, 11,15-octadecadienyl Tadecadienyl, 11,16-octadecadienyl, 11,17-octadecadienyl, 12,14-octadecadienyl, 12,15-octadecadienyl, 12,16-octadecadienyl, 12,17-octadecadienyl, 13,15-octadecadienyl, 13,16-octadecadienyl, 13,17-octadecadienyl, 14,16-octadecadienyl, 14,17-octadecadienyl, 15,17-octadecadienyl. C, １５～１８ Since the alkadienyl group contains two carbon-carbon double bonds, it can independently assume a cis or trans structure in each of them, and either structure is acceptable.

[0039] C ２～６ Alkylene group (X); C １～５ Alkyl alkyl group (R １ , R ２ ); C１～１７ Alkyl alkyl group, C ３～１７ Alkenyl group or C １５～１７ Alkadienyl group (R Ａ , R Ｂ ); C １～３ Alkylene group (R ３ ); C １～１２ Alkyl alkyl group, C ３～１８ Alkenyl group or C １５～１８ Alkadienyl group (R ４ , R ５ Examples of "substituents" that each of these "substituents" may have include halogen atoms, cyano groups, nitro groups, acyl groups (e.g., formyl group, acetyl group, propionyl group), further substituted amino groups, further substituted carbamoyl groups, further substituted thiocarbamoyl groups, further substituted sulfamoyl groups, further substituted hydroxyl groups, further substituted sulfanyl (SH) groups, and further substituted silyl groups. Examples of "further substituents" that these "substituents" may have include halogen atoms, cyano groups, nitro groups, amino groups, hydroxyl groups, and sulfanyl groups.

[0040] Compound (I) is R Ａ and R Ｂ In the embodiment, specifically, R Ａ and R Ｂ Each of these is -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ It is not a structure represented by ), but a C which may be substituted. １～１７ Alkyl alkyl groups, optionally substituted C ３～１７ Alkenyl group, or possibly substituted C １５～１７ Alkadienyl group (hereinafter referred to as "R") Ａ／Ｂ This is called "Group 1". ) That is, it does not contain two ester bonds, or -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ The structure represented by (hereinafter referred to as "R Ａ／ＢThis is called "Group 2." Depending on whether it contains two ester bonds, it can be classified into the following three types.

[0041] The first type is a compound represented by the following formula (II) (compound (II)). Formula (II) is the compound in formula (I) where R Ａ and R Ｂ R Ａ／Ｂ This corresponds to the case of Group 1 (which does not contain two ester bonds), and in this case, R Ａ and R Ｂ R Ａ１ and R Ｂ１ It is written as follows: In equation (II), R Ａ１ and R Ｂ１ The definitions of the other symbols are the same as in formula (I). Compound (II) has only one of the three side chains, i.e., R Ｃ Only the side chain containing -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ It is a cationic lipid that has a total of three ester bonds, including the two ester bonds contained in ). Ａ and R Ｂ R Ａ／Ｂ Group 1, i.e., C which may be substituted. １～１７ Alkyl alkyl groups, optionally substituted C ３～１７ Alkenyl group, or possibly substituted C １５～１７ If it is an alkadienyl group, R Ａ and R Ｂ They may be the same or different.

[0042] The second type is a compound represented by the following formula (III) (compound (III)). Formula (III) is the compound in which R in formula (I) Ａ R Ａ／Ｂ It is group 1 (it does not contain two ester bonds), R Ｂ However, R Ａ／Ｂ This corresponds to the case of group 2 (containing two ester bonds), and in this case R Ａ and R Ｂ RＡ１ and R Ｂ２ It is written as follows: In equation (III), R Ａ１ and R Ｂ２ The definitions of the other symbols are the same as in formula (I). Compound (III) has two of its three side chains, namely R Ｃ Side chains and R Ｂ２ The side chain containing -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ It is a cationic lipid that has a total of three ester bonds, including the two ester bonds contained in ). Ｂ and R Ｃ ga-R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ If the structure is represented by ), R Ｂ and R Ｃ R in the structure in ３ , R ４ and R ５ These may be the same or different.

[0043] The third type is a compound represented by the following formula (IV) (compound (IV)). Formula (IV) is the compound in which R Ａ and R Ｂ However, R Ａ／Ｂ This corresponds to the case of group 2 (containing two ester bonds), and in this case R Ａ and R Ｂ R Ａ２ and R Ｂ２ It is written as follows: In equation (IV), R Ａ２ and R Ｂ２ The definitions of the other symbols are the same as in formula (I). Compound (IV) has all three side chains, i.e., R Ｃ Side chain including R Ｂ２ Side chains and R Ａ２ All side chains containing -R ３ -Y １ -CH(R) ４ ) (Y ２ -R５ It is a cationic lipid that has a total of three ester bonds, including the two ester bonds contained in ). Ａ , R Ｂ and R Ｃ All of them are -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ If the structure is represented by ), R Ａ , R Ｂ and R Ｃ R in the structure in ３ , R ４ and R ５ These may be the same or different.

[0044] The salt of compound (I) is preferably a pharmacokinetically acceptable salt, such as a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, or a salt with a basic or acidic amino acid.

[0045] Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts and ammonium salts. Preferably, the salts are sodium salts, potassium salts, calcium salts, and magnesium salts, and more preferably sodium salts and potassium salts.

[0046] Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, and N,N-dibenzylethylenediamine.

[0047] Suitable examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Preferably, these are salts with hydrochloric acid or phosphoric acid.

[0048] Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0049] Suitable examples of salts with basic amino acids include salts with arginine, lysine, and ornithine.

[0050] Suitable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

[0051] The compounds of the present invention can be used as cationic lipids. In formula (I), W is -NR １ R ２ In that case, the site ionizes in a solvent with an appropriate pH to become a cation, for example, R １ and R ２ It is a methyl group, -NR １ R ２ as a dimethylamino group (-N(CH) ３ ) ２ When representing ), use the dimethylammonium ion (-N ＋ (CH ３ ) ２ H) is the result. On the other hand, in equation (I), W is -N ＋ R １１ R １２ R １３ (Z － Even if ) the part is in the solvent (Z － (It ionizes) to become a cation. Such cationic lipids can form complexes with multiple molecules in a solvent or dispersion medium. The above complex may contain other components in addition to the compound of the present invention. Examples of the above other components include other lipid components and nucleic acids.

[0052] Other lipid components mentioned above include structural lipids that can constitute lipid particles. Such structural lipids include, for example, sterols (e.g., cholesterol, cholesterol esters, cholesterol hemysuccinate, etc.); phospholipids (e.g., phosphatidylcholine (e.g., dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, lysophosphatidylcholine, dioleoylphosphatidylcholine, palmitoyloleoylphosphatidylcholine, dilinolenoylphosphatidylcholine, MC-1010 (NOF CORPORATION), MC-2020 (NOF CORPORATION), MC-4040 (NOF CORPORATION), MC-6060 (NOF CORPORATION), MC-8080 (NOF (e.g., CORPORATION), phosphatidylserine (e.g., dipalmitoylphosphatidylserine, distearoylphosphatidylserine, dioleoylphosphatidylserine, palmitoyloleoylphosphatidylserine, etc.), phosphatidylethanolamine (e.g., dipalmitoylphosphatidylethanolamine, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, palmitoyloleoylphosphatidylethanolamine, lysophosphatidylethanolamine, etc.), phosphatidylinositol, phosphatidic acid, etc.); and polyethylene glycol lipids (PEG lipids) (e.g., PEG-DAA, PEG-DAG, PEG-phospholipid conjugate, PEG-Cer, PEG-cholesterol, PEG-C-DOMG, 2KPEG-CMG, GM-020 (NOF) At least one selected from the group consisting of (e.g., CORPORATION), GS-020 (NOF CORPORATION), GS-050 (NOF CORPORATION), etc. can be used. In the present invention, it is preferable to use all three types of structural lipids: sterols (especially cholesterol), phospholipids (especially phosphatidylcholine), and polyethylene glycol lipids.

[0053] The ratio of the compound of the present invention to the structural lipid in the mixed lipid component forming the lipid particles of the present invention can be appropriately adjusted depending on the purpose and application. For example, the ratio of structural lipid to 1 mole of the compound of the present invention is usually 0.008 to 4 moles, preferably 0.4 to 1.5 moles. Alternatively, the ratio in the mixed lipid component is usually 1 to 4 moles of the compound of the present invention, 0 to 3 moles of sterols, 0 to 2 moles of phospholipids, and 0 to 1 mole of polyethylene glycol lipid. A more preferred embodiment when using a mixture of the compound of the present invention and other lipid components is a ratio of 1 to 1.5 moles of the compound of the present invention, 0 to 1.25 moles of sterols, 0 to 0.5 moles of phospholipids, and 0 to 0.125 moles of polyethylene glycol lipid.

[0054] The compounds of the present invention can be used to produce the lipid particles of the present invention. The lipid particles of the present invention refer to complexes that do not contain nucleic acids among the above-mentioned complexes. The shape of the lipid particles of the present invention is not particularly limited and includes, for example, complexes in which the compounds of the present invention etc. are assembled to form a spherical shape, complexes assembled without forming a specific shape, complexes dissolved in a solvent, and complexes uniformly or non-uniformly dispersed in a dispersion medium.

[0055] The lipid particles of the present invention (for example, lipid particles composed of the compound of the present invention and other structural lipids) can be used, for example, to produce a composition of the present invention containing the lipid particles and nucleic acids (particularly nucleic acids that are useful for pharmaceutical or research purposes). The composition of the present invention can be used as a pharmaceutical or reagent. In the composition of the present invention, it is preferable that as much of the nucleic acid as possible is encapsulated in the lipid particles (i.e., a high encapsulation rate).

[0056] "Nucleic acid" refers to any molecule formed by the polymerization of nucleotides and molecules having equivalent functions to nucleotides. Examples include RNA, which is a polymer of ribonucleotides; DNA, which is a polymer of deoxyribonucleotides; polymers of a mixture of ribonucleotides and deoxyribonucleotides; and nucleotide polymers containing nucleotide analogs. Furthermore, nucleotide polymers containing nucleic acid derivatives may also be included. Nucleic acids may be single-stranded or double-stranded. Double-stranded nucleic acids also include double-stranded nucleic acids in which one strand hybridizes with the other under stringent conditions.

[0057] Nucleotide analogs can be any molecule that has been modified from ribonucleotides, deoxyribonucleotides, RNA, or DNA to improve nuclease resistance or stability compared to RNA or DNA, to increase affinity with complementary nucleic acids, to increase cell permeability, or to make them visible. Nucleotide analogs can be naturally occurring or unnatural molecules, such as sugar-modified nucleotide analogs or phosphate diester-modified nucleotide analogs.

[0058] As sugar-modified nucleotide analogs, any chemical structural substance can be added to or substituted for part or all of the chemical structure of the sugar of a nucleotide. Specific examples include nucleotide analogs substituted with 2'-O-methylribose, nucleotide analogs substituted with 2'-O-propylribose, nucleotide analogs substituted with 2'-methoxyethoxyribose, nucleotide analogs substituted with 2'-O-methoxyethylribose, nucleotide analogs substituted with 2'-O-[2-(guanidium)ethyl]ribose, nucleotide analogs substituted with 2'-fluororibose, nucleic acid analogs in which the sugar portion is replaced with a morpholino ring (morpholino nucleic acids), bridged nucleotides (BNA) having two cyclic structures by introducing a cross-linking structure to the sugar portion, more specifically, locked nucleotides (LNA) in which the oxygen atom at the 2' position and the carbon atom at the 4' position are cross-linked via methylene, and ethylene cross-linked nucleotides (Ethylene Examples include bridged nucleic acids (ENA) [Nucleic Acid Research, 32, e175 (2004)], amide-bridged nucleic acids (AmNA) in which the 2' and 4' carbon atoms are bridged via an amide bond, as well as peptide nucleic acids (PNA) [Acc. Chem. Res., 32, 624 (1999)], oxypeptide nucleic acids (OPNA) [J. Am. Chem. Soc., 123, 4653 (2001)], and peptide ribonucleic acid (PRNA) [J. Am. Chem. Soc., 122, 6900 (2000)].

[0059] Phosphate diester bond-modified nucleotide analogs can be any nucleotide in which any chemical substance is added to or substituted for part or all of the phosphate diester bond in the chemical structure of the nucleotide. Specific examples include nucleotide analogs substituted with phosphorothioate bonds and nucleotide analogs substituted with N3'-P5' phosphoamide bonds [Cell Engineering, 16, 1463-1473 (1997)] [RNAi and Antisense Methods, Kodansha (2005)].

[0060] Nucleic acid derivatives can be any molecule to which another chemical substance has been added to the nucleic acid in order to improve nuclease resistance, stabilize it, increase affinity with complementary nucleic acid chains, increase cell permeability, or make it visible. Specific examples include 5'-polyamine-added derivatives, cholesterol-added derivatives, steroid-added derivatives, bile acid-added derivatives, vitamin-added derivatives, Cy5-added derivatives, Cy3-added derivatives, 6-FAM-added derivatives, and biotin-added derivatives.

[0061] The nucleic acids in the present invention are not particularly limited and may include, for example, nucleic acids intended for the improvement of diseases, symptoms, disorders, or pathological conditions, and for the alleviation or prevention of the onset of diseases, symptoms, disorders, or pathological conditions (which may be referred to as "treatment of diseases, etc." in this specification), or nucleic acids for regulating the expression of desired proteins that are useful for research purposes but do not contribute to the treatment of diseases, etc.

[0062] Information on disease-related genes or polynucleotides (hereinafter sometimes referred to as "disease-related genes") is available, for example, from the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and the National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.).

[0063] Specific examples of nucleic acids in the present invention include, for example, single-stranded DNA, double-stranded DNA, siRNA, miRNA, miRNA mimic, antisense nucleic acids, ribozymes, mRNA, circRNA, self-replicating RNA, gRNA, decoy nucleic acids, aptamers, etc., and may also be analogs or derivatives that have been artificially modified. Furthermore, nucleic acids may be linear or covalently closed circular. Preferred nucleic acids are DNA, RNA, such as single-stranded DNA, double-stranded DNA, siRNA, mRNA, circRNA, self-replicating RNA, and gRNA, or analogs or derivatives of these that have been artificially modified.

[0064] In the present invention, "siRNA" means a double-stranded RNA or its analogues having 10 to 30 bases, preferably 15 to 25 bases, and containing a complementary sequence. siRNA preferably has 1 to 3 overhanging bases, more preferably 2 bases, at its 3' end. The complementary sequence portion may be perfectly complementary or may contain non-complementary bases, but is preferably perfectly complementary.

[0065] The siRNA used in this invention is not particularly limited, and for example, siRNA for knocking down the expression of disease-related genes can be used. Disease-related genes refer to any genes or polynucleotides that produce transcription or translation products at abnormal levels or in abnormal forms in cells derived from affected tissue compared to non-disease control tissue or cells. In addition, the siRNA used in this invention can also be siRNA for regulating the expression of a desired protein useful for research.

[0066] In the present invention, "mRNA" means RNA containing a base sequence that can be translated into a protein. The mRNA in the present invention is not particularly limited as long as it is mRNA that can express a desired protein in a cell. Preferably, the mRNA is mRNA that is useful for pharmaceutical uses (e.g., disease treatment) and / or research purposes, and such mRNA is, for example, mRNA for expressing a marker protein such as luciferase in a cell.

[0067] In the present invention, "gRNA" means a guide RNA corresponding to the CRISPR system. The gRNA in the present invention may be in the form of a single RNA formed by the ligation of crRNA and tracrRNA, i.e., a chimeric RNA (sometimes called a single guide RNA, sgRNA, etc.), or it may be in the form of two unligated RNAs (a combination of two RNAs, or a combination of more than two RNAs).

[0068] In the present invention, "DNA" means DNA containing a base sequence that can be transcribed into mRNA. The DNA in the present invention is not particularly limited as long as it is DNA that can be transcribed into a desired mRNA within a cell. Preferably, the DNA is useful for pharmaceutical applications (e.g., gene therapy applications) and / or research purposes. Examples of such DNA include plasmid DNA (pDNA), single-stranded DNA (ssDNA), nanoplasmids, minicircle DNA (Minicircle), closed-end DNA (ceDNA), doggybone DNA (dbDNA), ministring DNA (msDNA), and linear DNA (linDNA). Examples of such DNA include DNA used to express marker proteins such as luciferase within a cell.

[0069] The DNA in this invention may include an enhancer or a promoter. The enhancer or promoter in this invention is not particularly limited as long as it can control the transcription to a desired mRNA within the cell. Examples of the above promoters or enhancers include the ApoE / hAAT enhancer or promoter, CAG promoter, CMV (Cytomegalovirus) promoter, RSV (Rous sarcoma virus) promoter or enhancer, SV40 promoter, DHFR (Dihydrofolate reducase) promoter, EF1α promoter, EF and CBA (Chicken β-Actin) promoter, PGK (Phosphoricerate Kinase) promoter, hSYN (human synapsin) promoter, MND promoter, RSV (Rous Sarcoma Virus LTR) promoter, and Chicken beta actin + intron promoter, TRE (tetracycline-responsive element) promoter, UBC (Ubiquitin C) promoter, MSCV U3 (Murine stem cell virus LTR) promoter, GALV U3 (Gibbon ape leukemia virus LTR) promoter, GUSB (Beta gluturonidase) promoter, MeCP2 promoter, GFAP (glial fibrillary acid protein) promoter, Human beta actin promoter, EBV (Epstein-Barr virus) promoter, SFFV (Spleen Focus) Examples include the Forming Virus LTR promoter. The CMV promoter or CAG promoter is preferred as the enhancer or promoter.

[0070] The diseases mentioned above are not limited to those listed below, but include, for example, the diseases (1) to (7) listed below. Unless a specific disease example is given, the information in parentheses indicates an example of a disease-related gene. The nucleic acids used in this invention also include nucleic acids that regulate the expression levels of these disease-related genes (or the proteins they encode).

[0071] (1) Hematological disorders: Anemia (CDAN1, CDA1, RPS19, DBA, PKLR, PK1, NT5C3, UMPH1, PSN1, RHAG, RH50A, NRAMP2, SPTB, ALAS2, ANH1, ASB, ABCB7, ABC7, ASAT), lymphocyte insufficiency syndromes (TAPBP, TPSN, TAP2, ABCB3, PSF2, RING11, MHC2TA, C2TA, RFX5), hemorrhagic disorders (TBXA2R, P2RX1, P2X1), H factor and Factor H-like factor 1 deficiency (HF1, CFH, HUS), factor V and factor VIII deficiency (MCFD2), factor VII deficiency (F7), factor X deficiency (F10), factor XI deficiency (F11), factor XII deficiency (F12, HAF), factor XIIIA deficiency (F13A1, F13A), factor XIIIB deficiency (F13B), Fanconi anemia (FANCA, FACA, FA1, FA, FAA, FAAP95, FAAP90, FLJ34064, FANCB, FAN CC, FACC, BRCA2, FANCD1, FANCD2, FANCD, FACD, FAD, FACE, FACE, FANCF, XRCC9, FANCG, BRIP1, BACH1, FANCJ, PHF9, FANCL, FAN CM, KIAA1596), hemophagocytic lymphohistiocytosis (PRF1, HPLH2, UNC13D, MUNC13-4, HPLH3, HLH3, FHL3), hemophilia A (F8, F8C, HEMA), hemophilia B (F9, HEMB), Blood disorders (PI, ATT, F5), leukocyte deficiencies (ITGB2, CD18, LCAMB, LAD, EIF2B1, EIF2BA, EIF2B2, EIF2B3, EIF2B5, LVWM, CACH, CLE, EIF2B4), sickle cell anemia (HBB), thalassemia (HBA2, HBB, HBD, LCRB, HBA1), von Willebrand disease (VWF), hypoalbuminemia, hypovolemia, severe congenital protein C deficiency, prothrombin deficiency, etc.

[0072] (2) Inflammatory and immune diseases: AIDS (KIR3DL1, NKAT3, NKB1, AMB11, KIR3DS1, IFNG, CXCL12, SDF1), autoimmune lymphoproliferative syndrome (TNFRSF6, APT1, FAS, CD95, ALPS1A), combined immunodeficiency (IL2RG, SCIDX1, SCIDX, IMD4), HIV infection (CCL5, SCYA5, D17S135E, TCP228, IL10, CSIF, CMKBR2, CCR2, DMKBR5, CCCKR5, CCR5), immunodeficiency (CD3E, CD3G, AICDA, AID, HIGM2, TNFRSF5, CD40, UNG, DGU, HIGM4, TNFSF5, CD40LG, HIGM1, IGM, FOXP3, IPE Inflammation (IL10, IL-1, IL-13, IL-17, IL-23, CTLA4), severe combined immunodeficiency (JAK3, JAKL, DCLRE1C, ATREMI) S, SCIDA, RAG1, RAG2, ADA, PTPRC, CD45, LCA, IL7R, CD3D, T3D, IL2RG, SCIDX1, SCIDX, IMD4), primary immunodeficiency, secondary immunodeficiency, multifocal motor neuropathy, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, etc.), Sjögren's syndrome, Behçet's disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis pus nephritis, discoid lupus erythematosus, Castleman's disease, ankylosing spondylitis, polymyositis, dermatomyositis, polyarteritis nodosa, mixed connective tissue disease, scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I and type II sugars. Urinary disease, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, radiation dermatitis, primary biliary cirrhosis, etc.

[0073] (3) Metabolic, hepatic, and renal diseases: Amyloid neuropathy (TTR, PALB), amyloidosis (APOA1, APP, AAA, CVAP, AD1, GSN, FGA, LYZ, TTR, PALB), non-alcoholic steatohepatitis and hepatic fibrosis (COL1A1), cirrhosis (KRT18, KRT8, CIRH1A, NAIC, TEX292, KI AA1988), cystic fibrosis (CFTR, ABCC7, CF, MRP7), glycogen storage disorders (SLC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM), hepatocellular adenoma (TCF1, HFN1A, MODY3), liver failure (SCOD1, S CO1), hepatic lipase deficiency (LIPC), hepatoblastoma (CTNNNB1, PDGFRL, PDGRL, PRLTS, AXIN1, AXIN, TP53, P53, LFS1, IGF2R, MPRI, MET, CASP8, MCH5), medullary polycystic kidney disease (UMOD, HNFJ, FJHN, MCKD2, ADMKD2), phenylketonuria (PAH) PKU1, QDPR, DHPR, PTS), polycystic kidney and liver diseases (FCYT, PKHD1, APKD, PDK1, PDK2, PDK4, PDKTS, PRKCSH, G19P1, PCLD, SEC63), Hunter syndrome, lysosomal storage diseases, Fabry disease, Pompe disease, Gaucher disease, mucopolysaccharidosis, hypoparathyroidism, Wilson's disease, etc.

[0074] (4) Neurological disorders: ALS (SOD1, ALS2, STEX, FUS, TARDBP, VEGF), Alzheimer's disease (APP, AAA, CVAP, AD1, APOE, AD2, PSEN2, AD4, STM2, APBB2, FE65L1, NOS3, PLAU, URK, ACE, DCP1, ACE1, MPO, PACIP1, PAXIP1L, PTIP, A2M, BLMH, BMH, PSEN1, AD3), Autism (BZRAP1, MDGA2, GLO1, MECP2, RTT, PPMX, MRX16, MRX79, NLGN3, NLGN4, KIAA1260, AUTSX2), Fragile X syndrome ( FMR2, FXR1, FXR2, mGLUR5), Huntington's disease (HD, IT15, PRNP, PRIP, JPH3, JP3, HDL2, TBP, SCA17), Parkinson's disease (NR4A2, NURR1, NOT, TINUR, SNCAIP, TBP, SCA17, SNCA, NACP, PARK1, PARK4, DJ1, DBH, NDUFV2), Rett syndrome (MECP2, RTT, PPMX, MRX16, MRX79, CDKL5, STK9), schizophrenia (GSK3, 5-HTT, COMT, DRD, SLC6A3, DAOA, DTNBP1), secretase-related disorders (APH-1), etc.

[0075] (5) Eye diseases: macular degeneration (Abcr, Ccl2, cp, Timp3, カテプシンD, Vld lr, Ccr2), cataract (CRYAA, CRYA1, CRYBB2, CRYB2, PITX3, B FSP2, CP49, CP47, PAX6, AN2, MGDA, CRYBA1, CRYB1, CR YGC, CRYG3, CCL, LIM2, MP19, CRYGD, CRYG4, BSFP2, CP4 9. CP47, HSF4, CTM, MIP, AQP0, CRYAB, CRYA2, CTPP2, CRYBB1, CRYGD, CRYG4, CRYA1, GJA8, CX50, CAE1, GJA3, CX46, CZP3, CAE3, CCM1, CAM, KRIT1), corneal turbidity (APOA1, TGFFB1, CSD2, CDGG1, CSD, BIGH3, CDG2, TASTD2, TROP2, M1S) 1. VSX1, RIX, PPCD, PPD, KTCN, COL8A2, FECD, PPCD2, PIP5K3, CFD), congenital hereditary flat cornea (KERA, CNA2), green cataract (MYOC, TIGR, GLC1A, JOAG, GPOA, OPTN, GLC1E, FIP2, HYPL, NRP, CYP1B1, GLC3A, OPA1, NTG, NPG, CYP1B1, GLC3A), leaver Congenital agrarian syndrome (CRB1, RP12, CRX, CORD2, CRD, RPGRIP1, LCA6, C ORD9, RPE65, RP20, AIPL1, LCA4, GUCY2D, GUC2D, LCA1, CORD6、RDH12、LCA3)、Macula ジストロフCー(ELOVL4、ADMD、STGD2 , STGD3, RDS, RP7, PRPH2, PRPH, AVMD, AOFMD, VMD2)なI.

[0076] (6) Neoplastic diseases: malignant tumors, neovascular glaucoma, infantile hemangioma, hereditary angioedema, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of breast cancer, etc., cancer (e.g., colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, etc.), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma, etc.), breast Cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor, etc.), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), liver cancer (e.g., primary liver cancer, extrahepatic cholangiocarcinoma, etc.), thyroid cancer (e.g., medullary thyroid carcinoma, etc.), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter, etc.), uterine cancer, brain tumor (e.g., pineal astrocytic tumor) (Piliocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, etc.), melanoma, sarcoma, bladder cancer, hematological cancers including multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinal sarcoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, ureteral cancer, testicular tumor, vulvar cancer, cervical cancer, uterine body cancer, uterine sarcoma, gestational trophoblastic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumor, soft tissue sarcoma, malignant lymphoma Hodgkin's disease, myelodysplastic syndrome, adult T-cell leukemia, chronic myeloproliferative disorders, pancreatic endocrine tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary origin, etc.), leukemia (e.g., acute leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, etc.), chronic leukemia (e.g., chronic lymphoblastic leukemia, chronic myeloid leukemia, etc.), myeloplastic syndromes, etc.), uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma, endometrial stromal tumor, etc.), myelofibrosis, etc.

[0077] (7) Other diseases: IgA nephropathy, aplastic anemia, sarcoidosis, Williams syndrome, Marfan syndrome, muscular dystrophy, spinocerebellar degeneration, hypoparathyroidism, pemphigus, bullous pemphigoid, amyotrophic lateral sclerosis, spina bifida, hypertrophic cardiomyopathy, idiopathic thrombocytopenic purpura, ankylosing spondylitis, osteomalacia, dermatomyositis, IgG4-related disease, Usher syndrome, Apert syndrome, Alport syndrome, Angelman syndrome, West syndrome, spinal muscular atrophy, Werner syndrome, Osler disease, Crouzon syndrome, Creutzfeldt-Jakob disease, POEMS syndrome Group, prion disease, Shy-Drager syndrome, Charcot-Marie-Tooth disease, Sturge-Weber syndrome, Stevens-Johnson syndrome, SMON, Sotos syndrome, Dravet syndrome, Noonan syndrome, Buerger disease, Hirschsprung's disease, Pfeiffer syndrome, Tetralogy of Fallot, phenylketonuria, Prader-Willi syndrome, porphyria, mitochondrial disease, maple syrup urine disease, familial hypercholesterolemia, familial Mediterranean fever, Kabuki syndrome, fulminant hepatitis, tuberous sclerosis, polyarteritis nodosa, thrombotic thrombocytopenic purpura, microscopic Polyangiitis, primary sclerosing cholangitis, primary biliary cholangitis, eosinophilic sinusitis, Takayasu's arteritis, osteogenesis imperfecta, mixed connective tissue disease, neuromyelitis optica, autoimmune hepatitis, autoimmune hemolytic anemia, xeroderma pigmentosum, progressive supranuclear palsy, adult Still's disease, syringomyelia, congenital myopathy, systemic sclerosis, multiple system atrophy, aortitis syndrome, corticobasal degeneration, biliary atresia, fatal familial insomnia, toxic epidermal necrolysis, idiopathic interstitial pneumonia, achondroplasia, pustular psoriasis, pulmonary arterial hypertension, inclusion body myositis, chronic inflammatory demyelinating polyneuropathy, chronic active EB virus infection, Retinitis pigmentosa, Cushing's disease, familial chronic pyoderma, autosomal dominant polycystic kidney disease, 1p36 deletion syndrome, 22q11.2 deletion syndrome, HTLV-1 associated myelopathy, Aicardi syndrome, Weaver syndrome, granulomatosis with polyangiitis, Ehlers-Danlos syndrome, Emanuel syndrome, Klippel-Trenaunay-Weber syndrome, Cockayne syndrome, Costello syndrome, Coffin-Siris syndrome, Coffin-Lowry syndrome, Smith-Maginis syndrome, thanatophoric dysplasia, Tangier disease, CHARGE syndrome, Budd-Chiari syndrome, peroxisomal disease,Myoclonic absence epilepsy, Moebius syndrome, Menkes disease, lymphangioleiomyomatosis, Rubinstein-Taybe syndrome, Leber's hereditary optic neuropathy, subacute sclerosing panencephalitis, ossification of the ligamentum flavum, familial benign chronic pemphigus, oculocutaneous albinism, giant cell arteritis, ossification of the posterior longitudinal ligament, extensive spinal stenosis, hypertrichosis IgD syndrome, relapsing polychondritis, tricuspid atresia, congenital ichthyosis, polysplenia syndrome, pseudoxanthoma elastica, delayed endolymphatic hydrops, Nakajo-Nishimura syndrome, hypophosphatasia, idiopathic portal hypertension, Nasu-Hakola disease, refractory frequent partial seizure status epilepticus, urea cycle disorders, pulmonary alveolar proteinosis, paroxysmal nocturnal hemoglobinuria, hypertrophic dermatoperiosteopathy, bronchiolitis obliterans Arima syndrome, status epilepticus (biphasic) acute encephalopathy, Epstein syndrome, Fanconi anemia, 4p deletion syndrome, 5p deletion syndrome, Ulrich disease, Occipital-Horn syndrome, Carney complex, galactose-1-phosphate uridyltransferase deficiency, Galloway-Mowat syndrome, Mowat-Wilson syndrome, Young-Simpson syndrome, Landau-Kleffner syndrome, Rossmund-Thomson syndrome, suppurative aseptic arthritis, pyoderma gangrenosum, acne syndrome, interstitial cystitis, megalymphatic malformation, eosinophilic granulomatosis with polyangiitis, autoimmune hemorrhagic disease XIII, congenital erythrodysplasia anemia, septal optic nerve malformation, branchio-otorenephrosis, etc.

[0078] The compositions of the present invention as pharmaceuticals can be manufactured by methods known in the pharmaceutical technology field using pharmaceutically acceptable carriers. Examples of dosage forms of the above pharmaceuticals include parenteral formulations (e.g., liquid formulations such as injections) containing conventional adjuvants such as buffers and / or stabilizers, and topical formulations such as ointments, creams, liquids, or plasters containing conventional pharmaceutical carriers.

[0079] The compositions of the present invention can be used to introduce active ingredients into a wide variety of cells, tissues, or organs. Examples of cells to which the compositions of the present invention can be applied include spleen cells, nerve cells, glial cells, pancreatic B cells, bone marrow cells, mesangial cells, Langerhans cells, epidermal cells, epithelial cells, endothelial cells, fibroblasts, fibrous cells, muscle cells (e.g., skeletal muscle cells, cardiomyocytes, myoblasts, muscle satellite cells), adipocytes, immune cells (e.g., macrophages, T cells, B cells, natural killer cells, mast cells, neutrophils, basophils, eosinophils, monocytes, megakaryocytes), synovial cells, chondrocytes, osteocytes, osteoblasts, osteoclasts, mammary gland cells, hepatocytes or stromal cells, egg cells, spermatocytes, or progenitor cells that can be differentiated into these cells, stem cells (e.g., induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells)), hematopoietic cells, oocytes, and fertilized eggs. Furthermore, tissues or organs to which the composition of the present invention can be applied include any tissue or organ in which the above-mentioned cells exist, such as the brain, various parts of the brain (e.g., olfactory bulb, amygdala, basal ganglia, hippocampus, thalamus, hypothalamus, subthalamic nucleus, cerebral cortex, medulla oblongata, cerebellum, occipital lobe, frontal lobe, temporal lobe, putamen, caudate nucleus, corpus callosum, substantia nigra), spinal cord, pituitary gland, stomach, pancreas, kidney, liver, gonads, thyroid gland, gallbladder, bone marrow, adrenal gland, skin, muscle, lung, digestive tract (e.g., large intestine, small intestine), blood vessels, heart, thymus, spleen, submandibular gland, peripheral blood, peripheral blood cells, prostate, testes, ovaries, placenta, uterus, bone, joints, and skeletal muscle. These cells, tissues, or organs may also be cancerous cancer cells or cancerous tissue.

[0080] The compounds, lipid particles, and compositions of the present invention are stable, low-toxicity, and safe to use. When the compositions of the present invention are used in vivo or as pharmaceuticals, the compositions should be administered to the target subject (e.g., humans or non-human mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys) (preferably humans)) in such a manner that an effective amount of nucleic acid is delivered to the target cells.

[0081] When the composition of the present invention is used in vivo or as a pharmaceutical, it can be safely administered orally or parenterally (e.g., topically, rectally, intravenously, etc.) by forming pharmaceutical preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, and orally disintegrating tablets), powders, granules, capsules (including soft capsules and microcapsules), liquids, lozenges, syrups, emulsions, suspensions, injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), topical preparations (e.g., nasal administration preparations, transdermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and intravenous infusions. These preparations may also be controlled-release formulations such as immediate-release formulations or sustained-release formulations (e.g., sustained-release microcapsules).

[0082] The method for producing the compound of the present invention will be described below.

[0083] The raw materials and reagents used in each step of the following manufacturing method, as well as the resulting compounds, may each form salts. Examples of such salts include those similar to those found in the compounds of the present invention described above.

[0084] If the compounds obtained in each step are free compounds, they can be converted to the desired salt by known methods. Conversely, if the compounds obtained in each step are salts, they can be converted to free compounds or other types of salts of the desired type by known methods.

[0085] The compounds obtained in each step can be used in subsequent reactions as reaction solutions or as crude products. Alternatively, the compounds obtained in each step can be isolated and / or purified from the reaction mixture by conventional methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and chromatography.

[0086] If the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as is.

[0087] In each step of the reaction, the reaction time may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 minute to 72 hours, preferably 10 minutes to 48 hours.

[0088] In the reaction of each step, the reaction temperature may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually -78°C to 300°C, preferably -78°C to 150°C.

[0089] In each step of the reaction, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually between 1 atmosphere and 20 atmospheres, preferably between 1 atmosphere and 3 atmospheres.

[0090] In the reactions of each step, a Microwave synthesis apparatus such as a Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually room temperature to 300°C, preferably room temperature to 250°C, and more preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0091] In each step of the reaction, unless otherwise specified, 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, of the reagent are used relative to the substrate. When the reagent is used as a catalyst, 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, of the reagent are used relative to the substrate. When the reagent also acts as the reaction solvent, the amount of the reagent equal to the solvent is used.

[0092] Unless otherwise specified, the reactions in each step are carried out without a solvent, or by dissolving or suspending the product in a suitable solvent. Specific examples of solvents include those described in the examples, or the following:

[0093] Alcohols: methanol, ethanol, isopropanol, isobutanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, heptane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water. The above solvents may be mixed in appropriate proportions of two or more types.

[0094] When a base is used in the reaction of each step, for example, the bases shown below, or the bases described in the examples, may be used.

[0095] Inorganic bases: sodium hydroxide, potassium hydroxide, magnesium hydroxide, etc.; Basic salts: sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, sec-butyllithium, etc.

[0096] When an acid or acidic catalyst is used in the reaction of each step, for example, the acids and acidic catalysts shown below, or the acids and acidic catalysts described in the examples, may be used.

[0097] Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0098] Unless otherwise specified, the reactions in each step are based on known methods, e.g., the 5th edition of the Experimental Chemistry Course, Volumes 13-19 (edited by the Chemical Society of Japan); the New Experimental Chemistry Course, Volumes 14-15 (edited by the Chemical Society of Japan); the Revised 2nd Edition of Precision Organic Chemistry (L. F. Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Chemistry The process is carried out according to the methods described in Procedures (by Jie Jack Li, published by Oxford University); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (supervised translation by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or according to the methods described in the examples.

[0099] In each step, the functional group protection or deprotection reaction is carried out according to known methods, such as those described in "Protective Groups in Organic Synthesis, 4th Edition" (Theodora W. Greene, Peter G. M. Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Edition" (P.J. Kocienski), published by Thiemé in 2004; or according to the methods described in the examples.

[0100] Examples of protecting groups for hydroxyl groups of alcohols and other substances, or phenolic hydroxyl groups, include ether-type protecting groups such as methoxymethyl ether, benzyl ether, p-methoxybenzyl ether, t-butyldimethylsilyl ether, t-butyldiphenylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate esters; sulfonic acid ester-type protecting groups such as methanesulfonic acid esters; and carbonate ester-type protecting groups such as t-butyl carbonate.

[0101] Examples of protecting groups for the carbonyl group of aldehydes include acetal-type protecting groups such as dimethyl acetal, and cyclic acetal-type protecting groups such as cyclic 1,3-dioxane.

[0102] Examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as cyclic 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone.

[0103] Examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl esters and benzyl esters; and amide-type protecting groups such as N,N-dimethylamide.

[0104] Examples of thiol protecting groups include ether-type protecting groups such as benzyl thioether, and ester-type protecting groups such as thioacetic acid esters, thiocarbonates, and thiocarbamates.

[0105] Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide.

[0106] Deprotection of protecting groups can be carried out using known methods, such as methods using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or reduction methods.

[0107] When reduction reactions are carried out in each step, the reducing agents used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyboron hydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and triacetoxyboron tetramethylammonium hydride; boranes such as boranetetrahydrofuran complexes; Raney nickel; Raney cobalt; hydrogen; and formic acid. In addition, catalysts such as palladium-carbon, Raney nickel, and Raney cobalt can be used in the presence of hydrogen or formic acid.

[0108] When oxidation reactions are carried out in each step, the oxidizing agents used include peracids such as m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, and t-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complexes; osmium tetroxide; zelen dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0109] When radical cyclization reactions are carried out in each step, the radical initiators used include azo compounds such as azobisisobutyronitrile (AIBN); water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA); triethylboron in the presence of air or oxygen; and benzoyl peroxide. In addition, the radical reaction reagents used include tributylstananne, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

[0110] When Wittig reactions are performed in each step, examples of Wittig reagents used include alkylidene phosphoranes. Alkylidene phosphoranes can be prepared by known methods, for example, by reacting a phosphonium salt with a strong base.

[0111] When carrying out the Horner-Emmons reaction in each step, the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0112] When carrying out the Friedel-Crafts reaction in each step, the reagents used include Lewis acids and acid chlorides or alkylating agents (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, organic or inorganic acids can be used instead of Lewis acids, and acid anhydrides such as acetic anhydride can be used instead of acid chlorides.

[0113] In each step of an aromatic nucleophilic substitution reaction, the reagents used are a nucleophile (e.g., amines, imidazoles, etc.) and a base (e.g., basic salts, organic bases, etc.).

[0114] In each step, when a nucleophilic addition reaction using a carbanion, a nucleophilic 1,4-addition reaction using a carbanion (Michael addition reaction), or a nucleophilic substitution reaction using a carbanion is performed, the bases used to generate the carbanion include organolithium compounds, metal alkoxides, inorganic bases, and organic bases.

[0115] When the Grignard reaction is carried out in each step, Grignard reagents include aryl magnesium halides such as phenylmagnesium bromide; and alkylmagnesium halides such as methylmagnesium bromide and isopropylmagnesium bromide. Grignard reagents can be prepared by known methods, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0116] In each step of the Knoevenagel condensation reaction, the reagents used are an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases).

[0117] In each step of the process, when performing the Vilsmeier-Haack reaction, phosphoryl chloride and amide derivatives (e.g., N,N-dimethylformamide) are used as reagents.

[0118] In each step of the process, when carrying out azidation reactions of alcohols, alkyl halides, and sulfonic acid esters, examples of azidating agents used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide. For example, when azidating alcohols, methods include using diphenylphosphoryl azide and 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), or using trimethylsilyl azide and a Lewis acid.

[0119] When reductive amination reactions are carried out in each step, the reducing agents used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, and formic acid. When the substrate is an amine compound, the carbonyl compounds used include paraformaldehyde, as well as aldehydes such as acetaldehyde and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines used include primary amines such as ammonia and methylamine, and secondary amines such as dimethylamine.

[0120] In each step of the process, when the Mitsunobu reaction is carried out, azodicarboxylic acid esters (e.g., diethyl azodicarboxylic acid (DEAD), diisopropyl azodicarboxylic acid (DIAD), etc.) and triphenylphosphine are used as reagents.

[0121] When esterification, amidation, or urea formation reactions are carried out in each step, the reagents used include acyl halogenated compounds such as esters, acid chlorides, and acid bromides; and activated carboxylic acids such as acid anhydrides, activated esters, and sulfated esters. Examples of carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and N,N'-dicyclohexylcarbodiimide (DCC); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate ester-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl phosphate azide (DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukoyama reagent); thionyl chloride; lower alkyl halomates such as ethyl chloroformate; and O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium Examples include hexafluorophosphate (HATU); sulfuric acid; or combinations thereof. Additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be added to the reaction.

[0122] When coupling reactions are carried out in each step, the metal catalysts used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(O), 1,1'-bis(diphenylphosphineno)ferrocenepalladium(II) chloride, and palladium(II) acetate; nickel compounds such as tetrakis(triphenylphosphine)nickel(O); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. Furthermore, a base may be added to the reaction, and examples of such bases include inorganic bases and basic salts.

[0123] In each step of the process, when a thiocarbonylation reaction is carried out, phosphorus pentasulfide is typically used as the thiocarbonylating agent. However, in addition to phosphorus pentasulfide, reagents having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lowesson reagent), may also be used.

[0124] When the Whl-Ziegler reaction is carried out in each step, halogenating agents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and sulfuryl chloride. Furthermore, the reaction can be accelerated by adding heat, light, or radical initiators such as benzoyl peroxide and azobisisobutyronitrile to the reaction.

[0125] In each step of the halogenation reaction, the halogenating agents used include halogens, hydrohalic acids, and acid halides of inorganic acids. Specifically, for chlorination, examples include chlorine, hydrochloric acid, thionyl chloride, and phosphorus oxychloride; for bromination, examples include bromine, 48% hydrobromic acid, or combinations thereof. Alternatively, a method may be used to obtain alkyl halides from alcohols by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide. Or, a method may be used to synthesize alkyl halides through a two-step reaction in which the alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0126] When carrying out the Arbuzov reaction in each step, the reagents used include alkyl halides such as ethyl bromoacetate, and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0127] When sulfonation reactions are carried out in each step, examples of sulfonating agents that can be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and trifluoromethanesulfonic anhydride.

[0128] In each step of the hydrolysis reaction, an acid or a base is used as the reagent. Furthermore, when performing acid hydrolysis of t-butyl esters, formic acid or triethylsilane may be added to reductively trap the by-product t-butyl cation.

[0129] When a dehydration reaction is carried out in each step, examples of dehydrating agents that can be used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, and polyphosphate.

[0130] When a decarboxylation reaction is carried out in each step, an acid may be used. Examples of acids include inorganic acids and organic acids.

[0131] When nucleophilic substitution reactions are carried out in each step, a base may be used. Examples of bases include metal alkoxides, inorganic bases, and organic bases.

[0132] Compound (I) can be produced, for example, by the following method. In this invention, particularly during esterification, it is possible to synthesize compound (I) with a desired structure by using appropriate raw materials according to the structure of the target compound (I). Furthermore, salts of compound (I) can be obtained by appropriate mixing with inorganic bases, organic bases, organic acids, or basic or acidic amino acids.

[0133] Scheme 1 below shows an example of the preparation method for compound (I). In Scheme 1, P １ represents a protecting group, and the other symbols are the same as in formula (I) (and the same in other schemes related to scheme 1). Also, in scheme 1, L represents a leaving group, and R Ａ , R Ｂ and R Ｃ These can be interchanged as appropriate.

[0134]

[0135] Scheme 2 below shows the R of compound (I) in Scheme 1. Ａ and / or R Ｂ However, R Ａ／Ｂ Group 1 (C may be replaced) １～１７ Alkyl alkyl groups, optionally substituted C ３～１７ Alkenyl group, may be substituted C １５～１７ If it is an alkadienyl group, that is, R Ａ and / or R Ｂ However, R expressed in equation (II) or equation (III) Ａ１ and / or R Ｂ１ The compound used for esterification in this case (R Ａ１ or R Ｂ１ The synthesis method for -COOH) is shown. In scheme 2, P ２ , P ３ , P ４ and P ５ represents a protecting group, R ａ , R ｂ , Rｃ , R ｄ and R ｇ R represents H, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkadienyl group. Ａ and / or R Ｂ It constitutes a part of R. ａ , R ｂ , R ｃ , R ｄ and R ｇ The number of carbon atoms, substituents, and structure are as per the target R Ａ and / or R Ｂ It is adjusted as needed to match the structure.

[0136]

[0137] Scheme 3 below shows the R of compound (I) in Scheme 1. Ａ and / or R Ｂ However, R Ａ／Ｂ Group 2: -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ ) if R Ａ and / or R Ｂ However, R expressed in equation (II) or equation (III) Ａ２ and / or R Ｂ２ The compound used for esterification in this case (R Ａ２ or R Ｂ２ -COOH), and the R of compound (I) Ｃ Compounds used for esterification (R Ｃ The synthesis method for -COOH) is shown. In scheme 3, P ６ , P ７ and P ８ represents a protecting group.

[0138]

[0139] The following scheme 4 shows the compound (R) used for esterification in scheme 3. ５ The synthesis method for -OH) is shown. In scheme 4, P ４ represents a protecting group, R ａ , Rｂ , R ｃ and R ｄ R represents H, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkadienyl group. ５ It constitutes a part of R. ａ , R ｂ , R ｃ and R ｄ The number of carbon atoms, substituents, and structure are as per the target R ５ It is adjusted as needed to match the structure.

[0140]

[0141] The following scheme 5 shows the compound (R) used for esterification in scheme 3. ５ The synthesis method for -COOH) is shown. In scheme 5, P ４ and P ５ R represents a protecting group. ａ , R ｂ , R ｃ and R ｄ R represents H, an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted alkadienyl group. ５ It constitutes a part of R. ａ , R ｂ , R ｃ and R ｄ The number of carbon atoms, substituents, and structure are as per the target R ５ It is adjusted as needed to match the structure.

[0142]

[0143] Scheme 6 below shows the synthesis method for the compound (W-X-COOH) used for esterification in Scheme 1. In Scheme 6, R ｅ represents an alkylene group that may be substituted, L represents a leaving group, and P ９ R represents a protecting group. ｅ The number of carbon atoms, substituents, and structure are adjusted as appropriate to match the desired structure of X.

[0144]

[0145] Hereinafter, a method for producing lipid particles containing the compound of the present invention and a composition for nucleic acid introduction (transfection) containing the lipid particles and a nucleic acid as an active ingredient will be described.

[0146] The lipid particles of the present invention can be produced by mixing the compound of the present invention (compound (I) or a salt thereof) as a cationic lipid with other lipid components if necessary, and then using a known method for preparing lipid particles from the lipid components. For example, the above (mixed) lipid components can be dissolved in an organic solvent, and the resulting organic solvent solution can be mixed with water or a buffer solution (for example, an emulsification method) to produce a lipid particle dispersion. The above mixing can be carried out using a microfluidic mixing system (for example, NanoAssemblr device (Precision NanoSystems)). The obtained lipid particles may be subjected to desalting or dialysis and sterile filtration. Further, pH adjustment and osmotic pressure adjustment may be performed as necessary.

[0147] The compound of the present invention can have a plurality of structures depending on the combination of the definitions of each symbol (substituent, etc.) in formula (I). For the production of lipid particles, as the compound of the present invention, one kind of compound (I) having a specific structure or a salt thereof may be used alone, or a plurality of kinds of compounds (I) or salts thereof having different structures may be mixed and used.

[0148] "Other lipid components" include structural lipids as described above, for example, sterols, phospholipids, and polyethylene glycol lipids. "Other lipid components" are used, for example, in an amount of 0.008 to 4 moles per 1 mole of the compound of the present invention. The compound of the present invention is preferably used by mixing with other lipid components (particularly, cholesterol, phosphatidylcholine, and polyethylene glycol lipid). A preferred embodiment when the compound of the present invention and other lipid components are mixed and used is a mixture of 1 to 4 moles of the compound of the present invention, 0 to 3 moles of sterols, 0 to 2 moles of phospholipids, and 0 to 1 mole of polyethylene glycol lipid. A more preferred embodiment when the compound of the present invention and other lipid components are mixed and used is a mixture of 1 to 1.5 moles of the compound of the present invention, 0 to 1.25 moles of sterols, 0 to 0.5 moles of phospholipids, and 0 to 0.125 moles of polyethylene glycol lipid.

[0149] The concentration of the compound of the present invention in the organic solvent solution described above, or the mixture of the compound of the present invention and other lipid components, is preferably 0.5 to 100 mg / mL.

[0150] Examples of the organic solvent include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tert-butanol, acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or a mixture thereof. The organic solvent may contain 0 to 20% of water or a buffer solution.

[0151] Examples of the buffer solution include acidic buffer solutions (for example, acetate buffer solution, citrate buffer solution, 2-morpholinoethanesulfonic acid (MES) buffer solution, phosphate buffer solution), and neutral buffer solutions (for example, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer solution, tris(hydroxymethyl)aminomethane (Tris) buffer solution, phosphate buffer solution, phosphate buffered saline (PBS)).

[0152] When mixing is performed using a microfluidic mixing system, it is preferable to mix 1 to 5 volumes of water or buffer solution with 1 volume of organic solvent solution. In this system, the flow rate of the mixture (mixture of organic solvent solution and water or buffer solution) is, for example, 0.01 to 20 mL / min, preferably 0.1 to 10 mL / min, and the temperature is, for example, 5 to 60°C, preferably 15 to 45°C.

[0153] The composition of the present invention can be produced as a lipid particle dispersion containing nucleic acids by adding nucleic acids to water or a buffer solution when producing lipid particles or a lipid particle dispersion. It is preferable to add the nucleic acids so that the concentration of nucleic acids in the water or buffer solution is, for example, 0.01 to 20 mg / mL, preferably 0.05 to 2.0 mg / mL.

[0154] Furthermore, the composition of the present invention can also be produced as a lipid particle dispersion containing the active ingredient by mixing lipid particles or a lipid particle dispersion with a nucleic acid or an aqueous solution thereof using a known method. The lipid particle dispersion can be prepared by dispersing lipid particles in a suitable dispersion medium. The aqueous solution of the active ingredient can be prepared by dissolving the active ingredient in a suitable solvent.

[0155] The content of the compound of the present invention in the composition of the present invention, excluding the dispersion medium and solvent, is usually 10 to 70% by weight, preferably 40 to 70% by weight.

[0156] The nucleic acid content in the composition of the present invention, excluding the dispersion medium and solvent, is typically 0.1 to 25% by weight, preferably 1 to 20% by weight.

[0157] The dispersion medium in a lipid particle dispersion or a dispersion containing a composition can be replaced with water or a buffer solution by dialysis. Dialysis is performed using an ultrafiltration membrane with a molecular weight cutoff of 10 to 20 K at 4°C to room temperature. Repeated dialysis may be performed. Tangential flow filtration (TFF) may be used to replace the dispersion medium. After replacing the dispersion medium, pH and osmotic pressure adjustments may be performed as needed. Examples of pH adjusting agents include sodium hydroxide, citric acid, acetic acid, triethanolamine, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate. Examples of osmotic pressure adjusting agents include inorganic salts such as sodium chloride, potassium chloride, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; polyols such as glycerol, mannitol, and sorbitol; and sugars such as glucose, fructose, lactose, and sucrose. The pH is usually adjusted to 6.5 to 8.0, preferably 7.0 to 7.8. The osmotic pressure is preferably adjusted to 250-350 Osm / kg.

[0158] The composition of the present invention may optionally contain components other than lipid particles and nucleic acids. Examples of such components include appropriate amounts of stabilizers and antioxidants.

[0159] Stabilizers are not particularly limited, but examples include sugars such as glycerol, mannitol, sorbitol, lactose, or sucrose.

[0160] Examples of antioxidants include ascorbic acid, uric acid, cysteine, tocopherol congeners (such as vitamin E and the four isomers of tocopherol α, β, γ, and δ), EDTA, and cysteine.

[0161] The following describes a method for analyzing lipid particles containing the compound of the present invention, and a composition containing said lipid particles and nucleic acids as active ingredients.

[0162] The particle size of lipid particles (in the composition) can be measured by known means. For example, it can be calculated as the Z-average particle size by cumulant analysis of the autocorrelation function using a particle size measuring device based on dynamic light scattering measurement technology, such as the Zetasizer Nano ZS (Malvern Instruments). The particle size (average particle size) of lipid particles (in the composition) is, for example, 10 to 200 nm, preferably 60 to 170 nm.

[0163] The concentration and encapsulation rate of nucleic acids (e.g., siRNA, mRNA) in the composition of the present invention can be measured by known means. For example, Quant-iT ＴＭ The concentration and encapsulation rate can be determined by fluorescently labeling nucleic acids with RiboGreen® (Invitrogen) and measuring the fluorescence intensity. The concentration of nucleic acids in the composition can be calculated using a standard curve created from nucleic acid aqueous solutions of known concentrations, and the encapsulation rate can be calculated based on the difference in fluorescence intensity with or without the addition of Triton-X100 (a surfactant for disintegrating lipid particles). The concentration of nucleic acids in the composition refers to the total concentration of nucleic acids encapsulated in lipid particles and those not encapsulated, while the encapsulation rate refers to the proportion of the total nucleic acids in the composition that are encapsulated in lipid particles.

[0164] The present invention will be further described in detail by the following examples, manufacturing examples, and test examples, which are not intended to limit the present invention and may be modified without departing from the scope of the present invention.

[0165] １ 1H NMR was measured using Fourier transform NMR. １ For 1H NMR analysis, software such as ACD / SpecManager (product name) was used. Proton peaks that are very gradual, such as those of hydroxyl groups and amino groups, may not be included in the description.

[0166] ​MS measurements were performed using LC / MS, HRMS, or MALDI / TOFMS. ESI, APCI, or MALDI ionization methods were used. The data recorded are the measured values ​​(found). Typically, molecular ion peaks are observed, but sometimes polyvalent ions or fragment ions are observed. In the case of salts, typically, molecular ion peaks of the free form, cation species, anionic species, or fragment ion peaks are observed.

[0167] The following abbreviations are used in the following examples: MS: Mass spectrum M: Molar concentration N: Normality CDCl ３ Deuterated chloroform DMSO-d ６ : Dimethyl sulfoxide １ ¹H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatography-mass spectrometry HRMS: High-resolution mass spectrometry ESI: Electrospray ionization APCI: Atmospheric pressure chemical ionization MALDI: Matrix-assisted laser desorption / ionization TOFMS: Time-of-flight mass spectrometry DCM: Dichloromethane DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide THF: Tetrahydrofuran MeOH: Methanol EtOH: Ethanol DMAP: 4-Dimethylaminopyridine TBAF: Tetrabutylammonium fluoride EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride DCC: N,N'-Dicyclohexylcarbodiimide HOBt: 1-hydroxybenzotriazole

[0168] Compounds of Examples 1 to 51 shown in Table 1 below were prepared according to the manufacturing methods described herein. More specific manufacturing methods for Examples 1, 2, 15, 33, and 49 are shown below.

[0169]

[0170] [Example 1] Dibutyl 10-[({4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoyl}oxy)methyl]-10-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-3,8,12,17-tetraoxanonadecane-1,19-geoate

[0171] A) Butyl 2-hydroxyoctanoate: 1-bromobutane (4.0 g) and potassium carbonate (863 mg) were added to a mixture of 2-hydroxyoctanoic acid (500 mg) and DMF (800 mL) at room temperature, and the mixture was stirred at 60°C for 18 hours. Water was added to the mixture, and it was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (515 mg). 1 H NMR (400 MHz, CDCl3) δ 5.26 (d, J=6.0 Hz, 1H), 4.16 - 3.91 (m, 3H), 1.68 - 1.42 (m, 4H), 1.38 - 1.18 (m, 10H), 0.95 - 0.80 (m, 6H).

[0172] B) 4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoic acid A mixture of butyl 2-hydroxyoctanoate (500 mg) and pyridine (10 mL) was mixed with DMAP (28 mg) and succinic anhydride (694 mg) at room temperature and stirred for 18 hours. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (498 mg). 1H NMR (400 MHz, CDCl3) δ 12.24 (br s, 1H), 4.88 (t, J=6.4 Hz, 1H), 4.16 - 3.98 (m, 2H), 2.69 - 2.53 (m, 2H), 2.49 - 2.43 (m, 2H), 1.81 - 1.67 (m, 2H), 1.61 - 1.47 (m, 2H), 1.41 - 1.19 (m, 10H), 0.94 - 0.79 (m, 6H).

[0173] C) 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(hydroxymethyl)propane-1,3-diol A mixture of 2,2-bis(hydroxymethyl)propane-1,3-diol (49.5 g), triethylamine (36.8 g), and DMA (300 mL) was stirred at room temperature, and a mixture of tert-butyldiphenylchlorosilane (50 g) and DMA (200 mL) was added dropwise over 1 hour. After 6 hours, ethyl acetate, water, and heptane were added to the mixture and stirred for 10 minutes. The mixture was separated into an aqueous layer (A) and an organic layer (B). Layer A was extracted with a mixed solvent of ethyl acetate and heptane, washed with 20% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution, saturated saline solution, and water, and then concentrated under reduced pressure (C). B was extracted with a mixed solvent of water and DMA, and the resulting aqueous layer was extracted with a mixed solvent of ethyl acetate and heptane. The resulting solution was then washed with 20% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution, saturated brine, and water, and concentrated under reduced pressure (D). C and D were mixed to obtain the title compound (78 g). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (dd, J=1.3, 7.8 Hz, 4H), 7.50 - 7.38 (m, 6H), 3.75 (s, 6H), 3.67 (s, 2H), 2.46 - 2.24 (br s, 3H), 1.08 (s, 9H).

[0174] D) 10-[({4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoyl}oxy)methyl]-10-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dihydroxy 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(hydroxymethyl)propane-1,3-diol (500 mg), 4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoic acid (1.48 g), and DMF (10 mL) were mixed with EDCI (896 mg) and DMAP (33 mg) at room temperature and stirred for 2 hours. After adding water to the mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.1 g). 1 H NMR (400 MHz, CDCl3) δ 7.55 - 7.53 (m, 4 H), 7.36 - 7.30 (m, 6 H), 4.93 - 4.89 (m, 3 H), 4.11 - 4.03 (m, 12 H), 3.54 (s, 2 H), 2.65 - 2.50 (m, 12 H), 1.80 - 1.74 (m, 6 H) 1.54 - 1.45 (m, 6 H), 1.43 - 1.28 (m, 30 H), 0.96 (s, 9 H), 0.88 - 0.81 (m, 18 H).

[0175] E) 10-[({4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoyl}oxy)methyl]-2,18-dihexyl-10-(hydroxymethyl)-4,7,13,16-tetraoxo-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dihydroxy acid 10-[({4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoyl}oxy)methyl]-10-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dibutyl acid (1.0 g) and THF (10 mL) were mixed with acetic acid (0.14 mL) and a THF solution of TBAF (1 M, 1.58 mL), and the mixture was stirred at room temperature for 12 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (450 mg). 1 H NMR (400 MHz, CDCl3) δ 5.04 - 4.98 (m, 3 H), 4.20 - 4.11 (m, 12 H), 3.57 (s, 2 H), 2.74 - 2.66 (m, 12 H), 1.82 - 1.73 (m, 6 H), 1.68 - 1.60 (m, 6 H), 1.43 - 1.28 (m, 30 H), 0.96 - 0.88 (m, 18 H).

[0176] F) Dibutyl 10-[({4-[(1-butoxy-1-oxooctan-2-yl)oxy]-4-oxobutanoyl}oxy)methyl]-10-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-3,8,12,17-tetraoxanonadecane-1,19-dioate 4-(dimethylamino)butanoic acid hydrochloride (147 mg), 10-[({4-[(1-butoxy-1-oxooctan-2-yl)oxy]-4-oxobutanoyl}oxy)methyl]-2,18-dihexyl-10-(hydroxymethyl)-4,7,13,16-tetraoxo-3,8,12,17-tetraoxanonadecane-1,19-dioic acid dibutyl (450 mg) and a mixture of DMF (5 mL), EDCI (209 mg) and DMAP (27 mg) were added and stirred at room temperature for 15 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (312 mg). 1 H NMR (400 MHz, CDCl3) δ 4.99 (t, J=6.30 Hz, 3 H), 4.21 - 4.09 (m, 14 H), 2.77 - 2.60 (m, 12 H), 2.59 - 2.46 (m, 2 H), 2.43 - 2.36 (m, 8 H), 1.94 - 1.79 (m, 8 H), 1.69 - 1.58 (m, 6 H), 1.45 - 1.27 (m, 30 H), 0.99 - 0.87 (m, 18 H). MS: [M+H] + 1144.7.

[0177] [Example 2] Dibutyl 10-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-10-{[(3-pentyloctanoyl)oxy]methyl}-3,8,12,17-tetraoxanonadecane-1,19-dioate

[0178] A) 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxy-2-(hydroxymethyl)propyl 3-pentyloctanoate: 3-pentyloctanoic acid (3.43 g) and DMF (100 mL) were mixed with EDCI (4.61 g), 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(hydroxymethyl)propane-1,3-diol (10.0 g), and DMAP (815 mg), and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate / petroleum ether. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (3.9 g). 1H NMR (400 MHz, CDCl3) δ 7.70 - 7.60 (m, 4H), 7.49 - 7.37 (m, 6H), 4.26 (s, 2H), 3.73 - 3.52 (m, 6H), 2.23 (d, J=6.8 Hz, 2H), 1.85 - 1.75 (m, 1H), 1.35 - 1.17 (m, 16H), 1.07 (s, 9H), 0.87 (t, J=7.0 Hz, 6H).

[0179] B) 10-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-10-{[(3-pentyloctanoyl)oxy]methyl}-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dihydroxy 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxy-2-(hydroxymethyl)propyl 3-pentyloctanoate (500 mg), 4-[(1-butoxy-1-oxooctane-2-yl)oxy]-4-oxobutanoic acid (720 mg) and DMF (5 mL) were mixed with EDCI (420 mg) and DMAP (32 mg) at room temperature and stirred for 3 hours. After adding water to the mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (940 mg). 1H NMR (400 MHz, CDCl3) δ 7.67 - 7.58 (m, 4 H), 7.49 - 7.36 (m, 6 H), 5.01 (t, J=6.32 Hz, 2 H), 4.22 - 4.07 (m, 10 H), 3.64 (s, 2 H), 2.75 - 2.51 (m, 8 H), 2.21 (d, J=6.88 Hz, 2 H) 1.89 - 1.78 (m, 5 H), 1.69 - 1.60 (m, 4 H), 1.45 - 1.24 (m, 36 H), 1.06 (s, 9 H), 0.97 - 0.87 (m, 18 H).

[0180] C) 2,18-dihexyl-10-(hydroxymethyl)-4,7,13,16-tetraoxo-10-{[(3-pentyloctanoyl)oxy]methyl}-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dibutyl dioxide (772 mg) and THF (8 mL) were mixed with acetic acid (119 mg) and a THF solution of TBAF (1 M, 1.32 mL), and the mixture was stirred at room temperature for 12 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (340 mg). 1 H NMR (400 MHz, CDCl3) δ 5.01 (t, J=6.32 Hz, 2 H), 4.28 - 4.07 (m, 10 H), 3.54 (s, 2 H), 2.80 - 2.60 (m, 8 H), 2.28 (d, J=6.88 Hz, 2 H), 1.92 - 1.77 (m, 5 H), 1.69 - 1.59 (m, 4 H), 1.44 - 1.22 (m, 36 H), 1.01 - 0.83 (m, 18 H).

[0181] D) Dibutyl 10-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,18-dihexyl-4,7,13,16-tetraoxo-10-{[(3-pentyloctanoyl)oxy]methyl}-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dibutyl 4-(dimethylamino)butyrate (91 mg), 2,18-dihexyl-10-(hydroxymethyl)-4,7,13,16-tetraoxo-10-{[(3-pentyloctanoyl)oxy]methyl}-3,8,12,17-tetraoxanonadecane-1,19-dibutyl dibutyl dibutyl (250 mg) and DMF (5 mL) were mixed and stirred at room temperature for 15 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (211 mg). 1 H NMR (400 MHz, CDCl3) δ 5.00 (t, J=6.30 Hz, 2 H), 4.22 - 4.09 (m, 12 H), 2.76 - 2.59 (m, 8 H), 2.49 - 2.27 (m, 10 H), 2.26 (d, J=6.85 Hz, 2 MS: [M+H] + 1042.7.

[0182] [Example 15] Dihexyl 9-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,16-dihexyl-9-{[(3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-geoate

[0183] A) Hexyl 2-hydroxyoctanoate A mixture of 2-hydroxyoctanoic acid (11.5 g) and DMF (120 mL) was mixed with potassium carbonate (19.8 g) and 1-iodohexane (19.8 g) at room temperature and stirred for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (13.3 g). 1 H NMR (400 MHz, CDCl3) δ 4.27 - 4.12 (m, 3H), 2.74 (d, J=5.6 Hz, 1H), 1.85 - 1.73 (m, 1H), 1.72 - 1.56 (m, 3H), 1.52 - 1.22 (m, 14H), 0.95 - 0.83 (m, 6H).

[0184] B) 3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoic acid A mixture of hexyl 2-hydroxyoctanoate (6 g) and toluene (60 mL) was mixed with 2,2-dimethyl-1,3-dioxane-4,6-dione (4.0 g) at room temperature and stirred at 120°C for 16 hours. The mixture was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (6.0 g). 1 H NMR (400 MHz, CDCl3) δ 5.08 (t, J=6.3 Hz, 1H), 4.22 - 4.08 (m, 2H), 3.55 (s, 2H), 1.93 - 1.82 (m, 2H), 1.70 - 1.58 (m, 2H), 1.46 - 1.23 (m, 14H), 0.97 - 0.82 (m, 6H).

[0185] C) 9-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,16-dihexyl-9-{[(3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dioxide A mixture of 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(hydroxymethyl)propane-1,3-diol (500 mg) and DCM (10 mL) was mixed with 3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoic acid (1.6 g) and DCC (1.4 g) at room temperature and stirred for 16 hours. The mixture was filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.58 g). 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.58 (m, 4H), 7.48 - 7.36 (m, 6H), 5.01 (t, J=6.3 Hz, 3H), 4.28 - 4.03 (m, 12H), 3.65 (s, 2H), 3.36 - 3.34 (m, 6H), 1.87 - 1.77 (m, 6H), 1.68 - 1.59 (m, 6H), 1.42 - 1.23 (m, 42H), 1.05 (s, 9H), 0.94 - 0.83 (m, 18H).

[0186] D) 2,16-dihexyl-9-{[(3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-9-(hydroxymethyl)-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dioxide 9-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,16-dihexyl-9-{[(3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dihydroxy acid (1.4 g) and THF (30 mL) were mixed with acetic acid (127 mg) and a THF solution of TBAF (1 M, 2.7 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (559 mg). 1 H NMR (400 MHz, CDCl3) δ 5.03 (t, J=6.3 Hz, 3H), 4.26 - 4.08 (m, 12H), 3.60 (br s, 2H), 3.50 (s, 6H), 2.86 (br s, 1H), 1.90 - 1.78 (m, 6H), 1.70 - 1.59 (m, 6H), 1.44 - 1.24 (m, 42H), 0.95 - 0.82 (m, 18H).

[0187] E) Dihexyl 9-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,16-dihexyl-9-{[(3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-geoate 2,16-Dihexyl-9-{[(3-{[1-(hexyloxy)-1-oxooctane-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-9-(hydroxymethyl)-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dihexyl acid (180 mg) and DMF (2 mL) were mixed with 4-(dimethylamino)butyrate (56 mg), EDCI (96 mg), and DMAP (12 mg), and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (190 mg). 1 H NMR (400 MHz, CDCl3) δ 5.02 (t, J=6.3 Hz, 3H), 4.28 - 4.06 (m, 14H), 3.49 (s, 6H), 2.97 - 2.15 (m, 10H), 1.98 - 1.79 (m, 8H), 1.71 - 1.64 (m, 3H), 1.64 - 1.57 (m, 3H), 1.44 - 1.25 (m, 42H), 0.95 - 0.84 (m, 18H). MS: [M+H] + 1186.7.

[0188] [Example 33] Dihexyl 9-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,16-diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-geoate

[0189] A) 15 g of 2-bromononanoic acid was stirred at room temperature, and 14.7 g of thionyl chloride was added dropwise, followed by stirring at 80°C for 1 hour. The mixture was cooled to 40°C, 22.7 g of bromine was added dropwise, and the mixture was stirred at 65°C for 15 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (22 g). 1 H NMR (400 MHz, CDCl3) δ 9.24 (br s, 1H), 4.28 - 4.19 (m, 1H), 2.12 - 1.97 (m, 2H), 1.54 - 1.46 (m, 10H), 0.95 - 0.84 (m, 3H).

[0190] B) 2-Hydroxynonanoic acid A mixture of 2-bromonanoic acid (23 g) and aqueous sodium hydroxide solution (2 M, 485 mL) was stirred at 85°C for 16 hours. The mixture was acidified with 1 M hydrochloric acid (pH = 3-4) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (14 g). 1 H NMR (400 MHz, CDCl3) δ 4.35 - 4.20 (m, J = 4.3, 7.5 Hz, 1H), 1.94 - 1.63 (m, 2H), 1.50 - 1.25 (m, 10H), 0.94 - 0.84 (m, 3H).

[0191] C) Hexyl 2-hydroxynonanoate A mixture of 2-hydroxynonanoic acid (13 g), 1-iodohexane (20.6 g), potassium carbonate (20.6 g), and DMF (350 mL) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (16 g). 1H NMR (400 MHz, CDCl3) δ 4.24 - 4.12 (m, 3H), 2.73 (d, J = 5.8 Hz, 1H), 1.85 - 1.58 (m, 4H), 1.48 - 1.25 (m, 16H), 0.90 (q, J = 6.9 Hz, 6H).

[0192] D) 3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoic acid A mixture of hexyl 2-hydroxynonanoate (8.8 g), 2,2-dimethyl-1,3-dioxane-4,6-dione (5.4 g), and toluene (200 mL) was stirred at 120°C for 16 hours. The mixture was concentrated under reduced pressure, poured into water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (4 g). 1 H NMR (400 MHz, CDCl3) δ 5.09 (t, J = 6.3 Hz, 1H), 4.21 - 4.11 (m, 2H), 3.56 (s, 2H), 1.93 - 1.81 (m, 2H), 1.72 - 1.60 (m, 2H), 1.46 - 1.22 (m, 16H), 0.96 - 0.84 (m, 6H).

[0193] E) 9-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,16-diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dioxide To a mixture of 2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(hydroxymethyl)propane-1,3-diol (1.8 g) and DMF (40 mL), EDCI (3.2 g), 3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoic acid (5.8 g) and DMAP (470 mg) were added at room temperature and the mixture was stirred for 12 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (4.05 g). 1 H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 1.5, 7.8 Hz, 4H), 7.48 - 7.34 (m, 6H), 5.01 (t, J = 6.3 Hz, 3H), 4.27 - 4.06 (m, 12H), 3.65 (s, 2H), 3.45 - 3.36 (m, 6H), 1.86 - 1.78 (m, 6H), 1.68 - 1.59 (m, 6H), 1.40 - 1.20 (m, 48H), 1.05 (s, 9H), 0.97 - 0.82 (m, 18H).

[0194] F) 2,16-Diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-9-(hydroxymethyl)-4,6,12,14-Tetraoxo-3,7,11,15-Tetraoxaheptadecane-1,17-Dihexyl dioxide 9-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,16-diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dihexyl acid (4 g) and THF (60 mL) were mixed with acetic acid (355 mg) and a THF solution of TBAF (1 M, 7.4 mL), and the mixture was stirred at room temperature for 12 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.24 g). 1 H NMR (400 MHz, CDCl3) δ 5.03 (t, J = 6.3 Hz, 3H), 4.27 - 4.08 (m, 12H), 3.60 (br s, 2H), 3.50 (s, 6H), 2.89 - 2.80 (m, 1H), 1.90 - 1.79 (m, 6H), 1.70 - 1.61 (m, 6H), 1.41 - 1.20 (m, 48H), 0.96 - 0.77 (m, 18H).

[0195] G) Dihexyl 9-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,16-diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-geoate 2,16-Diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-9-(hydroxymethyl)-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-dihexyl dihexyl acid (600 mg) and DMF (10 mL) were mixed with EDCI (258 mg), 4-(dimethylamino)butyrate (180 mg), and DMAP (33 mg), and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM) to obtain the title compound (530 mg). 1 H NMR (400 MHz, CDCl3) δ 5.01 (t, J = 6.3 Hz, 3H), 4.22 (s, 6H), 4.18 - 4.05 (m, 8H), 3.48 (s, 6H), 2.54 - 2.29 (m, 10H), 1.94 - 1.77 (m, 8H), 1.68 - 1.56 (m, 6H), 1.41 - 1.20 (m, 48H), 0.98 - 0.77 (m, 18H). MS: [M+H] + 1229.0.

[0196] [Example 49] 14-Heptyl-7,7-bis{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-N,N,N-trimethyl-4,10,12,15-tetraoxo-5,9,13,16-tetraoxadocosan-1-aminium iodide

[0197] Dihexyl 9-({[4-(dimethylamino)butanoyl]oxy}methyl)-2,16-diheptyl-9-{[(3-{[1-(hexyloxy)-1-oxononan-2-yl]oxy}-3-oxopropanoyl)oxy]methyl}-4,6,12,14-tetraoxo-3,7,11,15-tetraoxaheptadecane-1,17-geoate (2 g) and DCM (20 mL) were mixed with iodomethane (2.3 g) and stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to obtain the title compound (2.1 g). 1 H NMR (400 MHz, CDCl3) δ 5.00 (t, J = 6.3 Hz, 3H), 4.24 (s, 6H), 4.20 - 4.08 (m, 8H), 3.67 - 3.58 (m, 2H), 3.51 (s, 6H), 3.41 (s, 9H), 2.54 (t, J = 6.4 Hz, 2H), 2.16 - 2.05 (m, 2H), 1.89 - 1.80 (m, 6H), 1.69 - 1.61 (m, 6H), 1.41 - 1.24 (m, 48H), 0.94 - 0.81 (m, 18H).MS: [M+H] + 1243.2.

[0198] [Production Example] Production Example of DNA-Embedded Lipid Nanoparticles A lipid mixture containing cationic lipids obtained in the above example (cationic lipids: DPPC: Cholesterol: GM-020 = 60:10.6:28:1.4, molar ratio) was dissolved in 90% EtOH and 10% water to obtain a 15.0 mg / ml lipid solution. Luciferase (luc) DNA (Nature Technologies) was dissolved in 10 mM MES buffer pH 5.5 to obtain a 0.3 mg / ml nucleic acid solution. The obtained lipid solution and nucleic acid solution were mixed at room temperature using a NanoAssemblr (Precision Nanosystems) at a flow rate ratio of 3 ml / min : 6 ml / min to obtain a dispersion containing the composition. The obtained dispersion was dialyzed in water at room temperature for 1 hour and in PBS at 4°C for 23 hours using a Slyde-A-Lyzer (20K fractional molecular weight, Thermo Scientific). Next, the solution was filtered using a 0.2 μm syringe filter (Iwaki), and a 60% sucrose / PBS solution was added to create a 20% sucrose / PBS solution, which was stored at -80°C. The results of the analysis are shown in Table 2.

[0199] [Test Example] Example of Mouse Bioluminescence Imaging Evaluation Test: Lipid particles containing luciferase-encoding DNA were administered intravein (10 mL / kg iv) to ICrl:CD1 (ICR) mice. After administration of the lipid particles, luciferin (15 mg / mL) was administered to the mice (10 mL / kg ip), and the mice were placed in an IVIS (In Vivo Imaging System) device (PerkinElmer) under isoflurane inhalation anesthesia. Luminescence images were taken from the ventral (supine) side of the mice 15 minutes after luciferin administration. The amount of luminescence was quantified using IVIS software, and the evaluation was performed using the Total Flux value. A higher amount of luminescence indicates stronger expression of the protein encoded by the DNA encapsulated in the lipid particles. The measurement results are shown in Table 2.

[0200]

[0201] Lipid particles or compositions produced using the compound (cationic lipid) of the present invention enable the efficient introduction of active ingredients such as nucleic acids into various cells, tissues, or organs. Therefore, the compound, lipid particles, or compositions of the present invention can be used as a DDS (Drug Delivery System) technology in nucleic acid drugs. Furthermore, the compound, lipid particles, or compositions of the present invention can also be used as nucleic acid delivery reagents for research purposes.

Claims

1. Formula (I): [In formula (I), W is -NR １ R ２ or -N ＋ R １１ R １２ R １３ (Z － ), R １ and R ２ are each independently a hydrogen atom or an optionally substituted C １～５ alkyl group, R １１ , R １２ and R １３ are each independently an optionally substituted C １～５ alkyl group, Z － is an anion, X is an optionally substituted C ２～６ alkylene group, R Ａ and R Ｂ are each independently an optionally substituted C １～１７ alkyl group, an optionally substituted C ３～１７ alkenyl group, an optionally substituted C １５～１７ alkadienyl group, or -R ３ -Y １ -CH(R ４ )(Y ２ -R ５ ), R Ｃ is -R ３ -Y １ -CH(R ４ )(Y ２ -R ５ ), Y １ and Y ２ are each independently -CO-O- or -O-CO-, R ３ is an optionally substituted C １～３ alkylene group, R ４ is a hydrogen atom, an optionally substituted C １～１２ alkyl group, an optionally substituted C ３～１８ alkenyl group, or an optionally substituted C １５～１８ alkadienyl group, R ５ is an optionally substituted C １～１２ Alkyl alkyl groups, optionally substituted C ３～１８ Alkenyl group, or possibly substituted C １５～１８ It is an alkadienyl group, R Ａ , R Ｂ and R Ｃ All of them are -R ３ -Y １ -CH(R) ４ ) (Y ２ -R ５ If the structure is represented by ), R Ａ , R Ｂ and R Ｃ R in the structure in ３ , R ４ and R ５ Each of these may be the same or different. A compound represented by ] or a salt thereof.

2. Lipid particles containing the compound or a salt thereof described in claim 1.

3. A nucleic acid introduction composition containing nucleic acids and lipid particles according to claim 2.

4. The composition according to claim 3, wherein the nucleic acid is DNA or RNA.

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