Nucleic acid-containing lipid nanoparticles

Abstract

To provide a nucleic acid-containing lipid nanoparticle that is useful as a medicament and is more stable than conventional particles.SOLUTION: The present invention provides a nucleic acid-containing lipid nanoparticle comprising an analog of a fatty acid ester of glycerol, and a nucleic acid, wherein the analog is not hydrolyzable by a lipase.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to nucleic acid-containing lipid nanoparticles and the like. [Background technology]

[0002] To realize gene therapy, carriers for the efficient delivery of nucleic acids, such as plasmid DNA (pDNA), antisense oligodeoxynucleotides (ODN), and short interfering RNA (siRNA), to target cells in vivo have been developed. One known method for this purpose is to encapsulate nucleic acids in lipid particles and administer the complex to protect the nucleic acids from nucleases in vivo.

[0003] Patent Document 1 and Non-Patent Document 1 report methods for producing liposomes containing nucleic acids, etc., in which, for example, a solution of dried cationic lipids, a sodium citrate aqueous solution of siRNA, a neutral lipid, and a polyethylene glycolated phospholipid is dissolved in HEPES [N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)] Buffered Saline (hereinafter referred to as "HBS") and ethanol is added to diethyl ether to form a water-in-oil (W / O) emulsion, and the solutions are then mixed and treated by reverse phase evaporation to produce siRNA-encapsulating liposomes.

[0004] Patent Document 2 and Non-Patent Document 2 report a method for producing ODN-encapsulated liposomes by dissolving ODN in a citric acid aqueous solution of pH 3.8, adding an ethanol solution of lipids, and reducing the ethanol concentration to 20 v / v% to prepare ODN-encapsulated liposomes, filtering the liposomes through a sizing membrane, removing excess ethanol by dialysis, and then further dialyzing the sample at pH 7.5 to remove ODN attached to the liposome surface.

[0005] Furthermore, Patent Document 3 reports a method for producing pDNA-encapsulating liposomes by, for example, mixing a solution of pDNA dissolved in an aqueous citric acid solution with a solution of lipids dissolved in ethanol in a T-shaped mixer to reduce the ethanol concentration to 45 v / v%, and then adding a citrate buffer solution to reduce the ethanol concentration to 20 v / v%, thereby preparing pDNA-encapsulating liposomes; removing excess pDNA with an anion exchange resin; and removing excess ethanol by ultrafiltration.

[0006] Furthermore, Patent Document 4 reports a method for producing pDNA-encapsulated liposomes by complexing pDNA with cationic lipids as micelles in an organic solvent containing water, adding more lipid, and then removing the organic solvent by dialysis.

[0007] Patent Document 5 reports a method for producing pDNA-encapsulating liposomes by complexing pDNA with cationic lipids as micelles in an aqueous solution of a surfactant, adding more lipid, and then removing the surfactant by dialysis.

[0008] Meanwhile, Non-Patent Document 3 reports that in a test using lipid nanoparticles encapsulating doxorubicin, the ester bond at the sn-2 position of the phospholipid is hydrolyzed by phospholipase A2 (hereinafter also referred to as "PLA2"), resulting in efficient release of the encapsulated substance. In other words, when phospholipids, a component of lipid nanoparticles, are metabolized by phospholipase A2 in vivo, the stability of the particles containing the drug decreases. When the drug is a low-molecular-weight drug, the decreased particle stability promotes smooth release of the drug, thereby demonstrating its activity. On the other hand, when the encapsulated substance is a nucleic acid, even if released, it is poorly taken up into cells and is subject to enzymatic degradation, leading to loss of activity. The above-mentioned nucleic acid-encapsulated nanoparticles typically use lipids that are substrates for PLA2, making it difficult to prepare lipid particles with high stability.

[0009] Furthermore, Patent Document 6 discloses the use of 1,2-di-O-hexadecyl-sn-glycero-3-phosphocholine in a composition for oral administration and delivery of a biologically active agent, and that such a composition is stable in acid. However, there is no description of the use of this composition for delivery of nucleic acids. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] U.S. Patent Application Publication No. 2013 / 0149374 [Patent Document 2] Special Publication No. 2002-501511 [Patent Document 3] International Publication No. 2004 / 002453 Pamphlet [Patent Document 4] International Publication No. 96 / 40964 Brochure [Patent Document 5] U.S. Patent Application Publication No. 2010 / 0041152 [Patent Document 6] International Publication No. 2014 / 143806 Brochure [Non-patent literature]

[0011] [Non-Patent Document 1] Biochimica et Biophysica Acta, 2012, Vol. 1818, pp. 1633-1641 [Non-patent document 2] Biochimica et Biophysica Acta, 2001, Vol. 1510, pp. 152-166 Summary of the Invention [Problem to be solved by the invention]

[0012] An object of the present invention is to provide nucleic acid-containing lipid nanoparticles that are useful as pharmaceuticals and are more stable than conventional particles. [Means for solving the problem]

[0013] The present invention relates to the following: [1] Nucleic acid-containing lipid nanoparticles comprising a fatty acid ester analogue of glycerol that is not hydrolyzed by lipase and a nucleic acid. [2] The nucleic acid-containing lipid nanoparticles according to [1], wherein the glycerol fatty acid ester analogue is a glycerophospholipid analogue. [3] The nucleic acid-containing lipid nanoparticles according to [1] or [2], wherein the lipase is phospholipase A2. [4] The nucleic acid-containing lipid nanoparticles according to any one of [1] to [3], wherein the fatty acid ester analog of glycerol is a lipid represented by the following formula (1) or formula (2): [ka] (In formula (1), Rx 1 and Rx 2 are the same or different and are linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rx 3 is a negative charge, a hydrogen atom, or one of the following groups: [ka] ) [ka] (In formula (2), Rx 4 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, or Rx 41-CO-, Rx 41 is a linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rx 5 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; Rx 6 is a negative charge, a hydrogen atom, or one of the following groups: [ka] ) [5] The nucleic acid-containing lipid nanoparticles according to any one of [1] to [4], wherein the content of the fatty acid ester analogue of glycerol is 0.001 times or more by mole relative to the number of moles of the total lipid. [6] The nucleic acid-containing lipid nanoparticles according to any one of [1] to [5], further comprising a cationic lipid. [7] The nucleic acid-containing lipid nanoparticles according to [6], wherein the cationic lipid is lipid A; at least one of the following formulas (I), (II), (III), (IV), (V') and (V''); and / or lipid B; at least one of the following formulas (CL-I), (CL-II), (CL-III), (CL-IV), (CL-V), (CL-VI), (CL-VII), (CL-VIII), (CL-IX), (CL-X), (CL-XI), (CL-XII), (CL-XIII), (CL-XIV), (CL-XV), (CL-XVI), (CL-XVII), (CL-XVIII) and (CL-XIX). (Here, formula (I), formula (II), formula (III), formula (IV), formula (V'), and formula (V'') are represented by the structures described in the detailed description of the invention, which will be described later. In addition, formula (CL-I), formula (CL-II), formula (CL-III), formula (CL-IV), formula (CL-V), formula (CL-VI), formula (CL-VII), formula (CL-VIII), formula (CL-IX), formula (CL-X), formula (CL-XI), formula (CL-XII), formula (CL-XIII), formula (CL-XIV), formula (CL-XV), formula (CL-XVI), formula (CL-XVII), formula (CL-XVIII), and formula (CL-XIX) are represented by the structures described in the detailed description of the invention, which will be described later. The same applies hereinafter.) [8] The nucleic acid-containing lipid nanoparticles according to [7], wherein the cationic lipid is the lipid B. [9] The nucleic acid-containing lipid nanoparticles according to any one of [1] to [8], further comprising a lipid derivative or a fatty acid derivative of a water-soluble polymer.

[10] The nucleic acid-containing lipid nanoparticles according to [9], wherein the water-soluble polymer portion of the lipid derivative or fatty acid derivative of the water-soluble polymer is selected from the group consisting of polyethylene glycol, polyglycerin, polyethyleneimine, polyvinyl alcohol, polyacrylic acid, and polyacrylamide.

[11] The nucleic acid-containing lipid nanoparticles according to any one of [1] to

[10] , further comprising a neutral lipid.

[12] The nucleic acid-containing lipid nanoparticles according to

[11] , wherein the neutral lipid is selected from the group consisting of phospholipids, sterols, glyceroglycolipids, glycosphingolipids, and sphingoids.

[13] The nucleic acid-containing lipid nanoparticle according to any one of [1] to

[12] , wherein the nucleic acid is a nucleic acid that has an effect of suppressing the expression of a target gene by utilizing RNA interference (RNAi).

[14] The nucleic acid-containing lipid nanoparticles according to

[13] , wherein the target gene is a gene associated with tumor or inflammation.

[15] A method for stabilizing nucleic acid-containing lipid nanoparticles using a fatty acid ester analog of glycerol that is not hydrolyzed by lipase, wherein the fatty acid ester analog of glycerol may be an analog described in [1] to [5] above, and the nucleic acid-containing lipid nanoparticles may be any of the nucleic acid-containing lipid nanoparticles described in [1] to

[14] above.

[16] A method for introducing a nucleic acid into a cell, which uses the nucleic acid-containing lipid nanoparticles according to any one of [1] to

[14] .

[17] The method according to

[16] , wherein the cells are cells present in a mammalian tumor or an inflammatory site.

[18] The method according to

[16] or

[17] , wherein the cells are cells in the liver, stomach, lung, kidney, pancreas or spleen of a mammal.

[19] The method according to any one of

[16] to

[18] , wherein the method for introducing into cells is a method for introducing into cells by intravenous administration or subcutaneous administration.

[20] A method for treating cancer or an inflammatory disease, comprising administering the nucleic acid-containing lipid nanoparticle according to any one of [1] to

[14] to a mammal. [twenty one] The method of treatment according to

[20] , wherein the administration is intravenous or subcutaneous. [twenty two] A pharmaceutical comprising the nucleic acid-containing lipid nanoparticles according to any one of [1] to

[14] . [twenty three] The pharmaceutical composition according to

[22] , which is for intravenous or subcutaneous administration. [twenty four] A therapeutic agent for cancer or inflammatory disease, comprising the nucleic acid-containing lipid nanoparticles according to any one of [1] to

[14] . [twenty five] The therapeutic agent according to

[24] , which is for intravenous or subcutaneous administration.

[26] Formula (CL-XVIII) [ka] (In the formula, R 137 and R 138 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl, X 135 represents a hydrogen atom, a C1-C3 alkyl, a hydroxy C2-C4 alkyl, a group represented by the formula (C) [ka] (In the formula, X 136 and X 137 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 136 and X 137 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 132 is S or O, and p 115 is an integer of 2 to 4), formula (D) [ka] (In the formula, X 138 and X 139 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 138 and X 139may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 116 is an integer of 1 to 4), or formula (E) [ka] (In the formula, X 140 and X 141 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 140 and X 141 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 117 is an integer between 1 and 4. or a pharmaceutically acceptable salt thereof (cationic lipid).

[27] Formula (CL-XIX) [ka] (In the formula, R 139 and R 140 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl, L 133 is S or O, X 142 is a hydrogen atom, C1-C3 alkyl, hydroxy C2-C4 alkyl, formula (F) [ka] (In the formula, X 143 and X 144 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 143 and X 144 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 134 is S or O, and p 118 is an integer of 2 to 4), or formula (G) [ka] (In the formula, X 145 and X 146 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 145 and X 146 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 119 is an integer between 1 and 4. or a pharmaceutically acceptable salt thereof (cationic lipid). [Effects of the Invention]

[0014] INDUSTRIAL APPLICABILITY The present invention can provide nucleic acid-containing lipid nanoparticles that are useful as pharmaceuticals and are more stable than conventional particles. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a graph showing the amount of residual lipid in each preparation, where the vertical axis of the graph shows the amount of residual lipid (%) when the amount of residual lipid in the PLA2-untreated group is set to 1, and the horizontal axis shows each preparation. [Figure 2] 1 is a graph showing the amount of residual lipid in each preparation, where the vertical axis of the graph shows the amount of residual lipid (%) when the amount of residual lipid in the PLA2-untreated group is set to 1, and the horizontal axis shows each preparation. [Figure 3] 1 is a graph showing the amount of residual lipid in each preparation, where the vertical axis of the graph shows the amount of residual lipid (%) when the amount of residual lipid in the PLA2-untreated group is set to 1, and the horizontal axis shows each preparation. DETAILED DESCRIPTION OF THE INVENTION

[0016] Hereinafter, embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described below.

[0017] The nucleic acid-containing lipid nanoparticles of the present invention comprise a fatty acid ester analog of glycerol that is not hydrolyzed by lipase, and nucleic acid. The nucleic acid-containing lipid nanoparticles of the present invention can remain stable even when they come into contact with lipase, because the lipids in the particles are not easily decomposed.

[0018] In lipids having a fatty acid ester structure of glycerol (hereinafter also referred to as natural glycerol lipids), at least one hydroxyl group of glycerol and a fatty acid form an ester bond, and the ester bond is hydrolyzed by the action of lipase. The fatty acid ester analogue of glycerol in the present invention is a lipid having a structure in which the structure of the above-mentioned natural glycerol lipid is partially modified, and is not hydrolyzed by lipase.

[0019] In the present invention, "not hydrolyzed by lipase" means that when lipase is contacted with the nucleic acid-containing lipid nanoparticles of the present invention, typically 30% or more of the total amount of glycerol fatty acid ester analogues present in the nucleic acid-containing lipid nanoparticles are not hydrolyzed, preferably 50% or more, more preferably 70% or more, even more preferably 90% or more, and even more preferably 99% or more. The lipase is contacted with the analogue generally at 30 to 45°C, preferably 35 to 42°C, more preferably 37°C, for generally 0 minute to 48 hours, preferably 1 minute to 36 hours, more preferably 1 minute to 24 hours.

[0020] The fatty acid ester analogue of glycerol in the present invention is preferably 10 Å (10 Å) from the carbon atom at the sn-2 position of the glycerol backbone in a natural glycerol lipid represented by the following formula (NL1): -10 Preferably, the structural modification is within a range of 10 Å or less from the carbon atom at the sn-2 position, more preferably 8 Å or less, and even more preferably 6 Å or less. By modifying the structural modification within a range of 10 Å or less from the carbon atom at the sn-2 position, the nucleic acid-containing lipid nanoparticles tend to be less susceptible to the hydrolysis action of lipase, and the nucleic acid-containing lipid nanoparticles are stabilized. The lower limit of the range of structural modification is not particularly limited as long as it is equal to or greater than 0 Å. The range of 0 Å from the sn-2 carbon atom refers to the sn-2 carbon atom.

[0021] Here, structural modification means changing the structure near the glycerol backbone of a natural glycerol lipid, and is not particularly limited as long as it reduces the interaction with the active site of lipase. For example, it is possible to invert the asymmetric center in a natural glycerol lipid, that is, to change the L-form to a D-form; to change the ester bond between the glycerol backbone and the fatty acid to an ether bond (—O—), a thioether bond (—S—), an amino bond (—N(R p )―;R p are hydrogen atoms or organic groups), or an amide bond (―NHCO-), etc.; substituting one or more hydrogen atoms at the sn-1, sn-2, or sn-3 positions with an organic group; or introducing organic groups into the α, β, γ, or δ positions of the acyl group described below. Examples of the organic group include hydroxy, alkoxy, alkoxycarbonyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl portion of the alkoxy and alkoxycarbonyl is a C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, etc.

[0022] [ka]

[0023] a and b are independently the following acyl groups, and c is an acyl group, a phosphate group, a sugar, etc. However, when both a and c are acyl groups, they differ in the number of carbon atoms, etc., and have different structures, and are not identical.

[0024] [ka]

[0025] R'xx in the above acyl group includes linear or branched C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl, which may be substituted.

[0026] The fatty acid ester analog of glycerol in the present invention, that is, the analog of the natural glycerol lipid represented by formula (NL1), is preferably a glycerophospholipid analog.

[0027] The glycerophospholipid can be represented, for example, by the following formula (NL2), and the glycerophospholipid analogue is a structurally modified version of the lipid represented by the following formula (NL2).

[0028] [ka]

[0029] In formula (NL2), Rxx 1 and Rxx 2 are the same or different and are linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rxx 3 represents a hydrogen atom or the following groups:

[0030] [ka]

[0031] In formula (NL1) and formula (NL2), examples of the linear or branched C7-C23 alkyl include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, and tetracosyl.

[0032] The linear or branched C7-C23 alkenyl in formula (NL1) and formula (NL2) may be a linear or branched C7-C23 alkenyl containing 1 to 3 double bonds, such as (Z)-tridec-8-enyl, (Z)-tetradec-9-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadeca-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl. (E)-heptadeca-8-enyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl nyl, (10Z,13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, 3,7,11,15-tetramethylhexadec-2-enyl, and the like are exemplified, and preferred are (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, (Z)-pentadec-1-enyl, (Z)-hexadec-2-enyl, and the like. (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like are included, and more preferred are (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0033] In formula (NL1) and formula (NL2), the linear or branched C7-C23 alkynyl may be a linear or branched C8-24 alkynyl containing one to three triple bonds, such as dodec-11-ynyl, tridec-12-ynyl, pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, and the like, preferably pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, and the like, more preferably heptadec-8-ynyl, octadec-9-ynyl, and the like.

[0034] In formula (NL1) and formula (NL2), examples of the substituent in the linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl include hydroxy, alkoxy, alkoxycarbonyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl moiety in the alkoxy and alkoxycarbonyl is a C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, etc.

[0035] The glycerophospholipid represented by formula (NL2) may be, for example, phosphatidylcholine (PC) (specifically, soybean phosphatidylcholine, egg yolk phosphatidylcholine (EPC), distearoylphosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), dipalmitoylphosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), palmitoyloleoylphosphatidylcholine (POPC), dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), etc.), phosphatidylethanolamine (specifically, distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphoethanolamine (DMPE), 16-O-monomer phosphatidylcholine (DSPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphoethanolamine (DMPE), 16-O-monomer phosphatidylcholine (DOPC ... glycerophospholipids (specifically, sphingomyelin, ceramide phosphoethanolamine, ceramide phosphoglycerin ...

[0036] The lipase used in the present invention is not particularly limited as long as it is an enzyme that hydrolyzes fatty acid esters contained in natural glycerol lipids represented by formula (NL1). Examples of lipases include phospholipases, such as phospholipase A1, phospholipase A2, phospholipase B, lysophospholipase, phospholipase C, and phospholipase D. The fatty acid ester analog of glycerol in the present invention is preferably a fatty acid ester analog of glycerol that is not hydrolyzed by phospholipase A2.

[0037] The glycerophospholipid analog has a structure in which a part of the structure of the glycerophospholipid represented by the above formula (NL2) is modified. Specifically, the glycerophospholipid analog is preferably a lipid represented by the following formula (1) or (2).

[0038] [ka]

[0039] (In formula (1), Rx 1 and Rx 2 are the same or different and are linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rx 3 is a negative charge, a hydrogen atom, or one of the following groups: [ka] )

[0040] [ka]

[0041] (In formula (2), Rx 4is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, or Rx 41 -CO-, Rx 41 is a linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rx 5 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; Rx 6 is a negative charge, a hydrogen atom, or one of the following groups: [ka] )

[0042] Examples of the linear or branched C7-C23 alkyl, C7-C23 alkenyl, and C7-C23 alkenyl in formula (1) and formula (2) are the same as those of the C7-C23 alkyl, C7-C23 alkenyl, and C7-C23 alkenyl in formula (NL2).

[0043] Examples of linear or branched C8-C24 alkyl include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, and tetracosyl.

[0044] The linear or branched C8-C24 alkenyl may be a linear or branched C8-24 alkenyl containing 1 to 3 double bonds, such as (Z)-tridec-8-enyl, (Z)-tetradec-9-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (E)-heptadeca-8-enyl, nyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl, (10Z,13Z )-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, 3,7,11,15-tetramethylhexadec-2-enyl, and the like are preferred, and (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-3-enyl, (Z)-hexadeca-4-enyl, (Z)-heptadeca-5-enyl, (Z)-pentadeca-6-enyl, (Z)-pentadeca-7-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadeca-9-enyl, (Z)-heptadeca-1-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-3-enyl, (Z)-pentadeca-4-enyl, (Z)-pentadeca-5-enyl, (Z)-pentadeca-6-enyl, (Z)-pentadeca-7-enyl, (Z)-pentadeca-8-enyl, (Z)-pentadeca-9-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-3-enyl, (Z)- Examples thereof include (Z)-octadec-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like, and more preferably include (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0045] The linear or branched C8-C24 alkynyl may be a linear or branched C8-24 alkynyl containing one to three triple bonds, and examples thereof include dodec-11-ynyl, tridec-12-ynyl, pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., preferably pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., more preferably heptadec-8-ynyl, octadec-9-ynyl, etc.

[0046] Substituents in the linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C7-C23 alkyl, C7-C23 alkenyl, and C7-C23 alkynyl in formula (1) and formula (2) include hydroxy, alkoxy, alkoxycarbonyl, nitro, cyano, fluoro, chloro, bromo, etc. Of these substituents, the alkyl moiety in the alkoxy and alkoxycarbonyl is C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, etc.

[0047] The fatty acid ester analog of glycerol in the present invention may be a salt. When the fatty acid ester analog of glycerol is a salt, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, Rx in Formula (1) and Formula (2) 3 and Rx 6 is a hydrogen atom,

[0048] [ka] When the compound is an alkali metal salt such as sodium or potassium, or an ammonium salt (NH4 + It is preferable that the compound is a salt. Rx 3 and Rx 6 may be a negative charge. 3 and Rx 6 is a negative charge, Rx 3 and Rx 6 In other words, the negative charge means that the phosphate ester group in formula (1) and formula (2) is -PO4 2- This means that it is acceptable for the

[0049] The lipid represented by formula (2) may be any one of the optical isomers at the asymmetric carbon whose configuration is not specified, or may be a mixture containing these in any ratio.

[0050] Rxx in formula (NL2), formula (1) and formula (2) 3 , Rx 3 and Rx 6 Specifically, the inositol skeleton in is derived from the following inositol: In the following inositol structure, the hydroxyl group that forms a bond with phosphate is not particularly limited.

[0051] [ka]

[0052] Rxx 3 , Rx 3 and Rx 6 When the inositol skeleton is an inositol skeleton, it is preferably represented by the following formula:

[0053] [ka]

[0054] The groups in formula (1) and formula (2), i.e., C7-C23 alkyl, C7-C23 alkenyl, C7-C23 alkynyl, C8-C24 alkyl, C8-C24 alkenyl, and C8-C24 alkynyl, can be exemplified in the same manner as the groups in formula (NL1) and formula (NL2), and the same preferred groups can be mentioned. Furthermore, the groups in formula (1), formula (2), formula (NL1) and formula (NL2) may be any combination of the groups described for each group, or may be a combination of preferred groups.

[0055] Specific examples of the fatty acid ester analogues of glycerol that are not hydrolyzed by lipase in the nucleic acid-containing nanoparticles of the present invention include the following compounds.

[0056] [ka]

[0057] The fatty acid ester analogue of glycerol used in the present invention may be a commercially available product, or may be synthesized by using an organic synthesis technique.

[0058] For example, the lipid represented by formula (1) can be produced as follows, but the production method is not particularly limited.

[0059] [ka]

[0060] (In the formula, PG represents a protecting group. Rx 1 ,Rx 2 , Rx 3 is Rx in equation (1) 1 , Rx 2 , Rx 3 is equivalent to

[0061] Specifically, the hydroxy group of a known acetal X1 obtained from a sugar such as mannitol is protected with a protecting group (PG group), and the isopropylidene group is hydrolyzed to obtain diol X3. Diol X3 can also be obtained as a commercial product such as (S)-3-(benzyloxy)propane-1,2-diol. Next, diol X3 is converted to Rx 1 -CO-Cl and Rx 2 The protecting group (PG group) is then removed, and the resulting hydroxyl group is reacted with phosphorus oxychloride (V) in the presence of a base such as triethylamine, to give compound X4. 3 A compound represented by -OH can be reacted to give a lipid represented by formula (1). In the conversion of diol X3 to X4, the reaction may be carried out after protecting either the primary alcohol or the secondary alcohol with a protecting group. The protecting groups used in the synthesis of the lipid represented by formula (1) may be selected based on the reaction conditions and substrates, for example, by referring to Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999).

[0062] For example, the lipid represented by formula (2) can be produced as follows, but the production method is not particularly limited.

[0063] [ka]

[0064] (In the formula, PG represents a protecting group. 0 represents a linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl. Furthermore, X represents a halogen atom such as chlorine, bromine, or iodine, OMs, or OTs. Rx 4 , Rx5 , Rx 6 , Rx 41 is Rx in equation (2) 4 , Rx 5 , Rx 6 ,Rx 41 is equivalent to

[0065] Specifically, the hydroxy group of a known acetal X6 obtained from a sugar such as mannitol is protected with a protecting group (PG group), and the isopropylidene group is hydrolyzed to give a diol X8. Next, the diol X8 is reacted with, for example, Rx 0 By reacting with an electrophile represented by -CH2-X (reaction conditions for Williamson etherification can be referred to and applied), a diether X9 can be obtained. 42 -CO-Cl, etc., and then react with Rx 0 Compound X9 can be obtained by reacting the compound with an electrophile represented by -CH2-X. The protecting group (PG group) is then removed, and the resulting hydroxyl group is reacted with phosphorus oxychloride (V) in the presence of a base such as triethylamine. 3 A compound represented by -OH can be reacted to give a lipid represented by formula (2). In the conversion of diol X3 to X4, the reaction may be carried out after protecting either the primary alcohol or the secondary alcohol with a protecting group. The protecting group used in the synthesis of lipid (2) represented by formula (2) may be selected based on the reaction conditions and substrate, for example, with reference to Protective Groups in Organic Synthesis, third edition, T.W. Greene, John Wiley & Sons Inc. (1999).

[0066] The nucleic acid-containing lipid nanoparticles of the present invention preferably further contain a cationic lipid. The cationic lipid is not particularly limited as long as it is an amphipathic molecule having a lipid-affinity region containing one or more optionally substituted hydrocarbon groups and a cationic hydrophilic region containing at least one primary amino group, a secondary amino group, a tertiary amino group, and / or a quaternary ammonium group. Examples of the cationic lipid include a lipid (lipid A) having a hydrophilic portion containing one quaternary ammonium group and three independent hydrocarbon groups which may be substituted, and a lipid (lipid B) having a hydrophilic portion containing one optionally substituted amino group or one quaternary ammonium group and a hydrophobic portion containing two independent hydrocarbon groups which may be substituted.

[0067] In the present invention, a lipid (lipid A) having a hydrophilic portion with one quaternary ammonium group and three independent hydrocarbon groups, which may be substituted, is used to form nucleic acid-containing lipid nanoparticles together with a lipid derivative or fatty acid derivative of a water-soluble polymer and nucleic acid, thereby making it possible to obtain nucleic acid-containing lipid nanoparticles with superior physicochemical stability and physiological activity.

[0068] In the present invention, the lipid (lipid A) having a hydrophilic portion with one quaternary ammonium group and three independent hydrocarbon groups which may be substituted is not particularly limited as long as it is a molecule having one quaternary ammonium group as the hydrophilic portion and three independent hydrocarbon groups which may be substituted within the molecule, and is, for example, represented by the following structural formulas (A) to (C): In the following structural formulas (A) to (C), the "hydrophilic portion (Hydrophilic Unit)" represents the hydrophilic portion with one quaternary ammonium group, and the three "hydrophobic portions (Hydrophobic Units)" represent three independent hydrocarbon groups which may be substituted.

[0069] The quaternary ammonium group constituting the "hydrophilic unit" has 0 to 3 of its four bonds bonded to any 0 to 3 hydrocarbon groups constituting the "hydrophobic unit", and the remaining bonds bonded to an optionally substituted linear and / or cyclic hydrocarbon group, etc. The optionally substituted linear and / or cyclic hydrocarbon group constituting the "hydrophilic unit" may be any group consisting of carbon atoms and hydrogen atoms, but preferably has 1 to 10 carbon atoms, more preferably has 1 to 6 carbon atoms, and even more preferably has 1 to 3 carbon atoms.

[0070] Furthermore, the "hydrophilic unit" may have one or more ethers, esters, amides, etc. via carbon atoms in the optionally substituted linear and / or cyclic hydrocarbon groups, etc. that constitute it. Furthermore, examples of the substituents in the optionally substituted linear and / or cyclic hydrocarbon groups, etc. include carbamate, amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, etc.

[0071] The hydrocarbon group forming the "hydrophobic unit" may be any group consisting of 8 to 24 carbon atoms and hydrogen atoms. Hydrocarbon groups can be classified from the perspective of topology, including linear hydrocarbon groups, branched hydrocarbon groups, and cyclic hydrocarbon groups (e.g., cholesteryl groups, etc.), with linear or branched hydrocarbon groups being preferred. Hydrocarbon groups can also be classified based on the presence or absence of unsaturated bonds (double or triple bonds). Hydrocarbon groups with unsaturated bonds can also be classified based on the presence or absence of aromaticity, with hydrocarbon groups (alkyl) consisting of only saturated bonds or hydrocarbon groups with unsaturated bonds and no aromaticity (e.g., alkenyl or alkynyl) being preferred. The hydrocarbon group in lipid A is preferably a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl.

[0072] The hydrocarbon groups forming the "hydrophobic unit" may be bonded directly to the quaternary ammonium group of the "hydrophilic unit," or may be bonded to the quaternary ammonium group via a bond such as an ether, ester, or amide, or a linear and / or cyclic hydrocarbon group that may have a substituent that constitutes the "hydrophilic unit." Alternatively, as shown in structural formulas (B) and (C), two or three hydrocarbon groups forming the "hydrophobic unit" may be bonded via a carbon atom, and this carbon atom may be bonded to the quaternary ammonium group of the "hydrophilic unit" directly or via a bond such as an ether, ester, or amide, or a linear and / or cyclic hydrocarbon group that may have a substituent that constitutes the "hydrophilic unit."

[0073] [ka]

[0074] Examples of lipid A include lipids represented by the following formulae (I) to (IV), (V') and (V'').

[0075] Formula (I)

[0076] [ka] (In the formula, R 1 ~R 3 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 1 ~L 3 are the same or different and do not exist, or -Z 1 -(CY 1 Y 2 ) p1 -or-Z 2 -(CY 3 Y 4 ) p2 -Z 3 -(CY 5 Y 6 ) p3 -(In the formula, Y 1 ~Y 6 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 1 ~Z 3 are the same or different, -O-, -NY 7A -, -CO-O-, -O-CO-, -CO-NY 7B -,-NY 7C -CO- or -NY 7D -CO-0-, where Y 7A ~Y 7D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 1 ~p 3 are the same or different and are integers of 1 to 5, X 1 is an optionally substituted C1-C4 alkyl, A 1is a pharmaceutically acceptable anion), Formula (II)

[0077] [ka] (In the formula, R 4 ~R 6 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 4 ~L 6 are the same or different and do not exist, or -Z 4 -(CY 8 Y 9 ) p4 -or-Z 5 -(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 -(In the formula, Y 8 ~Y 13 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 4 ~Z 6 are the same or different, -O-, -NY 14A -, -CO-O-, -O-CO-, -CO-NY 14B -,-NY 14C -CO- or -NY 14D -CO-0-, where Y 14A ~Y 14D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 4 is an integer between 0 and 5, and p 5 is an integer from 1 to 5, and p 6 is an integer from 0 to 5), L 7 does not exist or -(CY 15 Y 16 ) p7 -,-(CY 17 Y 18 ) p8-Z 7 -(CY 19 Y 20 ) p9 -or-(CY 21 Y 22 ) p10 -Z 8 -(CY 23 Y 24 ) p11 -Z 9 -(CY 25 Y 26 ) p12 -(In the formula, Y 15 ~Y 26 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 7 ~Z 9 are the same or different, -O-, -NY 27A -, -CO-O-, -O-CO-, -CO-NY 27B -,-NY 27C -CO- or -NY 27D -CO-0-, where Y 27A ~Y 27D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 7 is an integer from 1 to 5, and p 8 is an integer between 0 and 5, and p 9 is an integer from 1 to 5, and p 10 is an integer between 0 and 5, and p 11 is an integer from 1 to 5, and p 12 is an integer from 1 to 5), B 1 teeth, [ka] (In the formula, X 2 and X 3 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 4 is an optionally substituted C1-C4 alkyl, and X 5 and X 6are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 7 is an optionally substituted C1-C4 alkyl, and Y 28 ~Y 37 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 10 and Z 11 -O-, -NY are the same or different 38A -, -CO-O-, -O-CO-, -CO-NY 38B -,-NY 38C -CO- or -NY 38D -CO-0-, where Y 38A ~Y 38D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 13 is an integer between 0 and 5, and p 14 ~p 17 are the same or different and are integers of 1 to 5, A 2 is a pharmaceutically acceptable anion), Formula (III)

[0078] [ka] (In the formula, R 7 ~R 9 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 8 ~L 10 are the same or different and do not exist, or -Z 12 -(CY 39 Y 40 ) p18 -or-Z 13 -(CY 41 Y 42 ) p19 -Z 14 -(CY 43 Y 44) p20 -(In the formula, Y 39 ~Y 44 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 12 ~Z 14 are the same or different, -O-, -NY 45A -, -CO-O-, -O-CO-, -CO-NY 45B -,-NY 45C -CO-, -NY 45D -CO-0- or -CO-, where Y 45A ~Y 45D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 18 is an integer between 0 and 5, and p 19 is an integer from 1 to 5, and p 20 is an integer from 0 to 5), L 11 does not exist or -(CY 46 Y 47 ) p21 -,-(CY 48 Y 49 ) p22 -Z 15 -(CY 50 Y 51 ) p23 -or-(CY 52 Y 53 ) p24 -Z 16 -(CY 54 Y 55 ) p25 -Z 17 -(CY 56 Y 57 ) p26 -(In the formula, Y 46 ~Y 57 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 15 ~Z 17 are the same or different, -O-, -NY 58A -, -CO-O-, -O-CO-, -CO-NY 58B -,-NY 58C -CO-, -NY 58D -CO-0- or -CO-, where Y 58A ~Y58D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 21 is an integer from 1 to 5, and p 22 is an integer between 0 and 5, and p 23 is an integer from 1 to 5, and p 24 is an integer between 0 and 5, and p 25 is an integer from 1 to 5, and p 26 is an integer from 1 to 5), L 12 does not exist or -(CY 59 Y 60 ) p27 -,-(CY 61 Y 62 ) p28 -Z 18 -(CY 63 Y 64 ) p29 -or-(CY 65 Y 66 ) p30 -Z 19 -(CY 67 Y 68 ) p31 -Z 20 -(CY 69 Y 70 ) p32 -(In the formula, Y 59 ~Y 70 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 18 ~Z 20 are the same or different, -O-, -NY 71A -, -CO-O-, -O-CO-, -CO-NY 71B -,-NY 71C -CO-, -NY 71D -CO-0- or -CO-, where Y 71A ~Y 71D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 27 is an integer from 1 to 5, and p 28 is an integer between 0 and 5, and p 29 is an integer between 0 and 5, and p 30 is an integer between 0 and 5, and p 31 is an integer from 1 to 5, and p 32is an integer from 0 to 5), J 1 and J. 2 Is the same or different CY 72 or N (wherein Y 72 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 acyloxy; B 2 teeth, [ka] (In the formula, X 8 and X 9 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 10 is an optionally substituted C1-C4 alkyl, and X 11 and X 12 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 13 is an optionally substituted C1-C4 alkyl, and Y 73 ~Y 82 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 21 and Z 22 -O-, -NY are the same or different 83A -, -CO-O-, -O-CO-, -CO-NY 83B -,-NY 83C -CO- or -NY 83D -CO-0-, where Y 83A ~Y 83D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 33 is an integer between 0 and 5, and p 34 ~p 37 are the same or different and are integers of 1 to 5, A 3is a pharmaceutically acceptable anion), Formula (IV)

[0079] [ka] (In the formula, R 10 ~R 12 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 13 does not exist or -Z 23 -(CY 84 Y 85 ) p38 -or-Z 24 -(CY 86 Y 87 ) p39 -Z 25 -(CY 88 Y 89 ) p40 -(In the formula, Y 84 ~Y 89 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 23 ~Z 25 are the same or different, -O-, -NY 90A -, -CO-O-, -O-CO-, -CO-NY 90B -,-NY 90C -CO- or -NY 90D -CO-0-, where Y 90A ~Y 90D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 38 ~p 40 are the same or different and are integers of 1 to 5, L 14 and L 15 are the same or different and do not exist, or -Z 26 -(CY 91 Y 92 ) p41 -or-Z 27 -(CY 93 Y 94 )p42 -Z 28 -(CY 95 Y 96 ) p43 -(In the formula, Y 91 ~Y 96 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 26 ~Z 28 are the same or different, -O-, -NY 97A -, -CO-O-, -O-CO-, -CO-NY 97B -,-NY 97C -CO-, -NY 97D -CO-0- or -CO-, where Y 97A ~Y 97D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 41 is an integer between 0 and 5, and p 42 is an integer from 1 to 5, and p 43 is an integer from 0 to 5), L 16 does not exist or -(CY 98 Y 99 ) p44 -,-(CY 100 Y 101 ) p45 -Z 29 -(CY 102 Y 103 ) p46 -or-(CY 104 Y 105 ) p47 -Z 30 -(CY 106 Y 107 ) p48 -Z 31 -(CY 108 Y 109 ) p49 -(In the formula, Y 98 ~Y 109 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 29 ~Z 31 are the same or different, -O-, -NY 110A -, -CO-O-, -O-CO-, -CO-NY 110B -,-NY 110C -CO-, -NY110D -CO-0- or -CO-, where Y 110A ~Y 110D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 44 is an integer from 1 to 5, and p 45 is an integer between 0 and 5, and p 46 is an integer from 1 to 5, and p 47 is an integer between 0 and 5, and p 48 is an integer from 1 to 5, and p 49 is an integer from 1 to 5), J 3 CY 111 or N (wherein Y 111 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 acyloxy; X 14 and X 15 are the same or different and optionally substituted C1-C4 alkyl, or are taken together with the adjacent nitrogen atom to form an optionally substituted C4-C6 heterocycle; A 4 is a pharmaceutically acceptable anion), or Formula (V') or Formula (V'')

[0080] [ka] (In the formula, R 13 ~R 18 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; Y 112 ~Y 115 are the same or different and each represent a hydrogen atom, hydroxy, or an optionally substituted C1-C4 alkyl; L 17 ~L 19 and L 22 ~L 24are the same or different and do not exist, or -Z 32 -(CY 116 Y 117 ) p51 -or-Z 33 -(CY 118 Y 119 ) p52 -Z 34 -(CY 120 Y 121 ) p53 -(In the formula, Y 116 ~Y 121 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 32 ~Z 34 are the same or different, -O-, -NY 122A -, -CO-O-, -O-CO-, -CO-NY 122B -,-NY 122C -CO-, -NY 122D -CO-0- or -CO-, where Y 122A ~Y 122D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 51 is an integer between 0 and 5, and p 52 is an integer from 1 to 5, and p 53 is an integer from 0 to 5), L 20 and L 25 are the same or different and do not exist, or -(CY 123 Y 124 ) p54 -,-(CY 125 Y 126 ) p55 -Z 35 -(CY 127 Y 128 ) p56 -or-(CY 129 Y 130 ) p57 -Z 36 -(CY 131 Y 132 ) p58 -Z 37 -(CY 133 Y 134 ) p59 -(In the formula, Y 123 ~Y 134are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 35 ~Z 37 are the same or different, -O-, -NY 135A -, -CO-O-, -O-CO-, -CO-NY 135B -,-NY 135C -CO-, -NY 135D -CO-0- or -CO-, where Y 135A ~Y 135D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 54 is an integer from 1 to 5, and p 55 is an integer between 0 and 5, and p 56 is an integer from 1 to 5, and p 57 is an integer between 0 and 5, and p 58 is an integer from 1 to 5, and p 59 is an integer from 1 to 5), L 21 and L 26 are the same or different and do not exist, or -(CY 136 Y 137 ) p60 -,-(CY 138 Y 139 ) p61 -Z 38 -(CY 140 Y 141 ) p62 -or-(CY 142 Y 143 ) p63 -Z 39 -(CY 144 Y 145 ) p64 -Z 40 -(CY 146 Y 147 ) p65 -(In the formula, Y 136 ~Y 147 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 38 ~Z 40 are the same or different, -O-, -NY 148A -, -CO-O-, -O-CO-, -CO-NY 148B -, -NR 148C -CO-, -NY148D -CO-0- or -CO-, where Y 148A ~Y 148D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 60 is an integer from 1 to 5, and p 61 is an integer between 0 and 5, and p 62 is an integer between 0 and 5, and p 63 is an integer between 0 and 5, and p 64 is an integer from 1 to 5, and p 65 is an integer from 0 to 5), B 3 and B 4 are the same or different, [ka] (In the formula, X 16 and X 17 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 18 is an optionally substituted C1-C4 alkyl, and X 19 and X 20 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 21 is an optionally substituted C1-C4 alkyl, and Y 149 ~Y 158 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 41 and Z 42 -O-, -NY are the same or different 159A -, -CO-O-, -O-CO-, -CO-NY 159B -,-NY 159C -CO- or -NY 159D -CO-0-, where Y 159A ~Y 159D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl, 66is an integer between 0 and 5, and p 67 ~p 70 are the same or different and are integers of 1 to 5, A 5 and A 6 are the same or different and are pharmaceutically acceptable anions) Examples of the compound include compounds represented by the following formula:

[0081] Hereinafter, the compounds represented by formulas (I) to (IV), (V'), and (V'') may be referred to as compounds (I) to (IV), (V'), and (V''), respectively. The same applies to compounds having other formula numbers.

[0082] The definition of each group in formulae (I) to (V'') is explained below. Examples of linear or branched C8-C24 alkyl include octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, and 2,6,10,14-tetramethylpentadecyl. , icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, tetracosyl, etc., preferably nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc., more preferably undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, etc.

[0083] Examples of linear or branched C9-C18 alkyl include nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, and 6,10,14-trimethylpentadecan-2-yl. Preferred are nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl. More preferred are undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and hexadecyl.

[0084] The linear or branched C8-C24 alkenyl may be a linear or branched C8-24 alkenyl containing 1 to 3 double bonds, such as (Z)-tridec-8-enyl, (Z)-tetradec-9-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (E)-heptadeca-8-enyl, nyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl, (10Z,13Z )-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, 3,7,11,15-tetramethylhexadec-2-enyl, and the like are preferred, and (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-3-enyl, (Z)-hexadeca-4-enyl, (Z)-heptadeca-5-enyl, (Z)-pentadeca-6-enyl, (Z)-pentadeca-7-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadeca-9-enyl, (Z)-heptadeca-1-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-3-enyl, (Z)-pentadeca-4-enyl, (Z)-pentadeca-5-enyl, (Z)-pentadeca-6-enyl, (Z)-pentadeca-7-enyl, (Z)-pentadeca-8-enyl, (Z)-pentadeca-9-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-1-enyl, (Z)-pentadeca-2-enyl, (Z)-pentadeca-3-enyl, (Z)- Examples thereof include (Z)-octadec-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like, and more preferably include (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0085] Examples of linear or branched C15-C20 alkenyl include (Z)-pentadeca-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (E)-heptadeca-8-enyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, and the like. enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl, ( (10Z,13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 3,7,11,15-tetramethylhexadec-2-enyl, and the like are mentioned, and preferred are (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadec-5-enyl, (Z)-octadec-6-enyl, and (Z)-heptadec-8-enyl. , (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like, and more preferably (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0086] In the present invention, C8-C24 alkenyl also encompasses groups having a cyclopropane ring in which a methylene biradical is formally added to the double bond of a linear or branched, optionally substituted C8-C24 alkenyl. For example, the following groups having a cyclopropane ring corresponding to (Z)-hexadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and (8Z,11Z)-heptadeca-8,11-dienyl are

[0087] [ka]

[0088] [ka] and

[0089] [ka] etc.

[0090] The linear or branched C8-C24 alkynyl may be a linear or branched C8-24 alkynyl containing one to three triple bonds, and examples thereof include dodec-11-ynyl, tridec-12-ynyl, pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., preferably pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., more preferably heptadec-8-ynyl, octadec-9-ynyl, etc.

[0091] Examples of C1-C4 alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, etc., preferably methyl, ethyl, etc., more preferably methyl.

[0092] The alkyl moiety of the optionally substituted C1-C4 alkoxy has the same meaning as the C1-C4 alkyl defined above.

[0093] Substituents in the linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl include hydroxy, alkoxy, alkoxycarbonyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl moiety in the alkoxy and alkoxycarbonyl has the same meaning as the C1-C4 alkyl defined above.

[0094] Substituents in the optionally substituted C1-C4 alkyl include amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, alkoxy, alkoxycarbonyl, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two alkyls in dialkylamino and dialkylcarbamoyl may be the same or different.

[0095] In the present invention, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl and morpholin-3-yl each include those having a C1-C3 alkyl such as methyl or ethyl bonded to a nitrogen atom in the ring. Examples of C1-C3 alkyl include methyl, ethyl, propyl, isopropyl, and cyclopropyl, preferably methyl and ethyl, more preferably methyl.

[0096] X 2 and X 3Examples of the C4-C6 heterocycle formed by combining X with the adjacent nitrogen atom include pyrrolidine, piperidine, morpholine, and azepane, and preferred examples include pyrrolidine and piperidine. 2 and X 3 Examples of substituents in the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom include optionally substituted C1-C4 alkyl (as defined above), amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, and the like. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, alkoxy, alkoxycarbonyl, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two alkyls in dialkylamino and dialkylcarbamoyl may be the same or different.

[0097] X 5 and X 6 The heterocyclic moiety and the substituent moiety of the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom have the same meanings as defined above.

[0098] X 8 and X 9 The heterocyclic moiety and the substituent moiety of the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom have the same meanings as defined above.

[0099] X 11 and X 12 The heterocyclic moiety and the substituent moiety of the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom have the same meanings as defined above.

[0100] X 14 and X 15 The heterocyclic moiety and the substituent moiety of the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom have the same meanings as defined above.

[0101] X 16 and X 17 The heterocyclic moiety and the substituent moiety of the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom have the same meanings as defined above.

[0102] X 19 and X 20 The heterocyclic moiety and the substituent moiety of the optionally substituted C4-C6 heterocycle formed by combining these with the adjacent nitrogen atom have the same meanings as defined above.

[0103] Examples of the acyl in C1-C4 acyloxy include formyl, acetyl, propanoyl, 2-methylpropanoyl, cyclopropanoyl, butanoyl, etc., and preferred is acetyl.

[0104] Substituents in the optionally substituted C1-C4 acyloxy include amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, alkoxy, alkoxycarbonyl, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two alkyls in dialkylamino and dialkylcarbamoyl may be the same or different.

[0105] The quaternary ammonium group refers to a group having a nitrogen atom with four covalent bonds between it and four carbon atoms. Unlike primary, secondary, or tertiary amines to which hydrogen atoms have been added, the quaternary ammonium group always has a positive charge regardless of the surrounding pH.

[0106] Examples of pharmaceutically acceptable anions include, but are not limited to, inorganic ions such as chloride ion, bromide ion, iodide ion, nitrate ion, sulfate ion, and phosphate ion, and organic acid ions such as acetate ion, oxalate ion, maleate ion, fumarate ion, citrate ion, benzoate ion, and methanesulfonate ion.

[0107] In formula (I), R 1 ~R 3 are preferably the same linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl, more preferably the same linear or branched C8-C24 alkyl or C8-C24 alkenyl, even more preferably the same linear or branched C15-C20 alkenyl or the same linear or branched C9-C18 alkyl, and most preferably the same linear C15-C20 alkenyl or the same linear C9-C18 alkyl.

[0108] L 1 ~L 3 are the same or different and do not exist, or -Z 1 -(CY 1 Y 2 ) p1 -or-Z 2 -(CY 3 Y 4 ) p2 -Z 3 -(CY 5 Y 6 ) p3 - and -Z 1 -(CY 1 Y 2 ) p1 - is preferred. Y 1 ~Y6 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Y 1 ~Y 6 is preferably a hydrogen atom. 1 ~Z 3 are the same or different, -O-, -NY 7A -, -CO-O-, -O-CO-, -CO-NY 7B -,-NY 7C -CO- or -NY 7D -CO-0-, -O-, -CO-O-, -O-CO-, -CO-NY 7B -,-NY 7C -CO- is preferred. 7A ~Y 7D are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl, and is preferably a hydrogen atom or methyl. 1 ~p 3 are the same or different and are integers of 1 to 5, preferably 1 or 2.

[0109] L 1 ~L 3 The -O-(CY 1 Y 2 ) p1 -, -CO-O-(CY 1 Y 2 ) p1 -, -O-CO-(CY 1 Y 2 ) p1 -,-CO-NY 7B -(CY 1 Y 2 ) p1 -or- NY 7C -CO-(CY 1 Y 2 ) p1 -, which may be the same or different, and -CO-O-(CY 1 Y 2 ) p1 - or -O-CO-(CY 1 Y 2 ) p1 It is more preferable that they are -, and it is even more preferable that they are identical -CO-O-(CH2)2-.

[0110] In formula (I), L 1 ~L 3 One or more of the following may be the same or different: -CO-O-(CY 1 Y 2 ) p1 - or -O-CO-(CY 1 Y 2 ) p1 - and R 1 ~R 3 are preferably identically straight-chain C15-C20 alkenyl or identically straight-chain C9-C18 alkyl.

[0111] L 1 ~L 3 At least one of the following is absent or -O-(CY 1 Y 2 ) p1 -, -O-CO-(CY 1 Y 2 ) p1 -or- NY 7C -CO-(CY 1 Y 2 ) p1 -, the positively charged nitrogen atom (N + ), -O-(CY 1 Y 2 ) p1 -, -O-CO-(CY 1 Y 2 ) p1 -or-NR 6 -CO-(CY 1 Y 2 ) p1 -R binds to 1 ~R 3are the same or different and each represents octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, More preferred are dodecyl, tetradecyl, hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0112] L 1 ~L 3 At least one of the following is -CO-O-(CY 1 Y 2 ) p1 -or- CO-NY 7B -(CY 1 Y 2 ) p1 -, -CO-O-(CY 1 Y 2 ) p1 -or- CO-NY 7B -(CY 1 Y 2 ) p1 -R binds to 1 ~R 3are the same or different and each represents nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8 (Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadec-10-enyl, (10Z,13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 2,6,10,14-tetramethylpentadeca-1-enyl, and the like are more preferred, and undecyl, tridecyl, pentadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, and the like are even more preferred.

[0113] X 1 is preferably methyl, hydroxypropyl or hydroxyethyl, more preferably methyl.

[0114] In formula (II), R 4 ~R 6 are preferably the same linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl, more preferably the same linear or branched C8-C24 alkyl or C8-C24 alkenyl, even more preferably the same linear or branched C15-C20 alkenyl or the same linear or branched C9-C18 alkyl, and most preferably the same linear C15-C20 alkenyl or the same linear C9-C18 alkyl.

[0115] L 4 ~L 6 are the same or different and do not exist, or -Z 4 -(CY8 Y 9 ) p4 -or-Z 5 -(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 - and -Z 4 -(CY 8 Y 9 ) p4 -or-Z 5 -(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 - is preferred, and -Z 4 -(CY 8 Y 9 ) p4 - is more preferable. Y 8 ~Y 13 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Y 8 ~Y 13 is preferably a hydrogen atom. 4 ~Z 6 are the same or different, -O-, -NY 14A -, -CO-O-, -O-CO-, -CO-NY 14B -,-NY 14C -CO- or -NY 14D -CO-0-, -O-, -CO-O-, -O-CO-, -CO-NY 14B -,-NY 14C -CO- is preferred. 27A ~Y 27D are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl, and is preferably a hydrogen atom or methyl. 4 is an integer between 0 and 5, and p 5 is an integer from 1 to 5, and p 6 are integers of 0 to 5, and preferably 1 or 2.

[0116] L4 ~L 6 The -O-(CY 8 Y 9 ) p4 -, -CO-O-(CY 8 Y 9 ) p4 -, -O-CO-(CY 8 Y 9 ) p4 -,-CO-NY 14B -(CY 8 Y 9 ) p4 -,-NY 14C -CO-(CY 8 Y 9 ) p4 -,-NY 14D -CO-O-(CY 8 Y 9 ) p4 - or -O-CO-(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 -, which may be the same or different, and -CO-O-(CY 8 Y 9 ) p4 -, -O-CO-(CY 8 Y 9 ) p4 - or -O-CO-(CY 10 Y 11 ) p5 -O-(CY 12 Y 13 ) p6 It is more preferable that they are -, and it is even more preferable that they are identical -CO-O-CH2-.

[0117] In formula (II), one or more of L4 to L6 may be the same or different and represent -CO-O-(CY 8 Y 9 ) p4 -, -O-CO-(CY 8 Y 9 ) p4 - or -O-CO-(CY 10 Y 11 ) p5-O-(CY 12 Y 13 ) p6 - and R 4 ~R 6 are preferably identically straight-chain C15-C20 alkenyl or identically straight-chain C9-C18 alkyl.

[0118] L 4 ~L 6 At least one of the following is absent or -O-(CY 8 Y 9 ) p4 -, -O-CO-(CY 8 Y 9 ) p4 -,-NY 14C -CO-(CY 8 Y 9 ) p4 -,-NY 14D -CO-O- or -O-CO-(CY 10 Y 11 ) p5 -(CY 12 Y 13 ) p6 -If L 7 The carbon atom adjacent to -O-(CY 8 Y 9 ) p4 -, -O-CO-(CY 8 Y 9 ) p4 -,-NY 14C -CO-(CY 8 Y 9 ) p4 -,-NY 14D -CO-O- or -O-CO-(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 -R binds to 7 ~R 9are the same or different and each represents octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadec-9,12,15-trienyl, Preferred are dodecyl, tetradecyl, hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0119] L 4 ~L 6 At least one of the following is -CO-O-(CY 8 Y 9 ) p4 -or- CO-NY 14B -(CY 8 Y 9 ) p4 -, -CO-O-(CY 8 Y 9 ) p4 -or- CO-NY 14B -(CY 8 Y 9 ) p4 -R binds to 4 ~R 6are the same or different and each represent nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadeca-10 -enyl, (10Z,13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, and the like are preferred, and undecyl, tridecyl, pentadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, and the like are more preferred.

[0120] L 7 does not exist or is -(CY 15 Y 16 ) p7 -,-(CY 17 Y 18 ) p8 -O-CO-(CY 19 Y 20 ) p9 -or-(CY 17 Y 18 ) p8 -NY 27C -CO-(CY 19 Y 20 ) p9 - is preferred, and is absent or -(CY 15 Y 16 ) p7 In this case, B 1 teeth, [ka] Preferably, -N + More preferably, it is (CH3)3.

[0121] L 7 -(CY 15 Y 16 ) p7 -If p 7 is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. 15 ~Y 16 is preferably a hydrogen atom. 1 As -N + It is preferably (CH3)3.

[0122] L 7 -(CY 17 Y 18 ) p8 -O-CO-(CY 19 Y 20 ) p9 -or-(CY 17 Y 18 ) p8 -NY 27C -CO-(CY 19 Y 20 ) p9 -If p 8 is 0 to 3, and p 9 is preferably 1 to 3, and p 8 is between 0 and 1, and p 9 is more preferably 1 to 3, and Y 17 ~Y 20 are hydrogen atoms, and Y 27C is preferably a hydrogen atom or methyl. 1 As -N + It is preferably (CH3)3.

[0123] X 2 and X 3 are preferably the same or different and are methyl or ethyl, or are joined together with the adjacent nitrogen atom to form an optionally substituted C4-C6 heterocycle, more preferably are the same and are methyl, or are joined together with the adjacent nitrogen atom to form pyrrolidine or piperidine, and even more preferably are the same and are methyl.

[0124] X 4 is preferably methyl, ethyl, hydroxypropyl, hydroxyethyl, or the like, and more preferably methyl. X 2 and X 3 are the same or different and are methyl or ethyl, and X 4 is preferably methyl, ethyl, hydroxypropyl, hydroxyethyl, etc., and X 2 ~X 4 More preferably, is methyl.

[0125] B 1 but, [ka] and L 7 does not exist or -(CY 15 Y 16 ) p7 -,-(CY 17 Y 18 ) p8 -O-CO-(CY 19 Y 20 ) p9 -or-(CY 17 Y 18 ) p8 -NY 27C -CO-(CY 19 Y 20 ) p9 In this case, B 1 but, [ka] and L 7 is absent or -NH-CO-(CH2) p9 -, -O-CO-(CH2) p9 -, -CH2-NH-CO-(CH2) p9 - or -CH2-O-CO-(CH2) p9 - is more preferable.

[0126] In formula (III), R 7 are preferably linear or branched C8-C24 alkyl or C8-C24 alkenyl, more preferably linear or branched C15-C20 alkenyl or linear or branched C9-C18 alkyl, and most preferably identically linear C15-C20 alkenyl or identically linear C9-C18 alkyl. 8 and R 9 is preferably a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl and is the same, more preferably a linear or branched C15-C20 alkenyl or a linear or branched C9-C18 alkyl and is the same, and most preferably a linear C15-C20 alkenyl or a linear C9-C18 alkyl and is the same.

[0127] L 8 does not exist or is 12 -(CY 39 Y 40 ) p18 -or-Z 13 -(CY 41 Y 42 ) p19 -Z 14 -(CY 43 Y 44 ) p20 - and does not exist or -Z 12 -(CY 39 Y 40 ) p18 - is preferred. 9 and L 10 are the same or different and do not exist, or -Z 12 -(CY 39 Y 40 ) p18 -or-Z 13 -(CY 41 Y 42 ) p19 -Z 14 -(CY 43 Y 44 )p20 - and is the same or different and does not exist or -Z 12 -(CY 39 Y 40 ) p18 - is preferred. Y 39 ~Y 44 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Y 39 ~Y 44 is preferably a hydrogen atom. 12 ~Z 14 are the same or different, -O-, -NY 45A -, -CO-O-, -O-CO-, -CO-NY 45B -,-NY 45C -CO-, -NY 45D -CO-O- or -CO-, and -CO-O-, -O-CO-, -CO-NY 45B -,-NY 45C Y is preferably -CO- or -CO-. 45A ~Y 45D are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl, and is preferably a hydrogen atom or methyl. 18 is an integer of 0 to 5, and is preferably 0 or 1. 19 is an integer of 1 to 5, preferably 1 or 2. 20 is an integer of 0 to 5, and is preferably 0 or 1.

[0128] L 8 ~L 10 One of them is -CO-O-(CY 39 Y 40 ) p18 - or -O-CO-(CY 39 Y 40 ) p18 - or L 8 ~L 10 Two or more of the -CO-O-(CY 39 Y 40 ) p18 or -O-CO-(CY 39 Y 40 ) p18 - and R7 ~R 9 is preferably a straight chain C15-C20 alkenyl or C9-C18 alkyl, and R 8 ~R 9 are preferably the same.

[0129] L 8 As for the cyclic amine, it does not exist or is -CO-O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -,-CO-NY 45B -(CY 39 Y 40 ) p18 -or- NY 45C -CO-(CY 39 Y 40 ) p18 - is preferably absent or -CO-O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -or- CO-NY 45B -(CY 39 Y 40 ) p18 - is more preferred, and is absent or -CO-O-(CH2) p18 -, -O-CO-(CH2) p18 - or -CO-NH-(CH2) p18 It is even more preferable that L 9 and L 10 The same or different, -CO-O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -,-CO-NY 45B -(CY 39 Y 40 ) p18 -or- NY 45C -CO-(CY 39 Y 40) p18 - is preferably the same or different, is not present, or is -CO-O-(CY 39 Y 40 ) p18 - or -O-CO-(CY 39 Y 40 ) p18 -, which may be the same or different and is not present or -CO-O-(CH2) p18 -, and more preferably, they are not identical or -CO-O-(CH2) p18 - is most preferred.

[0130] In formula (III), L 8 ~L 10 Either one of the following is absent or -CO-O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -,-CO-NY 45B -(CY 39 Y 40 ) p18 -or- NY 45C -CO-(CY 39 Y 40 ) p18 - or L 8 ~L 10 Two or more of the same or different groups are not present, or -CO-O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -,-CO-NY 45B -(CY 39 Y 40 ) p18 -or- NY 45C -CO-(CY 39 Y 40 ) p18 - and R 7 ~R 9 is preferably a straight chain C15-C20 alkenyl or C9-C18 alkyl, and R 8 ~R 9are preferably the same.

[0131] L 8 ~L 10 At least one of the following is absent or -O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -,-NY 45C -CO-(CY 39 Y 40 ) p18 -or- NY 45D -CO-0-(CY 39 Y 40 ) p18 -If J 1 Or J 2 , -O-(CY 39 Y 40 ) p18 -, -O-CO-(CY 39 Y 40 ) p18 -,-NY 45C -CO-(CY 39 Y 40 ) p18 -or- NY 45D -CO-0-(CY 39 Y 40 ) p18 -R binds to 7 ~R 9are the same or different and each represents octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadec-9,12,15-trienyl, Preferred are dodecyl, tetradecyl, hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0132] L 8 ~L 10 At least one of the following is -CO-O-(CY 39 Y 40 ) p18 -,-CO-NY 45B -(CY 39 Y 40 ) p18 -or-CO-(CY 39 Y 40 ) p18 In the case of -CO-O-(CY 39 Y 40 ) p18 -,-CO-NY 45B -(CY 39 Y 40 ) p18 -or-CO-(CY 39 Y 40 ) p18 R binds to 7 ~R 9are the same or different and each represent nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadeca-10 -enyl, (10Z,13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, and 2,6,10,14-tetramethylpentadeca-1-enyl are preferred, and undecyl, tridecyl, pentadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, and the like are more preferred.

[0133] L 11 does not exist or is -(CY 46 Y 47 ) p21 -,-(CY 48 Y 49 ) p22 -Z 15 -(CY 50 Y 51 ) p23 -or-(CY 52 Y 53 ) p24 -Z 16 -(CY 54 Y 55 ) p25 -Z 17 -(CY 56 Y 57 ) p26 - and does not exist or -(CY 46 Y 47 ) p21 -or-(CY 48 Y 49 ) p22 -Z 15 -(CY 50 Y 51 )p23 - is preferred. Y 46 ~Y 57 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Y 46 ~Y 57 is preferably a hydrogen atom. 15 ~Z 17 are the same or different, -O-, -NY 58A -, -CO-O-, -O-CO-, -CO-NY 58B -,-NY 58C -CO-, -NY 58D -CO-O- or -CO-, and -CO-O-, -O-CO-, -CO-NY 58B -,-NY 58C -CO- or -CO- is preferred, and -O-CO- or -NY is preferred. 58C -CO- is more preferred. 21 is an integer of 1 to 5, preferably 1 to 3. 22 is an integer of 0 to 5, preferably 0 to 3. 23 is an integer of 1 to 5, preferably 1 or 2.

[0134] L 11 does not exist or -(CY 46 Y 47 ) p21 -,-(CY 48 Y 49 ) p22 -O-CO-(CY 50 Y 51 ) p23 - or -(CY 48 Y 49 ) p22 -NY 58C -CO-(CY 50 Y 51 ) p23 - is preferred, and is absent or -(CY 46 Y 47 ) p21 -, more preferably absent or -(CH2) p2 It is even more preferable that

[0135] L12 is not present or -(CY 59 Y 60 ) p27 -, and is preferably absent or -(CH2) p27 It is preferably -, and more preferably absent, -CH2- or -(CH2)2-.

[0136] J 1 and J. 2 Is the same or different CY 72 or N and J 1 and J. 2 are the same or different and are preferably CH, C(OH) or N.

[0137] L 11 When does not exist, J 1 is preferably CH.

[0138] L 9 and L 10 does not exist, and L 12 -CO-(CH2) p29 - and J 1 is CH and J 2 In one preferred embodiment of the present invention, L is N. 8 Ga-CO-NY 45B -(CH2) p18 - and L 11 is absent or -(CH2) p21 - is preferred.

[0139] L 9 and L 10 does not exist, and L 12 -O-CO-(CH2) p29 - and J 1 and J. 2 In one preferred embodiment of the present invention, L is CH. 8 -O-CO-(CH2) p18 - and L 11 is preferably absent.

[0140] B2 teeth, [ka] Preferably, -N + More preferably, it is (CH3)3.

[0141] X 8 ~X 10 are the X 2 ~X 4 is synonymous with.

[0142] In formula (IV), R 10 is preferably a linear or branched C8-C24 alkyl or C8-C24 alkenyl, more preferably a linear or branched C15-C20 alkenyl or a linear or branched C9-C18 alkyl, and most preferably a linear C15-C20 alkenyl or a linear C9-C18 alkyl. 11 and R 12 is preferably a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl and is the same, more preferably a linear or branched C15-C20 alkenyl or a linear or branched C9-C18 alkyl and is the same, and most preferably a linear C15-C20 alkenyl or a linear C9-C18 alkyl and is the same.

[0143] L 13 does not exist or is 23 -(CY 84 Y 85 ) p38 -or-Z 24 -(CY 86 Y 87 ) p39 -Z 25 -(CY 88 Y 89 ) p40 - and not present or -Z 23 -(CY 84 Y85 ) p38 - is preferred. Y 84 ~Y 89 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Y 84 ~Y 89 is preferably a hydrogen atom. 23 ~Z 25 are the same or different, -O-, -NY 90A -, -CO-O-, -O-CO-, -CO-NY 90B -,-NY 90C -CO- or -NY 90D -CO-0-, -CO-O-, -O-CO-, -CO-NY 90B -or- NY 90C -CO- is preferred, and -CO-NY 90B - is more preferable. Y 90A ~Y 90D are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl, and is preferably a hydrogen atom or methyl. 38 ~p 40 are the same or different and are integers of 1 to 5, preferably 1 or 2.

[0144] L 13 As for the cyclic amine, it does not exist or is -CO-O-(CY 84 Y 85 ) p38 -, -O-CO-(CY 84 Y 85 ) p38 -,-CO-NY 90B -(CY 84 Y 85 ) p38 -, or -NY 90C -CO-(CY 84 Y 85 ) p38 - is preferably absent or -CO-O-(CH2) p38 -, -O-CO-(CH2) p38 - or -CO-NCH3-(CH2) p38 - is more preferred, and is absent or -CO-NCH3-(CH2)p38 It is even more preferable that

[0145] L 14 and L 15 are the same or different and do not exist, or -Z 26 -(CY 91 Y 92 ) p41 -or-Z 27 -(CY 93 Y 94 ) p42 -Z 28 -(CY 95 Y 96 ) p43 - and not present or -Z 26 -(CY 91 Y 92 ) p41 - is preferred. Y 91 ~Y 96 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Y 91 ~Y 96 is preferably a hydrogen atom. 26 ~Z 28 are the same or different, -O-, -NY 97A -, -CO-O-, -O-CO-, -CO-NY 97B -,-NY 97C -CO-, -NY 97D -CO-O- or -CO-, and -CO-O-, -O-CO-, -CO-NY 97B -,-NY 97C -CO- or -CO- is preferred. 97A ~Y 97D are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl, and is preferably a hydrogen atom or methyl. 41 is an integer of 0 to 5, preferably 0 to 2. 42 is an integer of 1 to 5, preferably 1 or 2. 43 is an integer of 0 to 5, preferably 0 to 2.

[0146] L 14 and L 15The groups may be the same or different, absent or -CO-O-(CY 91 Y 92 ) p41 -, -O-CO-(CY 91 Y 92 ) p41 -,-CO-NY 97B -(CY 91 Y 92 ) p41 -,-NY 97C -CO-(CY 91 Y 92 ) p41 -, -CO-(CY 91 Y 92 ) p41 -, which may be the same or different, is absent or -CO-O-(CY 91 Y 92 ) p41 -, -O-CO-(CY 91 Y 92 ) p41 -or-CO-(CY 91 Y 92 ) p41 -, which may be the same or different, is absent or -CO-O-(CH2) p41 -, -O-CO-(CH2) p41 More preferably, it is - or -CO-.

[0147] In formula (IV), L 13 -CO-O-(CY 84 Y 85 ) p38 -, -O-CO-(CY 84 Y 85 ) p38 -or- CO-NY 90B -(CY 84 Y 85 ) p38 - or L 14 and L 15 One of them is -CO-O-(CY 91 Y 92 ) p41 - or -O-CO-(CY 91 Y 92 ) p41 - or L 13-CO-O-(CY 84 Y 85 ) p38 -, -O-CO-(CY 84 Y 85 ) p38 -or- CO-NY 89B -(CY 84 Y 85 ) p38 - and L 14 and L 15 One of them is -CO-O-(CY 91 Y 92 ) p41 - or -O-CO-(CY 91 Y 92 ) p41 - or L 14 and L 15 are the same or different -CO-O-(CY 91 Y 92 ) p41 - or -O-CO-(CY 91 Y 92 ) p41 - or L 13 -CO-O-(CY 84 Y 85 ) p38 -, -O-CO-(CY 84 Y 85 ) p38 -or- CO-NY 89B -(CY 84 Y 85 ) p38 - and L 14 and L 15 are the same or different -CO-O-(CY 91 Y 92 ) p41 - or -O-CO-(CY 91 Y 92 ) p41 - and R 10 ~R 12 More preferably, R is a linear or branched C15-C20 alkenyl or C9-C18 alkyl. 11 and R 12 are preferably the same.

[0148] L 13However, it does not exist or -O-(CY 84 Y 85 ) p38 -,-NY 90A -(CY 84 Y 85 ) p38 -, -O-CO-(CY 84 Y 85 ) p38 -,-NY 90C -CO-(CY 84 Y 85 ) p38 -or- NY 90D -CO-0-(CY 84 Y 85 ) p38 - If R 10 is octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z) -icosa-11-enyl, (11Z,14Z)-icosa-11,14-dienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl or 3,7,11,15-tetramethylhexadec-2-enyl, and more preferably dodecyl, tetradecyl, hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl.

[0149] L 13 But -CO-O-(CY 84 Y 85 ) p38 -or- CO-NY 90B -(CY 84 Y 85 ) p38 - If R 10are nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadec-10-enyl, (10Z, (13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl or 2,6,10,14-tetramethylpentadeca-1-enyl is more preferred, and undecyl, tridecyl, pentadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl or (8Z,11Z)-heptadeca-8,11-dienyl is even more preferred.

[0150] Also, L 14 and L 15 At least one of the following is absent or -O-(CY 91 Y 92 ) p41 -,-NY 97A -(CY 91 Y 92 ) p41 -, -O-CO-(CY 91 Y 92 ) p41 -,-NY 97C -CO-(CY 91 Y 92 ) p41 -or- NY 97D -CO-0-(CY 91 Y 92 ) p41 -If J 3 , -O-(CY 91 Y 92 ) p41 -,-NY 97A -(CY 91 Y 92 ) p41 -, -O-CO-(CY 91 Y92 ) p41 -,-NY 97C -CO-(CY 91 Y 92 ) p41 -or- NY 97D -CO-0-(CY 91 Y 92 ) p41 -R binds to 11 and R 12 are the same or different and each represents octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, More preferably, it is dodecyl, tetradecyl, hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, or (9Z,12Z)-octadeca-9,12-dienyl.

[0151] L 14 and L 15 At least one of the following is -CO-O-(CY 91 Y 92 ) p41 -or- CO-NY 97B (CY 91 Y 92 ) p41 -, -CO-O-(CY 91 Y 92 ) p41 -or- CO-NY 97B (CY 91 Y 92 ) p41 -R binds to 11 and R 12are the same or different and each represent nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadeca-10-enyl, More preferably, it is undecyl, tridecyl, pentadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, or (8Z,11Z)-heptadeca-8,11-dienyl.

[0152] L 16 does not exist or -(CY 98 Y 99 ) p44 -,-(CY 100 Y 101 ) p45 -Z 29 -(CY 102 Y 103 ) p46 -or-(CY 104 Y 105 ) p47 -Z 30 -(CY 106 Y 107 ) p48 -Z 31 -(CY 108 Y 109 ) p49 - and does not exist or -(CY 98 Y 99 ) p44 -or-(CY 100 Y 101 ) p45 -Z 29 -(CY 102 Y 103 )p46 - is preferred, and is absent or -(CY 98 Y 99 ) p44 -,-(CY 100 Y 101 ) p45 -O-CO-(CY 102 Y 103 ) p46 -,-(CY 100 Y 101 ) p45 -NY 109C -CO-(CY 102 Y 103 ) p46 -or-CO-(CY 102 Y 103 ) p46 - is more preferred, and is absent or -(CH2) p44 - or -CO-(CH2) p46 It is even more preferable that

[0153] J 3 CY 111 or N, preferably CH or N. 3 When is N, L 14 does not exist, and L 15 is -CO- and L 16 does not exist or -(CY 98 Y 99 ) p44 - or L 14 does not exist, and L 15 does not exist, and L 16 HA-CO-(CY 102 Y 103 ) p46 - is more preferable.

[0154] X 14 and X 15 are the X 2 and X 3 is synonymous with.

[0155] In formula (V'), R 13is preferably a linear or branched C8-C24 alkyl or C8-C24 alkenyl, more preferably a linear or branched C15-C20 alkenyl or a linear or branched C9-C18 alkyl, and most preferably a linear C15-C20 alkenyl or a linear C9-C18 alkyl. 14 and R 15 is preferably a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl and are the same, more preferably a linear or branched C15-C20 alkenyl or a linear or branched C9-C18 alkyl and are the same, and most preferably a linear C15-C20 alkenyl or a linear C9-C18 alkyl and are the same.

[0156] L 17 ~L 19 are the same or different and do not exist, or -Z 32 -(CY 116 Y 117 ) p51 -or-Z 33 -(CY 118 Y 119 ) p52 -Z 34 -(CY 120 Y 121 ) p53 - and -Z 32 -(CY 116 Y 117 ) p51 - is preferred, and -O-(CY 116 Y 117 ) p51 - or -CO-O-(CY 116 Y 117 ) p51 It is more preferably -, and further preferably -O- or -CO-O-.

[0157] In formula (V'), L 17 ~L 19 are the same or different and are -O- or -CO-O-, and R 13 ~R15 is preferably a linear C15-C20 alkenyl or C9-C18 alkyl. 17 ~L 19 are identically -O- or -CO-O-, and R 13 ~R 15 are preferably identically straight-chain C15-C20 alkenyl or C9-C18 alkyl.

[0158] L 17 ~L 19 At least one of the following is absent or -O-(CY 116 Y 117 ) p51 -, -O-CO-(CY 116 Y 117 ) p51 -,-NY 122C -CO-(CY 116 Y 117 ) p518 -or- NY 122D -CO-0-(CY 116 Y 117 ) p51 -, the furanose ring or L 20 The carbon adjacent to -O-(CY 116 Y 117 ) p51 -, -O-CO-(CY 116 Y 117 ) p51 -,-NY 122C -CO-(CY 116 Y 117 ) p518 -or- NY 122D -CO-0-(CY 116 Y 117 ) p51 -R binds to 13 ~R 15are the same or different and each represents octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadec-9,12,15-trienyl, Preferred are dodecyl, tetradecyl, hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0159] L 17 ~L 19 At least one of the following is -CO-O-(CY 116 Y 117 ) p51 -,-CO-NY 122B -(CY 116 Y 117 ) p51 -or-CO-(CY 116 Y 117 ) p51 -, -CO-O-(CY 116 Y 117 ) p51 -,-CO-NY 122B -(CY 116 Y 117 ) p51 -or-CO-(CY 116 Y 117 ) p51 -R binds to 13 ~R 15are the same or different and each represent nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadeca-10 -enyl, (10Z,13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, and 2,6,10,14-tetramethylpentadeca-1-enyl are preferred, and undecyl, tridecyl, pentadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, and the like are more preferred.

[0160] L 20 does not exist or is -(CY 123 Y 124 ) p54 -,-(CY 125 Y 126 ) p55 -Z 35 -(CY 127 Y 128 ) p56 -or-(CY 129 Y 130 ) p57 -Z 36 -(CY 131 Y 132 ) p58 -Z 37 -(CY 133 Y 134 ) p59 - and -(CY 123 Y 124 ) p54 - is preferred, and -(CH2) p54 It is more preferably -, and even more preferably -CH2-.

[0161] L21 does not exist or is -(CY 136 Y 137 ) p60 -,-(CY 138 Y 139 ) p61 -Z 38 -(CY 140 Y 141 ) p62 -or-(CY 142 Y 143 ) p63 -Z 39 -(CY 144 Y 145 ) p64 -Z 40 -(CY 146 Y 147 ) p65 - and does not exist or -(CY 136 Y 137 ) p60 - is preferably absent or -(CH2) p60 - is more preferred, and absent is even more preferred.

[0162] B 3 teeth, [ka] Preferably, -N + More preferably, it is (CH3)3.

[0163] Y 112 and Y 113 are the same or different and are a hydrogen atom, hydroxy or an optionally substituted C1-C4 alkyl, are the same or different and are preferably a hydrogen atom or hydroxy, and are more preferably the same and are a hydrogen atom.

[0164] In formula (V″), R 16 ~R 18 , L 22 ~L 26 , B 4 , Y 114 ~Y 115 and A 6 are R 13~R 15 , L 17 ~L 21 , B 3 , Y 112 ~Y 113 and A 5 is synonymous with.

[0165] In formula (V'), Y 112 When is a hydrogen atom, it is preferable that the four substituents on the pyran ring are each substituted on a different carbon atom on the pyran ring. [ka] It is more preferable that L 17 ~L 19 are the same or different and are -O- or -CO-O-, and R 13 ~R 15 More preferably, L is a straight-chain C15-C20 alkenyl or C9-C18 alkyl; 17 ~L 19 are the same or different and are -O- or -CO-O-, and R 13 ~R 15 is a straight-chain C15-C20 alkenyl or C9-C18 alkyl; L 17 and L 21 does not exist and Y 113 is most preferably a hydrogen atom or hydroxy.

[0166] In formula (V″), it is preferable that the four substituents on the furan ring are each substituted on a different carbon atom on the furan ring. [ka] It is more preferable that L 22 ~L 24 are the same or different and are -O- or -CO-O-, and R 16 ~R 18More preferably, L is a straight-chain C15-C20 alkenyl or C9-C18 alkyl; 22 ~L 24 are the same or different and are -O- or -CO-O-, and R 16 ~R 18 is a straight-chain C15-C20 alkenyl or C9-C18 alkyl; L 22 and L 26 does not exist and Y 114 is most preferably a hydrogen atom or hydroxy.

[0167] In addition, formula B 1 , B 2 , B 3 and B 4 In the definition of [ka] In the definition of each formula, p 13 , p 33 and p 66 If is 0, then N + are Z 10 , Z 21 and Z 41 It bonds to the carbon adjacent to

[0168] The nucleic acid-containing lipid nanoparticles of the present invention preferably contain, among lipid A, a lipid represented by formula (II).

[0169] The nucleic acid-containing lipid nanoparticles of the present invention may contain cationic lipids other than lipids (lipid A) having a hydrophilic portion with one quaternary ammonium group and three independent hydrocarbon groups, which may be substituted. The cationic lipids other than lipid A used in the present invention are not particularly limited as long as they are amphiphilic molecules having a lipophilic region containing one or more optionally substituted hydrocarbon groups and a cationic hydrophilic region containing at least one primary amino group, secondary amino group, tertiary amino group, and / or quaternary ammonium group (excluding lipid A). However, lipids (lipid B) having a hydrophilic portion with one optionally substituted amino group or one quaternary ammonium group and a hydrophobic portion with two optionally substituted independent hydrocarbon groups are preferred.

[0170] In the present invention, the lipid (lipid B) containing a hydrophilic part having one amino group or one quaternary ammonium group, which may be substituted, and a hydrophobic part having two independent hydrocarbon groups, which may be substituted, in the same molecule is not particularly limited as long as it has one amino group or one quaternary ammonium group, which may be substituted as a hydrophilic part, in the molecule, and two independent hydrocarbon groups, which may be substituted, and is, for example, represented by the following structural formulas (D) and (E). In the following structural formulas (D) and (E), the "hydrophilic unit" represents a hydrophilic unit having one amino group or one quaternary ammonium group, which may be substituted, and the "hydrophobic unit" represents an independent hydrocarbon group, which may be substituted.

[0171] The amino group constituting the "Hydrophilic Unit" has 0 to 2 of its 3 bonds bonded to 0 to 2 of the hydrocarbon groups constituting the "Hydrophobic Unit", and the remaining bonds bonded to hydrogen or an optionally substituted linear and / or cyclic hydrocarbon group, etc. Furthermore, the quaternary ammonium group constituting the "Hydrophilic Unit" has 0 to 2 of its four bonds bonded to 0 to 2 of the hydrocarbon groups constituting the "Hydrophobic Unit", and the remaining bonds bonded to hydrogen or an optionally substituted linear and / or cyclic hydrocarbon group, etc. The optionally substituted chain and / or cyclic hydrocarbon group constituting the "hydrophilic unit" may be any group consisting of carbon atoms and hydrogen atoms, but preferably has 1 to 10 carbon atoms, more preferably has 1 to 6 carbon atoms, and even more preferably has 1 to 3 carbon atoms.

[0172] Furthermore, the "hydrophilic unit" may have one or more ethers, esters, amides, etc. via carbon atoms in the optionally substituted linear and / or cyclic hydrocarbon groups, etc. that constitute it. Furthermore, examples of the substituents in the optionally substituted linear and / or cyclic hydrocarbon groups, etc. include carbamate, amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, etc.

[0173] The hydrocarbon group forming the "hydrophobic unit" may be any group consisting of 8 to 24 carbon atoms and hydrogen atoms. Hydrocarbon groups can be classified from the perspective of topology, including linear hydrocarbon groups, branched hydrocarbon groups, and cyclic hydrocarbon groups (e.g., cholesteryl groups, etc.), with linear or branched hydrocarbon groups being preferred. Hydrocarbon groups can also be classified based on the presence or absence of unsaturated bonds (double or triple bonds), and hydrocarbon groups with unsaturated bonds can also be classified based on the presence or absence of aromaticity. Preferred hydrocarbon groups are hydrocarbon groups (alkyls) consisting of only saturated bonds or hydrocarbon groups with unsaturated bonds but no aromaticity (e.g., alkenyl or alkynyl). Preferred hydrocarbon groups in lipid A are linear or branched C8-C24 alkyls, C8-C24 alkenyls, and C8-C24 alkynyls.

[0174] The hydrocarbon groups forming the "hydrophobic unit" may be bonded directly to the amino group or quaternary ammonium group of the "hydrophilic unit," or may be bonded to the amino group or quaternary ammonium group via an ether, ester, amide, or other bond and a linear and / or cyclic hydrocarbon group that may have a substituent that constitutes the "hydrophilic unit." Alternatively, as shown in structural formula (E), the hydrocarbon groups forming two "hydrophobic units" are bonded via a carbon atom, and this carbon atom may be bonded to the amino group or quaternary ammonium group of the "hydrophilic unit" directly or via an ether, ester, amide, or other bond and a linear and / or cyclic hydrocarbon group that may have a substituent that constitutes the "hydrophilic unit."

[0175] [ka]

[0176] The cationic lipid in the nucleic acid-containing lipid nanoparticles of the present invention may be lipid A alone or lipid B alone, but preferably contains both lipid A and lipid B.

[0177] Examples of cationic lipids other than lipid A used in the present invention include cationic lipids described in WO 2013 / 089151, WO 2011 / 136368, WO 2014 / 007398, WO 2010 / 042877, and WO 2010 / 054401.

[0178] Examples of the lipid B used in the present invention include lipids represented by the following formulae (CL-I) to (CL-XIX).

[0179] Formula (CL-I)

[0180] [ka] (In the formula, R 101 and R 102 are the same or different and are linear or branched C10-C24 alkyl, C10-C24 alkenyl, or C10-C24 alkynyl, L 101 and L 102 are a hydrogen atom or together form a single bond or a C1-C3 alkylene; L 103 is a single bond, -CO- or -CO-O-, L 103 If is a single bond, X 101is a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl; L 103 When is -CO- or -CO-O-, X 101 is pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl, or morpholinyl; Formula (CL-II)

[0181] [ka] (In the formula, R 103 and R 104 are the same or different and are linear or branched C12-C24 alkyl, C12-C24 alkenyl, or C12-C24 alkynyl, p 101 and p 102 are the same or different and are integers from 0 to 3, L 106 and L 107 are a hydrogen atom or together form a single bond or a C2-C8 alkylene; L104 and L 105 are the same or different and are -O-, -CO-O- or -O-CO-, L 108 is a single bond, -CO- or -CO-O-, L 108 If is a single bond, X 102 is a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl; L 108 When is -CO- or -CO-O-, X 102 is pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl, or morpholinyl; Formula (CL-III)

[0182] [ka] (In the formula, R 105 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 106 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl or C8-C24 alkynyloxypropyl, X 103 and X 104 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene, or X 103 is L 111 together to form a C2-C8 alkylene, L 111 is a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl, amino, monoalkylamino, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, or dialkylcarbamoyl, or X 103 together to form a C2-C8 alkylene, L 109 is C1-C6 alkylene, L 110 is a single bond or C1-C6 alkylene, provided that L 109 and L 110 The sum of the carbon numbers of L is 7 or less. 111 is a hydrogen atom, L 110 is a single bond, and L 111 is X 103 When L is taken together with 110 is a single bond or is methylene or ethylene), Formula (CL-IV)

[0183] [ka] (In the formula, R 107 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 108 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl, C8-C24 alkynyloxypropyl, C8-C24 alkyloxyethoxyethyl, C8-C24 alkenyloxyethoxyethyl or C8-C24 alkynyloxyethoxyethyl, X 105 is a hydrogen atom, an optionally substituted C1-C4 alkyl, or -CO-(CH2) n -NY1Y2, n represents an integer of 1 to 4; Y1 and Y2 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene; Formula (CL-V)

[0184] [ka] (In the formula, R 109 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 110 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl or C8-C24 alkynyloxypropyl, L 112 is C1-C3 alkylene, X 105' is a hydrogen atom or a C1-C3 alkyl, Formula (CL-VI)

[0185] [ka] (In the formula, R 111 and R 112 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; X 106 and X 107 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene; p 103 , p 104 and p 105 are the same or different and are 0 or 1, where p 103 , p 104 and p 105 is not 0 at the same time, L 113 and L 114 are the same or different and are O, S or NH), Formula (CL-VII)

[0186] [ka] (In the formula, R 113 and R 114 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 115 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 acyloxy, X 109 and X 110 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene; L 115 is -CO-O-, -O-CO-, -NHCO- or -CONH-, p 106 is an integer between 0 and 3, p 107 is an integer between 1 and 4), Formula (CL-VIII)

[0187] [ka] (In the formula, R 116 and R 117 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C7-C20 alkyloxyC1-C3 alkyl, C7-C20 alkenyloxyC1-C3 alkyl or C7-C20 alkynyloxyC1-C3 alkyl; the C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl having a biodegradable group incorporated therein, or a C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl group having a biodegradable group at its terminal, The biodegradable group is -C(O)O- or -OC(O)- when incorporated, and is -C(O)O-C1-C4 alkyl or -OC(O)-C1-C4 alkyl when terminal; B 100 represents a hydrogen atom, a C1-C3 alkyl, a hydroxy C2-C4 alkyl, a C1-C3 dialkylamino C2-C4 alkyl, a group represented by the formula (A) [ka] (In the formula, X 111 and X 112 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 111 and X 112 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded,110 is an integer of 2 to 6), or formula (B) [ka] (In the formula, X 113 and X 114 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 113 and X 114 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 111 is an integer from 1 to 6), p 108 is an integer between 0 and 4, and p 109 is an integer from 1 to 4 (where p 108 is 0 and p 109 except when is 1), L 116 are the same or different and are hydrogen atoms or C1-C3 alkyls at each carbon atom to which they are bonded, L 117 are the same or different and are hydrogen atoms or C1-C3 alkyls at each carbon atom to which they are bonded, Formula (CL-IX)

[0188] [ka] (In the formula, X 115 and X 116 are the same or different and are a hydrogen atom or a C1-C3 alkyl, L 118 and L 119 are the same or different and are linear or branched, optionally substituted C8-C24 alkylene or C8-C24 alkenylene, M 101 and M 102 are the same or different and are -C=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -OC(S)-, -C(S)O-, -SS-, -C(R ’’ )=N-, -N=C(R ’’ )-, -C(R’’ )=NO-, -ON=C(R ’’ )-, -N(R ’’ )C(O)-, -C(O)N(R ’’ )-, -N(R ’’ )C(S)-, -C(S)N(R ’’ )-, -N(R ’’ )C(O)N(R ’’’ )-, -N(R ’’ )C(O)O-, -OC(O)N(R ’’ )- and -OC(O)O-; R ’’ and R ’’’ are the same or different and are a hydrogen atom or a C1-C3 alkyl, R 118 and R 119 are the same or different and are linear or branched, optionally substituted C1-C16 alkyl or C2-C16 alkenyl), Formula (CL-X)

[0189] [ka] (In the formula, X 117 and X 118 are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, a heterocyclyl, or a polyamine; or X 117 and X 118 may be taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycle which may contain, in addition to the nitrogen, one or two further heteroatoms selected from N, O and S; R 120 and R 121 are the same or different and are linear or branched, optionally substituted C4-C24 alkyl or C4-C24 alkenyl), Formula (CL-XI)

[0190] [ka] (In the formula, X 119 and X 120 are the same or different and are a hydrogen atom, a linear or branched optionally substituted C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, or C6-C20 acyl, R 122 and R 123 are the same or different and are linear or branched, optionally substituted C1-C30 alkyl, C2-C30 alkenyl, or C2-C30 alkynyl; p 112 , p 113 and p 114 are the same or different and are either 0 or any positive integer.) Formula (CL-XII)

[0191] [ka] (In the formula, X 121 and X 122 are the same or different and are a hydrogen atom, C1-C6 alkyl, cycloalkyl, or cycloalkenyl, or X 121 and X 122 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which they are attached, L 120 and L 121 are the same or different and are -O-, -OC(O)- or -(O)CO-; R 124 and R 125 are the same or different and each represents a linear or branched, optionally substituted C8-C24 alkyl or C8-C24 alkenyl), Formula (CL-XIII)

[0192] [ka] (In the formula, R 126 and R127 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 heteroalkyl, C8-C24 heteroalkenyl, or C8-C24 heteroalkynyl; X 123 is a hydrogen atom or an optionally substituted C1-C6 alkyl, X 124 is C1-C6 alkyl, -NR 4a R 4b or optionally substituted C-C alkyl or C-C heterocyclyl substituted by R 4a and R 4b are the same or different and are a hydrogen atom, —C(═NH)NH or an optionally substituted C1-C6 alkyl, or R 4a and R 4b may be taken together with the nitrogen atom to which they are attached to form an optionally substituted C3-C7 heterocyclyl; X 123 and X 124 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted C3-C7 heterocyclyl; However, X 123 and X 124 does not form imidazolyl, benzimidazolyl, or succinimidyl groups, and only one primary amine is present at X 123 and X 124 or any primary amine may be present on either X 123 and X 124 X does not exist on either 123 and X 124 is not a substituted amide, R 126 and R 127 is C11 alkyl or C15 alkyl, X 123 is not a hydrogen atom, R 126 and R 127 is C16 alkyl or C17 alkyl, R 126and R 127 is not replaced with OH, R 126 and R 127 When is a C17 alkyl, X 123 and X 124 is not replaced with OH, R 126 and R 127 When is C18 alkyl, X 124 is optionally substituted imidazolyl and unsubstituted Formula (CL-XIV)

[0193] [ka] (In the formula, X 125 and X 126 are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, a heterocyclyl, or a polyamine; or X 125 and X 126 may be taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycle which may contain, in addition to the nitrogen, one or two further heteroatoms selected from N, O and S; R 130 is a hydrogen atom or C1-C6 alkyl, R 128 and R 129 are the same or different and are linear or branched, optionally substituted C4-C24 alkyl or C4-C24 alkenyl, Y3 and Y4 are the same or different and each represent an oxygen atom or CH2; p115 is an integer from 0 to 2. Formula (CL-XV)

[0194] [ka] (In the formula, X 127 and X 128are the same or different, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; X 127 and X 128 together with the nitrogen atom to which they are attached form a heterocyclic ring having 1 to 2 nitrogen atoms, L 122 -C(O)O-, -OC(O)-, -C(O)N(X 130 )-, -N(X 130 )C(O)-, -OC(O)O-, -OC(O)N(X 130 )-, -N(X 130 )C(O)N(X 130 )-, or -N(X 130 )C(O)O-, X 130 each occurrence is independently a hydrogen atom or a C1-C3 alkyl; a is 1, 2, 3, 4, 5, or 6; b is 0, 1, 2, or 3; X 129 is absent, hydrogen or C1-C3 alkyl; R 131 and R 132 are the same or different and are alkyl having 12 to 24 carbon atoms, alkenyl having 12 to 24 carbon atoms, or alkoxy having 12 to 24 carbon atoms, each having one or more biodegradable groups, and the biodegradable groups are independently incorporated into the alkyl group having 12 to 24 carbon atoms, alkenyl group having 12 to 24 carbon atoms, or alkoxy group having 12 to 24 carbon atoms, or are present at the terminal of the alkyl group having 12 to 24 carbon atoms, alkenyl group having 12 to 24 carbon atoms, or alkoxy group having 12 to 24 carbon atoms; The biodegradable groups incorporated are -C(O)O-, -OC(O)-, -C(O)N(X 130 )-, or -N(X 130 )C(O)-, and those present at the terminal are -C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl, -C(O)N(X 130 )-C1-C4 alkyl, or -N(X 130 )C(O)—C1-C4 alkyl; R131 and R 132 has at least four carbon atoms between the biodegradable group and the tertiary carbon atom marked with an asterisk (*); Formula (CL-XVI)

[0195] [ka] (In the formula, R 133 and R 134 are the same or different and are linear or branched C1-C9 alkyl, C2-C11 alkenyl, or C2-C11 alkynyl, L 123 and L 124 are the same or different and are linear C5-C18 alkylene or linear C5-C18 alkenylene, or form a heterocycle together with the N to which they are attached; L 125 is a single bond or -C(O)-O-, L 125 When is -C(O)O-, -L 124 -CO-OR 134 is formed, L 127 is S or O, L 126 is a single bond, or a linear or branched C1-C6 alkylene, or forms a heterocycle together with N bonded via -C(O)-; L 128 is a linear or branched C1-C6 alkylene, and X 131 and X 132 are the same or different and each is hydrogen or a linear or branched C1-C6 alkyl; Formula (CL-XVII)

[0196] [ka] (In the formula, L131 is C2-C4 alkylene or -CH2-S-CH2CH2-, L 129 and L 130 are the same or different and each is C1-C6 alkyl; R 135 and R 136 are the same or different and are C10-C30 alkyl or C10-C30 alkenyl, X 133 and X 134 are the same or different and are hydrogen, C1-C6 alkyl, or -CH2CH2OH; Formula (CL-XVIII)

[0197] [ka]

[0198] (In the formula, R 137 and R 138 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl, X 135 represents a hydrogen atom, a C1-C3 alkyl, a hydroxy C2-C4 alkyl, a group represented by the formula (C) [ka] (In the formula, X 136 and X 137 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 136 and X 137 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 132 is S or O, and p 115 is an integer of 2 to 4), formula (D) [ka] (In the formula, X 138 and X 139 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 138 and X 139 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 116 is an integer of 1 to 4), or formula (E) [ka] (In the formula, X 140 and X 141 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 140 and X 141 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 117 is an integer between 1 and 4. Formula (CL-XIX)

[0199] [ka]

[0200] (In the formula, R 139 and R 140 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl, L 133 is S or O, X 142 is a hydrogen atom, C1-C3 alkyl, hydroxy C2-C4 alkyl, formula (F) [ka] (In the formula, X 143 and X 144 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 143 and X 144may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 134 is S or O, and p 118 is an integer of 2 to 4), or formula (G) [ka] (In the formula, X 145 and X 146 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 145 and X 146 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 119 is an integer between 1 and 4.

[0201] One aspect of the present invention is a compound represented by formula (CL-XVIII) or formula (CL-XIX), or a pharmaceutically acceptable salt thereof. In the compound represented by Formula (CL-XVIII) or Formula (CL-XIX) of the present invention, a hydrogen ion may be coordinated to the lone pair of electrons on the nitrogen atom in the structure, and in that case, a salt may be formed with a pharmaceutically acceptable anion. In the present invention, the compound represented by Formula (CL-XVIII) or Formula (CL-XIX) or a pharmaceutically acceptable salt thereof also includes a cationic lipid in which a hydrogen ion is coordinated to the lone pair of electrons on the nitrogen atom in the structure. In the present invention, examples of pharmaceutically acceptable anions include inorganic ions such as chloride ion, bromide ion, nitrate ion, sulfate ion, and phosphate ion, and organic acid ions such as acetate ion, oxalate ion, maleate ion, fumarate ion, citrate ion, benzoate ion, and methanesulfonate ion. Pharmaceutically acceptable salts of the compound of the present invention represented by Formula (CL-XVIII) or Formula (CL-XIX) include, for example, hydrochloride, bromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. Among the compounds represented by Formula (CL-XVIII) or Formula (CL-XIX) of the present invention, stereoisomers such as geometric isomers or optical isomers, or tautomers, etc. may exist, and Compound (I) of the present invention encompasses all possible isomers, including these, and mixtures thereof. Some or all of the atoms in Formula (CL-XVIII) or Formula (CL-XIX) of the present invention may be replaced with the corresponding isotope atoms, and the compounds represented by Formula (CL-XVIII) or Formula (CL-XIX) also include compounds replaced with these isotope atoms. For example, some or all of the hydrogen atoms in Compound (I) may be replaced with hydrogen atoms having an atomic weight of 2 (deuterium atoms). The compounds of the present invention in which some or all of the atoms in formula (CL-XVIII) or formula (CL-XIX) are replaced with the corresponding isotope atoms can be produced by methods similar to the above-mentioned production methods using commercially available building blocks. Furthermore, compounds of formula (CL-XVIII) or formula (CL-XIX) in which some or all of the hydrogen atoms are replaced with deuterium atoms can be produced, for example, by a method in which alcohols, carboxylic acids, etc. are deuterized using an iridium complex as a catalyst and heavy water as a deuterium source [see J. Am. Chem. Soc., Vol. 124, No. 10, 2092 (2002)].

[0202] In the definition of each group in formula (CL-I), examples of the linear or branched C10-C24 alkyl include decyl, undecyl, dodecyl, tridecyl, 6,10-dimethylundec-2-yl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, and tetracosyl, and preferred are decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl, and more preferred are tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0203] The linear or branched C10-C24 alkenyl may be a linear or branched C10-C24 alkenyl containing 1 to 3 double bonds, and examples thereof include (Z)-dodec-7-enyl, (Z)-tetradec-7-enyl, (Z)-tetradec-9-enyl, (Z)-hexadec-4-enyl, (Z)-hexadec-7-enyl, (E)-hexadec-7-enyl, and (Z)-hexadeca- 9-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, (7Z,10Z,13Z)-hexadeca-7,10,13-trienyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (Z)-octadec-11-enyl, (9Z,12Z,15Z)-octadeca-9,1 2,15-trienyl, (Z)-icos-11-enyl, (11Z,14Z)-icosa-11,14-dienyl, and the like, and preferred are (Z)-dodec-7-enyl, (Z)-tetradec-7-enyl, (Z)-hexadec-4-enyl, (Z)-hexadec-7-enyl, (E)-hexadec-7-enyl, (Z)-hexadec-9-enyl, (7Z,10Z)-hexadeca-7,10- dienyl, (7Z,10Z,13Z)-hexadeca-7,10,13-trienyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (11Z,14Z)-icosa-11,14-dienyl, and the like, more preferably (7Z,10Z)-hexadeca-7,10-dienyl or (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0204] The linear or branched C10-C24 alkynyl may be a linear or branched C10-C24 alkynyl containing one to three triple bonds, and examples thereof include dec-9-ynyl, dodec-4-ynyl, dodec-11-ynyl, tetradec-5-ynyl, tetradec-6-ynyl, hexadeca-7-ynyl, hexadeca-3,5-diynyl, hexadeca-5,7-diynyl, and octadec-9-ynyl, preferably hexadeca-7-ynyl or octadec-9-ynyl, and more preferably octadec-9-ynyl.

[0205] In addition, in formula (CL-I), R 101 and R 103 are preferably the same linear or branched C10-C24 alkyl, C10-C24 alkenyl or C10-C24 alkynyl, more preferably the same linear or branched C10-C24 alkyl or C10-C24 alkenyl, and even more preferably the same linear C10-C24 alkenyl.

[0206] Examples of C1-C3 alkylene include methylene, ethylene, and propylene, preferably methylene or ethylene, and more preferably methylene.

[0207] Examples of C1-C6 alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, sec-pentyl, neopentyl, tert-pentyl, cyclopentyl, hexyl, and cyclohexyl, and preferred are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, and hexyl, and more preferred are methyl, ethyl, and propyl.

[0208] Examples of C3-C6 alkenyl include allyl, 1-propenyl, butenyl, pentenyl, and hexenyl, and preferred are allyl.

[0209] The monoalkylamino and dialkylamino may each be amino substituted with one or two identical or different C1-C6 alkyl (as defined above), or C1-C6 alkyl (as defined above) substituted with amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidinyl, piperidyl, or morpholinyl, and examples thereof include methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, ethylmethylamino, methylpropylamino, butylmethylamino, methylpentylamino, hexylmethylamino, aminoethylamino, aminopropylamino, (aminoethyl)methylamino, and bis(aminoethyl)amino, and preferred are methylamino, ethylamino, dimethylamino, diethylamino, aminopropylamino, and bis(aminoethyl)amino, and more preferred are methylamino and dimethylamino.

[0210] The trialkylammonio may be ammonio substituted with three, identical or different, C1-C6 alkyl (as defined above), or C1-C6 alkyl (as defined above) substituted with amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidinyl, piperidyl, or morpholinyl, and examples thereof include trimethylammonio, ethyldimethylammonio, diethylmethylammonio, triethylammonio, tripropylammonio, tributylammonio, tripentylammonio, trihexylammonio, tris(aminoethyl)ammonio, (aminoethyl)dimethylammonio, and bis(aminoethyl)methylammonio, and preferred examples include trimethylammonio, triethylammonio, tris(aminoethyl)ammonio, (aminoethyl)dimethylammonio, and bis(aminoethyl)methylammonio, and more preferred examples include trimethylammonio.

[0211] In compound (CL-I), trialkylammonio may form a salt with a pharmaceutically acceptable anion (as defined above).

[0212] The alkoxy may be a C1-C6 alkyl (as defined above) or a hydroxy substituted with a C1-C6 alkyl (as defined above) substituted with amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidinyl, piperidyl or morpholinyl, such as methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, aminoethoxy or methylaminoethoxy, preferably methoxy, ethoxy, aminoethoxy or methylaminoethoxy, more preferably methoxy.

[0213] The monoalkylcarbamoyl and dialkylcarbamoyl may be carbamoyl substituted with one or two identical or different C1-C6 alkyl (as defined above), or C1-C6 alkyl (as defined above) substituted with amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidinyl, piperidyl, or morpholinyl, and examples thereof include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, and dimethylcarbamoyl. Examples thereof include methylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, butylmethylcarbamoyl, methylpentylcarbamoyl, hexylmethylcarbamoyl, aminoethylcarbamoyl, aminopropylcarbamoyl, (aminoethyl)methylcarbamoyl, and bis(aminoethyl)carbamoyl. Preferred examples include methylcarbamoyl, ethylcarbamoyl, and dimethylcarbamoyl. More preferred examples include methylcarbamoyl and dimethylcarbamoyl.

[0214] L 101 and L 102 is more preferably a hydrogen atom. In this case, R 101 and R 102are the same or different and are dodecyl, tetradecyl, (Z)-dodec-7-enyl, (Z)-tetradec-7-enyl, (Z)-hexadec-4-enyl, (Z)-hexadec-7-enyl, (E)-hexadec-7-enyl, (Z)-hexadec-9-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, (7Z,10Z,13Z)-hexadeca-7,10,13-trienyl, (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12- Preferably it is dienyl, more preferably it is (Z)-tetradec-7-enyl, (Z)-hexadec-7-enyl, (7Z,10Z)-hexadeca-7,10-dienyl or (9Z,12Z)-octadeca-9,12-dienyl, and even more preferably it is identically (Z)-tetradec-7-enyl, (Z)-hexadec-7-enyl or (7Z,10Z)-hexadeca-7,10-dienyl or (9Z,12Z)-octadeca-9,12-dienyl. In addition, L 101 and L 102 is a hydrogen atom, X 101 is more preferably a hydrogen atom, methyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a C1-C6 alkyl or C3-C6 alkenyl substituted with 1 to 3 of the same or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, even more preferably a hydrogen atom, methyl, or a C1-C6 alkyl or C3-C6 alkenyl substituted with 1 to 3 of the same or different amino, hydroxy or carbamoyl, and even more preferably a hydrogen atom, methyl, etc.

[0215] L 101 and L 102 are taken together to form a single bond or C1-C3 alkylene, R 101 and R 102are the same or different and include tetradecyl, hexadecyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15- It is preferably (Z)-icosa-11-enyl or (11Z,14Z)-icosa-11,14-dienyl, more preferably (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl, and even more preferably identically (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl.

[0216] L 101 and L 102 are taken together to form a single bond or C1-C3 alkylene, X 101 is more preferably a hydrogen atom, methyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a C1-C6 alkyl or C3-C6 alkenyl substituted with 1 to 3 of the same or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, even more preferably a hydrogen atom, methyl, or a C1-C6 alkyl or C3-C6 alkenyl substituted with 1 to 3 of the same or different amino, hydroxy or carbamoyl, and most preferably a hydrogen atom, methyl, or the like.

[0217] L 101 and L 102 When these are taken together to form a single bond, L 103 In one of the more preferred embodiments of the present invention, X is -CO- or -CO-O-, preferably -CO-. 101is preferably aminomethyl, 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 1,4-diaminobutyl, 1,5-diaminopentyl, 3-aminopropyl, 4-aminobutyl, or 5-aminopentyl, and more preferably 1,2-diaminoethyl, 1,3-diaminopropyl, 1,4-diaminobutyl, or 1,5-diaminopentyl. 101 and R 102 are the same or different and include tetradecyl, hexadecyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15 -trienyl or (Z)-icos-11-enyl or (11Z,14Z)-icosa-11,14-dienyl, more preferably (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl, and even more preferably identically (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl.

[0218] L 103 is more preferably a single bond.

[0219] L 103 If is a single bond, X 101is more preferably a hydrogen atom, methyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a C1-C6 alkyl or C3-C6 alkenyl substituted by one to three identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl, or the like, even more preferably a hydrogen atom, methyl, hydroxymethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-3-methoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-carbamoylethyl, 2-dimethylcarbamoylethyl, 1-methylpiperidin-4-yl, or the like, and most preferably a hydrogen atom or methyl.

[0220] L 103 If is -CO- or -CO-O-, then X 101 is pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a C1-C6 alkyl or C3-C6 alkenyl substituted with 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl, and more preferably at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl, morpholinyl, or the like; R 3is more preferably aminomethyl, 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 3-aminopropyl, 1,4-diaminobutyl, 4-aminobutyl, 1,5-diaminopentyl, 5-aminopentyl, (N,N-dimethylamino)methyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 1-hydroxy-2-aminoethyl, 1-amino-2-hydroxyethyl, or the like, and most preferably 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 3-aminopropyl, 1,4-diaminobutyl, 4-aminobutyl, 1,5-diaminopentyl, 5-aminopentyl, or the like.

[0221] L 103 is a single bond, and X 101 In one preferred embodiment of the present invention, R is a hydrogen atom. 101 and R 102 are the same or different and include dodecyl, tetradecyl, (Z)-dodec-7-enyl, (Z)-tetradec-7-enyl, (Z)-hexadec-4-enyl, (Z)-hexadec-7-enyl, (E)-hexadec-7-enyl, (Z)-hexadec-9-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, (7Z,10Z,13Z)-hexadeca-7,10,13-trienyl, (Z)-octadecyl Preferably, they are (Z)-octadeca-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl, more preferably they are the same or different and are (Z)-tetradec-7-enyl or (7Z,10Z)-hexadeca-7,10-dienyl, and even more preferably they are the same and are (Z)-tetradec-7-enyl, (Z)-hexadeca-7-enyl or (7Z,10Z)-hexadeca-7,10-dienyl.

[0222] L 103 is a single bond, and X 101 In one more preferred embodiment of the present invention, R is methyl. 101 and R 102are the same or different and are dodecyl, tetradecyl, (Z)-dodec-7-enyl, (Z)-tetradec-7-enyl, (Z)-hexadec-4-enyl, (Z)-hexadec-7-enyl, (E)-hexadec-7-enyl, (Z)-hexadec-9-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, (7Z,10Z,13Z)-hexadeca-7,10,13-trienyl, (Z)-octadec-9-enyl or (9Z,12Z Preferably, they are the same or different and are (Z)-tetradec-7-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, or (9Z,12Z)-octadeca-9,12-dienyl, more preferably they are the same or different and are (Z)-tetradec-7-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, or (9Z,12Z)-octadeca-9,12-dienyl, and even more preferably they are the same or different and are (Z)-tetradec-7-enyl, (7Z,10Z)-hexadeca-7,10-dienyl, or (9Z,12Z)-octadeca-9,12-dienyl.

[0223] In the definitions of each group in formula (CL-II), examples of the linear or branched C12-C24 alkyl include dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, and icosyl. , 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, or tetracosyl, and the like are preferred, and dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or icosyl are more preferred, and dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl are more preferred.

[0224] The linear or branched C12-C24 alkenyl may be a linear or branched C12-C24 alkenyl containing one to three double bonds, and examples thereof include (Z)-tridec-8-enyl, (Z)-tetradec-9-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, and (E)-heptadeca-8-enyl. -enyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl, (10Z,13Z) -nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, and 3,7,11,15-tetramethylhexadec-2-enyl, and preferred are (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, and (Z)-heptadeca -5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, or (9Z,12Z)-octadeca-9,12-dienyl, and more preferably (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, or (9Z,12Z)-octadeca-9,12-dienyl.

[0225] The linear or branched C12-C24 alkynyl may be a linear or branched C12-C24 alkynyl containing one to three triple bonds, such as dodec-11-ynyl, tridec-12-ynyl, pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, or octadec-9-ynyl, preferably pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, or octadec-9-ynyl, more preferably heptadec-8-ynyl or octadec-9-ynyl.

[0226] In the definitions of each group in formula (CL-II), C1-C3 alkylene, C1-C6 alkyl, and C3-C6 alkenyl have the same meanings as in formula (CL-I) above.

[0227] The monoalkylamino, dialkylamino, trialkylammonio, alkoxy, monoalkylcarbamoyl and dialkylcarbamoyl have the same meanings as in the formula (CL-I) above.

[0228] R 103 and R 104 are preferably the same linear or branched C12-C24 alkyl, C12-C24 alkenyl or C12-C24 alkynyl, and more preferably the same linear or branched C12-C24 alkyl or C12-C24 alkenyl.

[0229] L 104 and L 105 are more preferably the same -O-, -CO-O- or -O-CO-.

[0230] L 104 and L 105 When at least one of is -O- or -O-CO-, R 103 and R 104are the same or different and include dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-isopropyl More preferably, it is cos-11-enyl, (11Z,14Z)-icosa-11,14-dienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, or 3,7,11,15-tetramethylhexadec-2-enyl, and even more preferably it is tetradecyl, hexadecyl, octadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, or (9Z,12Z)-octadeca-9,12-dienyl.

[0231] L 104 and L 105 When at least one of is -CO-O-, R 103 and R 104 are tridecyl, pentadecyl, heptadecyl, nonadecyl, henicosyl, tricosyl, (Z)-tridec-8-enyl, (Z)-pentadec-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl, (E)-heptadeca-8-enyl, (Z)-heptadeca-10-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (Z)-nonadec-10-enyl, (10Z,13Z) More preferably, it is (11Z,14Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl or 2,6,10,14-tetramethylpentadeca-1-enyl, and even more preferably it is tridecyl, pentadecyl, heptadecyl, (Z)-pentadeca-8-enyl, (Z)-heptadeca-5-enyl, (Z)-heptadeca-8-enyl or (8Z,11Z)-heptadeca-8,11-dienyl.

[0232] p 101 and p 102 More preferably, are 0 or 1 at the same time.

[0233] L 106 and L 107 More preferably, L are taken together to form a single bond or a C1-C3 alkylene. 106 and L 107 are taken together to form a single bond or C1-C3 alkylene, X 102 is more preferably a hydrogen atom, methyl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or a C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, and Methyl, or a C1-C6 alkyl or C3-C6 alkenyl substituted with one to three identical or different amino, trialkylammonio, hydroxy, or carbamoyl groups is more preferred, and a hydrogen atom, methyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, aminomethyl, 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 1,4-diaminobutyl, 1,5-diaminopentyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, or 2-carbamoylethyl is most preferred. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, trialkylammonio, alkoxy, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two or three alkyls in dialkylamino, trialkylammonio, and dialkylcarbamoyl may be the same or different.

[0234] L106 and L 107 When these are taken together to form a single bond, L 108 is preferably —CO— or —CO—O—, more preferably —CO—.

[0235] L 106 and L 107 When these are taken together to form a single bond, p 101 and p 102 are preferably the same or different and are 1 to 3.

[0236] L 106 and L 107 is a hydrogen atom, X 102is preferably a hydrogen atom, methyl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, More preferably, it is C1-C6 alkyl or C3-C6 alkenyl substituted with one to three identical or different amino, trialkylammonio, hydroxy, or carbamoyl groups, and even more preferably it is a hydrogen atom, methyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, aminomethyl, 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 1,4-diaminobutyl, 1,5-diaminopentyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, or 2-carbamoylethyl. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, trialkylammonio, alkoxy, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl group. The two or three alkyl groups in dialkylamino, trialkylammonio, and dialkylcarbamoyl may be the same or different.

[0237] L 108 is preferably a single bond. 108 If is a single bond, L 104 and L 105 is preferably —O—.

[0238] L 108 If is a single bond, X 102is preferably a hydrogen atom, methyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or a C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, and is preferably a hydrogen atom, methyl, hydroxymethyl, 2-hydroxyethyl, 2,3-dihydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl More preferred are 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 2-carbamoylethyl, 2-dimethylcarbamoylethyl, or 1-methylpiperidin-4-yl, and even more preferred are hydrogen, methyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, or 2-carbamoylethyl. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, trialkylammonio, alkoxy, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two or three alkyls in dialkylamino, trialkylammonio, and dialkylcarbamoyl may be the same or different.

[0239] L 104 and L 105 is more preferably -O-. 108 is a single bond, and X 102 If is a hydrogen atom, L 104 and L 105 are preferably the same -CO-O- or -O-CO-, and more preferably -CO-O-.

[0240] L 108 When is -CO- or -CO-O-, L104 and L 105 are preferably the same -CO-O- or -O-CO-, and more preferably -CO-O-.

[0241] L 108 If is -CO- or -CO-O-, then X 102 is preferably pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted with 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl, or morpholinyl, and at least one of the substituents is preferably amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl, or morpholinyl; X 102 is more preferably aminomethyl, 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 3-aminopropyl, 1,4-diaminobutyl, 4-aminobutyl, 1,5-diaminopentyl, 5-aminopentyl, (N,N-dimethylamino)methyl, 2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl, 1-amino-2-hydroxyethyl, etc., and even more preferably aminomethyl, 1,2-diaminoethyl, 2-aminoethyl, 1,3-diaminopropyl, 3-aminopropyl, 1,4-diaminobutyl, 4-aminobutyl, 1,5-diaminopentyl, 5-aminopentyl, etc. Among these substituents, the alkyl moiety in monoalkylamino, dialkylamino, trialkylammonio, alkoxy, monoalkylcarbamoyl, and dialkylcarbamoyl has the same meaning as the C1-C6 alkyl defined above. The two or three alkyl groups in the dialkylamino, trialkylammonio and dialkylcarbamoyl may be the same or different.

[0242] L 104 and L 105are preferably the same -CO-O- or -O-CO-, and more preferably -CO-O-.

[0243] In the definitions of the groups in formulae (CL-III), (CL-IV) and (CL-V), the linear or branched C8-C24 alkyl, C8-C24 alkenyl and C8-C24 alkynyl have the same meanings as in formulae (I) to (IV), respectively, and the same groups are preferred.

[0244] In the definitions of the groups of formulae (CL-III), (CL-IV), and (CL-V), examples of the alkyl moiety in the C8-C24 alkyloxyethyl and C8-C24 alkyloxypropyl include those exemplified above for the linear or branched C8-C24 alkyl.

[0245] Examples of the alkynyl moiety in alkynyloxyethyl and alkynyloxypropyl include those exemplified above for the straight-chain or branched C8-C24 alkynyl.

[0246] R 105 and R 106 are preferably the same or different and are linear or branched C8-C24 alkyl or C8-C24 alkenyl, more preferably the same or different and are linear or branched C8-C24 alkenyl, and even more preferably the same or different and are linear C8-C24 alkenyl. 105 and R 106 are more preferably the same, and in that case, are preferably linear or branched C12-C24 alkyl, C12-C24 alkenyl, or C12-C24 alkynyl, and more preferably linear C12-C24 alkenyl. The linear or branched C12-C24 alkyl, C12-C24 alkenyl, and C12-C24 alkynyl each have the same meaning as in formula (CL-II).

[0247] R 105 and R106 are preferably the same or different and are linear or branched C8-C24 alkyl or C8-C24 alkenyl, more preferably the same or different and are linear or branched C8-C24 alkenyl, and even more preferably the same or different and are linear C8-C24 alkenyl. 105 and R 106 are more preferably the same, and in that case, they are preferably linear or branched C15-C20 alkyl, C15-C20 alkenyl, or C15-C20 alkynyl, and more preferably linear C15-C20 alkenyl. The linear or branched C15-C20 alkyl, C15-C20 alkenyl, and C15-C20 alkynyl each have the same meaning as in the formulas (I) to (IV), and the same groups are preferred.

[0248] R 105 and R 106 If they are different, R 105 is a linear or branched C15-C20 alkyl, C15-C20 alkenyl, or C15-C20 alkynyl; R 106 is preferably a linear or branched C8-C12 alkyl. Here, examples of the linear or branched C8-C12 alkyl include octyl, nonyl, decyl, undecyl, and dodecyl, and preferably octyl, decyl, or dodecyl.

[0249] R 105 is a linear C15-C20 alkenyl, and R 106 is more preferably a linear C8-C12 alkyl, and R 105 is (Z)-octadec-9-enyl or (9Z,12Z)-octadeca-9,12-dienyl, and R 106 More preferably, is octyl, decyl or dodecyl.

[0250] R 105 and R 106 If they are different, R 105is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl, and R 106 is also preferably C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl or C8-C24 alkynyloxypropyl. In this case, R 105 is a linear C8-C24 alkenyl, and R 106 is more preferably C8-C24 alkenyloxyethyl, and R 105 is (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, or (11Z,14Z)-icosa-11,14-dienyl, and R 106 is more preferably (Z)-octadec-9-enyloxyethyl, (9Z,12Z)-octadeca-9,12-dienyloxyethyl or (11Z,14Z)-icosa-11,14-dienyloxyethyl, and R 105 is (9Z,12Z)-octadeca-9,12-dienyl, and R 106 is most preferably (9Z,12Z)-octadeca-9,12-dienyloxyethyl.

[0251] R 105 and R 106are the same or different and are linear or branched C8-C24 alkyl or C8-C24 alkenyl, and when they are the same or different and are linear or branched C8-C24 alkyl or C8-C24 alkenyl, they are the same or different and are tetradecyl, hexadecyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-icos-11-enyl, (11Z,14Z)-icosa-11,14-dienyl or (Z)-docosa-13-enyl Preferably, they are the same or different and are hexadecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (Z)-icosa-11-enyl, or (11Z,14Z)-icosa-11,14-dienyl, more preferably they are the same or different and are (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, or (11Z,14Z)-icosa-11,14-dienyl, further preferably they are the same or different and are (9Z,12Z)-octadeca-9,12-dienyl, and most preferably they are the same and are (9Z,12Z)-octadeca-9,12-dienyl.

[0252] R 107 is the R 105 is synonymous with R 107 is R 105 Preferred are groups similar to those shown in R 108 is preferably a straight-chain C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl, C8-C24 alkynyloxypropyl, C8-C24 alkyloxyethoxyethyl, C8-C24 alkenyloxyethoxyethyl or C8-C24 alkynyloxyethoxyethyl, more preferably a straight-chain C8-C24 alkyloxyethyl, C8-C24 alkenyloxyethyl or C8-C24 alkynyloxyethyl. 107 is a linear C15-C20 alkenyl, and R 108is most preferably C8-C24 alkenyloxyethyl.

[0253] R 109 and R 110 are the R 105 and R 106 and R 109 and R 110 The same groups as those shown in the above are preferred, except that R 109 and R 110 are preferably identically linear or branched C15-C20 alkyl, C15-C20 alkenyl, or C15-C20 alkynyl, and more preferably identically (9Z,12Z)-octadeca-9,12-dienyl.

[0254] X 103 and X 104 In the above formula, C1-C3 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, and cyclopropyl, preferably methyl or ethyl, and more preferably methyl.

[0255] X 103 and X 104 Examples of the C2-C8 alkylene formed by combining these groups include ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene, preferably butylene, pentylene, and hexylene, and more preferably hexylene.

[0256] X 103 L 111 Examples of the C2-C8 alkylene formed together with the above include ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene, preferably propylene, butylene, and pentylene, more preferably propylene and butylene, and even more preferably propylene.

[0257] X 103 and X 104are the same or different and are methyl or ethyl, or are taken together to form butylene, pentylene or hexylene, or X 103 L 111 Preferably, X is taken together with the olefin to form ethylene, propylene, or butylene. 103 and X 104 are preferably the same or different and are methyl or ethyl, or are taken together to form butylene, pentylene or hexylene; X 103 L 111 together with X to form ethylene, propylene or butylene, 104 It is also preferred that X is methyl or ethyl. 103 and X 104 More preferably, X are identically methyl or together form hexylene; 103 L 111 together to form propylene or butylene, and X 104 It is also more preferred that is methyl.

[0258] L 111 In the formula (CL-I), C1-C6 alkyl, C3-C6 alkenyl, monoalkylamino, alkoxy, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meanings as those in the formula (CL-I).

[0259] L 111 is a hydrogen atom, C1-C6 alkyl, amino, monoalkylamino, hydroxy, alkoxy, or C1-C6 alkyl substituted with 1 to 3 identical or different amino, monoalkylamino, hydroxy, or alkoxy, or X 103 and preferably form a C2-C6 alkylene together, and is a hydrogen atom, methyl, amino, methylamino, hydroxy, methoxy, or methyl substituted with 1 to 3 identical or different amino or hydroxy groups, or X 103and more preferably form ethylene, propylene or butylene, and are a hydrogen atom, a C1-C3 alkyl, or a hydroxy, or X 103 More preferably, X is taken together with a hydrogen atom or X to form propylene or butylene. 103 Most preferably, together with propylene.

[0260] L 109 and L 110 In the formula, C1-C6 alkylene includes, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene, etc., and preferably methylene or ethylene, etc.

[0261] L 109 is preferably methylene, ethylene, propylene, or the like, more preferably methylene or ethylene, and L 110 is preferably a single bond, methylene, ethylene, or the like, and more preferably a single bond, methylene, or the like. 109 and L 110 The sum of the carbon atoms in X is preferably 1 to 3, and more preferably 2. 103 and X 104 are the same or different and are methyl, ethyl, etc., and L 111 is a hydrogen atom, methyl, amino, methylamino, hydroxy, methoxy, or methyl substituted with 1 to 3 identical or different amino or hydroxy groups, or X 103 and X 104 together form pentylene, hexylene, heptylene, etc., and L 111 is a hydrogen atom, methyl, amino, methylamino, hydroxy, methoxy, or methyl substituted with 1 to 3 identical or different amino or hydroxy groups, or X 103 and L 111 together form propylene, butylene, or pentylene, etc., and X 104 is preferably methyl or ethyl, and X 103 and X 104is methyl and L 111 is a hydrogen atom or X 103 and X 104 together form pentylene or hexylene, and L 111 is a hydrogen atom or X 103 and L 111 together to form propylene, and X 104 is more preferably methyl or the like. X 105 Examples of the C1-C4 alkyl in X include methyl, ethyl, propyl, isopropyl, butyl, cyclobutyl, etc., and preferably methyl. 105 is more preferably a hydrogen atom.

[0262] In the definition of each group in formula (CL-V), X 105’ In the formula, C1-C3 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, etc., preferably methyl, ethyl, or isopropyl, etc., more preferably methyl or ethyl, etc. 105’ is more preferably a hydrogen atom or methyl, and most preferably a hydrogen atom.

[0263] L 112 In the formula, examples of the C1-C3 alkylene include methylene, ethylene, and propylene, and preferred are methylene and ethylene.

[0264] In the definitions of each group in formula (CL-VI) and formula (CL-VII), the linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, and C8-C24 alkynyl have the same meanings as in formulas (I) to (V'') above, respectively.

[0265] R in formula (CL-VII) 115In the optionally substituted C1-C4 alkyl, examples of the C1-C4 alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, etc., preferably methyl, ethyl, etc., more preferably methyl. The alkyl moiety of the optionally substituted C1-C4 alkoxy has the same meaning as the C1-C4 alkyl defined above. Substituents in the optionally substituted C1-C4 alkyl include amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, alkoxy, alkoxycarbonyl, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two alkyls in dialkylamino and dialkylcarbamoyl may be the same or different.

[0266] Examples of the acyl in the optionally substituted C1-C4 acyloxy include formyl, acetyl, propanoyl, 2-methylpropanoyl, cyclopropanoyl, butanoyl, etc., and preferred is acetyl. Substituents in the optionally substituted C1-C4 acyloxy include amino, monoalkylamino, dialkylamino, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, hydroxy, alkoxy, alkoxycarbonyl, hydroxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, nitro, cyano, fluoro, chloro, bromo, etc. Among these substituents, the alkyl moieties in monoalkylamino, dialkylamino, alkoxy, alkoxycarbonyl, monoalkylcarbamoyl, and dialkylcarbamoyl have the same meaning as the C1-C4 alkyl defined above. The two alkyls in dialkylamino and dialkylcarbamoyl may be the same or different.

[0267] In formula (CL-VI), R 111 and R 112 are preferably the same linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl, and more preferably the same linear or branched C8-C24 alkyl or C8-C24 alkenyl.

[0268] R 111 and R 112are the same or different and include octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-icos-11-enyl, (11Z,14Z)-icosa-11,14-dienyl, 3,7,11 Preferably, they are the same or different and are dodecyl, tetradecyl, (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, or the like, more preferably, they are the same or different and are (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, or the like, and even more preferably, they are the same and are (Z)-hexadec-9-enyl, (Z)-octadec-6-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, or the like.

[0269] X 106 and X 107 are preferably the same or different and are methyl or ethyl, and more preferably are the same and are methyl.

[0270] X 106 and X 107 Examples of the C2-C8 alkylene formed by combining these groups include ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene, preferably butylene, pentylene, and hexylene, and more preferably butylene and pentylene.

[0271] X 106 and X 107 are preferably identically methyl or together form butylene, pentylene or hexylene.

[0272] p 103 and 104 are preferably 0 at the same time, and p 105 is preferably 1.

[0273] L 113 and L 114 and are preferably O at the same time.

[0274] In formula (CL-VII), R 113 and R 114 are preferably the same linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl, and more preferably the same linear or branched C8-C24 alkyl or C8-C24 alkenyl.

[0275] X 109 and X 110 The C1-C3 alkyl and C2-C8 alkylene in the formula (CL-VI) have the same meanings as those in the formula (CL-VI).

[0276] R 115 is preferably a hydrogen atom, hydroxy, methyl, methoxy, or the like, more preferably a hydrogen atom or hydroxy, or the like, and even more preferably a hydrogen atom.

[0277] L 115 is preferably -O-CO- or -NH-CO-. In this case, p 106 is 0 or 1, and p 107 is preferably an integer of 1 to 3, and p 106 is 0 and p 107 is more preferably 1 or 3.

[0278] L 115 When -CO-O-, p 106 is 0 and p 107 is preferably an integer of 2 to 4, and p 106 is 0 and p 107 It is more preferred that the number is 3.

[0279] L 115 When is -CO-NH-, p 106 is 0 and p 107 is preferably an integer of 2 to 4, and p 106 is 0 and p 107 It is more preferred that the number is 3.

[0280] The definition of each group in Formulae (CL-VIII) to (CL-XIX) may be the same as that in Formulae (I) to (V″), or may be the same as that in Formulae (CL-I) to (CL-VIII).

[0281] R in formula (CL-XVIII) 137 and R 138 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl.

[0282] R 137 and R 138 In the formula (I), examples of the linear or branched C8-C24 alkyl include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, and tetracosyl.

[0283] R 137 and R 138In the formula (I), the linear or branched C8-C24 alkenyl may be a linear or branched C8-C24 alkenyl containing 1 to 3 double bonds, and examples thereof include (Z)-tridec-8-enyl, (Z)-tetradec-9-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (E)-heptadeca -8-enyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl, (10Z, (13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, 3,7,11,15-tetramethylhexadec-2-enyl, and the like are listed, and preferred are (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, and (Z)-heptadec-1,5,9-trienyl. Examples thereof include tadec-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like, and more preferably include (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0284] R 137 and R 138In the formula (I), the linear or branched C8-C24 alkynyl may be a linear or branched C8-24 alkynyl containing one to three triple bonds, and examples thereof include dodec-11-ynyl, tridec-12-ynyl, pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., preferably pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., more preferably heptadec-8-ynyl, octadec-9-ynyl, etc.

[0285] R 137 and R 138 In the above, the C8-C24 alkyl, C8-24 alkenyl, and C8-C24 alkynyl contained in the C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, and C8-C24 alkynylthioethyl can be the same as the C8-C24 alkyl, C8-24 alkenyl, and C8-C24 alkynyl mentioned above, respectively.

[0286] X 135 Examples of C1-C3 alkyl in the formula include methyl, ethyl, n-propyl, and isopropyl. X 135 Examples of the hydroxy C2-C4 alkyl in the formula (I) include hydroxyethyl, hydroxypropyl, and hydroxybutyl. The hydroxy group may be substituted at any position.

[0287] X 136 , X 137 , X 138 , X 139 , X 140 and X 141 Examples of the C1 to C3 alkyl in the above formula include methyl, ethyl, n-propyl, and isopropyl. X 136 and X 137 , X 138 and X 139, X 140 and X 141 Examples of the C3-C6 nitrogen-containing heterocycle that can be formed by the above include pyrrolidine, piperidine, morpholine, and azepane.

[0288] R in formula (CL-XIX) 139 and R 140 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl.

[0289] R 139 and R 140 In the formula (I), examples of the linear or branched C8-C24 alkyl include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, 2,6,10-trimethylundecyl, pentadecyl, 3,7,11-trimethyldodecyl, hexadecyl, heptadecyl, octadecyl, 6,10,14-trimethylpentadecan-2-yl, nonadecyl, 2,6,10,14-tetramethylpentadecyl, icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl, docosyl, tricosyl, and tetracosyl.

[0290] R 139 and R 140In the formula (I), the linear or branched C8-C24 alkenyl may be a linear or branched C8-C24 alkenyl containing 1 to 3 double bonds, and examples thereof include (Z)-tridec-8-enyl, (Z)-tetradec-9-enyl, (Z)-pentadeca-8-enyl, (Z)-hexadec-9-enyl, (Z)-heptadeca-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (E)-heptadeca -8-enyl, (E)-octadec-9-enyl, (Z)-heptadeca-10-enyl, (Z)-octadec-11-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, (8Z,11Z,14Z)-octadeca-8,11,14-trienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-nonadec-10-enyl, (Z)-icos-11-enyl, (10Z, (13Z)-nonadeca-10,13-dienyl, (11Z,14Z)-icosa-11,14-dienyl, 2,6,10-trimethylundeca-1,5,9-trienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 2,6,10,14-tetramethylpentadec-1-enyl, 3,7,11,15-tetramethylhexadec-2-enyl, and the like are listed, and preferred are (Z)-pentadec-8-enyl, (Z)-hexadec-9-enyl, and (Z)-heptadec-1,5,9-trienyl. Examples thereof include tadec-5-enyl, (Z)-octadec-6-enyl, (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like, and more preferably include (Z)-heptadeca-8-enyl, (Z)-octadec-9-enyl, (8Z,11Z)-heptadeca-8,11-dienyl, (9Z,12Z)-octadeca-9,12-dienyl, and the like.

[0291] R 139 and R 140In the formula (I), the linear or branched C8-C24 alkynyl may be a linear or branched C8-24 alkynyl containing one to three triple bonds, and examples thereof include dodec-11-ynyl, tridec-12-ynyl, pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., preferably pentadec-6-ynyl, hexadeca-7-ynyl, pentadeca-4,6-diynyl, hexadeca-5,7-diynyl, heptadec-8-ynyl, octadec-9-ynyl, etc., more preferably heptadec-8-ynyl, octadec-9-ynyl, etc.

[0292] X 146 Examples of C1-C3 alkyl in the formula include methyl, ethyl, n-propyl, and isopropyl. X 146 Examples of the hydroxy C2-C4 alkyl in the formula (I) include hydroxyethyl, hydroxypropyl, and hydroxybutyl. The hydroxy group may be substituted at any position.

[0293] X 143 , X 144 , X 145 and X 146 Examples of the C1 to C3 alkyl in the above formula include methyl, ethyl, n-propyl, and isopropyl. X 143 and X 144 , X 145 and X 146 However, examples of the C3-C6 nitrogen-containing heterocycles that can be formed include pyrrolidine, piperidine, morpholine, and azepane.

[0294] Further, each group in Formula (CL-VIII) is described in WO 2016 / 002753, each group in Formula (CL-X) is described in WO 2009 / 129385, each group in Formula (CL-XI) is described in WO 2013 / 149140, each group in Formula (CL-XII) is described in WO 2009 / 129395, and each group in Formula (CL-XIII) is described in WO 2013 / 059496. Each group in formula (CL-XIV) may be a preferred embodiment of the corresponding group described in WO 2011 / 149733, each group in formula (CL-XV) in WO 2011 / 153493, each group in formula (CL-XVI) in WO 2015 / 074085, and each group in formula (CL-XVII) in WO 2013 / 064911.

[0295] L in formula (CL-IX) 118 and L 119 are the same or different and are preferably linear or branched C8-C24 alkylene or C8-C24 alkenylene, more preferably linear or branched C8-C20 alkylene or C8-C20 alkenylene.

[0296] X in formula (CL-X) 117 and X 118 The C1-C6 alkyl, heterocyclyl or polyamine may be substituted with 1 to 3 substituents selected from a halogen atom, R', OR', SR', CN, CO2R' or CONR'2. X in formula (CL-X) 117 and X 118 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycle which may contain, in addition to the nitrogen, one or two further heteroatoms selected from N, O and S, the monocyclic heterocycle may be substituted with one to three substituents selected from a halogen atom, R', OR', SR', CN, COR' or CONR'. Here, R' is a hydrogen atom or C1-C6 alkyl, and the C1-C6 alkyl represented by R' may be substituted with a halogen atom or OH.

[0297] R in formula (CL-X) 120 and R 121 are the same or different and are preferably linear or branched C4-C24 alkyl or C4-C24 alkenyl, more preferably linear or branched C4-C20 alkyl or C4-C20 alkenyl. The C4-C24 alkyl or C4-C24 alkenyl may be substituted with one or more substituents selected from a halogen atom, R', OR', SR', CN, CO2R' or CONR'2. Here, R' is a hydrogen atom or C1-C6 alkyl, and the C1-C6 alkyl represented by R' may be substituted with a halogen atom or OH.

[0298] X in formula (CL-XI) 119 and X 120 When is a linear or branched optionally substituted C6-C20 acyl, the structure other than the carbonyl group in the C6-C20 acyl may be a C5-C19 alkyl, a C5-C19 alkenyl, or a C5-C19 alkynyl.

[0299] R in formula (CL-XII) 124 and R 125 are the same or different and are preferably linear or branched C8-C24 alkyl or C8-C24 alkenyl, more preferably linear or branched C14-C20 alkyl or C14-C20 alkenyl.

[0300] X in formula (CL-XIV) 125 and X 126 The C1-C6 alkyl, heterocyclyl or polyamine may be substituted with 1 to 3 substituents selected from a halogen atom, R', OR', SR', CN, CO2R' or CONR'2. X in formula (CL-XIV) 125 and X 126 together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycle which may contain, in addition to the nitrogen, one or two further heteroatoms selected from N, O and S, the monocyclic heterocycle may be substituted with one to three substituents selected from a halogen atom, R', OR', SR', CN, COR' or CONR'. Here, R' is a hydrogen atom or C1-C6 alkyl, and the C1-C6 alkyl represented by R' may be substituted with a halogen atom or OH.

[0301] R in formula (CL-XIV) 128 and R 129 are the same or different and are preferably linear or branched C4-C24 alkyl or C4-C24 alkenyl, more preferably linear or branched C4-C20 alkyl or C4-C20 alkenyl. The C4-C24 alkyl or C4-C24 alkenyl may be substituted with one or more substituents selected from a halogen atom, R', OR', SR', CN, CO2R' or CONR'2. Here, R' is a hydrogen atom or C1-C6 alkyl, and the C1-C6 alkyl represented by R' may be substituted with a halogen atom or OH.

[0302] R in Formula (CL-XVIII) 137 and R 138 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl, preferably the same or different and are linear C8-C24 alkenyl. X 135is a hydrogen atom, C1-C3 alkyl, or hydroxyC2-C4 alkyl, and is represented by formula (C), (D), or (E), preferably a hydrogen atom or formula (C) or formula (D), more preferably a hydrogen atom or formula (E), and even more preferably a hydrogen atom.

[0303] R in formula (CL-XIX) 139 and R 140 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl or C8-C24 alkynyl, preferably the same or different and are linear C8-C24 alkenyl. L 133 is S or O, preferably S. X 142 is a hydrogen atom, C1-C3 alkyl, hydroxyC2-C4 alkyl, formula (F), or formula (G), preferably C1-C3 alkyl, more preferably methyl.

[0304] In the nucleic acid-containing lipid nanoparticles of the present invention, among the lipids B, lipids represented by formula (CL-I) and lipids represented by formula (CL-II) are preferred, with lipids represented by formula (CL-I) being more preferred.

[0305] Specific examples of lipid B used in the present invention are shown in Tables 1 to 15 below, but the lipid B used in the present invention is not limited to these.

[0306] [Table 1]

[0307] [Table 2]

[0308] [Table 3]

[0309]

Table 4

[0310]

Table 5

[0311]

Table 6

[0312]

Table 7

[0313]

Table 8

[0314]

Table 9

[0315]

Table 10

[0316]

Table 11

[0317]

Table 12

[0318]

Table 13

[0319]

Table 14

[0320] [Table 15]

[0321] Next, a method for producing lipid A used in the present invention will be described. In the production methods shown below, if the defined groups change under the conditions of the production method or are inappropriate for carrying out the production method, the target compound can be obtained by using methods for introducing and removing protecting groups commonly used in organic synthetic chemistry [for example, the methods described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999)]. In addition, the order of reaction steps such as introducing substituents can also be changed as necessary.

[0322] In addition, general unit reactions such as etherification ("Experimental Chemistry Lectures, 4th Edition, 20: Synthesis of Organic Compounds II," 4th Edition, p. 187, Maruzen (1992), etc.), amination ("Experimental Chemistry Lectures, 4th Edition, 20: Synthesis of Organic Compounds II," 4th Edition, p. 279, Maruzen (1992), etc.), esterification ("Experimental Chemistry Lectures, 4th Edition, 22: Synthesis of Organic Compounds IV," 4th Edition, p. 43, Maruzen (1992), etc.), and amidation ("Experimental Chemistry Lectures, 4th Edition, 22: Synthesis of Organic Compounds IV," 4th Edition, p. 137, Maruzen (1992), etc.) described in the production methods shown below can also be carried out using general reaction conditions described in existing literature.

[0323] Compound (I) can be obtained by either synthetic route 1 or 2, or a method similar thereto.

[0324] Compound (I) can be obtained from ammonia according to synthetic route 1.

[0325] [ka] (wherein Ms represents a methanesulfonyl group, and the other groups are as defined above).

[0326] Compound 2 can be obtained by reacting ammonia with compound 1 in a solvent (for example, a polar solvent such as tetrahydrofuran or methanol) at high temperature (for example, 80° C. or higher).

[0327] Compound 2 and compound 3 are reacted in the presence of a base (e.g., an inorganic base such as sodium hydroxide) at high temperatures (e.g., 100°C or higher) to obtain compound 4. No solvent is particularly required, but a high-boiling solvent (e.g., a polar solvent such as ethylene glycol) can also be used in some cases.

[0328] Compound 4 and compound 5 are reacted in the presence of a base (e.g., an inorganic base such as sodium hydroxide) at high temperature (e.g., 100°C or higher) to obtain compound 6. A solvent is not particularly required, but a high-boiling solvent (e.g., a polar solvent such as ethylene glycol) can also be used in some cases.

[0329] A microwave reactor can be suitably used in each of the above three heating reactions. In addition, instead of Compound 1, Compound 3, and Compound 5, the corresponding halides such as bromides or iodides can also be used.

[0330] R 1 -L 1 and R 2 -L 2 Compound 4, which is the same as R, can also be obtained from ammonia using an excess amount of compound 1. 2 -L 2 and R 3 -L 3 Compound 6, which is the same as R , can also be obtained from compound 2 by using an excess amount of compound 3. 1 -L 2 , R 2 -L 2and R 3 -L 3 Compound 6, which has the same structure, can also be obtained from ammonia using an excess amount of compound 1.

[0331] Compound (I) can be obtained by reacting Compound 6 with Compound 7 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at a high temperature (e.g., 100°C or higher). For example, the anion A of Compound (I) can be obtained by treating (I) with a suitable anion exchange resin. 1 can also be converted to another anion.

[0332] Compounds used in the reactions, such as Compound 1, Compound 3, Compound 5, and Compound 7, can be obtained as commercially available products, by the methods described in the Examples or methods similar thereto, or by methods known in the literature (for example, the methods described in "5th Edition Experimental Chemistry Lectures 13: Synthesis of Organic Compounds I," 5th Edition, p. 374, Maruzen (2005) or the like) or methods similar thereto.

[0333] Compound 1 also has the corresponding R 1 -L 1 It can also be obtained by treating the -OH with mesylic anhydride or mesylic acid chloride.

[0334] Furthermore, compound R 1 -L 1 Of -OH, L 1 Ga-Z 1 -(CY 1 Y 2 ) p1 - (each group has the same meaning as above) is R 1 -OMs, R 1 -OH, R 1 -NY 7A -H(Y 7A is as defined above) or R 1 -CO2H and HO-(CY 1 Y 2 ) p1 -O-PRO 1 , MsO-(CY 1 Y2 ) p1 -O-PRO 1 , HO2C-(CY 1 Y 2 ) p1 -O-PRO 1 or H-NY 7A -(CY 1 Y 2 ) p1 -O-PRO 1 (In the formula, PRO 1 can be obtained by treating the silyl protecting group (e.g., triethylsilyl (TES), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), etc.) with any one of the following protecting groups: etherification (using a strong base such as sodium hydride), amination (e.g., a substitution reaction), esterification (using a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), or amidation (e.g., using a similar condensing agent), followed by deprotection. In addition, compound R 1 -L 1 Of -OH, L 1 Ga-Z 2 -(CY 3 Y 4 ) p2 -Z 3 -(CY 5 Y 6 ) p3 Those in which each group is - (each group has the same meaning as above) can also be obtained by using a reaction substrate corresponding to the target compound and applying a known reaction once or multiple times.

[0335] Compounds 3 and 5 can be prepared in a similar manner to compound 1.

[0336] Compound (Ia) can be obtained from compound 8 according to synthetic route 2.

[0337] [ka] (In the formula, M 1 ~M3 are the same or different - (CY 1 Y 2 ) p1 -or-(CY 3 Y 4 ) p2 -Z 3 -(CY 5 Y 6 ) p3 - (wherein each group is as defined above), and other groups are as defined above).

[0338] Compound 8 and compound 9 are treated in a solvent (e.g., a halogenated solvent such as chloroform) with a base (e.g., an organic base such as triethylamine), a condensing agent (e.g., a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), and an activating agent (e.g., an activating agent such as N,N-dimethylaminopyridine) to obtain compound 10.

[0339] Compound 12 can be obtained by esterifying compound 10 and compound 11 in the same manner as above.

[0340] Furthermore, compound 12 and compound 13 are esterified in the same manner as above to obtain compound 14.

[0341] R 1 and R 2 Compound 12, which is the same as R, can also be obtained from compound 8 using an excess amount of compound 9. 2 and R 3 Compound 14, which is the same as R, can also be obtained from compound 10 by using an excess amount of compound 11. 1 , R 2 and R 3 Compound 14, which is the same as compound 14, can also be obtained from compound 8 by using an excess amount of compound 9.

[0342] Compound (Ia) can be obtained by reacting Compound 14 with Compound 15 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at a high temperature (e.g., 100°C or higher). For example, the anion A of Compound (Ia) can be obtained by treating Compound (Ia) with a suitable anion exchange resin. 1 can also be converted to another anion.

[0343] Compounds used in the reactions, such as Compound 8, Compound 9, Compound 11, Compound 14, and Compound 15, can be obtained as commercially available products, by the methods described in the Examples or methods similar thereto, or by methods known in the literature (for example, the methods described in "5th Edition Experimental Chemistry Lectures 14: Synthesis of Organic Compounds II," 5th Edition, p. 1, Maruzen (2005), "4th Edition Experimental Chemistry Lectures 22: Synthesis of Organic Compounds IV," 4th Edition, p. 1, Maruzen (1992), etc.) or methods similar thereto).

[0344] Compound (II) can be obtained by any of the following synthetic routes 3 to 16, or by a method similar to these routes.

[0345] Compound (IIa) can be obtained from compound 15 according to synthetic route 3.

[0346] [ka] (In the formula, M 7 does not exist and M 4 Ha-(CY 8 Y 9 ) p4 - or M 7 does not exist and M 4 Ha-(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 - or M 7 Ha-Z 5 -(CY 10 Y 11 )p5 -And M 4 Ha-(CY 12 Y 13 ) p6 - (wherein each group has the same meaning as defined above). 8 does not exist and M 5 Ha-(CY 8 Y 9 ) p4 - or M 8 does not exist and M 5 Ha-(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 - or M 8 Ha-Z 5 -(CY 10 Y 11 ) p5 -And M 5 Ha-(CY 12 Y 13 ) p6 - Furthermore, M 9 does not exist and M 6 Ha-(CY 8 Y 9 ) p4 - or M 9 does not exist and M 6 Ha-(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 - or M 9 Ha-Z 5 -(CY 10 Y 11 ) p5 -And M 6 Ha-(CY 12 Y 13 ) p6 -. The other groups are as defined above.

[0347] Compound 22 can be obtained by sequentially reacting compound 16 with compound 17, compound 19, and compound 21 under the same reaction conditions as in the esterification reaction of compound 8 and compound 9 in synthetic route 2.

[0348] Compound (IIa) can be obtained by reacting Compound 22 and Compound 23 under the same reaction conditions as those used to synthesize Compound (Ia) by reacting Compound 14 and Compound 15 in Synthetic Route 2. For example, the anion A of Compound (IIa) can be obtained by treating Compound (IIa) with a suitable anion exchange resin. 2 can also be converted to another anion.

[0349] Compounds used in the reactions, such as Compound 16, Compound 17, Compound 19, Compound 21, and Compound 23, can be obtained as commercially available products, by the methods described in the Examples or methods similar thereto, or by methods known in the literature (e.g., the methods described in "5th Edition Experimental Chemistry Lectures 14: Synthesis of Organic Compounds II," 5th Edition, p. 1, Maruzen (2005), "4th Edition Experimental Chemistry Lectures 22: Synthesis of Organic Compounds IV," 4th Edition, p. 1, Maruzen (1992), etc.) or methods similar thereto).

[0350] Compound 16 can also be obtained by synthetic routes 11 to 15 described below.

[0351] Among compound 17, M 7 Ga-Z 5 -(CY 10 Y 11 ) p5 - is R 4 -OMs, R 4 -OH, R 4 -NY 14A -H (Y 14A is as defined above) or R 4 -CO2H and HO-(CY 10 Y 11 ) p5 -CO-O-PRO 2 , MsO-(CY 10 Y 11 )p5 -CO-O-PRO 2 , HO2C-(CY 10 Y 11 ) p5 -CO-O-PRO 2 or H-NY 14A -(CY 10 Y 11 ) p5 -CO-O-PRO 2 (In the formula, PRO 2 can be obtained by reacting with any one of protecting groups for carboxylic acid (e.g., methyl, tert-butyl, benzyl, etc.) by any one of etherification (e.g., using a strong base such as sodium hydride), amination (e.g., substitution reaction), esterification (e.g., using a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), or amidation (e.g., using a similar condensing agent), followed by deprotection.

[0352] Compounds 19 and 21 can be prepared in a similar manner to compound 17.

[0353] In synthetic route 3, X 4 That is, compound (IIa) can also be obtained by first reacting compound 16 with compound 23, and then esterifying with compounds 17, 19, and 21 in that order.

[0354] Compound (IIb) can be obtained from compound 16 according to synthetic route 4.

[0355] [ka] (wherein each group has the same meaning as defined above)

[0356] Compound 25 can be obtained by reacting compound 16 with compound 24 in a solvent (e.g., an aprotic solvent such as tetrahydrofuran or toluene) in the presence of a base (e.g., an inorganic base such as sodium hydride) at high temperature (e.g., 100°C or higher).

[0357] Compound 25 and compound 26 can be etherified in the same manner as above to give compound 27.

[0358] Compound 27 and compound 28 can be etherified in the same manner as above to give compound 29.

[0359] A microwave reaction apparatus can be suitably used in each of the above three heating reactions. In addition, instead of compounds 24, 26, and 28, the corresponding bromides or iodides can also be used.

[0360] R 4 -M 7 and R 5 -M 8 Compound 27, which is the same as R, can also be obtained from compound 16 using an excess amount of compound 24. 5 -M 8 and R 6 -M 9 Compound 29, which is the same as R , can also be obtained from compound 25 using an excess amount of compound 26. 4 -M 7 , R 5 -M 8 and R 6 -M 9 Compound 29, which is the same as compound 16, can also be obtained by using an excess amount of compound 24.

[0361] Compound (IIb) can be obtained by reacting compound 29 with compound 23 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at elevated temperatures (e.g., 100°C or higher). For example, the anion A of compound (IIb) can be obtained by treating (IIb) with a suitable anion exchange resin. 2can also be converted to another anion.

[0362] Compounds used in the reactions, such as Compound 16, Compound 24, Compound 26, Compound 28, and Compound 23, can be obtained as commercially available products, by the methods described in the Examples or methods similar thereto, or by methods known in the literature (for example, the methods described in "5th Edition Experimental Chemistry Lectures 14: Synthesis of Organic Compounds II," 5th Edition, p. 1, Maruzen (2005), "5th Edition Experimental Chemistry Lectures 13: Synthesis of Organic Compounds I," 5th Edition, p. 374, Maruzen (2005), etc.) or methods similar thereto).

[0363] Compound 24 also has the corresponding R 4 -M 7 It can also be obtained by treating the -OH with mesylic anhydride or mesylic acid chloride.

[0364] Furthermore, compound R 4 -M 7 Of the -OH, M 7 Ga-Z 5 -(CY 10 Y 11 ) p5 - (each group has the same meaning as above) is R 4 -OMs, R 4 -OH, R 4 -NY 14A -H(Y 14A is as defined above) or R 4 -CO2H and HO-(CY 10 Y 11 ) p5 -O-PRO 1 , MsO-(CY 10 Y 11 ) p5 -O-PRO 1 , HO2C-(CY 10 Y 11 ) p5 -O-PRO 1 or H-NY 14A -(CY 10 Y 11 ) p5 -O-PRO 1(each group has the same meaning as above) can be obtained by carrying out any one of etherification, amination, esterification, or amidation reaction with the hydroxyl group, followed by deprotection.

[0365] Compounds 26 and 28 can be prepared in a similar manner to compound 24.

[0366] As shown in synthetic pathway 5, compound (IIc) can be obtained from compound 25 obtained in synthetic pathway 4 by appropriately combining the respective reactions, such as esterification, in synthetic pathway 3. Furthermore, as shown in synthetic pathway 5, compound (IId) can be obtained from compound 27 obtained in synthetic pathway 4 by appropriately combining the respective reactions, such as esterification, in synthetic pathway 3.

[0367] [ka] (wherein each group has the same meaning as defined above)

[0368] Compound (IIe) can be obtained from compound 30 according to synthetic route 6.

[0369] [ka] (In the formula, M 10 , M 11 and M 12 are each independently O or NY 14A and the other groups have the same meanings as defined above.

[0370] Compound 33 can be obtained by sequentially subjecting compound 30 to an esterification or amidation reaction with compound 17, compound 19, and compound 21.

[0371] Compound (IIe) can be obtained by reacting Compound 33 and Compound 23 under the same reaction conditions as those used to synthesize Compound (Ia) by reacting Compound 14 and Compound 15 in Synthetic Route 2. For example, the anion A of Compound (IIe) can be obtained by treating (IIe) with a suitable anion exchange resin. 2 can also be converted to another anion.

[0372] Compound 30 can also be obtained by the methods of synthetic routes 11 to 15 described below.

[0373] Compound (IIf) can be obtained from compound 34 according to synthetic route 7.

[0374] [ka] (wherein each group has the same meaning as defined above)

[0375] Compound 35 can be obtained by protecting compound 34 with an appropriate protecting group.

[0376] Compound 36 can be obtained by reacting compound 35 with compound 23 under the same reaction conditions as those used to synthesize compound (Ia) by reacting compound 14 with compound 15 in synthetic route 2, followed by deprotection under appropriate conditions.

[0377] Compound (IIf) can be obtained by sequentially esterifying or amidating compound 36 with compound 37, compound 39, and compound 41. For example, the anion A of compound (IIf) can be obtained by treating compound (IIf) with a suitable anion exchange resin. 2 can also be converted to another anion.

[0378] Compounds 34, 35 and 36 are commercially available or can be obtained by the methods described in the Examples or methods analogous thereto.

[0379] Among the compounds 37, M 10 NY 14A If R 4 -M 7 -OMs (compound 24) and Y 14A It can also be obtained by reacting with NH2. Compounds 37 and 39 can be prepared in a similar manner to compound 35.

[0380] Compound (IIf) can be prepared by sequentially esterifying / amidating compound 24 with compounds 37, 39, and 41, and then reacting compound 23 to give compound X, as described in Synthetic Route 8. 4 can also be obtained by introducing

[0381] [ka] (wherein each group has the same meaning as defined above)

[0382] Compound (IIg) can be obtained from ethyl cyanoacetate according to synthetic route 9.

[0383] [ka] (wherein Et represents an ethyl group, LAH represents lithium aluminum hydride, and the other groups are as defined above.)

[0384] Compound 42 can be obtained by reacting ethyl cyanoacetate with compound 24 in a solvent (e.g., an aprotic solvent such as tetrahydrofuran) in the presence of a base (e.g., an inorganic base such as sodium hydride) and, if necessary, an additive (e.g., an additive such as tetrabutylammonium iodide) at high temperature (e.g., 60°C or higher).

[0385] Compound 42 and compound 26 can be reacted in a solvent (e.g., an aprotic solvent such as tetrahydrofuran) in the presence of a base (e.g., an inorganic base such as sodium hydride) and, if necessary, an additive (e.g., an additive such as tetrabutylammonium iodide) at high temperature (e.g., 60°C or higher) to obtain 43.

[0386] R 4 and R 5 Compound 43, which is the same as compound 24, can also be obtained from ethyl cyanoacetate using an excess amount of compound 24.

[0387] Compound 43 can be reduced with an excess of lithium aluminum hydride (LAH) in a solvent (eg, an aprotic solvent such as tetrahydrofuran) to give compound 44.

[0388] Compound 47 can be obtained by reacting Compound 44 with Compound 45, Compound 46, and Compound 23 in sequence in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform). 2 , X 3 and X 4 Compound 47, in which the formula is the same as that of the compound 44, can also be obtained by using an excess amount of compound 45.

[0389] Compound (IIg) can be obtained by reacting Compound 47 with Compound 21 under the same reaction conditions as in the esterification reaction of Compound 8 with Compound 9 in Synthetic Route 2. For example, the anion A of Compound (IIg) can be obtained by treating (IIg) with a suitable anion exchange resin. 2 can also be converted to another anion.

[0390] Compounds 45 and 46 are similar to compound 23.

[0391] Compound (IIh) can be obtained from dimethyl malonate according to synthetic route 10.

[0392] [ka] (In the formula, Me represents a methyl group, LAH represents lithium aluminum hydride, and the other groups are as defined above.)

[0393] Compound 48 can be obtained by reacting dimethyl malonate with compound 24 in a solvent (e.g., an aprotic solvent such as acetonitrile) in the presence of a base (e.g., an inorganic base such as cesium carbonate) and, if necessary, an additive (e.g., an additive such as tetrabutylammonium iodide) under heating (e.g., 50°C).

[0394] Compound 50 can be obtained by reacting compound 48 with compound 49 in a solvent (e.g., an aprotic solvent such as acetonitrile) in the presence of acetic anhydride and a base (e.g., an inorganic base such as sodium hydride).

[0395] Compound 50 can be reduced with an excess of lithium aluminum hydride (LAH) in a solvent (eg, an aprotic solvent such as tetrahydrofuran) to give compound 51.

[0396] Compound 52 can be obtained by reacting compound 51 with compound 19 and compound 21 under the same reaction conditions as in the esterification of compound 8 and compound 9 in synthetic route 2.

[0397] Compound (IIh) can be obtained by reacting Compound 52 with Compound 53 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at elevated temperatures (e.g., 100°C or higher). For example, the anion A of Compound (IIh) can be obtained by treating (IIh) with a suitable anion exchange resin. 2 can also be converted to another anion.

[0398] Compound 49 can be obtained commercially, by the method described in the Examples or a method analogous thereto, or by a method known in the literature (e.g., the method described in Helvetica Chimica Acta, Vol. 92, No. 8, pp. 1644-1656, 2009, etc.), or a method analogous thereto.

[0399] Compounds 54 and 56 can be obtained according to synthetic route 11.

[0400] [ka] (wherein each group has the same meaning as defined above)

[0401] Compound 54 can be obtained by protecting the hydroxy of compound 53. Additionally, compound 53 is commercially available.

[0402] Compound 55 can be obtained by reacting compound 54 with compound 45 and compound 46.

[0403] Compound 56 can be obtained by deprotecting compound 55.

[0404] Compounds 58-65 can be obtained according to synthetic route 12.

[0405] [ka] (wherein Hal is a halogen atom such as chlorine, bromine, or iodine, and the other groups are as defined above.)

[0406] Compound 58 can be obtained by protecting the hydroxy of compound 57. Additionally, compound 57 is commercially available.

[0407] Compound 59 can be obtained by reacting compound 58 with a halogenating reagent (eg, chlorine, bromine, iodine, iodine chloride, etc.).

[0408] Compound 60 can be obtained by reacting compound 59 with ammonia. Compound 61 can be obtained by reacting compound 60 with compound 45. Compound 63 can be obtained by reacting compound 61 with compound 46. Compound 63 can also be obtained by reacting compound 59 with compound 62.

[0409] Compound 63 can be obtained by deprotecting compound 62.

[0410] Compound 64 can be obtained by oxidizing compound 58 with a suitable oxidizing agent (eg, potassium permanganate, Jones reagent, etc.).

[0411] Compounds 67-73 can be obtained according to synthetic route 13.

[0412] [ka] (wherein each group has the same meaning as defined above)

[0413] Compound 66 can be obtained by reacting compound 59 with a cyanide (eg, sodium cyanide, potassium cyanide, lithium cyanide, etc.).

[0414] Compound 67 can be obtained by reducing compound 66 with lithium aluminum hydride or the like.

[0415] Compound 68 can be obtained by reacting compound 67 with compound 45. Compound 69 can be obtained by reacting compound 68 with compound 46.

[0416] Compound 70 can be obtained by deprotecting compound 69.

[0417] Compound 71 can be obtained by hydrolyzing compound 66 with a base (eg, sodium hydroxide).

[0418] Compound 72 can be obtained by reducing compound 71 (eg, with borane).

[0419] Compound 73 can be obtained by reacting compound 72 with a halogenating reagent (eg, chlorine, bromine, iodine, iodine chloride, etc.).

[0420] By sequentially carrying out the reactions from compound 59 in synthetic route 13 on compound 73, it is possible to obtain compounds 67, 68, 69, 71, 72, and 73, in which the alkylene chain between each functional group (amino group, monoalkylamino group, dialkylamino group, carboxylic acid, hydroxy, and halogen) and the quaternary carbon is further extended. Furthermore, by repeating this process, the alkylene chain between each functional group and the quaternary carbon can be freely extended.

[0421] Compound 76 can be synthesized according to synthetic route 14.

[0422] [ka] (In the formula, M 13 Ha-(CH2) p201 - and M 15 Ha-(CH2) p202 - (wherein p 201 ~p 202 is an integer from 1 to 5), M 14 is -O-, -CO-O- or -NY 27A - and PRO 4 is M 14 To match the protecting group for hydroxy, 1 , a protecting group PRO for carboxylic acid 2 , or a protecting group for the amine PRO 3(for example, a carbamate protecting group such as tert-butoxycarbonyl, or a benzyl protecting group)

[0423] Compound 74 can be obtained by the methods described in synthetic routes 11 to 13 or methods similar thereto.

[0424] Compound 75 can be obtained by appropriately protecting and deprotecting compound 74.

[0425] Compound 76 can be obtained from compound 75 as a starting material by the methods described in synthetic routes 11 to 13 or methods similar thereto.

[0426] As described in Synthetic Route 15, Compounds 77 to 79 can be obtained by using Compound 76 as a starting material, and sequentially carrying out protection and deprotection, and a method similar to Synthetic Route 14.

[0427] [ka] (In the formula, M 16 and M 17 are -(CH2), respectively. p203 - and -(CH2) p204- (wherein, p 203 ~p 204 is an integer of 1 to 5), and the other groups are as defined above.

[0428] Compounds 82, 84, 87, 89, 92 and 95 can be synthesized according to synthetic route 16.

[0429] [ka] (In the formula, M 18 Ha-(CY 19 Y 20 ) p9 -or-(CY 23 Y 24 ) p11 -Z 9 -(CY 25Y 26 ) p12 -. Also, b 1 teeth [ka] where Ar is a p-nitrophenyl group, Hal is a halogen atom such as chlorine, bromine, or iodine, and the other groups are as defined above. When p13 is 0, N is directly bonded to Z 10 )

[0430] Compound 82 can be obtained by condensing compound 80 with compound 81 by esterification, followed by deprotection.

[0431] Compound 84 can be obtained by condensing compound 83 with compound 81 by amidation, followed by deprotection.

[0432] Compound 87 can be obtained by condensing compound 85 and compound 86 by esterification, followed by deprotection.

[0433] Compound 89 can be obtained by condensing compound 85 and compound 88 by amidation, followed by deprotection.

[0434] Compound 92 can be obtained by subjecting Compound 90 and Compound 91 to a nucleophilic substitution reaction, followed by deprotection.

[0435] Compound 95 can be obtained by transesterification of Compound 93 and Compound 94, followed by deprotection.

[0436] Compounds 80, 83, 85, 90 and 93 can be obtained by synthetic routes 12 to 15 or methods similar thereto.

[0437] Among compounds 81, 86, 88, 91 and 94, M 18 -(CY 19 Y 20 ) p9Those in which the formula is - can be obtained as a commercially available product, or by the method described in the Examples or a method similar thereto, or by converting the functional group of a commercially available product in accordance with a standard method. In this case, b 1 but [ka] For compounds where [ka] (In the formula, M 37 is -OH, -CO2H or NY 38 (However, Y 38 is a hydrogen atom or an optionally substituted C1-C4 alkyl)) with a corresponding appropriate fragment by etherification, amination, esterification, amidation, etc.

[0438] In addition, among compounds 81, 86, 88, 91 and 94, M 18 -(CY 23 Y 24 ) p11 -Z 9 -(CY 25 Y 26 ) p12 - is M among compounds 81, 86, 88, 91 and 94. 18 -(CY 19 Y 20 ) p9 - can be obtained by condensing a suitable corresponding fragment to a compound similar to the above by etherification, amination, esterification, amidation, etc.

[0439] Compound (III) can be obtained by the methods of synthetic routes 17 to 21 or methods similar thereto.

[0440] Compound (IIIa) can be obtained from compound 96 according to synthetic route 17.

[0441] [ka] (wherein each group has the same meaning as defined above)

[0442] Compound (IIIa) can be obtained by reacting Compound 96 with Compound 97 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at elevated temperatures (e.g., 100°C or higher). For example, the anion A of Compound (IIIa) can be obtained by treating (IIIa) with a suitable anion exchange resin. 3 can also be converted to another anion.

[0443] Compound 96 can be obtained by the method described in the Examples or a method analogous thereto, or by the method described in the literature (US Patent Application Publication No. 2012 / 0172411) or a method analogous thereto.

[0444] Compounds used in the reaction, such as Compound 97, can be obtained as commercially available products, by the methods described in the Examples or methods similar thereto, or by methods known in the literature or methods similar thereto.

[0445] Compound (IIIb) can be obtained from ethyl glyoxylate according to synthetic route 18.

[0446] [ka] (In the formula, M 19 Ha-(CY 50 Y 51 ) p23 -or-(CY 54 Y 55 ) p25 -Z 17 -(CY 56 Y 57 ) p26 - (wherein each group has the same meaning as defined above), and b 2 teeth [ka] and the other groups have the same meanings as defined above. When p33 is 0, N is directly linked to Z 21 )

[0447] Compound 101 is obtained by reacting ethyl glyoxylate with Grignard reagents 98, 99, and 100 in a solvent (e.g., an ethereal solvent such as tetrahydrofuran). 7 , R 8 and R 9 The same compound 101 can also be obtained by reacting an excess amount of compound 98 with ethyl glyoxylate.

[0448] Compound 101 and compound 102 are treated in a solvent (e.g., a halogenated solvent such as chloroform) with a base (e.g., an organic base such as triethylamine), a condensing agent (e.g., a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), and an activating agent (e.g., an activating agent such as N,N-dimethylaminopyridine) to obtain compound 103.

[0449] Compound (IIIb) can be obtained by reacting Compound 103 with Compound 97, 104, or 105 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at elevated temperatures (e.g., 100°C or higher). For example, the anion A of Compound (IIIb) can be obtained by treating Compound (IIIb) with a suitable anion exchange resin. 3 can also be converted to another anion.

[0450] Compound 98 is R 7 Compounds 99 and 100 are similar to compound 98. Compounds 99 and 100 are obtained by sequentially reacting -OH (commercially available, or obtained by the method described in the Examples or a method analogous thereto) with a mesylation reagent (mesylic anhydride or mesylic chloride, etc.), a bromide salt (magnesium bromide or lithium bromide, etc.), and metallic magnesium.

[0451] Compounds 104 and 105 are similar to compound 23. Compound 102 is similar to compound 54.

[0452] Compounds 108, 109, and 112 can be obtained from ammonia, ethyl formate, and compound 99, respectively, according to synthetic route 19.

[0453] [ka] (In the formula, M 21 is -OH and M 22 is HO-CO- and M 25 is -O-CO- or M 21 Ha-NY 45C -H and M 22 is HO-CO- and M 25 Ha-NY 45C -CO- or M 21 is -CO-OH and M 22 is HO- and M 25 is -CO-O- or M 21 is -CO-OH and M 22 is H-NY 14B -And M 25 HA-CO-NY 14B - Also, M 20 does not exist and M 23 Ha-(CY 39 Y 40 ) p18 - or M 20 does not exist and M 23 Ha-(CY 41 Y 42 ) p19 -Z 14 -(CY 43 Y 44 ) p20 -or M 20 Ha-Z 13 -(CY 41 Y 42 ) p19 -And M 23 Ha-(CY 43 Y44 ) p20 -. Furthermore, M 24 Ha-(CY 63 Y 64 ) p29 - or -(CY 67 Y 68 ) p31 -Z 20 -(CY 69 Y 70 ) p32 -, and the other groups have the same meanings as defined above.

[0454] Compound 108 can be obtained by reacting ammonia, compound 106, and compound 107 under the same reaction conditions as those for synthesizing compound 4 from ammonia in synthetic route 1.

[0455] Compound 109 can be obtained by reacting ethyl formate, compound 99, and compound 100 under the same reaction conditions as those for synthesizing compound 101 from ethyl glyoxylate in synthetic route 18.

[0456] Compound 112 can be obtained by condensing compound 110 and compound 111 by esterification or amidation, followed by deprotection.

[0457] Compounds 106 and 107 are similar to compound 1. Of the 110 compounds, M 21 is -OH, R 1 -L 1 The same as —OH. In addition, M 21 Ga-NY 45C The compound 110 having M is the same as the compound 37. 21 When is —CO—OH, ​​it is the same as compound 17.

[0458] Compound 111 can be obtained as a commercially available product, by a method described in the Examples or a method similar thereto, or by a method known in the literature (for example, the method described in "Experimental Chemistry Lectures 20, Synthesis of Organic Compounds II," 4th Edition, p. 187, Maruzen (1992) or the like) or a method similar thereto.

[0459] Compounds (IIIc) and (IIId) can be obtained from compounds 108 and 112, and compounds 109 and 112, respectively, according to synthetic route 20.

[0460] [ka] (wherein each group has the same meaning as defined above)

[0461] Compound (IIIc) can be obtained by condensing Compounds 108 and 112 by amidation, followed by the reaction of Compound 114, 1115, or 116.

[0462] Compound (IIId) can be obtained by condensing compounds 109 and 112 by esterification, followed by the reaction of compound 114, 1115, or 116.

[0463] It should be noted that, for example, the anion A of compound (IIIc) or (IIId) can be obtained by treating compound (IIIc) or (IIId) with a suitable anion exchange resin. 3 can also be converted to another anion.

[0464] The compounds used in the reaction are as described above.

[0465] Compound (IV) can be obtained by the methods of synthetic routes 11 and 12 below, or by methods similar to these methods.

[0466] Compound 127 can be obtained according to synthetic route 21.

[0467] [ka] (In the formula, M 26 and M 27 are the same or different - (CY 91 Y 92 ) p41 - and M 28 and M 29 are the same or different -O-CO-(CY 91 Y 92 ) p41 - or -CO-O-(CY 91 Y 92 ) p41 - and M 30 and M 31 are the same or different and do not exist, or -O-CO-(CY 91 Y 92 ) p41 - or -CO-O-(CY 91 Y 92 ) p41 -, and the other groups are as defined above.

[0468] Compound 121 can be obtained by sequentially condensing compound 118 with compound 119 and compound 120 via an esterification reaction, or by sequentially condensing compound 122 with compound 123 and compound 124 via an esterification reaction.

[0469] Compound 125 can be obtained by reacting Compound 121 with a deprotecting reagent (e.g., a deprotecting reagent such as tetra-n-butylammonium fluoride) in a solvent (e.g., an ethereal solvent such as tetrahydrofuran), or by sequentially adding Compound 126 and Compound 127 to ethyl formate in a solvent (e.g., an ethereal solvent such as tetrahydrofuran).

[0470] Compound 125 can be reacted with an oxidizing agent (e.g., an organic oxidizing agent such as the Dess-Martin reagent or an inorganic oxidizing agent such as pyridinium chlorochromate) in a solvent (e.g., an aprotic solvent such as chloroform) to obtain compound 128.

[0471] Compounds used in the reactions, such as Compound 118, Compound 119, Compound 120, Compound 122, Compound 123, Compound 124, Compound 126, and Compound 127, are commercially available, or can be obtained by the methods described in the Examples or methods similar thereto, or by methods known in the literature ("4th Edition Experimental Chemistry Lectures 22: Synthesis of Organic Compounds IV", 4th Edition, p. 1, Maruzen (1992), "4th Edition Experimental Chemistry Lectures 20: Synthesis of Organic Compounds II", 4th Edition, p. 1, Maruzen (1992), and "4th Edition Experimental Chemistry Lectures 25: Synthesis of Organic Compounds VII", 4th Edition, p. 59, Maruzen (1991), etc.) or methods similar thereto.

[0472] Compound (IVa) can be obtained from compound 128 according to synthetic route 22.

[0473] [ka] (wherein each group has the same meaning as defined above)

[0474] Compound 130 can be obtained by reacting compound 128 with compound 129 in a solvent (e.g., a halogen-based solvent such as 1,2-dichloroethane) with a reducing agent (e.g., a hydride compound such as sodium borohydride or triacetoxyborohydride) in the presence of an additive (e.g., an acid such as acetic acid).

[0475] Compound 130 and compound 131 are reacted in the presence of a base (e.g., an inorganic base such as sodium hydroxide) at high temperature (e.g., 100°C or higher) to obtain compound 132. No solvent is particularly required, but a solvent such as ethylene glycol can also be used in some cases.

[0476] Compound (IVa) can be obtained by reacting Compound 132 with Compound 133 in the presence or absence of a solvent (e.g., a halogenated solvent such as chloroform) at room temperature or at elevated temperatures (e.g., 100°C or higher). For example, the anion A of Compound (IVa) can be obtained by treating Compound (IVa) with a suitable anion exchange resin. 4 can also be converted to another anion.

[0477] Compounds used in the reactions, such as Compound 129, Compound 131, and Compound 133, can be obtained as commercially available products, by the methods described in the Examples or methods similar thereto, or by methods known in the literature (e.g., the methods described in International Publication No. 2010 / 042877, International Publication No. 2010 / 054401, "5th Edition Experimental Chemistry Lectures 13: Synthesis of Organic Compounds I," 5th Edition, p. 374, Maruzen (2005), etc.), or methods similar thereto).

[0478] Compound (IVb) can be obtained according to synthetic route 23.

[0479] [ka] (In the formula, M 32 does not exist or is -Z 27 -(CY 93 Y 94 ) p42 -, Ns represents an o-nitrobenzenesulfonyl group, and the other groups are as defined above.

[0480] Compound 134, compound 135, triphenylphosphine, and diethyl azodicarboxylate are reacted, and then the resulting condensation product is reacted with a thiol (e.g., dodecane-1-thiol, thiophenol, etc.) to remove the Ns group, thereby obtaining compound 136.

[0481] Compounds 136 and 137 are amidated to give compound 138.

[0482] Compound (IVb) can be obtained by reacting compound 138 with 139. For example, the anion A of compound (IVb) can be obtained by treating compound (IVb) with a suitable anion exchange resin. 4 can also be converted to another anion.

[0483] Compound 134 is R 11 -L 14 It can be obtained by reacting o-nitrobenzenesulfonyl chloride with -NH2. 11 -L 14 -NH2 can be obtained as a commercially available product, by the method described in the Examples or a method similar thereto, or by a method known in the literature (for example, the method described in "Experimental Chemistry Lectures 20, Synthesis of Organic Compounds II," 4th Edition, p. 279, Maruzen (1992)) or a method similar thereto.

[0484] Compounds used in the reaction, such as compounds 135, 137 and 139, can be obtained by any of the methods described above.

[0485] Compound (V'a) can be obtained according to synthetic route 24.

[0486] [ka] (wherein DMTr represents a 2',2''-dimethoxytrityl group, and M 33 is -(CY 123 R 124 ) p54 -,-(CY 125 Y 126 ) p55 -Z 35 -(CY 127 R 128 ) p56 -or-(CY 129 R 130 ) p57 -Z 36 -(CY 131 Y 132 ) p58 -Z 37 -(CY 133 Y134 ) p59 -Wow, M 34 , M 35 , and M 36 are each independently -O- or -CO-O-, and the other groups are the same as defined above.

[0487] Compound 141 can be obtained by reacting compound 140 with 2′,2″-dimethoxytrityl chloride.

[0488] Compound 142 can be obtained by subjecting compound 141 to a three-step etherification or esterification.

[0489] Compound 143 can be obtained by treating compound 142 with acid.

[0490] Compound 144 can be obtained by activating compound 143 with a halogenating agent and then treating it with the corresponding amine compound.

[0491] Compound (V'a) can be obtained by reacting Compound 144 with Compound 145. For example, the anion A of Compound (V'a) can be obtained by treating (V'a) with a suitable anion exchange resin. 5 can also be converted to another anion.

[0492] Compound 140 can be obtained as a commercially available product, as a natural product, or by a method described in the Examples or a method analogous thereto, or by a method known in the literature (e.g., the method described in "The Organic Chemistry of Sugars," edited by Daniel E. Levy et al., Taylor & Francis, 2005) or a method analogous thereto.

[0493] Compound (V″a) can be obtained by a method similar to that of synthetic route 25, using compound 146 as a starting material.

[0494] [ka] (wherein each group has the same meaning as defined above)

[0495] Compound 146 can be obtained as a commercially available product, as a natural product, or by a method described in the Examples or a method analogous thereto, or by a method known in the literature (e.g., the method described in "The Organic Chemistry of Sugars," edited by Daniel E. Levy et al., Taylor & Francis, 2005) or a method analogous thereto.

[0496] Compounds (I) to (V'') can be obtained by any of the methods of the above synthetic routes 1 to 25, or by appropriately combining methods similar to these methods.

[0497] The lipid represented by compound (CL-I) can be obtained by the method described in WO 2013 / 089151 or a method similar thereto.

[0498] The lipid represented by compound (CL-II) can be obtained by the method described in WO 2011 / 136368 or a method similar thereto.

[0499] The lipids represented by compound (CL-III), compound (CL-IV) and compound (CL-V) can be obtained by the method described in WO 2014 / 007398 or a method similar thereto.

[0500] The lipid represented by compound (CL-VI) can be obtained by the method described in WO 2010 / 042877 or a method similar thereto.

[0501] Compound (CL-VII) can be obtained by the method described in WO 2010 / 054401, the method described in WO 2013 / 059496, or a method analogous thereto.

[0502] Compound (CL-VIII) can be obtained by the method described in WO 2016 / 002753 or a method analogous thereto.

[0503] Compound (CL-IX) can be obtained by the method described below or a method similar thereto.

[0504] The following describes a method for producing the compound of the present invention. In the following production methods, if the defined groups are changed under the conditions of the production method or are inappropriate for carrying out the production method, the target compound can be produced by using a method for introducing and removing protecting groups commonly used in organic synthetic chemistry [e.g., the method described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999)]. Furthermore, the order of reaction steps such as introducing substituents can be changed as necessary.

[0505] Manufacturing method 1 Among compounds (CL-IX), X 115 and X 116 Compounds (CL-IXa) in which both are hydrogen atoms, and X 115 and X 116 The compound (CL-IXb) in which are the same can be produced by the following method.

[0506] [ka]

[0507] (In the formula, R 118 , R 119 , M 101 , M 102 , L118 and L 119 are the same as defined above, and X in IX-IIIa and IX-IIIb may be the same or different and represent a leaving group such as a chlorine atom, a bromine atom, an iodine atom, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, or p-toluenesulfonyloxy; R 141 is a hydrogen atom, methyl or ethyl, and R 142 is a hydrogen atom or methyl, or R 141 and R 142 together with the adjacent carbons to form a cyclopropyl ring (provided that R 141 is a hydrogen atom or ethyl, R 142 is not methyl)

[0508] Steps 26 and 27 Compound (IX-IIa) can be produced by reacting 2-amino-2-methyl-1,3-propanediol with compound (IX-IIIa) in the presence of 1 to 10 equivalents of a base, either without a solvent or in a solvent, at a temperature between room temperature and 200°C for 5 minutes to 100 hours. Compound (CL-IXa) can be produced by reacting compound (IX-IIa) with compound (IX-IIIb) in the presence of 1 to 10 equivalents of a base, either without a solvent or in a solvent, at a temperature between room temperature and 200°C for 5 minutes to 100 hours.

[0509] Examples of the solvent include dichloromethane, 1,2-dichloroethane, toluene, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, and pyridine, and these can be used alone or in combination.

[0510] Examples of the base include sodium methoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and n-butyllithium.

[0511] Compound (IX-IIIa) and compound (IX-IIIb) are commercially available products or can be obtained by known methods (e.g., "5th Edition Experimental Chemistry Lectures 13: Synthesis of Organic Compounds I," 5th Edition, p. 374, Maruzen (2005)) or methods analogous thereto.

[0512] R 118 -M 101 -L 118 and R 119 -M 102 -L 119 When these are the same, compound (CL-IXa) can be obtained by using 2 or more equivalents of compound (IX-IIIa) in step 26.

[0513] 2-Amino-2-methyl-1,3-propanediol can be obtained commercially.

[0514] Process 28 Compound (CL-IXb) can be produced by reacting compound (CL-IXa) with 2 to 20 equivalents of compound (IX-IV) in a solvent, preferably in the presence of 1 equivalent to a large excess of a reducing agent and, if necessary, preferably 1 to 10 equivalents of an acid, at a temperature between -20°C and 150°C for 5 minutes to 72 hours.

[0515] Examples of the solvent include methanol, ethanol, tert-butyl alcohol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and water, and these may be used alone or in combination.

[0516] The reducing agent includes, for example, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.

[0517] The acid includes, for example, hydrochloric acid, acetic acid, and the like.

[0518] Compound (IX-IV) can be obtained as a commercially available product.

[0519] Manufacturing method 2 Among compounds (CL-IX), X 115 and X 116 Compounds (CL-IXc) and (CL-IXd) which are different in structure can be prepared by the following method.

[0520] [ka]

[0521] (In the formula, R 118 , R 119 , M 101 , M 102 , L 118 , L 119 , R 141 , R 142 and X are as defined above, and R 143 is X 115 and PG represents a protecting group.

[0522] Process 29 Compound (IX-IIb) can be produced by protecting compound (CL-IXa) with a protecting group commonly used in organic synthetic chemistry [for example, a protecting group described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999)].

[0523] Process 30 Compound (IX-IIc) can be produced by reacting compound (IX-IIb) with compound (IX-IIIc) in the presence of 1 to 10 equivalents of a base, either without a solvent or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 72 hours.

[0524] Examples of the solvent include dichloromethane, 1,2-dichloroethane, toluene, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, pyridine, N,N-dimethylformamide, and N,N-dimethylacetamide, and these can be used alone or in combination.

[0525] Examples of the base include sodium methoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, n-butyllithium, potassium carbonate, cesium carbonate, and triethylamine.

[0526] Compound (IX-IIIc) can be obtained as a commercially available product.

[0527] Process 31 Compound (CL-IXc) can be obtained by removing the protecting group PG from compound (IX-IIc) by an appropriate method. The protecting group can be removed by a method commonly used in organic synthetic chemistry (e.g., the method described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999)). This method allows the production of the desired compound.

[0528] Process 32 Compound (CL-IXd) can be produced by reacting compound (CL-IXc) with 1 to 10 equivalents of compound (IX-IV) in a solvent, preferably in the presence of 1 equivalent to a large excess of a reducing agent and, if necessary, preferably 1 to 10 equivalents of an acid, at a temperature between -20°C and 150°C for 5 minutes to 72 hours.

[0529] Examples of the solvent, reducing agent, and acid include those exemplified in Step 28.

[0530] Manufacturing method 3 Among compounds (CL-IX), M 101 and M 102 Compounds (CL-IXc') and (CL-IXd'), in which each is -OC(O)-, can also be prepared by the following method.

[0531] [ka]

[0532] (In the formula, R 118 , R 119 , M 101 , M 102 , L 118 , L 119 , R 141 , R 142 , R 143 and PG are as defined above, and B and B ’ is a straight-chain or branched C1-C16 alkyl or C2-C16 alkenyl.

[0533] Process 33 Compound (IX-IId) can be produced by reacting compound (IX-IIc') with an oxidizing agent in a solvent at a temperature between -20°C and 150°C for 5 minutes to 72 hours.

[0534] Examples of oxidizing agents include ozone, osmium tetroxide / sodium periodate, and osmium tetroxide / lead tetraacetate.

[0535] Examples of the solvent include those exemplified in step 28.

[0536] Compound (IX-IIc') can be produced by the method described in Production Method 2.

[0537] Process 34 Compound (IX-IIe) can be produced by reacting compound (IX-IId) with an oxidizing agent in a solvent at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours.

[0538] Examples of the oxidizing agent include Jones reagent, pyridinium dichromate, ruthenium tetroxide, and sodium chlorite.

[0539] Examples of the solvent include tert-butyl alcohol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetone, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and water, and these can be used alone or in combination.

[0540] Step 35 and Step 36 Compound (IX-IIf) can be produced by reacting compound (IX-IIe) with compound (IX-Va) in the presence of 1 to 10 equivalents of a condensing agent and 1 to 10 equivalents of a base, either without a solvent or in a solvent, at a temperature between room temperature and 200°C for 5 minutes to 100 hours. Furthermore, compound (IX-IIc'') can be produced by reacting compound (IX-IIf) with compound (IX-Vb) in the presence of 1 to 10 equivalents of a condensing agent and 1 to 10 equivalents of a base, either without a solvent or in a solvent, at a temperature between room temperature and 200°C for 5 minutes to 100 hours.

[0541] Examples of solvents include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and pyridine, and these can be used alone or in combination.

[0542] Examples of condensing agents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate.

[0543] Examples of the base include potassium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, pyridine, and the like.

[0544] Compound (IX-Va) and compound (IX-Vb) can be obtained as commercially available products.

[0545] R 118 and R 119 When are the same, compound (IX-IIc″) can be obtained by using 2 or more equivalents of compound (IX-Va) in step 35.

[0546] Process 37 Compound (CL-IXc') can be obtained by removing the protecting group PG of compound (IX-IIc'') by an appropriate method. The protecting group can be removed by a method commonly used in organic synthetic chemistry (e.g., the removal method described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999) or the like), thereby producing the desired compound.

[0547] Process 38 Compound (CL-IXd') can be produced by reacting compound (CL-IXc') with 1 to 10 equivalents of compound (IX-IV) in a solvent, preferably in the presence of 1 equivalent to a large excess of a reducing agent and, if necessary, preferably 1 to 10 equivalents of an acid, at a temperature between -20°C and 150°C for 5 minutes to 72 hours.

[0548] As the solvent and acid, those exemplified in Step 28 can be used.

[0549] Among compounds (CL-IX), compounds other than the compounds (CL-IXa) to (CL-IXd) can be produced by using raw materials, reagents, etc. suitable for the structure of the target compound in accordance with the above-mentioned production method or by applying a general production method commonly used in organic synthetic chemistry.

[0550] The intermediates and target compounds in each of the above production methods can be isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. Alternatively, the intermediates can be subjected to the next reaction without any particular purification.

[0551] R 115 and R 116 are the same or different and are a hydrogen atom or a C1-C3 alkyl. R 115 and R 116 are the same or different and are preferably a hydrogen atom, methyl, ethyl or propyl, more preferably a hydrogen atom or methyl. (R 115 ,R 116 ) are preferably (hydrogen atom, hydrogen atom), (hydrogen atom, methyl), (methyl, methyl), and more preferably (hydrogen atom, methyl), (methyl, methyl).

[0552] L 118 and L 119are the same or different and are linear or branched C8-C24 alkylene or C8-C24 alkenylene. L 118 and L 119 are the same or different, and when they are alkylene, they are preferably linear C8-C24 alkylene, more preferably linear C8-C20 alkylene, and even more preferably linear C8-C12 alkylene. L 118 and L 119 are the same or different and are preferably octylene, nonylene, undecylene, tridecylene or pentadecylene, more preferably octylene, nonylene or undecylene. L 118 and L 119 are the same or different, and when they are alkenylene, they are preferably linear C8-C24 alkenylene, more preferably linear C10-C20 alkenylene, and even more preferably linear C10-C12 alkenylene. L 118 and L 119 are the same or different and are preferably (Z)-undec-9-enylene, (Z)-trideca-11-enylene, (Z)-tetradec-9-enylene, (Z)-hexadeca-9-enylene, (Z)-octadec-9-enylene, (Z)-octadec-11-enylene, or (9Z,12Z)-octadeca-9,12-dienylene. L 118 and L 119 are preferably the same.

[0553] M 101 and M 102 are the same or different and are -C=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -OC(S)-, -C(S)O-, -SS-, -C(R ’’ )=N-, -N=C(R ’’ )-, -C(R ’’ )=NO-, -ON=C(R ’’ )-, -N(R ’’ )C(O)-, -C(O)N(R ’’ )-, -N(R’’ )C(S)-, -C(S)N(R ’’ )-, -N(R ’’ )C(O)N(R ’’’ )-, -N(R 3 )C(O)O-, -OC(O)N(R ’’ )- and -OC(O)O-. M 101 and M 102 are the same or different, and are preferably —C═C—, —OC(O)—, —C(O)O—, —C(O)(NR ’’ )-, -N(R ’’ )C(O)-, -N(R ’’ )C(O)-, -N(R ’’ )C(O)N(R ’’’ )-, -N(R ’’ )C(O)O-, -OC(O)N(R ’’ )-, -OC(O)O-, and more preferably -C=C-, -OC(O)-, or -C(O)O-. M 101 and M 102 Regarding the bonds in each structure, using -OC(O)- as an example, R 118 -OC(O)-L 118 This means that the structure is as follows. M 101 and M 102 are preferably the same.

[0554] M 101 and M 102 R in ’’ and R ’’’ are the same or different and are a hydrogen atom or a C1-C3 alkyl. R ’’ and R ’’’ is preferably a hydrogen atom, methyl, ethyl or propyl, more preferably a hydrogen atom or methyl, and even more preferably a hydrogen atom.

[0555] R 118 and R 119 are the same or different and are linear or branched C1-C16 alkyl or C2-C16 alkenyl. R118 and R 119 is the same or different, and when it is alkyl, it is preferably a straight-chain C1-C16 alkyl, more preferably a straight-chain C2-C9 alkyl. R 118 and R 119 are the same or different and are preferably pentyl, octyl, nonyl, decyl or dodecyl. R 118 and R 119 are the same or different, and when they are alkenyl, they are preferably straight-chain C2-C16 alkenyl, more preferably straight-chain C3-C9 alkenyl. R 118 and R 119 are the same or different and are preferably (Z)-hept-2-ene, (Z)-oct-2-ene, (Z)-non-2-ene, (Z)-non-3-ene, non-8-ene, (Z)-dodec-2-ene, or (Z)-tridec-2-ene. R 118 and R 119 are preferably the same.

[0556] R 118 -M 101 -L 118 and R 119 -M 102 -L 119 are the same or different, R 118 and R 119 , M 101 and M 102 , L 118 and L 119 The groups may be combinations of the structures described for each group. R 118 -M 101 -L 118 and R 119 -M 102 -L 119 are preferably the same. R 118 -M 101 -L 118 and R 119 -M 102 -L 119are the same or different and are preferably (Z)-tetradec-9-enyl, (Z)-hexadec-9-enyl, (Z)-octadec-9-enyl, (E)-octadec-9-enyl, (Z)-octadec-11-enyl, (9Z,12Z)-octadeca-9,12-dienyl, (9Z,12Z,15Z)-octadeca-9,12,15-trienyl, (Z)-icosapentyl and (Z)-docosa-13-enyl, more preferably selected from the group consisting of (Z)-hexadec-9-enyl, (Z)-octadec-9-enyl, (9Z,12Z)-octadeca-9,12-dienyl, and (11Z,14Z)-icosa-11,14-dienyl. R 118 -M 101 -L 118 and R 119 -M 102 -L 119 are the same or different and preferably have the following structures (1) to (5), more preferably have the same structures (1) to (5).

[0557] [ka] wherein n is an integer from 1 to 4.

[0558] The lipid represented by compound (CL-X) can be obtained by the method described in WO 2009 / 129385 or a method similar thereto.

[0559] The lipid represented by compound (CL-XI) can be obtained by the method described in WO 2013 / 1491401 or a method similar thereto.

[0560] The lipid represented by compound (CL-XII) can be obtained by the method described in WO 2009 / 129395 or a method analogous thereto.

[0561] The lipid represented by compound (CL-XIII) can be obtained by the method described in WO 2013 / 059496 or a method similar thereto.

[0562] The lipid represented by compound (CL-XIV) can be obtained by the method described in WO 2011 / 149733 or a method similar thereto.

[0563] The lipid represented by formula (CL-XV) can be obtained by the method described in WO 2011 / 153493 or a method similar thereto.

[0564] The lipid represented by formula (CL-XVI) can be obtained by the method described in WO 2015 / 074085 or a method similar thereto.

[0565] The lipid represented by formula (CL-XVII) can be obtained by the method described in WO 2012 / 170952 or a method similar thereto.

[0566] The lipid represented by formula (CL-XVIII) can be synthesized according to the following method. Examples of methods for synthesizing the lipid represented by formula (CL-XVIII) include the following synthesis method I for formula (CL-XVIII) and synthesis method II for formula (CL-XVIII). (Synthesis Method I of Formula (CL-XVIII))

[0567] [ka]

[0568] (In the formula, R 137 , R 138 and X 135 are the same as defined above, and in compound (XVIII-a) and compound (XVIII-c), Ms represents a methanesulfonyl group, and X" represents a halogen atom.

[0569] Process 39 Compound (XVIII-b) can be obtained by thioetherifying compound (XVIII-a) with 2-mercaptoethanol in the presence of 1 to 10 equivalents of a base for 5 minutes to 100 hours, either in the absence of a solvent or in a solvent, to obtain an alcohol compound, followed by halogenating the alcohol. Chlorination is preferred as the halogenation reaction, and an example of this reaction is a method in which methanesulfonyl chloride is reacted in the presence of 1 to 10 equivalents of a base for 5 minutes to 100 hours, either in the absence of a solvent or in a solvent.

[0570] Examples of the solvent include methanol, ethanol, tert-butyl alcohol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and water, and these may be used alone or in combination.

[0571] Examples of the base include cesium carbonate, triethylamine, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and n-butyllithium.

[0572] Compound (XVIII-a) is commercially available or can be obtained by a known method (e.g., "5th Edition Experimental Chemistry Lectures 13: Synthesis of Organic Compounds I", 5th Edition, p. 374, Maruzen (2005)) or a method analogous thereto.

[0573] Process 40 Compound (XVIII-d) can be produced by reacting compound (XVIII-c) with N-(tert-butoxycarbonyl)-2-nitrobenzenesulfonamide in the presence of a base, either without a solvent or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 72 hours to obtain a carbamate intermediate, and then reacting the intermediate with an acid, either without a solvent or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 72 hours. In the step of reacting compound (XVIII-c) with N-(tert-butoxycarbonyl)-2-nitrobenzenesulfonamide, a phase transfer catalyst such as tetrabutylammonium iodide may also be used.

[0574] Examples of the solvent include the same solvents as in step 39. Examples of the base include the same bases as in step 39.

[0575] The acid includes, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, and the like.

[0576] Compound (XVIII-c) is commercially available or can be obtained by a known method (e.g., "5th Edition Experimental Chemistry Lectures 13: Synthesis of Organic Compounds I", 5th Edition, p. 374, Maruzen (2005)) or a method analogous thereto.

[0577] Process 41 Compound (XVIII-b) and compound (XVIII-d) are reacted in the presence of a base, either without a solvent or in a solvent, at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours to obtain a lipid represented by formula (CL-XVIII) (wherein X 135 is a hydrogen atom). In the reaction between compound (XVIII-b) and compound (XVIII-d), a phase transfer catalyst such as tetrabutylammonium iodide may also be used.

[0578] Process 42 A lipid represented by formula (CL-XVIII) (wherein X is a methyl group) can be obtained by N-alkylation, N-carbonylation, N-acylation, or N-sulfonylation using a known method (e.g., "5th Edition Experimental Chemistry Lecture 13: Synthesis of Organic Compounds I," 5th Edition, p. 374, Maruzen (2005)) or a method similar thereto. 135 is C1-C3 alkyl, hydroxy C2-C4 alkyl, or any of formula (C), formula (D), and formula (E).

[0579] (Synthesis Method II of Formula (CL-XVIII)) The lipid represented by formula (CL-XVIII) is a compound represented by the formula R 138 When is C8-C24 alkynyl C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl, it can be suitably produced by synthesis method II of formula (CL-XVIII).

[0580] [ka]

[0581] (In the formula, R 137 , X 135 are as defined above, and R 138 represents C8-C24 alkynyl C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl, and Ms in compound (XVIII-a) and compound (XVIII-g) represents a methanesulfonyl group, and Boc represents a benzyloxycarbonyl group.

[0582] Process 43 Compound (XVIII-e) can be obtained by reacting compound (XVIII-a) with potassium thioacetate, either without a solvent or in a solvent, at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours.

[0583] Examples of the solvent include methanol, ethanol, tert-butyl alcohol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and water, and these may be used alone or in combination.

[0584] Process 44 Compound (XVIII-g) can be obtained by reacting compound (XVIII-f) with methanesulfonyl chloride in the presence of a base at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours, either without a solvent or in a solvent.

[0585] Examples of the solvent include the same solvents as in step 43.

[0586] Examples of the base include cesium carbonate, triethylamine, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and n-butyllithium.

[0587] Process 45 Compound (XVIII-e) and compound (XVIII-g) are reacted with each other in the presence of a base, either without a solvent or in a solvent, at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours to obtain a thioether, and then the Boc group is removed by reacting the compound with compound (XVIII-e) in the presence of an acid, either without a solvent or in a solvent, at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours to obtain a lipid represented by formula (CL-XVIII) (X in the formula 135 is a hydrogen atom).

[0588] Examples of the solvent include the same solvents as in step 43. Examples of the base include the same bases as in step 43.

[0589] The acid includes, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, and the like.

[0590] Process 46 Step 46 can be carried out in the same manner as step 42 above.

[0591] The lipid represented by formula (CL-XIX) can be synthesized according to the following method. Examples of methods for synthesizing the lipid represented by formula (CL-XIX) include the following synthesis method I for formula (CL-XIX) and synthesis method II for formula (CL-XIX).

[0592] (Synthesis Method I of Formula (CL-XIX)) Synthesis method I of formula (CL-XIX) is 133 is preferably S.

[0593] [ka]

[0594] (In the formula, R 139 , R 140 , X 142 are the same as defined above, and Boc in compound (XIX-b) represents a benzyloxycarbonyl group.

[0595] Process 47 After protecting the N in azetidine-3,3-diyldimethanol (XIX-a) with a Boc group according to a conventional method, the dimesyl form is obtained by treating it with methanesulfonyl chloride in the presence of a base, either neat or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 72 hours. Further, the dimesyl form is reacted with S-potassium thioacetate, either neat or in a solvent, for 5 minutes to 72 hours to obtain compound (XIX-b).

[0596] Examples of the solvent include methanol, ethanol, tert-butyl alcohol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and water, and these may be used alone or in combination.

[0597] Examples of the base include cesium carbonate, triethylamine, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and n-butyllithium.

[0598] Process 48 Compound (XIX-b) and R 139 -OMs and R 140 The thioether form can be obtained by reacting -OMs (Ms is a methanesulfonyl group) in the presence of a base at a temperature between -20°C and 150°C for 5 minutes to 72 hours, either without a solvent or in a solvent. Furthermore, the obtained thioether compound is reacted in the presence of an acid, either without a solvent or in a solvent, at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours to remove the Boc group, thereby obtaining a lipid represented by formula (CL-XIX) (wherein X 142 is a hydrogen atom).

[0599] Examples of the base include the same bases as in step 47. Examples of the solvent include the same solvents as in step 47. The acid includes, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, and the like.

[0600] Process 49 A lipid represented by formula (CL-XIX) (where X is a methyl group) can be obtained by N-alkylation, N-carbonylation, and N-acylation using a known method (e.g., "5th Edition Experimental Chemistry Lecture 13: Synthesis of Organic Compounds I," 5th Edition, p. 374, Maruzen (2005)) or a method similar thereto. 142 is C1-C3 alkyl, hydroxy C2-C4 alkyl, formula (F), or formula (G).

[0601] (Synthesis Method II of Formula (CL-XIX)) Synthesis method II of formula (CL-XIX) is 133 is preferably O.

[0602] [ka]

[0603] Process 50 N in azetidine-3,3-diyldimethanol (XIX-a) is protected with a Boc group in a conventional manner, and then R 140 Compound (XIX-c) is obtained by reacting -OMs with the compound (XIX-c) in the presence of a base at a temperature between -20°C and 150°C for 5 minutes to 72 hours, either without a solvent or in a solvent.

[0604] Examples of the base include cesium carbonate, triethylamine, sodium methoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and n-butyllithium.

[0605] Examples of the solvent include methanol, ethanol, tert-butyl alcohol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and water, and these may be used alone or in combination.

[0606] Process 51 Compound (XIX-c) can be treated with methanesulfonyl chloride in the presence of a base, either neat or in a solvent, at a temperature between -20°C and 150°C for 5 minutes to 72 hours to obtain a mesylate. Compound (XIX-d) can be obtained by further reacting the mesylate with potassium thioacetate, either neat or in a solvent, for 5 minutes to 72 hours.

[0607] Examples of the base include the same bases as in step 50. The solvent may be the same as that used in step 50.

[0608] Process 52 Compound (XIX-d) and R 139 The thioether form can be obtained by reacting -OMs (Ms is a methanesulfonyl group) in the presence of a base at a temperature between -20°C and 150°C for 5 minutes to 72 hours, either without a solvent or in a solvent. Furthermore, the obtained thioether compound is reacted in the presence of an acid, either without a solvent or in a solvent, at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours to remove the Boc group, thereby obtaining a lipid represented by formula (CL-XIX) (wherein X 142 is a hydrogen atom).

[0609] Examples of the base include the same bases as in step 50. The solvent may be the same as that used in step 50. The acid includes, for example, hydrochloric acid, acetic acid, trifluoroacetic acid, and the like.

[0610] Process 53 Step 53 can be carried out in the same manner as step 49 above.

[0611] Specific examples of lipid A in the present invention are shown in Tables 16 to 31, but lipid A is not limited to these.

[0612] [Table 16]

[0613] [Table 17]

[0614] [Table 18]

[0615] [Table 19]

[0616] [Table 20]

[0617] [Table 21]

[0618] [Table 22]

[0619] [Table 23]

[0620] [Table 24]

[0621] [Table 25]

[0622] [Table 26]

[0623] [Table 27]

[0624] [Table 28]

[0625] [Table 29]

[0626] [Table 30]

[0627] [Table 31]

[0628] Lipid A in the nucleic acid-containing lipid nanoparticles of the present invention is preferably a lipid represented by formula (II), formula (V'), and formula (V"), among lipids represented by formula (I), formula (II), formula (III), formula (IV), formula (V'), and formula (V"), and more preferably a lipid represented by formula (II) and formula (V'). Among the lipids represented by formula (II), preferably, R 4 ~R 6 and more preferably, R 4~R 6 and more preferably, R in formula (II) is a lipid in which R 4 ~R 6 All of these lipids are linear C8-C24 alkyl. The lipid B to be combined with a lipid selected from the group consisting of formula (II), formula (V'), and formula (V") is preferably a lipid represented by formula (CL-I), formula (CL-II), formula (CL-III), formula (CL-IV), formula (CL-V), formula (CL-VI), formula (CL-VII), formula (CL-VIII), formula (CL-IX), formula (CL-XII), formula (CL-XIV), formula (CL-XVIII) and formula (CL-XIX), more preferably a lipid represented by formula (CL-XVIII) and formula (CL-XIX). Among the lipids represented by formula (CL-II), L in formula (CL-II) is preferred. 106 and L 107 are taken together to form a single bond or a C2-C8 alkylene, and p 101 and p 102 is an integer of 1 to 3, and more preferably, L in formula (CL-II) is 106 and L 107 together form a single bond, and p 101 and p 102 It is a lipid with a . A more preferred combination of lipid A and lipid B is a combination of lipid A represented by formula (II) and lipid B represented by formula (CL-XVIII) and / or formula (CL-XIX).

[0629] The nucleic acid used in the present invention may be any molecule formed by polymerizing nucleotides and / or molecules functionally equivalent to nucleotides, including, for example, ribonucleic acid (RNA), which is a polymer of ribonucleotides; deoxyribonucleic acid (DNA), which is a polymer of deoxyribonucleotides; chimeric nucleic acids consisting of RNA and DNA; and nucleotide polymers in which at least one nucleotide of these nucleic acids has been replaced with a molecule functionally equivalent to said nucleotide. The nucleic acid of the present invention also includes derivatives that at least partially contain a molecular structure formed by polymerizing nucleotides and / or molecules functionally equivalent to nucleotides. In the present invention, uracil (U) and thymine (T) can be interpreted interchangeably.

[0630] Examples of molecules having functions equivalent to those of nucleotides include nucleotide derivatives.

[0631] The nucleotide derivative may be, for example, any molecule in which the nucleotide has been modified. However, for example, molecules in which ribonucleotides or deoxyribonucleotides have been modified in order to improve nuclease resistance or stabilize them from other degradative factors, increase affinity with complementary nucleic acids, increase cell permeability, or enable visualization, compared to RNA or DNA, are preferably used.

[0632] Examples of nucleotide derivatives include sugar-modified nucleotides, phosphodiester bond-modified nucleotides, and base-modified nucleotides.

[0633] The sugar-modified nucleotide may be any nucleotide in which, for example, part or all of the chemical structure of the sugar of the nucleotide has been modified or substituted with any substituent, or substituted with any atom, but 2'-modified nucleotides are preferably used.

[0634] Examples of modifying groups in sugar-modified nucleotides include 2'-cyano, 2'-alkyl, 2'-substituted alkyl, 2'-alkenyl, 2'-substituted alkenyl, 2'-halogen, 2'-O-cyano, 2'-O-alkyl, 2'-O-substituted alkyl, 2'-O-alkenyl, 2'-O-substituted alkenyl, 2'-S-alkyl, 2'-S-substituted alkyl, 2'-S-alkenyl, 2'-S-substituted alkenyl, 2'-amino, 2'-NH-alkyl, 2'-NH-substituted alkyl, 2'-NH-amino. alkenyl, 2'-NH-substituted alkenyl, 2'-SO-alkyl, 2'-SO-substituted alkyl, 2'-carboxy, 2'-CO-alkyl, 2'-CO-substituted alkyl, 2'-Se-alkyl, 2'-Se-substituted alkyl, 2'-SiH-alkyl, 2'-SiH-substituted alkyl, 2'-ONO, 2'-NO, 2'-N, 2'-amino acid residues (amino acid carboxylic acids from which the hydroxyl has been removed), and 2'-O-amino acid residues (same as defined above).

[0635] Examples of sugar-modified nucleotides include bridged nucleic acids (BNAs), which have a structure in which a modified group at the 2' position is bridged to the carbon atom at the 4' position; more specifically, locked nucleic acids (LNAs), in which the oxygen atom at the 2' position and the carbon atom at the 4' position are bridged via a methylene, and ethylene bridged nucleic acids (ENAs) [Nucleic Acid Research, 32, e175 (2004)]; these are included in 2'-modified nucleotides.

[0636] Examples of sugar-modified nucleotides include peptide nucleic acid (PNA) [Acc. Chem. Res., 32, 624 (1999)], oxypeptide nucleic acid (OPNA) [J. Am. Chem. Soc., 123, 4653 (2001)], and peptide ribonucleic acid (PRNA) [J. Am. Chem. Soc., 122, 6900 (2000)].

[0637] The modifying group in the sugar-modified nucleotide is preferably 2'-cyano, 2'-halogen, 2'-O-cyano, 2'-alkyl, 2'-substituted alkyl, 2'-O-alkyl, 2'-O-substituted alkyl, 2'-O-alkenyl, 2'-O-substituted alkenyl, 2'-Se-alkyl or 2'-Se-substituted alkyl, and more preferably 2'-cyano, 2'-fluoro, 2'-chloro, 2'-bromo, 2'-trifluoromethyl, 2'-O-methyl, 2'-O-ethyl, 2'-O-isopropyl, 2'-O-trifluoromethyl, 2'- O-[2-(methoxy)ethyl], 2'-O-(3-aminopropyl), 2'-O-[2-(N,N-dimethylaminooxy)ethyl], 2'-O-[3-(N,N-dimethylamino)propyl], 2'-O-{2-[2-(N,N-dimethylamino)ethoxy]ethyl}, 2'-O-[2-(methylamino)-2-oxoethyl] or 2'-Se-methyl or the like is more preferred, 2'-O-methyl, 2'-O-ethyl, 2'-fluoro or the like is even more preferred, and 2'-O-methyl or 2'-O-ethyl is most preferred.

[0638] The preferred range of modifying groups in sugar-modified nucleotides can also be defined based on their size, with those corresponding to the size of fluoro to -O-butyl being preferred, and those corresponding to the size of -O-methyl to -O-ethyl being more preferred.

[0639] Examples of alkyl in the modifying group in a sugar-modified nucleotide include C1-C6 alkyl, more specifically C1-C6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, or hexyl.

[0640] Examples of alkenyl in the modifying group in the sugar-modified nucleotide include C3-C6 alkenyl, more specifically C3-C6 alkenyl such as allyl, 1-propenyl, butenyl, pentenyl, or hexenyl.

[0641] Examples of the halogen in the modifying group in the sugar-modified nucleotide include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0642] Examples of amino acids in the amino acid residue include aliphatic amino acids (specifically, glycine, alanine, valine, leucine, isoleucine, etc.), hydroxyamino acids (specifically, serine, threonine, etc.), acidic amino acids (specifically, aspartic acid, glutamic acid, etc.), acidic amino acid amides (specifically, asparagine, glutamine, etc.), basic amino acids (specifically, lysine, hydroxylysine, arginine, ornithine, etc.), sulfur-containing amino acids (specifically, cysteine, cystine, methionine, etc.), and imino acids (specifically, proline, 4-hydroxyproline, etc.).

[0643] Examples of the substituents in the substituted alkyl and substituted alkenyl in the modifying group in the sugar-modified nucleotide include halogen (as defined above), hydroxy, sulfanyl, amino, oxo, -O-alkyl (the alkyl portion of the -O-alkyl is as defined as the C1-C6 alkyl in the modifying group), -S-alkyl (the alkyl portion of the -S-alkyl is as defined as the C1-C6 alkyl in the modifying group), -NH-alkyl (the alkyl portion of the -NH-alkyl is as defined as the C1-C6 alkyl in the modifying group), dialkylaminooxy (the dialkylaminooxy wherein the two alkyl moieties are the same or different and are synonymous with the C1-C6 alkyl in the modifying group), dialkylamino (wherein the two alkyl moieties of the dialkylamino are the same or different and are synonymous with the C1-C6 alkyl in the modifying group), or dialkylaminoalkyloxy (wherein the two alkyl moieties of the dialkylaminoalkyloxy are the same or different and are synonymous with the C1-C6 alkyl in the modifying group, and the alkylene moiety is the C1-C6 alkyl in the modifying group with one hydrogen atom removed), and the number of substitutions is preferably 1 to 3.

[0644] The phosphodiester bond-modified nucleotide may be any nucleotide in which part or all of the chemical structure of the phosphodiester bond of the nucleotide has been modified or substituted with any substituent, or substituted with any atom, and examples thereof include a nucleotide in which the phosphodiester bond has been substituted with a phosphorothioate bond, a nucleotide in which the phosphodiester bond has been substituted with a phosphorodithioate bond, a nucleotide in which the phosphodiester bond has been substituted with an alkylphosphonate bond, or a nucleotide in which the phosphodiester bond has been substituted with a phosphoramidate bond.

[0645] A base-modified nucleotide may be any nucleotide in which part or all of the chemical structure of the nucleotide base has been modified or substituted with any substituent, or substituted with any atom, such as those in which the oxygen atom in the base has been substituted with a sulfur atom, those in which the hydrogen atom has been substituted with a C1-C6 alkyl group, those in which the methyl group has been substituted with a hydrogen atom or a C2-C6 alkyl group, and those in which the amino group has been protected with a protecting group such as a C1-C6 alkyl group or a C1-C6 alkanoyl group.

[0646] Further examples of nucleotide derivatives include those in which another chemical substance such as a lipid, phospholipid, phenazine, folate, phenanthridine, anthraquinone, acridine, fluorescein, rhodamine, coumarin, or dye is added to a nucleotide or a nucleotide derivative in which at least one of the sugar moiety, phosphodiester bond, or base is modified.Specific examples include 5'-polyamine-added nucleotide derivatives, cholesterol-added nucleotide derivatives, steroid-added nucleotide derivatives, bile acid-added nucleotide derivatives, vitamin-added nucleotide derivatives, green fluorescent dye (Cy3)-added nucleotide derivatives, red fluorescent dye (Cy5)-added nucleotide derivatives, fluorescein (6-FAM)-added nucleotide derivatives, and biotin-added nucleotide derivatives.

[0647] In the nucleic acid used in the present invention, a nucleotide or nucleotide derivative may form a bridged structure with another nucleotide or nucleotide derivative within the nucleic acid, such as an alkylene structure, a peptide structure, a nucleotide structure, an ether structure, an ester structure, or a structure combining at least one of these.

[0648] The nucleic acid used in the present invention preferably has a molecular weight of 1,000 kDa or less, more preferably 100 kDa or less, and even more preferably 30 kDa or less. In addition, the nucleic acid used in the present invention preferably includes a nucleic acid that suppresses the expression of a target gene, more preferably a nucleic acid that has the effect of suppressing the expression of a target gene using RNA interference (RNAi).

[0649] The target gene in the present invention is not particularly limited as long as it is a gene that produces and expresses mRNA. For example, genes related to tumors or inflammation are preferred, such as vascular endothelial growth factor (hereinafter abbreviated as VEGF), vascular endothelial growth factor receptor (hereinafter abbreviated as VEGFR), fibroblast growth factor, fibroblast growth factor receptor, platelet-derived growth factor, platelet-derived growth factor receptor, hepatocyte growth factor, hepatocyte growth factor receptor, Kruppel-like factor, Examples of such genes include genes encoding proteins such as VEGF gene, VEGFR gene, fibroblast growth factor gene, fibroblast growth factor receptor gene, platelet-derived growth factor gene, platelet-derived growth factor receptor gene, hepatocyte growth factor gene, hepatocyte growth factor receptor gene, KLF gene, Ets transcription factor gene, nuclear factor gene, hypoxia-inducible factor gene, cell cycle-related factor gene, chromosome replication-related factor gene, chromosome repair-related factor gene, microtubule-associated factor gene (e.g., CKAP5 gene, etc.), growth signal pathway-related factor gene (e.g., KRAS gene, etc.), growth-related transcription factor gene, and apoptosis-related factor (e.g., BCL-2 gene, etc.).

[0650] In the present invention, preferred target genes are genes expressed in the liver, lungs, kidneys, or spleen, with genes expressed in the liver being more preferred. Examples of such target genes include those encoding proteins such as the tumor- or inflammation-related genes, hepatitis B virus genome, hepatitis C virus genome, apolipoprotein (APO), hydroxymethylglutaryl (HMG) CoA reductase, kexin type 9 serine protease (PCSK9), factor XII, glucagon receptor, glucocorticoid receptor, leukotriene receptor, thromboxane A2 receptor, histamine H1 receptor, carbonic anhydrase, angiotensin-converting enzyme, renin, p53, tyrosine phosphatase (PTP), sodium-dependent glucose transporter, tumor necrosis factor, interleukin, hepcidin, transsilin, antithrombin, protein C, or matriptase enzyme (e.g., the TMPRSS6 gene).

[0651] The nucleic acid that suppresses the expression of a target gene may be any nucleic acid that contains a base sequence complementary to a portion of the base sequence of the mRNA of a gene (target gene) that encodes a protein or the like and that suppresses the expression of the target gene, such as double-stranded nucleic acids such as siRNA (short interference RNA) and miRNA (microRNA), or single-stranded nucleic acids such as shRNA (short hairpin RNA), antisense nucleic acid, or ribozyme, but double-stranded nucleic acids are preferred.

[0652] A nucleic acid containing a base sequence complementary to a portion of the base sequence of the mRNA of a target gene is called an antisense strand nucleic acid, and a nucleic acid containing a base sequence complementary to the base sequence of the antisense strand nucleic acid is also called a sense strand nucleic acid. The sense strand nucleic acid refers to a nucleic acid that pairs with the antisense strand nucleic acid to form a duplex, such as a nucleic acid consisting of a portion of the base sequence of a target gene.

[0653] A double-stranded nucleic acid is a nucleic acid in which two strands are paired to form a double-stranded portion. The double-stranded portion refers to a portion in which the nucleotides or derivatives thereof that constitute the double-stranded nucleic acid form base pairs to form a double strand. The base pairs that constitute the double-stranded portion are usually 15 to 27 base pairs, preferably 15 to 25 base pairs, more preferably 15 to 23 base pairs, even more preferably 15 to 21 base pairs, and particularly preferably 15 to 19 base pairs.

[0654] The antisense strand nucleic acid of the double-stranded nucleic acid may be, for example, a nucleic acid consisting of a partial sequence of the mRNA of the target gene, or a nucleic acid in which 1 to 3 bases, preferably 1 to 2 bases, and more preferably 1 base, have been substituted, deleted, or added to the nucleic acid, and which has activity of inhibiting the expression of a target protein. The single-stranded nucleic acid that constitutes the double-stranded nucleic acid usually consists of a stretch of 15 to 30 bases (nucleosides), preferably 15 to 29 bases, more preferably 15 to 27 bases, even more preferably 15 to 25 bases, particularly preferably 17 to 23 bases, and most preferably 19 to 21 bases.

[0655] Either or both of the antisense and sense strands constituting the double-stranded nucleic acid may have an additional nucleic acid on the 3' or 5' side following the duplex-forming portion that does not form a duplex. This non-duplex-forming portion is also called an overhang.

[0656] As a double-stranded nucleic acid having an overhang, for example, one having an overhang consisting of 1 to 4 bases, usually 1 to 3 bases, at the 3'-end or 5'-end of at least one strand is used, but one having an overhang consisting of 2 bases is preferably used, and one having an overhang consisting of dTdT or UU is more preferably used. The overhang can be present in only the antisense strand, only the sense strand, or both the antisense and sense strands, but double-stranded nucleic acid having overhangs in both the antisense and sense strands is preferably used.

[0657] A sequence following the double-strand-forming portion that partially or completely matches the base sequence of the mRNA of the target gene, or a sequence following the double-strand-forming portion that partially or completely matches the base sequence of the complementary strand of the mRNA of the target gene, may be used. Furthermore, examples of nucleic acids that suppress the expression of a target gene include nucleic acid molecules that generate the double-stranded nucleic acid by the action of ribonuclease such as Dicer (WO 2005 / 089287), and double-stranded nucleic acids that do not have overhangs at the 3' or 5' ends.

[0658] When the double-stranded nucleic acid is an siRNA, preferably, the sequence of at least the 1st to 17th bases (nucleosides) from the 5' end to the 3' end of the antisense strand is a sequence of bases complementary to a sequence of 17 consecutive bases in the mRNA of the target gene; more preferably, the sequence of the 1st to 19th bases from the 5' end to the 3' end of the antisense strand is a sequence of bases complementary to a sequence of 19 consecutive bases in the mRNA of the target gene, the sequence of the 1st to 21st bases is a sequence of bases complementary to a sequence of 21 consecutive bases in the mRNA of the target gene, or the sequence of the 1st to 25th bases is a sequence of bases complementary to a sequence of 25 consecutive bases in the mRNA of the target gene.

[0659] Furthermore, when the nucleic acid used in the present invention is an siRNA, preferably 10 to 70%, more preferably 15 to 60%, and even more preferably 20 to 50% of the sugars in the nucleic acid are riboses substituted with a modifying group at the 2' position. In the present invention, riboses substituted with a modifying group at the 2' position refer to ribose in which the hydroxy at the 2' position has been substituted with a modifying group, and the configuration may be the same as or different from that of the hydroxy at the 2' position of ribose, but preferably the configuration is the same as that of the hydroxy at the 2' position of ribose. The modifying group in the ribose substituted with a modifying group at the 2'-position in the sugar-modified nucleotide includes those exemplified in the definition of the modifying group in the 2'-modified nucleotide in the sugar-modified nucleotide, and a hydrogen atom. Preferred are 2'-cyano, 2'-halogen, 2'-O-cyano, 2'-alkyl, 2'-substituted alkyl, 2'-O-alkyl, 2'-O-substituted alkyl, 2'-O-alkenyl, 2'-O-substituted alkenyl, 2'-Se-alkyl, 2'-Se-substituted alkyl, and the like. 2'-cyano, 2'-fluoro, 2'-chloro, 2'-bromo, 2'-trifluoromethyl, 2'-O-methyl, 2'-O-ethyl, 2' -O-Isopropyl, 2'-O-trifluoromethyl, 2'-O-[2-(methoxy)ethyl], 2'-O-(3-aminopropyl), 2'-O-[2-(N,N-dimethyl)aminooxy]ethyl, 2'-O-[3-(N,N-dimethylamino)propyl], 2'-O-{2-[2-(N,N-dimethylamino)ethoxy]ethyl}, 2'-O-[2-(methylamino)-2-oxoethyl], 2'-Se-methyl, a hydrogen atom, and the like are more preferred, 2'-O-methyl, 2'-O-ethyl, 2'-fluoro, a hydrogen atom, and the like are even more preferred, and 2'-O-methyl and 2'-O-fluoro are most preferred.

[0660] The nucleic acid used in the present invention includes derivatives in which oxygen atoms contained in the phosphate moiety, ester moiety, etc. in the nucleic acid structure are substituted with other atoms such as sulfur atoms.

[0661] The sugars bound to the bases at the 5' ends of the antisense and sense strands may each have a 5'-hydroxyl modified with a phosphate group or the above-mentioned modifying group, or a group that can be converted to a phosphate group or the above-mentioned modifying group by a nuclease or the like in vivo.

[0662] The sugars bound to the bases at the 3' ends of the antisense and sense strands may each have a hydroxyl at the 3' position modified with a phosphate group or the above-mentioned modifying group, or a group that can be converted to a phosphate group or the above-mentioned modifying group by a nuclease or the like in vivo.

[0663] The single-stranded nucleic acid may be, for example, a nucleic acid consisting of a complementary sequence to a sequence of 15 to 27 consecutive bases (nucleosides), preferably 15 to 25 bases, more preferably 15 to 23 bases, even more preferably 15 to 21 bases, and particularly preferably 15 to 19 bases, of a target gene, or a nucleic acid in which 1 to 3 bases, preferably 1 to 2 bases, and more preferably 1 base, have been substituted, deleted, or added, and which has activity of inhibiting the expression of a target protein. The single-stranded nucleic acid preferably consists of a stretch of 10 to 30 bases (nucleosides), more preferably 10 to 27 bases, even more preferably 10 to 25 bases, and particularly preferably 10 to 23 bases.

[0664] The single-stranded nucleic acid may be one in which the antisense strand and sense strand constituting the double-stranded nucleic acid are linked via a spacer sequence (spacer oligonucleotide). The spacer oligonucleotide is preferably a single-stranded nucleic acid molecule of 6 to 12 bases, and the sequence at its 5' end is preferably two U's. An example of a spacer oligonucleotide is a nucleic acid having the sequence UUCAAGAGA. The order of the antisense strand and the sense strand connected by the spacer oligonucleotide may be either at the 5' end. The single-stranded nucleic acid is preferably, for example, a single-stranded nucleic acid such as shRNA having a duplex-forming portion formed by a stem-loop structure. Single-stranded nucleic acids such as shRNA are typically 50 to 70 bases long.

[0665] Nucleic acids having a length of 70 bases or less, preferably 50 bases or less, and more preferably 30 bases or less, which are designed to generate the above single-stranded or double-stranded nucleic acids by the action of ribonuclease or the like, may also be used.

[0666] The nucleic acids used in the present invention can be obtained using known RNA or DNA synthesis methods and RNA or DNA modification methods.

[0667] The nucleic acid-containing lipid nanoparticles of the present invention may contain one or more types of lipid A. The nucleic acid-containing lipid nanoparticles of the present invention may contain one or more types of lipid B. Furthermore, the nucleic acid-containing lipid nanoparticles of the present invention may contain a neutral lipid and / or a lipid derivative or a fatty acid derivative of a water-soluble polymer. The nucleic acid-containing lipid nanoparticles of the present invention may contain one or more types of lipid A and one or more types of lipid B.

[0668] The nucleic acid-containing lipid nanoparticles of the present invention can contain not only nucleic acids but also compounds that are chemically similar to nucleic acids (such as anionic polymers such as anionic peptides).

[0669] In the present invention, nucleic acids are dissolved in a water-miscible organic solvent together with cationic lipids and, if necessary, other lipids (lipid derivatives or fatty acid derivatives of water-soluble polymers, neutral lipids) (first lipid solution). In preparing the first lipid solution, nucleic acids may be dissolved in water or an aqueous buffer solution and added to a lipid organic solvent solution, or the lipid organic solvent solution may be added to the nucleic acid in water or an aqueous buffer solution. Furthermore, the lipid organic solvent solution may be added to lyophilized nucleic acids.

[0670] An organic solvent solution (first lipid solution) may be prepared using nucleic acid, cationic lipid, and, if necessary, other lipids (lipid derivatives or fatty acid derivatives of water-soluble polymers, neutral lipids), and then a third lipid solution may be prepared by adding an organic solvent solution (second lipid solution) to which a fatty acid ester analogue of glycerol that is not hydrolyzed by lipase, and, if necessary, a lipid derivative or fatty acid derivative of a water-soluble polymer, has been added.

[0671] In the present invention, the first or third lipid solution is mixed with water or an aqueous buffer solution, and the organic solvent concentration is rapidly reduced to obtain small lipid nanoparticles without aggregation. When mixing the first or third lipid solution with water or an aqueous buffer solution, the former may be added to the latter, or the latter may be added to the former. Alternatively, the former and the latter may be added to a container simultaneously while stirring. Furthermore, the former and the latter may be mixed in-line. In this case, for example, a T-connector or the like can be used as an in-line mixing device.

[0672] The average particle size of the nucleic acid-containing lipid nanoparticles of the present invention is affected by the nucleic acid, cationic lipid, and other lipids used, but can be freely controlled by various parameters in the manufacturing process. Those skilled in the art can determine the average particle size by preparing particle samples by appropriately changing various parameters in the manufacturing process necessary to control the average particle size of the nucleic acid-containing lipid nanoparticles of the present invention and measuring the average particle size of the obtained sample. Parameters necessary for controlling the average particle size include the nucleic acid concentration in the organic solvent solution, the concentration of each lipid, temperature, and the composition of the organic solvent. Other parameters necessary for controlling the average particle size include the temperature, the amount of water or aqueous buffer solution, and the addition rate of each liquid during the dilution of the nucleic acid and lipid organic solvent solution with water or aqueous buffer solution.

[0673] When phosphatidylcholine (PC) and cholesterol (Chol) are not contained, the concentration of the cationic lipid in the organic solvent solution before being mixed with water or an aqueous buffer solution is not particularly limited, but is preferably 1 to 2000 μM, more preferably 5 to 400 μM, even more preferably 10 to 200 μM, and most preferably 20 to 100 μM.

[0674] When PC and Chol are not contained, the concentration of nucleic acid in the organic solvent solution before being mixed with water or an aqueous buffer solution is not particularly limited, but is preferably 0.03 to 15 μM, more preferably 0.15 to 3.0 μM, and even more preferably 0.3 to 1.5 μM.

[0675] In the case where PC and Chol are not contained, the concentration of the lipid derivative or fatty acid derivative of the water-soluble polymer in the organic solvent solution before being mixed with water or an aqueous buffer solution is not particularly limited, but is preferably 0.5 to 200 μM, more preferably 2.5 to 40 μM, and even more preferably 5 to 20 μM.

[0676] When PC and Chol are not contained, the combined concentration of all lipids in the organic solvent solution before being mixed with water or an aqueous buffer solution is not particularly limited, but is preferably 5 to 2000 μM, more preferably 25 to 400 μM, and even more preferably 50 to 200 μM.

[0677] In the case of containing PC and Chol, the concentration of a lipid (lipid A) having one quaternary ammonium group as a hydrophilic moiety and three independent hydrocarbon groups which may be substituted in the organic solvent solution before being mixed with water or an aqueous buffer solution is preferably 0.2 to 1800 μM, more preferably 1 to 360 μM, even more preferably 2 to 180 μM, and most preferably 5 to 100 μM.

[0678] When PC and Chol are contained, the concentration of nucleic acid in the organic solvent solution before being mixed with water or an aqueous buffer solution is preferably 0.02 to 45 μM, more preferably 0.1 to 10 μM, even more preferably 0.2 to 5 μM, and most preferably 0.3 to 3 μM.

[0679] When PC and Chol are contained, the concentration of the lipid derivative or fatty acid derivative of the water-soluble polymer in the organic solvent solution before being mixed with water or an aqueous buffer solution is preferably 0.3 to 1000 μM, more preferably 1.5 to 200 μM, even more preferably 3 to 100 μM, and most preferably 5 to 50 μM.

[0680] When PC and Chol are contained, the concentration of the cationic lipid in the organic solvent solution before being mixed with water or an aqueous buffer solution is preferably 2.5 to 4200 μM, more preferably 12.5 to 840 μM, even more preferably 25 to 420 μM, and most preferably 50 to 210 μM.

[0681] When PC and Chol are contained, the concentration of the neutral lipid in the organic solvent solution before being mixed with water or an aqueous buffer solution is preferably 2.5 to 5000 μM, more preferably 12.5 to 1000 μM, even more preferably 25 to 500 μM, and most preferably 50 to 250 μM.

[0682] When PC and Chol are contained, the combined concentration of all lipids in the organic solvent solution before being mixed with water or an aqueous buffer solution is preferably 10 to 8000 μM, more preferably 50 to 1600 μM, even more preferably 100 to 800 μM, and most preferably 150 to 400 μM.

[0683] The temperature at which the organic solvent solution containing nucleic acids and lipids is prepared is not particularly limited as long as the nucleic acids and lipids are soluble, but is preferably 10 to 60° C., more preferably 20 to 50° C., and even more preferably 20 to 30° C. When the temperature is heated to 30° C. or higher, the solubility of the nucleic acids and lipids increases, allowing lipid nanoparticles to be produced with a smaller amount of solvent.

[0684] The organic solvent in the organic solvent solution containing nucleic acids and lipids is not particularly limited, but is preferably a C1-C6 alcohol such as methanol, ethanol, propanol, or butanol containing 0-50% (v / v) water, or a mixture thereof, more preferably ethanol or propanol containing 0-50% (v / v) water, and even more preferably ethanol containing 0-50% (v / v) water. Here, "% (v / v)" refers to the volume percentage of the solute in the total volume of the solution, and the same applies hereinafter.

[0685] An inorganic acid such as hydrochloric acid, acetic acid, or phosphoric acid, or a salt of such an acid, can be added to the solvent in the organic solvent solution containing nucleic acids and lipids. In this case, the pH of the solvent is preferably 1 to 7, more preferably 1 to 5, and even more preferably 2 to 4.

[0686] In the operation of adding water or an aqueous buffer solution to an organic solvent solution containing nucleic acids and lipids, the volume of the water or aqueous buffer solution used is not particularly limited, but is preferably 0.5 to 100 times, more preferably 1.5 to 20 times, and even more preferably 2.0 to 10 times the volume of the organic solvent solution of nucleic acids and lipids.

[0687] In this case, the concentration of the organic solvent after adding water or an aqueous buffer solution is not particularly limited, but is preferably 50% (v / v) or less, more preferably 40% (v / v) or less, even more preferably 30% (v / v) or less, and most preferably 20% (v / v) or less, relative to the resulting solution. The aqueous buffer solution is not particularly limited as long as it has a buffering effect, but examples thereof include an aqueous phosphate buffer solution, an aqueous citrate buffer solution, and an aqueous acetate buffer solution.

[0688] The temperature at which the above-mentioned addition operation is carried out is not particularly limited, but is preferably 10 to 60°C, more preferably 20 to 50°C, and even more preferably 20 to 30°C.

[0689] In the above-mentioned addition procedure, it is important to reduce the organic solvent solution quickly. Specifically, the organic solvent concentration is preferably changed from 70% (v / v) or more to 50% (v / v) or less within 1 minute, more preferably within 0.5 minutes, even more preferably within 0.1 minutes, and most preferably within 0.05 minutes.

[0690] When the nucleic acid-containing lipid nanoparticles of the present invention contain lipid A, the total number of lipid A molecules is not particularly limited, but the molar number of quaternary ammonium groups in lipid A is preferably 0.01 or more times the molar number of phosphorus atoms in the nucleic acid constituting the nucleic acid-containing lipid nanoparticles of the present invention, more preferably 0.1 to 10 times, even more preferably 0.1 to 4 times, even more preferably 0.1 to 2 times, and most preferably 0.1 to 1 times. When lipid B is contained in the nucleic acid-containing lipid nanoparticles of the present invention, the total number of lipid B molecules is not particularly limited, but the molar amount of lipid B is preferably 0.1 to 10 times the molar amount of phosphorus atoms in the nucleic acid constituting the nucleic acid-containing lipid nanoparticles of the present invention, more preferably 0.5 to 9 times, even more preferably 1 to 8 times, and most preferably 1.5 to 6 times.

[0691] When the nucleic acid-containing lipid nanoparticles of the present invention contain lipid A and lipid B, the ratio of the number of moles of lipid A to the number of moles of lipid B (number of moles of lipid A / number of moles of lipid B) is preferably 0.001 or more, more preferably 0.003 to 10, even more preferably 0.005 to 5, even more preferably 0.01 to 3, and most preferably 0.01 to 2.

[0692] In the nucleic acid-containing lipid nanoparticles of the present invention, the ratio of the number of moles of total lipids to the number of moles of nucleic acid (number of moles of total lipids / number of moles of nucleic acid) is preferably 50 or more, more preferably 100 to 1000, even more preferably 120 to 800, even more preferably 140 to 600, and most preferably 200 to 500.

[0693] When the nucleic acid-containing lipid nanoparticle of the present invention contains lipid B, the total number of molecules of lipid B in nucleic acid-containing lipid nanoparticle is not particularly limited, but is preferably 0.1 times molar amount or more relative to the mole number of total lipid, more preferably 0.15 times molar amount or more, more preferably 0.2 times molar amount or more, and even more preferably 0.25 times molar amount or more.In addition, the total number of molecules of lipid B in nucleic acid-containing lipid nanoparticle is not particularly limited, but is preferably 0.7 times molar amount or less relative to the mole number of total lipid, more preferably 0.65 times molar amount or less, and even more preferably 0.6 times molar amount or less. The total number of lipid B molecules in the nucleic acid-containing lipid nanoparticles is preferably 0.10 to 0.70 times the molar amount of the total lipids, more preferably 0.15 to 0.65 times the molar amount, even more preferably 0.20 to 0.65 times the molar amount, and most preferably 0.25 to 0.60 times the molar amount, within the combination of the above-mentioned preferred upper and lower limit ranges.

[0694] The nucleic acid-containing lipid nanoparticles of the present invention preferably further contain a neutral lipid. The neutral lipid may be any of simple lipids, complex lipids, or derived lipids, including, but not limited to, phospholipids, glyceroglycolipids, glycosphingolipids, sphingoids, sterols, etc. Furthermore, one or more types of neutral lipids may be used in combination. The neutral lipids referred to here refer to neutral lipids other than fatty acid ester analogues of glycerol that are not hydrolyzed by lipase.

[0695] When a neutral lipid is contained in the nucleic acid-containing lipid nanoparticles of the present invention, the total number of neutral lipid molecules is not particularly limited, but is preferably 0.10 to 0.75 times the molar amount of the total lipids (total lipids include fatty acid ester analogues of glycerol that are not hydrolyzed by lipase), more preferably 0.20 to 0.70 times the molar amount, even more preferably 0.20 to 0.65 times the molar amount, and most preferably 0.30 to 0.60 times the molar amount.

[0696] In the nucleic acid-containing lipid nanoparticles of the present invention, the amount of the fatty acid ester analogue of glycerol that is not hydrolyzed by lipase is preferably 0.001 times or more by mole relative to the number of moles of total lipids (total lipids include fatty acid ester analogues of glycerol that are not hydrolyzed by lipase), more preferably 0.001 to 0.75 times by mole, even more preferably 0.05 to 0.70 times by mole, even more preferably 0.10 to 0.65 times by mole, and most preferably 0.12 to 0.60 times by mole.

[0697] Examples of phospholipids in neutral lipids include phosphatidylcholine (PC) (specifically, soybean phosphatidylcholine, egg yolk phosphatidylcholine (EPC), distearoylphosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), dipalmitoylphosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), palmitoyloleoylphosphatidylcholine (POPC), and dimyristoylphosphatidylcholine (DMPC). , dioleoylphosphatidylcholine (DOPC), etc.), phosphatidylethanolamine (specifically distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphoethanolamine (DMPE), 16-0-monomethyl PE, 16-0-dimethyl PE, 18-1-trans PE, palmitoyloleoyl-phosphatidylethanolamine (POPE), 1 phospholipids (specifically, sphingomyelin, ceramide phosphoethanolamine, ceramide phosphoglycerol, ceramide phosphoglycerol, ceramide phosphoglycerol phosphate, etc.), glycerophosphonolipids, sphingophosphonolipids, natural lecithin (specifically, egg yolk lecithin, soybean lecithin, etc.), or hydrogenated phospholipids (specifically, hydrogenated soybean phosphatidylcholine, etc.), but are not limited to these.

[0698] Examples of glyceroglycolipids in neutral lipids include, but are not limited to, sulfoxyribosylglyceride, diglycosyldiglyceride, digalactosyldiglyceride, galactosyldiglyceride, and glycosyldiglyceride.

[0699] Examples of glycosphingolipids in neutral lipids include, but are not limited to, galactosylcerebroside, lactosylcerebroside, ganglioside, and the like.

[0700] Examples of sphingoids in neutral lipids include, but are not limited to, sphingan, icosasphingan, sphingosine, and derivatives thereof. Examples of derivatives include, but are not limited to, sphingan, icosasphingan, sphingosine, etc., in which -NH is converted to -NHCO(CH)CH (where x is an integer of 0 to 18, with 6, 12, or 18 being preferred).

[0701] Examples of sterols in neutral lipids include, but are not limited to, cholesterol (Chol), dihydrocholesterol, lanosterol, β-sitosterol, campesterol, stigmasterol, brassicasterol, ergocastrol, fucosterol, and 3β-[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol (DC-Chol).

[0702] Examples of polymers include, but are not limited to, proteins, albumin, dextran, polyfect, chitosan, dextran sulfate, and micelles composed of one or more polymers, such as poly-L-lysine, polyethyleneimine, polyaspartic acid, styrene-maleic acid copolymer, isopropylacrylamide-acrylpyrrolidone copolymer, polyethylene glycol-modified dendrimer, polylactic acid, polylactic acid-polyglycolic acid, or polyethylene glycolated polylactic acid, or salts thereof.

[0703] Here, examples of polymer salts include metal salts, ammonium salts, acid addition salts, organic amine addition salts, and amino acid addition salts. Metal salts include, but are not limited to, alkali metal salts such as lithium salts, sodium salts, and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts; and zinc salts. Ammonium salts include, but are not limited to, salts of ammonium or tetramethylammonium salts. Acid addition salts include, but are not limited to, inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, maleate, fumarate, and citrate. Organic amine addition salts include, but are not limited to, addition salts of morpholine or piperidine. Amino acid addition salts include, but are not limited to, addition salts of glycine, phenylalanine, aspartic acid, glutamic acid, and lysine.

[0704] Any of the nucleic acid-containing lipid nanoparticles of the present invention may contain, for example, lipid derivatives or fatty acid derivatives of one or more substances selected from sugars, peptides, nucleic acids, and water-soluble polymers, or surfactants.

[0705] The lipid or fatty acid derivative of one or more substances selected from sugars, peptides, nucleic acids, and water-soluble polymers, or surfactants, preferably includes glycolipids, or lipid or fatty acid derivatives of water-soluble polymers, more preferably lipid or fatty acid derivatives of water-soluble polymers. The lipid or fatty acid derivative of one or more substances selected from sugars, peptides, nucleic acids, and water-soluble polymers, or surfactants, is preferably a two-sided substance, with one part of the molecule having the property of binding to other components of the composition through, for example, hydrophobic affinity or electrostatic interaction, and the other part having the property of binding to the solvent used in the production of the composition through, for example, hydrophilic affinity or electrostatic interaction.

[0706] Examples of lipid or fatty acid derivatives of sugars, peptides, or nucleic acids include those obtained by binding sugars such as sucrose, sorbitol, lactose, etc.; peptides such as casein-derived peptides, egg white-derived peptides, soybean-derived peptides, and glutathione; or nucleic acids such as DNA, RNA, plasmids, siRNA, and ODN, to the neutral lipids mentioned in the definition of the composition above, or fatty acids such as stearic acid, palmitic acid, myristic acid, and lauric acid.

[0707] The lipid derivatives or fatty acid derivatives of sugars also include, for example, glyceroglycolipids or glycosphingolipids mentioned in the definition of the composition above.

[0708] Examples of lipid or fatty acid derivatives of water-soluble polymers include polyethylene glycol, polyglycerin, polyethyleneimine, polyvinyl alcohol, polyacrylic acid, polyacrylamide, oligosaccharides, dextrin, water-soluble cellulose, dextran, chondroitin sulfate, polyglycerin, chitosan, polyvinylpyrrolidone, polyaspartic acid amide, poly-L-lysine, mannan, pullulan, oligoglycerol, etc., or derivatives thereof, bound to a neutral lipid mentioned in the definition of the composition or a fatty acid such as stearic acid, palmitic acid, myristic acid, or lauric acid, and salts thereof, etc. More preferred are lipid or fatty acid derivatives of polyethylene glycol or polyglycerin, etc., and salts thereof, and even more preferred are lipid or fatty acid derivatives of polyethylene glycol, and salts thereof.

[0709] Examples of lipid or fatty acid derivatives of polyethylene glycol include polyethylene glycolated lipids [specifically, polyethylene glycol-phosphatidylethanolamine (more specifically, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG-DSPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG-DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG-DMPE), etc.], polyoxyethylene hydrogenated castor oil 60, Cremophor EL, etc.], polyethylene glycol sorbitan fatty acid esters (specifically, polyoxyethylene sorbitan monooleate, etc.), polyethylene glycol fatty acid esters, etc., and more preferably polyethylene glycolated lipids.

[0710] Examples of lipid derivatives or fatty acid derivatives of polyglycerin include polyglycerinated lipids (specifically, polyglycerin-phosphatidylethanolamine, etc.) or polyglycerin fatty acid esters, and more preferably polyglycerinated lipids.

[0711] Examples of surfactants include polyoxyethylene sorbitan monooleate (specifically, polysorbate 80, etc.), polyoxyethylene polyoxypropylene glycol (specifically, Pluronic F68, etc.), sorbitan fatty acid esters (specifically, sorbitan monolaurate, sorbitan monooleate, etc.), polyoxyethylene derivatives (specifically, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene lauryl alcohol, etc.), glycerin fatty acid esters, and polyethylene glycol alkyl ethers, and preferably, polyoxyethylene polyoxypropylene glycol, glycerin fatty acid esters, and polyethylene glycol alkyl ethers.

[0712] In the nucleic acid-containing lipid nanoparticles of the present invention, the total number of molecules of the lipid derivative and fatty acid derivative of the water-soluble polymer in the nucleic acid-containing lipid nanoparticles is not particularly limited, but is preferably 0.005 times or more molar amount relative to the number of moles of the total lipid, more preferably 0.01 to 0.30 times molar amount, even more preferably 0.02 to 0.25 times molar amount, even more preferably 0.03 to 0.20 times molar amount, even more preferably 0.04 to 0.15 times molar amount, and most preferably 0.04 to 0.12 times molar amount. In the present invention, total lipids include lipid A, lipid derivatives of water-soluble polymers, and fatty acid derivatives, and optionally lipid B and neutral lipids. That is, the number of moles of lipid A is calculated by subtracting from 1 the sum of the two moles of lipid derivatives of water-soluble polymers and fatty acid derivatives, and optionally the two moles of lipid B and neutral lipids, when the number of moles of total lipids is 1.

[0713] The nucleic acid-containing lipid nanoparticles of the present invention can also be surface-modified with, for example, a water-soluble polymer (see, for example, "Stealth Liposomes," edited by D.D. Lasic and F. Martin, USA, CRC Press Inc., 1995, pp. 93-102). Examples of water-soluble polymers that can be used for surface modification include polyethylene glycol, polyglycerin, polyethyleneimine, polyvinyl alcohol, polyacrylic acid, polyacrylamide, oligosaccharides, dextrin, water-soluble cellulose, dextran, chondroitin sulfate, polyglycerin, chitosan, polyvinylpyrrolidone, polyaspartic acid amide, poly-L-lysine, mannan, pullulan, and oligoglycerol, with polyethylene glycol, polyglycerin, polyethyleneimine, polyvinyl alcohol, polyacrylic acid, and polyacrylamide being preferred, and polyethylene glycol and polyglycerin being more preferred, but not limited to these. Furthermore, for surface modification, lipid derivatives or fatty acid derivatives (same as above) of one or more substances selected from sugars, peptides, nucleic acids, and water-soluble polymers, surfactants, etc. The surface modification is one method of incorporating lipid derivatives or fatty acid derivatives of one or more substances selected from sugars, peptides, nucleic acids, and water-soluble polymers, or surfactants, into the nucleic acid-containing lipid nanoparticles of the present invention.

[0714] Optionally, targeting ligands can be directly attached to the surface of the nucleic acid-containing lipid nanoparticles of the present invention by covalently linking them to the polar head residues of the lipid components of the nucleic acid-containing lipid nanoparticles of the present invention (see WO 2006 / 116107).

[0715] The average particle size of the nucleic acid-containing lipid nanoparticles of the present invention can be further adjusted after preparation. Methods for adjusting the average particle size include, for example, extrusion, mechanically crushing large multilamellar liposomes (MLVs) (specifically, using a Manton-Gaulin or microfluidizer) (see R.H. Muller, S. Benita, and B. Bohm, eds., "Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs," Scientific Publishers Stuttgart, Germany, 1998, pp. 267-294).

[0716] The size of the nucleic acid-containing lipid nanoparticles of the present invention is preferably 1.00 to 2000 nm, more preferably 10.0 to 500 nm, even more preferably 20.0 to 300 nm, and most preferably 20.0 to 150 nm.

[0717] The size of the nucleic acid-containing lipid nanoparticles of the present invention can be measured, for example, by dynamic light scattering.

[0718] By introducing the nucleic acid-containing lipid nanoparticles of the present invention into mammalian cells, the nucleic acid in the nucleic acid-containing lipid nanoparticles of the present invention can be introduced into the cells.

[0719] The nucleic acid-containing lipid nanoparticles of the present invention can be introduced into mammalian cells in vivo according to known in vivo transfection procedures. For example, by intravenously administering the nucleic acid-containing lipid nanoparticles of the present invention to mammals, including humans, they can be delivered to, for example, an organ or site where a tumor or inflammation has occurred, and the nucleic acid in the nucleic acid-containing lipid nanoparticles of the present invention can be introduced into cells in the target organ or site. Organs or sites where a tumor or inflammation has occurred include, but are not limited to, the stomach, large intestine, liver, lungs, spleen, pancreas, kidneys, bladder, skin, blood vessels, and eyeballs. Furthermore, by intravenously administering the nucleic acid-containing lipid nanoparticles of the present invention to mammals, including humans, they can be delivered to, for example, the liver, stomach, lungs, kidneys, pancreas, and / or spleen, and the nucleic acid in the nucleic acid-containing lipid nanoparticles of the present invention can be introduced into cells in the target organ or site. Liver, lung, spleen, and / or kidney cells may be normal cells, cells associated with tumors or inflammation, or cells associated with other diseases.

[0720] If the nucleic acid in the nucleic acid-containing lipid nanoparticles of the present invention is a nucleic acid that has the effect of suppressing the expression of a target gene using RNA interference (RNAi), the nucleic acid that suppresses the expression of the target gene can be introduced into mammalian cells in vivo, thereby suppressing the expression of the target gene. The subject of administration is preferably a human.

[0721] If the target gene in the nucleic acid-containing lipid nanoparticles of the present invention is, for example, a gene expressed in the liver, stomach, lungs, kidneys, pancreas, and / or spleen, preferably a gene expressed in the liver, the nucleic acid-containing lipid nanoparticles of the present invention can be used as a therapeutic or preventive agent for diseases related to the liver, stomach, lungs, kidneys, pancreas, or spleen, preferably a therapeutic or preventive agent for diseases related to the liver. That is, the present invention also provides a method for treating diseases related to the liver, stomach, lungs, kidneys, pancreas, or spleen, etc., in which the nucleic acid-containing lipid nanoparticles of the present invention described above are administered to a mammal. The recipient is preferably a human, and more preferably a human suffering from a disease related to the liver, stomach, lungs, kidneys, pancreas, or spleen.

[0722] The nucleic acid-containing lipid nanoparticles of the present invention can also be used as a tool to verify the effectiveness of suppressing target genes in in vivo drug efficacy evaluation models for therapeutic or preventive agents for diseases related to the liver, stomach, lungs, kidneys, pancreas, or spleen.

[0723] The nucleic acid-containing lipid nanoparticles of the present invention can also be used as formulations for the purposes of, for example, stabilizing the nucleic acid in biological components such as blood components (e.g., blood, digestive tract, etc.), reducing side effects, or increasing drug accumulation in tissues or organs containing the expression site of a target gene.

[0724] When the nucleic acid-containing lipid nanoparticles of the present invention are used as pharmaceuticals for the treatment or prevention of diseases related to the liver, lungs, kidneys, or spleen, it is desirable to use the administration route that is most effective for treatment, and examples of such administration include parenteral administration such as oral, intratracheal, rectal, subcutaneous, intramuscular, or intravenous administration, or oral administration, with intravenous, subcutaneous, or intramuscular administration being preferred, and intravenous administration being more preferred.

[0725] The dosage varies depending on the condition and age of the subject, the route of administration, etc., but may be administered so that the daily dosage converted into nucleic acid is approximately 0.1 μg to 1000 mg, for example.

[0726] Examples of formulations suitable for intravenous or intramuscular administration include injections. The dispersion of the composition prepared by the above-mentioned method can be used as is, for example, in the form of an injection, but the dispersion can also be used after removing the solvent by, for example, filtration, centrifugation, etc., or the dispersion can be freeze-dried and / or a dispersion to which an excipient such as mannitol, lactose, trehalose, maltose, or glycine has been added can be freeze-dried and used.

[0727] In the case of an injection, it is preferable to prepare the injection by mixing, for example, water, acid, alkali, various buffer solutions, physiological saline, or amino acid infusion with the dispersion of the composition or the composition from which the solvent has been removed or lyophilized. It is also possible to prepare the injection by adding, for example, antioxidants such as citric acid, ascorbic acid, cysteine, or EDTA, or isotonicity agents such as glycerin, glucose, or sodium chloride. It is also possible to add a cryopreservative such as glycerin and store the composition frozen. [Example]

[0728] The present invention will now be described in detail with reference to Examples, Reference Examples, Comparative Examples, and Test Examples, although the present invention is not limited to these Examples, Reference Examples, Comparative Examples, and Test Examples. The proton nuclear magnetic resonance spectra ( 1 H NMR was measured at 270 MHz, 300 MHz, or 400 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. Note that the usual notation for signal multiplicity is used, with br indicating an apparently broad signal.

[0729] (Synthesis of cationic lipids) The synthesis method of lipid A is shown in the following Reference Examples A1 to A71.

[0730] Reference example A1 N-methyl-2-(oleoyloxy)-N,N-bis(2-(oleoyloxy)ethyl)ethanaminium chloride (Compound I-1) Process 1 To a solution of triethanolamine (Sigma-Aldrich, 0.115 g, 0.771 mmol) in chloroform (5 mL), oleic acid (Tokyo Chemical Industry Co., Ltd., 0.784 g, 2.78 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (Tokyo Chemical Industry Co., Ltd., 0.591 g, 3.08 mmol), triethylamine (0.430 mL, 3.08 mmol), and N,N-dimethylaminopyridine (Nacalai Tesque, 0.024 g, 0.19 mmol) were added and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and then saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / hexane = 50 / 50 to 100 / 0) to obtain 2,2',2''-nitrilotris(ethane-2,1-diyl) trioleate (0.439 g, 0.466 mmol, yield 60%). ESI-MS m / z: 943 (M + H) + ; 1 H-NMR (CDCl3) δ:0.88 (t, J = 6.9 Hz, 9H), 1.23-1.36 (m, 60H), 1.58-1.63 (m, 6H), 1.98-2.04 (m,12H), 2.29 (t, J= 7.6 Hz, 6H), 2.83 (t, J = 6.1 Hz, 6H), 4.11 (t, J = 6.1 Hz,6H), 5.31-5.38 (m, 6H). Process 2 Methyl iodide (Tokyo Chemical Industry Co., Ltd., 3 mL) was added to 2,2',2''-nitrilotris(ethane-2,1-diyl) trioleate (0.439 g, 0.466 mmol) obtained in Step 1, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a small amount of methanol-chloroform (1:1) and loaded onto an ion-exchange resin (Dow Chemical, Dowex™ 1x-2 100 mesh, Cl type, approximately 20 volumes, pre-washed with water an...

Claims

1. A nucleic acid-containing lipid nanoparticle comprising a fatty acid ester analog of glycerol that is not hydrolyzed by lipase, and a nucleic acid, The nucleic acid-containing lipid nanoparticles, wherein the fatty acid ester analog of glycerol is a lipid represented by the following formula (2): 【Chemistry 3】 (In formula (2), Rx 4 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, or Rx 41 -CO-, Rx 41 is a linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rx 5 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; Rx 6 is a negative charge, a hydrogen atom, or one of the following groups: 【Chemistry 4】 Either:

2. 2. The nucleic acid-containing lipid nanoparticle according to claim 1, wherein the lipase is phospholipase A2.

3. 3. The nucleic acid-containing lipid nanoparticle according to claim 1, wherein the content of the fatty acid ester analogue of glycerol is 0.001 times or more by mole relative to the number of moles of the total lipid.

4. The nucleic acid-containing lipid nanoparticle according to any one of claims 1 to 3, further comprising a cationic lipid.

5. The nucleic acid-containing lipid nanoparticle according to claim 4, wherein the cationic lipid is lipid A; at least one of the following formulas (I) to (IV), (V'), and (V''); and / or lipid B; at least one of the following formulas (CL-I) to (CL-XIX). Formula (I) 【Chemistry 5】 (In the formula, R 1 ~R 3 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 1 ~L 3 are the same or different and do not exist, or -Z 1 -(CY 1 Y 2 ) p1 -or-Z 2 -(CY 3 Y 4 ) p2 -Z 3 -(CY 5 Y 6 ) p3 - (in the formula, Y 1 ~Y 6 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 1 ~Z 3 are the same or different, -O-, -NY 7A -, -CO-O-, -O-CO-, -CO-NY 7B -,-NY 7C -CO- or -NY 7D -CO-0-, where Y 7A ~Y 7D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 1 ~p 3 are the same or different and are integers from 1 to 5, X 1 is an optionally substituted C1-C4 alkyl, A 1 is a pharmaceutically acceptable anion), Formula (II) 【Chemistry 6】 (In the formula, R 4 ~R 6 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 4 ~L 6 are the same or different and do not exist, or -Z 4 -(CY 8 Y 9 ) p4 -or-Z 5 -(CY 10 Y 11 ) p5 -Z 6 -(CY 12 Y 13 ) p6 - (in the formula, Y 8 ~Y 13 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 4 ~Z 6 are the same or different, -O-, -NY 14A -, -CO-O-, -O-CO-, -CO-NY 14B -,-NY 14C -CO- or -NY 14D -CO-0-, where Y 14A ~Y 14D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 4 is an integer between 0 and 5, and p 5 is an integer from 1 to 5, and p 6 is an integer from 0 to 5), L 7 does not exist or -(CY 15 Y 16 ) p7 -,-(CY 17 Y 18 ) p8 -Z 7 -(CY 19 Y 20 ) p9 -or-(CY 21 Y 22 ) p10 -Z 8 -(CY 23 Y 24 ) p11 -Z 9 -(CY 25 Y 26 ) p12 - (in the formula, Y 15 ~Y 26 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 7 ~Z 9 are the same or different, -O-, -NY 27A -, -CO-O-, -O-CO-, -CO-NY 27B -,-NY 27C -CO- or -NY 27D -CO-0-, where Y 27A ~Y 27D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 7 is an integer from 1 to 5, and p 8 is an integer between 0 and 5, and p 9 is an integer from 1 to 5, and p 10 is an integer between 0 and 5, and p 11 is an integer from 1 to 5, and p 12 is an integer from 1 to 5), B 1 teeth, 【Chemistry 7】 (In the formula, X 2 and X 3 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 4 is an optionally substituted C1-C4 alkyl, and X 5 and X 6 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 7 is an optionally substituted C1-C4 alkyl, and Y 28 ~Y 37 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 10 and Z 11 -O-, -NY are the same or different 38A -, -CO-O-, -O-CO-, -CO-NY 38B -,-NY 38C -CO- or -NY 38D -CO-0-, where Y 38A ~Y 38D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 13 is an integer between 0 and 5, and p 14 ~p 17 are the same or different and are integers from 1 to 5, A 2 is a pharmaceutically acceptable anion), Formula (III) 【Chemistry 8】 (In the formula, R 7 ~R 9 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 8 ~L 10 are the same or different and do not exist, or -Z 12 -(CY 39 Y 40 ) p18 -or-Z 13 -(CY 41 Y 42 ) p19 -Z 14 -(CY 43 Y 44 ) p20 - (in the formula, Y 39 ~Y 44 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 12 ~Z 14 are the same or different, -O-, -NY 45A -, -CO-O-, -O-CO-, -CO-NY 45B -,-NY 45C -CO-, -NY 45D -CO-0- or -CO-, where Y 45A ~Y 45D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl; p 18 is an integer between 0 and 5, and p 19 is an integer from 1 to 5, and p 20 is an integer from 0 to 5), L 11 does not exist or -(CY 46 Y 47 ) p21 -,-(CY 48 Y 49 ) p22 -Z 15 -(CY 50 Y 51 ) p23 -or-(CY 52 Y 53 ) p24 -Z 16 -(CY 54 Y 55 ) p25 -Z 17 -(CY 56 Y 57 ) p26 - (in the formula, Y 46 ~Y 57 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 15 ~Z 17 are the same or different, -O-, -NY 58A -, -CO-O-, -O-CO-, -CO-NY 58B -,-NY 58C -CO-, -NY 58D -CO-0- or -CO-, where Y 58A ~Y 58D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 21 is an integer from 1 to 5, and p 22 is an integer between 0 and 5, and p 23 is an integer from 1 to 5, and p 24 is an integer between 0 and 5, and p 25 is an integer from 1 to 5, and p 26 is an integer from 1 to 5), L 12 does not exist or -(CY 59 Y 60 ) p27 -,-(CY 61 Y 62 ) p28 -Z 18 -(CY 63 Y 64 ) p29 -or-(CY 65 Y 66 ) p30 -Z 19 -(CY 67 Y 68 ) p31 -Z 20 -(CY 69 Y 70 ) p32 - (in the formula, Y 59 ~Y 70 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 18 ~Z 20 are the same or different, -O-, -NY 71A -, -CO-O-, -O-CO-, -CO-NY 71B -,-NY 71C -CO-, -NY 71D -CO-0- or -CO-, where Y 71A ~Y 71D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 27 is an integer from 1 to 5, and p 28 is an integer between 0 and 5, and p 29 is an integer between 0 and 5, and p 30 is an integer between 0 and 5, and p 31 is an integer from 1 to 5, and p 32 is an integer between 0 and 5) and J 1 and J. 2 Is the same or different CY 72 or N (wherein Y 72 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 acyloxy; B 2 teeth, 【Chemistry 9】 (In the formula, X 8 and X 9 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 10 is an optionally substituted C1-C4 alkyl, and X 11 and X 12 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 13 is an optionally substituted C1-C4 alkyl, and Y 73 ~Y 82 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 21 and Z 22 -O-, -NY are the same or different 83A -, -CO-O-, -O-CO-, -CO-NY 83B -,-NY 83C -CO- or -NY 83D -CO-0-, where Y 83A ~Y 83D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 33 is an integer between 0 and 5, and p 34 ~p 37 are the same or different and are integers from 1 to 5, A 3 is a pharmaceutically acceptable anion), Formula (IV) 【Chemistry 10】 (In the formula, R 10 ~R 12 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; L 13 does not exist or -Z 23 -(CY 83 Y 84 ) p38 -or-Z 24 -(CY 85 Y 86 ) p39 -Z 25 -(CY 87 Y 88 ) p40 - (in the formula, Y 83 ~Y 88 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 23 ~Z 25 are the same or different, -O-, -NY 89A -, -CO-O-, -O-CO-, -CO-NY 89B -,-NY 89C -CO- or -NY 89D -CO-0-, where Y 89A ~Y 89D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 38 ~p 40 are the same or different and are integers from 1 to 5, L 14 and L 15 are the same or different and do not exist, or -Z 26 -(CY 90 Y 91 ) p41 -or-Z 27 -(CY 92 Y 93 ) p42 -Z 28 -(CY 94 Y 95 ) p43 - (in the formula, Y 90 ~Y 95 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 26 ~Z 28 are the same or different, -O-, -NY 96A -, -CO-O-, -O-CO-, -CO-NY 96B -,-NY 96C -CO-, -NY 96D -CO-0- or -CO-, where Y 96A ~Y 96D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 41 is an integer between 0 and 5, and p 42 is an integer from 1 to 5, and p 43 is an integer from 0 to 5), L 16 does not exist or -(CY 97 Y 98 ) p44 -,-(CY 99 Y 100 ) p45 -Z 29 -(CY 101 Y 102 ) p46 -or-(CY 103 Y 104 ) p47 -Z 30 -(CY 105 Y 106 ) p48 -Z 31 -(CY 107 Y 108 ) p49 - (in the formula, Y 97 ~Y 108 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 29 ~Z 31 are the same or different, -O-, -NY 109A -, -CO-O-, -O-CO-, -CO-NY 109B -,-NY 109C -CO-, -NY 109D -CO-0- or -CO-, where Y 109A ~Y 109D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 44 is an integer from 1 to 5, and p 45 is an integer between 0 and 5, and p 46 is an integer from 1 to 5, and p 47 is an integer between 0 and 5, and p 48 is an integer from 1 to 5, and p 49 is an integer from 1 to 5), J 3 is CY 110 or N (wherein Y 110 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, or optionally substituted C1-C4 acyloxy; X 14 and X 15 are the same or different and optionally substituted C1-C4 alkyl, or are taken together with the adjacent nitrogen atom to form an optionally substituted C4-C6 heterocycle; A 4 is a pharmaceutically acceptable anion), Formula (V') or Formula (V'') 【Chemistry 11】 (In the formula, R 13 ~R 18 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; Y 111 ~Y 114 are the same or different and each represent a hydrogen atom, hydroxy, or an optionally substituted C1-C4 alkyl; L 17 ~L 19 and L 22 ~L 24 are the same or different and do not exist, or -Z 32 -(CY 115 Y 116 ) p51 -or-Z 33 -(CY 117 Y 118 ) p52 -Z 34 -(CY 119 Y 120 ) p53 - (in the formula, Y 115 ~Y 120 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 32 ~Z 34 are the same or different, -O-, -NY 121A -, -CO-O-, -O-CO-, -CO-NY 121B -,-NY 121C -CO-, -NY 121D -CO-0- or -CO-, where Y 121A ~Y 121D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 51 is an integer between 0 and 5, and p 52 is an integer from 1 to 5, and p 53 is an integer from 0 to 5), L 20 and L 25 are the same or different and do not exist, or -(CY 122 Y 123 ) p54 -,-(CY 124 Y 125 ) p5 5 -Z 35 -(CY 126 Y 127 ) p56 -or-(CY 128 Y 129 ) p57 -Z 36 -(CY 130 Y 131 ) p58 -Z 37 -(CY 132 Y 133 ) p59 - (in the formula, Y 122 ~Y 133 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 35 ~Z 37 are the same or different, -O-, -NY 134A -, -CO-O-, -O-CO-, -CO-NY 134B -,-NY 134C -CO-, -NY 134D -CO-0- or -CO-, where Y 134A ~Y 134D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 54 is an integer from 1 to 5, and p 55 is an integer between 0 and 5, and p 56 is an integer from 1 to 5, and p 57 is an integer between 0 and 5, and p 58 is an integer from 1 to 5, and p 59 is an integer from 1 to 5), L 21 and L 26 are the same or different and do not exist, or -(CY 135 Y 136 ) p60 -,-(CY 137 Y 138 ) p61 -Z 38 -(CY 139 Y 140 ) p62 -or-(CY 141 Y 142 ) p63 -Z 39 -(CY 143 Y 144 ) p64 -Z 40 -(CY 145 Y 146 ) p65 - (in the formula, Y 135 ~Y 146 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 38 ~Z 40 are the same or different, -O-, -NY 147A -, -CO-O-, -O-CO-, -CO-N Y 147B -, -NR 147C -CO-, -NY 147D -CO-0- or -CO-, where Y 147A ~Y 147D is the same or are different and are a hydrogen atom or an optionally substituted C1-C4 alkyl), p 60 is an integer from 1 to 5, and p 61 is an integer between 0 and 5, and p 62 is an integer between 0 and 5, and p 63 is an integer between 0 and 5, and p 64 is an integer from 1 to 5, and p 65 is an integer from 0 to 5), B 3 and B 4 are the same or different, 【Chemistry 12】 (In the formula, X 16 and X 17 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 18 is an optionally substituted C1-C4 alkyl, and X 19 and X 20 are the same or different and optionally substituted C1-C4 alkyl, or together with the adjacent nitrogen atom, form an optionally substituted C4-C6 heterocycle; X 21 is an optionally substituted C1-C4 alkyl, and Y 148 ~Y 157 are the same or different and each represents a hydrogen atom or an optionally substituted C1-C4 alkyl; Z 41 and Z 42 -O-, -NY are the same or different 158A -, -CO-O-, -O-CO-, -CO-NY 158B -,-NY 158C -CO- or -NY 158D -CO-0-, where Y 158A ~Y 158D are the same or different and each represent a hydrogen atom or an optionally substituted C1-C4 alkyl), p 66 is an integer between 0 and 5, and p 67 ~p 70 are the same or different and are integers from 1 to 5, A 5 and A 6 are the same or different and are pharmaceutically acceptable anions) Formula (CL-I) 【Chemistry 13】 (In the formula, R 101 and R 102 are the same or different and are linear or branched C10-C24 alkyl, C10-C24 alkenyl, or C10-C24 alkynyl, L 101 and L 102 are a hydrogen atom or together form a single bond or a C2-C8 alkylene; L 103 is a single bond, -CO- or -CO-O-, L 103 If is a single bond, X 101 is a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, L 103 When is -CO- or -CO-O-, X 101 is pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl or morpholinyl; Formula (CL-II) 【Chemistry 14】 (In the formula, R 103 and R 104 are the same or different and are linear or branched C12-C24 alkyl, C12-C24 alkenyl, or C12-C24 alkynyl, p 101 and p 102 are the same or different and are integers from 0 to 3, L 106 and L 107 are a hydrogen atom or together form a single bond or a C2-C8 alkylene; L 104 and L 105 are the same or different and are -O-, -CO-O- or -O-CO-, L 108 is a single bond, -CO- or -CO-O-, L 108 If is a single bond, X 102 is a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, L 108 When is -CO- or -CO-O-, X 102 is pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, dialkylamino, trialkylammonio, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, pyrrolidinyl, piperidyl or morpholinyl, wherein at least one of the substituents is amino, monoalkylamino, dialkylamino, trialkylammonio, pyrrolidinyl, piperidyl or morpholinyl; Formula (CL-III) 【Chemistry 15】 (In the formula, R 105 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 106 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl or C8-C24 alkynyloxypropyl, X 103 and X 104 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene, or X 103 is L 111 together to form a C2-C8 alkylene, L 111 is a hydrogen atom, C1-C6 alkyl, C3-C6 alkenyl, amino, monoalkylamino, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or C1-C6 alkyl or C3-C6 alkenyl substituted by 1 to 3 identical or different amino, monoalkylamino, hydroxy, alkoxy, carbamoyl, monoalkylcarbamoyl, or dialkylcarbamoyl, or X 103 together to form a C2-C8 alkylene, L 109 is C1-C6 alkylene, L 110 is a single bond or C1-C6 alkylene, provided that L 109 and L 110 The sum of the carbon numbers of L is 7 or less. 111 In the case of a hydrogen atom, L 110 is a single bond, and L 111 is X 103 When L is taken together with 110 is a single bond or is methylene or ethylene), Formula (CL-IV) 【Chemistry 16】 (In the formula, R 107 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 108 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl, C8-C24 alkynyloxypropyl, C8-C24 alkyloxyethoxyethyl, C8-C24 alkenyloxyethoxyethyl or C8-C24 alkynyloxyethoxyethyl, X 105 is a hydrogen atom or an optionally substituted C1-C4 alkyl), Formula (CL-V) 【Chemistry 17】 (In the formula, R 109 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 110 is a linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkyloxyethyl, C8-C24 alkyloxypropyl, C8-C24 alkenyloxyethyl, C8-C24 alkenyloxypropyl, C8-C24 alkynyloxyethyl or C8-C24 alkynyloxypropyl, L 112 is C1-C3 alkylene, X 105 ' is a hydrogen atom or a C1-C3 alkyl, Formula (CL-VI) 【Chemistry 18】 (In the formula, R 111 and R 112 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; X 106 and X 107 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene; p 103 , p 104 and p 105 are the same or different and are 0 or 1, where p 103 , p 104 and p 105 is not 0 at the same time, L 113 and L 114 are the same or different and are O, S or NH), Formula (CL-VII) 【Chemistry 19】 (In the formula, R 113 and R 114 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; R 115 is a hydrogen atom, hydroxy, optionally substituted C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 acyloxy, X 109 and X 110 are the same or different and are C1-C3 alkyl or together form C2-C8 alkylene; L 115 is -CO-O-, -O-CO-, -NHCO- or -CONH-, p 106 is an integer between 0 and 3, p 107 is an integer from 1 to 4), Formula (CL-VIII) 【Chemistry 20】 (In the formula, R 116 and R 117 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C7-C20 alkyloxyC1-C3 alkyl, C7-C20 alkenyloxyC1-C3 alkyl or C7-C20 alkynyloxyC1-C3 alkyl, B 100 represents a hydrogen atom, a C1-C3 alkyl, a hydroxy C2-C4 alkyl, a C1-C3 dialkylamino C2-C4 alkyl, a group represented by the formula (A) 【Chemical 21】 (In the formula, X 111 and X 112 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 111 and X 112 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 110 is an integer from 2 to 6), or formula (B): 【Chemical 22】 (In the formula, X 113 and X 114 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 113 and X 114 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 111 is an integer from 1 to 6), P 108 is an integer between 0 and 4, and P 109 is an integer between 1 and 4 (where P 108 is 0 and P 109 except when is 1), L 116 are the same or different and are hydrogen atoms or C1-C3 alkyls at each carbon atom to which they are bonded, L 117 are the same or different and are hydrogen atoms or C1-C3 alkyls at each carbon atom to which they are bonded; Formula (CL-IX) 【Chemical 23】 (In the formula, X 115 and X 116 are the same or different and are a hydrogen atom or a C1-C3 alkyl, L 118 and L 119 are the same or different and are linear or branched, optionally substituted C8-C24 alkylene or C8-C24 alkenylene, M 101 and M 102 are the same or different and are -C=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -OC(S)-, -C(S)O-, -SS-, -C(R '' )=N-, -N=C(R '' )-, -C(R '' )=NO-, -ON=C(R '' )-, -N(R '' )C(O)-, -C(O)N(R '' )-, -N(R '' )C(S)-, -C(S)N(R '' )-, -N(R '' )C(O)N(R ''' )-, -N(R '' )C(O)O-, -OC(O)N(R '' )- and -OC(O)O-; R '' and R ''' are the same or different and are a hydrogen atom or a C1-C3 alkyl, R 118 and R 119 are the same or different and each represents a linear or branched C1-C16 alkyl or C2-C16 alkenyl which may be substituted, Formula (CL-X) 【Chemistry 24】 (In the ceremony X 117 and X 118 are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, a heterocyclyl, or a polyamine; or X 117 and X 118 may together with the nitrogen to which they are attached form a 4- to 7-membered monocyclic heterocycle which may contain, in addition to the nitrogen, one or two further heteroatoms selected from N, O and S; R 120 and R 121 are the same or different and are linear or branched, optionally substituted C4-C24 alkyl or C4-C24 alkenyl), Formula (CL-XI) 【Chemistry 25】 (In the formula, X 119 and X 120 are the same or different and are a hydrogen atom, a linear or branched optionally substituted C1-C20 alkyl, C1-C20 alkenyl, C1-C20 alkynyl, or C6-C20 acyl, R 122 and R 123 are the same or different and are linear or branched, optionally substituted C1-C30 alkyl, C2-C30 alkenyl, or C2-C30 alkynyl; p 112 , p 113 and p 114 are the same or different and are 0 or any positive integer), Formula (CL-XII) 【Chemical 26】 (In the formula, X 121 and X 122 are the same or different and are a hydrogen atom, C1-C6 alkyl, cycloalkyl, or cycloalkenyl, or X 121 and X 122 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which they are attached. L 120 and L 121 are the same or different and are -O-, -OC(O)- or -(O)CO-; R 124 and R 125 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl or C8-C24 alkenyl), Formula (CL-XIII) 【Chemical 27】 (In the formula, R 126 and R 127 are the same or different and are linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 heteroalkyl, C8-C24 heteroalkenyl, or C8-C24 heteroalkynyl; X 123 is a hydrogen atom or an optionally substituted C1-C6 alkyl, X 124 is C1-C6 alkyl, -NR 4a R 4b or optionally substituted C-C alkyl or C-C heterocyclyl substituted by R 4a and R 4b are the same or different and may be hydrogen atoms, C(=NH)NH 2 or optionally substituted C1-C6 alkyl, or R 4a and R 4b may form an optionally substituted C3-C7 heterocyclyl; X 123 and X 124 may be taken together with the nitrogen atom to which they are attached to form an optionally substituted C3-C7 heterocyclyl; However, X 123 and X 124 does not form an imidazolyl, benzimidazolyl, or succinimidyl group, and only one primary amine is present at X 123 and X 124 or any primary amine may be present on either X 123 and X 124 X does not exist on either 123 and X 124 is not a substituted amide, R 126 and R 127 When is C11 alkyl or C15 alkyl, X 123 is not a hydrogen atom, R 126 and R 127 is C16 alkyl or C17 alkyl, R 126 and R 127 is not replaced with OH, R 126 and R 127 When is a C17 alkyl, X 123 and X 124 is not replaced with OH, R 126 and R 127 When is C18 alkyl, X 124 is unsubstituted with optionally substituted imidazolyl), Formula (CL-XIV) 【Chemical Formula 28】 (In the formula, X 125 and X 126 are the same or different and are a hydrogen atom, an optionally substituted C1-C6 alkyl, a heterocyclyl, or a polyamine; or X 125 and X 126 may together with the nitrogen to which they are attached form a 4- to 7-membered monocyclic heterocycle which may contain, in addition to the nitrogen, one or two further heteroatoms selected from N, O and S; R 130 is a hydrogen atom or C1-C6 alkyl, R 128 and R 129 are the same or different and are linear or branched, optionally substituted C4-C24 alkyl or C4-C24 alkenyl), Formula (CL-XV) 【Chemical 29】 (In the formula, X 127 and X 128 are each independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; X 127 and X 128 together with the nitrogen atom to which they are attached form a heterocyclic ring having 1 to 2 nitrogen atoms, L 122 is -C(O)O-, -OC(O)-, -C(O)N(X 130 )-,-N(X 130 )C(O)-, -OC(O)O-, -OC(O)N(X 130 )-, -N(X 130 )C(O)N(X 130 )- or -N(X 130 )C(O)O−, X 130 each occurrence is independently a hydrogen atom or a C1-C3 alkyl; a is 1, 2, 3, 4, 5, or 6; b is 0, 1, 2, or 3; X 129 is absent, hydrogen or C1-C3 alkyl; R 131 and R 132 are independently alkyl having 12 to 24 carbon atoms, alkenyl having 12 to 24 carbon atoms, or alkoxy having 12 to 24 carbon atoms, each of which has one or more biodegradable groups, and each biodegradable group is independently interrupted in the alkyl, alkenyl, or alkoxy group having 12 to 24 carbon atoms, or is substituted at the end of the alkyl, alkenyl, or alkoxy group having 12 to 24 carbon atoms (the interrupted biodegradable groups are -C(O)O-, -OC(O)-, -C(O)N(X 130 )- or -N(X 130 )C(O)-, and the terminal ones are -C(O)O-C1-C4 alkyl, -OC(O)-C1-C4 alkyl, -C(O)N(X 130 )-C1-C4 alkyl, or -N(X 130 )C(O)-C1-C4 alkyl), R 131 and R 132 has at least four carbon atoms between the biodegradable group and the tertiary carbon atom marked with an asterisk (*), Formula (CL-XVI) 【Chemistry 30】 (In the formula, R 133 and R 134 are the same or different and each is a linear or branched C1-C9 alkyl, C2-C11 alkenyl, or C2-C11 alkynyl; L 123 and L 124 are the same or different and each is a linear C5-C18 alkylene or a linear C5-C18 alkenylene, or forms a heterocycle together with N; L 125 is a single bond or -CO-O-, thereby forming -L 124 -CO-OR 134 is formed, L 127 is S or O, L 126 is a single bond, or a linear or branched C1-C6 alkylene, or forms a heterocycle together with N; L 128 is a linear or branched C1-C6 alkylene, and X 131 and X 132 are the same or different and each is hydrogen or a linear or branched C1-C6 alkyl. Formula (CL-XVII) 【Chemical 31】 (In the formula, L 131 is C2-C4 alkylene or -CH 2 -S-CH 2 CH 2 - and L 129 and L 130 are the same or different and each is C1-C6 alkyl; R 135 and R 136 are the same or different and are C10-C30 alkyl or C10-C30 alkenyl, X 133 and X 134 are the same or different and are hydrogen, C1-C6 alkyl, or -CH 2 CH 2 OH.) Formula (CL-XVIII) 【Chemical 32】 (In the formula, R 137 and R 138 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, C8-C24 alkylthioethyl, C8-24 alkenylthioethyl, or C8-C24 alkynylthioethyl, X 135 represents a hydrogen atom, a C1-C3 alkyl, a hydroxy C2-C4 alkyl, a group represented by the formula (C) 【Chemical 33】 (In the formula, X 136 and X 137 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 136 and X 137 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 132 is S or O, and p 115 is an integer of 2 to 4), formula (D) 【Chemical 34】 (In the formula, X 138 and X 139 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 138 and X 139 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 116 is an integer from 1 to 4), or formula (E): 【Chemical 35】 (In the formula, X 140 and X 141 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 140 and X 141 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 117 is an integer from 1 to 4. Formula (CL-XIX) 【Chemical 36】 (In the formula, R 139 and R 140 are the same or different and are linear or branched C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl, L 133 is S or O, X 142 represents a hydrogen atom, a C1-C3 alkyl, a hydroxy C2-C4 alkyl, a group represented by formula (F) 【Chemical 37】 (In the formula, X 143 and X 144 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 143 and X 144 may form a C2-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 134 is S or O, and p 118 is an integer of 2 to 4), or formula (G): 【Chemical 38】 (In the formula, X 145 and X 146 are the same or different and are a hydrogen atom or a C1-C3 alkyl, or X 145 and X 146 may form a C3-C6 nitrogen-containing heterocycle together with the nitrogen atom to which it is bonded, 119 is an integer between 1 and 4.

6. The nucleic acid-containing lipid nanoparticle according to claim 5, wherein the cationic lipid is lipid B.

7. The nucleic acid-containing lipid nanoparticle according to any one of claims 1 to 6, further comprising a conjugate of a water-soluble polymer and a lipid, or a conjugate of a water-soluble polymer and a fatty acid.

8. The nucleic acid-containing lipid nanoparticle of claim 7, wherein the water-soluble polymer moiety in the conjugate of a water-soluble polymer and a lipid, or the conjugate of a water-soluble polymer and a fatty acid, is selected from the group consisting of polyethylene glycol, polyglycerin, polyethyleneimine, polyvinyl alcohol, polyacrylic acid, and polyacrylamide.

9. The nucleic acid-containing lipid nanoparticle according to any one of claims 1 to 8, further comprising a neutral lipid.

10. 10. The nucleic acid-containing lipid nanoparticle according to claim 9, wherein the neutral lipid is selected from the group consisting of phospholipids, sterols, glyceroglycolipids, glycosphingolipids, and sphingoids.

11. The nucleic acid-containing lipid nanoparticle according to any one of claims 1 to 10, wherein the nucleic acid is a nucleic acid having an effect of suppressing the expression of a target gene using RNA interference (RNAi).

12. The nucleic acid-containing lipid nanoparticle of claim 11, wherein the target gene is a gene associated with tumor or inflammation.

13. 1. A method for stabilizing nucleic acid-containing lipid nanoparticles using a fatty acid ester analog of glycerol that is not hydrolyzed by lipase, comprising: The method, wherein the fatty acid ester analog of glycerol is a lipid represented by the following formula (2): 【Chemistry 41】 (In formula (2), Rx 4 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, C8-C24 alkynyl, or Rx 41 -CO-, Rx 41 is a linear or branched, optionally substituted C7-C23 alkyl, C7-C23 alkenyl, or C7-C23 alkynyl; Rx 5 is a linear or branched, optionally substituted C8-C24 alkyl, C8-C24 alkenyl, or C8-C24 alkynyl; Rx 6 is a negative charge, a hydrogen atom, or one of the following groups: 【Chemistry 42】 Either:

14. A composition for introducing a nucleic acid into a cell, comprising the nucleic acid-containing lipid nanoparticles according to any one of claims 1 to 12.

15. The composition of claim 14, wherein the cell is a cell in a tumor or an inflammatory site in a mammal.

16. 16. The composition of claim 14 or 15, wherein the cell is a cell in the liver, stomach, lung, kidney, pancreas or spleen of a mammal.

17. The composition according to any one of claims 14 to 16, wherein the method for introducing the composition into cells is by intravenous administration or subcutaneous administration.

18. A pharmaceutical comprising the nucleic acid-containing lipid nanoparticles according to any one of claims 1 to 12.

19. 19. The pharmaceutical composition of claim 18, which is for intravenous or subcutaneous administration.

20. A therapeutic agent for cancer or inflammatory disease, comprising the nucleic acid-containing lipid nanoparticles according to any one of claims 1 to 12.

21. 21. The therapeutic agent according to claim 20, for intravenous or subcutaneous administration.

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