Lipid composition

Abstract

The present application provides a lipid composition which enables excellent nucleic acid delivery to a wide variety of nucleic acids. According to the present application, a lipid composition comprising a first lipid which is a lipid represented by formula (1) or a salt thereof, a solid sterol, and a nucleic acid, the ratio of the number of moles of the first lipid in the lipid composition to the number of moles of the solid sterol in the lipid composition being 0.300 or greater and less than 1.299. In the formula, X represents -NR 1 - or -O-, R 1 represents a hydrogen atom, a hydrocarbon group, or the like, R 2 and R 3 each independently represent a hydrogen atom, a hydrocarbon group, or the like, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 each independently represent a hydrogen atom or an alkyl group, R 4 and R 5 , R 10 and R 5 , R 5 and R 12 , R 4 and R 6 , R 5 and R 6 , R 6 and R 7 , R 6 and R 10 , R 12 and R 7 , and R 7 and R 8 may be linked to each other to form a 4- to 7-membered ring which can contain an O atom, a, b, c, and d each independently represent an integer of 0 to 3, wherein a + b is 1 or greater and c + d is 1 or greater.

Description

[0001] This application is a divisional application of Chinese application number 202080079111.X, entitled "Lipid Composition", filed on November 13, 2020. Technical Field

[0002] This invention relates to a lipid composition comprising lipids and nucleic acids. Background Technology

[0003] Because technologies for delivering nucleic acids to cells have been continuously developed, nucleic acid pharmaceuticals are being actively developed. As one nucleic acid delivery technology, methods for administering nucleic acid-containing particles (liposomes or lipid particles) containing nucleic acids are known. In this technology, nucleic acid-containing particles are prepared using lipids having amino groups or the like that which become cationic at low pH, and nucleic acid delivery is achieved by imparting an appropriate charge to the particles. For example, as compounds contained in lipid particles, Patent Document 1 discloses a compound having ester groups, acetal groups, or the like as linkers connecting aliphatic groups and amino groups. Patent Document 2 discloses a compound having ethyleneoxy or amide groups, oxime groups, or the like as linkers connecting aliphatic groups and amino groups. Furthermore, in this specification, the aforementioned lipids having amino groups or the like that which become cationic at low pH are sometimes referred to as cationic lipids.

[0004] Furthermore, Patent Document 3 describes a cationic lipid for delivering bioactive agents to cells and tissues. Patent Document 4 describes a cationic lipid comprising lipid nanoparticles containing a compound called DLin-MC3-DMA.

[0005] Furthermore, the types and composition ratios of lipid compounds used in the manufacture of nucleic acid-containing particles were also studied. Patent Document 5 describes a nucleic acid-lipid particle comprising (a) nucleic acid; (b) approximately 50 mol% to approximately 85 mol% cationic lipids constituting the total lipids present in the particle; (c) approximately 13 mol% to approximately 49.5 mol% non-cationic lipids constituting the total lipids present in the particle; and (d) approximately 0.5 mol% to approximately 2 mol% complexed lipids constituting the total lipids present in the particle, which inhibit particle aggregation. Patent Document 6 describes a lipid formulation comprising 40 to 65% cationic lipids with a specific structure, 5 to 10% neutral lipids, 25 to 40% sterols, and 0.5 to 10% PEG or PEG-modified lipids.

[0006] Previous technical documents

[0007] Patent documents

[0008] Patent Document 1: International Publication Publication No. 2010 / 054401

[0009] Patent Document 2: International Publication Publication No. 2010 / 054405

[0010] Patent Document 3: International Publication Publication No. 2015 / 095340

[0011] Patent Document 4: U.S. Publication No. 2013 / 0245107

[0012] Patent Document 5: International Publication Publication No. 2009 / 127060

[0013] Patent Document 6: International Publication Publication No. 2010 / 144740 Summary of the Invention

[0014] The technical problem to be solved by the invention

[0015] As mentioned above, there have been reports on lipid compositions containing lipids and nucleic acids, but lipid compositions capable of delivering a wide variety of nucleic acids are desired. Furthermore, lipids containing amino groups are known to be toxic, therefore, techniques for more efficient nucleic acid delivery are required.

[0016] In view of this situation, the present invention aims to provide a lipid composition that enables excellent nucleic acid delivery to a wide range of nucleic acids.

[0017] means for solving technical problems

[0018] The inventors of this invention, through in-depth research to solve the aforementioned problems, confirmed that, in a lipid composition comprising a first lipid (as represented by formula (1) or a salt thereof), a sterol, and a nucleic acid, excellent nucleic acid delivery can be achieved by setting the ratio of the molar number of the first lipid in the lipid composition to the molar number of the sterol in the lipid composition to be 0.300 or more and less than 1.299, thus completing this invention. According to this invention, the following invention is provided.

[0019] <1> A lipid composition comprising a first lipid as a lipid or a salt thereof represented by formula (1), a sterol, and a nucleic acid, wherein in the lipid composition,

[0020] The ratio of the molar number of the first lipid in the lipid composition to the molar number of sterols in the lipid composition is greater than 0.300 and less than 1.299.

[0021] [Chemical Formula 1]

[0022]

[0023] In the formula, X represents -NR 1 -or-O-,

[0024] R 1 Represents a hydrocarbon group or R that contains 6 to 24 hydrogen atoms and carbon atoms. 21 -L 1 -R 22 - The group represented, R 21 L represents a hydrocarbon group with 1 to 24 carbon atoms. 1 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0025] [Chemical Formula 2]

[0026]

[0027] R 22 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0028] R 2 and R 3 Each independently represents a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or an R group. 31 -L 2 -R 32 - The group represented, R 31 L represents a hydrocarbon group with 1 to 24 carbon atoms. 2 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0029] [Chemical Formula 3]

[0030]

[0031] R 32 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0032] R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0033] R 4 With R 5 R 10 With R 5 R 5 With R 12 R 4 With R 6 R 5With R 6 R 6 With R 7 R 6 With R 10 R 12 With R 7 and R 7 With R 8 Any one or more groups can connect to each other to form a 4- to 7-membered ring that can contain O atoms.

[0034] The substituents on alkyl groups with 1 to 18 carbon atoms that can be substituted are hydroxyl, carboxyl, and -NR. 45 R 46 The amino group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -O(CO)OR are represented. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0035] The substituents on the substituted or unsubstituted aryl group and the substituted or unsubstituted heteroaryl group are alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0036] a, b, c, and d each independently represent integers from 0 to 3, where a+b is greater than or equal to 1, and c+d is greater than or equal to 1.

[0037] <2> The lipid composition according to <1>, wherein,

[0038] Sterols are cholesterol or its derivatives.

[0039] <3> The lipid composition according to <1> or <2> further comprises lipids having a nonionic hydrophilic polymeric structure.

[0040] <4> According to the lipid composition described in <3>, wherein,

[0041] Lipids with nonionic hydrophilic polymer structures are lipids with polyethylene glycol structures.

[0042] <5> The lipid composition according to <4>, wherein,

[0043] Lipids with a polyethylene glycol structure are lipids with both diacylglycerol and polyethylene glycol structures.

[0044] <6> The lipid composition according to any one of <3> to <5>, wherein,

[0045] The content of lipids with nonionic hydrophilic polymeric structures is 0.2–10 mol% relative to the total lipid content.

[0046] <7> The lipid composition according to any one of <1> to <6>, wherein,

[0047] The content of lipid 1 relative to the total lipids is 20–55 mol%.

[0048] <8> The lipid composition according to any one of <1> to <7>, wherein,

[0049] Sterols comprise 20–70 mol% of the total lipid content.

[0050] <9> The lipid composition according to any one of <1> to <8>, wherein,

[0051] The content of nucleic acids relative to the total lipids is 1-25% by mass.

[0052] <10> The lipid composition according to any one of <1> to <9>, wherein,

[0053] The compound represented by formula (1) is the same as the compound represented by formula (2).

[0054] [Chemical Formula 4]

[0055]

[0056] In the formula, R 2 and R 3 Each independently represents a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or an R group. 31 -L 2 -R 32 -The group that represents,

[0057] R 31 Represents hydrocarbon groups with 1 to 24 carbon atoms.

[0058] L 2 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0059] [Chemical Formula 5]

[0060]

[0061] R 32 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0062] R 5 Represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0063] R 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0064] The substituents on alkyl groups with 1 to 18 carbon atoms that can be substituted are hydroxyl, carboxyl, and -NR. 45 R 46 The amino group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -O(CO)OR are represented. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0065] The substituents on the substituted or unsubstituted aryl group and the substituted or unsubstituted heteroaryl group are alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0066] e represents 2 or 3.

[0067] <11> The lipid composition according to <10>, wherein,

[0068] In equation (2),

[0069] R 2 and R 3 At least one of them represents a hydrocarbon group containing more than one unsaturated bond with 3 to 24 carbon atoms, or R 2 and R 3 Represent R independently 31 -L 2 -R 32 - The group represented, or R 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another group in the group represents hydrocarbon groups with 3 to 24 carbon atoms.

[0070] R 5 It indicates an unsubstituted alkyl group having 1 to 18 carbon atoms, or a group marked with -O(CO)-R 42 or-(CO)OR 43 Alkyl groups with 1 to 18 carbon atoms that are substituted.

[0071] R 7 and R 8 Each alkyl group, having 1 to 4 carbon atoms, is represented independently.

[0072] R 31 L 2 R 32 R 42 and R 43 The definition is the same as that of <10>.

[0073] <12> The lipid composition according to any one of <1> to <11> further comprises a pharmaceutically acceptable carrier.

[0074] <13> The lipid composition according to any one of <1> to <12> is a composition for introducing nucleic acids into cells.

[0075] <14> The lipid composition according to any one of <1> to <12> is a composition for in vivo nucleic acid delivery.

[0076] Invention Effects

[0077] The lipid composition of the present invention can achieve excellent nucleic acid delivery. Detailed Implementation

[0078] The present invention will now be described in detail.

[0079] In this specification, “~” indicates that the values ​​recorded before and after it are the minimum and maximum values, respectively, and encompass the range.

[0080] The lipid composition of the present invention is a lipid composition comprising a first lipid as a lipid or a salt thereof represented by formula (1), sterols and nucleic acids, wherein the molar ratio of the first lipid in the lipid composition to the molar ratio of the sterols in the lipid composition is 0.300 or more and less than 1.299.

[0081] <Regarding the ratio of the molar number of the first lipid in the lipid composition to the molar number of sterols in the lipid composition>

[0082] In the lipid composition of the present invention, the ratio of the molar number of the first lipid in the lipid composition to the molar number of the sterols in the lipid composition is 0.300 or more and less than 1.299, thus the lipid composition of the present invention can achieve excellent nucleic acid delivery.

[0083] The lower limit of the ratio of the molar number of the first lipid in the lipid composition to the molar number of sterols in the lipid composition is preferably 0.350 or more, but may also be 0.400 or more, 0.500 or more, or 0.600 or more.

[0084] The upper limit of the ratio of the molar number of the first lipid in the lipid composition to the molar number of sterols in the lipid composition is preferably 1.250 or less, and may also be 1.200 or less.

[0085] <Lipids or their salts represented by formula (1)>

[0086] The lipid composition of the present invention comprises a lipid or a salt thereof represented by formula (1).

[0087] [Chemical Formula 6]

[0088]

[0089] In the formula, X represents -NR 1 -or-O-,

[0090] R 1 Represents a hydrocarbon group or R that contains 6 to 24 hydrogen atoms and carbon atoms. 21 -L 1 -R 22 - The group represented, R 21 L represents a hydrocarbon group with 1 to 24 carbon atoms.1 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0091] [Chemical Formula 7]

[0092]

[0093] R 22 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0094] R 2 and R 3 Each independently represents a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or an R group. 31 -L 2 -R 32 - The group represented, R 31 L represents a hydrocarbon group with 1 to 24 carbon atoms. 2 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0095] [Chemical Formula 8]

[0096]

[0097] R 32 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0098] R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0099] R 4 With R 5 R 10 With R 5 R 5 With R 12 R 4 With R 6 R 5 With R 6 R 6 With R 7 R 6 With R 10 R 12 With R 7 and R 7 With R 8Any one or more groups can connect to each other to form a 4- to 7-membered ring that can contain O atoms.

[0100] The substituents on alkyl groups with 1 to 18 carbon atoms that can be substituted are hydroxyl, carboxyl, and -NR. 45 R 46 The amino group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -O(CO)OR are represented. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0101] The substituents of substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups are alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0102] a, b, c, and d each independently represent integers from 0 to 3, where a+b is greater than or equal to 1, and c+d is greater than or equal to 1.

[0103] As R 1 Hydrocarbon groups with 6 to 24 carbon atoms and R 2 and R 3The hydrocarbon group having 3 to 24 carbon atoms is preferably alkyl, alkenyl, or ynyl, more preferably alkyl or alkenyl. The alkyl groups having 6 to 24 carbon atoms and the alkyl groups having 3 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkyl groups having 6 to 24 carbon atoms are preferably alkyl groups having 6 to 20 carbon atoms, and the alkyl groups having 3 to 24 carbon atoms are more preferably alkyl groups having 6 to 20 carbon atoms. Specifically, examples include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, tetramethylhexadecyl (preferably 3,7,11,15-tetramethylhexadecyl), heptadecanyl, octadecyl, nonadecanyl, eicosyl, etc. The alkenyl groups having 6 to 24 carbon atoms and the alkenyl groups having 3 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkenyl group having 6 to 24 carbon atoms is preferably an alkenyl group having 6 to 20 carbon atoms, and the alkenyl group having 3 to 24 carbon atoms is more preferably an alkenyl group having 6 to 20 carbon atoms. Specifically, examples include hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl (preferably (Z)-hexadec-9-enyl), hexadecadienyl, heptadecenyl (preferably (Z)-heptadec-8-enyl), heptadecadienyl (preferably (8Z,11Z)-heptadec-8,11-dienyl), octadecenyl (preferably (Z)-octadec-9-enyl), octadecadienyl (preferably (9Z,12Z)-octadec-9,12-dienyl), nonadecanenyl, eicosene (preferably (Z)-eicosene-11-enyl), eicosene (preferably (11Z,14Z)-eicosene-11,14-dienyl), etc. The alkynyl group with 6 to 24 carbon atoms is preferably an alkynyl group with 6 to 20 carbon atoms, and the alkynyl group with 3 to 24 carbon atoms is more preferably an alkynyl group with 6 to 20 carbon atoms. Specifically, examples include hexynyl, heptyynyl, octyynyl, nonynyl, decanynyl, undecanynyl, dodecanynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecynyl, heptadecynyl, and octadecynyl. All of the above alkenyl groups preferably have one or two double bonds, and all alkynyl groups preferably have one or two triple bonds.

[0104] As for R 21 and R 31The hydrocarbon group having 1 to 24 carbon atoms is preferably an alkyl group having 10 to 24 carbon atoms, an alkenyl group having 10 to 24 carbon atoms, or an alkynyl group having 10 to 24 carbon atoms. The alkyl group having 10 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkyl group having 10 to 24 carbon atoms is preferably an alkyl group having 12 to 24 carbon atoms. Specifically, examples include decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, tetramethylhexadecyl (preferably 3,7,11,15-tetramethylhexadecyl), heptadecanyl, octadecyl, 2-butylhexyl, 2-butyloctyl, 1-pentylhexyl, 2-pentylheptyl, 3-pentyloctyl, 1-hexylheptyl, 1-hexylnonyl, 2 Alkenes with 10 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. Specifically, examples include decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl (preferably (Z)-twelfthoc-8-enyl), tetradecenyl (preferably tetradecen-9-enyl), pentadecenyl (preferably (Z)-pentadec-8-enyl), hexadecenyl (preferably (Z)-hexadecen-9-enyl), hexadecadienyl, heptadecenyl (preferably (Z)-heptadecen-8-enyl), heptadecadienyl (preferably (8Z,11Z)-heptadecen-8,11-dienyl), octadecenyl (preferably (Z)-octadecen-9-enyl), and octadecadienyl (preferably (9Z,12Z)-octadecen-9,12-dienyl). Alkynyl groups with 10 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. Specifically, examples include decynyl, undecynyl, dodecaynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecaynyl, and octadecynyl. Preferably, all of the above alkenyl groups have one or two double bonds, and all of the ynyl groups preferably have one or two triple bonds.

[0105] As for R 22 and R 32The linker group is a divalent hydrocarbon linker with 1 to 18 carbon atoms, preferably an alkylene group with 1 to 18 carbon atoms or an alkenyl group with 2 to 18 carbon atoms. The alkylene group with 1 to 18 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 1 to 12, more preferably 1 to 10, and even more preferably 2 to 10. Specifically, examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, and dodecamethylene. The alkenyl group with 2 to 18 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 1 to 12, more preferably 2 to 10.

[0106] As L 1 The preferred range is -O(CO)O-, -O(CO)- or -(CO)O-, more preferably -O(CO)- or -(CO)O-.

[0107] As L 2 The preferred range is -O(CO)O-, -O(CO)- or -(CO)O-, more preferably -O(CO)- or -(CO)O-.

[0108] Regarding R 4 R 6 R 9 R 10 R 11 and R 12 The alkyl group having 1 to 18 substitutable carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 1 to 12. Specifically, examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. When the alkyl group has substituents, hydroxyl, carboxyl, -O(CO)OR are preferred. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The indicated group is more preferably -O(CO)-R 42 or-(CO)OR 43 The group represented.

[0109] Regarding R 5 R 7 and R 8The alkyl group having 1 to 18 substitutable carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 1 to 12, more preferably 1 to 8. Specifically, examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. When the alkyl group has substituents, hydroxyl, carboxyl, or -O(CO)OR groups are preferred. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The indicated group is more preferably -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented.

[0110] Examples of 4- to 7-membered rings that can contain O atoms include acridine rings, pyrrolidine rings, piperidine rings, morpholine rings, and aziridine-heptane rings, with 6-membered rings being preferred, and piperidine rings and morpholine rings being even more preferred.

[0111] Regarding R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 When the substituent in the alkyl group having 1 to 18 carbon atoms is a substituted or unsubstituted aryl group, the number of carbon atoms is preferably 6 to 22, more preferably 6 to 18, and even more preferably 6 to 10. Specifically, examples include phenyl, naphthyl, anthraceneyl, and phenanthrene. As substituents on the aryl group, alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms are preferred. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The indicated group is more preferably hydroxyl or carboxyl. Examples of substituted aryl groups include hydroxyphenyl and carboxyphenyl.

[0112] Regarding R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11and R 12 When the substituent in the alkyl group having 1 to 18 carbon atoms is a substituted or unsubstituted heteroaryl group, the number of carbon atoms is preferably 1 to 12, more preferably 1 to 6. Specifically, examples include pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, and oxazolyl. As substituents on the heteroaryl group, alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms are preferred. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The indicated group is more preferably hydroxyl or carboxyl. Examples of substituted or unsubstituted heteroaryl groups include hydroxypyridinyl, carboxypyridinyl, and pyridonyl group.

[0113] As for R 41 R 42 R 43 R 44 R 45 and R 46The hydrocarbon group having 1 to 18 carbon atoms is preferably an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or an alkynyl group having 2 to 18 carbon atoms, more preferably an alkyl group having 1 to 18 carbon atoms or an alkenyl group having 2 to 18 carbon atoms. The alkyl group having 1 to 18 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 3 to 18, more preferably 5 to 18. Specifically, examples include propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, etc. The alkenyl group having 2 to 18 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 3 to 18, more preferably 5 to 18. Specifically, examples include allyl, isoprenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl (preferably (Z)-2-nonenyl or (E)-2-nonenyl), decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl (preferably (Z)-twelfthoc-8-enyl), tetradecenyl (preferably tetradecen-9-enyl), pentadecenyl (preferably (Z)-pentadec-8-enyl), hexadecenyl (preferably (Z)-hexadecen-9-enyl), hexadecadienyl, heptadecenyl (preferably (Z)-heptadecen-8,11-enyl), heptadecenyl (preferably (8Z,11Z)-heptadecen-8,11-dienyl), octadecenyl (preferably (Z)-octadecen-9-enyl), and octadecadienyl (preferably (9Z,12Z)-octadecen-9,12-dienyl). The alkynyl group with 2 to 18 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The number of carbon atoms is preferably 3 to 18, more preferably 5 to 18. Specifically, examples include propynyl, butynyl, pentynyl, hexynyl, hepynyl, octyynyl, nonynyl, decynyl, undeynyl, dodeynyl, tetradecynyl, decaynyl, hexadecynyl, heptadecynyl, and octadecynyl.

[0114] When X represents -NR 1 - When, R is preferred 1 Represents hydrocarbon groups or R with 6 to 24 carbon atoms. 21 -L 1 -R 22 - The group indicated. In this case, R is preferred. 2 and R 3 One of them is a hydrogen atom; R 2 and R 3 Another group in the group that represents a hydrocarbon group with 6 to 24 carbon atoms, or R. 31 -L 2 -R 32- The group to be represented.

[0115] When X represents -O-, R is preferred. 2 and R 3 Each independently represents a hydrocarbon group or R with 6 to 24 carbon atoms. 31 -L 2 -R 32 - The group to be represented.

[0116] R 4 R 6 R 9 R 10 R 11 and R 12 Hydrogen atoms are preferred.

[0117] R 5 Preferably, it is an alkyl group with 1 to 18 carbon atoms, and can be converted to -O(CO)-R 42 or-(CO)OR 43 Alkyl groups having 1 to 18 carbon atoms that can be substituted, alkyl groups having 1 to 18 carbon atoms that can be substituted by aryl groups, and alkyl groups having 1 to 18 carbon atoms that can be substituted by hydroxyl groups. When it is an alkyl group, it can react with R. 4 R 6 R 10 and R 12 They are interconnected to form a ring that can contain O atoms. Preferably, the ring is an alkyl group having 1 to 18 carbon atoms, and can be linked by -O(CO)-R. 42 or-(CO)OR 43 Alkyl groups having 1 to 18 carbon atoms that can be substituted, alkyl groups having 1 to 12 carbon atoms that can be substituted with aryl groups, alkyl groups having 1 to 8 carbon atoms that can be substituted with hydroxyl groups, more preferably alkyl groups having 1 to 18 carbon atoms, and alkyl groups that can be substituted with -O(CO)-R 42 or-(CO)OR 43 Alkyl groups with 1 to 18 carbon atoms that are substituted.

[0118] Preferred R 7 and R 8 Each is independently a hydrogen atom, a hydrocarbon group with 1 to 18 carbon atoms, and can be converted to -O(CO)-R 42 or-(CO)OR 43 The substituted alkyl group having 1 to 18 carbon atoms, the alkyl group having 1 to 8 carbon atoms that can be substituted with an aryl group, or the alkyl group having 1 to 8 carbon atoms that can be substituted with a hydroxyl group, or R 7 With R 8 They connect to each other to form 4- to 7-membered rings that can contain O atoms.

[0119] R 5 With R 7 Or R8 They are not interconnected and do not form a loop.

[0120] a+b is preferably 1 or 2, more preferably 1. c+d is preferably 1 or 2, more preferably 1.

[0121] The compound represented by formula (1) is preferably the compound represented by formula (1-1) below.

[0122] [Chemical Formula 9]

[0123]

[0124] R 24 Represents a hydrocarbon group or R that contains 6 to 24 hydrogen atoms and carbon atoms. 21 -L 1 -R 22 - The group represented, R 21 L represents a hydrocarbon group with 1 to 24 carbon atoms. 1 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0125] [Chemical Formula 10]

[0126]

[0127] R 22 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0128] R 25 Represents a hydrocarbon group or R with 3 to 24 carbon atoms, consisting of hydrogen atoms. 31 -L 2 -R 32 - The group represented, R 31 L represents a hydrocarbon group with 1 to 24 carbon atoms. 2 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0129] [Chemical Formula 11]

[0130]

[0131] R 32 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0132] R 4 R 5 R 6 R 7 R 8 R 10 and R 12Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0133] R 4 With R 5 R 10 With R 5 R 5 With R 12 R 4 With R 6 R 5 With R 6 R 6 With R 7 R 6 With R 10 R 12 With R 7 and R 7 With R 8 Any one or more groups can be interconnected to form a 4- to 7-membered ring containing O atoms. R is preferred. 5 With R 7 Or R 8 They are not interconnected and do not form a loop.

[0134] The substituents on alkyl groups with 1 to 18 carbon atoms that can be substituted are hydroxyl, carboxyl, and -NR. 45 R 46 The amino group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -O(CO)OR are represented. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0135] The substituents on the substituted or unsubstituted aryl group and the substituted or unsubstituted heteroaryl group are alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45and R 46 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0136] R in equation (1-1) 4 R 5 R 6 R 7 R 8 R 10 and R 12 The definition and preferred range are the same as those in equation (1).

[0137] R in equation (1-1) 24 Preferably, the alkyl or alkenyl groups have 6 to 24 carbon atoms. The alkyl groups with 6 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkyl groups with 6 to 24 carbon atoms are preferably alkyl groups with 8 to 20 carbon atoms. Specifically, examples include octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, tetramethylhexadecyl (preferably 3,7,11,15-tetramethylhexadecyl), heptadecanyl, octadecyl, nonadecanyl, and eicosyl. The alkenyl groups with 6 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkenyl groups with 6 to 24 carbon atoms are preferably alkenyl groups with 8 to 20 carbon atoms. Specifically, examples include octenyl, nonenyl, decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl (preferably (Z)-hexadec-9-enyl), hexadecadienyl, heptadecenyl (preferably (Z)-heptadec-8-enyl), heptadecadienyl (preferably (8Z,11Z)-heptadec-8,11-dienyl), octadecenyl (preferably (Z)-octadec-9-enyl), octadecadienyl (preferably (9Z,12Z)-octadec-9,12-dienyl), nonadecenyl, eicoseneyl (preferably (Z)-eicosene-11-enyl), eicoseneyl (preferably (11Z,14Z)-eicosene-11,14-dienyl), etc.

[0138] The alkenyl groups mentioned above preferably have one or two double bonds.

[0139] R in equation (1-1) 25Preferably, the alkyl or alkenyl groups have 6 to 24 carbon atoms. The alkyl groups with 6 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkyl groups with 6 to 24 carbon atoms are preferably alkyl groups with 7 to 20 carbon atoms. Specifically, examples include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, trimethyldodecyl (preferably 3,7,11-trimethyldodecyl), tetradecyl, pentadecyl, hexadecyl, tetramethylhexadecyl (preferably 3,7,11,15-tetramethylhexadecyl), heptadecanyl, octadecyl, etc. The alkenyl groups with 6 to 24 carbon atoms can be straight-chain or branched, and can be chain-like or cyclic. The alkenyl groups with 6 to 24 carbon atoms are preferably alkenyl groups with 8 to 20 carbon atoms. Specifically, examples include octenyl, nonenyl, decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl (preferably (Z)-hexadec-9-enyl), hexadecadienyl, heptadecenyl (preferably (Z)-heptadec-8-enyl), heptadecadienyl (preferably (8Z,11Z)-heptadec-8,11-dienyl), octadecenyl (preferably (Z)-octadec-9-enyl), octadecadienyl (preferably (9Z,12Z)-octadec-9,12-dienyl), nonadecenyl, eicoseneyl (preferably (Z)-eicosene-11-enyl), eicoseneyl (preferably (11Z,14Z)-eicosene-11,14-dienyl), etc.

[0140] The alkenyl groups mentioned above preferably have one or two double bonds.

[0141] In the preferred method,

[0142] X represents -O-;

[0143] R 2 R 3 R 31 L 2 and R 32 The definition is the same as that in equation (1).

[0144] R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0145] The definitions of substituents on alkyl groups with 1 to 18 carbon atoms that can be substituted, as well as substituents on substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups, are the same as those in formula (1).

[0146] a+b is 1, and c+d is 1 or 2.

[0147] In a further preferred embodiment, the compound represented by formula (1) is the compound represented by formula (2) below.

[0148] [Chemical Formula 12]

[0149]

[0150] In the formula, R 2 and R 3 Each independently represents a hydrogen atom, a hydrocarbon group with 3 to 24 carbon atoms, or an R group. 31 -L 2 -R 32 -The group that represents,

[0151] R 31 Represents hydrocarbon groups with 1 to 24 carbon atoms.

[0152] L 2 means -O(CO)O-, -O(CO)-, -(CO)O-, -O- or

[0153] [Chemical Formula 13]

[0154]

[0155] R 32 A divalent linker indicates a hydrocarbon linker with 1 to 18 carbon atoms.

[0156] R 5 Represents a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0157] R 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms that can be substituted.

[0158] The substituents on alkyl groups with 1 to 18 carbon atoms that can be substituted are hydroxyl, carboxyl, and -NR. 45 R 46 The amino group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -O(CO)OR are represented. 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0159] The substituents on the substituted or unsubstituted aryl group and the substituted or unsubstituted heteroaryl group are alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms.

[0160] e represents 2 or 3.

[0161] R 2 R 3 R 5 R 7 and R 8 The definition is the same as that in equation (1).

[0162] In equation (2), R is preferred. 7 and R 8 Each independently represents either a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, regarding R 5 The substituents on the alkyl groups with 1 to 18 carbon atoms are hydroxyl, substituted or unsubstituted aryl, -O(CO)OR 41 -O(CO)-R 42 -(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each group independently represents a hydrocarbon group having 1 to 18 carbon atoms, and the substituents on the substituted or unsubstituted aryl groups are alkyl, hydroxyl, carboxyl, or -NR groups having 1 to 18 carbon atoms. 45 R 46 The amino group, -O(CO)OR 41 -O(CO)-R 42-(CO)OR 43 or -OR 44 The group represented, R 41 R 42 R 43 R 44 R 45 and R 46 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0163] In equation (2), R is further optimized. 2 and R 3 Each independently represents a hydrocarbon group or R with 3 to 24 carbon atoms. 31 -L 2 -R 32 - The group represented by L 2 Represents -O(CO)- or -(CO)O-, R 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and the substituents on the alkyl groups having 1 to 18 carbon atoms that can be substituted are unsubstituted aryl groups, -O(CO)-R 42 or-(CO)OR 43 R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0164] In equation (2), R is further optimized. 2 and R 3 R represents either a hydrogen atom or a hydrocarbon group with 3 to 24 carbon atoms, respectively. 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and the substituents on the alkyl groups having 1 to 18 carbon atoms that can be substituted are unsubstituted aryl groups, -O(CO)-R 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0165] In equation (2), R is preferred. 2 and R 3 At least one of them represents R 31 -L 2 -R 32 - The group represented by L 2 Represents -O(CO)- or -(CO)O-, R 7 and R 8Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and the substituents on the alkyl groups having 1 to 18 carbon atoms that can be substituted are unsubstituted aryl groups, -O(CO)-R 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0166] In equation (2), R is further optimized. 2 and R 3 Represent R independently 31 -L 2 -R 32 - The group represented by L 2 Represents -O(CO)- or -(CO)O-, R 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and the substituents on the alkyl groups having 1 to 18 carbon atoms that can be substituted are unsubstituted aryl groups, -O(CO)-R 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0167] In equation (2), R is preferred. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another group in the group that represents hydrocarbons with 3 to 24 carbon atoms is L. 2 Represents -O(CO)- or -(CO)O-, R 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and the substituents on the alkyl groups having 1 to 18 carbon atoms that can be substituted are unsubstituted aryl groups, -O(CO)-R 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0168] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R2 and R 3 Another hydrocarbon group in the group that represents 6 carbon atoms is L. 2 Represents -O(CO)- or -(CO)O-, R 7 and R 8 Each can independently represent a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, and the substituents on the alkyl groups having 1 to 18 carbon atoms that can be substituted are -O(CO)-R. 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0169] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another hydrocarbon group in the group that represents 6 carbon atoms is L. 2 Represents -O(CO)- or -(CO)O-, R 5 R represents an alkyl group having 1 to 18 hydrogen atoms or carbon atoms. 7 and R 8 Each can be independently represented by an alkyl group having 1 to 18 hydrogen atoms or carbon atoms.

[0170] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another hydrocarbon group in the group that represents 6 carbon atoms is L. 2 Represents -O(CO)- or -(CO)O-, R 5 R represents an alkyl group having 1 to 18 hydrogen atoms or carbon atoms. 7 and R 8 Each can be independently represented by an alkyl group having 1 to 18 hydrogen atoms or carbon atoms, with e representing 2.

[0171] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another group in the group that represents hydrocarbons with 3 to 5 carbon atoms is L.2 Represents -O(CO)- or -(CO)O-, R 5 R represents an alkyl group having 1 to 18 hydrogen atoms or carbon atoms. 7 and R 8 Each can be independently represented by an alkyl group having 1 to 18 hydrogen atoms or carbon atoms.

[0172] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another group in the group that represents hydrocarbons with 3 to 5 carbon atoms is L. 2 Represents -O(CO)- or -(CO)O-, R 5 R represents an alkyl group having 1 to 18 hydrogen atoms or carbon atoms. 7 and R 8 Each can be independently represented by an alkyl group having 1 to 18 hydrogen atoms or carbon atoms, with e representing 2.

[0173] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another hydrocarbon group in the group that represents 6 carbon atoms is L. 2 Represents -O(CO)- or -(CO)O-, R 5 R represents a hydrogen atom or an alkyl group having 1 to 18 substituted carbon atoms. 7 and R 8 Each of the following groups independently represents either a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, wherein the substituent on the substituted alkyl group having 1 to 18 carbon atoms is -O(CO)-R. 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each of the 1 to 18 carbon atoms is represented independently by a hydrocarbon group.

[0174] In equation (2), R is further optimized. 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another hydrocarbon group in the group that represents 6 carbon atoms is L. 2Represents -O(CO)- or -(CO)O-, R 5 R represents a hydrogen atom or an alkyl group having 1 to 18 substituted carbon atoms. 7 and R 8 Each of the following groups independently represents either a hydrogen atom or an alkyl group having 1 to 18 carbon atoms, wherein the substituent on the substituted alkyl group having 1 to 18 carbon atoms is -O(CO)-R. 42 or-(CO)OR 43 The group represented, R 42 and R 43 Each group independently represents a hydrocarbon group with 1 to 18 carbon atoms, and e represents 2.

[0175] In equation (2), the preferred method is as follows:

[0176] R 2 and R 3 At least one of them represents a hydrocarbon group containing more than one unsaturated bond with 3 to 24 carbon atoms, or R 2 and R 3 Represent R independently 31 -L 2 -R 32 - The group represented, or R 2 and R 3 One of them represents R 31 -L 2 -R 32 - The group represented, R 2 and R 3 Another group in the group represents hydrocarbon groups with 3 to 24 carbon atoms.

[0177] R 5 It indicates an unsubstituted alkyl group having 1 to 18 carbon atoms, or a group marked with -O(CO)-R 42 or-(CO)OR 43 Alkyl groups with 1 to 18 carbon atoms that are substituted.

[0178] R 7 and R 8 Each alkyl group, having 1 to 4 carbon atoms, is represented independently.

[0179] (Here, R) 31 L 2 R 32 R 42 and R 43 The definition is the same as the definition in equation (2).

[0180] The compound represented by formula (1) can form a salt.

[0181] Examples of salts that are basic groups include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts of organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid, and trifluoroacetic acid; and salts of sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

[0182] Examples of salts that are part of an acidic group include salts of alkali metals such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium; ammonium salts; and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenylethylamine, 1-diphenylhydroxymethylamine, and N,N'-dibenzylethylenediamine.

[0183] Among the salts mentioned above, pharmaceutically acceptable salts can be cited as preferred options.

[0184] As preferred examples of compounds represented by formula (1), the compounds described in Examples 1 to 135 described later can be cited, but the present invention should not be construed as being limited thereto.

[0185] The compounds described in Examples 1 to 135 are referred to as Compound 1 to Compound 135, respectively.

[0186] Among the above, compounds 24, 30, 31, 50, 56, 69, 88, 89, 91, 93, 103, 112, 118, 119, 134, and 135 are particularly preferred.

[0187] The method for manufacturing the compound represented by formula (1) will be explained.

[0188] The compound represented by formula (1) can be manufactured by combining known methods, for example, by the manufacturing method shown below.

[0189] [Manufacturing Method 1]

[0190] [Chemical Formula 14]

[0191]

[0192] As in the formula, R a and R b Represents the leaving basis; R c R d and R e Indicates an amino protecting group or an imino protecting group; R 1R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 The leaving group has the same meaning as described above. Examples of such groups include chloro, fluorine, bromine, trichloromethoxy, 4-nitrophenoxy, 2,4-dinitrophenoxy, 2,4,6-trichlorophenoxy, pentafluorophenoxy, 2,3,5,6-tetrafluorophenoxy, imidazolyl, triazolyl, 3,5-dioxo-4-methyl-1,2,4-oxadiazolyl, and N-hydroxysuccinimide. Examples of protecting groups, such as tert-butoxycarbonyl, benzyloxycarbonyl, 2-nitrobenzenesulfonyl, and benzyl, are also included.

[0193] (1-1)

[0194] Compounds of formula [3] are known, for example, 4-nitrobenzene chloroformate, 1,1'-carbonyldiimidazole, triphosgene and phosgene.

[0195] The compound of formula [4] can be produced by reacting the compound of formula [2] with the compound of formula [3] in the presence of a base.

[0196] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents can be used in combination.

[0197] Ethers are a preferred solvent, with tetrahydrofuran being a more preferred solvent.

[0198] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [2].

[0199] Inorganic or organic bases can be used as the base in this reaction. Organic bases are preferred, and specifically, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, or N,N-dimethylaminopyridine are examples.

[0200] The amount of alkali used is 1 to 50 times the molar amount of the compound in formula [2], preferably 1 to 10 times the molar amount.

[0201] The amount of compound [3] used is not particularly limited, and it can be 0.3 to 10 times (v / w) of the amount of compound [2].

[0202] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0203] (1-2)

[0204] Compounds of formula [5] are known, for example, di((9Z,12Z)-octadec-9,12-dien-1-yl)amine and dihexadecylamine.

[0205] The compound of formula [6] can be produced by reacting the compound of formula [4] with the compound of formula [5] in the presence of a base.

[0206] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents can be used in combination.

[0207] Ethers are a preferred solvent, with tetrahydrofuran being a more preferred solvent.

[0208] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [4].

[0209] Inorganic or organic bases can be used as the base in this reaction. Organic bases are preferred, and specifically, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, or N,N-dimethylaminopyridine are examples.

[0210] The amount of alkali used is 1 to 50 times the molar amount of the compound of formula [4], preferably 1 to 10 times the molar amount.

[0211] The amount of compound [5] used is not particularly limited, and it can be 1 to 10 times (v / w) of the amount of compound [4].

[0212] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0213] (1-3)

[0214] Compounds of formula [2A] include, for example, tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-hydroxyethyl)carbamate and tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)carbamate, etc.

[0215] The compound of formula [6A] can be manufactured by reacting the compound of formula [2A] with the compound of formula [3] in the presence of a base, and then reacting the compound of formula [4A] with the compound of formula [5] in the presence of a base.

[0216] The reaction can be carried out in accordance with manufacturing methods (1-1) and (1-2).

[0217] (1-4)

[0218] The compound of formula [6] can be manufactured by deprotecting the compound of formula [6A].

[0219] The reaction can be carried out, for example, by following the method described in TW Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696–926, 2007, John Wiley & Sons, INC.

[0220] [Manufacturing Method 2]

[0221] [Chemical Formula 15]

[0222]

[0223] As in the formula, R a and R b Represents the leaving basis; R c R d and R e Indicates an amino protecting group or an imino protecting group; R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 The leaving group has the same meaning as described above. Examples of such groups include chloro, fluorine, bromine, trichloromethoxy, 4-nitrophenoxy, 2,4-dinitrophenoxy, 2,4,6-trichlorophenoxy, pentafluorophenoxy, 2,3,5,6-tetrafluorophenoxy, imidazolyl, triazolyl, 3,5-dioxo-4-methyl-1,2,4-oxadiazolyl, and N-hydroxysuccinimide. Examples of protecting groups, such as tert-butoxycarbonyl, benzyloxycarbonyl, 2-nitrobenzenesulfonyl, and benzyl, are also included.

[0224] (2-1)

[0225] Compounds of formula [3] are known, for example, 4-nitrobenzene chloroformate, 1,1'-carbonyldiimidazole, triphosgene and phosgene.

[0226] The compound of formula [8] can be produced by reacting the compound of formula [7] with the compound of formula [3] in the presence of a base.

[0227] The reaction can be carried out in accordance with manufacturing method (1-1).

[0228] (2-2)

[0229] The compound of formula [9] can be produced by reacting the compound of formula [8] with the compound of formula [2] in the presence of a base.

[0230] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents can be used in combination.

[0231] Ethers are a preferred solvent, with tetrahydrofuran being a more preferred solvent.

[0232] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [8].

[0233] Inorganic or organic bases can be used as the base in this reaction. Organic bases are preferred, and specifically, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, or N,N-dimethylaminopyridine are examples.

[0234] The amount of alkali used is 1 to 50 times the molar amount of the compound of formula [8], preferably 1 to 10 times the molar amount.

[0235] The amount of compound [2] used is not particularly limited, and it can be 1 to 10 times (v / w) the amount of compound [8].

[0236] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0237] (2-3)

[0238] Compounds of formula [2A] are known, for example, tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-hydroxyethyl)carbamate and tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)carbamate, etc.

[0239] The compound of formula [9] can be manufactured by reacting the compound of formula [8] with the compound of formula [2A] in the presence of a base, and then deprotecting the compound of formula [9A] in the presence of a base.

[0240] The reaction can be carried out in accordance with manufacturing methods (2-2) and (1-4).

[0241] [Manufacturing Method 3]

[0242] [Chemical Formula 16]

[0243]

[0244] As in the formula, R a R b and R g Represents the leaving basis; R f R represents an alkyl group having 1 to 18 carbon atoms; 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 and R 42 It has the same meaning as above. "Leaving groups, for example, include chloro, fluorine, bromine, trichloromethoxy, 4-nitro-phenoxy, 2,4-dinitrophenoxy, 2,4,6-trichlorophenoxy, pentafluorophenoxy, 2,3,5,6-tetrafluorophenoxy, imidazolyl, triazolyl, 3,5-dioxo-4-methyl-1,2,4-oxadiazolyl, N-hydroxysuccinimide, etc."

[0245] (3-1)

[0246] Compounds of formula [3] are known, for example, 4-nitrobenzene chloroformate, 1,1'-carbonyldiimidazole, triphosgene and phosgene.

[0247] The compound of formula [8] can be produced by reacting the compound of formula [7] with the compound of formula [3] in the presence of a base.

[0248] The reaction can be carried out in accordance with manufacturing method (1-1).

[0249] (3-2)

[0250] Compounds of formula [2B] are known, for example, 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(-1-ethanol) and 2,2'-((3-(diethylamino)propyl)azanediyl)bis(-1-ethanol).

[0251] The compound of formula [9B] can be produced by reacting the compound of formula [8] with the compound of formula [2B] in the presence of a base.

[0252] The reaction can be carried out in accordance with manufacturing method (2-2).

[0253] (3-3)

[0254] Compounds of formula [10A] are known, for example, dodecanoic acid, decanoic acid, nonanoic acid and octanoic acid.

[0255] The compound of formula [9C] can be manufactured by reacting the compound of formula [9B] with the compound of formula [10A] in the presence of a condensing agent or acyl halide and a base.

[0256] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents can be used in combination.

[0257] Ethers are a preferred solvent, with tetrahydrofuran being a more preferred solvent.

[0258] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [9B].

[0259] Inorganic or organic bases can be used as the base in this reaction. Organic bases are preferred, and specifically, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, or N,N-dimethylaminopyridine are examples.

[0260] The amount of base used is 1 to 50 times the molar amount of the compound of formula [9B], preferably 1 to 10 times the molar amount.

[0261] Examples of condensing agents used in this reaction include carbodiimides such as N,N'-dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; carbonyl derivatives such as carbonyl diimidazole; acidic azides such as diphenylphosphoric acid azide; acidic cyanides such as diethyl azide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-benzotriazol-1-yl-1,1,3,3-tetramethylurea-hexafluorophosphate; and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea-hexafluorophosphate.

[0262] Examples of acyl halides used in this reaction include carboxyl halides such as acetyl chloride and trifluoroacetyl chloride; sulfonyl halides such as methanesulfonyl chloride and toluenesulfonyl chloride; and chloroformates such as ethyl chloroformate and isobutyl chloroformate.

[0263] The amount of compound of formula [10A] is not particularly limited, and it can be 1 to 10 times (v / w) the amount of compound of formula [9B].

[0264] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0265] (3-4)

[0266] Compounds of formula [10B] are known, for example, dodecanoyl chloride, decanoyl chloride, nonanoyl chloride and octanoyl chloride.

[0267] The compound of formula [9C] can be produced by reacting the compound of formula [9B] with the compound of formula [10B] in the presence of a base.

[0268] The compound of formula [10B] can be manufactured by reacting the compound of formula [10A] with thionyl chloride or oxalyl chloride.

[0269] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents can be used in combination.

[0270] Ethers are a preferred solvent, with tetrahydrofuran being a more preferred solvent.

[0271] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [9B].

[0272] Inorganic or organic bases can be cited as examples of bases used in this reaction.

[0273] The amount of base used is 1 to 50 times the molar amount of the compound of formula [9B], preferably 1 to 10 times the molar amount.

[0274] The amount of compound of formula [10B] used is not particularly limited, and it can be 1 to 10 times (v / w) the amount of compound of formula [2B].

[0275] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0276] Next, the synthesis of the compound of formula [2], which is the raw material for manufacturing the compound of the present invention, will be described.

[0277] [Manufacturing Method 4]

[0278] [Chemical Formula 17]

[0279]

[0280] As in the formula, R h and R i Represents the leaving basis; R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 The leaving group has the same meaning as above. Examples of such leaving groups include chloro, bromo, iodo, methanesulfonyl, 4-toluenesulfonyl, chloromethanesulfonyl, trifluoromethanesulfonyl, etc.

[0281] (4-1)

[0282] Compounds of formula

[12] are known, for example, 2-chloro-N,N-dimethylethyl-1-amine, 4-(2-chloroethyl)morpholine, 2-chloro-N,N-diethylethyl-1-amine, 2-bromo-N,N-diethylethyl-1-amine, 3-chloro-N,N-diethylethyl-1-amine, etc.

[0283] The compound of formula [2] can be produced by reacting the compound of formula

[11] with the compound of formula

[12] in the presence or absence of a base.

[0284] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include alcohols, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water. These solvents can be used in combination.

[0285] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula

[11] .

[0286] Inorganic or organic bases can be used as the base in this reaction. The amount of base used is 1 to 10,000 moles, preferably 1 to 5,000 moles, relative to the compound of formula

[11] .

[0287] The amount of compound

[12] used is not particularly limited, and it can be 1 to 10 times (v / w) the amount of compound

[11] .

[0288] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0289] (4-2)

[0290] Compounds of formula

[14] are known, for example, 2-bromo-1-ethanol and 3-bromo-1-propanol.

[0291] The compound of formula [2] can be produced by reacting the compound of formula

[13] with the compound of formula

[14] in the presence or absence of a base.

[0292] The reaction can be carried out in accordance with manufacturing method (4-1).

[0293] [Manufacturing Method 5]

[0294] [Chemical Formula 18]

[0295]

[0296] As in the formula, R j Represents the leaving basis; R k R represents an alkyl group having 1 to 18 carbon atoms; 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 and R 43 It has the same meaning as above. "Leaving groups, for example, include chloro, bromine, iodo, methanesulfonyl, 4-toluenesulfonyl, chloromethanesulfonyl, trifluoromethanesulfonyl, etc."

[0297] (5-1)

[0298] Compounds of formula [15A] are known, for example, heptyl acrylate.

[0299] The compound of formula [2] can be produced by reacting the compound of formula [2C] with the compound of formula [15A] in the presence or absence of a base.

[0300] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include alcohols, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water. These solvents can be used in combination.

[0301] Preferred solvents include ethers or nitriles, with tetrahydrofuran or acetonitrile being more preferred.

[0302] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [2C].

[0303] Inorganic or organic bases can be cited as examples of bases used in this reaction.

[0304] The amount of base used is 1 to 10,000 times molar, preferably 1 to 5,000 times molar, relative to the compound of formula [2C].

[0305] The amount of compound of formula [15A] is not particularly limited, and it can be 1 to 10 times (v / w) the amount of compound of formula

[13] .

[0306] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0307] (5-2)

[0308] Compounds of formula [15B] are known, for example, heptyl 3-chloropropionate.

[0309] The compound of formula [2] can be produced by reacting the compound of formula [2C] with the compound of formula [15B] in the presence or absence of a base.

[0310] The reaction can be carried out in accordance with manufacturing method (4-1).

[0311] [Manufacturing Method 6]

[0312] [Chemical Formula 19]

[0313]

[0314] As in the formula, R g and R l Represents the leaving basis; R m R represents an alkyl group having 1 to 18 carbon atoms; 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 and R 42 It has the same meaning as above. "Leaving groups, for example, include chloro, bromo, iodo, methanesulfonyl, 4-toluenesulfonyl, chloromethanesulfonyl, trifluoromethanesulfonyl, trichloromethoxy, 4-nitrophenoxy, 2,4-dinitrophenoxy, 2,4,6-trichlorophenoxy, pentafluorophenoxy, 2,3,5,6-tetrafluorophenoxy, imidazolyl, triazolyl, 3,5-dioxo-4-methyl-1,2,4-oxadiazolyl, N-hydroxysuccinimide, etc."

[0315] (6-1)

[0316] Compounds of formula [10A] are known, for example, dodecanoic acid, decanoic acid, nonanoic acid and octanoic acid.

[0317] The compound of formula [2] can be manufactured by reacting the compound of formula [2B] with the compound of formula [10A] in the presence of a condensing agent or acyl halide and a base.

[0318] The reaction can be carried out in accordance with manufacturing method (3-3).

[0319] (6-2)

[0320] Compounds of formula [10B] are known, for example, dodecanoyl chloride, decanoyl chloride, nonanoyl chloride and octanoyl chloride.

[0321] The compound of formula [2] can be produced by reacting the compound of formula [2B] with the compound of formula [10B] in the presence of a base.

[0322] The reaction can be carried out in accordance with the manufacturing method (3-4).

[0323] (6-3)

[0324] Compounds of formula

[16] are known, for example, heptyl 3-chloropropionate.

[0325] The compound of formula [2] can be produced by reacting the compound of formula [2C] with the compound of formula

[16] in the presence or absence of a base.

[0326] The reaction can be carried out in accordance with manufacturing method (4-1).

[0327] [Manufacturing Method 7]

[0328] [Chemical Formula 20]

[0329]

[0330] In the formula, R n R o and R p R represents an alkyl group having 1 to 17 carbon atoms; 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 42 and R 43 It has the same meaning as above.

[0331] (7-1)

[0332] Compounds of formula [17A] are known, for example, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, pentanaldehyde, hexanal, heptaldehyde, and octanaldehyde.

[0333] The compound of formula [2] can be produced by reacting the compound of formula [2C] with the compound of formula [17A] in the presence or absence of a reducing agent, a reducing catalyst, and an acid.

[0334] The solvents used in this reaction are not particularly limited as long as they do not affect the reaction. Examples include alcohols, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water. These solvents can be used in combination.

[0335] The amount of solvent used is not particularly limited, and can be 1 to 500 times (v / w) relative to the compound of formula [2C].

[0336] Inorganic acids or organic acids can be cited as examples of acids used in this reaction.

[0337] The amount of acid used is 0.01 to 10,000 times molar, preferably 0.05 to 100 times molar, relative to the compound of formula [2C].

[0338] Examples of reducing agents used in this reaction include sodium triacetoxyborohydride, sodium cyanoborohydride, 2-methylpyridineborane, formic acid, and hydrogen.

[0339] Examples of reduction catalysts used in this reaction include palladium-carbon, palladium hydroxide-carbon, platinum-carbon, rhodium-carbon, and ruthenium-carbon.

[0340] The amount of compound of formula [17A] is not particularly limited, and it can be 1 to 10 times (v / w) the amount of compound of formula

[13] .

[0341] The reaction can be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0342] (7-2)

[0343] Compounds of formula [17B] are known, for example, 2-oxoethyl octanoate and 2-oxoethyl nonanoate.

[0344] The compound of formula [2] can be produced by reacting the compound of formula [2C] with the compound of formula [17B] in the presence or absence of a reducing agent, a reducing catalyst, and an acid.

[0345] The reaction can be carried out in accordance with the manufacturing method (7-1).

[0346] (7-3)

[0347] Compounds of formula [17C] are known, for example, heptyl 3-oxopropionate and octyl 3-oxopropionate.

[0348] The compound of formula [2] can be produced by reacting the compound of formula [2C] with the compound of formula [17C] in the presence or absence of a reducing agent, a reducing catalyst or not, and in the presence or absence of an acid or not.

[0349] The reaction can be carried out in accordance with the manufacturing method (7-1).

[0350] When isomers (e.g., optical isomers, geometric isomers, and tautomers) are present in the compounds used in the above manufacturing methods, these isomers can also be used.

[0351] Furthermore, these solvates, hydrates, and crystals of various shapes can also be used when they are present.

[0352] In the above manufacturing method, compounds containing amino, hydroxyl, or carboxyl groups can be protected with conventional protecting groups beforehand, and after the reaction, these protecting groups can be removed using methods known to the public.

[0353] The compounds obtained by the above manufacturing methods can be induced into other compounds, for example, by undergoing well-known reactions such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or by appropriately combining these reactions.

[0354] In the lipid composition of the present invention, the content of the lipid or its salt represented by formula (1) relative to the total lipids is preferably 20 mol% or more and 55 mol% or less, more preferably 22 mol% or more and 55 mol% or less. When the nucleic acid is mRNA, the content of the lipid or its salt represented by formula (1) relative to the total lipids is more preferably 25 mol% or more and 52 mol% or less, further preferably 32 mol% or more and 48 mol% or less. When the nucleic acid is siRNA, the content of the lipid or its salt represented by formula (1) relative to the total lipids is more preferably 32 mol% or more and 55 mol% or less, further preferably 37 mol% or more and 55 mol% or less, and particularly preferably 47 mol% or more and 55 mol% or less.

[0355] <Sterools>

[0356] The lipid compositions of the present invention comprise sterols.

[0357] In the lipid composition of the present invention, by including sterols in the oil phase, the membrane fluidity can be reduced, thereby achieving a stabilizing effect on lipid particles.

[0358] The use of sterols is not particularly limited, and examples include cholesterol, phytosterols (such as sitosterol, stigmasterol, fucosterol, spinachsterol, and brassicosterol), ergosterol, cholesterol ketones, cholesterolenones, coprosterol, cholesterol-2'-hydroxyethyl ether, and cholesterol-4'-hydroxybutyl ether. Among these, cholesterol or its derivatives are preferred.

[0359] In the lipid composition of the present invention, the content of sterols relative to the total lipids is preferably 20 mol% to 70 mol%. When the nucleic acid is mRNA, the content of sterols relative to the total lipids is more preferably 30 mol% to 66 mol%, and even more preferably 30 to 60 mol%. When the nucleic acid is siRNA, the content of sterols relative to the total lipids is more preferably 45 mol% to 68 mol%, even more preferably 45 mol% to 63 mol%, and particularly preferably 45 mol% to 52 mol%.

[0360] <Lipids with nonionic hydrophilic polymeric structures>

[0361] The lipid composition of the present invention comprises lipids having a nonionic hydrophilic polymeric structure.

[0362] By including lipids with nonionic hydrophilic polymer structures in the oil phase, the dispersion and stabilization effect of lipid particles can be obtained.

[0363] Examples of nonionic hydrophilic polymers are not particularly limited and can include nonionic vinyl polymers, nonionic polyamino acids, nonionic polyesters, nonionic polyethers, nonionic natural polymers, nonionic modified natural polymers, block polymers or graft copolymers with two or more of these polymers as structural units.

[0364] Among these nonionic hydrophilic polymers, nonionic polyethers, nonionic polyesters, nonionic polyamino acids, or nonionic synthetic peptides are preferred, more preferably nonionic polyethers or nonionic polyesters, even more preferably nonionic polyethers or nonionic monoalkoxy polyethers, and especially preferably polyethylene glycol (hereinafter also referred to as PEG). That is, as a lipid having a nonionic hydrophilic polymer structure, a lipid having a polyethylene glycol structure is preferred.

[0365] Lipids that are nonionic hydrophilic polymers are not particularly limited, and examples include PEG-modified phosphoethanolamine, diacylglycerol PEG derivatives, dialkylglycerol PEG derivatives, cholesterol PEG derivatives, and ceramide PEG derivatives. Among these, diacylglycerol PEG is preferred. That is, lipids having both a diacylglycerol structure and a polyethylene glycol structure are preferred. The acyl group of the diacylglycerol moiety is more preferably an acyl group with 12 to 22 carbon atoms.

[0366] When a lipid with nonionic hydrophilic polymers has a PEG chain, the weight-average molecular weight of the PEG chain is preferably 500 to 5000, more preferably 750 to 3000.

[0367] Nonionic hydrophilic polymer chains can be branched and can also have substituents such as hydroxymethyl groups.

[0368] In the lipid composition of the present invention, the content of lipids having a nonionic hydrophilic polymeric structure relative to the total lipids is preferably 0.2 mol% to 10 mol%, more preferably 0.2 mol% to 5 mol%. When the nucleic acid is mRNA, the content of lipids having a nonionic hydrophilic polymeric structure relative to the total lipids is more preferably 0.2 mol% to 5 mol%, further preferably 0.2 to 3 mol%, and most preferably 0.5 mol% to 2.5 mol%. When the nucleic acid is siRNA, the content of lipids having a nonionic hydrophilic polymeric structure relative to the total lipids is more preferably 0.2 mol% to 2.3 mol%, more preferably 1.2 mol% to 2.3 mol%.

[0369] <Amphoteric Lipids>

[0370] The lipid compositions of the present invention may contain zwitterionic lipids or may not contain zwitterionic lipids.

[0371] Phospholipids are preferred as zwitterionic lipids. While not particularly limited to phospholipids, examples include phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin, with phosphatidylcholine and phosphatidylethanolamine being preferred. Furthermore, as zwitterionic lipids, they can be used alone or in combination with various other zwitterionic lipids.

[0372] Phosphatidylcholine is not particularly limited and can be exemplified by soy lecithin (SPC), hydrogenated soy lecithin (HSPC), egg yolk lecithin (EPC), hydrogenated egg yolk lecithin (HEPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1,2-distearatel-sn-glycerol-3-phosphate choline (DSPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), and 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), etc.

[0373] Among the above, 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1,2-distearate-sn-glycerol-3-phosphate choline (DSPC), and 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC) are more preferred.

[0374] Phosphatidylethanolamines are not particularly limited in their application; examples include 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE), 1,2-distearate-sn-glycerol-3-phosphate ethanolamine (DSPE), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), and 1,2-dilinoleoyl-sn-glycerol-3-phosphate ethanolamine (DLo). PE), 1,2-diphydanyl-sn-glycerol-3-phosphate ethanolamine (D(Phy)PE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate ethanolamine (POPE), 1,2-bistetradecyl-sn-glycerol-3-phosphate ethanolamine, 1,2-bishexadecyl-sn-glycerol-3-phosphate ethanolamine, 1,2-bisoctadecyl-sn-glycerol-3-phosphate ethanolamine, 1,2-diphydanyl-sn-glycerol-3-phosphate ethanolamine, etc.

[0375] Of the above, 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE) is more preferred.

[0376] Sphingomyelin is not particularly limited; examples include sphingomyelin derived from egg yolks and sphingomyelin derived from milk.

[0377] In the lipid composition of the present invention, the content of zwitterionic lipids relative to the total lipids is preferably 0 mol% to 35 mol%. When the nucleic acid is mRNA, the content of zwitterionic lipids relative to the total lipids is preferably 0 mol% to 35 mol%, more preferably 0 mol% to 30 mol%, and even more preferably 0 mol% to 25 mol%. When the nucleic acid is siRNA, the content of zwitterionic lipids relative to the total lipids is preferably 0 mol%.

[0378] When the lipid composition of the present invention contains zwitterionic lipids, the lower limit of the content of zwitterionic lipids relative to the total lipids is not particularly limited, but is generally 0.5 mol% or more, preferably 1 mol% or more, and more preferably 2 mol% or more.

[0379] <Nucleic Acid>

[0380] The lipid composition of the present invention comprises nucleic acids. Examples of nucleic acids include plasmids, single-stranded DNA, double-stranded DNA, siRNA (small interfering RNA), miRNA (microRNA), mRNA, antisense nucleic acids, ribozymes, aptamers, saRNA, sgRNA, etc., and any one of these may be included. Furthermore, modified nucleic acids may also be included.

[0381] In the lipid composition of the present invention, the content of nucleic acid relative to the total lipids is preferably 0.5 to 50% by mass, more preferably 1 to 25% by mass, even more preferably 1.5 to 20% by mass, and particularly preferably 2 to 15% by mass. Furthermore, the content of total lipids relative to nucleic acid is preferably 2 to 200%, more preferably 4 to 200%, even more preferably 6 to 100%, and particularly preferably 8 to 75%.

[0382] <Method for manufacturing lipid compositions>

[0383] A method for manufacturing the lipid composition of the present invention will be described.

[0384] The method for manufacturing the lipid composition is not particularly limited, and it can be manufactured by dissolving all or part of the oil-soluble components of the lipid composition in an organic solvent or the like to form an oil phase, dissolving the water-soluble components in water to form an aqueous phase, and then mixing the oil phase and the aqueous phase. A micro mixer, or an emulsifier such as a homogenizer, an ultrasonic emulsifier, or a high-pressure jet emulsifier can be used for emulsification during mixing.

[0385] Alternatively, it can be manufactured by using a solution containing lipids, preparing a dried mixture containing lipids by vacuum drying based on an evaporator or spray drying based on a spray dryer, adding the mixture to an aqueous solvent, and further emulsifying it using the aforementioned emulsifier or the like.

[0386] As an example of a method for manufacturing a lipid composition containing nucleic acids, a method including the following steps can be cited:

[0387] Step (a) involves dissolving the components of a lipid composition in an organic solvent to obtain an oil phase;

[0388] Process (b) involves mixing the oil phase obtained in process (a) with the aqueous phase containing water-soluble components such as nucleic acids;

[0389] Step (c) involves diluting the mixture containing the oil phase and the aqueous phase obtained in step (b) to obtain a dispersion of lipid particles.

[0390] Step (d) involves removing the aforementioned organic solvent from the dispersion of lipid particles obtained in step (c); and

[0391] Step (e) is to adjust the concentration of the dispersion of lipid particles obtained in step (d).

[0392] In step (a), the components classified as lipids are dissolved in an organic solvent (such as alcohols or esters, like ethanol). The total lipid concentration after dissolution in the organic solvent is not particularly limited, but is typically 1 mmol / L to 100 mmol / L, preferably 5 mmol / L to 50 mmol / L, and more preferably 10 mmol / L to 30 mmol / L.

[0393] In step (b), the aqueous phase can be obtained by dissolving nucleic acids (e.g., siRNA, antisense nucleic acids, miRNA, mRNA, etc.) in water or a buffer solution. Antioxidants and other components can be added as needed. The mixing ratio (mass ratio) of the aqueous phase and the oil phase is preferably 5:1 to 1:1, more preferably 4:1 to 2:1.

[0394] In step (d), the method for removing organic solvents from the dispersion of lipid particles is not particularly limited, and conventional methods can be used, such as dialysis using solutions like phosphate-buffered saline or sucrose-Tris buffer to remove organic solvents.

[0395] In step (e), the concentration of the dispersion obtained in step (d) can be adjusted. When diluting, solutions such as phosphate-buffered saline, physiological saline, or sucrose-Tris buffer can be used as diluents to dilute to an appropriate concentration. When concentrating, the dispersion obtained in step (d) can be concentrated by ultrafiltration using an ultrafiltration membrane. It is preferable to use the concentrated dispersion directly, or preferably to adjust it to the desired concentration using the diluent after concentration.

[0396] As a solution usable in dialysis in step (d) or dilution in step (e), excipients and buffers may be added. Examples of excipients include sugars. Examples of sugars include sucrose, trehalose, maltose, glucose, lactose, fructose, mannitol, sorbitol, inositol, xylitol, etc. Examples of buffers include ACES, BES, Bicine, CAPS, CHES, DIPSO, EPPS, HEPES, HEPPSO, MES, MOPS, MOPSO, TAPS, TAPSO, TES, Tricine, etc.

[0397] To prepare a pharmaceutical composition from the lipid particle dispersion of the present invention, aseptic filtration is preferred. As a filtration method, hollow fiber membranes, reverse osmosis membranes, membrane filters, etc., can be used to remove unwanted substances from the lipid particle dispersion. In the present invention, although not particularly limited, filtration is preferably performed using a filter with a pore size capable of sterilization (preferably a 0.2 μm sterilization filter). Furthermore, aseptic filtration is preferably performed after step (c) or step (d).

[0398] Furthermore, the dispersion of lipid particles of the present invention can be freeze-dried or freeze-dried as needed. The dispersion of lipid particles of the present invention can be freeze-dried or freeze-dried using conventional methods, and the methods are not particularly limited.

[0399] <About lipid compositions>

[0400] The compositions of the present invention are preferably composed of lipid particles. Lipid particles refer to particles composed of lipids, including lipid aggregates, micelles, and compositions having a structure selected from liposomes; however, the structure of the lipid particles is not limited to these as long as the composition contains lipids. Liposomes include those having a lipid bilayer structure, containing an aqueous phase internally, and having a single-layered bilayer membrane; and multilayered liposomes with multiple overlapping layers. The present invention may include any type of liposome.

[0401] The morphology of lipid particles can be confirmed by observation using electron microscopy or structural analysis using X-rays. For example, by using Cryo transmission electron microscopy (CryoTEM), it can be confirmed whether lipid particles, like liposomes, have a lipid bilayer structure (lamellar structure) and an inner water layer, or whether they have a core with high electron density inside the particle and filled with lipid-based components. Small-angle X-ray scattering (SAXS) measurements can also confirm the presence or absence of a lipid bilayer structure (lamellar structure) in lipid particles.

[0402] The particle size of the lipid particles is not particularly limited, but is preferably 10–1000 nm, more preferably 30–500 nm, even more preferably 50–250 nm, and especially preferably 50–200 nm. The particle size of the lipid particles can be determined by conventional methods (e.g., dynamic light scattering, laser diffraction, etc.).

[0403] <Utilization of Lipid Compositions>

[0404] As an example of utilizing the lipid composition of the present invention, nucleic acids (e.g., genes, etc.) can be introduced into cells by introducing a lipid composition containing nucleic acids into cells. Furthermore, when the lipid composition of the present invention contains nucleic acids with pharmaceutical uses, the lipid composition can be administered to living organisms as a nucleic acid drug. That is, the lipid composition of the present invention is preferably a composition for introducing nucleic acids into cells.

[0405] When the lipid compositions of the present invention are used as nucleic acid drugs, the lipid compositions of the present invention can be administered to living organisms alone or in combination with pharmaceutically acceptable carriers (also known as administration media, such as saline or phosphate buffer).

[0406] The concentration of the lipid composition (lipid particles) in the mixture with a pharmaceutically acceptable carrier is not particularly limited and can typically be set from 0.05% by mass to 90% by mass. Furthermore, other pharmaceutically acceptable additives, such as pH-adjusting buffers, osmotic pressure regulators, etc., can be added to the nucleic acid drug comprising the lipid composition of the present invention.

[0407] The route of administration for administering the nucleic acid drug comprising the lipid composition of the present invention is not particularly limited, and administration can be performed by any method. Examples of administration methods include oral administration, non-oral administration (intra-articular administration, intravenous administration, intra-arterial administration, subcutaneous administration, intradermal administration, intravitreal administration, intraperitoneal administration, intramuscular administration, intravaginal administration, intravesical administration, intrathecal administration, pulmonary administration, rectal administration, colonic administration, buccal administration, nasal administration, intracisional administration, inhalation, etc.). Non-oral administration is preferred, and intravenous injection, subcutaneous injection, intradermal injection, or intramuscular injection are preferred methods of administration. The nucleic acid drug comprising the lipid composition of the present invention can also be administered by direct injection to the disease site.

[0408] The dosage form of the lipid composition of the present invention is not particularly limited. When administered orally, the lipid composition of the present invention can be combined with suitable excipients to be used in the form of tablets, lozenges, capsules, pills, suspensions, syrups, etc. Furthermore, when administered non-orally, the lipid composition of the present invention can be appropriately combined with additives such as antioxidants, buffers, antibacterial agents, isotonic sterile injections, suspending agents, solubilizers, thickeners, stabilizers, or preservatives.

[0409] <Nucleic Acid Delivery Vector>

[0410] The lipid composition of the present invention can retain nucleic acids at a high content, and is therefore very useful as a nucleic acid delivery carrier. According to the nucleic acid delivery carrier of the present invention, nucleic acids can be introduced into cells, for example, by transfecting the lipid composition into cells in vitro or in vivo. Furthermore, the nucleic acid delivery carrier of the present invention is also useful as a nucleic acid delivery carrier in nucleic acid drugs. That is, the lipid composition of the present invention is useful as a composition for in vitro or in vivo (preferably in vivo) nucleic acid delivery.

[0411] Next, embodiments will be given to illustrate the present invention, but the present invention is not limited to these embodiments.

[0412] Example

[0413] Unless otherwise specified, automated purification devices ISOLERA (Biotage) or YFLC W-prep 2XY (YAMAZEN CORPORATION) medium-pressure liquid chromatographs were used for column chromatography-based purification.

[0414] Unless otherwise specified, the carriers used in silica gel column chromatography are Chromatorex Q-Pack SI 50 (FUJI SILYSIA CHEMICAL LTD.), High-Flash Column W001, W002, W003, W004, or W005 (YAMAZEN CORPORATION).

[0415] The NH silicone used is Chromatorex Q-Pack NH 60 (FUJI SILYSIA CHEMICAL LTD.).

[0416] Tetramethylsilane was used as an internal standard. NMR spectra were determined using either a Bruker AV300 (manufactured by Bruker) or a Bruker AV400 (manufactured by Bruker), and total δ values ​​were expressed in ppm.

[0417] MS spectra were measured using an ACQUITY SQD LC / MS System (manufactured by Waters Corporation).

[0418] <Compound Synthesis>

[0419] [Example 1] (1)

[0421] [Chemical Formula 21]

[0422]

[0423] Potassium carbonate (70.4 g) and sodium iodide (2.54 g) were added to a solution of (6Z,9Z)-18-bromooctadec-6,9-diene (131 g), 2-nitrobenzenesulfonamide (34.4 g), and N,N-dimethylformamide (830 mL), and the mixture was stirred at 80 °C for 5 hours. The reaction mixture was cooled to room temperature, and hexane (300 mL) and water (600 mL) were added. After separating the organic layer, the mixture was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2-nitro-N,N-bis((9Z,12Z)-octadec-9,12-dien-1-yl)benzenesulfonamide (96.7 g).

[0424] 1H-NMR(CDCl3)δ:8.03-7.99(1H,m),7.69-7.58(3H,m),5.43-5.28(8H,m),3.26(4H,t,J=6.0Hz),2.7 7(4H,t,J=6.0Hz),2.09-2.00(8H,m),1.56-1.45(4H,m),1.40-1.19(32H,m),0.89(6H,t,J=6.0Hz). (2)

[0426] [Chemical Formula 22]

[0427]

[0428] A mixture of 2-nitro-N,N-di((9Z,12Z)-octadec-9,12-dien-1-yl)benzenesulfonamide (96.7 g), dodecyl mercaptan (54.9 mL), acetonitrile (400 mL), and tetrahydrofuran (400 mL) was added to a 10.0 mol / L potassium hydroxide aqueous solution (47.5 mL), and stirred at 40 °C for 2 hours. The reaction mixture was cooled to room temperature, and hexane (400 mL), tert-butyl methyl ether (100 mL), and water (200 mL) were added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 57.7 g of di((9Z,12Z)-octadec-9,12-dien-1-yl)amine.

[0429] 1 H-NMR(CDCl3)δ:5.43-5.28(8H,m),2.77(4H,t,J=6.0Hz), 2.58(4H,t,J=6.0Hz), 2.09-1.99(8H,m),1.56-1.45(4H,m),1.40-1.19(32H,m),0.89(6H,t,J=6.0Hz).

[0430] MSm / z(M+H): 514. (3)

[0432] [Chemical Formula 23]

[0433]

[0434] 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol (9.36 mL) was added to a tetrahydrofuran (150 mL) solution of 11.7 g of 4-nitrobenzene chloroformate, and the mixture was stirred at room temperature for 1 hour. Di((9Z,12Z)-octadec-9,12-dien-1-yl)amine (15.0 g) and triethylamine (16.3 mL) were added to the reaction mixture, and the mixture was stirred at 50 °C for 4 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (150 mL) and water (100 mL) were added. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (methanol-chloroform). The oily substance obtained by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) was purified to give 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate (11.2 g).

[0435] 1 H-NMR(CDCl3)δ:5.42-5.23(8H,m),4.17(2H,t,J=6.0Hz),3.26-3.08(4H,m),2.77(4H,t,J=6.0Hz),2.67(2H,t,J=6.0Hz),2.54(2H,t,J= 6.0Hz),2.39(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),2.12-1.97(8H,m),1.57-1.43(4H,m),1.42-1.18(32H,m),0.89(6H,t,J=6.0Hz).

[0436] MSm / z(M+H): 687.

[0437] [Example 2] (1)

[0439] [Chemical Formula 24]

[0440]

[0441] N,N,N'-trimethylethane-1,2-diamine (5 mL) was added to a 10 mL ethanol solution of 1.67 mL of 3-bromo-1-propanol, and the mixture was stirred at 60 °C for 8 hours. The solvent in the reaction mixture was removed by vacuum distillation, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 1.2 g of 3-((2-(dimethylamino)ethyl)(methyl)amino)-1-propanol.

[0442] MSm / z(M+H): 161. (2)

[0444] [Chemical Formula 25]

[0445]

[0446] In Example 1(3), 3-((2-(dimethylamino)ethyl)(methyl)amino)-1-propanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 3-((2-(dimethylamino)ethyl)(methyl)amino)propyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0447] 1 H-NMR(CDCl3)δ:5.44-5.27(8H,m),4.09(2H,t,J=6.0Hz),3.25-3.09(4H,m),2.77(4H,t,J=6.0Hz),2.50-2.34(6H,m),2. 25(3H,s),2.24(6H,s),2.10-1.99(8H,m),1.86-1.74(2H,m),1.58-1.43(4H,m),1.42-1.18(32H,m),0.89(6H,t,J=6.0Hz)

[0448] MSm / z(M+H):701.

[0449] [Example 3] (1)

[0451] [Chemical Formula 26]

[0452]

[0453] A 12.0 mol / L sodium hydroxide aqueous solution (5 mL) was added to a solution of piperin-4-ol (2.0 g) and 2-chloro-N,N-dimethylethyl-1-amine hydrochloride (5.69 g) in water (5 mL), and the mixture was stirred at room temperature for 9 hours. Dichloromethane and water were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layer and extract were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 1-(2-(dimethylamino)ethyl)piperidine-4-ol (1.3 g).

[0454] MSm / z(M+H): 173. (2)

[0456] [Chemical Formula 27]

[0457]

[0458] In Example 1(3), 1-(2-(dimethylamino)ethyl)piperidin-4-ol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 1-(2-(dimethylamino)ethyl)piperidin-4-yl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0459] 1 H-NMR(CDCl3)δ:5.43-5.28(8H,m),4.75-4.66(1H,m),3.24-3.10(4H,m),2. 77(4H,t,J=6.0Hz),2.72-2.60(2H,m),2.50-2.39(4H,m),2.37-2.27(2H,m) ,2.24(6H,s),2.09-1.99(8H,m),1.97-1.85(2H,m),1.76-1.65(2H,m),1.66 -1.58(8H,m),1.56-1.43(4H,m),1.41-1.19(32H,m),0.89(6H,t,J=6.0Hz).

[0460] MSm / z(M+H): 713.

[0461] [Example 4] (1)

[0463] [Chemical Formula 28]

[0464]

[0465] In Example 3(1), piperidine-3-ol was used instead of piperidine-4-ol, and otherwise 1-(2-(dimethylamino)ethyl)piperidine-3-ol was obtained by the same method as in Example 3(1).

[0466] MSm / z(M+H): 173. (2)

[0468] [Chemical Formula 29]

[0469]

[0470] In Example 1(3), 1-(2-(dimethylamino)ethyl)piperidin-3-ol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 1-(2-(dimethylamino)ethyl)piperidin-3-yl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0471] 1 H-NMR(CDCl3)δ:5.43-5.28(8H,m),4.78-4.68(1H,m),3.26-3.06(4H,m),2.94-2.87(1H,m),2.77(4H,t,J=6.0Hz),2.70-2.61(1H,m) ,2.52-2.38(4H,m),2.24(6H,s),2.16-1.99(10H,m),1.97-1.87(1H,m),1.77-1.43(7H,m),1.41-1.19(32H,m),0.89(6H,t,J=6.0Hz).

[0472] MSm / z(M+H): 713.

[0473] [Example 5] (1)

[0475] [Chemical Formula 30]

[0476]

[0477] 14.9 g of 4-(2-chloroethyl)morpholine hydrochloride was added to a suspension of 2-(methylamino)-1-ethanol (3.0 g) and potassium carbonate (22.1 g) in ethanol (60 mL), and the mixture was stirred at 60 °C for 4 hours, followed by stirring under reflux for 3 hours. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 5.5 g of 2-(methyl(2-morpholinylethyl)amino)-1-ethanol.

[0478] MSm / z(M+H): 189. (2)

[0480] [Chemical Formula 31]

[0481]

[0482] In Example 1(3), 2-(methyl(2-morpholinylethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-(methyl(2-morpholinylethyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0483] 1 H-NMR(CDCl3)δ:5.46-5.25(8H,m),4.16(2H,t,J=6.0Hz),3.71(4H,t,J=6.0Hz),3.25-3.09(4H,m),2.27(4H,t,J=6.0Hz),2.67(2H,t,J=6 .0Hz),2.62-2.53(2H,m),2.52-2.42(6H,m),2.32(3H,s),2.11-1.97(8H,m),1.55-1.44(4H,m),1.42-1.17(32H,m),0.89(6H,t,J=6.0Hz).

[0484] MSm / z(M+H): 729.

[0485] [Example 6] (1)

[0487] [Chemical Formula 32]

[0488]

[0489] In Example 5(1), 2-(ethylamino)-1-ethanol was used instead of 2-(methylamino)-1-ethanol. Otherwise, 2-(ethyl(2-morpholinylethyl)amino)-1-ethanol was obtained using the same method as in Example 5(1).

[0490] MSm / z(M+H):203. (2)

[0492] [Chemical Formula 33]

[0493]

[0494] In Example 1(3), 2-(ethyl(2-morpholinylethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-(ethyl(2-morpholinylethyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0495] 1 H-NMR(CDCl3)δ:5.45-5.24(8H,m),4.12(2H,t,J=6.0Hz),3.70(4H,t,J=6.0Hz),3.27-3.06(4H,m),2.82-2.69(6H,m),2.69-2.54 (4H,m),2.52-2.39(6H,m),2.12-1.97(8H,m),1.55-1.42(4H,m),1.41-1.17(32H,m),1.03(3H,t,J=6.0Hz),0.89(6H,t,J=6.0Hz).

[0496] MSm / z(M+H): 743.

[0497] [Example 7] (1)

[0499] [Chemical Formula 34]

[0500]

[0501] In Example 5(1), 2-chloro-N,N-diethyl-1-amine hydrochloride was used instead of 4-(2-chloroethyl)morpholine hydrochloride. Otherwise, 2-((2-(diethylamino)ethyl)(methyl)amino)-1-ethanol was obtained using the same method as in Example 5(1).

[0502] MSm / z(M+H): 175. (2)

[0504] [Chemical Formula 35]

[0505]

[0506] In Example 1(3), 2-((2-(diethylamino)ethyl)(methyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((2-(diethylamino)ethyl)(methyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0507] 1H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.16(2H,t,J=6.0Hz),3.25-3.09(4H,m),2.77(4H,t,J=6.0Hz),2.67(2H,t,J=6.0Hz),2.60- 2.49(8H,m),2.32(3H,s),2.12-1.96(8H,m),1.56-1.44(4H,m),1.42-1.17(32H,m),1.02(6H,t,J=6.0Hz),0.89(6H,t,J=6.0Hz).

[0508] MSm / z(M+H): 715.

[0509] [Example 8] (1)

[0511] [Chemical Formula 36]

[0512]

[0513] In Example 2(1), 2-bromo-1-ethanol was used instead of 3-bromo-1-propanol, and N,N,N'-trimethylpropane-1,3-diamine was used instead of N,N,N'-trimethylethane-1,2-diamine. Otherwise, 2-((3-(dimethylamino)propyl)(methyl)amino)-1-ethanol was obtained using the same method as in Example 2(1).

[0514] MSm / z(M+H): 161. (2)

[0516] [Chemical Formula 37]

[0517]

[0518] In Example 1(3), 2-((3-(dimethylamino)propyl)(methyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((3-(dimethylamino)propyl)(methyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0519] 1H-NMR(CDCl3)δ:5.43-5.28(8H,m),4.16(2H,t,J=6.0Hz),3.25-3.10(4H, m),2.77(4H,t,J=6.0Hz),2.63(2H,t,J=6.0Hz),2.42(2H,t,J=6.0Hz),2.2 8(3H,s),2.27(2H,t,J=6.0Hz),2.21(6H,s),2.04(8H,q,J=6.0Ha),1.67- 1.58(2H,m),1.56-1.43(4H,m),1.40-1.19(32H,m),0.89(6H,t,J=6.0Hz).

[0520] MSm / z(M+H):701.

[0521] [Example 9] (1)

[0523] [Chemical Formula 38]

[0524]

[0525] In Example 1(3), tert-butyl (2-((tert-butoxycarbonyl)amino)ethyl)(2-hydroxyethyl)carbamate was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0526] 1 H-NMR(CDCl3)δ:5.44-5.27(8H,m),4.20-4.09(1H,m),3.51-3.10(10H,m),2.77(4H,t,J= 6.0Hz),2.10-1.99(8H,m),1.64-1.48(4H,m),1.41-1.23(32H,m),0.89(6H,t,J=6.0Hz). (2)

[0528] [Chemical Formula 39]

[0529]

[0530] A mixture of 0.6 g of 2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate, 0.2 mL of water, and 0.5 mL of dichloromethane was added to trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 30 minutes. Toluene was added to the reaction mixture, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (methanol-chloroform, NH silica gel) to give 0.3 g of 2-((2-aminoethyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate.

[0531] 1 H-NMR(CDCl3)δ:5.43-5.28(8H,m),4.18(2H,t,J=6.0Hz),3.24-3.11(4H,m),2.87(2H,t,J=6.0Hz),2.80(2H,t,J=6.0Hz),2 .77(4H,t,J=6.0Hz),2.70(2H,t,J=6.0Hz),2.09-2.00(8H,m),1.59-1.44(4H,m),1.40-1.19(32H,m),0.89(6H,t,J=6.0Hz).

[0532] MSm / z(M+H): 645.

[0533] [Example 10]

[0534] [Chemical Formula 40]

[0535]

[0536] In Example 1(3), bis(hexadecylamine) was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl bis(hexadecylcarbamate) was obtained by the same method as in Example 1(3).

[0537] 1 H-NMR (CDCl3) δ: 4.17 (2H, t, J = 6.0Hz), 3.23-3.12 (4H, m), 2.67 (2H, t, J = 6.0Hz), 2.54 (2H, t, J = 6.0Hz), 2.3 9(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),1.55-1.38(4H,m),1.35-1.18(52H,m),0.88(6H,t,J=6.0Hz).

[0538] MSm / z(M+H): 639.

[0539] [Example 11]

[0540] [Chemical Formula 41]

[0541]

[0542] In Example 1(3), di((Z)-keto-2-en-1-yl)8,8'-azanediyl dioctanoate synthesized according to the method described in WO2016 / 081029A1 was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, (Z)-keto-2-en-1-yl 2,5-dimethyl-10-(8-(((Z)-keto-2-en-1-yl)oxy)-8-oxooctyl)-9-oxo-8-oxo-2,5,10-triazaoctadecane-18-ester was obtained using the same method as in Example 1(3).

[0543] 1 H-NMR(CDCl3)δ:5.70-5.46(4H,m),4.61(4H,d,J=6.0Hz),4.16(2H,t,J=6.0Hz),3.23-3.09(4H,m),2.66(2H,t,J=6.0Hz),2.61-2.45(2H,m),2 .42-2.25(2H,m),2.31(3H,s),2.23(6H,s),2.15-2.05(4H,m),1.65-1. 56(4H,m),1.55-1.43(4H,m),1.39-1.20(32H,m),0.88(6H,t,J=6.0Hz).

[0544] MSm / z(M+H): 723.

[0545] [Example 12]

[0546] [Chemical Formula 42]

[0547]

[0548] In Example 1(3), di((E)-keto-2-en-1-yl)8,8'-azaalkyldiyl dioctanoate synthesized according to the method described in WO2016 / 081029A1 was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, (E)-keto-2-en-1-yl 2,5-dimethyl-10-(8-(((E)-keto-2-en-1-yl)oxy)-8-oxooctyl)-9-oxo-8-oxo-2,5,10-triazaoctadecane-18-ester was obtained by the same method as in Example 1(3).

[0549] 1 H-NMR(CDCl3)δ:5.83-5.70(2H,m),5.61-5.49(2H,m),4.50(4H,d,J=6.0Hz), 4.16(2H,t,J=6.0Hz),3.24-3.09(4H,m),2.67(2H,t,J=6.0Hz),2.54(2H,t,J= 6.0Hz),2.38(2H,t,J=6.0Hz),2.31(3H,s),2.24(6H,s),2.09-2.00(4H,m),1. 65-1.56(4H,m),1.55-1.44(4H,m),1.41-1.23(32H,m),0.88(6H,t,J=6.0Hz).

[0550] MSm / z(M+H): 723.

[0551] [Example 13]

[0552] [Chemical Formula 43]

[0553]

[0554] In Example 1(3), dinonyl 8,8'-azaalkyldiyl dioctyl ester synthesized according to the method described in WO2016 / 081029A1 was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, nonyl 2,5-dimethyl-10-(8-(nonoxy)-8-oxooctyl)-9-oxo-8-oxo-2,5,10-triazaoctadecane-18-ester was obtained by the same method as in Example 1(3).

[0555] 1H-NMR(CDCl3)δ:4.20-4.01(6H,m),3.24-3.09(4H,m),2.71-2.51(4H,m),2.44-2.38(2H,m ),2.31(3H,s),2.26(6H,s),1.79-1.43(12H,m),1.37-1.23(40H,m),0.88(6H,t,J=6.0Hz).

[0556] MSm / z(M+H): 727.

[0557] [Example 14] (1)

[0559] [Chemical Formula 44]

[0560]

[0561] In Example 1(1), 6-bromo-1-hexanol was used instead of (6Z,9Z)-18-bromooctadec-6,9-diene, and N,N-bis(6-hydroxyhexyl)-2-nitrobenzenesulfonamide was obtained by the same method as in Example 1(1).

[0562] To a mixture of N,N-bis(6-hydroxyhexyl)-2-nitrobenzenesulfonamide (2.13 g), triethylamine (0.58 mL), and tetrahydrofuran (5 mL), (Z)-keto-2-en-1-ylcarbonochloridate (3.15 g) was added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain (Z)-6-((N-(6-hydroxyhexyl)-2-nitrophenyl)sulfonamido)hexyl keto-2-en-1-ylcarbonate (1.67 g).

[0563] 1 H-NMR(CDCl3)δ:8.04-7.97(1H,m),7.71-7.59(3H,m),5.72-5.51(2H,m),4.68(2H,d,J=6.0Hz), 4.12(2H,t,J=6.0Hz), 3.65-3.59(2H,m),3.30-3.24(4H,m),2.14-2.07(2H,m),1.66-1.48(8H,m),1.40-1.22(16H,m),0.88(3H,t,J=6.0Hz).

[0564] To the obtained mixture of (Z)-6-((N-(6-hydroxyhexyl)-2-nitrophenyl)sulfonamide)hexyl ketone-2-en-1-yl carbonate (1.67 g), (Z)-4-nitrophenyl ketone-2-en-1-yl carbonate (1.84 g), triethylamine (1.7 mL), and tetrahydrofuran (17 mL), 4-dimethylaminopyridine (0.37 g) was added, and the mixture was stirred at 50 °C for 6 hours. After cooling the reaction mixture to room temperature, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (((2-nitrophenyl)sulfonyl)azanediyl)bis(hexane-6,1-diyl)bis((Z)-ketone-2-en-1-yl)bis(carbonate) (1.96 g).

[0565] 1 H-NMR(CDCl3)δ:8.04-7.97(1H,m),7.71-7.59(3H,m),5.72-5.51(4H,m),4.68(4H,d,J=6.0Hz),4.12(4H,t,J= 6.0Hz), 3.27(4H,t,J=6.0Hz), 2.14-2.07(4H,m), 1.66-1.48(8H,m), 1.40-1.22(24H,m), 0.88(6H,t,J=6.0Hz). (2)

[0567] [Chemical Formula 45]

[0568]

[0569] Cesium carbonate (2.51 g) was added to a mixture of (((2-nitrophenyl)sulfonyl)azanidinediyl)bis(hexane-6,1-diyl)bis((Z)-one-2-en-1-yl)bis(carbonate) (1.01 g), dodecane-1-thiol (1.05 mL), and acetonitrile (10 mL), and the mixture was stirred at 50 °C for 10 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give azanidinediylbis(hexane-6,1-diyl)bis((Z)-one-2-en-1-yl)bis(carbonate) (1.59 g).

[0570] 1H-NMR(CDCl3)δ:5.73-5.50(4H,m),4.68(4H,d,J=6.0Hz),4.12(4H,t,J=6.0Hz),2.61(4H,t ,J=6.0Hz),2.15-2.05(4H,m),1.73-1.46(8H,m),1.42-1.24(24H,m),0.88(6H,t,J=6.0Hz). (3)

[0572] [Chemical Formula 46]

[0573]

[0574] In Example 1(3), aziridinedibis(hexane-6,1-diyl)di((Z)-keto-2-en-1-yl)bis(carbonate) was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, 2-((2-(dimethylamino)ethyl)(methyl)amino)ethylbis(6-(((((Z)-keto-2-en-1-yl)oxy)carbonyl)oxy)hexyl)carbamate was obtained by the same method as in Example 1(3).

[0575] 1 H-NMR(CDCl3)δ:5.73-5.50(4H,m),4.67(4H,d,J=6.0Hz),4.20-4.08(6H,m),3.24-3.10(4H,m),2.66(2H,d,J=6.0Hz),2.53(2H,t,J=6. 0Hz),2.38(2H,t,J=6.0Hz),2.31(3H,s),2.24(6H,s),2.15-2.06(4H,m),1.72-1.45(8H,m),1.42-1.23(24H,m),0.88(6H,t,J=6.0Hz).

[0576] MSm / z(M+H): 727.

[0577] [Example 15] (1)

[0579] [Chemical Formula 47]

[0580]

[0581] (Z)-1-bromooctadec-9-ene (4.53 g) was added to a suspension of 1-nonylamine (1.95 g) and potassium carbonate (1.87 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 80 °C for 9 hours. The reaction mixture was cooled to room temperature, and water (40 mL) and hexane (40 mL) were added. After separating the organic layer, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (Z)-N-nonyloctadec-9-ene-1-amine (1.72 g).

[0582] MSm / z(M+H): 394. (2)

[0584] [Chemical Formula 48]

[0585]

[0586] In Example 1(3), (Z)-N-nonyloctadec-9-en-1-amine was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl(Z)-nonyl(octadec-9-en-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0587] 1 H-NMR(CDCl3)δ:5.41-5.29(2H,m),4.17(2H,t,J=6.0Hz),3.24-3.11(4H,m),2.68(2H,t,J=6.0Hz),2.54(2H,t,J=6.0Hz),2.3 8(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),2.08-1.93(4H,m),1.56-1.43(4H,m),1.38-1.18(34H,m),0.89(6H,t,J=6.0Hz).

[0588] MSm / z(M+H): 567.

[0589] [Example 16] (1)

[0591] [Chemical Formula 49]

[0592]

[0593] In Example 15(1), (6Z,9Z)-18-bromooctadec-6,9-diene was used instead of (Z)-1-bromooctadec-9-ene. Otherwise, (9Z,12Z)-N-nonyloctadec-9,12-diene-1-amine was obtained using the same method as in Example 15(1).

[0594] MSm / z(M+H): 392. (2)

[0596] [Chemical Formula 50]

[0597]

[0598] In Example 1(3), (9Z,12Z)-N-nonyloctadec-9,12-dien-1-amine was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, 2-((2-(dimethylamino)ethyl)(methyl)amino)ethylnonyl((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate was obtained by the same method as in Example 1(3).

[0599] 1 H-NMR(CDCl3)δ:5.43-5.29(4H,m),4.17(2H,t,J=6.0Hz),3.25-3.11(4H,m),2.77(2H,t,J=6.0Hz),2.68(2H,t,J=6.0Hz),2.54(2H,t,J =6.0Hz),2.38(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),2.10-1.99(4H,m),1.56-1.43(4H,m),1.41-1.19(28H,m),0.92-0.85(6H,m).

[0600] MSm / z(M+H): 565.

[0601] [Example 17]

[0602] [Chemical Formula 51]

[0603]

[0604] In Example 1(3), dioctylamine was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine, and 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl dioctylcarbamate was obtained by the same method as in Example 1(3).

[0605] 1 H-NMR (CDCl3) δ: 4.17 (2H, t, J = 6.0Hz), 3.24-3.12 (4H, m), 2.68 (2H, t, J = 6.0Hz), 2.54 (2H, t, J = 6.0Hz), 2.3 9(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),1.55-1.43(4H,m),1.34-1.19(20H,m),0.88(6H,t,J=6.0Hz).

[0606] MSm / z(M+H): 414.

[0607] [Example 18]

[0608] [Chemical Formula 52]

[0609]

[0610] In Example 1(3), dinonylamine was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine. Otherwise, 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl dinonylcarbamate was obtained by the same method as in Example 1(3).

[0611] 1 H-NMR (CDCl3) δ: 4.17 (2H, t, J = 6.0Hz), 3.24-3.12 (4H, m), 2.68 (2H, t, J = 6.0Hz), 2.54 (2H, t, J = 6.0Hz), 2.3 9(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),1.55-1.43(4H,m),1.34-1.19(24H,m),0.88(6H,t,J=6.0Hz).

[0612] MSm / z(M+H): 442.

[0613] [Example 19]

[0614] [Chemical Formula 53]

[0615]

[0616] In Example 1(3), didecylamine was used instead of (9Z,12Z9-di((9Z,12Z)-octadec-9,12-dien-1-yl)amine, and 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl didecylcarbamate was obtained by the same method as in Example 1(3).

[0617] 1 H-NMR (CDCl3) δ: 4.17 (2H, t, J = 6.0Hz), 3.23-3.12 (4H, m), 2.67 (2H, t, J = 6.0Hz), 2.54 (2H, t, J = 6.0Hz), 2.3 9(2H,t,J=6.0Hz),2.32(3H,s),2.24(6H,s),1.55-1.38(4H,m),1.35-1.18(28H,m),0.88(6H,t,J=6.0Hz).

[0618] MSm / z(M+H): 470.

[0619] [Example 20] (1)

[0621] [Chemical Formula 54]

[0622]

[0623] A mixture of (6Z,9Z,28Z,31Z)-heptadecane-6,9,28,31-tetraen-19-ol (5.0 g), triethylamine (4.0 mL), and tetrahydrofuran (25 mL) synthesized according to the method described in WO2010 / 054401A1 was added to 4-nitrobenzene chloroformate (3.8 g), and the mixture was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give (6Z,9Z,28Z,31Z)-heptadecane-6,9,28,31-tetraen-19-yl(4-nitrophenyl) carbonate (6.25 g).

[0624] 1 H-NMR(CDCl3)δ:8.31-8.24(2H,m),7.42-7.35(2H,m),5.44-5.27(8H,m),4.87-4.76(1H,m),2.77 (4H,t,J=6.0Hz),2.11-1.99(8H,m),1.74-1.57(4H,m),1.44-1.21(36H,m),0.89(6H,t,J=6.0Hz). (2)

[0626] [Chemical Formula 55]

[0627]

[0628] To a mixture of (6Z,9Z,28Z,31Z)-heptadecane-6,9,28,31-tetraen-19-yl(4-nitrophenyl)carbonate (0.89 g), 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol (0.30 mL), triethylamine (0.27 mL), and tetrahydrofuran (5 mL), 4-dimethylaminopyridine (0.23 g) was added, and the mixture was stirred at 60 °C for 6 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate (0.36 g).

[0629] 1 H-NMR(CDCl3)δ:5.44-5.27(8H,m),4.73-4.62(1H,m),4.22(2H,t,J=6.0Hz),2.77(4H,t,J=6.0Hz),2.71(2H,t,J=6.0Hz),2.58-2.50 (2H,m),2.43-2.35(2H,m),2.32(3H,s),2.24(6H,s),2.11-1.97(8H,m),1.63-1.48(4H,m),1.42-1.19(36H,m),0.89(6H,t,J=6.0Hz).

[0630] MSm / z(M+H): 702.

[0631] [Example 21]

[0632] [Chemical Formula 56]

[0633]

[0634] In Example 20(2), 2-(methyl(2-morpholinylethyl)amino)-1-ethanol synthesized in Example 5(1) was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-(methyl(2-morpholinylethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0635] 1H-NMR(CDCl3)δ:5.46-5.25(8H,m),4.73-4.61(1H,m),4.21(2H,t,J=6.0Hz),3.71(4H,t,J=6.0Hz),2.77(4H,t,J=6.0Hz),2.71(2H,t,J=6 .0Hz),2.62-2.54(2H,m),2.51-2.43(6H,m),2.32(3H,s),2.13-1.98(8H,m),1.65-1.46(4H,m),1.43-1.20(36H,m),0.89(6H,t,J=6.0Hz).

[0636] MSm / z(M+H): 744.

[0637] [Example 22]

[0638] [Chemical Formula 57]

[0639]

[0640] In Example 20(2), 2-(ethyl(2-morpholinylethyl)amino)-1-ethanol synthesized in Example 6(1) was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-(ethyl(2-morpholinylethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0641] 1 H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.74-4.60(1H,m),4.17(2H,t,J=6.0Hz),3.71(4H,t,J=6.0Hz),2.84-2.72(6H,m),2.70-2.54 (4H,m),2.52-2.39(6H,m),2.12-1.94(8H,m),1.66-1.47(4H,m),1.44-1.18(36H,m),1.03(3H,t,J=6.0Hz),0.89(6H,t,J=6.0Hz).

[0642] MSm / z(M+H): 758.

[0643] [Example 23]

[0644] [Chemical Formula 58]

[0645]

[0646] In Example 20(2), 2-((2-(diethylamino)ethyl)(methyl)amino)-1-ethanol synthesized in Example 7(1) was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((2-(diethylamino)ethyl)(methyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0647] 1 H-NMR(CDCl3)δ:5.44-5.27(8H,m),4.72-4.61(1H,m),4.21(2H,t,J=6.0Hz),2.77(4H,t,J=6.0),2.70(2H,t,J=6.0Hz),2.59-2 .49(8H,m),2.31(3H,s),2.14-1.94(8H,m),1.64-1.47(4H,m),1.43-1.19(36H,m),1.02(6H,t,J=6.0Hz),0.89(6H,t,J=6.0Hz).

[0648] MSm / z(M+H): 730.

[0649] [Example 24] (1)

[0651] [Chemical Formula 59]

[0652]

[0653] In Example 5(1), 2-chloro-N,N-dimethylethyl-1-amine hydrochloride was used instead of 4-(2-chloroethyl)morpholine hydrochloride, and 2-(ethylamino)-1-ethanol was used instead of 2-(methylamino)-1-ethanol. Otherwise, 2-((2-(dimethylamino)ethyl)(ethyl)amino)-1-ethanol was obtained by the same method as in Example 5(1).

[0654] MSm / z(M+H): 161. (2)

[0656] [Chemical Formula 60]

[0657]

[0658] In Example 20(2), 2-((2-(dimethylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((2-(dimethylamino)ethyl)(ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0659] 1 H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.73-4.61(1H,m),4.18(2H,t,J=6.0Hz),2.83-2.71(6H,m),2.67-2.55(4H,m),2.42-2.3 3(2H,m),2.24(6H,s),2.12-1.98(8H,m),1.64-1.50(4H,m),1.45-1.19(36H,m),1.03(3H,t,J=6.0Hz),0.89(6H,t,J=6.0Hz).

[0660] MSm / z(M+H): 716.

[0661] [Example 25] (1)

[0663] [Chemical Formula 61]

[0664]

[0665] In Example 5(1), 2-chloro-N,N-dimethylethyl-1-amine hydrochloride was used instead of 4-(2-chloroethyl)morpholine hydrochloride, and 2-(isopropylamino)-1-ethanol was used instead of 2-(methylamino)-1-ethanol. Otherwise, 2-((2-(dimethylamino)ethyl)(isopropyl)amino)-1-ethanol was obtained by the same method as in Example 5(1).

[0666] MSm / z(M+H): 175. (2)

[0668] [Chemical Formula 62]

[0669]

[0670] In Example 20(2), 2-((2-(dimethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((2-(dimethylamino)ethyl)(isopropyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0671] 1 H-NMR(CDCl3)δ:5.46-5.26(8H,m),4.73-4.61(1H,m),4.10(2H,t,J=6.0H z),2.98-2.85(1H,m),2.77(4H,t,J=6.0Hz),2.69(2H,t,J=6.0Hz),2.60- 2.52(2H,m),2.37-2.29(2H,m),2.24(6H,s),2.10-1.99(8H,m),1.58-1.4 9(4H,m),1.45-1.20(36H,m),0.99(6H,d,J=6.0Hz),0.89(6H,t,J=6.0Hz).

[0672] MSm / z(M+H): 730.

[0673] [Example 26] (1)

[0675] [Chemical Formula 63]

[0676]

[0677] In Example 5(1), tert-butyl (2-bromoethyl)carbamate was used instead of 4-(2-chloroethyl)morpholine hydrochloride. Otherwise, tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)carbamate was obtained by the same method as in Example 5(1).

[0678] MSm / z(M+H): 219. (2)

[0680] [Chemical Formula 64]

[0681]

[0682] In Example 20(2), tert-butyl (2-((2-hydroxyethyl)(methyl)amino)ethyl)carbamate was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, tert-butyl (2-((2-(((6Z,9Z,28Z,31Z)-heptacarbon-6,9,28,31-tetraen-19-yl)oxy)ethyl)(methyl)amino)ethyl)carbamate was obtained by the same method as in Example 20(2).

[0683] 1 H-NMR(CDCl3)δ:5.45-5.26(8H,m),5.04(1H,bs),4.76-4.62(1H,m),4.20(2H,t,J=6.0Hz),3.25-3.12(2H,m),2.77(4H,t,J=6.0Hz),2.68(2H, t,J=6.0Hz),2.52(2H,t,J=6.0Hz),2.28(3H,s),2.12-1.96(8H,m),1.6 2-1.50(4H,m),1.45(9H,s),1.62-1.50(36H,m),0.89(6H,t,J=6.0Hz).

[0684] MSm / z(M+H): 774. (3)

[0686] [Chemical Formula 65]

[0687]

[0688] In Example 9(2), tert-butyl (2-((2-(((((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl)oxy)ethyl)(methyl)amino)ethyl)carbamate synthesized in Example 26(2) was used instead of 2-((tert-butoxycarbonyl)(2-((tert-butoxycarbonyl)amino)ethyl)amino)ethyl di((9Z,12Z)-octadec-9,12-dien-1-yl)carbamate. Otherwise, 2-((2-aminoethyl)(methyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl)carbonate was obtained by the same method as in Example 9(2).

[0689] 1H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.73-4.61(1H,m),4.22(2H,t,J=6.0Hz),2.82-2.72(6H,m),2.68(2H,t,J=6.0Hz) ,2.47(2H,t,J=6.0Hz),2.29(3H,s),2.11-1.98(8H,m),1.62-1.44(4H,m),1.42-1.19(36H,m),0.89(6H,t,J=6.0Hz).

[0690] MSm / z(M+H): 674.

[0691] [Example 27] (1)

[0693] [Chemical Formula 66]

[0694]

[0695] 14.2 g of 2-bromo-1-ethanol was added to an ethanol (50 mL) suspension of N,N'-dimethylethane-1,2-diamine (5.0 g) and potassium carbonate (17.2 g), and the mixture was stirred at 60 °C for 5 hours. The reaction mixture was cooled to room temperature, and after filtering out the insoluble matter, the solvent was removed by vacuum distillation to obtain 10.2 g of 2,2'-(ethane-1,2-diylbis(methylazonyl))bis(-1-ethanol).

[0696] MSm / z(M+H): 177. (2)

[0698] [Chemical Formula 67]

[0699]

[0700] In Example 20(2), 2,2'-(ethane-1,2-diylbis(methylazonyl))bis(-1-ethanol) was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, (6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl(2-((2-((2-hydroxyethyl)(methyl)amino)ethyl)(methyl)amino)ethyl)carbonate was obtained using the same method as in Example 20(2).

[0701] 1H-NMR(CDCl3)δ:5.44-5.27(8H,m),4.73-4.61(1H,m),4.23(2H,t,J=6.0Hz),3.56(2H,t,J=6.0Hz),2.82-2.67(6H, m),2.58-2.52(6H,m),2.31(6H,s),2.11-1.99(8H,m),1.63-1.46(4H,m),1.42-1.20(36H,m),0.89(6H,t,J=6.0Hz).

[0702] MSm / z(M+H): 732.

[0703] [Example 28] (1)

[0705] [Chemical Formula 68]

[0706]

[0707] In Example 5(1), 2,2'-azaalkyldiylbis(-1-ethanol) was used instead of 2-(methylamino)-1-ethanol, and 2-chloro-N,N-dimethylethyl-1-amine hydrochloride was used instead of 4-(2-chloroethyl)morpholine hydrochloride. Otherwise, 2,2'-((2-(dimethylamino)ethyl)azaalkyldiyl)bis(-1-ethanol) was obtained by the same method as in Example 5(1).

[0708] MSm / z(M+H): 177. (2)

[0710] [Chemical Formula 69]

[0711]

[0712] In Example 20(2), 2,2'-((2-(dimethylamino)ethyl)azonidinediyl)bis(-1-ethanol) was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, 2-((2-(dimethylamino)ethyl)(2-hydroxyethyl)amino)ethyl)((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0713] 1H-NMR(CDCl3)δ:5.45-5.25(8H,m),4.73-4.62(1H,m),4.21(2H,t,J=6.0Hz),3.53(2H,t,J=6.0Hz),2.89(2H,t,J=6.0Hz),2.77(4H,t,J=6.0 Hz),2.73-2.64(4H,m),2.37(2H,t,J=6.0Hz),2.23(6H,s),2.10-1.98(8H,m),1.65-1.46(4H,m),1.43-1.18(36H,m),0.89(6H,t,J=6.0Hz).

[0714] MSm / z(M+H): 732.

[0715] [Example 29] (1)

[0717] [Chemical Formula 70]

[0718]

[0719] A mixture of ((19Z,22Z)-octadec-19,22-dien-11-ol (1.0 g), triethylamine (1.0 mL), and tetrahydrofuran (5.0 mL) synthesized according to the method described in WO2015 / 005253A1 was added with 1.0 g of 4-nitrobenzene chloroformate, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2.0 g of 4-nitrophenyl ((19Z,22Z)-octadec-19,22-dien-11-yl) carbonate.

[0720] 1 H-NMR(CDCl3)δ:8.28(2H,d,J=9.0Hz),7.38(2H,d,J=9.0Hz),5.43-5.28(4H,m),4.87-4.77(1H,m), 2.77(2H,t,J=6.0Hz),2.10-1.99(4H,m),1.76-1.60(4H,m),1.43-1.20(32H,m),0.92-0.83(6H,m). (2)

[0722] [Chemical Formula 71]

[0723]

[0724] In Example 20(2), 4-nitrophenyl ((19Z,22Z)-octadec-19,22-dien-11-yl) carbonate was used instead of (6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl (4-nitrophenyl) carbonate. Otherwise, 2-((2-(dimethylamino)ethyl)(methyl)amino)ethyl ((19Z,22Z)-octadec-19,22-dien-11-yl) carbonate was obtained by the same method as in Example 20(2).

[0725] 1 H-NMR(CDCl3)δ:5.44-5.26(4H,m),4.73-4.62(1H,m),4.22(2H,t,J=6.0Hz),2.77(2H,t,J=6.0Hz),2.71(2H,t,J=6.0Hz),2.54(2H,t,J =6.0Hz),2.39(2H,t,J=6.0Hz),2.31(3H,s),2.24(6H,s),2.11-1.97(4H,m),1.65-1.45(4H,m),1.42-1.19(32H,m),0.93-0.84(6H,m).

[0726] MSm / z(M+H): 580.

[0727] [Example 30] (1)

[0729] [Chemical Formula 72]

[0730]

[0731] Potassium carbonate (18.6 g) was added to a mixture of 2-(ethylamino)-1-ethanol (4.0 g), 2-bromo-N,N-diethylethyl-1-amine hydrobromide (17.6 g), and ethanol (80 mL), and the mixture was stirred under reflux for 7 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol (6.5 g) as a pale yellow oil.

[0732] MSm / z(M+H): 189. (2)

[0734] [Chemical Formula 73]

[0735]

[0736] In Example 20(2), 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(diethylamino)ethyl)(ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0737] 1 H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.72-4.60(1H,m),4.17(2H,t,J=6.6Hz),2.83-2.69(6H,m),2.65-2.46( 10H,m),2.13-1.96(8H,m),1.65-1.47(4H,m),1.43-1.20(36H,m),1.09-0.98(9H,m),0.89(6H,t,J=6.6Hz).

[0738] MSm / z(M+H): 744.

[0739] [Example 31] (1)

[0741] [Chemical Formula 74]

[0742]

[0743] Potassium carbonate (8.0 g) was added to a mixture of 2-(propylamino)-1-ethanol (2.0 g), 2-chloro-N,N-dimethylethyl-1-amine hydrochloride (4.2 g), and ethanol (40 mL), and the mixture was stirred under reflux for 9 hours. The reaction mixture was cooled to room temperature, unwanted substances were filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 0.87 g of 2-((2-(dimethylamino)ethyl)(propyl)amino)-1-ethanol, a yellow oil. MS m / z (M+H): 175. (2)

[0745] [Chemical Formula 75]

[0746]

[0747] In Example 20(2), 2-((2-(dimethylamino)ethyl)(propyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dimethylamino)ethyl)(propyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0748] 1 H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.73-4.61(1H,m),4.17(2H,t,J=6.0Hz),2.85-2.70(6H,m),2.66-2.56(2H, m),2.51-2.41(2H,m),2.41-2.32(2H,m),2.24(6H,s),2.12-1.95(8H,m),1.66-1.18(42H,m),0.96-0.81(9H,m).

[0749] MSm / z(M+H): 730.

[0750] [Example 32] (1)

[0752] [Chemical Formula 76]

[0753]

[0754] In Example 31(1), 2-(cyclohexylamino)-1-ethanol was used instead of 2-(propylamino)-1-ethanol. Otherwise, a yellow oily substance of 2-(cyclohexyl(2-(dimethylamino)ethyl)amino)-1-ethanol was obtained by the same method as in Example 31(1).

[0755] MSm / z(M+H): 215. (2)

[0757] [Chemical Formula 77]

[0758]

[0759] In Example 20(2), 2-(cyclohexyl(2-(dimethylamino)ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-(cyclohexyl(2-(dimethylamino)ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0760] 1 H-NMR(CDCl3)δ:5.45-5.25(8H,m),4.74-4.59(1H,m),4.08(2H,t,J=6.6Hz),2.85-2.70(6H,m),2.68-2.57(2H,m),2.48-2.37(1H,m) ,2.37-2.29(2H,m),2.24(6H,s),2.13-1.94(8H,m),1.85-1.69(4H,m),1.66-1.49(4H,m),1.46-1.09(42H,m),0.89(6H,t,J=6.6Hz).

[0761] MSm / z(M+H): 770.

[0762] [Example 33]

[0763] [Chemical Formula 78]

[0764]

[0765] In Example 29(2), 2-((2-(dimethylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dimethylamino)ethyl)(ethyl)amino)ethyl((19Z,22Z)-octadec-19,22-dien-11-yl) carbonate was obtained by the same method as in Example 29(2).

[0766] 1H-NMR(CDCl3)δ:5.45-5.27(4H,m),4.73-4.62(1H,m),4.18(2H,t,J=4.8Hz),2.83-2.71(4H,m),2.67-2.55(4H,m),2.42-2. 34(2H,m),2.24(6H,s),2.12-1.97(4H,m),1.67-1.47(4H,m),1.43-1.19(32H,m),1.03(3H,t,J=5.4Hz),0.95-0.82(6H,m).

[0767] MSm / z(M+H): 594.

[0768] [Example 34]

[0769] [Chemical Formula 79]

[0770]

[0771] N,N'-dicyclohexylcarbodiimide (9.0 g) was added to a mixture of 1,2,3-propanetriol (2.0 g), oleic acid (12.3 g), 4-dimethylaminopyridine (5.3 g), and tetrahydrofuran (100 mL), and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance, 2-hydroxypropane-1,3-dimethyldioleate (2.5 g).

[0772] 1 H-NMR(CDCl3)δ:5.41-5.28(4H,m),4.22-4.04(5H,m),2.35(4H,t,J=7.2Hz),2 .05-1.97(8H,m),1.68-1.56(4H,m),1.40-1.23(40H,m),0.88(6H,t,J=7.5Hz).

[0773] To a mixture of 2-hydroxypropane-1,3-dimethyldioleate (500 mg), triethylamine (0.34 mL), and tetrahydrofuran (5 mL), 4-nitrobenzene chloroformate (246 mg) was added, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol (0.26 g), triethylamine (0.23 mL), and 4-dimethylaminopyridine (0.20 g) were added, and the mixture was stirred at 70 °C for 5 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Purification of the residue by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) yielded a colorless oily substance, 2-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)propane-1,3-dimethyldioleate (74 mg).

[0774] 1 H-NMR(CDCl3)δ:5.42-5.27(4H,m),5.13-5.04(1H,m),4.38-4.27(2H,m),4.25-4.10(4H,m),2.83-2.73(2H,m),2.67-2.54(4H,m),2. 43-2.29(6H,m),2.24(6H,s),2.08-1.93(8H,m),1.68-1.46(4H,m),1.40-1.18(40H,m),1.03(3H,t,J=5.1Hz),0.88(6H,t,J=5.4Hz).

[0775] MSm / z(M+H): 808.

[0776] [Example 35]

[0777] [Chemical Formula 80]

[0778]

[0779] In Example 34, (9Z,12Z)-octadec-9,12-dienoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 2-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)propane-1,3-diyl(9Z,9'Z,12Z,12'Z)-bis(octadec-9,12-dienoic acid ester), was obtained using the same method as in Example 34.

[0780] 1H-NMR(CDCl3)δ:5.44-5.28(8H,m),5.13-5.03(1H,m),4.38-4.29(2H,m),4.25-4.13(4H,m),2.83-2.72(6H,m),2.66-2.55(4H,m),2. 42-2.28(6H,m),2.24(6H,s),2.13-1.95(8H,m),1.68-1.50(4H,m),1.42-1.23(28H,m),1.03(3H,t,J=5.4Hz),0.89(6H,t,J=5.4Hz).

[0781] MSm / z(M+H): 804.

[0782] [Example 36] (1)

[0784] [Chemical Formula 81]

[0785]

[0786] Under ice-cold conditions, a boron trifluoride diethyl ether complex (46.2 mL) was added to a mixture of benzaldehyde (30.0 g), 6-bromo-1-hexanol (56.1 g), triethylsilane (67.5 mL), and toluene (300 mL), and the mixture was stirred for 40 minutes at the same temperature. Water was added to the reaction mixture, the organic layer was separated, washed with a saturated sodium bicarbonate aqueous solution, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance (((6-bromohexyl)oxy)methyl)benzene (73.5 g).

[0787] 1 H-NMR(CDCl3)δ:7.38-7.23(5H,m),4.50(2H,s),3.47(2H,t,J=6.6Hz),3.4 0(2H,t,J=6.6Hz),1.92-1.81(2H,m),1.68-1.58(2H,m),1.52-1.35(4H,m).

[0788] A mixture of (((6-bromohexyl)oxy)methyl)benzene (66.7 g) and tetrahydrofuran (200 mL) was added dropwise to a mixture of magnesium (7.5 g) and tetrahydrofuran (40 mL), and stirred at room temperature for 1 hour. Under ice-cold conditions, a mixture of ethyl formate (8.3 g) and tetrahydrofuran (100 mL) was added to the reaction mixture, and stirred at the same temperature for 1 hour. Under ice-cold conditions, the reaction mixture was injected into a 10% sulfuric acid aqueous solution (330 mL), followed by the addition of hexane (300 mL). The organic layer was separated, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was then added to tetrahydrofuran (200 mL), ethanol (100 mL), and a 10 mol / L potassium hydroxide aqueous solution, and stirred at 40 °C for 1 hour. Hexane (200 mL) and water (100 mL) were added to the reaction mixture. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 25.3 g of 1,13-bis(benzyloxy)-7-tetaneol, a colorless oil.

[0789] 1 H-NMR(CDCl3)δ:7.36-7.24(10H,m),4.50(4H,s),3.61-3.54(1H,m),3.46(4H,t,J=6.6Hz),1.68-1.56(4H,m),1.48-1.26(16H,m).

[0790] A mixture of 24.0 g of 1,13-bis(benzyloxy)-7-tridecaneol, 10.0 g of 10% palladium hydroxide on carbon (10.0 g), and 240 mL of methanol was stirred at 50 °C for 3 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, and after filtering off insoluble matter with diatomaceous earth, the solvent was removed by distillation under reduced pressure. Ethyl acetate (40 mL) was added to the residue, and the solid was filtered off, washed with ethyl acetate, and dried under reduced pressure to give 11.7 g of 1,7,13-tridecanetriol as a white solid.

[0791] 1 H-NMR(CDCl3)δ:3.70-3.55(5H,m),1.64-1.24(20H,m). (2)

[0793] [Chemical Formula 82]

[0794]

[0795] To a mixture of 1,7,13-tetrazoletriol (5.0 g), oleic acid (13.4 g), triethylamine (18.2 mL), 4-dimethylaminopyridine (0.26 g), and N,N-dimethylformamide (25 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.3 g) was added, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance, 7-hydroxytetrazole-1,3-dimethyldioleate (3.6 g).

[0796] 1 H-NMR(CDCl3)δ:5.41-5.28(4H,m),4.06(4H,t,J=6.6Hz),3.63-3.53(1H,m),2.2 9(4H,t,J=7.2Hz),2.06-1.96(8H,m),1.68-1.20(64H,m),0.88(6H,t,J=7.2Hz).

[0797] 4-Nitrophenyl chloroformate (161 mg) was added to a mixture of 7-hydroxytridecane-1,3-dimethyldioleate (400 mg), triethylamine (0.22 mL), and tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 5 hours. 2-((2-(dimethylamino)ethyl)(ethyl)amino)

[0798] 1-ethanol (0.26 g), triethylamine (0.22 mL), and 4-dimethylaminopyridine (0.19 g) were mixed and stirred at 70 °C for 4 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give a colorless oily 7-(((2-((2-(dimethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethyldioleate (138 mg).

[0799] 1H-NMR(CDCl3)δ:5.41-5.26(4H,m),4.72-4.63(1H,m),4.18(2H,t,J=6.4H z),4.04(4H,t,J=6.8Hz),2.77(2H,t,J=6.8Hz),2.66-2.56(4H,m),2.43- 2.34(2H,m),2.34-2.25(4H,m),2.24(6H,s),2.09-1.94(8H,m),1.70-1.4 7(12H,m),1.44-1.19(52H,m),1.03(3H,t,J=7.2),0.88(6H,t,J=6.8Hz).

[0800] MSm / z(M+H): 948.

[0801] [Example 37] (1)

[0803] [Chemical Formula 83]

[0804]

[0805] Sodium triacetoxyborohydride (1.8 g) was added to a mixture of 2-((2-(dimethylamino)ethyl)amino)-1-ethanol (250 mg), hexanal (0.35 mL), acetic acid (0.16 mL), and tetrahydrofuran (2.5 mL), and the mixture was stirred at room temperature for 2 hours. Methanol was added to the reaction mixture under ice-cold conditions, and the mixture was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give a colorless oily substance of 2-((2-(dimethylamino)ethyl)(hexyl)amino)-1-ethanol (400 mg).

[0806] MSm / z(M+H):217. (2)

[0808] [Chemical Formula 84]

[0809]

[0810] In Example 20(2), 2-((2-(dimethylamino)ethyl)(hexyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dimethylamino)ethyl)(hexyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0811] 1H-NMR(CDCl3)δ:5.45-5.27(8H,m),4.72-4.62(1H,m),4.17(2H,t,J=6.4Hz),2.84-2.71(6H,m),2.65-2.57(2H,m),2.53- 2.54(2H,m),2.41-2.32(2H,m),2.23(6H,s),2.12-1.97(8H,m),1.68-1.49(4H,m),1.48-1.20(44H,m),0.97-0.83(9H,m).

[0812] MSm / z(M+H): 772.

[0813] [Example 38] (1)

[0815] [Chemical Formula 85]

[0816]

[0817] In Example 31(1), 2-(butylamino)-1-ethanol was used instead of 2-(propylamino)-1-ethanol. Otherwise, a yellow oily substance of 2-(butyl(2-(dimethylamino)ethyl)amino)-1-ethanol was obtained by the same method as in Example 31(1).

[0818] MSm / z(M+H): 189. (2)

[0820] [Chemical Formula 86]

[0821]

[0822] In Example 20(2), 2-(butyl(2-(dimethylamino)ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-(butyl(2-(dimethylamino)ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0823] 1H-NMR(CDCl3)δ:5.44-5.26(8H,m),4.72-4.61(1H,m),4.17(2H,t,J=6.4Hz),2.84-2.71(6H,m),2.67-2.57(2H,m),2.54- 2.44(2H,m),2.42-2.33(2H,m),2.23(6H,s),2.12-1.96(8H,m),1.67-1.48(4H,m),1.48-1.19(40H,m),0.97-0.84(9H,m).

[0824] MSm / z(M+H): 744.

[0825] [Example 39] (1)

[0827] [Chemical Formula 87]

[0828]

[0829] In Example 30(1), 2-(butylamino)-1-ethanol was used instead of 2-(ethylamino)-1-ethanol. Otherwise, a pale yellow oily substance of 2-(butyl(2-(diethylamino)ethyl)amino)-1-ethanol was obtained by the same method as in Example 30(1).

[0830] MSm / z(M+H):217. (2)

[0832] [Chemical Formula 88]

[0833]

[0834] In Example 20(2), 2-(butyl(2-(diethylamino)ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-(butyl(2-(diethylamino)ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained by the same method as in Example 20(2).

[0835] 1H-NMR(CDCl3)δ:5.43-5.28(8H,m),4.71-4.62(1H,m),4.16(2H,t,J=6.4Hz),2.83-2.70(6H,m),2.65-2.43( 10H,m),2.11-1.96(8H,m),1.65-1.49(4H,m),1.46-1.19(40H,m),1.02(6H,t,J=7.2Hz),0.96-0.83(9H,m).

[0836] MSm / z(M+H): 772.

[0837] [Example 40] (1)

[0839] [Chemical Formula 89]

[0840]

[0841] In Example 31(1), 2-(pentylamino)-1-ethanol was used instead of 2-(propylamino)-1-ethanol. Otherwise, 2-((2-(dimethylamino)ethyl)(pentyl)amino)-1-ethanol, a brown oily substance, was obtained by the same method as in Example 31(1).

[0842] MSm / z(M+H):203. (2)

[0844] [Chemical Formula 90]

[0845]

[0846] In Example 20(2), 2-((2-(dimethylamino)ethyl)(pentyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dimethylamino)ethyl)(pentyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0847] 1H-NMR(CDCl3)δ:5.43-5.26(8H,m),4.72-4.61(1H,m),4.17(2H,t,J=6.0Hz),2.83-2.70(6H,m),2.65-2.57(2H,m),2.53- 2.43(2H,m),2.41-2.32(2H,m),2.23(6H,s),2.11-1.97(8H,m),1.65-1.49(4H,m),1.48-1.19(42H,m),0.95-0.83(9H,m).

[0848] MSm / z(M+H): 758.

[0849] [Example 41] (1)

[0851] [Chemical Formula 91]

[0852]

[0853] To a mixture of 1,7,13-tetrazoletriol (5.0 g), oleic acid (13.4 g), triethylamine (18.2 mL), 4-dimethylaminopyridine (0.26 g), and N,N-dimethylformamide (25 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.3 g) was added, and the mixture was stirred at room temperature for 15 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance, 7-hydroxytetrazole-1,3-dimethyldioleate (3.6 g).

[0854] 1 H-NMR(CDCl3)δ:5.41-5.28(4H,m),4.06(4H,t,J=6.6Hz),3.63-3.53(1H,m),2.2 9(4H,t,J=7.2Hz),2.06-1.96(8H,m),1.68-1.20(64H,m),0.88(6H,t,J=7.2Hz).

[0855] A mixture of 7-hydroxytridecane-1,3-dimethyl dioleate (3.6 g), triethylamine (2.0 mL), and tetrahydrofuran (36 mL) was added to a mixture of 4-nitrobenzene chloroformate (1.4 g), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 4.1 g of 7-(((4-nitrophenoxy)carbonyl)oxy)tridecane-1,13-dimethyl dioleate, a pale yellow oil.

[0856] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.1Hz),7.39(2H,dd,J=7.2Hz,2.1Hz),5.40-5.28(4H,m),4.86-4.76(1H,m),4.06 (4H,t,J=6.6Hz),2.29(4H,t,J=7.2Hz),2.05-1.96(8H,m),1.74-1.56(12H,m),1.42-1.21(52H,m),0.88(6H,t,J=7.2Hz). (2)

[0858] [Chemical Formula 92]

[0859]

[0860] 4-Dimethylaminopyridine (0.79 g) was added to a mixture of 7-(((4-nitrophenoxy)carbonyl)oxy)tridecane-1,13-diyl dioleate (2.0 g), 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol (1.2 g), triethylamine (0.91 mL), and tetrahydrofuran (20 mL), and the mixture was stirred under reflux for 8 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-diyl dioleate (1.7 g).

[0861] 1H-NMR(CDCl3)δ:5.39-5.27(4H,m),4.71-4.62(1H,m),4.17(2H,t,J=6.4Hz),4.04(4H,t,J=6.8Hz),2.76(2H,t,J=6.0Hz),2.66-2.46 (10H,m),2.29(4H,t,J=7.6Hz),2.08-1.94(8H,m),1.69-1.48(12H,m),1.41-1.19(52H,m),1.07-0.97(9H,m),0.88(6H,t,J=7.2Hz).

[0862] MSm / z(M+H): 976.

[0863] [Example 42] (1)

[0865] [Chemical Formula 93]

[0866]

[0867] Potassium carbonate (8.0 g) was added to a mixture of 2-(isopropylamino)-1-ethanol (2.0 g), 2-bromo-N,N-diethylethyl-1-amine hydrobromide (7.6 g), and ethanol (20 mL), and the mixture was stirred under reflux for 7 hours. The reaction mixture was cooled to room temperature, unwanted substances were filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol (3.5 g) as a pale yellow oil.

[0868] MSm / z(M+H):203. (2)

[0870] [Chemical Formula 94]

[0871]

[0872] In Example 20(2), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(diethylamino)ethyl)(isopropyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0873] 1H-NMR(CDCl3)δ:5.45-5.27(8H,m),4.72-4.61(1H,m),4.10(2H,t,J=6.8Hz),2.96-2.85(1H,m),2.83-2.74(4H,m),2.68(2H,t,J =6.8Hz),2.60-2.41(8H,m),2.12-1.96(8H,m),1.65-1.48(4H,m),1.45-1.19(36H,m),1.10-0.95(12H,m),0.89(6H,t,J=6.8Hz).

[0874] MSm / z(M+H): 758.

[0875] [Example 43]

[0876] [Chemical Formula 95]

[0877]

[0878] In Example 41(2), 2-((2-(dimethylamino)ethyl)(hexyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily substance, 7-(((2-((2-(dimethylamino)ethyl)(hexyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethyldioleate, was obtained by the same method as in Example 41(2).

[0879] 1 H-NMR(CDCl3)δ:5.42-5.26(4H,m),4.73-4.60(1H,m),4.17(2H,t,J=5.7 Hz),4.04(4H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),2.67-2.56(2H,m),2.55 -2.44(2H,m),2.42-2.34(2H,m),2.29(4H,t,J=7.5Hz),2.23(6H,s),2.10 -1.93(8H,m),1.69-1.49(12H,m),1.48-1.19(60H,m),0.95-0.81(9H,m).

[0880] MSm / z(M+H): 1004.

[0881] [Example 44] (1)

[0883] [Chemical Formula 96]

[0884]

[0885] In Example 30(1), 2-(propylamino)-1-ethanol was used instead of 2-(ethylamino)-1-ethanol. Otherwise, a pale yellow oily substance of 2-((2-(diethylamino)ethyl)(propyl)amino)-1-ethanol was obtained by the same method as in Example 30(1).

[0886] MSm / z(M+H):203. (2)

[0888] [Chemical Formula 97]

[0889]

[0890] In Example 20(2), 2-((2-(diethylamino)ethyl)(propyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(diethylamino)ethyl)(propyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0891] 1 H-NMR(CDCl3)δ:5.46-5.24(8H,m),4.73-4.61(1H,m),4.16(2H,t,J=6.6Hz),2.83-2.70(6H,m),2.65-2.41( 10H,m),2.11-1.96(8H,m),1.64-1.51(4H,m),1.49-1.21(38H,m),1.02(6H,t,J=7.2Hz),0.95-0.81(9H,m).

[0892] MSm / z(M+H): 758.

[0893] [Example 45]

[0894] [Chemical Formula 98]

[0895]

[0896] In Examples 41(1) and (2), (9Z,12Z)-octadec-9,12-dienoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-diyl(9Z,9'Z,12Z,12'Z)-bis(octadec-9,12-dienoic acid ester), was obtained by the same method as in Examples 41(1) and (2).

[0897] 1 H-NMR(CDCl3)δ:5.46-5.24(8H,m),4.73-4.61(1H,m),4.17(2H,t,J=6.6Hz),4.04(4H,t,J=6.6Hz),2.83-2.71(6H,m),2.66-2.47( 10H,m),2.29(4H,t,J=8.1Hz),2.13-1.96(8H,m),1.69-1.50(12H,m),1.44-1.21(40H,m),1.08-0.97(9H,m),0.89(6H,t,J=6.6Hz).

[0898] MSm / z(M+H): 972.

[0899] [Example 46]

[0900] [Chemical Formula 99]

[0901]

[0902] In Examples 41(1) and (2), (Z)-hexadec-9-enoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-diyl(9Z,9'Z)-bis(hexadec-9-enoic acid ester), was obtained by the same method as in Examples 41(1) and (2).

[0903] 1 H-NMR(CDCl3)δ:5.40-5.27(4H,m),4.73-4.61(1H,m),4.17(2H,t,J=6.6Hz),4.04(4H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),2.66-2.45 (10H,m),2.29(4H,t,J=7.2Hz),2.09-1.93(8H,m),1.70-1.48(12H,m),1.43-1.20(44H,m),1.11-0.97(9H,m),0.88(6H,t,J=6.6Hz).

[0904] MSm / z(M+H): 920.

[0905] [Example 47]

[0906] [Chemical Formula 100]

[0907]

[0908] In Examples 41(1) and (2), (Z)-tetradecano-9-enoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-diyl(9Z,9'Z)-bis(tetradecano-9-enoic acid ester), was obtained by the same method as in Examples 41(1) and (2).

[0909] 1 H-NMR (CDCl3) δ: 5.44-5.24 (4H, m), 4.73-4.61 (1H, m), 4.17 (2H, t, J = 6.0Hz), 4.04 (4H, t, J = 6.6Hz), 2.76 (2H, t, J = 6.6Hz), 2.67-2. 46(10H,m),2.29(4H,t,J=7.8Hz),2.11-1.92(8H,m),1.71-1.47(12H,m),1.45-1.21(36H,m),1.09-0.96(9H,m),0.95-0.83(6H,m).

[0910] MSm / z(M+H): 864.

[0911] [Example 48]

[0912] [Chemical Formula 101]

[0913]

[0914] In Examples 41(1) and (2), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, the colorless oily 7-(((2-((2-(diethylamino)ethyl)(isopropyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dioleate was obtained by the same method as in Examples 41(1) and (2).

[0915] 1H-NMR(CDCl3)δ:5.41-5.27(4H,m),4.72-4.61(1H,m),4.17-3.99(6H,m),2.95-2.86(1H,m),2.68(2H,t,J=6.4Hz),2.60-2.42(8H ,m),2.28(4H,t,J=8.0Hz),2.08-1.93(8H,m),1.69-1.48(12H,m),1.43-1.20(52H,m),1.09-0.95(12H,m),0.88(6H,t,J=6.8Hz).

[0916] MSm / z(M+H): 990.

[0917] [Example 49] (1)

[0919] [Chemical Formula 102]

[0920]

[0921] In Example 30(1), N-(2-bromoethyl)-N-propylpropyl-1-amine hydrobromide was used instead of 2-bromo-N,N-diethylethyl-1-amine hydrobromide. Otherwise, a colorless oily substance of 2-((2-(dipropylamino)ethyl)(ethyl)amino)-1-ethanol was obtained by the same method as in Example 30(1).

[0922] MSm / z(M+H):217. (2)

[0924] [Chemical Formula 103]

[0925]

[0926] In Example 20(2), 2-((2-(dipropylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dipropylamino)ethyl)(ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0927] 1H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.74-4.61(1H,m),4.17(2H,t,J=6.0Hz),2.84-2.70(6H,m),2.65-2.46(6H,m),2. 43-2.31(4H,m),2.13-1.97(8H,m),1.66-1.52(4H,m),1.50-1.21(40H,m),1.03(3H,t,J=6.6Hz),0.95-0.80(12H,m).

[0928] MSm / z(M+H): 772.

[0929] [Example 50] (1)

[0931] [Chemical Formula 104]

[0932]

[0933] A mixture of 22.0 g of 10-ethoxy-10-oxodecanoic acid, 22.0 mL of thionyl chloride, and 0.1 mL of N,N-dimethylformamide was stirred under reflux for 1 hour and 30 minutes. The solvent was removed by vacuum distillation, yielding ethyl 10-chloro-10-oxodecanoate as the crude product.

[0934] At -78°C, 1.0 mol / L magnesium dodecyl bromide-diethyl ether solution (190 mL) was added dropwise to a suspension of zinc(II) chloride (13.0 g) in tetrahydrofuran (284 mL). After heating to 0°C, the mixture was stirred at the same temperature for 30 minutes. Tetra(triphenylphosphine)palladium(O) (2.8 g) and ethyl 10-chloro-10-oxodecanoate were added to the reaction mixture, and the mixture was stirred at 0°C for 1 hour. 1.0 mol / L hydrochloric acid aqueous solution (50 mL) and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give ethyl 10-oxodocanoic acid (13.2 g), a brown oil.

[0935] A mixture of ethyl 10-oxodocosalicylic acid (22.0 g) and 2-butyl-1-octanol (31.9 g) was added to tetraisopropyl titanate (1.7 g), and the mixture was stirred at 110 °C for 17 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 11.7 g of 2-butyloctyl 10-oxodocosalicylic acid as a pale yellow solid.

[0936] Sodium borohydride (4.2 g) was added to a mixture of 2-butyloctyl-10-oxodocosalicylic acid (11.7 g), methanol (47 mL), and tetrahydrofuran (47 mL) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then injected into a mixture of ice and water, followed by the addition of 1.0 mol / L hydrochloric acid aqueous solution (22 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 7.8 g of 2-butyloctyl-10-hydroxydocosalicylic acid ester as a white solid.

[0937] 1 H-NMR(CDCl3)δ:3.96-3.98(2H,d),3.58(1H,s),2.27-2.31(2H,t),1.60 -1.63(2H,t),1.38-1.43(6H,d),1.26-1.29(46H,m),0.86-0.89(9H,m). (2)

[0939] [Chemical Formula 105]

[0940]

[0941] A mixture of 2-butyloctyl 10-hydroxydocosahexaenoate (500 mg), triethylamine (0.43 mL), and tetrahydrofuran (5 mL) was added to a solution of 4-nitrobenzene chloroformate (408 mg), and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily compound, 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)docosahexaenoate (750 mg).

[0942] 1H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.1Hz),7.39(2H,dd,J=7.2Hz,2.1Hz),4.86-4.77(1H,m),3. 97(2H,d,J=6.0Hz),2.30(2H,t,J=7.2Hz),1.74-1.55(7H,m),1.40-1.21(46H,m),0.92-0.85(9H,m). (3)

[0944] [Chemical Formula 106]

[0945]

[0946] In Example 41(2), 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)docosahexaenoate was used instead of 7-(((4-nitrophenoxy)carbonyl)oxy)tridecane-1,13-dioleate. Otherwise, a colorless oily 2-butyloctyl 12-dodecyl-3,6-diethyl-10-oxo-9,11-dioxa-3,6-diaza-eicosene-21-ester was obtained by the same method as in Example 41(2).

[0947] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.17(2H,t,J=6.6Hz),3.97(2H,d,J=6.0Hz),2.76(2H,t,J=6.6Hz),2.67-2. 46(10H,m),2.29(2H,t,J=7.8Hz),1.67-1.48(7H,m),1.39-1.18(46H,m),1.10-0.98(9H,m),0.96-0.82(9H,m).

[0948] MSm / z(M+H): 740.

[0949] [Example 51] (1)

[0951] [Chemical Formula 107]

[0952]

[0953] In Example 30(1), 2-(benzylamino)-1-ethanol was used instead of 2-(ethylamino)-1-ethanol. Otherwise, a pale yellow oily substance of 2-(benzyl(2-(diethylamino)ethyl)amino)-1-ethanol was obtained by the same method as in Example 30(1).

[0954] MSm / z(M+H): 251. (2)

[0956] [Chemical Formula 108]

[0957]

[0958] In Example 20(2), 2-(benzyl(2-(diethylamino)ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-(benzyl(2-(diethylamino)ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0959] 1 H-NMR(CDCl3)δ:7.36-7.19(5H,m),5.46-5.27(8H,m),4.72-4.61(1H,m),4.18(2H,t,J=6.0Hz),3.68(2H,s),2.84-2.73(6H, m),2.69-2.42(8H,m),2.13-1.97(8H,m),1.65-1.49(4H,m),1.42-1.19(36H,m),0.98(6H,t,J=7.2Hz),0.89(6H,t,J=6.6Hz).

[0960] MSm / z(M+H): 806.

[0961] [Example 52] (1)

[0963] [Chemical Formula 109]

[0964]

[0965] In Example 37(1), octanal was used instead of hexanal, and otherwise, a colorless oily substance, 2-((2-dimethylamino)ethyl)(octyl)amino)-1-ethanol, was obtained using the same method as in Example 37(1).

[0966] MSm / z(M+H): 245. (2)

[0968] [Chemical Formula 110]

[0969]

[0970] In Example 20(2), 2-((2-dimethylamino)ethyl)(octyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dimethylamino)ethyl)(octyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0971] 1 H-NMR(CDCl3)δ:5.45-5.24(8H,m),4.73-4.62(1H,m),4.17(2H,t,J=6.0Hz),2.84-2.71(6H,m),2.67-2.56(2H,m),2.53- 2.43(2H,m),2.43-2.31(2H,m),2.23(6H,s),2.12-1.96(8H,m),1.66-1.51(4H,m),1.47-1.19(48H,m),0.96-0.80(9H,m).

[0972] MSm / z(M+H): 800.

[0973] [Example 53] (1)

[0975] [Chemical Formula 111]

[0976]

[0977] In Example 37(1), dodecaldehyde was used instead of hexanal, and otherwise, a colorless oily substance, 2-((2-(dimethylamino)ethyl)(dodecyl)amino)-1-ethanol, was obtained by the same method as in Example 37(1).

[0978] MSm / z(M+H): 301. (2)

[0980] [Chemical Formula 112]

[0981]

[0982] In Example 20(2), 2-((2-(dimethylamino)ethyl)(dodecyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-((2-(dimethylamino)ethyl)(dodecyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[0983] 1 H-NMR(CDCl3)δ:5.46-5.25(8H,m),4.72-4.61(1H,m),4.17(2H,t,J=6.6Hz),2.85-2.70(6H,m),2.66-2.57(2H,m),2.54- 2.43(2H,m),2.42-2.32(2H,m),2.23(6H,s),2.11-1.97(8H,m),1.66-1.50(4H,m),1.47-1.17(56H,m),0.97-0.81(9H,m).

[0984] MSm / z(M+H): 856.

[0985] [Example 54]

[0986] [Chemical Formula 113]

[0987]

[0988] In Example 41(2), 2-((2-(dipropylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol, and otherwise, a colorless oily 7-(((2-((2-(dipropylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethyldioleate was obtained by the same method as in Example 41(2).

[0989] 1H-NMR(CDCl3)δ:5.41-5.26(4H,m),4.73-4.60(1H,m),4.17(2H,t,J=6.0Hz),4.04(4H,t,J=6.6Hz),2.75(2H,t,J=6.6Hz),2.65-2.46(6H,m),2 .43-2.34(4H,m),2.28(4H,t,J=7.2Hz),2.10-1.95(8H,m),1.69-1.51( 12H,m),1.50-1.19(56H,m),1.03(3H,t,J=7.5Hz),0.94-0.81(12H,m).

[0990] MSm / z(M+H): 1004.

[0991] [Example 55]

[0992] [Chemical Formula 114]

[0993]

[0994] In Example 41(2), 2-(benzyl(2-(diethylamino)ethyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 7-(((2-(benzyl(2-(diethylamino)ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dioleate was obtained by the same method as in Example 41(2).

[0995] 1 H-NMR(CDCl3)δ:7.36-7.17(5H,m),5.42-5.27(4H,m),4.71-4.61(1H,m),4 .19(2H,t,J=6.6Hz),4.04(4H,t,J=7.2Hz),3.68(2H,s),2.79(2H,t,J=6.0 Hz),2.67-2.42(8H,m),2.28(4H,t,J=8.1Hz),2.08-1.93(8H,m),1.69-1.4 9(12H,m),1.42-1.20(52H,m),0.97(6H,t,J=7.2Hz),0.88(6H,t,J=6.6Hz).

[0996] MSm / z(M+H): 1038.

[0997] [Example 56] (1)

[0999] [Chemical Formula 115]

[1000]

[1001] In Example 41(1), 2-hexyldecanoic acid was used instead of oleic acid, and otherwise, a colorless oily substance, 7-(((4-nitrophenoxy)carbonyl)oxy)tetane-1,13-dimethylbis(2-hexyldecanoate), was obtained by the same method as in Example 41(1).

[1002] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.1Hz),7.39(2H,dd,J=7.2Hz,2.1Hz),4.86-4.76(1 H,m),4.07(4H,t,J=6.6Hz),2.36-2.25(2H,m),1.72-1.20(68H,m),0.87(12H,t,J=6.0Hz). (2)

[1004] [Chemical Formula 116]

[1005]

[1006] In Example 41(2), 7-(((4-nitrophenoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-hexyldecanoate) was used instead of 7-(((4-nitrophenoxy)carbonyl)oxy)tridecane-1,13-dimethyldioleate. Otherwise, a colorless oily product of 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-hexyldecanoate) was obtained by the same method as in Example 41(2).

[1007] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.17(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.6Hz ),2.67-2.46(10H,m),2.36-2.23(2H,m),1.68-1.16(68H,m),1.09-0.97(9H,m),0.94-0.81(12H,m).

[1008] MSm / z(M+H): 924.

[1009] [Example 57]

[1010] [Chemical Formula 117]

[1011]

[1012] In Examples 41(1) and (2), 8-(2-octylcyclopropyl)octanoic acid synthesized according to the method described in the European Journal of Medicinal Chemistry, 2016, 109, pp. 134-145 was used instead of oleic acid. Otherwise, a colorless oily substance of 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(8-(2-octylcyclopropyl)octanoic acid)) was obtained using the same method as in Examples 41(1) and (2).

[1013] 1 H-NMR(CDCl3)δ:4.72-4.62(1H,m),4.18(2H,t,J=6.6Hz),4.05(4H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),2.66-2.47(10H,m),2.29(4H,t ,J=8.1Hz),1.69-1.48(12H,m),1.45-1.08(60H,m),1.08-0.97(9H,m),0.88(6H,t,J=7.2Hz),0.71-0.51(6H,m),-0.29--0.38(2H,m).

[1014] MSm / z(M+H): 1004.

[1015] [Example 58]

[1016] [Chemical Formula 118]

[1017]

[1018] In Examples 41(1) and (2), 2-heptylundecanoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-heptylundecanoic acid), was obtained by the same method as in Examples 41(1) and (2).

[1019] 1H-NMR(CDCl3)δ:4.72-4.62(1H,m),4.17(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=5.7Hz) ,2.65-2.47(10H,m),2.36-2.24(2H,m),1.69-1.17(76H,m),1.08-0.98(9H,m),0.88(12H,t,J=7.5Hz).

[1020] MSm / z(M+H): 980.

[1021] [Example 59]

[1022] [Chemical Formula 119]

[1023]

[1024] In Examples 41(1) and (2), 2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctanoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-diylbis(2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctanoic acid ester), was obtained using the same method as in Examples 41(1) and (2).

[1025] 1 H-NMR(CDCl3)δ:4.73-4.62(1H,m),4.17(2H,t,J=6.6Hz),4.11-3.95(4H,m),2.76(2H,t, J=6.0Hz),2.65-2.46(10H,m),2.19-2.06(2H,m),1.86-1.13(40H,m),1.10-0.79(57H,m).

[1026] MSm / z(M+H): 980.

[1027] [Example 60]

[1028] [Chemical Formula 120]

[1029]

[1030] In Examples 41(1) and (2), 2-pentylheptanoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-pentylheptanoate), was obtained by the same method as in Examples 41(1) and (2).

[1031] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.17(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.0Hz) ,2.65-2.47(10H,m),2.37-2.25(2H,m),1.69-1.19(52H,m),1.07-0.98(9H,m),0.87(12H,t,J=6.6Hz).

[1032] MSm / z(M+H): 812.

[1033] [Example 61]

[1034] [Chemical Formula 121]

[1035]

[1036] In Example 50(3), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-butyloctyl-12-dodecyl-3-ethyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained by the same method as in Example 50(3).

[1037] 1 H-NMR(CDCl3)δ:4.73-4.60(1H,m),4.10(2H,t,J=6.6Hz),3.97(2H,d,J=6.0Hz),2.97-2.85(1H,m),2.68(2H,t,J=7.2Hz) ,2.60-2.41(8H,m),2.29(2H,t,J=7.8Hz),1.66-1.48(7H,m),1.40-1.20(46H,m),1.07-0.95(12H,m),0.94-0.81(9H,m).

[1038] MSm / z(M+H): 754.

[1039] [Example 62]

[1040] [Chemical Formula 122]

[1041]

[1042] In Example 56(2), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(isopropyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-hexyldecanoate), was obtained by the same method as in Example 56(2).

[1043] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.15-3.99(6H,m),2.97-2.84(1H,m),2.68(2H,t,J=6.6Hz),2. 60-2.41(8H,m),2.37-2.23(2H,m),1.69-1.16(68H,m),1.10-0.95(12H,m),0.87(12H,t,J=6.6Hz).

[1044] MSm / z(M+H): 938.

[1045] [Example 63] (1)

[1047] [Chemical Formula 123]

[1048]

[1049] A mixture of 2-(methylamino)-1-ethanol (3 g), potassium carbonate (6.6 g), 1-bromopropane (5.6 mL), and acetonitrile (30 mL) was stirred at 60 °C for 9 hours and 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give 4.3 g of a colorless oily 2-(methyl(propyl)amino)-1-ethanol.

[1050] MSm / z(M+H): 118.

[1051] Under ice-cold conditions, methanesulfonic anhydride (1.9 g) was added dropwise to a mixture of 2-(methyl(propyl)amino)-1-ethanol (1.2 g) and acetonitrile (10 mL), and the mixture was stirred at 0 °C for 30 min, followed by stirring at room temperature for 30 min. 2-(isopropylamino)-1-ethanol (2.0 g) and N,N-diisopropylethylamine (2.0 mL) were added to the reaction mixture, and the mixture was stirred at 70 °C for 25 h 30 min. After cooling the reaction mixture to room temperature, potassium carbonate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to give 0.3 g of a yellow oily substance, 2-(isopropyl(2-(methyl(propyl)amino)ethyl)amino)-1-ethanol.

[1052] MSm / z(M+H):203. (2)

[1054] [Chemical Formula 124]

[1055]

[1056] In Example 20(2), 2-(isopropyl(2-(methyl(propyl)amino)ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily substance (6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl(2-(isopropyl(2-(methyl(propyl)amino)ethyl)amino)ethyl) carbonate was obtained using the same method as in Example 20(2).

[1057] 1 H-NMR(CDCl3)δ:5.45-5.26(8H,m),4.73-4.62(1H,m),4.09(2H,t,J=6.6 Hz),2.97-2.86(1H,m),2.77(4H,t,J=6.0Hz),2.69(2H,t,J=7.2Hz),2.62 -2.51(2H,m),2.44-2.35(2H,m),2.35-2.27(2H,m),2.23(3H,s),2.11-1 .96(8H,m),1.66-1.20(42H,m),0.98(6H,d,J=6.6Hz),0.94-0.82(9H,m).

[1058] MSm / z(M+H): 758.

[1059] [Example 64] (1)

[1061] [Chemical Formula 125]

[1062]

[1063] Iodomethane (1.9 mL) was added dropwise to a solution of 3 g of 2-(isopropylamino)-1-ethanol in 30 mL of dichloromethane under ice-cold conditions. The mixture was stirred for 1 hour and 15 minutes at the same temperature, followed by stirring at room temperature for 6 hours and 50 minutes. Potassium carbonate and water were added to the reaction mixture, and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform, NH silica gel) to give a colorless oily substance of 2-(isopropyl(methyl)amino)-1-ethanol (2.2 g).

[1064] MSm / z(M+H): 118.

[1065] Under ice-cold conditions, methanesulfonic anhydride (2.6 g) was added to a mixture of 2-(isopropyl(methyl)amino)-1-ethanol (1.5 g), N,N-diisopropylethylamine (2.5 mL), and acetonitrile (15 mL), and the mixture was stirred at room temperature for 4 hours and 50 minutes. 2-(propylamino)-1-ethanol (4.3 mL) was then added to the reaction mixture, and the mixture was stirred at 70 °C for 23 hours and 30 minutes. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to give a yellow oily substance, 2-((2-(isopropyl(methyl)amino)ethyl)(propyl)amino)-1-ethanol (0.7 g).

[1066] MSm / z(M+H):203. (2)

[1068] [Chemical Formula 126]

[1069]

[1070] In Example 20(2), 2-((2-(isopropyl(methyl)amino)ethyl)(propyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily substance (6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl(2-((2-(isopropyl(methyl)amino)ethyl)(propyl)amino)ethyl) carbonate was obtained using the same method as in Example 20(2).

[1071] 1 H-NMR(CDCl3)δ:5.46-5.26(8H,m),4.74-4.60(1H,m),4.17(2H,t,J=6.6Hz),2.87-2.70(7H,m),2.65-2.54(2H,m) ,2.51-2.40(4H,m),2.21(3H,s),2.12-1.95(8H,m),1.64-1.20(42H,m),1.00(6H,d,J=6.6Hz),0.94-0.81(9H,m).

[1072] MSm / z(M+H): 758.

[1073] [Example 65] (1)

[1075] [Chemical Formula 127]

[1076]

[1077] Under ice-cold conditions, ethyl 2-(diethoxyphosphoryl)ethyl acetate (9.4 mL) was added dropwise to a suspension of 60 wt% sodium hydride (1.7 g) in tetrahydrofuran (60 mL), and the mixture was stirred at the same temperature for 30 minutes. 9-Heptadecanone (1.5 g) was added to the reaction mixture, and the mixture was stirred under reflux for 16 hours. The reaction mixture was cooled to room temperature, and after being injected into ice water, ethyl acetate was added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily ethyl 3-octyl undec-2-enoate (1.2 g).

[1078] 1 H-NMR(CDCl3)δ:5.61(1H,s),4.14(2H,q,J=6.6Hz),2.58(2H,t,J=7.2Hz),2.12(2H,t,J=7.2Hz),1.50-1.20(27H,m),0.91-0.85(6H,m).

[1079] Ammonium formate (1.4 g) was added to a mixture of ethyl 3-octyl undecanoate-2-enoate (1.2 g), 10% palladium-carbon (0.35 g), and methanol (24 mL), and the mixture was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature, and the insoluble matter was removed by filtration with diatomaceous earth. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give ethyl 3-octyl undecanoate (1.1 g), a colorless oil.

[1080] 1 H-NMR (CDCl3) δ: 4.12 (2H, q, J = 7.2Hz), 2.21 (2H, d, J = 6.6Hz), 2.05-2.04 (1H, m), 1.34-1.20 (31H, m), 0.88 (6H, 6.6Hz).

[1081] A mixture of ethyl 3-octylundecanoate (1.1 g) and ethanol (10 mL) was mixed with 5 mL of 5 mol / L sodium hydroxide aqueous solution and stirred at 80 °C for 5 hours. The reaction mixture was cooled to room temperature, and 1 mol / L hydrochloric acid aqueous solution was added until acidic, followed by the addition of ethyl acetate. The organic layer was separated, washed with saturated sodium chloride aqueous solution, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 1.1 g of 3-octylundecanoic acid as a colorless oil.

[1082] 1 H-NMR (CDCl3) δ: 2.28 (2H, d, J = 6.6Hz), 1.90-1.79 (1H, m), 1.35-1.19 (28H, m), 0.88 (6H, t, J = 6.6Hz). (2)

[1084] [Chemical Formula 128]

[1085]

[1086] In Examples 41(1) and (2), 3-octylundecanoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(3-octylundecanoic acid), was obtained by the same method as in Examples 41(1) and (2).

[1087] 1 H-NMR(CDCl3)δ:4.74-4.62(1H,m),4.17(2H,t,J=6.6Hz),4.04(4H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),2.66-2.47 (10H,m),2.22(4H,d,J=6.6Hz),1.90-1.76(2H,m),1.70-1.17(76H,m),1.10-0.97(9H,m),0.88(12H,t,J=6.6Hz).

[1088] MSm / z(M+H): 1008

[1089] [Example 66]

[1090] [Chemical Formula 129]

[1091]

[1092] In Examples 50(1), (2) and (3), 12-ethoxy-12-oxododecanoic acid was used instead of 10-ethoxy-10-oxodecanoic acid, and 1.0 mol / L decyl magnesium bromide-diethyl ether solution was used instead of 1.0 mol / L dodecyl magnesium bromide-diethyl ether solution. Otherwise, a colorless oily 2-butyloctyl-12-decyl-3,6-diethyl-10-oxo-9,11-dioxa-3,6-diazatriatriane-23-ester was obtained using the same method as in Examples 50(1), (2) and (3).

[1093] 1 H-NMR (CDCl3) δ: 4.73-4.61 (1H, m), 4.17 (2H, t, J = 6.6Hz), 3.97 (2H, d, J = 5.7Hz), 2.76 (2H, t, J = 6.6Hz), 2.66-2. 46(10H,m),2.30(2H,t,J=7.2Hz),1.70-1.47(7H,m),1.41-1.20(46H,m),1.11-0.98(9H,m),0.95-0.82(9H,m).

[1094] MSm / z(M+H): 740.

[1095] [Example 67]

[1096] [Chemical Formula 130]

[1097]

[1098] In Examples 65(1) and (2), 7-tetadecanone was used instead of 9-heptadecanone. Otherwise, a colorless oily substance of 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tetadecan-1,13-dimethylbis(3-hexylnonanoic acid) was obtained by the same method as in Examples 65(1) and (2).

[1099] 1H-NMR(CDCl3)δ:4.73-4.62(1H,m),4.17(2H,t,J=6.6Hz),4.04(4H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),2.67-2.45 (10H,m),2.22(4H,d,J=6.6Hz),1.89-1.77(2H,m),1.67-1.17(60H,m),1.08-0.98(9H,m),0.88(12H,t,J=6.6Hz).

[1100] MSm / z(M+H): 896.

[1101] [Example 68]

[1102] [Chemical Formula 131]

[1103]

[1104] In Examples 50(1), (2) and (3), a 1.0 mol / L decyl magnesium bromide-diethyl ether solution was used instead of a 1.0 mol / L dodecyl magnesium bromide-diethyl ether solution. Otherwise, a colorless oily 2-butyloctyl-12-decyl-3,6-diethyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Examples 50(1), (2) and (3).

[1105] 1 H-NMR(CDCl3)δ:4.73-4.60(1H,m),4.17(2H,t,J=6.6Hz),3.97(2H,J=5.4Hz),2.76(2H,t,J=6.0Hz),2.67-2.4 6(10H,m),2.29(2H,t,J=7.8Hz),1.68-1.50(7H,m),1.39-1.20(42H,m),1.07-0.98(9H,m),0.94-0.83(9H,m).

[1106] MSm / z(M+H): 712.

[1107] [Example 69]

[1108] [Chemical Formula 132]

[1109]

[1110] In Example 68, 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-butyloctyl-12-decyl-3-ethyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 68.

[1111] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.10(2H,t,J=6.6Hz),3.97(2H,d,J=6.0Hz),2.99-2.83(1H,m),2.68(2H,t,J=6.6Hz) ,2.62-2.41(8H,m),2.29(2H,t,J=7.2Hz),1.69-1.47(7H,m),1.40-1.19(42H,m),1.10-0.96(12H,m),0.94-0.83(9H,m).

[1112] MSm / z(M+H): 726.

[1113] [Example 70] (1)

[1115] [Chemical Formula 133]

[1116]

[1117] In Example 65(1), 8-pentadecanone was used instead of 9-heptadecone, and 3-heptyldecanoic acid, a colorless oil, was otherwise obtained using the same method as in Example 65(1).

[1118] 1 H-NMR (CDCl3) δ: 2.28 (2H, d, J = 6.6Hz), 1.90-1.79 (1H, m), 1.35-1.19 (24H, m), 0.88 (6H, t, J = 6.6Hz). (2)

[1120] [Chemical Formula 134]

[1121]

[1122] A mixture of 3-heptyldecanoic acid (974 mg), 1,7,13-tetranetriol (2.49 g), triethylamine (3.5 mL), 4-dimethylaminopyridine (51 mg), and dichloromethane (20 mL) was added to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.07 g), and stirred at room temperature for 4 days. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily 7-hydroxytetrane-1,13-dimethylbis(3-heptyldecanoate) (1.03 g) and a colorless oily 7,13-dihydroxytetranyl-3-heptyldecanoate (1.03 g).

[1123] 7-Hydroxytridecane-1,13-dimethylbis(3-heptyldecanoate) 1 H-NMR (CDCl3) δ: 4.05 (4H, t, J = 6.6Hz), 3.61-3.54 (1H, m), 2.22 (4H, d, J = 7.2Hz), 1.88-1.20 (70H, m), 0.88 (12H, t, J = 6.6Hz).

[1124] 7,13-Dihydroxytridecyl-3-heptyldecanoate 1 H-NMR (CDCl3) δ: 4.05 (2H, t, J = 6.6Hz), 3.68-3.55 (3H, m), 2.22 (2H, d, J = 6.6Hz), 1.88-1.77 (1H, m), 1.68-1.20 (44H, m), 0.88 (6H, t, J = 6.6Hz). (3)

[1126] [Chemical Formula 135]

[1127]

[1128] In Examples 20(1) and (2), 7-hydroxytridecane-1,13-dimethylbis(3-heptyldecanoate) was used instead of (6Z,9Z,28Z,31Z)-heptadecane-6,9,28,31-tetraen-19-ol, and 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily substance of 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(3-heptyldecanoate) was obtained by the same method as in Examples 20(1) and (2).

[1129] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.17(2H,t,J=6.6Hz),4.04(4H,t,J=7.2Hz),2.76(2H,t,J=6.0Hz),2.66-2.46 (10H,m),2.22(4H,d,J=7.2Hz),1.91-1.76(2H,m),1.67-1.15(68H,m),1.08-0.97(9H,m),0.88(12H,t,J=6.6Hz).

[1130] MSm / z(M+H): 952.

[1131] [Example 71] (1)

[1133] [Chemical Formula 136]

[1134]

[1135] In Example 36(1), 5-bromo-1-pentanol was used instead of 6-bromo-1-hexanol, and otherwise, 1,6,11-undecanetriol, a white solid, was obtained by the same method as in Example 36(1).

[1136] 1 H-NMR(CDCl3)δ:3.70-3.55(5H,m),1.64-1.24(16H,m). (2)

[1138] [Chemical Formula 137]

[1139]

[1140] In Examples 56(1) and (2), 1,6,11-undecanetriol was used instead of 1,7,13-tetanetriol. Otherwise, the colorless oily product 6-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)undecane-1,11-dimethylbis(2-hexyldecanoate) was obtained by the same method as in Examples 56(1) and (2).

[1141] 1H-NMR(CDCl3)δ:4.72-4.63(1H,m),4.17(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.6Hz) ,2.66-2.47(10H,m),2.37-2.23(2H,m),1.71-1.18(64H,m),1.10-0.98(9H,m),0.88(12H,t,J=7.2Hz).

[1142] MSm / z(M+H): 896.

[1143] [Example 72] (1)

[1145] [Chemical Formula 138]

[1146]

[1147] A mixture of diethyl 3-oxoglutarate (4.0 g) and 20% sodium ethoxide-ethanol solution (6.7 g) was stirred at 80 °C for 20 minutes, followed by the addition of ethyl 8-bromooctanoate (5.0 g) and stirring for 4 hours. Then, 6.7 g of 20% sodium ethoxide-ethanol solution was added to the reaction mixture, and after stirring for 5 minutes, ethyl 8-bromooctanoate (5.0 g) was added and stirred for 3 hours. After cooling the reaction mixture to room temperature, hexane and 10 mL of 20% ammonium chloride aqueous solution were added. The organic layer was separated, and the solvent was removed by distillation under reduced pressure to obtain tetraethyl-9-oxoheptadecano-1,8,10,17-tetracarboxylic acid ester (10.3 g) as the crude product.

[1148] The resulting mixture of tetraethyl 9-oxoheptadecano-1,8,10,17-tetracarboxylate (2.5 g), acetic acid (4.0 mL), and 30% hydrochloric acid aqueous solution (8.0 mL) was stirred at 115 °C for 6 hours. After cooling the reaction mixture to room temperature, the solvent was removed by distillation under reduced pressure, and water and acetone were added. The solid was filtered off, washed with water and acetone, and dried under reduced pressure to give 0.6 g of 10-oxonadecanedioic acid as a white solid.

[1149] 1 H-NMR(DMSO-d6)δ:2.38(4H,t,J=7.2Hz), 2.18(4H,t,J=7.2Hz), 1.54-1.38(8H,m), 1.31-1.18(16H,m).

[1150] A mixture of 10-oxonane sebacic acid (610 mg), 2-butyl-1-octanol (663 mg), triethylamine (1.25 mL), 4-dimethylaminopyridine (217 mg), and dichloromethane (6 mL) was added to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (853 mg), and stirred at room temperature for 2 days. A 10% potassium hydrogen sulfate aqueous solution (12 mL), hexane (6 mL), and ethyl acetate (6 mL) were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily compound, bis(2-butyloctyl)-10-oxonane sebacic acid (612 mg).

[1151] 1 H-NMR(CDCl3)δ: 3.97(4H,d,J=6.0Hz), 2.38(4H,t,J=7.2Hz), 2.30(4H,t,J=7.2Hz), 1.66-1.49(10H,m), 1.36-1.23(48H,m), 0.92-0.83(12H,m).

[1152] Sodium borohydride (35 mg) was added to a mixture of bis(2-butyloctyl)-10-oxonane sebacate (612 mg) and methanol (6 mL) under ice-cold conditions, and the mixture was stirred at the same temperature for 1 hour. Under ice-cold conditions, 10% potassium hydrogen sulfate aqueous solution (6 mL) and hexane (6 mL) were added to the reaction mixture. The organic layer was separated, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily compound, bis(2-butyloctyl)-10-hydroxynonadecanedioic acid (369 mg).

[1153] 1 H-NMR (CDCl3) δ: 3.97 (4H, d, J = 6.0Hz), 3.62-3.52 (1H, m), 2.30 (4H, t, J = 7.2Hz), 1.66-1.53 ​​(10H, m), 1.45-1.20 (52H, m), 0.92-0.83 (12H, m).

[1154] A mixture of bis(2-butyloctyl)10-hydroxynonadecanedioic acid (369 mg), triethylamine (0.30 mL), and tetrahydrofuran (2 mL) was added to a solution of 4-nitrobenzene chloroformate (218 mg), and the mixture was stirred at room temperature for 17 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily bis(2-butyloctyl)10-(((4-nitrophenoxy)carbonyl)oxy)nonadecanedioic acid ester (436 mg).

[1155] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,1.8Hz),7.38(2H,dd,J=7.2Hz,1.8Hz),4.86-4.74(1H,m),3.9 7(4H,d,J=6.0Hz),2.30(4H,t,J=7.2Hz),1.66-1.53(10H,m),1.45-1.20(52H,m),0.92-0.83(12H,m). (2)

[1157] [Chemical Formula 139]

[1158]

[1159] In Example 41(2), bis(2-butyloctyl)10-(((4-nitrophenoxy)carbonyl)oxy)nonadecanedioate was used instead of 7-(((4-nitrophenoxy)carbonyl)oxy)tetane-1,13-dioleate. Otherwise, a colorless oily bis(2-butyloctyl)10-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)nonadecanedioate was obtained by the same method as in Example 41(2).

[1160] 1 H-NMR(CDCl3)δ:4.71-4.62(1H,m),4.17(2H,t,J=6.6Hz),3.96(4H,d,J=6.0Hz),2.76(2H,t,J=6.6Hz),2.64-2.48(10H,m),2. 29(4H,t,J=7.2Hz),1.66-1.50(10H,m),1.36-1.20(52H,m),1.03(3H,t,J=7.2Hz),1.02(6H,t,J=7.2Hz),0.93-0.84(12H,m).

[1161] MSm / z(M+H): 896.

[1162] [Example 73] (1)

[1164] [Chemical Formula 140]

[1165]

[1166] In Example 36(1), 4-bromo-1-butanol was used instead of 6-bromo-1-hexanol, and otherwise, 1,5,9-nonanetriol, a white solid, was obtained by the same method as in Example 36(1).

[1167] 1 H-NMR(CDCl3)δ:3.70-3.55(5H,m),1.64-1.24(12H,m). (2)

[1169] [Chemical Formula 141]

[1170]

[1171] In Examples 56(1) and (2), 1,5,9-nonanetriol was used instead of 1,7,13-tetanetriol. Otherwise, a colorless oily substance, 5-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)nonane-1,9-dimethylbis(2-hexyldecanoate), was obtained by the same method as in Examples 56(1) and (2).

[1172] 1 H-NMR(CDCl3)δ:4.74-4.63(1H,m),4.17(2H,t,J=5.7Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.6Hz) ,2.66-2.48(10H,m),2.36-2.24(2H,m),1.70-1.16(60H,m),1.09-0.98(9H,m),0.88(12H,t,J=6.6Hz).

[1173] MSm / z(M+H): 868.

[1174] [Example 74] (1)

[1176] [Chemical Formula 142]

[1177]

[1178] Decanoic acid (3.0 g) was added dropwise to a 60 wt% sodium hydride tetrahydrofuran (30 mL) suspension under ice-cold conditions, and the mixture was stirred for 30 minutes at the same temperature. At the same temperature, a 1.5 mol / L lithium diisopropylamide-tetrahydrofuran-heptane-ethylbenzene solution (13.9 mL) was added to the reaction mixture, and after stirring for 30 minutes at room temperature, 1-iodooctane (3.8 mL) was added dropwise, and the mixture was stirred at 45 °C for 6 hours.

[1179] Under ice-cold conditions, the reaction mixture was injected into a mixture of 1 mol / L hydrochloric acid aqueous solution and ethyl acetate. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2-octyldecanoic acid (2.62 g) as a yellow oil.

[1180] 1 H-NMR(CDCl3)δ:2.43-2.30(1H,m),1.72-1.20(28H,m),0.88(6H,t,J=6.6Hz). (2)

[1182] [Chemical Formula 143]

[1183]

[1184] In Examples 41(1) and (2), 2-octyldecanoic acid was used instead of oleic acid. Otherwise, a colorless oily substance, 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-octyldecanoate), was obtained by the same method as in Examples 41(1) and (2).

[1185] 1 H-NMR(CDCl3)δ:4.73-4.60(1H,m),4.17(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.0Hz) ,2.66-2.47(10H,m),2.37-2.24(2H,m),1.70-1.16(76H,m),1.11-0.98(9H,m),0.88(12H,t,J=6.6Hz).

[1186] MSm / z(M+H): 980.

[1187] [Example 75]

[1188] [Chemical Formula 144]

[1189]

[1190] In Example 50, a 1.0 mol / L nonylmagnesium bromide-diethyl ether solution was used instead of a 1.0 mol / L dodecyl magnesium bromide-diethyl ether solution. Otherwise, a colorless oily 2-butyloctyl-3,6-diethyl-12-nonyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 50.

[1191] 1 H-NMR (CDCl3) δ: 4.73-4.60 (1H, m), 4.18 (2H, t, J = 6.6Hz), 3.97 (2H, d, J = 5.7Hz), 2.76 (2H, t, J = 6.6Hz), 2.66-2. 47(10H,m),2.30(2H,t,J=7.8Hz),1.69-1.47(7H,m),1.41-1.19(40H,m),1.09-0.97(9H,m),0.94-0.83(9H,m).

[1192] MSm / z(M+H): 698.

[1193] [Example 76]

[1194] [Chemical Formula 145]

[1195]

[1196] In Examples 74(1) and (2), nonanoic acid was used instead of decanoic acid, and 1-iodoheptane was used instead of 1-iodooctane. Otherwise, the colorless oily substance 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-heptylnonanoic acid) was obtained by the same method as in Examples 74(1) and (2).

[1197] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.18(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.6Hz) ,2.66-2.48(10H,m),2.37-2.23(2H,m),1.68-1.16(68H,m),1.08-0.97(9H,m),0.87(12H,t,J=6.6Hz).

[1198] MSm / z(M+H): 924.

[1199] [Example 77]

[1200] [Chemical Formula 146]

[1201]

[1202] In Examples 74(1) and (2), octanoic acid was used instead of decanoic acid, and 1-iodohexane was used instead of 1-iodooctane. Otherwise, the colorless oily product 7-(((2-((2-(diethylamino)ethyl)(ethyl)amino)ethoxy)carbonyl)oxy)tridecane-1,13-dimethylbis(2-hexyloctanoate) was obtained by the same method as in Examples 74(1) and (2).

[1203] 1 H-NMR(CDCl3)δ:4.73-4.60(1H,m),4.17(2H,t,J=6.6Hz), 4.05(4H,t,J=6.6Hz), 2.76(2H,t,J=6.6Hz) ,2.67-2.45(10H,m),2.37-2.24(2H,m),1.72-1.15(60H,m),1.12-0.96(9H,m),0.87(12H,t,J=6.6Hz).

[1204] MSm / z(M+H): 868.

[1205] [Example 78] (1)

[1207] [Chemical Formula 147]

[1208]

[1209] To a mixture of 7,13-dihydroxytridecyl 3-heptyl decanoate (500 mg), decanoic acid (195 mg), triethylamine (0.43 mL), 4-dimethylaminopyridine (38 mg), and dichloromethane (10 mL) synthesized in Examples 70(1) and (2), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg) was added, and the mixture was stirred at room temperature for 18 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 13-(decanoyloxy)-7-hydroxytridecyl 3-heptyl decanoate (469 mg) as a colorless oil.

[1210] 1H-NMR(CDCl3)δ:4.06(4H,t,J=6.6Hz),3.63-3.53(1H,m),2.29(2H,t,J=7.2Hz),2 .22(2H,d,J=7.2Hz),1.88-1.78(1H,m),1.68-1.20(60H,m),0.88(9H,t,J=6.6Hz). (2)

[1212] [Chemical Formula 148]

[1213]

[1214] In Examples 20(1) and (2), 13-(decyloxy)-7-hydroxytridecyl 3-heptyldecanoate was used instead of (6Z,9Z,28Z,31Z)-heptadecane-6,9,28,31-tetraen-19-ol, and 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 12-(6-(decyloxy)hexyl)-3,6-diethyl-10-oxo-9,11-dioxa-3,6-diazo-octadecane-18-yl 3-heptyldecanoate was obtained using the same method as in Examples 20(1) and (2).

[1215] 1 H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.17(2H,t,J=6.0Hz),4.04(4H,t,J=6.6Hz),2.76(2H,t,J=6.6Hz),2.67-2.45(10H,m) ,2.29(2H,t,J=8.1Hz),2.22(2H,d,J=7.2Hz),1.87-1.78(1H,m),1.70-1.18(58H,m),1.11-0.97(9H,m),0.93-0.82(9H,m).

[1216] MSm / z(M+H): 854.

[1217] [Example 79] (1)

[1219] [Chemical Formula 149]

[1220]

[1221] Iodoethane (3.4 mL) was added dropwise to a 30 mL solution of 2-(methylamino)-1-ethanol (3.0 g) in acetonitrile under ice-cold conditions, and the mixture was stirred for 1 hour and 45 minutes at the same temperature, followed by stirring at 60 °C for 3 hours and 10 minutes. Potassium carbonate and water were added to the reaction mixture, and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give 3.4 g of a colorless oily 2-(ethyl(methyl)amino)-1-ethanol.

[1222] MSm / z(M+H): 104.

[1223] Under ice-cold conditions, a tetrahydrofuran solution (20 mL) of methanesulfonic anhydride (7.6 g) was added dropwise to a mixture of 2-(ethyl(methyl)amino)-1-ethanol (3.0 g), 4-dimethylaminopyridine (0.36 g), N,N-diisopropylethylamine (9.9 mL), and tetrahydrofuran (60 mL). The mixture was stirred at 0 °C for 15 minutes, then at room temperature for 3 hours and 45 minutes. 2-(tert-butylamino)-1-ethanol (6.0 g), sodium iodide (0.45 g), and water (1 mL) were added to the reaction mixture, and the mixture was stirred at 75 °C for 30 hours. After cooling the reaction mixture to room temperature, the solvent was removed by distillation under reduced pressure. Water and a 2 mol / L sodium hydroxide aqueous solution were then added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to obtain 0.15 g of 2-(tert-butyl(2-(ethyl(methyl)amino)ethyl)amino)-1-ethanol, a yellow oil.

[1224] MSm / z(M+H):203. (2)

[1226] [Chemical Formula 150]

[1227]

[1228] In Example 20(2), 2-(tert-butyl(2-(ethyl(methyl)amino)ethyl)amino)-1-ethanol was used instead of 2-((2-(dimethylamino)ethyl)(methyl)amino)-1-ethanol. Otherwise, a colorless oily 2-(tert-butyl(2-(ethyl(methyl)amino)ethyl)amino)ethyl((6Z,9Z,28Z,31Z)-heptadec-6,9,28,31-tetraen-19-yl) carbonate was obtained using the same method as in Example 20(2).

[1229] 1H-NMR(CDCl3)δ:5.44-5.25(8H,m),4.73-4.62(1H,m),4.06(2H,t,J=7.5Hz),2.84-2.73(6H,m),2.72-2.59(2H,m),2.50-2. 34(4H,m),2.25(3H,s),2.11-1.97(8H,m),1.65-1.48(4H,m),1.43-1.19(36H,m),1.12-1.01(12H,m),0.89(6H,t,J=6.6Hz).

[1230] MSm / z(M+H): 758.

[1231] [Example 80] (1)

[1233] [Chemical Formula 151]

[1234]

[1235] Under ice-cold conditions, a 1 mol / L solution of hexylmagnesium bromide in tetrahydrofuran (200 mL) was added dropwise to a solution of glutaric anhydride (27.3 g) in tetrahydrofuran (273 mL), and the mixture was stirred at the same temperature for 1 hour. Under ice-cold conditions, a 2 mol / L aqueous hydrochloric acid solution (240 mL) was added to the reaction mixture, followed by the addition of ethyl acetate (270 mL). The organic layer was separated, washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane), and hexane (10 mL) was added. The solid was filtered off, washed with hexane, and dried under reduced pressure to obtain a white solid of 5-oxoundecanoic acid (16.0 g).

[1236] 1 H-NMR (CDCl3) δ: 2.50 (2H, t, J = 7.2Hz), 2.40 (4H, t, J = 7.2Hz), 2.02-1.80 (2H, m), 1.63-1.48 (2H, m), 1.37-1.20 (6H, m), 0.88 (3H, t, J = 6.6Hz).

[1237] A mixture of 5-oxoundecanoic acid (4.0 g), 2-butyl-1-octanol (3.7 g), triethylamine (8.4 mL), 4-dimethylaminopyridine (1.22 g), and dichloromethane (40 mL) was added to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.8 g), and the mixture was stirred at 40 °C for 3 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 7.3 g of 2-butyloctyl-5-oxoundecanoic acid, a colorless oil.

[1238] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.1Hz), 2.47 (2H, t, J = 7.2Hz), 2.39 (2H, t, J = 7.2Hz), 2.33 (2 H,t,J=7.2Hz),1.95-1.83(2H,m),1.66-1.49(3H,m),1.36-1.20(22H,m),0.92-0.82(9H,m).

[1239] Sodium borohydride (1.1 g) was added to a mixture of 2-butyloctyl 5-oxoundecanoic acid (7.3 g), tetrahydrofuran (35 mL), and methanol (35 mL) under ice-cold conditions, and the mixture was stirred for 30 minutes at the same temperature. Under ice-cold conditions, 2.0 mol / L hydrochloric acid aqueous solution (35 mL) and hexane (35 mL) were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance, 2-butyloctyl 5-hydroxyundecanoate (6.3 g).

[1240] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.7Hz), 3.65-3.53 (1H, m), 2.35 (2H, t, J = 7.2Hz), 1.87-1.20 (32H, m), 0.92-0.84 (9H, m).

[1241] A mixture of 2-butyloctyl 5-hydroxyundecanoate (1.62 g), triethylamine (2.38 mL), and tetrahydrofuran (16 mL) was added to a mixture of 4-nitrobenzene chloroformate (1.71 g), and the mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance of 2-butyloctyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoic acid (1.99 g).

[1242] 1 H-NMR(CDCl3)δ:8.28(2H,d,J=9.3Hz),7.39(2H,d,J=9.3Hz),4.88-4.77(1H,m),3.99(2H, d,J=6.0Hz),2.41-2.31(2H,m),1.80-1.48(7H,m),1.44-1.20(24H,m),0.92-0.83(9H,m). (2)

[1244] [Chemical Formula 152]

[1245]

[1246] A mixture of 2-butyloctyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoic acid (500 mg), 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol (527 mg), triethylamine (0.787 mL), and tetrahydrofuran (2.5 mL) was added to 4-dimethylaminopyridine (342 mg), and the mixture was stirred at 60 °C for 10 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give a colorless oily substance, 2-butyloctyl 3,6-diethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester (356 mg).

[1247] 1H-NMR(CDCl3)δ:4.73-4.64(1H,m),4.22-4.12(2H,m),3.97(2H,d,J=5.1Hz),2.76(2H,t,J=6.6Hz),2.64-2.4 9(10H,m),2.32(2H,t,J=6.6Hz),1.73-1.50(7H,m),1.36-1.20(24H,m),1.06-0.99(9H,m),0.92-0.84(9H,m).

[1248] MSm / z(M+H): 586.

[1249] [Example 81]

[1250] [Chemical Formula 153]

[1251]

[1252] In Example 80(2), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Example 80(2).

[1253] 1 H-NMR(CDCl3)δ:4.73-4.64(1H,m),4.15-4.04(2H,m),3.97(2H,d,J=5.4Hz),2.97-2.83(1H,m),2.68(2H,t,6.6Hz),2 .58-2.43(8H,m),2.32(2H,t,J=6.6Hz),1.73-1.50(7H,m),1.36-1.20(24H,m),1.06-0.96(12H,m),0.92-0.84(9H,m).

[1254] MSm / z(M+H): 600.

[1255] [Example 82] (1)

[1257] [Chemical Formula 154]

[1258]

[1259] In Example 80(1), 2-hexyl-1-decyl alcohol was used instead of 2-butyl-1-octanol. Otherwise, 2-hexyldecyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoic acid, a colorless oil, was obtained by the same method as in Example 80(1).

[1260] 1 H-NMR(CDCl3)δ:8.27(2H,dd,J=6.6Hz,1.8Hz),7.38(2H,dd,J=6.6Hz,1.8Hz),4.88-4.78(1H,m),3 .98(2H,d,J=6.0Hz),2.41-2.30(2H,m),1.79-1.53(7H,m),1.42-1.20(32H,m),0.92-0.83(9H,m). (2)

[1262] [Chemical Formula 155]

[1263]

[1264] In Example 80(2), 2-hexyldecyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoic acid was used instead of 2-butyloctyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3,6-diethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Example 80(2).

[1265] 1 H-NMR(CDCl3)δ:4.73-4.64(1H,m),4.23-4.12(2H,m),3.97(2H,d,J=5.7Hz),2.76(2H,t,J=6.6Hz),2.64-2.4 8(10H,m),2.32(2H,t,J=6.6Hz),1.75-1.50(7H,m),1.36-1.20(32H,m),1.06-0.99(9H,m),0.92-0.84(9H,m).

[1266] MSm / z(M+H): 642.

[1267] [Example 83]

[1268] [Chemical Formula 156]

[1269]

[1270] In Example 82(2), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Example 82(2).

[1271] 1 H-NMR(CDCl3)δ:4.73-4.64(1H,m),4.17-4.03(2H,m),3.97(2H,d,J=6.0Hz), 2.97-2.84(1H,m),2.68(2H,t,J=6.6Hz), 2.57-2.42(8H,m),2.32(2H,t,J=6.6Hz),1.73-1.50(7H,m),1.38-1.19(32H,m),1.06-0.96(12H,m),0.92-0.84(9H,m).

[1272] MSm / z(M+H): 656.

[1273] [Example 84] (1)

[1275] [Chemical Formula 157]

[1276]

[1277] A mixture of 10-methoxy-10-oxodecanoic acid (47.6 g), thionyl chloride (47.6 mL), and N,N-dimethylformamide (0.1 mL) was stirred for 1 hour under reflux. The solvent was removed by vacuum distillation to give methyl 10-chloro-10-oxodecanoate (59.7 g), a brown oil.

[1278] 1 H-NMR (CDCl3) δ: 3.67 (3H, s), 2.88 (2H, t, J = 7.2Hz), 2.30 (2H, t, J = 7.2Hz), 1.75-1.57 (4H, m), 1.38-1.25 (8H, m).

[1279] At -78°C, a 1.0 mol / L solution of magnesium hexyl bromide in diethyl ether (440 mL) was added dropwise to a suspension of zinc(II) chloride (30.0 g) in tetrahydrofuran (500 mL). After heating to 0°C, the mixture was stirred at the same temperature for 30 minutes. While ice-cold, tetra(triphenylphosphine)palladium(O) (6.4 g) was added to the reaction mixture, followed by the dropwise addition of methyl 10-chloro-10-oxodecanoate (59.7 g) at the same temperature, and the mixture was stirred at the same temperature for 1 hour. A 1.0 mol / L aqueous hydrochloric acid solution (200 mL) and ethyl acetate (600 mL) were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution (560 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a white solid of methyl 10-oxohexadecanoate (50.6 g).

[1280] 1 H-NMR(CDCl3)δ:3.67(3H,s),2.38(4H,t,J=7.2Hz),2.30(2H,t,7.2Hz),1.65-1.49(6H,m),1.35-1.20(14H,m),0.88(3H,t,J=7.2Hz).

[1281] A mixture of methyl 10-oxohexadecanate (15.0 g) and 2-butyl-1-octanol (14.7 g) was added with tetraisopropyl titanate (1.5 g), and the mixture was stirred at 110 °C for 1 hour. Water (1 mL) was added to the reaction mixture, and after stirring at room temperature for 15 minutes, the mixture was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily product of 2-butyloctyl 10-oxohexadecanate (21.6 g).

[1282] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.6Hz), 2.38 (4H, t, J = 7.6Hz), 2.29 (2H, t, J = 7.6Hz), 1.65-1.50 (7H, m), 1.35-1.20 (30H, m), 0.92-0.83 (9H, m).

[1283] Sodium borohydride (2.8 g) was added to a mixture of 2-butyloctyl 10-oxohexadecanoate (21.6 g), methanol (86 mL), and tetrahydrofuran (86 mL) under ice-cold conditions, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was then injected into a mixture of ice (80 g) and water (80 g), followed by the addition of 1.0 mol / L hydrochloric acid aqueous solution (110 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated sodium chloride aqueous solution (200 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 18.0 g of 2-butyloctyl 10-hydroxyhexadecanoate, a colorless oil.

[1284] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 6.0Hz), 3.61-3.54 (1H, m), 2.30 (2H, t, J = 7.6Hz), 1.65-1.56 (3H, m), 1.48-1.22 (38H, m), 0.92-0.83 (9H, m).

[1285] A mixture of 2-butyloctyl 10-hydroxyhexadecanoate (1.50 g), triethylamine (1.43 mL), and tetrahydrofuran (15 mL) was added to a solution of 4-nitrobenzene chloroformate (1.03 g), and the mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid (2.07 g).

[1286] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.1Hz),7.39(2H,dd,J=7.2Hz,2.1Hz),4.86-4.76( 1H,m),3.97(2H,d,J=5.7Hz),2.30(2H,t,J=7.2Hz),1.74-1.20(41H,m),0.92-0.85(9H,m). (2)

[1288] [Chemical Formula 158]

[1289]

[1290] 4-Dimethylaminopyridine (183 mg) was added to a mixture of 2-butyloctyl-10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid (300 mg), 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol (304 mg), triethylamine (0.211 mL), and tetrahydrofuran (6 mL), and the mixture was stirred at 80 °C for 8 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Purification of the residue by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) yielded a colorless oily substance, 2-butyloctyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazacobala-21-ester (296 mg).

[1291] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.10(2H,t,J=6.6Hz),3.97(2H,d,J=6.0Hz),2.97-2.85(1H,m),2.68(2H,t,J=7.2Hz) ,2.63-2.40(8H,m),2.29(2H,t,J=7.2Hz),1.68-1.47(7H,m),1.40-1.19(34H,m),1.10-0.96(12H,m),0.95-0.79(9H,m).

[1292] MSm / z(M+H): 670.

[1293] [Example 85] (1)

[1295] [Chemical Formula 159]

[1296]

[1297] Potassium carbonate (7.9 g) was added to a mixture of 2,2'-azaalkyldiylbis(-1-ethanol) (2.0 g), 2-bromo-N,N-diethylethyl-1-amine hydrobromide (7.4 g), and ethanol (40 mL), and the mixture was stirred under reflux for 8 hours. The reaction mixture was cooled to room temperature, unwanted substances were filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 2,2'-((2-(diethylamino)ethyl)azaalkyldiyl)bis(-1-ethanol) (2.3 g), a pale yellow oil.

[1298] MSm / z(M+H): 205. (2)

[1300] [Chemical Formula 160]

[1301]

[1302] In Example 84(2), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(-1-ethanol) was used instead of 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 84(2).

[1303] 1 H-NMR(CDCl3)δ:4.75-4.61(1H,m),4.21(2H,t,J=6.6Hz),3.97(2H,d,J=5.7Hz),3.55(2H,t,J=5.1Hz),2.89(2H,t,J=6.6Hz),2.76- 2.65(4H,m),2.64-2.41(6H,m),2.30(2H,t,J=8.1Hz),1.72-1.45(7H,m),1.40-1.20(34H,m),1.13-0.98(6H,m),0.96-0.81(9H,m).

[1304] MSm / z(M+H): 672.

[1305] [Example 86]

[1306] [Chemical Formula 161]

[1307]

[1308] To a mixture of 2-butyloctyl-3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester (250 mg), dodecanoic acid (112 mg), triethylamine (0.31 mL), 4-dimethylaminopyridine (136 mg), and dichloromethane (5 mL) synthesized in Example 85(2), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (142 mg) was added, and the mixture was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. Purification of the residue by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) yielded a colorless oily substance, 2-butyloctyl 6-(2-(dodecanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazacobala-21-ester (177 mg).

[1309] 1 H-NMR(CDCl3)δ:4.72-4.60(1H,m),4.21-4.08(4H,m),3.97(2H,d,J=6.0Hz),2.88-2.75(4H,m),2.73-2.43( 8H,m),2.29(4H,t,J=7.5Hz),1.70-1.46(9H,m),1.39-1.18(50H,m),1.12-0.97(6H,m),0.95-0.81(12H,m).

[1310] MSm / z(M+H): 854.

[1311] [Example 87]

[1312] [Chemical Formula 162]

[1313]

[1314] In Example 86, decanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl 6-(2-(decanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 86.

[1315] 1H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.22-4.07(4H,m),3.97(2H,d,J=6.0Hz),2.89-2.77(4H,m),2.74-2.43( 8H,m),2.30(4H,t,J=8.1Hz),1.68-1.46(9H,m),1.40-1.18(46H,m),1.13-0.97(6H,m),0.95-0.80(12H,m).

[1316] MSm / z(M+H): 826.

[1317] [Example 88]

[1318] [Chemical Formula 163]

[1319]

[1320] In Example 86, octanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-(octanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 86.

[1321] 1 H-NMR(CDCl3)δ:4.71-4.62(1H,m),4.20-4.08(4H,m),3.97(2H,d,J=5.6Hz),2.89-2.77(4H,m),2.73-2.42( 8H,m),2.29(4H,t,J=7.6Hz),1.68-1.48(9H,m),1.39-1.18(42H,m),1.10-0.98(6H,m),0.94-0.81(12H,m).

[1322] MSm / z(M+H): 798.

[1323] [Example 89] (1)

[1325] [Chemical Formula 164]

[1326]

[1327] In Example 84(1), 2-hexyl-1-decyl alcohol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily product of 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate was obtained by the same method as in Example 84(1).

[1328] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.4Hz),7.39(2H,dd,J=7.2Hz,2.4Hz),4.85-4.77( 1H,m),3.97(2H,d,J=5.6Hz),2.30(2H,t,J=7.6Hz),1.72-1.20(49H,m),0.92-0.85(9H,m). (2)

[1330] [Chemical Formula 165]

[1331]

[1332] In Example 84(2), 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate, and otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaeicosane-21-ester was obtained by the same method as in Example 84(2).

[1333] 1 H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.10(2H,t,J=6.6Hz),3.97(2H,d,J=5.7Hz),2.97-2.87(1H,m),2.68(2H,t,J=6.6Hz) ,2.62-2.40(8H,m),2.29(2H,t,J=7.2Hz),1.69-1.49(7H,m),1.40-1.19(42H,m),1.12-0.95(12H,m),0.93-0.82(9H,m).

[1334] MSm / z(M+H): 726.

[1335] [Example 90] (1)

[1337] [Chemical Formula 166]

[1338]

[1339] In Example 85(1), 3-chloro-N,N-diethylpropyl-1-amine was used instead of 2-bromo-N,N-diethylethyl-1-amine hydrobromide. Otherwise, a colorless oily substance of 2,2'-((3-(diethylamino)propyl)azanidinediyl)bis(-1-ethanol) was obtained by the same method as in Example 85(1).

[1340] MSm / z(M+H): 219. (2)

[1342] [Chemical Formula 167]

[1343]

[1344] In Example 85(2), 2,2'-((3-(diethylamino)propyl)azanidinediyl)bis(-1-ethanol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanidinediyl)bis(-1-ethanol), and otherwise, a colorless oily 2-butyloctyl-3-ethyl-13-hexyl-7-(2-hydroxyethyl)-11-oxo-10,12-dioxa-3,7-diazadocosahexadecane-22-ester was obtained using the same method as in Example 85(2).

[1345] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.17(2H,t,J=6.0Hz),3.97(2H,d,J=6.0Hz),3.58(2H,t,J=5.4Hz),2.76(2H,t,J=5.7H z),2.67-2.40(10H,m),2.30(2H,t,J=8.1Hz),1.76-1.46(9H,m),1.38-1.19(34H,m),1.12-0.98(6H,m),0.94-0.82(9H,m).

[1346] MSm / z(M+H): 686.

[1347] [Example 91]

[1348] [Chemical Formula 168]

[1349]

[1350] In Example 86, oleic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-(oleoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 86.

[1351] 1 H-NMR(CDCl3)δ:5.38-5.28(2H,m),4.72-4.63(1H,m),4.21-4.06(4H,m),3.97(2H,d,J=6.0Hz),2.90-2.76(4H,m),2.74-2.44( 8H,m),2.29(4H,t,J=7.8Hz),2.07-1.93(4H,m),1.68-1.45(9H,m),1.38-1.17(54H,m),1.11-0.96(6H,m),0.94-0.81(12H,m).

[1352] MSm / z(M+H): 936.

[1353] [Example 92]

[1354] [Chemical Formula 169]

[1355]

[1356] In Examples 84(1) and (2), 8-methoxy-8-oxooctanoic acid was used instead of 10-methoxy-10-oxodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazanonadecan-19-ester was obtained by the same method as in Examples 84(1) and (2).

[1357] 1 H-NMR(CDCl3)δ:4.72-4.59(1H,m),4.17-4.04(2H,m),3.97(2H,d,J=5.4Hz), 2.97-2.84(1H,m),2.69(2H,t,J=6.6Hz), 2.64-2.42(8H,m),2.29(2H,t,J=7.2Hz),1.68-1.46(7H,m),1.40-1.18(30H,m),1.14-0.94(12H,m),0.93-0.82(9H,m).

[1358] MSm / z(M+H): 642.

[1359] [Example 93]

[1360] [Chemical Formula 170]

[1361]

[1362] In Example 86, 2-Butyloctyl 3-ethyl-13-hexyl-7-(2-hydroxyethyl)-11-oxo-10,12-dioxa-3,7-diazadocosapentadecane-22-ester was used instead of 2-Butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazadocosapentadecane-21-ester, and oleic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-Butyloctyl 3-ethyl-13-hexyl-7-(2-(oleoyloxy)ethyl)-11-oxo-10,12-dioxa-3,7-diazadocosapentadecane-22-ester was obtained using the same method as in Example 86.

[1363] 1 H-NMR(CDCl3)δ:5.42-5.27(2H,m),4.72-4.59(1H,m),4.21-4.07(4H,m),3.97(2H,d,J=6.0Hz),2.86-2.71(4H,m),2.65-2.35( 8H,m),2.29(4H,t,J=7.2H),2.07-1.94(4H,m),1.70-1.48(11H,m),1.41-1.19(54H,m),1.11-0.97(6H,m),0.96-0.82(12H,m).

[1364] MSm / z(M+H): 950.

[1365] [Example 94]

[1366] [Chemical Formula 171]

[1367]

[1368] In Example 92, 2-hexyl-1-decyl alcohol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazanonadecan-19-ester was obtained using the same method as in Example 92.

[1369] 1H-NMR(CDCl3)δ:4.71-4.62(1H,m),4.16-4.04(2H,m),3.96(2H,d,J=6.0Hz), 2.97-2.85(1H,m),2.68(2H,t,J=6.6Hz), 2.64-2.41(8H,m),2.29(2H,t,J=7.5Hz),1.70-1.47(7H,m),1.41-1.19(38H,m),1.11-0.95(12H,m),0.93-0.83(9H,m).

[1370] MSm / z(M+H): 698.

[1371] [Example 95]

[1372] [Chemical Formula 172]

[1373]

[1374] In Examples 84(1) and (2), 6-methoxy-6-oxohexanoic acid was used instead of 10-methoxy-10-oxodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaheptadecane-17-ester was obtained by the same method as in Examples 84(1) and (2).

[1375] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.16-4.04(2H,m),3.96(2H,d,J=5.7Hz), 2.97-2.85(1H,m),2.68(2H,t,J=6.6Hz), 2.63-2.42(8H,m),2.30(2H,t,J=8.1Hz),1.69-1.49(7H,m),1.44-1.20(26H,m),1.12-0.95(12H,m),0.94-0.82(9H,m).

[1376] MSm / z(M+H): 614.

[1377] [Example 96]

[1378] [Chemical Formula 173]

[1379]

[1380] In Example 95, 2-hexyl-1-decyl alcohol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily substance of 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaheptadecane-17-ester was obtained using the same method as in Example 95.

[1381] 1 H-NMR(CDCl3)δ:4.73-4.62(1H,m),4.17-4.04(2H,m),3.96(2H,d,J=5.7Hz), 2.98-2.83(1H,m),2.68(2H,t,J=6.6Hz), 2.62-2.41(8H,m),2.30(2H,t,J=7.8Hz),1.69-1.49(7H,m),1.42-1.18(34H,m),1.12-0.96(12H,m),0.93-0.81(9H,m).

[1382] MSm / z(M+H): 670.

[1383] [Example 97]

[1384] [Chemical Formula 174]

[1385]

[1386] In Example 85, 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate, and otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 85.

[1387] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.20(2H,t,J=6.6Hz),3.96(2H,d,J=5.4Hz),3.54(2H,t,J=5.4Hz),2.89(2H,t,J=6.0Hz),2.76-2 .63(4H,m),2.62-2.42(6H,m),2.29(2H,t,J=7.5Hz),1.72-1.46(7H,m),1.39-1.18(42H,m),1.04(6H,t,J=7.2Hz),0.94-0.80(9H,m).

[1388] MSm / z(M+H): 728.

[1389] [Example 98]

[1390] [Chemical Formula 175]

[1391]

[1392] In Example 86, 2-hexyldecyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester, and decanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 6-(2-(decanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was obtained using the same method as in Example 86.

[1393] 1 H-NMR(CDCl3)δ:4.72-4.63(1H,m),4.22-4.08(4H,m),3.96(2H,d,J=5.4Hz),2.88-2.76(4H,m),2.75-2.43(8 H,m),2.29(4H,t,J=7.2Hz),1.68-1.50(9H,m),1.39-1.16(54H,m),1.03(6H,t,J=6.6Hz),0.95-0.82(12H,m).

[1394] MSm / z(M+H): 882.

[1395] [Example 99]

[1396] [Chemical Formula 176]

[1397]

[1398] In Example 98, octanoic acid was used instead of decanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-(2-(octanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 98.

[1399] 1H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.21-4.07(4H,m),3.96(2H,d,J=5.1Hz),2.90-2.76(4H,m),2.76-2.42( 8H,m),2.29(4H,t,J=7.8Hz),1.68-1.47(9H,m),1.39-1.19(50H,m),1.12-0.96(6H,m),0.95-0.82(12H,m).

[1400] MSm / z(M+H): 854.

[1401] [Example 100]

[1402] [Chemical Formula 177]

[1403]

[1404] In Example 98, hexanoic acid was used instead of decanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-6-(2-(hexanoyloxy)ethyl)-12-hexyl-10-oxo-9,11-dioxa-3,6-diazaeicosane-21-ester was obtained using the same method as in Example 98.

[1405] 1 H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.21-4.07(4H,m),3.96(2H,d,J=5.7Hz),2.90-2.77(4H,m),2.73-2.41( 8H,m),2.29(4H,t,J=7.2Hz),1.70-1.46(9H,m),1.42-1.18(46H,m),1.13-0.97(6H,m),0.95-0.81(12H,m).

[1406] MSm / z(M+H): 826.

[1407] [Example 101]

[1408] [Chemical Formula 178]

[1409]

[1410] In Example 80(2), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(1-ethanol) was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Example 80(2).

[1411] 1 H-NMR(CDCl3)δ:4.75-4.64(1H,m),4.25-4.15(2H,m),3.97(2H,d,J=6.0Hz),3.54(2H,t,J=5.4Hz),2.89(2H,t,J=6.6Hz),2.75-2.6 3(4H,m),2.60-2.42(6H,m),2.33(2H,t,J=6.6Hz),1.73-1.50(7H,m),1.39-1.20(24H,m),1.03(6H,t,J=7.2Hz),0.95-0.81(9H,m).

[1412] MSm / z(M+H): 602.

[1413] [Example 102]

[1414] [Chemical Formula 179]

[1415]

[1416] In Example 85(2), 2-hexyldecyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoic acid was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Example 85(2).

[1417] 1H-NMR(CDCl3)δ:4.75-4.63(1H,m)4.25-4.14(2H,m),3.97(2H,d,J=6.0Hz),3.54(2H,t,J=4.8Hz),2.89(2H,t,J=6.0Hz),2.76-2.6 3(4H,m),2.60-2.43(6H,m),2.33(2H,t,J=7.5Hz),1.73-1.48(7H,m),1.40-1.17(32H,m),1.03(6H,t,J=7.2Hz),0.96-0.78(9H,m).

[1418] MSm / z(M+H): 658.

[1419] [Example 103]

[1420] [Chemical Formula 180]

[1421]

[1422] In Example 86, nonanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-(nonanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 86.

[1423] 1 H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.21-4.09(4H,m),3.97(2H,d,J=6.0Hz),2.88-2.47(4H,m),2.72-2.62(2H,m),2.5 8-2.46(6H,m),2.29(4H,t,J=7.8Hz),1.69-1.50(9H,m),1.40-1.19(44H,m),1.01(6H,t,J=7.2Hz),0.95-0.82(12H,m).

[1424] MSm / z(M+H): 812.

[1425] [Example 104]

[1426] [Chemical Formula 181]

[1427]

[1428] In Example 86, heptanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-6-(2-(heptayloxy)ethyl)-12-hexyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 86.

[1429] 1 H-NMR(CDCl3)δ:4.72-4.60(1H,m),4.20-4.06(4H,m),3.97(2H,d,J=5.1Hz),2.89-2.76(4H,m),2.71-2.62(2H,m),2.5 8-2.46(6H,m),2.30(4H,t,J=8.1Hz),1.68-1.47(9H,m),1.39-1.19(40H,m),1.02(6H,t,J=6.6Hz),0.95-0.83(12H,m).

[1430] MSm / z(M+H): 784.

[1431] [Example 105]

[1432] [Chemical Formula 182]

[1433]

[1434] In Example 86, hexanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-6-(2-(hexanoyloxy)ethyl)-12-hexyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 86.

[1435] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.21-4.08(4H,m),3.97(2H,d,J=5.4Hz),2.89-2.76(4H,m),2.72-2.62(2H,m),2.5 9-2.45(6H,m),2.30(4H,t,J=8.1Hz),1.71-1.47(9H,m),1.40-1.19(38H,m),1.02(6H,t,J=6.6Hz),0.94-0.82(12H,m).

[1436] MSm / z(M+H): 770.

[1437] [Example 106]

[1438] [Chemical Formula 183]

[1439]

[1440] In Example 86, 2-Butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-21-ester. Otherwise, a colorless oily 2-butyloctyl 6-(2-(dodecanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 86.

[1441] 1 H-NMR(CDCl3)δ:4.74-4.64(1H,m),4.21-4.07(4H,m),3.97(2H,d,J=6.0Hz),2.89-2.76(4H,m),2.72-2.63(2H,m),2. 58-2.46(6H,m),2.37-2.25(4H,m),1.74-1.50(9H,m),1.39-1.19(40H,m),1.02(6H,t,J=6.6Hz),0.95-0.83(12H,m).

[1442] MSm / z(M+H): 784.

[1443] [Example 107]

[1444] [Chemical Formula 184]

[1445]

[1446] In Example 106, decanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl 6-(2-(decanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 106.

[1447] 1H-NMR(CDCl3)δ:4.74-4.64(1H,m),4.22-4.07(4H,m),3.97(2H,d,J=6.0Hz),2.88-2.75(4H,m),2.72-2.62(2H,m),2. 58-2.46(6H,m),2.37-2.25(4H,m),1.74-1.52(9H,m),1.40-1.19(36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[1448] MSm / z(M+H): 756.

[1449] [Example 108]

[1450] [Chemical Formula 185]

[1451]

[1452] In Example 106, octanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-(octanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 106.

[1453] 1 H-NMR(CDCl3)δ:4.74-4.64(1H,m),4.21-4.08(4H,m),3.97(2H,d,J=6.0Hz),2.88-2.76(4H,m),2.72-2.62(2H,m),2. 58-2.46(6H,m),2.37-2.27(4H,m),1.74-1.50(9H,m),1.40-1.19(32H,m),1.02(6H,t,J=7.2Hz),0.95-0.83(12H,m).

[1454] MSm / z(M+H): 728.

[1455] [Example 109]

[1456] [Chemical Formula 186]

[1457]

[1458] In Example 86, 2-hexyldecyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-21-ester. Otherwise, a colorless oily 2-hexyldecyl 6-(2-(dodecanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 86.

[1459] 1 H-NMR(CDCl3)δ:4.74-4.64(1H,m),4.21-4.06(4H,m),3.97(2H,d,J=5.4Hz),2.88-2.76(4H,m),2.71-2.63(2H,m),2. 57-2.46(6H,m),2.36-2.25(4H,m),1.72-1.52(9H,m),1.39-1.20(48H,m),1.02(6H,t,J=7.5Hz),0.95-0.81(12H,m).

[1460] MSm / z(M+H): 840.

[1461] [Example 110]

[1462] [Chemical Formula 187]

[1463]

[1464] In Example 109, decanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 6-(2-(decanoyloxy)ethyl)-3-ethyl-12-hexyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 109.

[1465] 1 H-NMR(CDCl3)δ:4.75-4.63(1H,m),4.21-4.07(4H,m),3.97(2H,d,J=5.7Hz),2.88-2.76(4H,m),2.71-2.62(2H,m),2. 58-2.45(6H,m),2.36-2.26(4H,m),1.73-1.52(9H,m),1.38-1.19(44H,m),1.02(6H,t,J=7.2Hz),0.95-0.81(12H,m).

[1466] MSm / z(M+H): 812.

[1467] [Example 111]

[1468] [Chemical Formula 188]

[1469]

[1470] In Example 109, octanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-hexyldecyl-3-ethyl-12-hexyl-6-(2-(octanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 109.

[1471] 1 H-NMR(CDCl3)δ:4.75-4.63(1H,m),4.22-4.07(4H,m),3.96(2H,d,J=5.1Hz),2.88-2.76(4H,m),2.71-2.63(2H,m),2. 58-2.45(6H,m),2.37-2.24(4H,m),1.74-1.52(9H,m),1.39-1.19(40H,m),1.02(6H,t,J=6.6Hz),0.96-0.83(12H,m).

[1472] MSm / z(M+H): 784.

[1473] [Example 112]

[1474] [Chemical Formula 189]

[1475]

[1476] In Examples 80(1) and (2), 2-octyl-1-dodecanool was used instead of 2-butyl-1-octanol, and 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-octyldodecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Examples 80(1) and (2).

[1477] 1H-NMR(CDCl3)δ:4.75-4.63(1H,m),4.18-4.02(2H,m),3.96(2H,d,J=6.0Hz),2.97-2.83(1H,m),2.68(2H,t,J=7.2Hz), 2.60-2.41(8H,m),2.32(2H,t,J=6.6Hz),1.74-1.50(7H,m),1.39-1.16(40H,m),1.09-0.95(12H,m),0.93-0.80(9H,m).

[1478] MSm / z(M+H): 712.

[1479] [Example 113]

[1480] [Chemical Formula 190]

[1481]

[1482] In Examples 80(1) and (2), 2-decyltetra-1-decyl alcohol was used instead of 2-butyl-1-octanol, and 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily 2-decyltetradecyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Examples 80(1) and (2).

[1483] 1 H-NMR(CDCl3)δ:4.75-4.63(1H,m),4.17-4.02(2H,m),3.96(2H,d,J=5.4Hz), 2.97-2.85(1H,m),2.68(2H,t,J=6.6Hz), 2.60-2.42(8H,m),2.32(2H,t,J=7.2Hz),1.74-1.49(7H,m),1.39-1.17(48H,m),1.09-0.95(12H,m),0.94-0.81(9H,m).

[1484] MSm / z(M+H): 768.

[1485] [Example 114]

[1486] [Chemical Formula 191]

[1487]

[1488] In Examples 84(1) and (2), 4-ethoxy-4-oxobutyric acid was used instead of 10-methoxy-10-oxodecanoic acid, and 2-hexyl-1-decanol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazapentadecan-15-ester was obtained by the same method as in Examples 84(1) and (2).

[1489] 1 H-NMR(CDCl3)δ:4.77-4.67(1H,m),4.18-4.04(2H,m),3.97(2H,d,J=5.4Hz),2.97-2.84(1H,m),2.68(2H,t,J=7.5Hz) ,2.61-2.30(10H,m),2.02-1.78(2H,m),1.70-1.48(3H,m),1.41-1.17(32H,m),1.11-0.95(12H,m),0.94-0.81(9H,m).

[1490] MSm / z(M+H): 642.

[1491] [Example 115]

[1492] [Chemical Formula 192]

[1493]

[1494] In Examples 80(1) and (2), (Z)-octadec-9-en-1-ol was used instead of 2-butyl-1-octanol, and 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol was used instead of 2-((2-(diethylamino)ethyl)(ethyl)amino)-1-ethanol. Otherwise, a colorless oily (Z)-octadec-9-en-1-yl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Examples 80(1) and (2).

[1495] 1H-NMR(CDCl3)δ:5.41-5.26(2H,m),4.74-4.64(1H,m),4.15-4.01(4H,m),2.97-2.85(1H,m),2.68(2H,t,J=6.6Hz),2.60-2.42( 8H,m),2.31(2H,t,J=7.2Hz),2.08-1.94(4H,m),1.74-1.50(10H,m),1.41-1.19(28H,m),1.07-0.95(12H,m),0.92-0.82(6H,m).

[1496] MSm / z(M+H): 682.

[1497] [Example 116]

[1498] [Chemical Formula 193]

[1499]

[1500] In Examples 84(1) and (2), 7-ethoxy-7-oxoheptanoic acid was used instead of 10-methoxy-10-oxodecanoic acid, and 2-hexyl-1-decanol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazo-octadecane-18-ester was obtained by the same method as in Examples 84(1) and (2).

[1501] 1 H-NMR(CDCl3)δ:4.72-4.62(1H,m),4.17-4.03(2H,m),3.96(2H,d,J=6.0Hz), 2.97-2.85(1H,m),2.68(2H,t,J=7.5Hz), 2.60-2.41(8H,m),2.29(2H,t,J=7.8Hz),1.68-1.48(7H,m),1.41-1.18(36H,m),1.08-0.95(12H,m),0.93-0.81(9H,m).

[1502] MSm / z(M+H): 684.

[1503] [Example 117]

[1504] [Chemical Formula 194]

[1505]

[1506] In Examples 84(1) and (2), 9-methoxy-9-oxonanoic acid was used instead of 10-methoxy-10-oxodecanoic acid, and 2-hexyl-1-decanol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaeicosane-20-ester was obtained by the same method as in Examples 84(1) and (2).

[1507] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.15-4.03(2H,m),3.96(2H,d,J=5.1Hz), 2.98-2.84(1H,m),2.68(2H,t,J=6.6Hz), 2.60-2.42(8H,m),2.29(2H,t,J=7.2Hz),1.68-1.47(7H,m),1.40-1.19(40H,m),1.08-0.95(12H,m),0.93-0.81(9H,m).

[1508] MSm / z(M+H): 712.

[1509] [Example 118]

[1510] [Chemical Formula 195]

[1511]

[1512] In Example 98, oleic acid was used instead of decanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-12-hexyl-6-(2-(oleoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 98.

[1513] 1 H-NMR(CDCl3)δ:5.38-5.28(2H,m),4.71-4.61(1H,m),4.21-4.08(4H,m),3.96(2H,d,J=6.0Hz),2.87-2.76(4H,m),2.71-2.63(2H,m),2.5 7-2.45(6H,m),2.29(4H,t,J=7.2Hz),2.06-1.94(4H,m),1.67-1.49(9H,m),1.39-1.18(62H,m),1.02(6H,t,J=7.2Hz),0.95-0.82(12H,m).

[1514] MSm / z(M+H): 992.

[1515] [Example 119]

[1516] [Chemical Formula 196]

[1517]

[1518] In Example 106, oleic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-12-hexyl-6-(2-(oleoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 106.

[1519] 1 H-NMR(CDCl3)δ:5.40-5.28(2H,m),4.74-4.63(1H,m),4.22-4.07(4H,m),3.97(2H,d,J=6.0Hz),2.88-2.76(4H,m),2.73-2.62(2H,m),2. 59-2.45(6H,m),2.37-2.25(4H,m),2.08-1.94(4H,m),1.73-1.50(9H,m),1.41-1.18(44H,m),1.02(6H,t,J=6.6Hz),0.96-0.82(12H,m).

[1520] MSm / z(M+H): 866.

[1521] [Example 120]

[1522] [Chemical Formula 197]

[1523]

[1524] In Example 109, oleic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-hexyldecyl-3-ethyl-12-hexyl-6-(2-(oleoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained using the same method as in Example 109.

[1525] 1H-NMR(CDCl3)δ:5.40-5.28(2H,m),4.73-4.64(1H,m),4.21-4.07(4H,m),3.96(2H,d,J=5.1Hz),2.88-2.76(4H,m),2.72-2.62(2H,m),2. 58-2.45(6H,m),2.37-2.24(4H,m),2.07-1.94(4H,m),1.73-1.51(9H,m),1.39-1.19(52H,m),1.02(6H,t,J=6.6Hz),0.94-0.81(12H,m).

[1526] MSm / z(M+H): 922.

[1527] [Example 121]

[1528] [Chemical Formula 198]

[1529]

[1530] In Examples 84(1) and (2), 2-octyl-1-dodecanool was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-octyldodecyl 3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained by the same method as in Examples 84(1) and (2).

[1531] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.15-4.06(2H,m),3.96(2H,d,J=6.0Hz), 2.97-2.84(1H,m),2.68(2H,t,J=6.6Hz), 2.59-2.42(8H,m),2.29(2H,t,J=8.1Hz),1.68-1.48(7H,m),1.38-1.19(50H,m),1.09-0.96(12H,m),0.93-0.82(9H,m).

[1532] MSm / z(M+H): 782.

[1533] [Example 122] (1)

[1535] [Chemical Formula 199]

[1536]

[1537] Acryloyl chloride (0.45 mL) was added to a mixture of 1-heptanol (0.86 mL), triethylamine (1.55 mL), and tetrahydrofuran (5.00 mL) under ice-cold conditions, and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give heptyl acrylate (0.57 g), a colorless oil.

[1538] Triethylamine (1.24 mL) was added to a mixture of the obtained heptyl acrylate (0.57 g), 2-((2-(diethylamino)ethyl)amino)-1-ethanol dihydrochloride (0.52 g), and tetrahydrofuran (10 mL), and the mixture was stirred under reflux for 8 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give a colorless oily product, heptyl 3-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)propionate (0.21 g).

[1539] MSm / z(M+H): 331. (2)

[1541] [Chemical Formula 200]

[1542]

[1543] In Example 84(2), 3-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)heptaester was used instead of 2-((2-(diethylamino)ethyl)(isopropyl)amino)-1-ethanol. Otherwise, a colorless oily 2-butyloctyl-3-ethyl-6-(3-(heptoxy)-3-oxopropyl)-12-hexyl-10-oxo-9,11-dioxa-3,6-diazaeicosane-21-ester was obtained by the same method as in Example 84(2).

[1544] 1H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.20-4.11(2H,m),4.06(2H,t,J=6.6Hz), 3.96(2H,d,J=6.0Hz), 2.87(2H,t,J=6.6Hz), 2.77(2H,d, J=6.0Hz),2.64-2.41(10H,m),2.29(2H,t,J=7.2Hz),1.66-1.50(9H,m),1.37-1.22(42H,m),1.02(6H,t,J=6.6Hz),0.92-0.84(12H,m).

[1545] MSm / z(M+H): 798.

[1546] [Example 123] (1)

[1548] [Chemical Formula 201]

[1549]

[1550] Under ice-cold conditions, 18.8 mL of ethyl 2-(diethoxyphosphoryl)ethyl acetate was added dropwise to a suspension of 3.3 g of 60 wt% sodium hydride in 80 mL of tetrahydrofuran, and the mixture was stirred at the same temperature for 30 minutes. 2.0 g of 6-undecone was added to the reaction mixture, and the mixture was stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature and then injected into ice water before the addition of ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2.8 g of ethyl 3-pentyloctyl-2-enoate, a colorless oil.

[1551] 1 H-NMR (CDCl3) δ: 5.61 (1H, s), 4.14 (2H, q, J = 6.6Hz), 2.58 (2H, t, J = 7.2Hz), 2.12 (2H, t, J = 7.2Hz), 1.50-1.20 (15H, m), 0.89 (6H, t, J = 6.6Hz).

[1552] Ammonium formate (4.4 g) was added to a mixture of ethyl 3-pentyloctyl-2-enoate (2.8 g), 10% palladium-carbon (0.84 g), and methanol (56 mL), and the mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature, and the insoluble matter was removed by filtration with diatomaceous earth. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give ethyl 3-pentyloctylate (2.8 g) as a colorless oil.

[1553] 1 H-NMR (CDCl3) δ: 4.12 (2H, q, J = 7.2Hz), 2.22 (2H, t, J = 6.6Hz), 2.05-2.04 (1H, m), 1.34-1.20 (19H, m), 0.88 (6H, t, J = 6.6Hz).

[1554] Under ice-cold conditions, a solution of 2.8 g of ethyl 3-pentyl octanoate in 10 mL of tetrahydrofuran was added dropwise to a mixture of 9.3 mL of 2.5 mol / L lithium aluminum hydride-tetrahydrofuran solution and 50 mL of tetrahydrofuran. The mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and after being injected into ice water under ice-cold conditions, the insoluble matter was filtered off with diatomaceous earth. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance, 3-pentyl-1-octanol (2.2 g).

[1555] 1 H-NMR(CDCl3)δ:3.71-3.62(2H,m),1.57-1.49(2H,m),1.35-1.20(17H,m),0.88(6H,t,J=6.6Hz). (2)

[1557] [Chemical formula 202]

[1558]

[1559] In Example 84(1), 3-pentyl-1-octanol was used instead of 2-butyl-1-octanol, and otherwise, a colorless oily substance of 3-pentyloctyl-10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid was obtained by the same method as in Example 84(1).

[1560] 1 H-NMR(CDCl3)δ:8.31-8.25(2H,m),7.41-7.36(2H,m),4.86-4.77(1H,m),3.97 (2H,d,J=5.4Hz),2.30(2H,t,J=7.5Hz),1.72-1.20(43H,m),0.92-0.85(9H,m). (3)

[1562] [Chemical formula 203]

[1563]

[1564] In Example 85(2), 3-pentyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid. Otherwise, a colorless oily 3-pentyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 85(2).

[1565] 1 H-NMR(CDCl3)δ:4.74-4.06(1H,m),4.20(2H,t,J=6.0Hz),4.08(2H,t,J=6.6Hz),3.54(2H,t,J=4.5Hz),2.88(2H,,t,J=5.7Hz),2.75-2 .63(4H,m),2.60-2.41(6H,m),2.28(2H,t,J=7.8Hz),1.72-1.47(8H,m),1.44-1.14(35H,m),1.03(6H,t,J=7.2Hz),0.94-0.81(9H,m).

[1566] MSm / z(M+H): 686.

[1567] [Example 124] (1)

[1569] [Chemical Formula 204]

[1570]

[1571] In Example 74(1), undecanoic acid was used instead of decanoic acid, and 1-iodononane was used instead of 1-iodooctane. Otherwise, 2-nonylundecanoic acid, a colorless oil, was obtained by the same method as in Example 74(1).

[1572] 1 H-NMR(CDCl3)δ:2.29-2.41(1H,m),1.68-1.20(32H,m),0.88(6H,t,J=6.6Hz). (2)

[1574] [Chemical Formula 205]

[1575]

[1576] Under ice-cold conditions, a tetrahydrofuran solution of 2-nonylundecanoic acid (3.0 g) in 10 mL was added dropwise to a mixture of 2.5 mol / L lithium aluminum hydride-tetrahydrofuran solution (7.6 mL) and tetrahydrofuran (60 mL). The mixture was stirred at the same temperature for 30 minutes, then stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction mixture, and after being injected into ice water under ice-cold conditions, the insoluble matter was filtered off with diatomaceous earth. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily substance, 2-nonyl-1-undecanoic acid (2.8 g).

[1577] 1 H-NMR(CDCl3)δ:3.57-3.51(2H,m),1.50-1.20(33H,m),0.88(6H,t,J=6.6Hz). (3)

[1579] [Chemical Formula 206]

[1580]

[1581] In Examples 84(1) and (2), 2-nonyl-1-undecaneol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-nonylundecyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester was obtained by the same method as in Examples 84(1) and (2).

[1582] 1 H-NMR(CDCl3)δ:4.76-4.62(1H,m),4.18-4.02(2H,m),3.96(2H,d,J=5.7Hz),2.97-2.84(1H,m),2.68(2H,t,J=7.2Hz) ,2.60-2.42(8H,m),2.36-2.27(2H,m),1.76-1.49(7H,m),1.39-1.19(40H,m),1.09-0.94(12H,m),0.93-0.83(9H,m).

[1583] MSm / z(M+H): 712.

[1584] [Example 125]

[1585] [Chemical Formula 207]

[1586]

[1587] In Example 86, 3-pentyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester, and octanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 3-pentyloctyl 3-ethyl-12-hexyl-6-(2-(octanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was obtained using the same method as in Example 86.

[1588] 1 H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.21-4.02(6H,m),2.88-2.75(4H,m),2.71-2.62(2H,m),2.58-2.45(6H ,m),2.34-2.22(4H,m),1.68-1.48(10H,m),1.44-1.17(43H,m),1.02(6H,t,J=6.6Hz),0.94-0.81(12H,m).

[1589] MSm / z(M+H): 812.

[1590] [Example 126]

[1591] [Chemical Formula 208]

[1592]

[1593] In Example 86, 3-pentyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester, and nonanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 3-pentyloctyl 3-ethyl-12-hexyl-6-(2-(nonanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was obtained using the same method as in Example 86.

[1594] 1H-NMR(CDCl3)δ:4.73-4.59(1H,m),4.23-4.01(6H,m),2.90-2.76(4H,m),2.72-2.62(2H,m),2.58-2.45(6H ,m),2.35-2.22(4H,m),1.69-1.47(10H,m),1.44-1.18(45H,m),1.02(6H,t,J=7.5Hz),0.96-0.80(12H,m).

[1595] MSm / z(M+H): 826.

[1596] [Example 127] (1)

[1598] [Chemical Formula 209]

[1599]

[1600] In Example 84(1), a 1.0 mol / L pentyl magnesium bromide-tetrahydrofuran solution was used instead of a 1.0 mol / L hexyl magnesium bromide-diethyl ether solution, and 2-hexyl-1-decanol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily substance of 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)pentadecanoic acid was obtained by the same method as in Example 84(1).

[1601] 1 H-NMR(CDCl3)δ:8.31-8.25(2H,m),7.41-7.35(2H,m),4.87-4.75(1H,m),3.96 (2H,d,J=6.0Hz),2.30(2H,t,J=7.2Hz),1.72-1.20(47H,m),0.93-0.83(9H,m). (2)

[1603] [Chemical Formula 210]

[1604]

[1605] In Example 84(2), 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)pentadecanoic acid was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-6-isopropyl-10-oxo-12-pentyl-9,11-dioxa-3,6-diazaeicosane-21-ester was obtained by the same method as in Example 84(2).

[1606] 1 H-NMR(CDCl3)δ:4.72-4.62(1H,m),4.10(2H,t,J=6.6Hz),3.96(2H,d,J=6.0Hz),2.98-2.82(1H,m),2.68(2H,t,J=6.6Hz) ,2.59-2.42(8H,m),2.29(2H,t,J=7.2Hz),1.66-1.47(7H,m),1.40-1.18(40H,m),1.06-0.96(12H,m),0.92-0.84(9H,m).

[1607] MSm / z(M+H): 712.

[1608] [Example 128] (1)

[1610] [Chemical Formula 211]

[1611]

[1612] In Example 124(2), 2-pentylheptanoic acid was used instead of 2-nonylundecanoic acid, and otherwise, 2-pentyl-1-heptanol, a colorless oil, was obtained by the same method as in Example 124(2).

[1613] 1 H-NMR(CDCl3)δ:3.57-3.51(2H,m),1.50-1.20(17H,m),0.88(6H,t,J=6.6Hz). (2)

[1615] [Chemical Formula 212]

[1616]

[1617] In Example 84(1), 2-pentyl-1-heptanol was used instead of 2-butyl-1-octanol, and otherwise, 2-pentylheptyl-10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid, a colorless oil, was obtained by the same method as in Example 84(1).

[1618] 1 H-NMR(CDCl3)δ:8.28(2H,dd,J=7.2Hz,2.1Hz),7.39(2H,dd,J=7.2Hz,2.1Hz),4.86-4.76( 1H,m),3.97(2H,d,J=6.0Hz),2.30(2H,t,J=7.2Hz),1.74-1.20(41H,m),0.92-0.85(9H,m). (3)

[1620] [Chemical Formula 213]

[1621]

[1622] In Example 85(2), 2-pentylheptyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid. Otherwise, a colorless oily 2-pentylheptyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazaeicosane-21-ester was obtained by the same method as in Example 85(2).

[1623] 1 H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.20(2H,t,J=6.0Hz),3.97(2H,d,J=5.4Hz),3.54(2H,t,J=4.5Hz),2.88(2H,t,J=6.6Hz),2.74-2 .64(4H,m),2.59-2.44(6H,m),2.29(2H,t,J=7.2Hz),1.75-1.45(7H,m),1.40-1.19(34H,m),1.02(6H,t,J=7.2Hz),0.92-0.84(9H,m).

[1624] MSm / z(M+H): 672.

[1625] [Example 129]

[1626] [Chemical Formula 214]

[1627]

[1628] In Example 86, 2-pentylheptyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester, and octanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-pentylheptyl 3-ethyl-12-hexyl-6-(2-(octanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was obtained using the same method as in Example 86.

[1629] 1H-NMR(CDCl3)δ:4.73-4.61(1H,m),4.21-4.07(4H,m),3.97(2H,d,J=5.4Hz),2.88-2.77(4H,m),2.72-2.62(2H,m),2.5 8-2.45(6H,m),2.29(4H,t,J=7.2Hz),1.69-1.48(9H,m),1.41-1.18(42H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[1630] MSm / z(M+H): 798.

[1631] [Example 130]

[1632] [Chemical Formula 215]

[1633]

[1634] In Example 86, 2-pentylheptyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester, and nonanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-pentylheptyl 3-ethyl-12-hexyl-6-(2-(nonanoyloxy)ethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester was obtained using the same method as in Example 86.

[1635] 1 H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.22-4.08(4H,m),3.97(2H,d,J=6.0Hz),2.88-2.75(4H,m),2.72-2.62(2H,m),2.6 0-2.46(6H,m),2.29(4H,t,J=7.5Hz),1.70-1.47(9H,m),1.41-1.18(44H,m),1.02(6H,t,J=6.6Hz),0.95-0.81(12H,m).

[1636] MSm / z(M+H): 812.

[1637] [Example 131]

[1638] [Chemical Formula 216]

[1639]

[1640] In Example 85(2), 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)pentadecanoic acid was used instead of 2-butyloctyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-6-(2-hydroxyethyl)-10-oxo-12-pentyl-9,11-dioxa-3,6-diazaeicosano-21-ester was obtained using the same method as in Example 85(2).

[1641] 1 H-NMR(CDCl3)δ:4.74-4.62(1H,m),4.20(2H,t,J=6.0Hz),3.96(2H,d,J=5.7Hz),3.54(2H,t,J=4.5Hz),2.89(2H,t,J=6.0Hz),2.75-2 .64(4H,m),2.60-2.43(6H,m),2.29(2H,t,J=7.8Hz),1.67-1.49(7H,m),1.41-1.19(40H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(9H,m).

[1642] MSm / z(M+H): 714.

[1643] [Example 132]

[1644] [Chemical Formula 217]

[1645]

[1646] In Example 86, 2-hexyldecyl 3-ethyl-6-(2-hydroxyethyl)-10-oxo-12-pentyl-9,11-dioxa-3,6-diazacotetradecane-21-ester was used instead of 2-butyloctyl 3-ethyl-12-hexyl-6-(2-hydroxyethyl)-10-oxo-9,11-dioxa-3,6-diazacotetradecane-21-ester, and octanoic acid was used instead of dodecanoic acid. Otherwise, a colorless oily 2-hexyldecyl 3-ethyl-6-(2-(octanoyloxy)ethyl)-10-oxo-12-pentyl-9,11-dioxa-3,6-diazacotetradecane-21-ester was obtained using the same method as in Example 86.

[1647] 1H-NMR(CDCl3)δ:4.72-4.61(1H,m),4.22-4.06(4H,m),3.96(2H,d,J=6.0Hz),2.88-2.76(4H,m),2.72-2.62(2H,m),2.5 8-2.45(6H,m),2.29(4H,t,J=7.2Hz),1.68-1.48(9H,m),1.39-1.18(48H,m),1.02(6H,t,J=6.6Hz),0.94-0.82(12H,m).

[1648] MSm / z(M+H): 840.

[1649] [Example 133] (1)

[1651] [Chemical Formula 218]

[1652]

[1653] In Examples 124(1) and (2), nonanoic acid was used instead of undecanoic acid, and 1-iodoheptane was used instead of 1-iodononane. Otherwise, 2-heptyl-1-nonanol, a colorless oil, was obtained by the same method as in Examples 124(1) and (2).

[1654] 1 H-NMR(CDCl3)δ:3.57-3.51(2H,m),1.50-1.20(25H,m),0.88(6H,t,J=6.6Hz). (2)

[1656] [Chemical Formula 219]

[1657]

[1658] In Examples 84(1) and (2), 2-heptyl-1-nonanol was used instead of 2-butyl-1-octanol. Otherwise, a colorless oily 2-heptylnonyl-3-ethyl-12-hexyl-6-isopropyl-10-oxo-9,11-dioxa-3,6-diazaeicosane-21-ester was obtained by the same method as in Examples 84(1) and (2).

[1659] 1H-NMR(CDCl3)δ:4.72-4.62(1H,m),4.10(2H,t,J=6.6Hz),3.96(2H,d,J=6.0Hz),2.97-2.85(1H,m),2.68(2H,t,J=6.9Hz) ,2.60-2.41(8H,m),2.29(2H,t,J=7.2Hz),1.67-1.47(7H,m),1.39-1.19(42H,m),1.08-0.95(12H,m),0.94-0.82(9H,m).

[1660] MSm / z(M+H): 726.

[1661] [Example 134] (1)

[1663] [Chemical Formula 220]

[1664]

[1665] At room temperature, 2-hexyl-1-octanol (4.4 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9 g), 4-dimethylaminopyridine (0.9 g), and triethylamine (8.6 mL) were added to a solution of 4.0 g of 10-bromodecanoic acid in 80 mL of dichloromethane, and the mixture was stirred overnight at this temperature. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 3.4 g of 2-hexyloctyl 10-bromodecanoate, a colorless oil.

[1666] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 6.0Hz), 3.41 (2H, t, J = 6.6Hz), 2.30 (2H, t, J = 7.5Hz), 1.91-1.78 (2H, m), 1.69-1.19 (33H, m), 0.89 (6H, t, J = 7.5Hz). (2)

[1668] [Chemical Formula 221]

[1669]

[1670] At room temperature, N-octylamine (1.1 mL) and potassium carbonate (1.9 g) were added to a solution of 1.0 g of 2-hexyloctyl 10-bromodecanoate in 5 mL of N,N-dimethylformamide, and the mixture was stirred at 60 °C for 4 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give 806 mg of 2-hexyloctyl 10-(octylamino)decanoate, a pale yellow oil.

[1671] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 6.0Hz), 2.58 (4H, t, J = 7.2Hz), 2.29 (2H, t, J = 7.2Hz), 1.68-1.20 (47H, m), 0.92-0.84 (9H, m). (3)

[1673] [Chemical Formula 222]

[1674]

[1675] At room temperature, octanoic acid (0.79 mL), 1-(3-dimethylamino)ethyl)azonidinediyl)bis(ethane-1-ol) (1.0 g) in dichloromethane (20 mL), 1.4 g of octanoic acid hydrochloride, 1.2 g of 1-dimethylaminopyridine, and 2.1 mL of triethylamine were added to a solution of 2,2'-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)ethyl octanoate (1.4 g), 4-dimethylaminopyridine (1.2 g), and the mixture was stirred at this temperature for 12 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 541 mg of 2-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)ethyl octanoate, a colorless oil.

[1676] 1 H-NMR(CDCl3)δ:4.15(2H,t,J=5.4Hz),3.54(2H,t,J=5.4Hz),2.84(2H,t,J=6.0Hz),2.72-2.63(4H,m),2 .59-2.44(6H,m),2.30(2H,t,J=7.2Hz),1.78-1.19(10H,m),1.03(6H,t,J=7.2Hz),0.88(3H,t,J=6.6Hz). (4)

[1678] [Chemical Formula 223]

[1679]

[1680] At room temperature, 311 mg of 4-nitrophenyl chloroformate was added to a solution of 500 mg of 2-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)ethyl octanoate in tetrahydrofuran (6 mL), and the mixture was stirred at this temperature for 1 hour. At room temperature, 300 mg of 2-hexyl octanoate of 10-(octylamino)decanoate and 0.34 mL of triethylamine were added to the reaction mixture, and the mixture was stirred at 60 °C for 3 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Purification of the residue by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) yielded a colorless oily substance, 2-hexyloctyl-3-ethyl-6-(2-(octanoyloxy)ethyl)-11-octyl-10-oxo-9-oxa-3,6,11-triazacotetradecane-21-ester (117 mg).

[1681] 1 H-NMR(CDCl3)δ:4.16-4.07(4H,m),3.97(2H,d,J=6.0Hz),3.24-3.09(4H,m),2.84-2.75(4H,m),2.71-2.61(2H,m),2. 58-2.46(6H,m),2.34-2.23(4H,m),1.68-1.42(5H,m),1.36-1.18(52H,m),1.02(6H,t,J=7.5Hz),0.93-0.83(12H,m).

[1682] MSm / z(M+H): 853.

[1683] [Example 135] (1)

[1685] [Chemical Formula 224]

[1686]

[1687] Under ice-cold conditions, a 1 mol / L solution of hexyl magnesium bromide in tetrahydrofuran (200 mL) was added dropwise to a solution of glutaric anhydride (27.3 g) in tetrahydrofuran (273 mL), and the mixture was stirred for 1 hour at the same temperature. Under ice-cold conditions, a 2 mol / L aqueous hydrochloric acid solution (240 mL) was added to the reaction mixture, followed by the addition of ethyl acetate (270 mL). The organic layer was separated, washed with water (80 mL) and a saturated sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane), and hexane (10 mL) was added. The solid was filtered off, washed with hexane (10 mL), and dried under reduced pressure to obtain a white solid of 5-oxoundecanoic acid (16.0 g).

[1688] 1 H-NMR (CDCl3) δ: 2.50 (2H, t, J = 7.2Hz), 2.40 (4H, t, J = 7.2Hz), 2.02-1.80 (2H, m), 1.63-1.48 (2H, m), 1.37-1.20 (6H, m), 0.88 (3H, t, J = 6.6Hz).

[1689] A mixture of 5-oxoundecanoic acid (2.8 g), 2-pentyl-1-heptanol (2.3 g), and toluene (5.6 mL) was mixed with p-toluenesulfonic acid monohydrate (0.13 g) and stirred at 110 °C for 1.5 h. After cooling the reaction mixture to room temperature, it was purified by silica gel column chromatography (ethyl acetate-hexane) to give a colorless oily product, 2-pentylheptyl 5-oxoundecanoate (3.8 g).

[1690] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.1Hz), 2.47 (2H, t, J = 7.2Hz), 2.39 (2H, t, J = 7.2Hz), 2.33 (2 H,t,J=7.2Hz),1.95-1.83(2H,m),1.66-1.49(3H,m),1.36-1.20(22H,m),0.92-0.82(9H,m).

[1691] Sodium borohydride (0.47 g) was added to a mixture of 2-pentylheptyl 5-oxoundecanoate (3.8 g), methanol (15 mL), and toluene (15 mL) under ice-cold conditions, and the mixture was stirred for 30 minutes at the same temperature. At the same temperature, water (6 mL) and a 1.0 mol / L hydrochloric acid aqueous solution (6 mL) were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2-pentylheptyl 5-hydroxyundecanoate (3.5 g), a pale yellow oil.

[1692] 1 H-NMR (CDCl3) δ: 3.97 (2H, d, J = 5.7Hz), 3.65-3.53 (1H, m), 2.35 (2H, t, J = 7.2Hz), 1.87-1.20 (32H, m), 0.92-0.84 (9H, m).

[1693] To a solution of 0.50 g of 2-pentylheptyl 5-hydroxyundecanoate in tetrahydrofuran (5.0 mL), 0.33 g of 1,1'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 30 hours. Water (10 mL) and hexane (20 mL) were added to the reaction mixture. The organic layer was separated, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give 0.64 g of a pale yellow oil, 1-oxo-1-((2-pentylheptyl)oxy)undecane-5-yl 1H-imidazolium-1-carboxylic acid ester.

[1694] 1 H-NMR(CDCl3)δ:8.14-8.12(1H,m),7.43-7.41(1H,m),7.08-7.06(1H,m),5.11-5.04(1H,m),3.9 7(2H,d,J=5.6Hz),2.38-2.32(2H,m),1.80-1.54(7H,m),1.40-1.22(24H,m),0.91-0.85(9H,m). (2)

[1696] [Chemical Formula 225]

[1697]

[1698] A mixture of decanoic acid (15.8 g), 2-bromoethanol (10.0 g), and toluene (30 mL) was mixed with p-toluenesulfonic acid monohydrate (0.41 g) and stirred at 130 °C for 2 hours. After cooling the reaction mixture to room temperature, water (100 mL) was added, and the organic layer was separated. The mixture was washed with 10% sodium bicarbonate aqueous solution (55 mL) and saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain 22.2 g of decanoic acid 2-bromoethyl, a pale yellow oil.

[1699] 1 H-NMR(CDCl3)δ: 4.38(2H,t,J=6.4Hz), 3.51(2H,t,J=6.4Hz), 2.35(2H,t,J=7.6Hz), 1.68-1.60(2H,m), 1.35-1.20(12H,m), 0.88(3H,t,J=7.2Hz).

[1700] A mixture of 2-((2-(diethylamino)ethyl)amino)-1-ethanol (5.0 g), potassium carbonate (8.6 g), and acetonitrile (25 mL) was mixed with 2-bromoethyl decanoate (9.6 g) and stirred at 80 °C for 1.5 h. After cooling the reaction mixture to room temperature, water (25 mL) and ethyl acetate (50 mL) were added, and the organic layer was separated. The solvent was removed by vacuum distillation. The residue was then mixed with 30% hydrochloric acid aqueous solution (12.5 mL), water (12.5 mL), and ethyl acetate (50 mL), and the aqueous layer was separated. The aqueous layer was adjusted to pH 10 by adding 10% sodium hydroxide aqueous solution (55 mL), followed by the addition of ethyl acetate. The organic layer was then separated and dried using anhydrous sodium sulfate. After removing the solvent by vacuum distillation, the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate-hexane) to obtain ethyl 2-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)decanoate (2.54 g), which is a colorless oil.

[1701] 1 H-NMR(CDCl3)δ:4.15(2H,t,J=6.0Hz),3.55-3.53(2H,m),2.84(2H,t,J=6.0Hz),2.71-2.64(4H,m),2.58-2.45(6 H,m),2.30(2H,t,J=7.2Hz),1.64-1.57(2H,m),1.35-1.22(12H,m),1.03(6H,t,J=7.2Hz),0.88(3H,t,J=7.2Hz). (3)

[1703] [Chemical Formula 226]

[1704]

[1705] Potassium carbonate (0.20 g) was added to a mixture of 1-oxo-1-((2-pentylheptyl)oxy)undecane-5-yl 1H-imidazolium-1-carboxylic acid ester (0.64 g), ethyl 2-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)decanoate (0.56 g), and acetonitrile (2.5 mL), and the mixture was stirred at 80 °C for 2 hours. After cooling the reaction mixture to room temperature, ethyl acetate (5 mL) was added, insoluble matter was filtered off, and the solvent was removed by vacuum distillation. After adding ethyl acetate (20 mL) to the obtained residue, it was washed with water (10 mL) and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain 0.68 g of 2-pentylheptyl-6-(2-(decanoyloxy)ethyl)-3-ethyl-12-pentyl-10-oxo-9,11-dioxa-3,6-diazahexadecane-16-ester as a colorless oil.

[1706] 1 H-NMR(CDCl3)δ:4.72-4.65(1H,m),4.22-4.09(4H,m),3.97(2H,d,J=5.6Hz),2.86-2.77(4H,m),2.70-2.64(2H,m),2. 55-2.48(6H,m),2.35-2.27(4H,m),1.71-1.55(9H,m),1.36-1.20(36H,m),1.02(6H,t,J=7.2Hz),0.94-0.82(12H,m).

[1707] MSm / z(M+H): 755.

[1708] Experiment 1: Preparation of nucleic acid lipid particles and determination of reporter protein knockout rate in mice

[1709] <Preparation of Nucleic Acid Lipid Particles>

[1710] Compounds 24, 30, 31, 50, 56, 69, 88, 89, 103, 112, 118, 119 and 134, which were produced in the above examples, will be used as the first lipid.

[1711] Furthermore, for comparison, a lipid having the following structure (comparative compound C) was synthesized and used using the method described in Patent Document 6.

[1712] [Chemical Formula 227]

[1713]

[1714] Furthermore, for comparison, a lipid having the following structure (comparative compound D) was synthesized and used using the method described in Patent Document 3.

[1715] The structure of the compound in Example 13 of WO2015 / 95340

[1716] [Chemical Formula 228]

[1717]

[1718] The first lipid, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine, product name: COATSOME MC-8080; NOF corporation), cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.), and DMG-PEG2000 (product name: SUNBRIGHT(R)GM-020; NOF corporation) were dissolved in ethanol at the molar ratios recorded in Table 1 to obtain an oil phase with a total lipid concentration of 20 mmol / L.

[1719] 5 mg of siFVII of the sequence described in Molecular Therapy (2009), pages 17, 878, was dissolved in 1 mL of sterile water and diluted with 10 mmol / L acetate buffer at pH 4 to obtain an aqueous phase with a nucleic acid concentration of 19.7 μmol / L. Subsequently, using a syringe pump and a micromixer (refer to Japanese Patent No. 5288254), the mixture was prepared to an aqueous phase:oil phase volume ratio of 3:1, and the mixture was diluted 2-fold with phosphate-buffered saline (PBS) to obtain a dispersion of nucleic acid lipid particles.

[1720] The ratio of the molar number of the first lipid in the lipid composition to the molar number of sterols in the lipid composition is shown in Table 1.

[1721] The weight ratio of nucleic acids to total lipids during mixing is also recorded in Table 1.

[1722] [Table 1]

[1723]

[1724] <Particle Size Determination>

[1725] The particle size of the lipid particles in the undiluted state was determined.

[1726] The measurement results are shown in Table 2.

[1727] <Evaluation of siRNA Inclusion Rate>

[1728] (Total nucleic acid concentration quantification)

[1729] 30 μL of 3 mol / L sodium acetate aqueous solution and 9 μL of glycogen were added to 60 μL of lipid particles containing nucleic acids. Then, 1.5 mL of ethanol was added to dissolve the lipids, precipitating only the nucleic acids. The mixture was then centrifuged to remove the supernatant. After air-drying for at least 15 minutes, water was added to redissolve the precipitate, and the total nucleic acid concentration was quantified using a Nanodrop NF1000 (Thermo Fisher Scientific).

[1730] (Quantification of nucleic acid concentration in the external aqueous phase)

[1731] Quantification was performed using the Quant-iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific) according to the protocol. First, the 20×TE buffer included in the kit was diluted with water to prepare a 1×TE buffer. Note that TE stands for Tris / EDTA (ethylenediaminetetraacetic acid). To quantify only the nucleic acids in the aqueous phase, the lipid particle dispersion containing the nucleic acids was diluted 10,000-fold with the 1×TE buffer.

[1732] 100 μL of lipid particle dispersion diluted 10,000 times was placed into a 96-well plate. Then, 100 μL of RiboGreen reagent (the reagent included in the Quanti-iT Ribogreen RNA Assay Kit) diluted 2,000 times with 1×TE buffer was added to the sample. The concentration of nucleic acids in the external aqueous phase was quantified by measuring fluorescence (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm) using an Infinite F200 (TECAN) microplate reader.

[1733] (Calculation of Hierarchy)

[1734] Using the quantitative results of the total nucleic acid concentration and the nucleic acid concentration in the external aqueous phase obtained in the above process, the nucleic acid content of the nucleic acid lipid particles is calculated according to the following formula.

[1735] Nucleic acid content (%) = (Total nucleic acid concentration - Nucleic acid concentration in external aqueous phase) ÷ Total nucleic acid concentration × 100

[1736] The calculation results are shown in Table 2.

[1737] <Factor VII (FVII) Protein Assay>

[1738] Factor VII (FVII) protein assays were performed according to the method described in Nature Biotechnology (2010) 28, 172-176. C57BL6 / J mice were randomly assigned to groups (n=3). A dispersion of nucleic acid lipid particles prepared in the section on "Preparation of Nucleic Acid Lipid Particles" was administered via tail vein at a dose of 0.1 mg / kg. For comparison, an equal volume of PBS was administered via tail vein. Plasma was obtained 24 hours after administration via the posterior vena cava. The amount of FVII protein was quantified using the obtained plasma and the Biophen FVII assay kit (Aniara).

[1739] The amount of FVII in the plasma samples of each individual in the PBS-treated group was set as 100%, and the relative ratio of the amount of FVII in the plasma samples of each individual was used as the measured value. The results are shown in Table 2.

[1740] [Table 2]

[1741] Particle size (nm) Content (%) Protein content relative to FVII (%) Comparative Example 201 65.9 74 30 Comparative Example 201 68.4 83 44 Comparative Example 203 65.9 82 35 Comparative Example 204 73.7 82 23 Example 201 79.1 81 18 Example 202 76.8 80 13 Example 203 76.8 74 10 Comparative Example 205 66.7 86 34 Comparative Example 206 66.2 82 23 Example 204 73.3 81 16 Example 205 81.9 64 1 Example 206 77.4 53 3 Example 207 74.5 64 5 Example 208 73.2 56 3 Example 209 74.6 74 4 Example 210 81.7 62 14 Example 211 72.5 65 4 Example 212 75.8 71 3 Example 213 70.7 93 5 Example 214 72.8 90 2 Example 215 151.1 47 16 Example 216 69.7 89 3 Example 217 74.3 93 9 Example 218 86.2 93 1 Example 219 79.5 86 4

[1742] Compared to the comparative examples of nucleic acid lipid compositions, the nucleic acid lipid compositions of the present invention exhibit stronger FVII inhibitory activity and demonstrate excellent nucleic acid delivery performance.

[1743] Experimental Example 2: Determination of Pharmacokinetic (PK) Data (Liver Volume)

[1744] <Preparation of Nucleic Acid Lipid Particles>

[1745] Compounds 56, 88, and 89, prepared in the above examples, were used as the first lipid. Dispersions of nucleic acid lipid particles as described in Table 3 were obtained using the same method as in <Preparation of Nucleic Acid Lipid Particles> of Experimental Example 1.

[1746] The ratio of the molar number of the first lipid in the lipid composition to the molar number of sterols in the lipid composition is recorded in Table 3.

[1747] The weight ratio of nucleic acids to total lipids during mixing is also recorded in Table 3.

[1748] [Table 3]

[1749]

[1750]

[1751] <Particle Size Determination>

[1752] The particle size of the lipid particles was determined using the same method as in Example 1.

[1753] The measurement results are shown in Table 4.

[1754] <Evaluation of siRNA Inclusion Rate>

[1755] The siRNA incorporation rate was evaluated using the same method as in Experiment 1.

[1756] The calculation results are shown in Table 4.

[1757] <Determination of Liver Volume>

[1758] C57BL6 / J mice were administered a dispersion of nucleic acid lipid particles prepared in the "Preparation of Nucleic Acid Lipid Particles" section via tail vein at a dose of 0.1 mg / kg. Twenty-four hours after administration, livers were removed, rapidly frozen in liquid nitrogen, and then cryo-pulverized using a multi-bead shaker. After thawing on ice, 0.25% Triton-PBS was added to obtain a liver homogenate. The resulting liver homogenate was reverse transcribed using the Taqman MicroRNA Reverse Transcription kit (Applied Biosystems, 4366597) and Factor VII reverse transcription primers (Applied Biosystems). The reverse transcribed samples were quantified using the Taqman MGB Gene Expression Kit (Applied Biosystems, 4324036), Taqman Universal PCR Master Mix, No AmpErase UNG (Applied Biosystems, 4364341), and by real-time PCR.

[1759] The measurement results are shown in Table 4.

[1760] [Table 4]

[1761] Particle size (nm) Content (%) liver accumulation Comparative Example 301 72.0 65 5.2 Example 301 81.9 64 6.3 Comparative Example 302 77.6 44 5.7 Example 302 77.4 53 9.0 Comparative Example 303 74.5 61 3.5 Example 303 74.5 64 3.9

[1762] Compared to the nucleic acid lipid compositions of comparative examples, the nucleic acid lipid compositions of the present invention exhibit stronger accumulation in the liver.

[1763] Experimental Example 3: Preparation of lipid particles within mRNA and determination of reporter protein expression rate in mice

[1764] <Preparation of lipid particles within EPO mRNA>

[1765] The compounds listed in Table 5, 1,2-distearate-sn-glycerol-3-phosphocholine (product name: COATSOME(R)MC-8080; NOF corporation), L-α-phosphatidylethanolamine (product name: COATSOME(R)MC-8181; NOF corporation), cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.), and 1,2-dimyristoyl-rac-glycerol-3-(methylpolyoxyethylene 2000) (hereinafter, DMG-PEG2000) (product name: SUNBRIGHT(R)GM-020; NOF corporation) were dissolved in ethanol at the molar ratios listed in Table 5, with a total lipid concentration of 20 mmol / L, to obtain the oil phase.

[1766] EPO mRNA (product name: CleanCap FLuc mRNA (5 molU); TriLink) was diluted with 50 mmol / L citrate buffer at pH 4 at a total lipid concentration to mRNA concentration weight ratio of approximately 16:1 to 64:1 to obtain an aqueous phase. Subsequently, the aqueous phase was mixed with the oil phase at a volume ratio of 3:1 using NanoAssemblr (Precision NanoSystems), and the mixture was diluted 1.5 times with phosphate-buffered saline (PBS) to obtain a dispersion of mRNA lipid particles. This dispersion was then dialyzed with 10% sucrose aqueous solution using a dialysis power kit (Slide-A-Lyzer G2, MWCO: 10 kDa, Thermo Fisher Scientific) to remove ethanol, yielding lipid particles within the EPO mRNA.

[1767] <Preparation of lipid particles within FLuc mRNA>

[1768] The compounds listed in Table 6, 1,2-distearate-sn-glycerol-3-phosphocholine (product name: COATSOME(R)MC-8080; NOF corporation), L-α-phosphatidylethanolamine (product name: COATSOME(R)MC-8181; NOF corporation), cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.), and 1,2-dimyristoyl-rac-glycerol-3-(methylpolyoxyethylene 2000) (hereinafter, DMG-PEG2000) (product name: SUNBRIGHT(R)GM-020; NOF corporation) were dissolved in ethanol at the molar ratios listed in Table 6, with a total lipid concentration of 20 mmol / L, to obtain the oil phase.

[1769] FLuc mRNA (product name: CleanCap EPO mRNA (5 molU); TriLink) was diluted with 50 mmol / L citrate buffer at pH 4 at a total lipid concentration to mRNA concentration weight ratio of approximately 19:1 to 64:1 to obtain an aqueous phase. Subsequently, the aqueous phase was mixed with the oil phase at a volume ratio of 3:1 using NanoAssemblr (Precision NanoSystems), and the mixture was diluted 1.5 times with phosphate-buffered saline (PBS) to obtain a dispersion of mRNA lipid particles. This dispersion was then dialyzed with 10% sucrose aqueous solution using a dialysis power kit (Slide-A-Lyzer G2, MWCO: 10 kDa, Thermo Fisher Scientific) to remove ethanol, yielding lipid particles within the FLuc mRNA.

[1770] [Table 5]

[1771]

[1772] [Table 6]

[1773]

[1774] <Particle Size Determination>

[1775] The size of lipid particles within the mRNA was determined using the Zeta potential-particle size assay system ELS-Z2 (Otsuka Electronics Co., Ltd.) after dilution to 10-fold with phosphate-buffered saline (PBS). The results are shown in Tables 7 and 8.

[1776] <Evaluation of mRNA incorporation>

[1777] (Total mRNA concentration quantification)

[1778] Add 15–30 μL of 3 mol / L sodium acetate aqueous solution and 4.5–9 μL of glycogen to 30–60 μL of lipid particles containing mRNA. Then add 0.75–1.5 mL of ethanol to dissolve the lipids, precipitating only the mRNA. Centrifuge to remove the supernatant. After air-drying for at least 15 minutes, redissolve in water and determine the concentration using a Nanodrop NF1000 (ThermoFisher Scientific) to quantify the total mRNA concentration.

[1779] (Quantification of mRNA concentration in the external aqueous phase)

[1780] Quantification was performed using the Quant-iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific) according to the protocol. First, the 20×TE buffer included in the kit was diluted with water to prepare a 1×TE buffer. TE stands for Tris / EDTA (ethylenediaminetetraacetic acid). To quantify only the mRNA in the aqueous phase, the lipid particle dispersion containing the mRNA was diluted 10,000-fold with 1×TE buffer. 100 μL of the 10,000-fold diluted lipid particle dispersion was placed in a 96-well plate. Subsequently, 100 μL of RiboGreen reagent (included in the Quanti-iT Ribogreen RNA Assay Kit) diluted 2,000-fold with 1×TE buffer was added to the sample. The concentration of mRNA in the aqueous phase was quantified by measuring fluorescence (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm) using an Infinite F200 (TECAN) microplate reader.

[1781] (Calculation of Hierarchy)

[1782] Using the quantitative results of the total mRNA concentration and the mRNA concentration in the external aqueous phase obtained in the above procedures, the mRNA content of the mRNA lipid particles was calculated according to the following formula. The results are shown in Tables 7 and 8.

[1783] mRNA concentration (%) = (Total mRNA concentration - mRNA concentration in external aqueous phase) ÷ Total mRNA concentration × 100

[1784] <EPO enzyme activity assay>

[1785] In C57BL / 6J mice, a dispersion of mRNA lipid particles prepared in the above-described "Preparation of EPO mRNA Containing Lipid Particles" was administered intravenously at a dose of 0.1 mg / kg mRNA. Blood was collected from the posterior vena cava 20–24 hours after administration to obtain plasma. Human EPO enzyme activity was quantified using the obtained plasma and the Abcam Erythropoietin (EPO) Human ELISA Kit.

[1786] The results are shown in Table 7.

[1787] <Luciferase (luciferase) luminescence assay>

[1788] C57BL / 6J mice were administered a dispersion of mRNA lipid particles prepared in the above-described <Preparation of FLuc mRNA Including Lipid Particles> via tail vein at a dose of 0.1 mg / kg. Five hours after administration, the livers were extracted following exsanguination-based euthanasia with 150 mg / kg of D-fluorescein potassium (FUJIFILM Wako Pure Chemical Corporation) administered intraperitoneally. The luminescence intensity was quantified using the IVIS Imaging System (PerkinElmer).

[1789] The results are shown in Table 8. In Table 8, Luciferase [P / S] represents Photons / sec (light intensity).

[1790] [Table 7]

[1791] Particle size (nm) Content (%) EPO [mU / mL] Comparative Example 401 65.0 86 1100 Example 401 126.0 91 62717 Example 402 108.0 93 39146 Comparative Example 402 132.5 86 - Example 403 69.0 90 3812 Example 404 85.9 91 11202 Comparative Example 403 111.3 90 - Comparative Example 404 186.7 100 369 Example 405 70.9 100 6222 Example 406 78.0 100 29879 Example 407 134.0 100 64968 Example 408 67.7 93 31451 Example 409 59.9 91 25468 Example 410 64.4 93 4455 Example 411 84.1 95 2378 Example 412 79.1 91 3863 Example 413 86.8 98 21632 Comparative Example 405 60.3 77 852 Example 414 98.8 97 40213 Example 415 101.5 96 19728

[1792] [Table 8]

[1793] Particle size (nm) Content (%) Luciferase [P / S] Example 501 111.9 57 3.8.E+09 Example 502 139.3 73 1.3.E+09 Comparative Example 501 56.6 91 1.0.E+08 Example 503 116.7 82 2.9.E+09 Example 504 74.8 85 4.4.E+09 Example 505 59.3 81 9.0.E+08 Example 506 53.3 75 9.1.E+08 Example 507 134.4 91 2.9.E+09 Example 508 82.9 89 1.4.E+09 Comparative Example 502 139.2 76 6.9.E+08

[1794] Compared to the comparative examples of nucleic acid lipid compositions, the nucleic acid lipid compositions of the present invention exhibit stronger inhibitory activity on reporter protein expression.

[1795] Experiment 4: Preparation of lipid particles within mRNA and determination of reporter protein expression rate in mice

[1796] <Preparation of Nucleic Acid Lipid Particles>

[1797] Compounds 107, 129, and 135, which were produced in the above examples, will be used as the first lipid.

[1798] <Preparation of lipid particles within EPO mRNA>

[1799] The compounds listed in Table 9, 1,2-distearate-sn-glycerol-3-phosphocholine (product name: COATSOME(R)MC-8080; NOF corporation), 1,2-phosphatidylethanolamine (product name: COATSOME(R)ME-8181; NOF corporation), cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.), and 1,2-dimyristoyl-rac-glycerol-3-(methylpolyoxyethylene 2000) (hereinafter, DMG-PEG2000) (product name: SUNBRIGHT(R)GM-020; NOF corporation) were dissolved in ethanol at the molar ratios listed in Table 9, with a total lipid concentration of 12.5 mmol / L, to obtain the oil phase.

[1800] EPO mRNA (product name: CleanCap EPO mRNA (5 moU); TriLink) was dissolved in CA buffer at pH 4 with a total lipid to mRNA weight ratio of approximately 16:1 to 64:1 after mixing with the oil phase to obtain an aqueous phase. Subsequently, the aqueous phase was mixed with the oil phase at a volume ratio of 3:1 using NanoAssemblr (Precision NanoSystems), and the mixture was diluted 1.5 times with phosphate-buffered saline (PBS) to obtain a dispersion of mRNA lipid particles. This dispersion was then dialyzed with 20 mM Tris buffer containing 8% sucrose using a dialysis power kit (Slide-A-Lyzer G2, MWCO: 10 kDa, Thermo Fisher Scientific) to remove ethanol, yielding lipid particles within the EPO mRNA.

[1801] [Table 9]

[1802]

[1803] <Preparation of lipid particles within FLuc mRNA>

[1804] The compounds listed in Table 10, 1,2-phosphatidylethanolamine (product name: COATSOME(R)ME-8181; NOFcorporation), 1,2-dioleoyl-sn-glycerol-3-phosphocholine (hereinafter, DOPC) (product name: COATSOME(R)MC-8181; NOF corporation), cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.), and 1,2-dimyristoyl-rac-glycerol-3-(methylpolyoxyethylene 2000) (hereinafter, DMG-PEG2000) (product name: SUNBRIGHT(R)GM-020; NOF corporation) were dissolved in ethanol at the molar ratios listed in Table 10, with a total lipid concentration of 12.5 mmol / L, to obtain the oil phase.

[1805] FLuc mRNA (product name: CleanCap FLuc mRNA; TriLink) was dissolved in CA buffer at pH 4 with a total lipid to mRNA weight ratio of approximately 16:1 to 64:1 after mixing with the oil phase to obtain an aqueous phase. Subsequently, the aqueous phase was mixed with the oil phase at a volume ratio of 3:1 using NanoAssemblr (Precision NanoSystems), and the mixture was diluted 1.5 times with phosphate-buffered saline (PBS) to obtain a dispersion of mRNA lipid particles. This dispersion was then dialyzed with 20 mM Tris buffer containing 8% sucrose using a dialysis power kit (Slide-A-Lyzer G2, MWCO: 10kD, Thermo Fisher Scientific) to remove ethanol, yielding lipid particles within the FLuc mRNA.

[1806] [Table 10]

[1807]

[1808] <Particle Size Determination>

[1809] The size of lipid particles within the mRNA was determined using the Zeta potential-particle size assay system ELS-Z2 (Otsuka Electronics Co., Ltd.) after a 5-fold dilution with phosphate-buffered saline (PBS). The results are shown in Tables 11 and 12.

[1810] <Evaluation of mRNA incorporation>

[1811] (Total mRNA concentration quantification)

[1812] 100 μL of lipid particles containing mRNA and 900 μL of methanol were added to dissolve the lipids, and the absorbance at 260 nm was measured using a spectrophotometer (Thermo Fisher Scientific) to quantify the total mRNA concentration.

[1813] (Quantification of mRNA concentration in the external aqueous phase)

[1814] Quantification was performed using the Quant-iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific) according to the protocol. First, the 20×TE buffer included in the kit was diluted with water to prepare a 1×TE buffer. TE stands for Tris / EDTA (ethylenediaminetetraacetic acid). To quantify only the mRNA in the aqueous phase, the lipid particle dispersion holding the mRNA was diluted 50-fold with 1×TE buffer. 100 μL of the 50-fold diluted lipid particle dispersion was placed in a 96-well plate. Subsequently, 100 μL of RiboGreen reagent (included in the Quanti-iT Ribogreen RNA Assay Kit) diluted 2000-fold with 1×TE buffer was added to the sample. The concentration of mRNA in the aqueous phase was quantified by measuring fluorescence (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm) using an Infinite F200 (TECAN) microplate reader.

[1815] (Calculation of Hierarchy)

[1816] Using the quantitative results of the total mRNA concentration and the mRNA concentration in the external aqueous phase obtained in the above procedures, the mRNA content of mRNA lipid particles was calculated according to the following formula. The results are shown in Tables 11 and 12.

[1817] mRNA concentration (%) = (Total mRNA concentration - mRNA concentration in external aqueous phase) ÷ Total mRNA concentration × 100

[1818] <EPO enzyme activity assay>

[1819] In ICR mice, a dispersion of mRNA lipid particles prepared in the above-described "Preparation of EPO mRNA Containing Lipid Particles" was administered intravenously at a dose of 0.1 mg / kg mRNA. Six hours after administration, blood was collected from the posterior vena cava to obtain plasma. The activity of human EPO enzyme was quantified using the obtained plasma and the ab119522 Erythropoietin (EPO) Human Elisa Kit (Abcam).

[1820] The results are shown in Table 11.

[1821] [Table 11]

[1822] Particle size (nm) Content (%) EPO [mU / mL] Comparative Example 601 97.6 93.2 1.02.E+05 Example 601 88.9 98.1 2.69.E+05 Example 602 90.2 99.5 2.53.E+05 Example 603 82.5 99.6 6.49.E+05 Example 604 109.6 99.7 6.10.E+05 Example 605 90.8 99.6 3.90.E+05 Example 606 118.3 99.3 4.17.E+05 Example 607 106.2 97.5 5.30.E+05

[1823] Compared to the comparative examples of nucleic acid lipid compositions, the nucleic acid lipid compositions of the present invention exhibit higher reporter protein expression rates.

[1824] <Luciferase (luciferase) luminescence assay>

[1825] In ICR mice, a dispersion of mRNA lipid particles prepared in the above-described "Preparation of FLuc mRNA Containing Lipid Particles" was administered as a single dose of 1 μg of mRNA to a location more closely within the rectus femoris muscle on the dorsal side. Five hours and 50 minutes after administration, 150 mg / kg of D-fluorescein potassium (FUJIFILM Wako Pure Chemical Corporation) was administered intraperitoneally. Six hours after administration, under isoflurane anesthesia, luminescence was measured using an IVIS Imaging System (PerkinElmer) in a prone position. The region of interest (ROI) was set with the entire hind limb on the administration side inserted, and the luminescence intensity (photons / sec) was quantified using LivingImage Software (PerkinElmer).

[1826] The results are shown in Table 12.

[1827] [Table 12]

[1828] Particle size (nm) Content (%) Total flux (p / s) Example 608 83.9 100 3.79E+08 Example 609 83.5 100 4.60E+08 Example 610 82.9 100 1.69E+09 Example 611 126.4 98.8 1.08E+09 Example 612 114.8 97.5 1.50E+09 Example 613 85.9 99.7 7.74.E+08 Example 614 83.7 99.4 8.62.E+08 Example 615 148.6 98.5 7.03.E+08 Example 616 93.6 98.8 1.21.E+09 Example 617 86.6 98.4 1.08.E+09 Example 618 148.3 97.6 3.96.E+08

[1829] Compared to the nucleic acid lipid compositions of comparative examples, the nucleic acid lipid compositions of the present invention exhibit good luminescence.

Claims

1. The lipid or its salt represented by formula (1), [Chemical Formula 1] 2. A lipid composition comprising the lipid or salt thereof of claim 1, sterols, lipids having a nonionic hydrophilic polymeric structure, and nucleic acids, wherein the molar ratio of the lipid or salt thereof of claim 1 to the molar ratio of the sterols thereof in the lipid composition is 0.300 or more and less than 1.

299.

3. A lipid composition comprising the lipid of claim 1 or a salt thereof, sterols, and lipids having a nonionic hydrophilic polymeric structure.

4. The lipid composition according to claim 2 or 3, in, The lipid or its salt as described in claim 1 has a content of 20-55 mol% relative to the total lipids.

5. The lipid composition according to claim 4, wherein, Sterols comprise 20–70 mol% of the total lipid content. The content of lipids with nonionic hydrophilic polymeric structures is 0.2–10 mol% relative to the total lipid content.

6. The lipid composition according to claim 4, further comprising a pharmaceutically acceptable carrier.

7. The lipid composition according to claim 2 or 3, wherein it is a composition for introducing nucleic acids into cells.

8. The lipid composition according to claim 2 or 3, wherein it is a composition for in vivo nucleic acid delivery.

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