Compound or salt thereof, lipid composition, pharmaceutical composition and delivery vehicle

Abstract

The present invention addresses the problem of providing a compound or a salt thereof that constitutes a lipid composition capable of achieving high nucleic acid encapsulation efficiency and excellent nucleic acid delivery, and also providing a lipid composition, a pharmaceutical composition, and a delivery vehicle using the compound or the salt thereof. According to the present invention, a compound represented by formula (1) or a salt thereof can be provided. In the formula, R1, R2, R3 and R4 each independently represent a hydrogen atom or an optionally substituted hydrocarbon group having 1-24 carbon atoms, R5 and R6 each independently represent an optionally substituted hydrocarbon group having 1-18 carbon atoms, R7, R8 and R9 each independently represent a hydrocarbon group having 2-8 carbon atoms, and R5 and R6 or R5 and R7 may form a 4-7-membered ring together. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound or a salt thereof that can easily introduce nucleic acid into cells, etc. The present invention also relates to a lipid composition, a pharmaceutical composition, and a delivery carrier containing the compound or the salt thereof. Background Art

[0002] Nucleic acid drugs have clear mechanisms of action against diseases and are known to have minimal side effects, making them highly anticipated as next-generation pharmaceuticals. For example, nucleic acid drugs using small interfering RNA (siRNA) can inhibit the expression of sequence-specific target genes within cells. As a result, they can alleviate or treat diseases and symptoms caused by abnormal expression of specific genes or genomes. For these nucleic acid drugs to function effectively, they must be delivered into cells.

[0003] As the method that nucleic acid is efficiently delivered to cell, there is the method using viral vectors (viral vector) such as retrovirus (Retroviruses) or adenovirus (Adenoviruses).Using in the method for viral vector, although gene import efficiency is high, the size of the gene imported has limitation or is worrying aspect immunogenicity and safety.On the other hand, the gene import carried out by lipid composition is not restricted to importing gene, can solve the above problems, so its research and development is actively carried out.

[0004] Patent Document 1 discloses a compound having an ester group as a linking group linking an aliphatic group and an amino group as a compound contained in a lipid composition. Patent Document 1 describes the use of a lipid composition containing this compound to deliver nucleic acids to mouse cells.

[0005] Patent Document 2 describes an amino lipid represented by a predetermined formula (1) or a salt thereof, and also describes a lipid composition containing the amino lipid or a salt thereof. Patent Document 2 describes the use of the lipid composition for delivering nucleic acids into mouse cells.

[0006] Patent Document 3 describes a lipid composition comprising an amino lipid represented by the predetermined formula (1) or a salt thereof, a nonionic lipid, a lipid having a nonionic hydrophilic polymer structure, and a nucleic acid, and optionally containing a zwitterionic lipid. Patent Document 3 describes the use of this lipid composition for the delivery of nucleic acids into mouse cells.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: International Publication No. WO2010 / 054401

[0010] Patent Document 2: International Publication No. WO2019 / 235635

[0011] Patent Document 3: International Publication No. WO2020 / 246581 Summary of the Invention

[0012] Technical issues to be solved by the invention

[0013] Further research is underway into lipid compositions that can function as vectors and compounds that constitute these lipid compositions, with the hope of developing compounds that can achieve excellent nucleic acid delivery.

[0014] In view of this situation, the present invention aims to provide a compound or a salt thereof constituting a lipid composition capable of achieving high nucleic acid encapsulation efficiency and excellent nucleic acid delivery. Furthermore, the present invention aims to provide a lipid composition, a pharmaceutical composition, and a delivery vector using the above-mentioned compound or a salt thereof, capable of achieving high nucleic acid encapsulation efficiency and excellent nucleic acid delivery.

[0015] Means for solving technical problems

[0016] The present inventors conducted intensive research to solve the above-mentioned problems and confirmed that a lipid composition prepared using a compound represented by the following formula (1) or a salt thereof exhibits high nucleic acid encapsulation efficiency and excellent nucleic acid delivery, thereby completing the present invention. According to the present invention, the following inventions can be provided.

[0017] <1> A compound or a salt thereof, wherein the compound is represented by the following formula (1):

[0018] [Chemical Formula 1]

[0019]

[0020] Where R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms,

[0021] R 1 、R 2 、R 3 and R 4 The substituents on the optionally substituted hydrocarbon group having 1 to 24 carbon atoms represented by are each independently -C(O)OR 11 、-OC(O)-R 12 、-OR 13、-CO-R 14 、-OC(O)OR 15 or -SSR 16 ,

[0022] R 11 、R 12 、R 13 、R 14 、R 15 and R 16 Each independently represents the 17 Substituted hydrocarbon group having 1 to 24 carbon atoms, R 17 represents a hydrocarbon group having 1 to 12 carbon atoms,

[0023] R 5 and R 6 each independently represents an optionally substituted hydrocarbon group having 1 to 18 carbon atoms,

[0024] R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by are independently -OH, -COOH, -NR 21 R 22 、-OC(O)OR 23 、-C(O)OR 24 、-OC(O)-R 25 、-OR 26 、-C(O)NR 27 R 28 、-NR 29 C(O)R 30 、-N(R 31 )S(O)2R 32 、-N(R 33 )C(O)N(R 34 )R 35 、-N(R 36 )C(S)N(R 37 )R 38 、-OC(O)N(R 39 )R 40 or -N(R 41 )C(O)OR 42 ,

[0025] R 21 and R 22 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms,

[0026] R 23 、R 24 、R 25 、R 26 、R27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms, R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 40 、R 41 and R 42 The substituent on the hydrocarbon group having 1 to 24 carbon atoms which may be substituted is an aryl group having 6 to 20 carbon atoms, a heterocyclic group, -OH, -COOH or -NR 51 R 52 , R 51 and R 52 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms,

[0027] R 7 、R 8 and R 9 each independently represents a hydrocarbon group having 2 to 8 carbon atoms,

[0028] R 5 With R 6 or R 5 With R 7 They can form a 4- to 7-membered ring together.

[0029] <2> The compound according to <1>, wherein

[0030] R 1 Indicates -R 1a -L 1-R 1b , R 1a represents a hydrocarbon group having 1 to 18 carbon atoms, L 1 represents -C(O)O-, -OC(O)-, -OC(O)O- or -SS-, R 1b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0031] R 3 Indicates -R 3a -L 3 -R 3b , R 3a represents a hydrocarbon group having 1 to 18 carbon atoms, L 3 represents -C(O)O-, -OC(O)-, -OC(O)O- or -SS-, R 3b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0032] R 2 and R 4 Each independently represents a hydrocarbon group having 1 to 18 carbon atoms which may be substituted, R 2 and R 4 The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by are each independently -C(O)OR 11 、-OC(O)-R 12 、-OR 13 、-CO-R 14 、-OC(O)OR 15 or -SSR 16 ,

[0033] R 11 、R 12 、R 13 、R 14 、R 15 and R 16 each independently represents a hydrocarbon group having 1 to 18 carbon atoms,

[0034] R 5 and R 6 Each independently represents a hydrocarbon group having 1 to 12 carbon atoms which may be substituted,

[0035] R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by are each independently -OH, -OR 26 、-C(O)NR 27 R 28 or -NR 29 C(O)R 30 ,

[0036] R26 、R 27 、R 28 、R 29 and R 30 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, R 26 、R 27 、R 28 、R 29 and R 30 The substituent on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by represents an aryl group or a heterocyclic group having 6 to 10 carbon atoms,

[0037] R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 8.

[0038] <3> The compound according to <1>, wherein

[0039] R 1 Indicates -R 1a -L 1 -R 1b , R 1a represents a hydrocarbon group having 1 to 18 carbon atoms, L 1 Indicates -C(O)O- or -OC(O)-, R 1b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0040] R 3 Indicates -R 3a -L 3 -R 3b , R 3a represents a hydrocarbon group having 1 to 18 carbon atoms, L 3 Indicates -C(O)O- or -OC(O)-, R 3b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0041] R 2 and R 4 each independently represents a hydrocarbon group having 1 to 10 carbon atoms,

[0042] R 5 and R 6 Each independently represents a hydrocarbon group having 1 to 6 carbon atoms which may be substituted,

[0043] R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 6 carbon atoms represented by are independently -OH, -OR 26 、-C(O)NR27 R 28 or -NR 29 C(O)R 30 ,

[0044] R 26 、R 27 、R 28 、R 29 and R 30 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, R 26 、R 27 、R 28 、R 29 and R 30 The substituent on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by represents an aryl group having 6 to 10 carbon atoms,

[0045] R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 8.

[0046] <4> A compound or a salt thereof, the compound being selected from the following compounds:

[0047] ((2-(Diethylamino)ethyl)azepinediyl)bis(ethane-2,1-diyl)bis(dioctylcarbamate);

[0048] [Chemical Formula 2]

[0049]

[0050] Bis(2-hexyloctyl)11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0051] [Chemical Formula 3]

[0052]

[0053] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0054] [Chemical Formula 4]

[0055]

[0056] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0057] [Chemical Formula 5]

[0058]

[0059] Bis(2-hexyloctyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0060] [Chemical Formula 6]

[0061]

[0062] Bis(2-pentylheptyl)4,14-dibutyl-9-(2-(diethylamino)ethyl)-5,13-dioxo-6,12-dioxa-4,9,14-triazaheptadecanedioate;

[0063] [Chemical Formula 7]

[0064]

[0065] Bis(2-pentylheptyl)4,14-dibutyl-9-(3-(diethylamino)propyl)-5,13-dioxo-6,12-dioxa-4,9,14-triazaheptadecanedioate;

[0066] [Chemical Formula 8]

[0067]

[0068] Bis(2-pentylheptyl)9-(2-(diethylamino)ethyl)-5,13-dioxo-4,14-dipropyl-6,12-dioxa-4,9,14-triazaheptadecanedioate;

[0069] [Chemical Formula 9]

[0070]

[0071] Bis(2-pentylheptyl)9-(3-(diethylamino)propyl)-5,13-dioxo-4,14-dipropyl-6,12-dioxa-4,9,14-triazaheptadecanedioate;

[0072] [Chemical Formula 10]

[0073]

[0074] Bis(2-pentylheptyl)8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-dipropyl-5,11-dioxa-3,8,13-triazapentadecanedioate;

[0075] [Chemical Formula 11]

[0076]

[0077] Bis(2-pentylheptyl)8-(3-(diethylamino)propyl)-4,12-dioxo-3,13-dipropyl-5,11-dioxa-3,8,13-triazapentadecanedioate;

[0078] [Chemical Formula 12]

[0079]

[0080] 2-(2-(2-(bis(2-decanoyloxyethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-decanoyloxyethyl)amino)ethyldecanoate;

[0081] [Chemical Formula 13]

[0082]

[0083] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diisopropyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0084] [Chemical Formula 14]

[0085]

[0086] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diisopropyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0087] [Chemical Formula 15]

[0088]

[0089] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-6,16-dipropyl-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0090] [Chemical Formula 16]

[0091]

[0092] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-6,16-dipropyl-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0093] [Chemical Formula 17]

[0094]

[0095] Bis(2-butyloctyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0096] [Chemical Formula 18]

[0097]

[0098] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diisobutyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0099] [Chemical Formula 19]

[0100]

[0101] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diisobutyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0102] [Chemical Formula 20]

[0103]

[0104] 2-(2-(2-(bis(2-dodecanoyloxyethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-dodecanoyloxyethyl)amino)ethyl dodecanoate;

[0105] [Chemical Formula 21]

[0106]

[0107] Bis(2-pentylheptyl)6,16-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0108] [Chemical Formula 22]

[0109]

[0110] Bis(2-pentylheptyl)6,16-dibutyl-11-(3-(diethylamino)propyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0111] [Chemical Formula 23]

[0112]

[0113] Bis(2-hexyloctyl)6,16-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0114] [Chemical Formula 24]

[0115]

[0116] Bis(2-hexyloctyl)6,16-dibutyl-11-(3-(diethylamino)propyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0117] [Chemical Formula 25]

[0118]

[0119] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandioate;

[0120] [Chemical Formula 26]

[0121]

[0122] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandioate;

[0123] [Chemical Formula 27]

[0124]

[0125] Decyl 2-(2-(2-(bis(2-decyloxy-2-oxo-ethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-decyloxy-2-oxo-ethyl)amino)acetate;

[0126] [Chemical Formula 28]

[0127]

[0128] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-6,16-dipentyl-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0129] [Chemical Formula 29]

[0130]

[0131] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-6,16-dipentyl-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0132] [Chemical formula 30]

[0133]

[0134] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diheptyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0135] [Chemical Formula 31]

[0136]

[0137] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diheptyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0138] [Chemical Formula 32]

[0139]

[0140] Didodecyl 8-(2-(diethylamino)ethyl)-3,13-bis(2-(dodecyloxy)-2-oxoethyl)-4,12-dioxo-5,11-dioxa-3,8,13-triazapentadecanedioate;

[0141] [Chemical Formula 33]

[0142]

[0143] Diundecyl 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-bis(2-oxo-2-(undecanyloxy)ethyl)-5,11-dioxa-3,8,13-triazapentadecanedioate;

[0144] [Chemical Formula 34]

[0145]

[0146] Ditridecyl 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-bis(2-oxo-2-(tridecyloxy)ethyl)-5,11-dioxa-3,8,13-triazapentadecanedioate;

[0147] [Chemical Formula 35]

[0148]

[0149] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0150] [Chemical Formula 36]

[0151]

[0152] Bis(2-pentylheptyl)11-(4-(diethylamino)butyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0153] [Chemical Formula 37]

[0154]

[0155] Bis(2-hexyloctyl)11-(3-(diethylamino)propyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0156] [Chemical Formula 38]

[0157]

[0158] Bis(2-hexyloctyl)11-(4-(diethylamino)butyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate;

[0159] [Chemical Formula 39]

[0160]

[0161] 1-heptyl 21-(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0162] [Chemical Formula 40]

[0163]

[0164] 1-heptyl 21-(2-hexyloctyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0165] [Chemical Formula 41]

[0166]

[0167] 1-octyl 21-(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0168] [Chemical Formula 42]

[0169]

[0170] 1-(2-Hexyloctyl)21-octyl 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0171] [Chemical Formula 43]

[0172]

[0173] 21-heptyl 1-(2-hexyloctyl) 6-decyl-11-(2-(diethylamino)ethyl)-16-octyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0174] [Chemical Formula 44]

[0175]

[0176] 1-(2-hexyloctyl)21-octyl6-decyl-11-(2-(diethylamino)ethyl)-16-octyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate;

[0177] [Chemical Formula 45]

[0178]

[0179] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate

[0180] [Chemical Formula 46]

[0181]

[0182] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-8,16-dioxo-7,17-dipentyl-9,15-dioxa-7,12,17-triazatricosanediolate

[0183] [Chemical Formula 47]

[0184]

[0185] Bis(2-hexyloctyl)7,17-dibutyl-12-(2-(diethylamino)ethyl)-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate

[0186] [Chemical Formula 48]

[0187]

[0188] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate

[0189] [Chemical Formula 49]

[0190]

[0191] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-8,16-dioxo-7,17-dipentyl-9,15-dioxa-7,12,17-triazatricosanediolate

[0192] [Chemical Formula 50]

[0193]

[0194] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate

[0195] [Chemical Formula 51]

[0196]

[0197] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate

[0198] [Chemical Formula 52]

[0199]

[0200] <5> A lipid composition comprising the compound or a salt thereof according to any one of <1> to <4> and a lipid.

[0201] <6> The lipid composition according to <5>, wherein

[0202] The lipid is at least one lipid selected from the group consisting of neutral lipids and lipids having nonionic hydrophilic polymer chains.

[0203] <7> The lipid composition according to <5> or <6>, further comprising a sterol.

[0204] <8> The lipid composition according to any one of <5> to <7>, further comprising at least one selected from the group consisting of nucleic acids, proteins, peptides, and low molecular weight substances.

[0205] <9> A pharmaceutical composition comprising the lipid composition according to any one of <5> to <8>.

[0206] <10> A delivery vehicle comprising the lipid composition according to any one of <5> to <8>.

[0207] Effects of the Invention

[0208] By using the compounds of the present invention, lipid compositions, pharmaceutical compositions, and delivery vectors capable of achieving high nucleic acid encapsulation efficiency and excellent nucleic acid delivery can be manufactured. The lipid compositions, pharmaceutical compositions, and delivery vectors of the present invention can achieve high nucleic acid encapsulation efficiency and excellent nucleic acid delivery. DETAILED DESCRIPTION

[0209] Hereinafter, the present invention will be described in detail.

[0210] In this specification, "to" represents a range including the numerical values ​​described before and after it as the minimum value and the maximum value, respectively.

[0211] <Compounds of the present invention>

[0212] The present invention relates to a compound represented by the following formula (1) or a salt thereof.

[0213] [Chemical Formula 53]

[0214]

[0215] Where R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms,

[0216] R 1 、R 2 、R 3 and R 4 The substituents on the optionally substituted hydrocarbon group having 1 to 24 carbon atoms represented by are each independently -C(O)OR 11 、-OC(O)-R 12 、-OR 13 、-CO-R 14 、-OC(O)OR 15 or -SSR 16 ,

[0217] R 11 、R 12 、R 13 、R 14 、R 15 and R 16 Each independently represents the 17 Substituted hydrocarbon group having 1 to 24 carbon atoms, R 17 represents a hydrocarbon group having 1 to 12 carbon atoms,

[0218] R 5 and R 6 each independently represents an optionally substituted hydrocarbon group having 1 to 18 carbon atoms,

[0219] R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by are independently -OH, -COOH, -NR 21 R 22 、-OC(O)OR 23 、-C(O)OR 24、-OC(O)-R 25 、-OR 26 、-C(O)NR 27 R 28 、-NR 29 C(O)R 30 、-N(R 31 )S(O)2R 32 、-N(R 33 )C(O)N(R 34 )R 35 、-N(R 36 )C(S)N(R 37 )R 38 、-OC(O)N(R 39 )R 40 or -N(R 41 )C(O)OR 42 ,

[0220] R 21 and R 22 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms,

[0221] R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms, R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38、R 39 、R 40 、R 41 and R 42 The substituent on the hydrocarbon group having 1 to 24 carbon atoms which may be substituted is an aryl group having 6 to 20 carbon atoms, a heterocyclic group, -OH, -COOH or -NR 51 R 52 , R 51 and R 52 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms,

[0222] R 7 、R 8 and R 9 each independently represents a hydrocarbon group having 2 to 8 carbon atoms,

[0223] R 5 With R 6 or R 5 With R 7 They can form a 4- to 7-membered ring together.

[0224] The hydrocarbon group having 1 to 24 carbon atoms, the hydrocarbon group having 1 to 18 carbon atoms, the hydrocarbon group having 1 to 12 carbon atoms, and the hydrocarbon group having 1 to 8 carbon atoms are preferably each an alkyl group, an alkenyl group, or an alkynyl group.

[0225] The alkyl group may be a straight chain or a branched chain, and may be chain-shaped or cyclic. Specifically, methyl, ethyl, 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, tetramethylhexadecyl (preferably, 3,7,11,15-tetramethylhexadecyl), heptadecyl, octadecyl, 2-butylhexyl, 2-butyloctyl, 1-pentylhexyl 1-Hexylheptyl, 1-Hexylnonyl, 2-Hexyloctyl, 2-Hexyldecyl, 3-Hexylnonyl, 1-heptyloctyl, 2-heptylnonyl, 2-heptylundecyl, 3-heptyldecyl, 1-octylnonyl, 2-octyldecyl, 2-octyldodecyl, 3-octylundecyl, 2-nonylundecyl, 3-nonyldodecyl, 2-decyldodecyl, 2-decyltetradecyl, 3-decyltridecyl, 2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl and the like.

[0226] The alkenyl group may be straight-chain or branched, and may be chain-shaped or cyclic. Specifically, allyl, isoprenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl (preferably (Z)-2-nonenyl or (E)-2-nonenyl), decenyl, undecenyl, dodecenyl, dodecadienyl, tridecenyl (preferably (Z)-tridec-8-enyl), tetradecenyl (preferably tetradec-9-enyl), pentadecenyl (preferably (Z)-pentadecan-8-enyl), hexadecanyl (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), and the like can be mentioned.

[0227] The alkynyl group may be straight-chain or branched, and may be chain-shaped or cyclic. Specifically, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tetradecynyl, pentadecynyl, hexadecynyl, heptadecenyl, octadecynyl, etc. may be mentioned.

[0228] The alkenyl groups mentioned above preferably have one or two double bonds, and the alkynyl groups preferably have one or two triple bonds.

[0229] R 7 、R 8 and R 9 The hydrocarbon group having 2 to 8 carbon atoms represented by is preferably an alkylene group, an alkenylene group, or an alkynylene group.

[0230] The alkylene, alkenylene or alkynylene group having 2 to 8 carbon atoms may be linear or branched, and may be chain or cyclic.

[0231] Specific examples include ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, and octamethylene.

[0232] The aryl group having 6 to 20 carbon atoms is preferably an aryl group having 6 to 18 carbon atoms, and more preferably an aryl group having 6 to 10 carbon atoms. Specific examples thereof include phenyl, naphthyl, anthryl, and phenanthryl.

[0233] The heterocyclic group refers to a heteroaryl group or a heteroaliphatic ring group.

[0234] A heteroaryl group refers to an aromatic heterocyclic group, which may be an aromatic heterocyclic ring, an aromatic hydrocarbon ring, a heteroaliphatic ring, or an aromatic heterocyclic group formed by condensing aliphatic hydrocarbon rings. It is preferably a monocyclic nitrogen-containing heteroaryl group, a monocyclic oxygen-containing heteroaryl group, a monocyclic sulfur-containing heteroaryl group, a monocyclic nitrogen-containing oxygen-containing heteroaryl group, a monocyclic nitrogen-containing sulfur-containing heteroaryl group, a bicyclic nitrogen-containing heteroaryl group, a bicyclic oxygen-containing heteroaryl group, a bicyclic sulfur-containing heteroaryl group, a bicyclic nitrogen-containing oxygen-containing heteroaryl group, or a bicyclic nitrogen-containing sulfur-containing heteroaryl group. A 5-membered heteroaryl group is a monocyclic heteroaryl group having 5 atoms constituting the ring.

[0235] Furthermore, the aromatic heterocycle refers to an aromatic ring having a heteroatom in a ring member. The aromatic heterocycle, aromatic hydrocarbon ring, heteroaliphatic ring or aliphatic hydrocarbon ring may be condensed, and is preferably a monocyclic nitrogen-containing aromatic heterocycle, a monocyclic oxygen-containing aromatic heterocycle, a monocyclic sulfur-containing aromatic heterocycle, a monocyclic nitrogen-containing and oxygen-containing aromatic heterocycle, a monocyclic nitrogen-containing and sulfur-containing aromatic heterocycle, a bicyclic nitrogen-containing and oxygen-containing aromatic heterocycle, a bicyclic oxygen-containing and sulfur-containing aromatic heterocycle, a bicyclic nitrogen-containing and oxygen-containing aromatic heterocycle or a bicyclic nitrogen-containing and sulfur-containing aromatic heterocycle.

[0236] Monocyclic nitrogen-containing heteroaryl groups include pyrrolinyl, pyrrolyl, tetrahydropyridinyl, pyridinyl, imidazolinyl, imidazolyl, pyrazolinyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazolyl, and tetrazolyl groups, wherein the ring contains at least one nitrogen atom and is aromatic (the heteroaryl group may be partially saturated). The heteroaryl group may be further fused with another aromatic ring or an aliphatic ring.

[0237] The monocyclic oxygen-containing heteroaryl group refers to a heteroaryl group such as a furyl group or a pyranyl group, wherein the ring contains at least one oxygen atom and is aromatic (the heteroaryl group may be partially saturated). The heteroaryl group may be further condensed with another aromatic ring or an aliphatic ring.

[0238] The monocyclic nitrogen-containing and oxygen-containing heteroaryl group includes oxazolyl, isoxazolyl, oxadiazolyl, etc. The heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.

[0239] The monocyclic nitrogen-containing and sulfur-containing heteroaryl group includes thiazolyl, isothiazolyl, thiadiazolyl, etc. The heteroaryl group may be further condensed with another aromatic ring or aliphatic ring.

[0240] The bicyclic nitrogen-containing heteroaryl group includes indolyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl, pyridopyrazyl, purinyl, pteridinyl, 5,6,7,8-tetrahydrophthalazinyl, 5,6,7,8-tetrahydrocinnolinyl, 1,2,3,4-tetrahydropyrido[2,3-d]pyridazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyridazinyl, ]pyridazinyl, 5,6,7,8-tetrahydropyrido[3,2-c]pyridazinyl, 5,6,7,8-tetrahydropyrido[4,3-c]pyridazinyl, 6,7-dihydro-5H-cyclopenta[d]pyridazinyl, 6,7-dihydro-5H-cyclopenta[c]pyridazinyl, 2,3-dihydro-1H-pyrrolo[2,3-d]pyridazinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyridazinyl, 6,7-dihydro-5H-pyrrolo[3,2-c]pyridazinyl, 6,7-dihydro-5H-pyrrolo[3,4-c]pyridazinyl, and 6,7-dihydro-5H-pyrrolo[2,3-c]pyridazinyl, wherein the ring is aromatic and contains at least one nitrogen atom (the heteroaryl group may be partially saturated).

[0241] The bicyclic oxygen-containing heteroaryl group refers to a bicyclic heteroaryl group having an aromatic ring containing at least one oxygen atom, such as benzofuranyl, isobenzofuranyl, and chromenyl (the heteroaryl group may be partially saturated).

[0242] The bicyclic nitrogen-containing and oxygen-containing heteroaryl groups include benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, dihydropyranopyridyl, dihydrodioxinopyridyl, dihydropyridoxadienyl, 3,4-dihydro-2H-pyrano[2,3-d]pyridazinyl, 7,8-dihydro-5H-pyrano[3,4-d]pyridazinyl, 7,8-dihydro-6 Bicyclic heteroaryl groups having an aromatic ring containing at least one nitrogen atom and at least one oxygen atom, such as H-pyrano[3,2-c]pyridazinyl, 7,8-dihydro-5H-pyrano[4,3-c]pyridazinyl, 2,3-dihydrofuro[2,3-d]pyridazinyl, 5,7-dihydrofuro[3,4-d]pyridazinyl, 6,7-dihydrofuro[3,2-c]pyridazinyl, 5,7-dihydrofuro[3,4-c]pyridazinyl, and 5,6-dihydrofuro[2,3-c]pyridazinyl (the heteroaryl group may be partially saturated).

[0243] The heteroaliphatic cyclic group refers to a nitrogen-containing heteroaliphatic cyclic group, an oxygen-containing heteroaliphatic cyclic group, a sulfur-containing heteroaliphatic cyclic group, a nitrogen-containing oxygen-containing heteroaliphatic cyclic group, a nitrogen-containing sulfur-containing heteroaliphatic cyclic group, a hybrid bicyclic group or a heterospirocyclic group.

[0244] Furthermore, the heteroaliphatic ring refers to an aliphatic ring having a heteroatom as a ring member, and preferably includes a nitrogen-containing heteroaliphatic ring, an oxygen-containing heteroaliphatic ring, a sulfur-containing heteroaliphatic ring, a nitrogen-containing and oxygen-containing heteroaliphatic ring, a nitrogen-containing and sulfur-containing heteroaliphatic ring, a hybrid linked ring, and a heterospiro ring.

[0245] The nitrogen-containing heteroaliphatic ring group refers to a heteroaliphatic ring group containing at least one nitrogen atom, such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, and homopiperazinyl, in which the ring is not aromatic. The nitrogen-containing heteroaliphatic ring group may be further fused with another aromatic ring or aliphatic ring.

[0246] The oxygen-containing heteroaliphatic ring group refers to tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, 1,3-dioxanyl, etc. The oxygen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or aliphatic ring.

[0247] The nitrogen-containing and oxygen-containing heteroaliphatic ring group refers to a morpholinyl group, a 1,4-oxazepanyl group, etc. The nitrogen-containing and oxygen-containing heteroaliphatic ring group may be further condensed with another aromatic ring or an aliphatic ring.

[0248] Heteroaliphatic ring C 1-8 Alkyl refers to a linear, branched or cyclic C group to which a heteroaliphatic ring group such as pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl, pyrrolidinyloctyl, piperidinylmethyl or tetrahydrofurylmethyl is bonded. 1-8 alkyl.

[0249] In formula (1), the following are preferred:

[0250] R 1 Indicates -R 1a -L 1 -R 1b , R 1a represents a hydrocarbon group having 1 to 18 carbon atoms, L 1 represents -C(O)O-, -OC(O)-, -OC(O)O- or -SS-, R 1b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0251] R 3 Indicates -R 3a -L 3 -R3b , R 3a represents a hydrocarbon group having 1 to 18 carbon atoms, L 3 represents -C(O)O-, -OC(O)-, -OC(O)O- or -SS-, R 3b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0252] R 2 and R 4 Each independently represents a hydrocarbon group having 1 to 18 carbon atoms which may be substituted, R 2 and R 4 The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by are each independently -C(O)OR 11 、-OC(O)-R 12 、-OR 13 、-CO-R 14 、-OC(O)OR 15 or -SSR 16 ,

[0253] R 11 、R 12 、R 13 、R 14 、R 15 and R 16 each independently represents a hydrocarbon group having 1 to 18 carbon atoms,

[0254] R 5 and R 6 Each independently represents a hydrocarbon group having 1 to 12 carbon atoms which may be substituted,

[0255] R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by are each independently -OH, -OR 26 、-C(O)NR 27 R 28 or -NR 29 C(O)R 30 ,

[0256] R 26 、R 27 、R 28 、R 29 and R 30 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, R 26 、R 27 、R 28 、R 29 and R 30The substituent on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by represents an aryl group or a heterocyclic group having 6 to 10 carbon atoms,

[0257] R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 8.

[0258] In formula (1), the following is further preferred:

[0259] R 1 Indicates -R 1a -L 1 -R 1b , R 1a represents a hydrocarbon group having 1 to 18 carbon atoms, L 1 Indicates -C(O)O- or -OC(O)-, R 1b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0260] R 3 Indicates -R 3a -L 3 -R 3b , R 3a represents a hydrocarbon group having 1 to 18 carbon atoms, L 3 Indicates -C(O)O- or -OC(O)-, R 3b represents a hydrocarbon group having 1 to 18 carbon atoms,

[0261] R 2 and R 4 each independently represents a hydrocarbon group having 1 to 10 carbon atoms,

[0262] R 5 and R 6 Each independently represents a hydrocarbon group having 1 to 6 carbon atoms which may be substituted,

[0263] R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 6 carbon atoms represented by are independently -OH, -OR 26 、-C(O)NR 27 R 28 or -NR 29 C(O)R 30 ,

[0264] R 26 、R 27 、R 28 、R 29 and R 30Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, R 26 、R 27 、R 28 、R 29 and R 30 The substituent on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by represents an aryl group having 6 to 10 carbon atoms,

[0265] R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 8.

[0266] In formula (1), the most preferred is as follows:

[0267] R 1 Indicates -R 1a -L 1 -R 1b , R 1a represents a hydrocarbon group having 1 to 5 carbon atoms, L 1 Represents -C(O)O-, R 1b represents a hydrocarbon group having 7 to 14 carbon atoms,

[0268] R 3 Indicates -R 3a -L 3 -R 3b , R 3a represents a hydrocarbon group having 1 to 5 carbon atoms, L 3 Represents -C(O)O-, R 3b represents a hydrocarbon group having 7 to 14 carbon atoms,

[0269] R 2 and R 4 each independently represents a hydrocarbon group having 3 to 8 carbon atoms,

[0270] R 5 and R 6 Each independently represents a hydrocarbon group having 2 carbon atoms,

[0271] R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 4.

[0272] The compounds of the present invention can form salts.

[0273] Examples of the salt in the basic group include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; salts with 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 with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

[0274] Examples of the salt of the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with 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.

[0275] Among the above-mentioned salts, preferred salts include pharmacologically acceptable salts.

[0276] Preferred specific examples of the compound of the present invention include the compounds described in Examples 1 to 51 described later, but the present invention should not be construed as being limitative thereto.

[0277] The compounds described in Examples 1 to 51 are referred to as Compound 1 to Compound 51, respectively.

[0278] Among the above, preferred are compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 12, compound 13, compound 14, compound 15, compound 16, compound 17, compound 18, compound 20, compound 21, compound 23, compound 24, compound 25, compound 26, compound 27, compound 32, compound 33, compound 34, compound 35, compound 36, compound 37, compound 38, compound 40 and compound 42.

[0279] More preferred are Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 17, Compound 20, Compound 23, Compound 24, Compound 25, Compound 26, Compound 27, Compound 33, Compound 35, Compound 36, Compound 37, Compound 38, Compound 40 and Compound 42.

[0280] Compound 1, compound 2, compound 3, compound 4, compound 5, compound 17, compound 25, compound 26, compound 27, compound 33, compound 35, compound 36, compound 37, compound 38, compound 40 and compound 42 are further preferred.

[0281] Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 17, Compound 35, Compound 36, Compound 37, Compound 38, Compound 40 and Compound 42 are particularly preferred.

[0282] The most preferred are Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 and Compound 37.

[0283] Furthermore, the compounds of the present invention also include compounds having the following structures.

[0284] [Chemical Formula 54]

[0285]

[0286] [Chemical Formula 55]

[0287]

[0288] [Chemical Formula 56]

[0289]

[0290] [Chemical Formula 57]

[0291]

[0292] [Chemical Formula 58]

[0293]

[0294] [Chemical Formula 59]

[0295]

[0296] [Chemical Formula 60]

[0297]

[0298] [Chemical Formula 61]

[0299]

[0300] [Chemical Formula 62]

[0301]

[0302] [Chemical Formula 63]

[0303]

[0304] [Chemical Formula 64]

[0305]

[0306] [Chemical Formula 65]

[0307]

[0308] <Manufacturing method>

[0309] The method for producing the compound of the present invention will be described.

[0310] The compound of the present invention can be produced by combining known methods, and can be produced, for example, by the production method shown below.

[0311] [Manufacturing method 1]

[0312] A method for producing a compound of formula [1] from a compound of formula [2].

[0313] [Chemical Formula 66]

[0314]

[0315] Where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 Has the same meaning as above; R 8a 、R 9a and R A It represents a hydrocarbon group having 1 to 7 carbon atoms.

[0316] (1-1)

[0317] The compound of formula [3A] can be produced by reacting the compound of formula [2] in the presence of water and an acid, and in the presence or absence of a solvent.

[0318] Examples of the acid that can be used in this reaction include inorganic acids and organic acids, preferably organic acids, and specific examples include formic acid, acetic acid, trifluoroacetic acid, 4-toluenesulfonic acid, and methanesulfonic acid, with formic acid being more preferred.

[0319] The amount of the acid used is 1 to 100 times (v / w), preferably 1 to 10 times (v / w), the amount of the compound of formula [2].

[0320] The amount of water used is 0.1 to 100 times (v / w), preferably 0.1 to 10 times (v / w), the amount of the compound of formula [2].

[0321] The solvent that can be used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used as a mixture.

[0322] The amount of the solvent used is not particularly limited, and may be 0.1 to 50 times (v / w) the amount of the compound of formula [2].

[0323] The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 5 minutes to 48 hours.

[0324] (1-2)

[0325] The compound of formula [1] can be produced by reacting a compound of formula [3A] with a compound of formula [4] in the presence of a reducing agent.

[0326] As the compound of formula [4], for example, N,N-diethylethylenediamine and N,N-diethyl-1,3-diaminopropane are known.

[0327] The solvent that can be used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, alcohols, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used as a mixture.

[0328] Preferred solvents include esters, with ethyl acetate being more preferred.

[0329] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound of formula [3A].

[0330] Examples of the reducing agent that can be used in this reaction include sodium borohydride, sodium cyanoborohydride, pyridine borane, 2-picoline borane, and sodium triacetoxyborohydride, with sodium triacetoxyborohydride being more preferred.

[0331] The amount of the reducing agent used may be 1 to 100 times the mole, preferably 1 to 10 times the mole, of the compound of formula [3A].

[0332] The amount of the compound of formula [4] used may be 0.1 to 1 times the molar amount of the compound of formula [3A].

[0333] The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 5 minutes to 48 hours.

[0334] (1-3)

[0335] The compound of formula [5] can be produced by reacting the compound of formula [3A] with the compound of formula [4] in the presence of a reducing agent.

[0336] This reaction may be carried out according to the production method (1-2), and the compound of formula [4] may be used in an amount of 1 to 10 times the molar amount of the compound of formula [3A].

[0337] (1-4)

[0338] The compound of formula [1] can be produced by reacting a compound of formula [3B] with a compound of formula [5] in the presence of a reducing agent.

[0339] This reaction may be carried out according to the production method (1-2), and the compound of formula [3B] may be used in an amount of 1 to 10 times the molar amount of the compound of formula [5].

[0340] [Manufacturing method 2]

[0341] A method for producing a compound of formula [2] from compounds of formula [6] and formula [7].

[0342] [Chemical Formula 67]

[0343]

[0344] Where R 1 、R 2 、R 9a and R A Has the same meaning as above; X 1 and X 2 Indicates separation from the base.

[0345] Examples of the leaving group include a chloro group, a fluoro group, a bromo group, a trichloromethoxy group, a 4-nitrophenoxy group, a 2,4-dinitrophenoxy group, a 2,4,6-trichlorophenoxy group, a pentafluorophenoxy group, a 2,3,5,6-tetrafluorophenoxy group, an imidazolyl group, a triazolyl group, a 3,5-dioxo-4-methyl-1,2,4-oxadiazolidinyl group, and an N-hydroxysuccinimide group.

[0346] (2-1)

[0347] The compound of formula [9] can be produced by reacting the compound of formula [7] with the compound of formula [8] in the presence or absence of a base.

[0348] As the compound of formula [8], for example, 1,1′-carbonylbis(1,2,4-triazole), 1,1′-carbonyldiimidazole, 4-nitrophenyl chloroformate, triphosgene, and phosgene are known.

[0349] The solvent that can be used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used as a mixture.

[0350] Preferred solvents include ethers, with tetrahydrofuran being more preferred.

[0351] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound of formula [7].

[0352] Examples of the base that can be used in this reaction include inorganic bases and organic bases. The base is preferably an organic base, and specific examples include triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine.

[0353] The amount of the base used may be 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound of formula [7].

[0354] The amount of the compound of formula [3] used is not particularly limited, and may be 1 to 10 times the molar amount of the compound of formula [2].

[0355] The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 5 minutes to 48 hours.

[0356] (2-2)

[0357] The compound of formula [2] can be produced by reacting a compound of formula [6] with a compound of formula [9] in the presence of a base.

[0358] As the compound of formula [6], for example, dioctylamine is known.

[0359] The solvent that can be used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used as a mixture.

[0360] Preferred solvents include nitriles, with acetonitrile being more preferred.

[0361] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound of formula [6].

[0362] Examples of the base that can be used in this reaction include inorganic bases and organic bases. Specifically, examples include potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, lithium phosphate, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine.

[0363] The amount of the base used may be 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound of formula [6].

[0364] The amount of the compound of formula [9] used is not particularly limited, but may be 0.1 to 10 times the molar amount of the compound of formula [6].

[0365] The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 5 minutes to 48 hours.

[0366] [Manufacturing method 3]

[0367] A method for producing a compound of formula [6A].

[0368] [Chemical Formula 68]

[0369]

[0370] Where R 2 、R 1a and R 1b Has the same meaning as above; X 3 represents a hydroxyl group and a leaving group; X 4 represents a leaving group; the leaving group has the same meaning as above.

[0371] (3-1)

[0372] The compound of formula [12A] can be produced by reacting the compound of formula [10A] with the compound of formula [11A] in the presence or absence of an acid, in the presence or absence of a condensing agent or an acid halide, and in the presence or absence of a base.

[0373] As the compound of formula [10A], for example, 5-bromovaleric acid, chloroacetyl chloride, etc. are known.

[0374] As the compound of formula [11A], for example, 2-butyl-1-octanol, 2-pentyl-1-heptanol, 1-decanol, etc. are known.

[0375] The solvent that can be used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used as a mixture.

[0376] Preferred solvents include aromatic hydrocarbons and ethers, with toluene and tetrahydrofuran being more preferred.

[0377] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound of formula [10A].

[0378] Examples of the acid that can be used in this reaction include inorganic acids and organic acids. The acid is preferably a sulfonic acid, and specific examples thereof include sulfuric acid, 4-toluenesulfonic acid, and methanesulfonic acid.

[0379] Examples of the condensing agent that can be used in this reaction include carbodiimides such as N,N'-dicyclohexylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; carbonyls such as carbonyldiimidazole; acid azides such as diphenylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; ureas such as O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.

[0380] Examples of the acid halide that can be used in the reaction include carboxylic acid halides such as acetyl chloride and trifluoroacetyl chloride; sulfonic acid halides such as methanesulfonyl chloride and p-toluenesulfonyl chloride (Tosyl chloride); and chloroformates such as ethyl chloroformate and isobutyl chloroformate.

[0381] Examples of the base that can be used in this reaction include inorganic bases and organic bases, preferably organic bases, and specific examples include triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine.

[0382] The amount of the base used may be 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound of formula [10A].

[0383] The amount of the compound of formula [11A] used is not particularly limited, and may be 0.8 to 10 times the amount (v / w) of the compound of formula [10A].

[0384] The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 5 minutes to 48 hours.

[0385] (3-2)

[0386] The compound of formula [6A] can be produced by reacting a compound of formula [12A] with a compound of formula

[13] in the presence or absence of a base and in the presence or absence of an additive.

[0387] As the compound of formula

[13] , for example, 1-butylamine, 1-hexylamine, etc. are known.

[0388] The solvent that can be used in the reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons. These solvents may be used as a mixture.

[0389] Preferred solvents include nitriles and ethers, with acetonitrile and tetrahydrofuran being more preferred.

[0390] The amount of the solvent used is not particularly limited, and may be 1 to 500 times (v / w) the amount of the compound of formula [12A].

[0391] Examples of the base that can be used in this reaction include inorganic bases and organic bases. Specifically, examples include potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, lithium phosphate, triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, and N,N-dimethylaminopyridine. Potassium carbonate is more preferred.

[0392] The amount of the base used may be 1 to 50 times the mole, preferably 1 to 10 times the mole, of the compound of formula [12A].

[0393] The amount of the compound of formula

[13] used is not particularly limited, and may be 1 to 10 times the molar amount of the compound of formula [12A].

[0394] Specific examples of the additive that can be used in the reaction include lithium iodide, sodium iodide, potassium iodide, benzyltriethylammonium iodide, and benzyltriethylammonium bromide.

[0395] The amount of the additive used may be 0.1 to 10 times the molar amount of the compound of formula [12A].

[0396] The reaction can be carried out at -30 to 150°C, preferably at 0 to 100°C, for 5 minutes to 48 hours.

[0397] [Manufacturing method 4]

[0398] A method for producing a compound of formula [6B].

[0399] [Chemical Formula 69]

[0400]

[0401] Where R 2 、R 1a 、R 1b 、X 3 and X 4 Has the same meaning as above.

[0402] (4-1)

[0403] The compound of formula [12B] can be produced by the same method as production method (3-1) by using the compound of formula [10B] instead of formula [10A] and the compound of formula [11B] instead of formula [11A].

[0404] (4-2)

[0405] The compound of formula [6B] can be produced by the same method as in production method (3-2) by using the compound of formula [12B] instead of formula [12A].

[0406] [Manufacturing method 5]

[0407] A method for producing a compound of formula [6C].

[0408] [Chemical Formula 70]

[0409]

[0410] Where R 1a 、R 1b and X 3 Has the same meaning as above; R B represents an amino protecting group.

[0411] (5-1)

[0412] The compound of formula

[15] can be produced by reacting a compound of formula [10B] with a compound of formula

[14] in the presence or absence of an acid, in the presence or absence of a condensing agent or an acid halide, and in the presence or absence of a base.

[0413] As the compound of formula [10B], for example, decanoic acid and decanoyl chloride are known.

[0414] As the compound of formula

[15] , for example, tert-butylbis(2-hydroxyethyl)carbamate is known.

[0415] This reaction may be carried out according to the production method (3-1).

[0416] (5-2)

[0417] The compound of formula [6C] can be produced by deprotecting the compound of formula

[15] .

[0418] This reaction can be carried out, for example, according to the method described in TW Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696-926, 2007, John Wiley & Sons, Inc.

[0419] [Manufacturing method 6]

[0420] A method for producing a compound of formula [6D].

[0421] [Chemical Formula 71]

[0422]

[0423] Where R 1a 、R 1b and R B Has the same meaning as above.

[0424] (6-1)

[0425] The compound of formula [6D] can be produced by reacting a compound of formula

[11] with a compound of formula

[16] in the presence or absence of an acid, in the presence or absence of a condensing agent or an acid halide, and in the presence or absence of a base.

[0426] As the compound of formula

[11] , for example, 1-decanol is known.

[0427] As the compound of formula

[16] , for example, N-(tert-butoxycarbonyl)iminodiacetic acid is known.

[0428] This reaction may be carried out according to the production method (3-1).

[0429] (6-2)

[0430] The compound of formula [6D] can be produced by deprotecting the compound of formula

[17] .

[0431] This reaction may be carried out according to Production Method (3-2).

[0432] When the compound used in the above production method has isomers (for example, optical isomers, geometric isomers, tautomers, etc.), these isomers can also be used.

[0433] Furthermore, when solvates, hydrates, and crystals of various shapes exist, these solvates, hydrates, and crystals of various shapes can also be used.

[0434] Among the compounds used in the above production methods, compounds having amino, hydroxyl or carboxyl groups, for example, these groups can be protected in advance with common protecting groups, and these protecting groups can be removed by known methods after the reaction.

[0435] The compound obtained by the above-mentioned production method can be derived into other compounds by subjecting it to known reactions such as condensation, addition, oxidation, reduction, dislocation, substitution, halogenation, dehydration or hydrolysis, or by appropriately combining these reactions.

[0436] <Lipid composition>

[0437] In the present invention, a composition containing the compound of the present invention or a salt thereof can be prepared. When preparing a lipid composition, in addition to the compound of the present invention, at least one lipid selected from the group consisting of sterols and lipids having nonionic hydrophilic polymer chains can also be used. The lipid composition may further contain a neutral lipid. The lipid composition may further contain a nucleic acid.

[0438] In the lipid composition of the present invention, the amount of the compound represented by formula (1) or a salt thereof is preferably 20 mol% to 80 mol%, more preferably 30 mol% to 70 mol%, and even more preferably 35 mol% to 65 mol% relative to the total lipid mass.

[0439] <Sterol>

[0440] The lipid composition of the present invention preferably contains a sterol. By containing a sterol in the lipid composition of the present invention, membrane fluidity can be reduced, thereby achieving a stabilizing effect on the lipid composition.

[0441] Sterols are not particularly limited, and examples thereof include cholesterol, phytosterols (sitosterol, stigmasterol, fucosterol, spinasterol, brassicasterol, etc.), ergosterol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, etc. Among these, cholesterol is preferred.

[0442] In the lipid composition of the present invention, the amount of sterol added is preferably 10 mol% to 70 mol%, more preferably 20 mol% to 65 mol%, and even more preferably 25 mol% to 60 mol%, relative to the total lipid mass.

[0443] Neutral lipids

[0444] The lipid composition of the present invention may contain a neutral lipid. As the neutral lipid, there is no particular limitation, and examples thereof include phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, etc., preferably phosphatidylcholine. Furthermore, as the neutral lipid, it may be a single neutral lipid or a combination of multiple different neutral lipids.

[0445] The phosphatidylcholine is not particularly limited, and examples thereof include soybean lecithin (SPC), hydrogenated soybean lecithin (HSPC), egg yolk lecithin (EPC), hydrogenated egg yolk lecithin (HEPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), 1-palmitoyl-2-oleoylphosphatidylcholine (POPC), and dioleoylphosphatidylcholine (DOPC).

[0446] The phosphatidylethanolamine is not particularly limited, and examples thereof include dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine (DOPE), dilinoleoylphosphatidylethanolamine (DLoPE), diphytanoylphosphatidylethanolamine (D(Phy)PE), 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE), ditetradecylphosphatidylethanolamine, dihexadecylphosphatidylethanolamine, dioctadecylphosphatidylethanolamine, and diphytylphosphatidylethanolamine.

[0447] The sphingomyelin is not particularly limited, and examples thereof include egg yolk-derived sphingomyelin and milk-derived sphingomyelin.

[0448] The ceramide is not particularly limited, and examples thereof include egg yolk-derived ceramide and milk-derived ceramide.

[0449] In the lipid composition of the present invention, the amount of the neutral lipid added is preferably 0 mol% to 55 mol%, more preferably 0 mol% to 40 mol%, relative to the total amount of the constituent lipid components.

[0450] <Lipids with nonionic hydrophilic polymer chains>

[0451] The lipid composition of the present invention may contain a lipid having a nonionic hydrophilic polymer chain in the oil phase. In the present invention, by containing a lipid having a nonionic hydrophilic polymer chain in the oil phase, a dispersion stabilization effect of the lipid composition can be obtained.

[0452] Examples of nonionic hydrophilic polymers are not particularly limited and include nonionic vinyl polymers, nonionic polyamino acids, nonionic polyesters, nonionic polyethers, nonionic natural polymers, nonionic modified natural polymers, and block polymers or graft copolymers having two or more of these polymers as structural units.

[0453] Among these nonionic hydrophilic polymers, nonionic polyethers, nonionic polyesters, nonionic polyamino acids or nonionic synthetic polypeptides are preferred, nonionic polyethers or nonionic polyesters are more preferred, nonionic polyethers or nonionic monoalkoxy polyethers are even more preferred, and polyethylene glycol (hereinafter also referred to as PEG) is particularly preferred.

[0454] The lipid having a nonionic hydrophilic polymer chain is not particularly limited, and examples thereof include PEG-modified phosphoethanolamine, diacylglycerol PEG derivatives, monoacylglycerol PEG derivatives, dialkylglycerol PEG derivatives, cholesterol PEG derivatives, and ceramide PEG derivatives. Among these, monoacylglycerol PEG or diacylglycerol PEG is preferred.

[0455] The weight average molecular weight of the PEG chain of the nonionic hydrophilic polymer derivative is preferably 500 to 5,000, more preferably 750 to 3,000.

[0456] The nonionic hydrophilic polymer chain may be branched or may have a substituent such as a hydroxymethyl group.

[0457] In the lipid composition of the present invention, the amount of lipid having a nonionic hydrophilic polymer chain is preferably 0.1 mol% to 12 mol%, more preferably 0.3 mol% to 6 mol%, and even more preferably 0.5 mol% to 5 mol%, relative to the total lipid mass.

[0458] <Nucleic acids, proteins, peptides and low molecular weight molecules>

[0459] The lipid composition of the present invention may contain at least one selected from the group consisting of nucleic acids, proteins, peptides, and low molecular weight substances.

[0460] As nucleic acids, plasmid DNA, nanoplasmid DNA, single-stranded DNA, double-stranded DNA, siRNA (small interfering RNA: small interfering RNA), miRNA (micro RNA: micro RNA), mRNA, antisense oligonucleotides (also called ASO), ribozymes, nucleic acid aptamers, dsRNA, saRNA, sgRNA, shRNA, tRNA, circular RNA, etc. can be listed, and any one of them can be contained. In addition, modified nucleic acids can be contained. As nucleic acids, RNA is particularly preferred, and RNA with a base number of 5 to 20,000 bases is preferred.

[0461] In the lipid composition of the present invention, the mass ratio of lipid to nucleic acid is preferably 2 to 1000, more preferably 3 to 500, further preferably 5 to 200, and particularly preferably 5 to 100.

[0462] Examples of proteins, peptides, and low molecular weight substances include intracellular proteins, intracellular peptides, membrane-permeable proteins, membrane-permeable peptides, secreted proteins, secreted peptides, synthetic proteins, synthetic peptides, natural low molecular weight compounds, synthetic low molecular weight compounds, and compounds having antitumor activity.

[0463] More specifically, proteins include CRISPR-Cas proteins or zinc fingers (Zinc-Finger), gene editing-related proteins such as TALEN, hormones such as erythropoietin, in vivo factors such as VEGF, cancer antigen proteins or antibodies, etc. As peptides, functional domains or recognition domains of the above proteins can be listed. It can contain mRNA or DNA encoding the above proteins.

[0464] As a peptide, natural ones are preferred. In addition, the peptide structure may be linear or cyclic. When the peptide is cyclic, examples of the connecting portion of the ring include amide bonds, disulfide bonds, and the like.

[0465] Examples of low molecular weight compounds include anticancer agents, antibacterial agents, and antifungal agents. These proteins, peptides, and low molecular weight compounds may or may not have physiological activity in vivo. Here, low molecular weight compounds refer to organic compounds with a molecular weight of approximately 1,000 or less.

[0466] <Method for producing lipid composition>

[0467] The method for producing the lipid composition of the present invention will be described.

[0468] The method for producing the lipid composition is not particularly limited and can be produced 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 mixing the oil phase and the aqueous phase. A micro mixer can be used for mixing, or emulsification can be performed using an emulsifier such as a homogenizer, an ultrasonic emulsifier, a high-pressure jet emulsifier, or the like.

[0469] Alternatively, the lipid-containing solution can be dried under reduced pressure using an evaporator or spray-dried using a spray dryer to prepare a dry mixture containing the lipid, which is then added to an aqueous solvent and emulsified using the aforementioned emulsifier.

[0470] An example of a method for producing a lipid composition containing nucleic acid is a method comprising the following steps.

[0471] Step (a); dissolving the constituent components of the lipid composition containing the compound of the present invention in an organic solvent to obtain an oil phase and dissolving the nucleic acid in an aqueous solvent to obtain an aqueous phase

[0472] Step (b); a step of mixing the oil phase and the aqueous phase obtained in step (a) to obtain a dispersion of lipid particles

[0473] Step (c); diluting the dispersion of lipid particles obtained in step (b); Step (d); removing the organic solvent from the dispersion of lipid particles;

[0474] Step (e); Step of adjusting the concentration of the lipid particle dispersion

[0475] In step (a), the components of the lipid composition containing the compound of the present invention are dissolved in an organic solvent (alcohol or ester such as ethanol). The total lipid concentration is not particularly limited, but is generally 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.

[0476] The aqueous phase can be obtained by dissolving nucleic acid (for example, siRNA, mRNA, antisense nucleic acid, etc.) in water or a buffer. The concentration of the nucleic acid is not particularly limited, but is preferably 1 to 1000 μg / mL, more preferably 10 to 500 μg / mL. Components such as buffer components or antioxidants for pH adjustment can be added as needed. The pH of the aqueous phase is preferably 2.0 to 7.0, more preferably 3.0 to 6.0. As buffer components, acetic acid, citric acid, malic acid, phosphoric acid, MES, HEPES, etc. can be preferably used to adjust the pH, and salts such as sodium chloride and potassium chloride can be added as needed to adjust the ionic strength, or sugars or sugar alcohols such as sucrose, trehalose, and mannitol can be added to adjust the osmotic pressure.

[0477] In step (b), the oil phase and the aqueous phase can be mixed by any method, either batch or inline using a flow device. Inline mixing is preferably performed using a microfluidic device, and examples of such devices include Y-type mixers, T-type mixers, herringbone mixers, annular micromixers, and impact jet mixers. The mixing ratio (volume ratio) of the aqueous phase to the oil phase is preferably 5:1 to 1:1, and more preferably 4:1 to 2:1.

[0478] In operation (c), by mixing the dispersion of lipid particles with a dilute solution, the organic solvent can be reduced and the lipid particles can be stabilized. The dilute solution can be water and can include the adjustment of pH or ionic strength. The composition contained in the dilute solution can be arbitrarily selected according to purpose. For example, a buffer solution (for example, citrate buffer, citrate buffered saline, acetate buffer, acetate buffered saline, phosphate buffered saline, Tris buffer, MES buffer, HEPES buffer, etc.) can be used to adjust pH. In addition, sodium chloride, potassium chloride, sucrose, trehalose, fructose or mannitol, etc. can be contained to adjust ionic strength or osmotic pressure, and the solution of these additives further added in the buffer solution can also be used.

[0479] The dispersion liquid and the dilute solution of lipid granule can be mixed with any method, can be intermittent, also can be the online mode that has used stream device.The stream device used during mixing can use Y-type mixer, T-type mixer etc.And, after oil phase and water are mixed, the time till mixed dilute solution is not particularly limited, preferably after oil phase and water are mixed, implement dilution within 30 seconds, more preferably implement dilution within 10 seconds.

[0480] The mixing ratio (liquid volume ratio) of the lipid particle dispersion and the dilution solution is preferably 1:0.5 to 1:10, more preferably 1:1 to 1:5.

[0481] In some embodiments, the dispersion liquid of lipid granules can be repeatedly mixed with diluent according to purpose in operation (c).And, the diluent used can be identical or different.In the dispersion liquid of lipid granules, the particle diameter of lipid granules changes according to pH sometimes, so the pH regulation of dispersion liquid becomes important.Therefore, for example, in order to regulate the pH of the dispersion liquid of the lipid granules after mixing with diluent, it is possible to use the buffer solution with the concentration and pH that is suitable for it or the buffer solution also containing other components.

[0482] Moreover, multiple dilution processes can be implemented continuously, and the interval between a dilution process and the next dilution process can be set arbitrarily. For example, the interval can be 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours or 24 hours.

[0483] Furthermore, the pH of the lipid particle dispersion after step (c) is preferably pH 3.0 to pH 10.0, more preferably pH 3.5 to pH 9.0, and particularly preferably pH 4.0 to pH 8.5.

[0484] The size of the lipid composition can be adjusted as needed. The method for adjusting the size is not particularly limited, and the particle size can be reduced using an extruder or the like.

[0485] Furthermore, the dispersion containing the lipid composition of the present invention can be frozen or freeze-dried by a conventional method.

[0486] In step (d), as the method for removing the organic solvent from the dispersion liquid of lipid particles, it is not particularly limited and common methods can be used. For example, as dialysate, pH buffers such as phosphate buffered saline, Tris buffer can be used, and additives such as arbitrary salt or sugar can be added as needed to regulate osmotic pressure or protect it from freezing.

[0487] In operation (e), the concentration of the dispersion liquid of the lipid particles obtained in operation (d) can be adjusted. When diluting, solutions such as phosphate buffered saline, physiological saline, Tris buffer, Tris buffer containing sucrose can be used as diluents and diluted to appropriate concentrations. When concentrating, the dispersion liquid obtained in operation (d) can be concentrated by ultrafiltration using an ultrafiltration membrane. Preferably, the concentrated dispersion liquid is directly used, and it is also preferred to use the diluent to be adjusted to the desired concentration after concentrating.

[0488] Furthermore, in some embodiments, the organic solvent removal step (step (d)) and the concentration adjustment step (step (e)) can be performed continuously using tangential flow filtration (TFF). In this step, the organic solvent removal step and the concentration adjustment step can be performed in any order. The organic solvent removal step and the concentration adjustment step can each be performed multiple times as needed.

[0489] As a solution that can be used for dialysis in step (d) or dilution in step (e), an excipient, a cryoprotectant, a buffer or an antioxidant can be added. As an excipient or cryoprotectant, it is not particularly limited, and sugars or sugar alcohols can be mentioned. As sugars, for example, sucrose, trehalose, maltose, glucose, lactose, fructose, etc. can be mentioned, and as sugar alcohols, for example, mannitol, sorbitol, inositol, xylitol, etc. can be mentioned. As a buffer, it is not particularly limited, and for example, ACES, BES, Bicine, CAPS, CHES, DIPSO, EPPS, HEPES, HEPPSO, MES, MOPS, MOPSO, TAPS, TAPSO, TES, Tricine, trishydroxymethylaminomethane, phosphoric acid, acetic acid, citric acid, etc. can be mentioned. As an antioxidant, EDTA, ascorbic acid, tocopherol, etc. can be mentioned.

[0490] In order to make the dispersion liquid of lipid granules of the present invention into pharmaceutical composition, preferably carry out aseptic filtration.As filtering method, hollow fiber membrane, reverse osmosis membrane, membrane filter etc. can be used to remove insoluble material from the dispersion liquid of lipid granules.Though not particularly limited in the present invention, preferably utilize the filter (preferably 0.2 μ m filtration sterilizing filter) with the aperture that can be sterilized to filter.And, aseptic filtration is preferably carried out after operation (d) or operation (e).

[0491] Furthermore, the dispersion of the lipid particles of the present invention can be subjected to freezing or freeze-drying as needed. The dispersion of the lipid particles of the present invention can be subjected to freezing or freeze-drying by a conventional method, and the method is not particularly limited.

[0492] <About lipid composition>

[0493] In the present invention, lipid composition can be lipid particles.Lipid particles refer to particles made of lipids, including compositions with any structure selected from lipid aggregates, micelles, liposomes, lipid nanoparticles (LNP), liposome complexes of lipid aggregation, as long as the composition containing lipids, the structure of lipid particles is not limited to these. As liposomes, there is a lipid bilayer structure, with an aqueous phase inside, a double membrane as a single-layer liposome, a multilayer liposome with multilayer overlap. The present invention can include any liposome.

[0494] The morphology of lipid particles can be confirmed by electron microscopic observation or structural analysis using X-rays. For example, by using the method of Cryo transmission electron microscopy (CryoTEM method), it is possible to confirm whether lipid particles are lipid bilayer structures (lamellar structures) and structures with inner water layers as liposomes, or whether the particle interior has a core with a high electron density and has a structure filled with constituents headed by lipids. It is also possible to confirm whether lipid particles have lipid bilayer structures (lamellar structures) by measuring small-angle X-ray scattering (SAXS).

[0495] The particle size of the lipid particles of the present invention is not particularly limited, but is preferably 10 to 1000 nm, more preferably 30 to 500 nm, and even more preferably 50 to 250 nm. The particle size of the lipid particles can be measured by conventional methods (eg, dynamic light scattering, laser diffraction, etc.).

[0496] <Utilization of lipid compositions>

[0497] As an example of the use of the lipid composition of the present invention, nucleic acids, proteins, peptides or low molecules can be introduced into cells by introducing the lipid composition containing nucleic acids, proteins, peptides or low molecules into cells. In addition, when the lipid composition of the present invention contains nucleic acids, proteins, peptides or low molecules with medical uses, the lipid composition can be administered to a living body as a pharmaceutical composition.

[0498] Furthermore, the lipid composition may be one that does not contain nucleic acids, proteins, peptides, or low molecules and contains only lipid components. By preparing a lipid composition containing only lipid components and then mixing it with nucleic acids, proteins, peptides, or low molecules, a lipid composition containing nucleic acids, proteins, peptides, or low molecules can also be obtained.

[0499] When the lipid composition of the present invention is used as a pharmaceutical composition, it can be administered to a living body alone or in a mixture with a pharmaceutically acceptable administration medium (eg, physiological saline or phosphate buffer).

[0500] The concentration of the lipid composition in the mixture with the pharmaceutically acceptable carrier is not particularly limited and can generally be set to 0.05% to 90% by mass. In addition, other pharmaceutically acceptable additives such as pH regulating buffers, osmotic pressure regulators, etc. can be added to the pharmaceutical composition containing the lipid composition of the present invention.

[0501] The route of administration when the pharmaceutical composition containing the lipid composition of the present invention is administered is not particularly limited, and can be administered by any method. As administration, oral administration, parenteral 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, colon administration, buccal administration, nasal administration, intracisternal administration, suction etc.) can be enumerated. Preferably parenteral administration, as administration, preferably intravenous injection, subcutaneous injection, intradermal injection or intramuscular injection. The pharmaceutical composition containing the lipid composition of the present invention can also be administered by being directly injected into the disease site.

[0502] 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 appropriate excipients and used in the form of tablets, buccal tablets, capsules, pills, suspensions, syrups, etc. In addition, the preparation suitable for parenteral administration can appropriately contain additives such as antioxidants, buffers, antibacterial agents, isotonic sterile injections, suspending agents, solubilizers, thickeners, stabilizers or preservatives.

[0503] Delivery vehicle

[0504] The lipid composition of the present invention can keep nucleic acid with high encapsulation efficiency, and is therefore very useful as the delivery vector of nucleic acid. According to utilizing the delivery vector of the present invention, for example, nucleic acid etc. can be imported into cell by mixing the lipid composition obtained with nucleic acid and transfecting in vitro (in vitro) or in vivo (in vivo). Also, utilizing the delivery vector of the present invention to be also useful as the nucleic acid delivery vector in nucleic acid drug. That is, the lipid composition of the present invention is useful as the composition for carrying out nucleic acid delivery in vitro, semi-vivo (ex vivo) or in vivo (preferably in vivo).

[0505] Next, the present invention will be described with reference to Examples, but the present invention is not limited to these.

[0506] Example

[0507] Unless otherwise specified, purification by column chromatography used an automated purification apparatus ISOLERA (Biotage Japan Ltd.), a medium-pressure separation and purification apparatus Purif-espoir-2 (Shoko Science Co., Ltd.), or a medium-pressure liquid chromatograph YFLC W-prep 2XY (YAMAZEN CORPORATION).

[0508] Unless otherwise specified, Chromatorex Q-Pack SI 50 (FUJI SILYSIA CHEMICAL LTD.) or High-Flash Column W001, W002, W003, W004, or W005 (YAMAZEN CORPORATION) was used as a support for silica gel column chromatography.

[0509] Chromatorex Q-Pack NH 60 (Fuji Silysia Chemical Ltd.) was used as the NH silica gel.

[0510] The NMR spectrum was measured using Bruker AVNEO400 (manufactured by Bruker) using tetramethylsilane as an internal standard, and the total δ value was expressed in ppm.

[0511] MS spectra were measured using ACQUITY SQD LC / MS System (manufactured by Waters).

[0512] [Comparative Example 1]

[0513] [Chemical Formula 72]

[0514]

[0515] The synthesis was carried out according to the example described in WO2020 / 246581 (2-hexyloctyl 3-ethyl-6-(2-(octanoyloxy)ethyl)-11-octyl-10-oxo-9-oxa-3,6,11-triazaheneicosane-21-oic acid ester).

[0516] [Example 1] (1)

[0518] [Chemical Formula 73]

[0519]

[0520] Under ice-cooling, 4-nitrophenyl chloroformate (11.3 g) was divided into two portions and added to a mixture of 2,2-diethoxyethanol (5.0 g), tetrahydrofuran (25 mL) and triethylamine (15.6 mL), and stirred under ice-cooling for 1 hour. Water (25 mL) and hexane (25 mL) were added to the reaction mixture under ice-cooling, and the organic layer was separated. The obtained organic layer was washed with water (25 mL) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2,2-diethoxyethyl (4-nitrophenyl) carbonate (12.2 g) as a light yellow oil.

[0521] 1 H-NMR (CDCl3) δ: 8.30-8.26 (2H, m), 7.41-7.37 (2H, m), 4.79 (1H, t, J = 5.3Hz), 4. 28(2H,d,J=5.3Hz),3.80-3.72(2H,m),3.66-3.58(2H,m),1.26(6H,t,J=7.0Hz). (2)

[0523] [Chemical Formula 74]

[0524]

[0525] A mixture of 2,2-diethoxyethyl (4-nitrophenyl) carbonate (1.0 g), acetonitrile (5 mL), dioctylamine (0.84 g) and triethylamine (0.93 mL) was stirred at 60°C for 5 hours. Ethyl acetate (5 mL), hexane (5 mL) and water were added to the reaction mixture cooled to room temperature, and the organic layer was separated. The obtained organic layer was washed with water (25 mL) and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2,2-diethoxyethyl N,N-dioctylcarbamate (1.1 g) as a light yellow oil.

[0526] 1 H-NMR (CDCl3) δ: 24.69 (1H, t, J = 5.5Hz), 4.08 (2H, d, J = 5.5Hz), 3.75-3.67 (2H, m), 3.61-3 .53(2H,m),3.22-3.15(4H,m),1.55-1.47(4H,m),1.33-1.20(26H,m),0.90-0.85(6H,m). (3)

[0528] [Chemical Formula 75]

[0529]

[0530] A mixture of 2,2-diethoxyethyl N,N-dioctylcarbamate (1.0 g), formic acid (10 mL), and water (2.5 mL) was stirred at 50°C for 4 hours, then toluene was added and distilled under reduced pressure. Toluene was added again, and the distillation under reduced pressure was repeated twice to obtain 2-oxoethyl N,N-dioctylcarbamate (0.98 g) as a pale yellow oily crude product.

[0531] 1 H-NMR(CDCl3)δ: 9.63(1H,s),4.63(2H,s),3.27-3.21(4H,m),1.61-1.48(4H,m),1.32-1.22(20H,m),0.90-0.86(6H,m). (4)

[0533] [Chemical Formula 76]

[0534]

[0535] To a solution of 2-oxoethyl N,N-dioctylcarbamate (0.815 g) in ethyl acetate (8 mL) were added N,N-diethylethylenediamine (0.145 g), acetic acid (74 mg), and sodium triacetoxyborohydride (1.58 g) at room temperature, and the mixture was stirred at room temperature for 5 hours. After adding 20% ​​aqueous potassium carbonate (27 mL) to the reaction mixture, the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain ((2-(diethylamino)ethyl)azadiyl)bis(ethane-2,1-diyl)bis(dioctylcarbamate) (0.574 g) as a colorless oil.

[0536] 1 H-NMR(CDCl3)δ: 4.11(4H,t,J=6.3Hz), 3.23-3.11(8H,m), 2.80(4H,t,J=6.3Hz), 2.68-2.64(2H,m), 2.55-2.49(6H,m),1.65-1.43(8H,m),1.34-1.18(40H,m),1.01(6H,t,J=7.1Hz),0.90-0.85(12H,m).

[0537] MS m / z (M+H): 740.

[0538] [Example 2] (1)

[0540] [Chemical Formula 77]

[0541]

[0542] To a mixture of 2-hexyl-1-octanol (5.0 g) and 5-bromovaleric acid (4.6 g) in toluene (25 mL) was added sulfuric acid (0.5 mL), followed by stirring at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-hexyloctyl 5-bromovaleric acid (8.2 g) as a colorless oil.

[0543] 1 H-NMR (CDCl3) δ: 3.98 (2H, d, J = 5.7Hz), 3.42 (2H, t, J = 6.5Hz), 2.34 (2H, t, J = 7.2Hz), 1.94- 1.87(2H,m),1.82-1.74(2H,m),1.65-1.57(1H,m),1.32-1.23(20H,m),0.90-0.86(6H,m). (2)

[0545] [Chemical Formula 78]

[0546]

[0547] To a mixture of 2-hexyloctyl 5-bromovaleric acid (1.2 g), n-octylamine (1.2 g) and 1-methyl-2-pyrrolidone (6 mL) was added potassium carbonate (1.3 g) and stirred at 60 ° C for 5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (12 mL) and water (6 mL) were added and the organic layer was separated. After the organic layer was washed with saturated brine, anhydrous sodium sulfate was added for drying and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain 2-hexyloctyl 5-(octylamino) pentanoic acid (1.25 g) as a light yellow oil.

[0548] 1 H-NMR (CDCl3) δ: 3.96 (2H, d, J = 5.8Hz), 2.63-2.52 (4H, m), 2.32 (2H, t, J = 7.4Hz ),2.06-1.98(1H,m),1.70-1.40(7H,m),1.34-1.20(30H,m),0.90-0.87(9H,m). (3)

[0550] [Chemical Formula 79]

[0551]

[0552] A mixture of 2-hexyloctyl 5-(octylamino)pentanoic acid (1.25 g), acetonitrile (4 mL), 2,2-diethoxyethyl (4-nitrophenyl) carbonate (0.49 g), and triethylamine (0.46 mL) was stirred at 60°C for 4 hours. Ethyl acetate (4 mL) and water (4 mL) were added to the reaction mixture, which had been cooled to room temperature, and the organic layer was separated. The resulting organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-hexyloctyl 5-(((2,2-diethoxyethoxy)carbonyl)(octyl)amino)pentanoic acid (0.83 g) as a light yellow oil.

[0553] 1 H-NMR (CDCl3) δ: 4.69 (1H, t, J = 5.4Hz), 4.08 (2H, d, J = 5.5Hz), 3.97 (2H, d, J = 5.7Hz), 3.74-3.62 (2H, m), 3.60- 3.52(2H,m),3.26-3.14(4H,m),2.36-2.30(2H,m),1.65-1.46(7H,m),1.33-1.19(36H,m),0.90-0.85(9H,m). (4)

[0555] [Chemical formula 80]

[0556]

[0557] A mixture of 2-hexyloctyl 5-(((2,2-diethoxyethoxy)carbonyl)(octyl)amino)pentanoic acid (0.83 g), formic acid (6 mL), and water (1.5 mL) was stirred at 50°C for 3 hours, then toluene was added and distilled under reduced pressure. Toluene was added again, and the distillation under reduced pressure was repeated twice to obtain 2-hexyloctyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid (0.94 g) as a pale yellow oily crude product.

[0558] 1H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.7Hz), 3.25-3.11(8H,m), 2.79(4H,t,J=6.4Hz), 2.69-2.63(2H,m) ,2.56-2.47(6H,m),2.36-2.29(4H,m),1.64-1.49(14H,m),1.32-1.21(60H,m),1.01(6H,t,J=7.0Hz),0.90-0.85(18H,m). (5)

[0560] [Chemical Formula 81]

[0561]

[0562] To a solution of 2-hexyloctyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid (0.73 g) in ethyl acetate (8 mL) were added N,N-diethylethylenediamine (0.083 g), acetic acid (43 mg), and sodium triacetoxyborohydride (0.91 g) at room temperature, and the mixture was stirred for 5 hours. A 20% aqueous potassium carbonate solution (10 mL) was added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain bis(2-hexyloctyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate (0.39 g) as a pale yellow oil.

[0563] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.7Hz), 3.25-3.11(8H,m), 2.79(4H,t,J=6.4Hz), 2.69-2.63(2H,m) ,2.56-2.47(6H,m),2.36-2.29(4H,m),1.64-1.49(14H,m),1.32-1.21(60H,m),1.01(6H,t,J=7.0Hz),0.90-0.85(18H,m).

[0564] MS m / z (M+H): 1108.

[0565] [Example 3]

[0566] [Chemical Formula 82]

[0567]

[0568] In Example 2(1), except that 2-pentyl-1-heptanol was used instead of 2-hexyl-1-octanol, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 2.

[0569] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.8Hz), 3.26-3.11(8H,m), 2.79(4H,t,J=6.3Hz), 2.69-2.63(2H,m) ,2.54-2.48(6H,m),2.36-2.29(4H,m),1.65-1.45(14H,m),1.35-1.91(52H,m),1.00(6H,t,J=7.1Hz),0.90-0.86(18H,m).

[0570] MS m / z (M+H): 1052.

[0571] [Example 4] (1)

[0573] [Chemical Formula 83]

[0574]

[0575] 1,1'-Carbonylbis(1,2,4-triazole) (18.3 g) was added to a solution of 2,2-diethoxyethanol (10.0 g) in tetrahydrofuran (100 mL), heated to 30°C, and stirred for 1 hour. After the reaction mixture was cooled to room temperature, hexane (100 mL) and saturated aqueous sodium bicarbonate (100 mL) were added, and the organic layer was separated. The resulting organic layer was washed with water (50 mL) and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2,2-diethoxyethyl 1H-1,2,4-triazole-1-carboxylate (10.4 g) as a colorless oil.

[0576] 1H-NMR (CDCl3) δ: 8.83 (1H, s), 8.09 (1H, s), 4.87 (1H, t, J = 5.3Hz), 4.49 (2H ,d,J=5.3Hz),3.80-3.73(2H,m),3.66-3.56(2H,m),1.23(6H,t,J=7.0Hz). (2)

[0578] [Chemical formula 84]

[0579]

[0580] 4-Toluenesulfonic acid monohydrate (168 mg) was added to a mixture of 2-pentyl-1-heptanol (6.0 g) and 5-bromovaleric acid (6.4 g) in toluene (30 mL) at room temperature. The mixture was then stirred for 2 hours under reflux using a Dean-Stark apparatus while removing water. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-pentylheptyl 5-bromovaleric acid (10.8 g) as a colorless oil.

[0581] 1 H-NMR(CDCl3)δ: 3.98(2H,d,J=5.8Hz), 3.42(2H,t,J=6.6Hz), 2.35(2H,t,J=7.2Hz), 1.94-1 .87(2H,m),1.82-1.74(2H,m),1.65-1.59(1H,m),1.34-1.23(16H,m),0.89(6H,t,J=6.9Hz). (3)

[0583] [Chemical Formula 85]

[0584]

[0585] To a mixture of 2-pentylheptyl 5-bromovaleric acid (1.2 g), n-hexylamine (1.05 g) and acetonitrile (6 mL) was added potassium carbonate (1.45 g) and stirred at 60 ° C for 1 hour. After the reaction mixture was cooled to room temperature, ethyl acetate (24 mL) and water (12 mL) were added and the organic layer was separated. After the organic layer was washed with water and saturated brine, anhydrous sodium sulfate was added for drying and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate-hexane) to obtain 5-(hexylamino) pentanoic acid 2-pentylheptyl ester (0.864 g) as a light yellow oil.

[0586] 1H-NMR(CDCl3)δ: 3.96(2H,d,J=5.8Hz), 2.62-2.55(4H,m), 2.32(2H,t,J=7.4Hz), 1.70-1.43(8H,m), 1.34-1.20(22H,m), 0.90-0.85(9H,m). (4)

[0588] [Chemical Formula 86]

[0589]

[0590] A mixture of 2-pentylheptyl 5-(hexylamino)pentanoate (0.86 g), 2,2-diethoxyethyl 1H-1,2,4-triazole-1-carboxylate (0.53 g), acetonitrile (4.3 mL), triethylamine (0.65 mL), and N,N-dimethylaminopyridine (10 mg) was stirred at 60°C for 2 hours. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture, which had been cooled to room temperature, and the organic layer was separated. The resulting organic layer was washed with saturated ammonium chloride and saturated brine, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate-hexane) to obtain 2-pentylheptyl 5-(((2,2-diethoxyethoxy)carbonyl)(hexyl)amino)pentanoic acid (0.95 g) as a colorless oil.

[0591] 1 H-NMR (CDCl3) δ: 4.69 (1H, t, J = 5.5Hz), 4.08 (2H, d, J = 5.5Hz), 3.97 (2H, d, J = 5.7Hz), 3.74-3.67 (2H, m), 3.60- 3.52(2H,m),3.26-3.14(4H,m),2.35-2.30(2H,m),1.65-1.48(7H,m),1.33-1.19(28H,m),0.90-0.86(9H,m). (5)

[0593] [Chemical Formula 87]

[0594]

[0595] A mixture of 2-pentylheptyl 5-(((2,2-diethoxyethoxy)carbonyl)(hexyl)amino)valeric acid (0.95 g), formic acid (4 mL), and water (1 mL) was stirred at 40°C for 2 hours, then toluene was added and distilled under reduced pressure. Toluene was added again, and the distillation under reduced pressure was repeated twice to obtain 2-pentylheptyl 5-(hexyl((2-oxoethoxy)carbonyl)amino)valeric acid as a pale yellow oil as a crude product.

[0596] 1 H-NMR (CDCl3) δ: 9.62 (1H, s), 4.63-4.60 (2H, m), 3.97 (2H, d, J = 5.7Hz), 3.30-3.17 ( 4H,m),2.36-2.31(2H,m),1.66-1.50(7H,m),1.34-1.21(22H,m),0.90-0.86(9H,m). (6)

[0598] [Chemical Formula 88]

[0599]

[0600] To a solution of 2-pentylheptyl 5-(hexyl((2-oxoethoxy)carbonyl)amino)pentanoic acid, a crude product of Example 4(5), in ethyl acetate (10 mL), N,N-diethylethylenediamine (0.127 g) and sodium triacetoxyborohydride (1.14 g) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. After adding a 10% aqueous potassium carbonate solution (10 mL) to the reaction mixture, the organic layer was separated, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate-hexane) to obtain bis(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate (0.67 g) as a pale yellow oil.

[0601] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.97(4H,d,J=5.8Hz), 3.25-3.10(8H,m), 2.79(4H,t,J=6.4Hz), 2.68-2.64(2H,m) ,2.54-2.49(6H,m),2.35-2.29(4H,m),1.64-1.45(14H,m),1.33-1.21(44H,m),1.01(6H,t,J=7.1Hz),0.90-0.86(18H,m).

[0602] MS m / z (M+H): 996.

[0603] [Example 5]

[0604] [Chemical Formula 89]

[0605]

[0606] In Example 2(1), except that n-hexylamine was used instead of n-octylamine, bis(2-hexyloctyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 2.

[0607] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.7Hz), 3.25-3.12(8H,m), 2.79(4H,t,J=6.3Hz), 2.69-2.64(2H,m) ,2.54-2.49(6H,m),2.35-2.29(4H,m),1.64-1.45(14H,m),1.34-1.20(52H,m),1.01(6H,t,J=7.1Hz),0.90-0.86(18H,m).

[0608] MS m / z (M+H): 1052.

[0609] [Example 6] (1)

[0611] [Chemical formula 90]

[0612]

[0613] 2-pentylheptyl 3-chloropropionic acid was obtained as a pale yellow oily substance in the same manner as in Example 4(2) except that 3-chloropropionic acid was used instead of 5-bromovaleric acid.

[0614] 1 H-NMR (CDCl3) δ: 4.04 (2H, d, J = 5.7Hz), 3.76 (2H, t, J = 6.7Hz), 2.80 (2H, t, J = 6.7Hz), 1.67-1.60 (1H, m), 1.35-1.21 (16H, m), 0.89 (6H, t, J = 6.9Hz). (2)

[0616] [Chemical Formula 91]

[0617]

[0618] In Example 4(3), 2-pentylheptyl 3-chloropropionic acid was used instead of 2-pentylheptyl 5-bromovaleric acid, n-butylamine was used instead of n-hexylamine, and benzyltriethylammonium bromide was used as an additive. 2-pentylheptyl 3-(butylamino)propionic acid ester was obtained as a light yellow oily substance in the same manner as in Example 4(3).

[0619] 1 H-NMR(CDCl3)δ: 3.99(2H,d,J=5.7Hz), 2.88(2H,t,J=6.5Hz), 2.61(2H,t,J=7.2Hz), 2.52(2H,t,J=6.5Hz), 1.65-1.21(22H,m), 0.93-0.86(9H,m). (3)

[0621] [Chemical Formula 92]

[0622]

[0623] In Example 2(3), except that 2-pentylheptyl 3-(butylamino)propionate was used instead of 2-hexyloctyl 5-(octylamino)pentanoic acid, bis(2-pentylheptyl) 4,14-dibutyl-9-(2-(diethylamino)ethyl)-5,13-dioxo-6,12-dioxa-4,9,14-triazaheptadecanedioate was obtained as a colorless oily substance in the same manner as in Example 2.

[0624] 1 H-NMR(CDCl3)δ: 4.14-4.08(4H,m), 3.98(4H,d,J=5.8Hz), 3.54-3.45(4H,m), 3.27-3.16(4H,m), 2.80(4H,t,J= 6.4Hz),2.67-2.48(12H,m),1.66-1.45(6H,m),1.36-1.21(36H,m),1.01(6H,t,J=7.1Hz),0.94-0.86(18H,m).

[0625] MS m / z (M+H): 884.

[0626] [Example 7]

[0627] [Chemical Formula 93]

[0628]

[0629] In Example 6 (3), except that N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine, bis(2-pentylheptyl)-4,14-dibutyl-9-(3-(diethylamino)propyl)-5,13-dioxo-6,12-dioxa-4,9,14-triazaheptadecanedioate was obtained as a colorless oily substance in the same manner as in Example 6.

[0630] 1 H-NMR(CDCl3)δ: 4.14-4.08(4H,m),3.98(4H,d,J=5.8Hz),3.53-3.45(4H,m),3.27-3.17(4H,m),2.76(4H,t,J=6.6Hz),2 .63-2.48(10H,m),2.43-2.38(2H,m),1.66-1.45(8H,m),1.35-1.21(36H,m),1.01(6H,t,J=7.1Hz),0.94-0.86(18H,m).

[0631] MS m / z (M+H): 898.

[0632] [Example 8]

[0633] [Chemical Formula 94]

[0634]

[0635] Except that n-propylamine was used instead of n-butylamine in Example 6 (2), bis(2-pentylheptyl)9-(2-(diethylamino)ethyl)-5,13-dioxo-4,14-dipropyl-6,12-dioxa-4,9,14-triazaheptadecanedioate was obtained as a colorless oily substance in the same manner as in Example 6.

[0636] 1 H-NMR(CDCl3)δ: 4.13-4.09(4H,m),3.98(4H,d,J=5.8Hz),3.54-3.45(4H,m),3.24-3.14(4H,m),2.80(4H,t,J= 6.4Hz),2.67-2.48(12H,m),1.65-1.50(6H,m),1.34-1.21(32H,m),1.01(6H,t,J=7.1Hz),0.94-0.85(18H,m).

[0637] MS m / z (M+H): 856.

[0638] [Example 9]

[0639] [Chemical Formula 95]

[0640]

[0641] Except that n-propylamine was used instead of n-butylamine in Example 6(2) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 6(3), bis(2-pentylheptyl)9-(3-(diethylamino)propyl)-5,13-dioxo-4,14-dipropyl-6,12-dioxa-4,9,14-triazaheptadecanedioate was obtained as a colorless oily substance in the same manner as in Example 6.

[0642] 1 H-NMR(CDCl3)δ: 4.13-4.09(4H,m),3.98(4H,d,J=5.8Hz),3.54-3.44(4H,m),3.24-3.14(4H,m),2.77(4H,t,J=6.4Hz),2 .63-2.47(10H,m),2.44-2.38(2H,m),1.65-1.50(8H,m),1.35-1.21(32H,m),1.00(6H,t,J=7.1Hz),0.90-0.86(18H,m).

[0643] MS m / z (M+H): 870.

[0644] [Example 10] (1)

[0646] [Chemical Formula 96]

[0647]

[0648] Chloroacetyl chloride (1.82 g) was added to a solution of 2-pentyl-1-heptanol (2.00 g) in tetrahydrofuran (20 mL), and pyridine (2.6 mL) was added under ice-cooling. The mixture was stirred at room temperature for 20 minutes, and water (20 mL) and hexane (10 mL) were added to the reaction mixture, followed by separation of the organic layer. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of 2-pentylheptyl 2-chloroacetate (3.85 g).

[0649] 1 H-NMR (CDCl3) δ: 4.10 (2H, d, J = 5.8Hz), 4.06 (2H, s), 1.79-1.61 (1H, m), 1.35-1.22 (16H, m), 0.89 (6H, t, J = 7.0Hz). (2)

[0651] [Chemical Formula 97]

[0652]

[0653] In Example 2(2), except that 2-pentylheptyl 2-chloroacetate was used instead of 2-hexyloctyl 5-bromovaleric acid, and n-propylamine was used instead of n-octylamine, bis(2-pentylheptyl) 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-dipropyl-5,11-dioxa-3,8,13-triazapentadecanedioate was obtained as a colorless oily substance in the same manner as in Example 2.

[0654] 1 H-NMR(CDCl3)δ: 4.13-4.06(4H,m),4.04-3.92(8H,m),3.29-3.21(4H,m),2.84-2.71(4H,m),2.69-2.60(2H,m),2.5 6-2.45(6H,m),1.66-1.58(2H,m),1.58-1.50(4H,m),1.35-1.21(32H,m),1.01(6H,t,J=7.0Hz),0.91-0.86(18H,m).

[0655] MS m / z (M+H): 828.

[0656] [Example 11]

[0657] [Chemical Formula 98]

[0658]

[0659] In Example 10(2), except that N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine, bis(2-pentylheptyl)8-(3-(diethylamino)propyl)-4,12-dioxo-3,13-dipropyl-5,11-dioxa-3,8,13-triazapentadecanedioate was obtained as a colorless oily substance in the same manner as in Example 10.

[0660] 1 H-NMR(CDCl3)δ: 4.14-4.06(4H,m),4.04-3.92(8H,m),3.29-3.21(4H,m),2.81-2.68(4H,m),2.58-2.47(6 H,m),2.44-2.37(2H,m),1.64-1.49(8H,m),1.34-1.21(32H,m),1.01(6H,t,J=7.1Hz),0.91-0.86(18H,m).

[0661] MS m / z (M+H): 842.

[0662] [Example 12] (1)

[0664] [Chemical Formula 99]

[0665]

[0666] Under ice cooling, decanoyl chloride (11 mL) was added dropwise to a solution of tert-butyl N,N-bis(2-hydroxyethyl)carbamate (5.00 g) and triethylamine (8.15 mL) in tetrahydrofuran (50 mL), followed by stirring at room temperature for 4 hours. Hexane (50 mL) and water (50 mL) were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with water (50 mL) and saturated brine, then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain ((tert-butoxycarbonyl)azadiyl)bis(ethane-2,1-diyl)bis(decanoic acid) (13.1 g) as a crude yellow oil.

[0667] 1 H-NMR(CDCl3)δ: 4.21-4.13(4H,m),3.52-3.44(4H,m),2.30(4H,t,J=7.5Hz) ,1.67-1.55(4H,m),1.46(9H,s),1.33-1.23(24H,m),0.88(6H,t,J=6.8Hz). (2)

[0669] [Chemical Formula 100]

[0670]

[0671] Trifluoroacetic acid (20 mL) was added to a mixture of ((tert-butoxycarbonyl)azadiyl)bis(ethane-2,1-diyl)bis(decanoic acid) (13.0 g) and water (1 mL) at room temperature, and the mixture was stirred overnight. The mixture was evaporated under reduced pressure, and hexane (60 mL), ethyl acetate (30 mL), and 20% aqueous potassium carbonate solution (40 mL) were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain azadiylbis(ethane-2,1-diyl)bis(decanoic acid) (7.39 g) as a pale yellow oil.

[0672] MS m / z (M+H): 415. (3)

[0674] [Chemical Formula 101]

[0675]

[0676] In Example 4(4), except that azadiylbis(ethane-2,1-diyl)bis(decanoic acid) was used instead of 2-pentylheptyl 5-(hexylamino)pentanoate, 2-(2-(2-(bis(2-decanoyloxyethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-decanoyloxyethyl)amino)ethyldecanoate was obtained as a colorless oil by the same method as in Example 4(4), Example 4(5) and Example 4(6).

[0677] 1 H-NMR(CDCl3)δ: 4.22-4.11(12H,m),3.56-3.49(8H,m),2.79(4H,t,J=6.4Hz),2.68-2.63(2H,m),2.54-2.47(6H ,m),2.30(8H,t,J=7.5Hz),1.64-1.54(8H,m),1.33-1.22(48H,m),1.01(6H,t,J=7.1Hz),0.88(12H,t,J=6.8Hz).

[0678] MS m / z (M+H): 1084.

[0679] [Example 13]

[0680] [Chemical Formula 102]

[0681]

[0682] In Example 4(3), except that isopropylamine was used instead of n-hexylamine, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diisopropyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0683] 1H-NMR(CDCl3)δ: 4.32-4.05(2H,m),4.11(4H,t,J=6.3Hz), 4.00(4H,d,J=5.8Hz), 3.15-3.02(4H,m),2.80(4H,t,J=6.4Hz), 2.68-2.64(2H,m),2.5 4-2.49(6H,m),2.32(4H,t,J=7.0Hz),1.64-1.53(10H,m),1.34-1.21(32 H,m),1.13(12H,d,J=6.8Hz),1.01(6H,t,J=7.1Hz),0.90-0.86(12H,m).

[0684] MS m / z (M+H): 912.

[0685] [Example 14]

[0686] [Chemical Formula 103]

[0687]

[0688] Except that isopropylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diisopropyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0689] 1 H-NMR (CDCl3) δ: 4.30-4.05 (2H, m), 4.11 (4H, t, J = 6.4Hz), 3.97 (4H, d, J = 5.8Hz),3.16-3.00(4H,m),2.77(4H,t,J=6.4Hz),2.57-2.47(6H,m),2.43 -2.39(2H,m),2.32(4H,t,J=7.0Hz),1.66-1.53(12H,m),1.35-1.21(32H, m), 1.13 (12H, d, J = 6.8Hz), 1.00 (6H, t, J = 7.1Hz), 0.88 (12H, t, J = 6.9Hz).

[0690] MS m / z (M+H): 926.

[0691] [Example 15]

[0692] [Chemical Formula 104]

[0693]

[0694] In Example 4(3), except that n-propylamine was used instead of n-hexylamine, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-6,16-dipropyl-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0695] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.8Hz), 3.26-3.09(8H,m), 2.79(4H,t,J=6.3Hz), 2.68-2.64(2H,m) ,2.54-2.49(6H,m),2.34-2.31(4H,m),1.66-1.49(14H,m),1.35-1.21(32H,m),1.01(6H,t,J=7.1Hz),0.90-0.85(18H,m).

[0696] MS m / z (M+H): 912.

[0697] [Example 16]

[0698] [Chemical Formula 105]

[0699]

[0700] Except that n-propylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-6,16-dipropyl-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0701] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.97(4H,d,J=5.8Hz), 3.26-3.09(8H,m), 2.76(4H,t,J=6.4Hz), 2.57-2.48(6H,m) ,2.43-2.39(2H,m),2.34-2.31(4H,m),1.66-1.49(16H,m),1.36-1.21(32H,m),1.01(6H,t,J=7.1Hz),0.90-0.84(18H,m).

[0702] MS m / z (M+H): 926.

[0703] [Example 17]

[0704] [Chemical Formula 106]

[0705]

[0706] In Example 4(2), except that 2-butyl-1-octanol was used instead of 2-pentyl-1-heptanol, bis(2-butyloctyl)-11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0707] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.97(4H,d,J=5.8Hz), 3.25-3.12(8H,m), 2.80(4H,t,J=6.4Hz), 2.70-2.62(2H,m ),2.58-2.46(6H,m),2.34-2.31(4H,m),1.65-1.45(14H,m),1.35-1.21(44H,m),1.07-0.97(6H,m),0.90-0.86(18H,m).

[0708] MS m / z (M+H): 997.

[0709] [Example 18]

[0710] [Chemical Formula 107]

[0711]

[0712] In Example 4(3), except that isobutylamine was used instead of n-hexylamine, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diisobutyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0713] 1H-NMR(CDCl3)δ: 4.13-4.07(4H,m),3.97(4H,d,J=5.8Hz),3.26-3.09(4H,m),3.06-2.99(4H,m),2.79(4H,t,J=6.3Hz),2.68-2.64(2H,m),2 .54-2.49(6H,m),2.35-2.30(4H,m),1.95-1.85(2H,m),1.65-1.51(1 0H,m),1.35-1.21(32H,m),1.01(6H,t,J=7.1Hz),0.90-0.85(24H,m).

[0714] MS m / z (M+H): 940.

[0715] [Example 19]

[0716] [Chemical Formula 108]

[0717]

[0718] Except that isobutylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diisobutyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0719] 1 H-NMR(CDCl3)δ: 4.13-4.07(4H,m),3.97(4H,d,J=5.8Hz),3.26-3.12(4H,m),3.05-2.99(4H,m),2.76(4H,t,J=6.4Hz),2.57-2.48(6H,m),2 .43-2.39(2H,m),2.35-2.30(4H,m),1.95-1.84(2H,m),1.65-1.51(1 2H,m),1.35-1.21(32H,m),1.01(6H,t,J=7.1Hz),0.90-0.85(24H,m).

[0720] MS m / z (M+H): 954.

[0721] [Example 20]

[0722] [Chemical Formula 109]

[0723]

[0724] 2-(2-(2-(bis(2-dodecanoyloxyethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-dodecanoyloxyethyl)amino)ethyl dodecanoate was obtained as a colorless oily substance in the same manner as in Example 12, except that dodecanoyl chloride was used instead of decanoyl chloride.

[0725] 1 H-NMR(CDCl3)δ: 4.22-4.11(12H,m),3.56-3.49(8H,m),2.79(4H,t,J=6.4Hz),2.68-2.63(2H,m),2.55-2.48(6H ,m),2.30(8H,t,J=7.5Hz),1.64-1.54(8H,m),1.33-1.22(64H,m),1.01(6H,t,J=7.1Hz),0.88(12H,t,J=6.8Hz).

[0726] [Example 21]

[0727] [Chemical Formula 110]

[0728]

[0729] Except that n-butylamine was used instead of n-hexylamine in Example 4(3), bis(2-pentylheptyl)6,16-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0730] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.8Hz), 3.25-3.13(8H,m), 2.79(4H,t,J=6.4Hz), 2.68-2.64(2H,m) ,2.55-2.49(6H,m),2.34-2.31(4H,m),1.66-1.44(14H,m),1.35-1.20(36H,m),1.01(6H,t,J=7.1Hz),0.92-0.87(18H,m).

[0731] MS m / z (M+H): 940.

[0732] [Example 22]

[0733] [Chemical Formula 111]

[0734]

[0735] Except that n-butylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)6,16-dibutyl-11-(3-(diethylamino)propyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0736] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.97(4H,d,J=5.8Hz), 3.24-3.13(8H,m), 2.76(4H,t,J=6.4Hz), 2.55-2.48(6H,m) ,2.43-2.40(2H,m),2.34-2.31(4H,m),1.66-1.44(16H,m),1.35-1.20(36H,m),1.00(6H,t,J=7.1Hz),0.93-0.87(18H,m).

[0737] MS m / z (M+H): 954.

[0738] [Example 23]

[0739] [Chemical Formula 112]

[0740]

[0741] Except that 2-hexyl-1-octanol was used instead of 2-pentyl-1-heptanol in Example 4(2), and n-butylamine was used instead of n-hexylamine in Example 4(3), bis(2-hexyloctyl)-6,16-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0742] 1H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.96(4H,d,J=5.7Hz), 3.27-3.12(8H,m), 2.79(4H,t,J=6.3Hz), 2.72-2.61(2H,m) ,2.60-2.44(6H,m),2.32(4H,t,J=6.2Hz),1.66-1.44(14H,m),1.36-1.20(44H,m),1.08-0.96(6H,m),0.95-0.83(18H,m).

[0743] MS m / z (M+H): 996.

[0744] [Example 24]

[0745] [Chemical Formula 113]

[0746]

[0747] In Example 4(2), 2-hexyl-1-octanol was used instead of 2-pentyl-1-heptanol, in Example 4(3), n-butylamine was used instead of n-hexylamine, and in Example 4(6), N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine. In the same manner as in Example 4, bis(2-hexyloctyl)-6,16-dibutyl-11-(3-(diethylamino)propyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosane dioate was obtained as a colorless oily substance.

[0748] 1 H-NMR (CDCl3) δ: 4.09 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.26-3.12 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.66-2. 36(8H,m),2.32(4H,t,J=6.2Hz),1.66-1.43(16H,m),1.36-1.18(44H,m),1.08-0.95(6H,m),0.95-0.83(18H,m).

[0749] MS m / z (M+H): 1010.

[0750] [Example 25]

[0751] [Chemical Formula 114]

[0752]

[0753] Except that 6-bromohexanoic acid was used instead of 5-bromovaleric acid in Example 4(2), bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioic acid was obtained as a colorless oily substance in the same manner as in Example 4.

[0754] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.96(4H,d,J=5.7Hz), 3.25-3.10(8H,m), 2.79(4H,t,J=6.2Hz), 2.72-2.61(2H,m) ,2.58-2.43(6H,m),2.30(4H,t,J=7.4Hz),1.69-1.44(14H,m),1.36-1.19(48H,m),1.07-0.96(6H,m),0.93-0.82(18H,m).

[0755] MS m / z (M+H): 1024.

[0756] [Example 26]

[0757] [Chemical Formula 115]

[0758]

[0759] Except that 6-bromohexanoic acid was used instead of 5-bromovaleric acid in Example 4(2), and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioic acid ester was obtained as a colorless oily substance by the same method as in Example 4.

[0760] 1 H-NMR (CDCl3) δ: 4.09 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.24-3.08 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.64-2. 35(8H,m),2.30(4H,t,J=7.4Hz),1.68-1.44(16H,m),1.35-1.18(48H,m),1.09-0.95(6H,m),0.93-0.84(18H,m).

[0761] MS m / z (M+H): 1038.

[0762] [Example 27] (1)

[0764] [Chemical Formula 116]

[0765]

[0766] To a mixture of N-(tert-butoxycarbonyl)iminodiacetic acid (2.00 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.97 g) in dichloromethane (20 mL) were added 1-decanol (2.71 g), triethylamine (5.98 mL), and N,N-dimethylaminopyridine (1.05 g) at room temperature, and the mixture was stirred for 10 minutes. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.97 g) was added to the reaction mixture, and the mixture was stirred at 40°C for 6 hours. Water (20 mL) was added to the reaction mixture, and the organic layer was separated. Ethyl acetate (20 mL) was added to the aqueous layer, and the organic layer was washed with saturated brine, combined with the previously obtained organic layer, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain didecyl 2,2′-((tert-butoxycarbonyl)azepinediyl) diacetate (3.70 g) as a pale yellow oil.

[0767] 1 H-NMR(CDCl3)δ: 4.16-3.98(8H,m),1.68-1.54(8H,m),1.44(9H,s),1.37-1.23(24H,m),0.88(6H,t,J=6.8Hz). (2)

[0769] [Chemical Formula 117]

[0770]

[0771] Under ice cooling, trifluoroacetic acid (3.0 mL) was added to a mixture of didecyl 2,2'-((tert-butoxycarbonyl)azepine diyl) diacetate (2.00 g), toluene (1.0 mL), and water (0.15 mL). The mixture was stirred at 30°C for 4 hours and then distilled under reduced pressure. Toluene (20 mL) was added to the residue, and the distillation under reduced pressure was repeated three times. Hexane (30 mL) was added to the resulting residue and stirred. The precipitated solid was collected by filtration to obtain trifluoroacetic acid salt of didecyl 2,2'-azepine diyl diacetate (2.15 g) as a white solid.

[0772] 1H-NMR (CDCl3) δ: 5.24 (2H, brs), 4.21 (4H, t, J = 6.8Hz), 4.01 (4H, s), 1.70-1.58 (4H, m), 1.40-1.19 (28H, m), 0.88 (6H, t, J = 6.8Hz). (3)

[0774] [Chemical Formula 118]

[0775]

[0776] A mixture of didecyl 2,2'-azadiyl diacetate trifluoroacetate (1.50 g), 2,2-diethoxyethyl 1H-1,2,4-triazole-1-carboxylate (0.65 g), acetonitrile (6 mL), triethylamine (1.19 mL), and N,N-dimethylaminopyridine (0.35 g) was stirred at 50°C for 4 hours. Ethyl acetate (10 mL) and water (5 mL) were added to the reaction mixture, which had been cooled to room temperature, and the organic layer was separated. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain didecyl 2,2'-(((2,2-diethoxyethoxy)carbonyl)azadiyl) diacetate (1.13 g) as a colorless oil.

[0777] 1 H-NMR (CDCl3) δ: 4.65 (1H, t, J = 5.5Hz), 4.17-4.07 (10H, m), 3.75-3.64 (2H, m), 3 .60-3.50(2H,m),1.69-1.50(8H,m),1.39-1.17(30H,m),0.88(6H,t,J=6.8Hz). (4)

[0779] [Chemical Formula 119]

[0780]

[0781] In Example 4(5), except that didecyl 2,2'-(((2,2-diethoxyethoxy)carbonyl)azadiyl)diacetate was used instead of (((2,2-diethoxyethoxy)carbonyl)(hexyl)amino)pentanoic acid, decyl 2-(2-(2-(bis(2-decyloxy-2-oxo-ethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-decyloxy-2-oxo-ethyl)amino)acetate was obtained as a colorless oily substance by the same method as in Example 4(5) and Example 4(6).

[0782] 1 H-NMR(CDCl3)δ: 4.19-4.04(20H,m),2.83-2.72(4H,m),2.66-2.58(2H,m),2.56-2.43(6 H,m),1.67-1.49(16H,m),1.37-1.19(48H,m),1.06-0.95(6H,m),0.88(12H,t,J=6.8Hz).

[0783] MS m / z (M+H): 1084.

[0784] [Example 28]

[0785] [Chemical Formula 120]

[0786]

[0787] Except that n-pentylamine was used instead of n-hexylamine in Example 4(3), bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-6,16-dipentyl-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0788] 1 H-NMR (CDCl3) δ: 4.10, (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.27-3.09 (8H, m), 2.79 (4H, t, J = 6.2Hz), 2.73-2. 41(8H,m),2.32(4H,t,J=6.4Hz),1.67-1.44(14H,m),1.38-1.16(40H,m),1.10-0.96(6H,m),0.94-0.82(18H,m).

[0789] MS m / z (M+H): 968.

[0790] [Example 29]

[0791] [Chemical Formula 121]

[0792]

[0793] Except that n-pentylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-6,16-dipentyl-8,14-dioxa-6,11,16-triazaheneicosane dioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0794] 1 H-NMR (CDCl3) δ: 4.09 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.7Hz), 3.27-3.10 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.63-2. 37(8H,m),2.32(4H,t,J=6.6Hz),1.70-1.44(16H,m),1.38-1.17(40H,m),1.10-0.95(6H,m),0.92-0.84(18H,m).

[0795] MS m / z (M+H): 982.

[0796] [Example 30]

[0797] [Chemical Formula 122]

[0798]

[0799] In Example 4(3), except that n-heptylamine was used instead of n-hexylamine, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diheptyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0800] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.96(4H,d,J=5.8Hz), 3.28-3.09(8H,m), 2.79(4H,t,J=6.4Hz), 2.73-2.60(2H,m) ,2.59-2.41(6H,m),2.32(4H,t,J=6.3Hz),1.68-1.44(14H,m),1.36-1.18(48H.m),1.07-0.95(6H,m),0.92-0.81(18H,m).

[0801] MS m / z (M+H): 1025.

[0802] [Example 31]

[0803] [Chemical formula 123]

[0804]

[0805] Except that n-heptylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diheptyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0806] 1 H-NMR (CDCl3) δ: 4.09 (4H, t, J = 6.6Hz), 3.96 (4H, d, J = 5.8Hz), 3.26-3.09 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.65-2. 36(8H,m),2.32(4H,t,J=6.3Hz),1.67-1.43(16H,m),1.37-1.17(48H,m),1.07-0.95(6H,m),0.93-0.81(18H,m).

[0807] MS m / z (M+H): 1039.

[0808] [Example 32]

[0809] [Chemical Formula 124]

[0810]

[0811] In Example 27(1), except that 1-dodecanol was used instead of 1-decanol, didodecyl 8-(2-(diethylamino)ethyl)-3,13-bis(2-(dodecyloxy)-2-oxoethyl)-4,12-dioxo-5,11-dioxa-3,8,13-triazapentadecanedioate was obtained as a colorless oily substance in the same manner as in Example 27.

[0812] 1 H-NMR(CDCl3)δ: 4.20-4.03(20H,m),2.82-2.73(4H,m),2.67-2.58(2H,m),2.57-2.43(6 H,m),1.68-1.51(16H,m),1.37-1.19(64H,m),1.07-0.95(6H,m),0.88(12H,t,J=6.8Hz).

[0813] MS m / z (M+H): 1196.

[0814] [Example 33]

[0815] [Chemical Formula 125]

[0816]

[0817] In Example 27(1), except that 1-undecanol was used instead of 1-decanol, diundecyl 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-bis(2-oxo-2-(undecanoxy)ethyl)-5,11-dioxa-3,8,13-triazapentadecanedioate was obtained as a colorless oily substance in the same manner as in Example 27.

[0818] 1 H-NMR(CDCl3)δ: 4.21-4.06(20H,m),2.85-2.72(4H,m),2.66-2.57(2H,m),2.56-2.41(6 H,m),1.69-1.48(16H,m),1.37-1.19(56H,m),1.06-0.94(6H,m),0.88(12H,t,J=6.8Hz).

[0819] MS m / z (M+H): 1140.

[0820] [Example 34]

[0821] [Chemical Formula 126]

[0822]

[0823] In Example 27(1), except that 1-tridecanol was used instead of 1-decanol, ditridecyl 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-bis(2-oxo-2-(tridecyloxy)ethyl)-5,11-dioxa-3,8,13-triazapentadecanedioate was obtained as a colorless oily substance in the same manner as in Example 27.

[0824] 1 H-NMR(CDCl3)δ: 4.19-4.06(20H,m),2.84-2.71(4H,m),2.68-2.56(2H,m),2.55-2.41(6 H,m),1.69-1.49(16H,m),1.38-1.18(72H,m),1.07-0.95(6H,m),0.88(12H,t,J=6.8Hz).

[0825] [Example 35]

[0826] [Chemical Formula 127]

[0827]

[0828] Except that n-octylamine was used instead of n-hexylamine in Example 4(3) and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0829] 1 H-NMR (CDCl3) δ: 4.09 (4H, t, J = 6.5Hz), 3.96 (4H, d, J = 5.8Hz), 3.27-3.09 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.66-2. 36(8H,m),2.32(4H,t,J=6.2Hz),1.68-1.43(16H,m),1.36-1.18(52H,m),1.08-0.95(6H,m),0.93-0.83(18H,m).

[0830] MS m / z (M+H): 1067.

[0831] [Example 36]

[0832] [Chemical Formula 128]

[0833]

[0834] Except that n-octylamine was used instead of n-hexylamine in Example 4(3) and 4-(diethylamino)butylamine was used instead of N,N-diethylethylenediamine in Example 4(6), bis(2-pentylheptyl)11-(4-(diethylamino)butyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosane dioate was obtained as a colorless oily substance in the same manner as in Example 4.

[0835] 1H-NMR(CDCl3)δ: 4.08(4H,t,J=6.5Hz), 3.96(4H,d,J=5.8Hz), 3.26-3.10(8H,m), 2.75(4H,t,J=6.4Hz), 2.62-2 .36(8H,m),2.35-2.27(4H,m),1.66-1.37(18H,m),1.36-1.18(52H,m),1.09-0.95(6H,m),0.92-0.82(18H,m).

[0836] MS m / z (M+H): 1081.

[0837] [Example 37]

[0838] [Chemical Formula 129]

[0839]

[0840] In Example 4(6), except that 2-hexyloctyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid was used instead of 2-pentylheptyl 5-(hexyl((2-oxoethoxy)carbonyl)amino)pentanoic acid, and N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine, bis(2-hexyloctyl)11-(3-(diethylamino)propyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanediolate was obtained by the same method as in Example 4(6).

[0841] 1 H-NMR (CDCl3) δ: 4.09 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.8Hz), 3.27-3.07 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.67-2. 36(8H,m),2.32(4H,t,J=6.4Hz),1.67-1.44(16H,m),1.36-1.16(60H,m),1.06-0.96(6H,m),0.92-0.82(18H,m).

[0842] MS m / z (M+H): 1123.

[0843] [Example 38]

[0844] [Chemical Formula 130]

[0845]

[0846] In Example 4(6), except that 2-hexyloctyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid was used instead of 2-pentylheptyl 5-(hexyl((2-oxoethoxy)carbonyl)amino)pentanoic acid, and 4-(diethylamino)butylamine was used instead of N,N-diethylethylenediamine, bis(2-hexyloctyl)11-(4-(diethylamino)butyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained by the same method as in Example 4(6).

[0847] 1 H-NMR (CDCl3) δ: 4.08 (4H, t, J = 6.4Hz), 3.96 (4H, d, J = 5.7Hz), 3.27-3.08 (8H, m), 2.75 (4H, t, J = 6.5Hz), 2.64-2 .37(8H,m),2.36-2.27(4H,m),1.68-1.36(18H,m),1.35-1.17(60H,m),1.06-0.95(6H,m),0.93-0.80(18H,m).

[0848] MS m / z (M+H): 1137.

[0849] [Example 39] (1)

[0851] [Chemical Formula 131]

[0852]

[0853] 5-Heptyl bromopentanoate was obtained as a colorless oily substance in the same manner as in Example 4(2) except that 1-heptanol was used instead of 2-pentyl-1-heptanol.

[0854] 1 H-NMR(CDCl3)δ: 4.06(2H,t,J=6.8Hz), 3.42(2H,t,J=6.6Hz), 2.34(2H,t,J=7.3Hz), 1.93-1 .87(2H,m),1.82-1.74(2H,m),1.67-1.58(2H,m),1.37-1.24(8H,m),0.89(3H,t,J=6.9Hz). (2)

[0856] [Chemical Formula 132]

[0857]

[0858] 5-(Octylamino)heptyl pentanoate was obtained as a colorless oily substance in the same manner as in Example 4(3) except that 5-bromovalerate was used instead of 2-pentylheptyl 5-bromovaleric acid and n-octylamine was used instead of n-hexylamine.

[0859] 1 H-NMR(CDCl3)δ: 4.06(2H,t,J=6.8Hz), 2.66-2.59(4H,m), 2.33(2H,t,J=7.3Hz), 1.71-1.48(9H,m), 1.36-1.22(18H,m), 0.90-0.86(6H,m). (3)

[0861] [Chemical Formula 133]

[0862]

[0863] 5-(((2,2-diethoxyethoxy)carbonyl)(octyl)amino)heptyl pentanoate was obtained as a colorless oily substance by the same method as in Example 4(4), except that 5-(octylamino)heptyl pentanoate was used instead of 2-pentylheptyl 5-(hexylamino)pentanoate.

[0864] 1 H-NMR(CDCl3)δ: 4.71-4.67(1H,m),4.09-4.03(4H,m),3.75-3.67(2H,m),3.61-3.53(2H,m),3 .26-3.14(4H,m),2.35-2.29(2H,m),1.64-1.46(8H,m),1.33-1.19(24H,m),0.90-0.85(6H,m). (4)

[0866] [Chemical Formula 134]

[0867]

[0868] In Example 4(5), 5-(((2,2-diethoxyethoxy)carbonyl)(octyl)amino)heptyl pentanoate was used instead of 2-pentylheptyl 5-(((2,2-diethoxyethoxy)carbonyl)(hexyl)amino)pentanoic acid, and 5-(octyl((2-oxoethoxy)carbonyl)amino)heptyl pentanoate was obtained as a colorless oil by the same method as in Example 4(5).

[0869] 1H-NMR (CDCl3) δ: 9.63 (1H, s), 4.61 (2H, d, J = 3.6Hz), 4.06 (2H, t, J = 6.7Hz), 3.32-3.22 (4H,m),2.36-2.32(2H,m),1.66-1.50(8H,m),1.36-1.22(18H,m),0.90-0.86(6H,m). (5)

[0871] [Chemical Formula 135]

[0872]

[0873] To a solution of 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid heptyl ester (0.60 g) in ethyl acetate (6 mL) were added N,N-diethylethylenediamine (0.33 g), acetic acid (0.10 mL), and sodium triacetoxyborohydride (0.92 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the separated organic layer was washed with saturated brine. Anhydrous sodium sulfate was added for drying, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate-hexane) to obtain heptyl 3-ethyl-11-octyl-10-oxo-9-oxa-3,6,11-triazahexadecyl-16-oate (0.57 g) as a colorless oil.

[0874] 1 H-NMR (CDCl3) δ: 4.19 (2H, t, J = 5.5Hz), 4.05 (2H, t, J = 6.7Hz), 3.29-3.10 (4H, m), 2.89 (2H, t, J = 5.4Hz), 2.83-2. 50(8H,m),2.32(2H,t,J=6.8Hz),1.88-1.46(10H,m),1.37-1.19(16H,m),1.14-0.96(6H,m),0.91-0.82(6H,m). (6)

[0876] [Chemical Formula 136]

[0877]

[0878] To a solution of heptyl 3-ethyl-11-octyl-10-oxo-9-oxa-3,6,11-triazahexadecyl-16-oate (0.15 g) in ethyl acetate (2 mL) were added 2-pentylheptyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid (0.21 g) and sodium triacetoxyborohydride (0.12 g) of the synthetic intermediate of Example (3) at room temperature, and the mixture was stirred at the same temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the separated organic layer was washed with saturated brine. Anhydrous sodium sulfate was added for drying, and the solvent was distilled off under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate-hexane) to obtain 1-heptyl 21-(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate (0.21 g) as a colorless oil.

[0879] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 4.05(2H,t,J=6.8Hz), 3.96(2H,d,J=5.8Hz), 3.27-3.09(8H,m), 2.79(4H,t,J=6.2Hz), 2.73 -2.61(2H,m),2.60-2.42(6H,m),2.38-2.26(4H,m),1.68-1.44(17H,m),1.38-1.19(42H,m),1.09-0.95(6H,m),0.93-0.82(15H,m).

[0880] MS m / z (M+H): 982.

[0881] [Example 40]

[0882] [Chemical Formula 137]

[0883]

[0884] In Example 39 (6), except that 2-hexyloctyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid obtained in Example 2 (4) was used instead of 2-pentylheptyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid, 1-heptyl 21-(2-hexyloctyl)11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance in the same manner as in Example 39.

[0885] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 4.05(2H,t,J=6.8Hz), 3.96(2H,d,J=5.8Hz), 3.27-3.08(8H,m), 2.79(4H,t,J=6.2Hz), 2.72 -2.61(2H,m),2.60-2.42(6H,m),2.36-2.27(4H,m),1.68-1.44(17H,m),1.37-1.17(46H,m),1.10-0.96(6H,m),0.94-0.82(15H,m).

[0886] MS m / z (M+H): 1010.

[0887] [Example 41]

[0888] [Chemical Formula 138]

[0889]

[0890] 1-Octyl 21-(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate was obtained as a colorless oily substance in the same manner as in Example 39 (1), except that 1-octanol was used instead of 1-heptanol.

[0891] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 4.05(2H,t,J=6.8Hz), 3.96(2H,d,J=5.7Hz), 3.27-3.06(8H,m), 2.79(4H,t,J=6.3Hz), 2.72 -2.61(2H,m),2.60-2.44(6H,m),2.38-2.27(4H,m),1.70-1.43(17H,m),1.36-1.15(44H,m),1.09-0.95(6H,m),0.92-0.81(15H,m).

[0892] MS m / z (M+H): 996.

[0893] [Example 42]

[0894] [Chemical Formula 139]

[0895]

[0896] In Example 39(1), 1-octanol was used instead of 1-heptanol, and in Example 39(6), 2-hexyloctyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid obtained in Example 2(4) was used instead of 2-pentylheptyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid. 1-(2-hexyloctyl)21-octyl 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained by the same method as in Example 39.

[0897] 1 H-NMR (CDCl3) δ: 4.10 (4H, t, J = 6.4Hz), 4.05 (2H, t, J = 6.8Hz), 3.96 (2H, d, J = 5.7Hz), 3.27-3.09 (8H, m), 2.79 (4H, t, J = 6.0HZ), 2.72 -2.61(2H,m),2.60-2.42(6H,m),2.37-2.28(4H,m),1.68-1.43(17H,m),1.38-1.17(48H,m),1.06-0.96(6H,m),0.93-0.81(15H,m).

[0898] MS m / z (M+H): 1024.

[0899] [Example 43]

[0900] [Chemical Formula 140]

[0901]

[0902] In Example 39 (6), 2-hexyloctyl 5-(decyl((2-oxoethoxy)carbonyl)amino)pentanoic acid obtained by the same method as in Example 4 was used instead of 2-pentylheptyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid. In addition, 21-heptyl 1-(2-hexyloctyl) 6-decyl-11-(2-(diethylamino)ethyl)-16-octyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneconedioate was obtained as a colorless oily substance by the same method as in Example 39 (6).

[0903] 1H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 4.05(2H,t,J=6.8Hz), 3.96(2H,d,J=5.7Hz), 3.26-3.08(8H,m), 2.79(4H,t,J=6.3Hz), 2.72 -2.60(2H,m),2.59-2.44(6H,m),2.36-2.27(4H,m),1.71-1.43(17H,m),1.36-1.17(50H,m),1.07-0.95(6H,m),0.94-0.82(15H,m).

[0904] MS m / z (M+H): 1038.

[0905] [Example 44]

[0906] [Chemical Formula 141]

[0907]

[0908] In Example 39(1), 1-octanol was used instead of 1-heptanol, and in Example 39(6), 2-hexyloctyl 5-(decyl((2-oxoethoxy)carbonyl)amino)pentanoic acid obtained by the same method as in Example 4 was used instead of 2-pentylheptyl 5-(octyl((2-oxoethoxy)carbonyl)amino)pentanoic acid. In addition, 1-(2-hexyloctyl)21-octyl6-decyl-11-(2-(diethylamino)ethyl)-16-octyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanediol was obtained by the same method as in Example 39.

[0909] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 4.05(2H,t,J=6.8Hz), 3.96(2H,d,J=5.7Hz), 3.27-3.09(8H,m), 2.79(4H,t,J=6.3Hz), 2.73 -2.60(2H,m),2.59-2.43(6H,m),2.37-2.27(4H,m),1.69-1.41(17H,m),1.38-1.17(52H,m),1.07-0.96(6H,m),0.93-0.81(15H,m).

[0910] MS m / z (M+H): 1052.

[0911] [Example 45]

[0912] [Chemical Formula 142]

[0913]

[0914] Except that 6-bromohexanoic acid was used instead of 5-bromovaleric acid in Example 4(2), and n-heptylamine was used instead of n-hexylamine in Example 4(3), bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioic acid was obtained as a colorless oily substance by the same method as in Example 4.

[0915] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.3Hz), 3.97(4H,d,J=5.8Hz), 3.28-3.08(8H,m), 2.79(4H,t,J=6.4Hz), 2.72-2.60(2H,m) ,2.59-2.42(6H,m),2.30(4H,t,J=7.5Hz),1.70-1.41(14H,m),1.38-1.16(52H.m),1.08-0.95(6H,m),0.95-0.81(18H,m).

[0916] MS m / z (M+H): 1053.

[0917] [Example 46]

[0918] [Chemical Formula 143]

[0919]

[0920] Except that 6-bromohexanoic acid was used instead of 5-bromovaleric acid in Example 4(2), and n-pentylamine was used instead of n-hexylamine in Example 4(3), bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-8,16-dioxo-7,17-dipentyl-9,15-dioxa-7,12,17-triazatricosane dioic acid was obtained as a colorless oily substance by the same method as in Example 4.

[0921] 1H-NMR (CDCl3) δ: 4.10 (4H, t, J = 6.4Hz), 3.97 (4H, d, J = 5.8Hz), 3.28-3.08 (8H, m), 2.79 (4H, t, J = 6.4Hz), 2.72-2.60 (2H, m), 2 .59-2.42(6H,m),2.30(4H,t,J=6.2Hz),1.70-1.41(14H,m),1.38-1.16(44H.m),1.01(6H,t,J=7.1Hz),0.95-0.81(18H,m).

[0922] MS m / z (M+H): 996.

[0923] [Example 47]

[0924] [Chemical formula 144]

[0925]

[0926] In Example 4(2), 2-hexyl-1-octanol was used instead of 2-pentyl-1-heptanol, 6-bromohexanoic acid was used instead of 5-bromovaleric acid, and in Example 4(3), n-butylamine was used instead of n-hexylamine. In the same manner as in Example 4, bis(2-hexyloctyl)7,17-dibutyl-12-(2-(diethylamino)ethyl)-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioic acid was obtained as a colorless oily substance.

[0927] 1 H-NMR (CDCl3) δ: 4.10 (4H, t, J = 6.3Hz), 3.97 (4H, d, J = 5.7Hz), 3.26-3.09 (8H, m), 2.79 (4H, t, J = 6.3Hz), 2.72-2.61 (2H, m), 2 .57-2.45(6H,m),2.30(4H,t,J=7.5Hz),1.66-1.44(14H,m),1.38-1.17(48H,m),1.01(6H,t,J=7.1Hz),0.95-0.83(18H,m).

[0928] MS m / z (M+H): 1024.

[0929] [Example 48]

[0930] [Chemical Formula 145]

[0931]

[0932] In Example 4(2), 6-bromohexanoic acid was used instead of 5-bromovaleric acid, in Example 4(3), n-heptylamine was used instead of n-hexylamine, and in Example 4(6), N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine. In the same manner as in Example 4, bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate was obtained as a colorless oily substance.

[0933] 1 H-NMR (CDCl3) δ: 4.10 (4H, t, J = 6.4Hz), 3.97 (4H, d, J = 5.8Hz), 3.28-3.08 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.61-2.45 (6H, m), 2 .45-2.36(2H,m),2.30(4H,t,J=7.5Hz),1.70-1.41(16H,m),1.38-1.16(52H.m),1.00(6H,t,J=7.1Hz),0.95-0.81(18H,m).

[0934] MS m / z (M+H): 1066.

[0935] [Example 49]

[0936] [Chemical Formula 146]

[0937]

[0938] In Example 4(2), 6-bromohexanoic acid was used instead of 5-bromovaleric acid, in Example 4(3), n-pentylamine was used instead of n-hexylamine, and in Example 4(6), N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine. In the same manner as in Example 4, bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-8,16-dioxo-7,17-dipentyl-9,15-dioxa-7,12,17-triazatricosanediolate was obtained as a colorless oily substance.

[0939] 1H-NMR (CDCl3) δ: 4.10 (4H, t, J = 6.4Hz), 3.97 (4H, d, J = 5.8Hz), 3.28-3.08 (8H, m), 2.76 (4H, t, J = 6.4Hz), 2.61-2.45 (6H, m), 2 .45-2.36(2H,m),2.30(4H,t,J=6.6Hz),1.70-1.41(16H,m),1.38-1.16(44H.m),1.01(6H,t,J=7.1Hz),0.95-0.81(18H,m).

[0940] MS m / z (M+H): 1010.

[0941] [Example 50]

[0942] [Chemical Formula 147]

[0943]

[0944] Except that 6-bromohexanoic acid was used instead of 5-bromovaleric acid in Example 4(2), and n-octylamine was used instead of n-hexylamine in Example 4(3), bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosane dioic acid was obtained as a colorless oily substance by the same method as in Example 4.

[0945] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=5.9Hz), 3.97(4H,d,J=5.8Hz), 3.26-3.07(8H,m), 2.79(4H,t,J=6.4Hz), 2.72-2.60(2H,m),2 .56-2.45(6H,m),2.30(4H,t,J=7.5Hz),1.70-1.40(14H,m),1.38-1.16(56H.m),1.01(6H,t,J=7.1Hz),0.93-0.83(18H,m).

[0946] MS m / z (M+H): 1080.

[0947] [Example 51]

[0948] [Chemical Formula 148]

[0949]

[0950] In Example 4(2), 6-bromohexanoic acid was used instead of 5-bromovaleric acid, in Example 4(3), n-octylamine was used instead of n-hexylamine, and in Example 4(6), N,N-diethyl-1,3-diaminopropane was used instead of N,N-diethylethylenediamine. In the same manner as in Example 4, bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate was obtained as a colorless oily substance.

[0951] 1 H-NMR(CDCl3)δ: 4.10(4H,t,J=6.4Hz), 3.97(4H,d,J=5.8Hz), 3.26-3.07(8H,m), 2.79(4H,t,J=6.4Hz), 2.76(4H,t,J=6.4Hz) ,2.60-2.45(6H,m),2.30(4H,t,J=7.5Hz),1.70-1.40(16H,m),1.38-1.16(56H.m),1.00(6H,t,J=7.1Hz),0.93-0.83(18H,m).

[0952] MS m / z (M+H): 1094.

[0953] Experimental Example 1: Preparation of mRNA-encapsulated lipid nanoparticles and determination of reporter protein expression in mice

[0954] Preparation of EPO mRNA-encapsulated lipid nanoparticles

[0955] The compounds listed in Table 1, neutral lipids, cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.), and 1,2-dimyristoyl-rac-glycero-3-(methylpolyoxyethylene 2000) (hereinafter, DMG-PEG2000) (product name: SUNBRIGHT(R) GM-020; NOF corporation) were dissolved in ethanol at a molar ratio of ionized lipid:neutral lipid:cholesterol:DMG-PEG2000=50:10:38.5:1.5 mol% and in a total lipid concentration of 12.5 mmol / L to obtain an oil phase.

[0956] As the neutral lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine (product name: COATSOME(R) MC-8080; NOF Corporation) (hereinafter referred to as DSPC) or L-α-dioleoylphosphatidylethanolamine (hereinafter referred to as DOPE) (product name: COATSOME(R) ME-8181; NOF Corporation) was used.

[0957] EPO mRNA (product name: CleanCap EPO mRNA (5moU); TriLink) was diluted using 50mmol / L citrate buffer at pH 4.0 to a weight ratio of total lipid concentration to mRNA concentration of approximately 20:1 to 64:1, thereby obtaining an aqueous phase. Subsequently, the aqueous phase and the oil phase were mixed using a NanoAssemblr (Precision NanoSystems) in a volume ratio of aqueous phase:oil phase = 3:1. The mixture was diluted 2-fold using either phosphate-buffered saline (PBS), water, or 20mmol / L Tris buffer (pH 7.4) to obtain a dispersion of mRNA lipid nanoparticles. The dispersion was dialyzed against 20mmol / L Tris buffer (pH 7.4) containing 8% sucrose using a dialysis cassette (Slide-A-Lyzer G2, MWCO: 10kD, Thermo Fisher Scientific) to remove ethanol and obtain EPO mRNA-encapsulated lipid nanoparticles.

[0958] <Measurement of particle size>

[0959] The particle size of the mRNA-encapsulating lipid nanoparticles was measured by diluting the lipid nanoparticle dispersion 5-fold with phosphate-buffered saline (PBS) using a particle size measuring apparatus NanoSAQLA (Otsuka Electronics Co., Ltd.).

[0960] Evaluation of mRNA Encapsulation Efficiency

[0961] (Total mRNA concentration quantification)

[0962] EPO mRNA was diluted with MilliQ water to prepare a two-fold dilution series from 100 μg / mL to 3.1 μg / mL, and a calibration curve solution was prepared. 50 μL of the calibration curve solution or mRNA lipid nanoparticles was mixed with 450 μL of methanol to prepare an assay solution.

[0963] The absorbance at 260 nm and 330 nm of each assay solution was measured using a UV plate reader (Multiskan Go, Thermo Fisher Scientific). The absorbance at 330 nm was subtracted from the absorbance at 260 nm to obtain the absorbance of each assay solution. The absorbance of each sample assay solution was used to calculate the total aqueous nucleic acid concentration based on a calibration curve.

[0964] (Quantification of mRNA concentration in the external aqueous phase)

[0965] The Quant-iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific) was used to quantify the external aqueous phase nucleic acid concentration using the standard addition method. First, the 20× TE buffer contained in the above-mentioned kit was diluted with water to prepare a 1× TE buffer. In addition, TE stands for Tris / EDTA (ethylenediaminetetraacetic acid). EPO mRNA was diluted with TE buffer to a final concentration of 0 to 400 ng / mL, thereby preparing a nucleic acid dilution series. After mixing 10 μL of mRNA lipid nanoparticles diluted 5-fold with TE buffer and 90 μL of the nucleic acid dilution series in a 96-well plate, 100 μL of RiboGreen reagent diluted 200-fold with TE buffer was added to each well, and fluorescence was measured using a fluorescence plate reader (Infinite 200Pro M nano+, TECAN) (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm). Based on the results obtained, the external aqueous phase nucleic acid concentration of each assay solution was calculated according to the standard addition method.

[0966] (Calculation of encapsulation efficiency)

[0967] Using the quantitative results of the total mRNA concentration and the mRNA concentration in the external aqueous phase obtained in the above steps, the mRNA encapsulation efficiency of the mRNA lipid nanoparticles was calculated according to the following formula. The results are shown in Table 1.

[0968] mRNA encapsulation efficiency (%) = (total mRNA concentration - mRNA concentration in the external aqueous phase) ÷ total mRNA concentration × 100

[0969] [Table 1]

[0970] Particle size and nucleic acid encapsulation efficiency of nucleic acid-encapsulated lipid nanoparticles

[0971]

[0972] <EPO enzyme activity assay>

[0973] The dispersion of mRNA lipid nanoparticles prepared in the above-mentioned <Preparation of EPO mRNA encapsulated lipid nanoparticles> was intravenously administered to ICR mice in a manner such that the mRNA dosage was 0.1 mg / kg. Six hours after administration, blood was collected from the posterior vena cava to obtain plasma. The obtained plasma was used and human EPO enzyme activity was quantified using Erythropoietin (EPO) Human Elisa Kit (Abcam). Regarding the quantitative value, the relative EPO protein amount when Comparative Example 1 is set to 1 is recorded.

[0974] The results are shown in Table 2.

[0975] [Table 2]

[0976]

[0977] Compared with the nucleic acid lipid composition of the comparative example, the nucleic acid lipid composition of the present invention showed a higher EPO protein expression rate.

Claims

1. A compound or a salt thereof, wherein the compound is represented by the following formula (1): [Chemical Formula 1] Where R 1 、R 2 、R 3 and R 4 Each independently represents a hydrogen atom, or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms, R 1 、R 2 、R 3 and R 4 The substituents on the optionally substituted hydrocarbon group having 1 to 24 carbon atoms represented by are each independently -C(O)OR 11 、-OC(O)-R 12 、-OR 13 、-CO-R 14 、-OC(O)OR 15 or -SSR 16 , R 11 、R 12 、R 13 、R 14 、R 15 and R 16 Each independently represents the 17 Substituted hydrocarbon group having 1 to 24 carbon atoms, R 17 represents a hydrocarbon group having 1 to 12 carbon atoms, R 5 and R 6 each independently represents an optionally substituted hydrocarbon group having 1 to 18 carbon atoms, R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by are independently -OH, -COOH, -NR 21 R 22 、-OC(O)OR 23 、-C(O)OR 24 、-OC(O)-R 25 、-OR 26 、-C(O)NR 27 R 28 、-NR 29 C(O)R 30 、-N(R 31 )S(O)2R 32 、-N(R 33 )C(O)N(R 34 )R 35 、-N(R 36 )C(S)N(R 37 )R 38 、-OC(O)N(R 39 )R 40 or -N(R 41 )C(O)OR 42 , R 21 and R 22 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 40 、R 41 and R 42 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 24 carbon atoms, R 23 、R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 36 、R 37 、R 38 、R 39 、R 40 、R 41 and R 42 The substituent on the hydrocarbon group having 1 to 24 carbon atoms which may be substituted is an aryl group having 6 to 20 carbon atoms, a heterocyclic group, -OH, -COOH or -NR 51 R 52 , R 51 and R 52 Each independently represents a hydrogen atom or a hydrocarbon group having 1 to 8 carbon atoms, R 7 、R 8 and R 9 each independently represents a hydrocarbon group having 2 to 8 carbon atoms, R 5 With R 6 or R 5 With R 7 They can form a 4- to 7-membered ring together.

2. The compound or salt thereof according to claim 1, wherein R 1 Indicates -R 1a -L 1 -R 1b , R 1a represents a hydrocarbon group having 1 to 18 carbon atoms, L 1 represents -C(O)O-, -OC(O)-, -OC(O)O- or -SS-, R 1b represents a hydrocarbon group having 1 to 18 carbon atoms, R 3 Indicates -R 3a -L 3 -R 3b , R 3a represents a hydrocarbon group having 1 to 18 carbon atoms, L 3 represents -C(O)O-, -OC(O)-, -OC(O)O- or -SS-, R 3b represents a hydrocarbon group having 1 to 18 carbon atoms, R 2 and R 4 Each independently represents a hydrocarbon group having 1 to 18 carbon atoms which may be substituted, R 2 and R 4 The substituents on the optionally substituted hydrocarbon group having 1 to 18 carbon atoms represented by are each independently -C(O)OR 11 、-OC(O)-R 12 、-OR 13 、-CO-R 14 、-OC(O)OR 15 or -SSR 16 , R 11 、R 12 、R 13 、R 14 、R 15 and R 16 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, R 5 and R 6 Each independently represents a hydrocarbon group having 1 to 12 carbon atoms which may be substituted, R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by are each independently -OH, -OR 26 、-C(O)NR 27 R 28 or -NR 29 C(O)R 30 , R 26 、R 27 、R 28 、R 29 and R 30 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, R 26 、R 27 、R 28 、R 29 and R 30 The substituent on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by represents an aryl group or a heterocyclic group having 6 to 10 carbon atoms, R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 8.

3. The compound or salt thereof according to claim 1, wherein R 1 Indicates -R 1a -L 1 -R 1b , R 1a represents a hydrocarbon group having 1 to 18 carbon atoms, L 1 Indicates -C(O)O- or -OC(O)-, R 1b represents a hydrocarbon group having 1 to 18 carbon atoms, R 3 Indicates -R 3a -L 3 -R 3b , R 3a represents a hydrocarbon group having 1 to 18 carbon atoms, L 3 Indicates -C(O)O- or -OC(O)-, R 3b represents a hydrocarbon group having 1 to 18 carbon atoms, R 2 and R 4 each independently represents a hydrocarbon group having 1 to 10 carbon atoms, R 5 and R 6 Each independently represents a hydrocarbon group having 1 to 6 carbon atoms which may be substituted, R 5 and R 6 The substituents on the optionally substituted hydrocarbon group having 1 to 6 carbon atoms represented by are independently -OH, -OR 26 、-C(O)NR 27 R 28 or -NR 29 C(O)R 30 , R 26 、R 27 、R 28 、R 29 and R 30 Each independently represents a hydrogen atom or an optionally substituted hydrocarbon group having 1 to 12 carbon atoms, R 26 、R 27 、R 28 、R 29 and R 30 The substituent on the optionally substituted hydrocarbon group having 1 to 12 carbon atoms represented by represents an aryl group having 6 to 10 carbon atoms, R 7 、R 8 and R 9 Each independently represents -(CH2) n -, n represents an integer from 2 to 8.

4. A compound or a salt thereof, wherein the compound is selected from the following compounds: ((2-(Diethylamino)ethyl)azepinediyl)bis(ethane-2,1-diyl)bis(dioctylcarbamate); [Chemical Formula 2] Bis(2-hexyloctyl)11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 3] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 4] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 5] Bis(2-hexyloctyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 6] Bis(2-pentylheptyl)4,14-dibutyl-9-(2-(diethylamino)ethyl)-5,13-dioxo-6,12-dioxa-4,9,14-triazaheptadecanedioate; [Chemical Formula 7] Bis(2-pentylheptyl)4,14-dibutyl-9-(3-(diethylamino)propyl)-5,13-dioxo-6,12-dioxa-4,9,14-triazaheptadecanedioate; [Chemical Formula 8] Bis(2-pentylheptyl)9-(2-(diethylamino)ethyl)-5,13-dioxo-4,14-dipropyl-6,12-dioxa-4,9,14-triazaheptadecanedioate; [Chemical Formula 9] Bis(2-pentylheptyl)9-(3-(diethylamino)propyl)-5,13-dioxo-4,14-dipropyl-6,12-dioxa-4,9,14-triazaheptadecanedioate; [Chemical Formula 10] Bis(2-pentylheptyl)8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-dipropyl-5,11-dioxa-3,8,13-triazapentadecanedioate; [Chemical Formula 11] Bis(2-pentylheptyl)8-(3-(diethylamino)propyl)-4,12-dioxo-3,13-dipropyl-5,11-dioxa-3,8,13-triazapentadecanedioate; [Chemical Formula 12] 2-(2-(2-(bis(2-decanoyloxyethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-decanoyloxyethyl)amino)ethyldecanoate; [Chemical Formula 13] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diisopropyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 14] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diisopropyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 15] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-6,16-dipropyl-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 16] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-6,16-dipropyl-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 17] Bis(2-butyloctyl)11-(2-(diethylamino)ethyl)-6,16-dihexyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 18] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diisobutyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 19] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diisobutyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 20] 2-(2-(2-(bis(2-dodecanoyloxyethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-dodecanoyloxyethyl)amino)ethyl dodecanoate; [Chemical Formula 21] Bis(2-pentylheptyl)6,16-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 22] Bis(2-pentylheptyl)6,16-dibutyl-11-(3-(diethylamino)propyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 23] Bis(2-hexyloctyl)6,16-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 24] Bis(2-hexyloctyl)6,16-dibutyl-11-(3-(diethylamino)propyl)-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 25] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandioate; [Chemical Formula 26] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-dihexyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosandioate; [Chemical Formula 27] Decyl 2-(2-(2-(bis(2-decyloxy-2-oxo-ethyl)carbamoyloxy)ethyl-(2-(diethylamino)ethyl)amino)ethoxycarbonyl-(2-decyloxy-2-oxo-ethyl)amino)acetate; [Chemical Formula 28] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-6,16-dipentyl-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 29] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-6,16-dipentyl-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical formula 30] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-6,16-diheptyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 31] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-diheptyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 32] Didodecyl 8-(2-(diethylamino)ethyl)-3,13-bis(2-(dodecyloxy)-2-oxoethyl)-4,12-dioxo-5,11-dioxa-3,8,13-triazapentadecanedioate; [Chemical Formula 33] Diundecyl 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-bis(2-oxo-2-(undecanyloxy)ethyl)-5,11-dioxa-3,8,13-triazapentadecanedioate; [Chemical Formula 34] Ditridecyl 8-(2-(diethylamino)ethyl)-4,12-dioxo-3,13-bis(2-oxo-2-(tridecyloxy)ethyl)-5,11-dioxa-3,8,13-triazapentadecanedioate; [Chemical Formula 35] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 36] Bis(2-pentylheptyl)11-(4-(diethylamino)butyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 37] Bis(2-hexyloctyl)11-(3-(diethylamino)propyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 38] Bis(2-hexyloctyl)11-(4-(diethylamino)butyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosandioate; [Chemical Formula 39] 1-heptyl 21-(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 40] 1-heptyl 21-(2-hexyloctyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 41] 1-octyl 21-(2-pentylheptyl) 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 42] 1-(2-Hexyloctyl)21-octyl 11-(2-(diethylamino)ethyl)-6,16-dioctyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 43] 21-heptyl 1-(2-hexyloctyl) 6-decyl-11-(2-(diethylamino)ethyl)-16-octyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 44] 1-(2-hexyloctyl)21-octyl6-decyl-11-(2-(diethylamino)ethyl)-16-octyl-7,15-dioxo-8,14-dioxa-6,11,16-triazaheneicosanedioate; [Chemical Formula 45] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 46] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-8,16-dioxo-7,17-dipentyl-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 47] Bis(2-hexyloctyl)7,17-dibutyl-12-(2-(diethylamino)ethyl)-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 48] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-diheptyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 49] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-8,16-dioxo-7,17-dipentyl-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 50] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 51] Bis(2-pentylheptyl)12-(3-(diethylamino)propyl)-7,17-dioctyl-8,16-dioxo-9,15-dioxa-7,12,17-triazatricosanediolate [Chemical Formula 52] A lipid composition comprising the compound or a salt thereof according to any one of claims 1 to 4 and a lipid.

6. The lipid composition according to claim 5, wherein The lipid is at least one lipid selected from the group consisting of neutral lipids and lipids having nonionic hydrophilic polymer chains.

7. The lipid composition according to claim 5 or 6, further comprising a sterol.

8. The lipid composition according to any one of claims 5 to 7, further comprising at least one selected from the group consisting of nucleic acids, proteins, peptides and low molecules.

9. A pharmaceutical composition comprising the lipid composition according to any one of claims 5 to 8.

10. A delivery vehicle comprising the lipid composition according to any one of claims 5 to 8.

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