Compound or salt thereof, lipid particle and pharmaceutical composition

Abstract

The present invention addresses the problem of providing: a compound or a salt thereof which constitutes lipid particles that make it possible to achieve a high nucleic acid encapsulation rate and excellent nucleic acid delivery; and lipid particles and a pharmaceutical composition which use the same and make it possible to achieve a high nucleic acid encapsulation rate and excellent nucleic acid delivery. The present invention provides a compound represented by formula (1) or a salt thereof. In the formula, the symbols have the meanings as defined in the specification of the present application.

Description

[Technical Field]

[0001] The present invention relates to a compound or a salt thereof, as well as lipid particles and pharmaceutical compositions using the same. [Background technology]

[0002] Nucleic acid drugs have a clear mechanism of action against diseases and few side effects, making them promising next-generation pharmaceuticals. For example, nucleic acid drugs using siRNA (small interfering RNA) can inhibit the expression of target genes in a sequence-specific manner within cells. As a result, diseases and symptoms caused by the abnormal expression of specific genes or groups of genes can be alleviated or treated. In order for these nucleic acids to function, they must be delivered into cells.

[0003] Methods for efficiently delivering nucleic acids into cells include methods using viral vectors such as retroviruses and adenoviruses. While methods using viral vectors have high gene transfer efficiency, they are limited in the size of the gene to be transferred and have concerns about immunogenicity and safety. On the other hand, gene transfer using lipid particles is not limited in the gene to be transferred and can solve the above problems, so its development is actively underway.

[0004] As compounds to be contained in lipid particles, Patent Document 1 discloses compounds having an ester group, acetal group, or the like as a linking group connecting an aliphatic group and an amino group. Patent Document 2 also describes a compound having an alkylenediamine structure such as an ethylenediamine structure, and states that lipid particles containing this compound exhibit a high nucleic acid encapsulation rate and excellent nucleic acid delivery. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2010 / 054401 Pamphlet [Patent Document 2] International Publication No. 2019 / 235635 Brochure Summary of the Invention [Problem to be solved by the invention]

[0006] Further exploration is being conducted into lipid particles that can function as vectors and the compounds that make them up, and there is a desire to develop compounds that can achieve excellent nucleic acid delivery.

[0007] In view of the above circumstances, the present invention aims to provide a compound or a salt thereof that constitutes lipid particles that can achieve a high nucleic acid encapsulation rate and excellent nucleic acid delivery, and lipid particles and pharmaceutical compositions that use the compound and can achieve a high nucleic acid encapsulation rate and excellent nucleic acid delivery. [Means for solving the problem]

[0008] As a result of extensive research aimed at solving the above problems, the present inventors have confirmed that lipid particles prepared using a compound represented by the following formula (1) or a salt thereof exhibit a high nucleic acid encapsulation rate and excellent nucleic acid delivery, leading to the completion of the present invention. According to the present invention, the following inventions are provided:

[0009] <1> A compound represented by the following formula (1) or a salt thereof: [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , and -OR56 and optionally substituted with one or more substituents selected from R 4 represents a hydrocarbon group having 1 to 8 carbon atoms, R 5 and R 6 are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 where R 5 and R 6 are both hydrocarbon groups having 1 to 8 carbon atoms, R 7 -R 10 -L 2 -R 11 -L 3 -R 12 indicates, R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 may be substituted with The above aryl group having 6 to 20 carbon atoms includes -OH, -COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 may be substituted with R 58 represents a hydrocarbon group having 1 to 12 carbon atoms, R 57 -OH, COOH, -NR 61 R 62 , -OC(O)OR63 , -C(O)OR 64 , -OC(O)-R 65 , -OR 66 Shows. R 61 and R 62 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 63 ,R 64 ,R 65 , and R 66 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R 63 ,R 64 ,R 65 , and R 66 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 68 may be substituted with The above aryl group having 6 to 20 carbon atoms includes -OH, -COOH, -NR 61 R 62 , -OC(O)OR 63 , -C(O)OR 64 , -OC(O)-R 65 , -OR 66 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 67 may be substituted with R 68 represents a hydrocarbon group having 1 to 12 carbon atoms, L 1 , L 2 , and L 3 each independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 8 represents a hydrocarbon group having 1 to 12 carbon atoms, R 9 represents a hydrocarbon group having 1 to 24 carbon atoms, R 10 represents a hydrocarbon group having 1 to 8 carbon atoms, R 11 represents a hydrocarbon group having 1 to 24 carbon atoms, R 12 represents a hydrocarbon group having 1 to 24 carbon atoms, R 9 , and R 12The hydrocarbon group represented by is an aryl group, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 and R 53 , R 54 , R 55 , and R 58 is defined as above, R 11 The hydrocarbon group represented by is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 and R 53 , R 54 , and R 55 The definition of is as above. <2> R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, and R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by may be substituted with —OH, R 4 represents a hydrocarbon group having 1 to 8 carbon atoms, R 5 and R 6 are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 where R 5 and R 6 are both hydrocarbon groups having 1 to 8 carbon atoms, R 7 But -R 10 -L 2 -R 11 -L 3 -R 12 indicates, L 1 , and L 3 each independently represents -C(O)O- or -OC(O)-. L 2represents -OC(O)O-, -C(O)O-, or -OC(O)-. R 8 represents a hydrocarbon group having 1 to 8 carbon atoms, R 9 represents a hydrocarbon group having 1 to 16 carbon atoms, R 10 represents a hydrocarbon group having 1 to 8 carbon atoms, R 11 represents a hydrocarbon group having 1 to 9 carbon atoms, R 12 represents a hydrocarbon group having 1 to 16 carbon atoms, R 9 , and R 12 The hydrocarbon group represented by is an aryl group or -SR 58 may be substituted with R 58 represents a hydrocarbon group having 1 to 8 carbon atoms, R 11 The hydrocarbon group represented by is -C(O)OR 55 , or -OC(O)-R 56 may be substituted with R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 16 carbon atoms, R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 and R 58 The definition of is as above, <1> or a salt thereof. <3> A compound represented by the following formula (1-1) or a salt thereof: <1> or a salt thereof. [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -OR 56 may be substituted with R 4 represents a hydrocarbon group having 1 to 8 carbon atoms, R 5 and R 6 are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 where R 5 and R 6 are both hydrocarbon groups having 1 to 8 carbon atoms, L 1 represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-; R 8 represents a hydrocarbon group having 1 to 12 carbon atoms, R 9 represents a hydrocarbon group having 1 to 24 carbon atoms, and R 9 The hydrocarbon group represented by is an aryl group, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 may be substituted with R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 may be substituted with The above aryl group having 6 to 20 carbon atoms includes -OH, -COOH, -NR51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 may be substituted with R 58 represents a hydrocarbon group having 1 to 12 carbon atoms, R 57 -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 Shows. R 13 represents a hydrocarbon group having 1 to 8 carbon atoms, R 14 -R 15 -L 5 -R 16 indicates R 15 represents a hydrocarbon group having 1 to 24 carbon atoms, and L 5 indicates -OC(O)O-, -C(O)O-, -OC(O)-, or -O-, and R 16 represents a hydrocarbon group having 1 to 24 carbon atoms, R 15 The hydrocarbon group having 1 to 24 carbon atoms is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 and R 53 , R 54 , and R 55 is defined as above, R 16 The hydrocarbon group having 1 to 24 carbon atoms represented by is an aryl group having 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 and R 53 , R 54 , R 55 , and R 58The definition of is as above. <4> In formula (1-1), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, and R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by may be substituted with —OH, R 4 represents a hydrocarbon group having 1 to 8 carbon atoms, R 5 and R 6 are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 where R 5 and R 6 are both hydrocarbon groups having 1 to 8 carbon atoms, L 1 represents -C(O)O- or -OC(O)-, R 8 represents a hydrocarbon group having 1 to 8 carbon atoms, R 9 represents a hydrocarbon group having 1 to 18 carbon atoms, and R 9 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, or -SR 58 may be substituted with R 58 represents a hydrocarbon group having 1 to 8 carbon atoms, R 13 represents a hydrocarbon group having 1 to 8 carbon atoms, R 14 -R 15 -L 5 -R 16 indicates R 15 represents a hydrocarbon group having 1 to 18 carbon atoms, and L 5 indicates -OC(O)O-, and R 16 represents a hydrocarbon group having 1 to 18 carbon atoms, R 15 The hydrocarbon group having 1 to 18 carbon atoms is -C(O)OR 55 , or -OC(O)-R 56may be substituted with R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 16 carbon atoms; R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 and R 58 is defined as above, R 16 The hydrocarbon group having 1 to 18 carbon atoms represented by is an aryl group or -SR 58 and R 58 The definition of is as above, <3> or a salt thereof. <5> A compound represented by the following formula (1-2) or a salt thereof: <1> or a salt thereof. [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -OR 56 may be substituted with R 4 and R 8 each independently represents a hydrocarbon having 1 to 8 carbon atoms, R 21 and R 22 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, R 23 and R 24 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, R 25and R 26 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, L 21 and L 22 each independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-; R 25 and R 26 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 may be substituted with R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 , R 54 , R 55 and R 56 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, The above aryl group having 6 to 20 carbon atoms is OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 and optionally substituted by R 57 -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 Shows. R 58 represents a hydrocarbon group having 1 to 12 carbon atoms. <6> In formula (1-2), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, and R 1 and R 2The hydrocarbon group represented by may be substituted with —OH, R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, R 4 and R 8 each independently represents a hydrocarbon having 1 to 8 carbon atoms, R 21 and R 22 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 23 and R 24 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 25 and R 26 each independently represents a hydrocarbon group having 1 to 16 carbon atoms, L 21 and L 22 each independently represents -C(O)O- or -OC(O)-; <5> or a salt thereof. <7> In formula (1-2), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, R 4 and R 8 each independently represents a hydrocarbon having 1 to 8 carbon atoms, R 21 and R 22 each independently represents a hydrocarbon group having 1 to 6 carbon atoms, R 23 and R 24 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 25 and R 26 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, L 21 and L 22 each independently represents -C(O)O- or -OC(O)-; <5> or a salt thereof. <8> A compound represented by the following formula (1-3) or a salt thereof: <1> or a salt thereof. [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -OR 56 may be substituted with R 4 and R 8 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 31 , R 32 , R 33 , and R 34 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, R 35 , R 36 , R 37 , and R 38 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, L 31 , L 32 , L 33 , and L 34 each independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-; R 35 , R 36 , R 37 , and R 38 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or SR 58 may be substituted with R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 , R 54 , R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, The above aryl group having 6 to 20 carbon atoms is OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 and optionally substituted by R 57 -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 Shows. R 58 represents a hydrocarbon group having 1 to 12 carbon atoms. <9> In formula (1-3), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, and R 1 and R 2 The hydrocarbon group represented by may be substituted with —OH, R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, R 4 and R 8 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 31 , R 32 , R 33 , and R 34 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 35 , R 36 , R 37, and R 38 each independently represents a hydrocarbon group having 1 to 16 carbon atoms, L 31 , L 32 , L 33 , and L 34 each independently represents -C(O)O- or -OC(O)-; R 35 , R 36 , R 37 , and R 38 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, or SR 58 may be substituted with R 58 represents a hydrocarbon group having 1 to 8 carbon atoms; <8> or a salt thereof. <10> In formula (1-3), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, R 4 and R 8 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 31 , R 32 , R 33 , and R 34 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 35 , R 36 , R 37 , and R 38 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, L 31 , L 32 , L 33 , and L 34 each independently represents -C(O)O- or -OC(O)-; R 35 , R 36 , R 37 , and R 38 The hydrocarbon group represented by is -SR 58 may be substituted with R 58 represents a hydrocarbon group having 1 to 8 carbon atoms; <8> or a salt thereof. <11> In formula (1-3), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, R 4 and R 8 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 31 , R 32 , R 33 , and R 34 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 35 , R 36 , R 37 , and R 38 are each independently, -SR 58 represents a hydrocarbon group having 1 to 12 carbon atoms substituted with R 58 represents a hydrocarbon group having 1 to 8 carbon atoms, L 31 , L 32 , L 33 , and L 34 each independently represents -C(O)O- or -OC(O)-; <8> or a salt thereof. <12> In formula (1-3), R 1 and R 2 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R 3 represents a hydrocarbon group having 2 to 4 carbon atoms, R 4 and R 8 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 31 , R 32 , R 33 , and R 34 each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R35 , R 36 , R 37 , and R 38 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, L 31 , L 32 , L 33 , and L 34 each independently represents -C(O)O- or -OC(O)-; <8> or a salt thereof. <13> A compound or a salt thereof described below: Bis(2-butyloctyl) 16-(3-(diethylamino)propyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate; [ka] Bis(2-butyloctyl) 11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(2-(dimethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(4-(diethylamino)butyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-5,19-dihexyl-7,17-dioxo-6,8,16,18-tetraoxa-12-azatricosane dioate; [ka] Bis(2-pentylheptyl)13-(2-(diethylamino)ethyl)-5,21-dihexyl-7,19-dioxo-6,8,18,20-tetraoxa-13-azapentacosanedioate; [ka] Bis(2-pentylheptyl)10-(2-(diethylamino)ethyl)-4,16-dihexyl-6,14-dioxo-5,7,13,15-tetraoxa-10-azanonadecandioate; [ka] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dimethyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-diethyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-dipropyl-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)5,17-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-dipentyl-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-diheptyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-((3r,5r,7r)-adamantan-1-yl)ethyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14, 16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-5,17-dipropyl-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Diheptyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(heptyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Dihexyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Dioctyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(octyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Dinonyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(nonyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] 1-Heptyl 21-hexyl 11-(2-(diethylamino)ethyl)-5-(4-(heptyloxy)-4-oxobutyl)-17-(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Diheptyl 11-(3-(diethylamino)propyl)-5,17-bis(4-(heptyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Diheptyl 10-(2-(diethylamino)ethyl)-4,16-bis(3-(heptyloxy)-3-oxopropyl)-6,14-dioxo-5,7,13,15-tetraoxa-10-azanonadecandioate; [ka] 1-Hexyl 21-octyl 11-(2-(diethylamino)ethyl)-5-(4-(hexyloxy)-4-oxobutyl)-17-(4-(octyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(2-(hexylthio)ethyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-(2-(hexylthio)ethoxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] Bis(8-(methylthio)octyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-((8-(methylthio)octyl)oxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; [ka] <14> <1> from <13> 1. A lipid particle comprising the compound according to any one of the above or a salt thereof and a lipid. <15> The lipid is at least one lipid selected from the group consisting of sterols and lipids having a nonionic hydrophilic polymer chain; <14> The lipid particle according to claim 1. <16> It also contains neutral lipids, <14> or <15> The lipid particle according to claim 1. <17> Further comprising nucleic acid, <14> from <16> 1. The lipid particle according to any one of the above. <18> The nucleic acid includes a nucleic acid having 50 or more bases. <17> The lipid particle according to claim 1. <19> <14> from <18> A pharmaceutical composition comprising the lipid particle according to any one of the above items as an active ingredient. [Effects of the Invention]

[0010] By using the compound of the present invention, it is possible to produce lipid particles and pharmaceutical compositions that can achieve a high nucleic acid encapsulation rate and excellent nucleic acid delivery. The lipid particles and pharmaceutical compositions of the present invention can achieve a high nucleic acid encapsulation rate and excellent nucleic acid delivery. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described in detail below. In this specification, the symbol "to" indicates a range that includes the numerical values ​​before and after it as the minimum and maximum values, respectively.

[0012] <Compound of the Present Invention> The compound of the present invention is represented by the following formula (1):

[0013] [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , and -OR 56 and optionally substituted with one or more substituents selected from R 4 represents a hydrocarbon group having 1 to 8 carbon atoms, R5 and R 6 are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 where R 5 and R 6 are both hydrocarbon groups having 1 to 8 carbon atoms, R 7 -R 10 -L 2 -R 11 -L 3 -R 12 indicates, R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 may be substituted with The above aryl group having 6 to 20 carbon atoms includes -OH, -COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 may be substituted with R 58 represents a hydrocarbon group having 1 to 12 carbon atoms, R 57 -OH, COOH, -NR 61 R 62 , -OC(O)OR 63 , -C(O)OR 64 , -OC(O)-R 65 , -OR 66 Shows. R 61and R 62 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 63 ,R 64 ,R 65 , and R 66 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R 63 ,R 64 ,R 65 , and R 66 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 68 may be substituted with The above aryl group having 6 to 20 carbon atoms includes -OH, -COOH, -NR 61 R 62 , -OC(O)OR 63 , -C(O)OR 64 , -OC(O)-R 65 , -OR 66 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 67 may be substituted with R 68 represents a hydrocarbon group having 1 to 12 carbon atoms, L 1 , L 2 , and L 3 each independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-. R 8 represents a hydrocarbon group having 1 to 12 carbon atoms, R 9 represents a hydrocarbon group having 1 to 24 carbon atoms, R 10 represents a hydrocarbon group having 1 to 8 carbon atoms, R 11 represents a hydrocarbon group having 1 to 24 carbon atoms, R 12 represents a hydrocarbon group having 1 to 24 carbon atoms, R 9 , and R 12 The hydrocarbon group represented by is an aryl group, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58and R 53 , R 54 , R 55 , and R 58 is defined as above, R 11 The hydrocarbon group represented by is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 and R 53 , R 54 , and R 55 The definition of is as above.

[0014] 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, the hydrocarbon group having 2 to 8 carbon atoms, and the hydrocarbon group having 1 to 8 carbon atoms are preferably an alkyl group, an alkenyl group, or an alkynyl group, respectively.

[0015] The alkyl group may be linear or branched, and may be linear or cyclic. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a cyclobutyl group, a pentyl group, a cyclopentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a trimethyldodecyl group (preferably a 3,7,11-trimethyldodecyl group), a tetradecyl group, a pentadecyl group, a hexadecyl group, a tetramethylhexadecyl group (preferably a 3,7,11,15-tetramethylhexadecyl group), a heptadecyl group, an octadecyl group, a 2-butylhexyl group, and a 2-butyloctyl group. , 1-pentylhexyl group, 2-pentylheptyl group, 3-pentyloctyl group, 1-hexylheptyl group, 1-hexylnonyl group, 2-hexyloctyl group, 2-hexyldecyl group, 3-hexylnonyl group, 1-heptyloctyl group, 2-heptylnonyl group, 2-heptylundecyl group, 3-heptyldecyl group, 1-octylnonyl group, 2-octyldecyl group, 2-octyldodecyl group, 3-octylundecyl group, 2-nonylundecyl group, 3-nonyldodecyl group, 2-decyldodecyl group, 2-decyltetradecyl group, 3-decyltridecyl group, 2-(4,4-dimethylpentan-2-yl)-5,7,7-trimethyloctyl group, and the like.

[0016] The alkenyl group may be linear or branched, linear or cyclic. Specifically, it includes an allyl group, a prenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group (preferably, a (Z)-2-nonenyl group or an (E)-2-nonenyl group), a decenyl group, an undecenyl group, a dodecenyl group, a dodecadienyl group, a tridecenyl group (preferably, a (Z)-trideca-8-enyl group), a tetradecenyl group (preferably, a tetradec-9-enyl group), and a pentadecenyl group (preferably, a (Z)-pentadeca-8-enyl group). , a hexadecenyl group (preferably a (Z)-hexadecan-9-enyl group), a hexadecadienyl group, a heptadecenyl group (preferably a (Z)-heptadecan-8-enyl group), a heptadecadienyl group (preferably a (8Z,11Z)-heptadecan-8,11-dienyl group), an octadecenyl group (preferably a (Z)-octadecan-9-enyl group), an octadecadienyl group (preferably a (9Z,12Z)-octadecan-9,12-dienyl group), and the like.

[0017] The alkynyl group may be linear or branched, open-chain or cyclic, and specific examples thereof include a propargyl group, a butynyl group, a pentynyl group, a hexynyl group, a heptynyl group, an octynyl group, a nonynyl group, a decynyl group, an undecynyl group, a dodecynyl group, a tetradecynyl group, a pentadecynyl group, a hexadecynyl group, a heptadecynyl group, and an octadecynyl group.

[0018] Preferably, all of the above alkenyl groups have one or two double bonds, and preferably, all of the alkynyl groups have one or two triple bonds.

[0019] -(C1-C12 hydrocarbon group)-R 67 The hydrocarbon group having 1 to 12 carbon atoms is preferably an alkylene group having 1 to 12 carbon atoms or an alkenylene group having 2 to 12 carbon atoms. The alkylene group having 1 to 12 carbon atoms and the alkenylene group having 2 to 12 carbon atoms may be linear or branched, and may be linear or cyclic. Specific examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, an octamethylene group, a nonamethylene group, a decamethylene group, and an undecamethylene group.

[0020] The aryl group preferably has 6 to 20 carbon atoms, more preferably 6 to 18, and even more preferably 6 to 10. Specific examples include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.

[0021] R 1 and R 2 are each independently preferably a hydrocarbon group having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms. R 3 represents a hydrocarbon group preferably having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms. R 1 , R 2 and R 3 The hydrocarbon group represented by may preferably be substituted with —OH.

[0022] L 1 , and L 3 are each independently preferably -C(O)O- or -OC(O)-. L 2 preferably represents —OC(O)O—, —C(O)O—, or —OC(O)—.

[0023] R 8 represents a hydrocarbon group preferably having 1 to 10 carbon atoms, and more preferably a hydrocarbon group having 1 to 8 carbon atoms. R 9 represents a hydrocarbon group preferably having 1 to 20 carbon atoms, and more preferably a hydrocarbon group having 1 to 16 carbon atoms. R 11 represents a hydrocarbon group preferably having 1 to 16 carbon atoms, and more preferably a hydrocarbon group having 1 to 9 carbon atoms. R 12represents a hydrocarbon group preferably having 1 to 20 carbon atoms, and more preferably a hydrocarbon group having 1 to 16 carbon atoms. R 9 , and R 12 The hydrocarbon group represented by is preferably an aryl group or -SR 58 where R 58 represents a hydrocarbon group preferably having 1 to 8 carbon atoms. R 11 The hydrocarbon group represented by is preferably —C(O)OR 55 , or -OC(O)-R 56 where R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 16 carbon atoms; R 55 , and R 56 The hydrocarbon group represented by is preferably an aryl group having 6 to 20 carbon atoms or -SR 58 and R 58 The definition of is as above.

[0024] The compound represented by formula (1) is preferably, as a first example, a compound represented by the following formula (1-1). [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -OR 56 may be substituted with R 4 represents a hydrocarbon group having 1 to 8 carbon atoms, R5 and R 6 are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R 8 -L 1 -R 9 where R 5 and R 6 are both hydrocarbon groups having 1 to 8 carbon atoms, L 1 represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-; R 8 represents a hydrocarbon group having 1 to 12 carbon atoms, R 9 represents a hydrocarbon group having 1 to 24 carbon atoms, and R 9 The hydrocarbon group represented by is an aryl group, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 may be substituted with R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R 53 ,R 54 ,R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 may be substituted with The above aryl group having 6 to 20 carbon atoms includes -OH, -COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 may be substituted with R 58 represents a hydrocarbon group having 1 to 12 carbon atoms, R 57 -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 Shows. R 13 represents a hydrocarbon group having 1 to 8 carbon atoms, R 14 -R 15 -L 5 -R 16 indicates R 15 represents a hydrocarbon group having 1 to 24 carbon atoms, and L 5 indicates -OC(O)O-, -C(O)O-, -OC(O)-, or -O-, and R 16 represents a hydrocarbon group having 1 to 24 carbon atoms, R 15 The hydrocarbon group having 1 to 24 carbon atoms is -OC(O)OR 53 , -C(O)OR 54 , or -OC(O)-R 55 and R 53 , R 54 , and R 55 is defined as above, R 16 The hydrocarbon group having 1 to 24 carbon atoms represented by is an aryl group having 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 and R 53 , R 54 , R 55 , and R 58 The definition of is as above.

[0025] In formula (1-1), R 1 and R 2 are each independently preferably a hydrocarbon group having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms. R 3represents a hydrocarbon group preferably having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms. R 1 , R 2 and R 3 The hydrocarbon group represented by may preferably be substituted with —OH.

[0026] L 1 preferably represents —C(O)O— or —OC(O)—. R 8 represents a hydrocarbon group preferably having 1 to 10 carbon atoms, and more preferably a hydrocarbon group having 1 to 8 carbon atoms. R 9 preferably represents a hydrocarbon group having 1 to 18 carbon atoms, and R 9 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, or -SR 58 may be substituted with R 14 is preferably -R 15 -L 5 -R 16 indicates R 15 represents a hydrocarbon group having 1 to 18 carbon atoms, and L 5 indicates -OC(O)O-, and R 16 represents a hydrocarbon group having 1 to 18 carbon atoms. R 15 The hydrocarbon group having 1 to 18 carbon atoms represented by is preferably —C(O)OR 55 , or -OC(O)-R 56 may be substituted with R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 16 carbon atoms; R 55 , and R 56 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -SR 58 and R 58 The definition of is as above. R 16 The hydrocarbon group having 1 to 18 carbon atoms represented by is preferably an aryl group or -SR 58 and R 58 The definition of is as above.

[0027] A second example of the compound represented by formula (1) is preferably a compound represented by the following formula (1-2). [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -OR 56 may be substituted with R 4 and R 8 each independently represents a hydrocarbon having 1 to 8 carbon atoms, R 21 and R 22 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, R 23 and R 24 each independently represents a hydrocarbon group having 1 to 12 carbon atoms, R 25 and R 26 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, L 21 and L 22 each independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-; R 25 and R 26 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -SR 58 may be substituted with R 51and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 , R 54 , R 55 and R 56 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, The above aryl group having 6 to 20 carbon atoms is OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 and optionally substituted by R 57 -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 Shows. R 58 represents a hydrocarbon group having 1 to 12 carbon atoms.

[0028] In formula (1-2), R 1 and R 2 R each independently represents a hydrocarbon group preferably having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms. 1 and R 2 The hydrocarbon group represented by may be substituted with -OH, but is more preferably a hydrocarbon group without any substituents.

[0029] R 3 represents a hydrocarbon group preferably having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0030] R 21 and R 22are each independently preferably a hydrocarbon group having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 8 carbon atoms, and even more preferably a hydrocarbon group having 1 to 6 carbon atoms. R 23 and R 24 are each independently preferably a hydrocarbon group having 1 to 10 carbon atoms, more preferably a hydrocarbon group having 1 to 8 carbon atoms. R 25 and R 26 are each independently preferably a hydrocarbon group having 1 to 20 carbon atoms, more preferably a hydrocarbon group having 1 to 16 carbon atoms, and even more preferably a hydrocarbon group having 1 to 12 carbon atoms. L 21 and L 22 are each independently preferably -C(O)O- or -OC(O)-.

[0031] A third example of the compound represented by formula (1) is preferably a compound represented by the following formula (1-3). [ka] During the ceremony, R 1 and R 2 each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R 3 represents a hydrocarbon group having 2 to 8 carbon atoms, and R 1 , R 2 and R 3 The hydrocarbon group represented by is -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or -OR 56 may be substituted with R 4 and R 8 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 31 , R 32 , R 33 , and R 34each independently represents a hydrocarbon group having 1 to 12 carbon atoms, R 35 , R 36 , R 37 , and R 38 each independently represents a hydrocarbon group having 1 to 24 carbon atoms, L 31 , L 32 , L 33 , and L 34 each independently represents -OC(O)O-, -C(O)O-, -OC(O)-, or -O-; R 35 , R 36 , R 37 , and R 38 The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , or SR 58 may be substituted with R 51 and R 52 each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R 53 , R 54 , R 55 , and R 56 each independently represents a hydrocarbon group having 1 to 18 carbon atoms, The above aryl group having 6 to 20 carbon atoms is OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 or -(a hydrocarbon group having 1 to 12 carbon atoms)-R 57 and optionally substituted by R 57 -OH, COOH, -NR 51 R 52 , -OC(O)OR 53 , -C(O)OR 54 , -OC(O)-R 55 , -OR 56 Shows. R 58represents a hydrocarbon group having 1 to 12 carbon atoms.

[0032] In formula (1-3), R 1 and R 2 R each independently represents a hydrocarbon group preferably having 1 to 12 carbon atoms, more preferably a hydrocarbon group having 1 to 6 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms. 1 and R 2 The hydrocarbon group represented by may be substituted with -OH, but is more preferably a hydrocarbon group without any substituents.

[0033] R 3 represents a hydrocarbon group preferably having 2 to 6 carbon atoms, and more preferably a hydrocarbon group having 2 to 4 carbon atoms.

[0034] R 31 , R 32 , R 33 , and R 34 are each independently preferably a hydrocarbon group having 1 to 10 carbon atoms, more preferably a hydrocarbon group having 1 to 8 carbon atoms, and even more preferably a hydrocarbon group having 1 to 3 carbon atoms.

[0035] R 35 , R 36 , R 37 , and R 38 R each independently represents a hydrocarbon group having preferably 1 to 20 carbon atoms, more preferably a hydrocarbon group having 1 to 16 carbon atoms, and even more preferably a hydrocarbon group having 1 to 12 carbon atoms. 35 , R 36 , R 37 , and R 38 The hydrocarbon group represented by is preferably an aryl group having 6 to 20 carbon atoms, or SR 58 More preferably, it is substituted with -SR 58 may be substituted with. R 35 , R 36 , R 37 , and R 38 are each independently particularly preferably -SR 58or represents a hydrocarbon group having 1 to 12 carbon atoms substituted with

[0036] L 31 , L 32 , L 33 , and L 34 are each independently preferably -C(O)O- or -OC(O)-.

[0037] R 58 represents a hydrocarbon group preferably having 1 to 10 carbon atoms, and more preferably a hydrocarbon group having 1 to 8 carbon atoms.

[0038] The compound of the present invention may form a salt. Examples of salts of basic groups include salts with mineral 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. Salts of acidic groups include, for example, 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-phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Of the above salts, preferred salts include pharmacologically acceptable salts.

[0039] Specific preferred examples of the compound of the present invention include the compounds described in Examples 1 to 44 below, but the present invention should not be construed as being limited thereto. The compounds described in Examples 1 to 44 are referred to as Compound 1 to Compound 44, respectively.

[0040] Among the above, Compound 3, Compound 8, Compound 10, Compound 11, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 27, Compound 28, Compound 29, Compound 32, Compound 33, Compound 34, Compound 37, Compound 38, Compound 39, Compound 42, Compound 43, and Compound 44 are preferred.

[0041] <Manufacturing method> The method for producing the compound of the present invention will now be described. The compound of the present invention can be produced by combining known methods, for example, according to the production method shown below.

[0042] [Manufacturing method 1] [ka] "During the ceremony, R a and R b is the leaving group; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 has the same meaning as above. Examples of leaving groups include a chloro group, a fluoro group, a bromo group, a trichloromethoxy group, a 4-nitro-phenoxy 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-oxadiazolidyl group, and an N-hydroxysuccinimidyl group.

[0043] (1-1) Known examples of compounds of formula [3] include 1,1'-carbonyldiimidazole, 4-nitrophenyl chloroformate, triphosgene, and phosgene. The compound of formula [4] can be produced by reacting the compound of formula [2] with the compound of formula [3] in the presence or absence of a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, and these solvents may be used in combination. Preferred solvents include ethers, with tetrahydrofuran being more preferred. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [2]. The base used in this reaction may be an inorganic base or an organic base, preferably an organic base, such as triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, or N,N-dimethylaminopyridine. The amount of the base used may be 1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of formula [2]. The amount of the compound of formula [3] used is not particularly limited, but may be 0.3 to 10 times (v / w) the amount of the compound of formula [2]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0044] (1-2) Known examples of compounds of formula [5] include 2,2'-((2-diethylamino)ethyl)azanediyl)bis(ethan-1-ol), 2,2'-((2-dimethylamino)ethyl)azanediyl)bis(ethan-1-ol), and 2,2'-((3-(diethylamino)propyl)azanediyl)bis(ethan-1-ol). The compound of formula [1] can be produced by reacting a compound of formula [4] with a compound of formula [5] in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, and these solvents may be used in combination. Preferred solvents include nitriles, with acetonitrile being more preferred. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [4]. The base used in this reaction may be an inorganic or organic base, such as 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, or N,N-dimethylaminopyridine. The amount of the base used may be 1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of formula [4]. The amount of the compound of formula [5] used is not particularly limited, but may be 0.1 to 10 times (v / w) the amount of the compound of formula [4]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0045] (1-3) Known examples of compounds of formula [5] include 2-((2-(diethylamino)ethyl)(ethyl)amino)ethan-1-ol and 2-((2-(diethylamino)ethyl)(isopropyl)amino)ethan-1-ol. The compound of formula [1] can be produced by reacting a compound of formula [4] with a compound of formula [6] in the presence of a base. This reaction may be carried out according to the production method (1-2).

[0046] [Manufacturing method 2] [ka] "During the ceremony, R c and R e is the leaving group; R d and R g represents a hydrocarbon group having 1 to 12 carbon atoms or hydrogen; R f represents a hydrocarbon group having 1 to 18 carbon atoms; R h represents a hydrocarbon group having 1 to 12 carbon atoms; M represents an alkali metal, alkaline earth metal, or hydrogen; R i -MgCl, -MgBr, -MgI or -Li; R 21 , R 23 , and R 25 has the same meaning as above. Examples of leaving groups include a chloro group, a fluoro group, a bromo group, a trichloromethoxy group, a 4-nitro-phenoxy 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-oxadiazolidyl group, and an N-hydroxysuccinimidyl group.

[0047] (2-1) Known examples of compounds of formula [8] include potassium ethyl malonate. 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 and in the presence or absence of anhydrous magnesium chloride. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, and these solvents may be used in combination. Preferred solvents include nitriles, with acetonitrile being more preferred. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [7]. The base used in this reaction may be an inorganic base or an organic base, preferably an organic base, such as triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, or N,N-dimethylaminopyridine. The amount of the base used may be 1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of the formula [7]. The amount of the compound of formula [8] used is not particularly limited, but may be 0.1 to 10 times (v / w) the amount of the compound of formula [7]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0048] (2-2) Known examples of compounds of formula

[10] include ethyl 8-bromooctanoate. The compound of formula [11A] can be prepared by reacting the compound of formula [9] with the compound of formula

[10] in the presence or absence of a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, and these solvents may be used in combination. Preferred solvents include alcohols, with ethanol and methanol being more preferred. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [9]. The base used in this reaction may be an inorganic or organic base, such as 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, or N,N-dimethylaminopyridine. The amount of the base used may be 0.1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of the formula [9]. The amount of the compound of formula [8] used is not particularly limited, but may be 0.1 to 10 times (v / w) the amount of the compound of formula [9]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0049] (2-3) The compound of formula [11B] can be produced by hydrolysis of the compound of formula [11A] in the presence of a base or an acid. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these solvents may be used in combination. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [11A]. The base used in this reaction may be an inorganic base or an organic base, preferably an inorganic base, such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, sodium phosphate, or lithium phosphate. The acid used in this reaction may be an inorganic or organic acid, preferably an inorganic acid, such as hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, or phosphoric acid. The amount of the base used may be 0.1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of formula [11A]. The amount of the acid used may be 0.01 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of formula [11A]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0050] (2-4) For example, hexylmagnesium bromide is known as a compound of formula

[13] . The compound of formula [11B] can be prepared by reacting a compound of formula

[12] with a compound of formula

[13] . The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, amides, and aromatic hydrocarbons, and these solvents may be used in combination. Preferred solvents include ethers, with tetrahydrofuran being more preferred. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula

[12] . The amount of the compound of formula

[13] used is not particularly limited, but may be 0.8 to 10 times (v / w) the amount of the compound of formula

[12] . This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0051] (2-5) Known examples of compounds of formula

[14] include 2-butyl-1-octanol and 2-pentyl-1-heptanol. The compound of formula [11C] can be produced by reacting the compound of formula [11B] with the 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. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, and aromatic hydrocarbons, and these solvents may be used in combination. Preferred solvents include aromatic hydrocarbons and ethers, with toluene and tetrahydrofuran being more preferred. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [11B]. The acid used in this reaction may be an inorganic or organic acid. The acid is preferably a sulfonic acid, such as sulfuric acid, 4-toluenesulfonic acid, or methanesulfonic acid. Condensing agents used in this reaction include, for example, 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; and uroniums such as O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. Examples of the acid halide used in this reaction include carboxylic acid halides such as acetyl chloride and trifluoroacetyl chloride; sulfonic acid halides such as methanesulfonyl chloride and tosyl chloride; and chloroformates such as ethyl chloroformate and isobutyl chloroformate. The base used in this reaction may be an inorganic base or an organic base, preferably an organic base, such as triethylamine, N,N-diisopropylethylamine, 4-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene, or N,N-dimethylaminopyridine. The amount of the base used may be 1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of formula [11B]. The amount of the compound of formula

[14] used is not particularly limited, but may be 0.8 to 10 times (v / w) the amount of the compound of formula [11B]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0052] (2-6) The compound of formula [2A] can be produced by reduction of the compound of formula [11C] in the presence of a reducing agent. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include halogenated hydrocarbons, ethers, esters, amides, nitriles, alcohols, sulfoxides, aromatic hydrocarbons, and water, and these solvents may be used in combination. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula [11A]. The reducing agent used in this reaction includes, for example, boron compounds such as sodium borohydride. The amount of the reducing agent used may be 0.1 to 50 times by mole, preferably 1 to 10 times by mole, relative to the compound of the formula [11A]. This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0053] [Manufacturing method 3] [ka] "During the ceremony, R 31 , R 32 , R35 , and R 36 has the same meaning as above.

[0054] (3-1) Known compounds of the formula [2A] include, for example, 1-heptanol, 2-(hexylthio)ethan-1-ol, and 8-(methylthio)octan-1-ol. The compound of formula

[17] can be produced by reacting the compound of formula

[15] with the 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. This reaction may be carried out according to the production method (2-5).

[0055] (3-2) The compound of formula [2B] can be produced by reduction of the compound of formula

[17] in the presence of a reducing agent. This reaction may be carried out according to the production method (2-6).

[0056] [Manufacturing method 4] [ka] "During the ceremony, R j and R k is the leaving group; R 1 , R 2 , R 3 , R 4 and R 8 has the same meaning as above. Examples of leaving groups include a chloro group, a fluoro group, a bromo group, a trichloromethoxy group, a 4-nitro-phenoxy 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-oxadiazolidyl group, and an N-hydroxysuccinimidyl group.

[0057] (4-1) Known examples of compounds of formula

[19] include 2-chloro-N,N-diethylethan-1-amine, 3-chloro-N,N-diethylpropan-1-amine, and 2-bromo-N,N-diethylethan-1-amine. The compound of formula [5] can be prepared by reacting the compound of formula

[18] with the compound of formula

[19] in the presence or absence of a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include alcohols, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these solvents may be used in combination. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula

[18] . The base used in this reaction may be an inorganic base or an organic base, and the amount of the base used may be 1 to 10,000 times by mole, preferably 1 to 5,000 times by mole, relative to the compound of formula

[18] . The amount of the compound of formula

[19] used is not particularly limited, but may be 1 to 10 times (v / w) the amount of the compound of formula

[18] . This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0058] (4-2) Known examples of compounds of formula

[20] include 2-bromo-1-ethanol and 3-bromo-1-propanol. The compound of formula [5] can be prepared by reacting the compound of formula

[20] with the compound of formula

[21] in the presence or absence of a base. The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include alcohols, halogenated hydrocarbons, ethers, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water, and these solvents may be used in combination. The amount of the solvent used is not particularly limited, but may be 1 to 500 times (v / w) the amount of the compound of formula

[20] . The base used in this reaction may be an inorganic base or an organic base, and the amount of the base used may be 1 to 10,000 times, preferably 1 to 5,000 times, the moles of the compound of formula

[20] . The amount of the compound of formula

[21] used is not particularly limited, but may be 1 to 10 times (v / w) the amount of the compound of formula

[20] . This reaction may be carried out at -30 to 150°C, preferably 0 to 100°C, for 5 minutes to 48 hours.

[0059] In the compounds used in the above-mentioned production methods, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist, these isomers can also be used. In addition, when solvates, hydrates and various forms of crystals exist, these solvates, hydrates and various forms of crystals can also be used.

[0060] In the compounds used in the above-mentioned production methods, for example, compounds having an amino group, a hydroxyl group, a carboxyl group, or the like can have these groups protected in advance with a conventional protecting group, and after the reaction, these protecting groups can be removed by a method known per se. The compounds obtained by the above-mentioned production methods can be derived into other compounds by subjecting them to reactions known per se, such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration, or hydrolysis, or by appropriately combining these reactions.

[0061] <Lipid particles> In the present invention, lipid particles containing the compound of the present invention or its salt can be prepared.When preparing lipid particles, in addition to the compound of the present invention, at least one lipid selected from the group consisting of sterol and lipids having nonionic hydrophilic polymer chains can be used.The lipid particles can further contain neutral lipids.The lipid particles can further contain nucleic acids.

[0062] In the lipid particles of the present invention, the amount of the compound of the present invention is preferably 20 mol % to 80 mol %, more preferably 35 mol % to 70 mol %, and even more preferably 40 mol % to 65 mol %, based on the total lipid amount.

[0063] <Sterol> The lipid particles of the present invention preferably contain a sterol, which can reduce membrane fluidity and provide a stabilizing effect for the lipid particles. Examples of sterols include, but are not limited to, cholesterol, phytosterols (sitosterol), stigmasterol, fucosterol, spinasterol, brassicasterol, ergosterol, cholestanone, cholestenone, coprostanol, cholesteryl-2'-hydroxyethyl ether, cholesteryl-4'-hydroxybutyl ether, etc. Among these, cholesterol is preferred. In the lipid particles of the present invention, the amount of sterol blended is preferably 10 mol % to 60 mol %, more preferably 20 mol % to 55 mol %, and even more preferably 25 mol % to 50 mol %, relative to the total lipid amount.

[0064] <Neutral lipids> The lipid particles of the present invention may contain a neutral lipid. The neutral lipid is not particularly limited, but may include phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, etc., and phosphatidylcholine is preferred. The neutral lipid may be a single neutral lipid or a combination of multiple different neutral lipids.

[0065] Phosphatidylcholines include, but are not limited to, 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).

[0066] Examples of phosphatidylethanolamines include, but are not limited to, dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylethanolamine (DOPE), dilinoleoylphosphatidylethanolamine (DLoPE), diphytanoylphosphatidylethanolamine (D(Phy)PE), 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE), ditetradecylphosphatidylethanolamine, dihexadecylphosphatidylethanolamine, dioctadecylphosphatidylethanolamine, and diphytanylphosphatidylethanolamine.

[0067] Examples of sphingomyelin include, but are not limited to, egg yolk-derived sphingomyelin and milk-derived sphingomyelin. The ceramide is not particularly limited, but examples thereof include egg yolk-derived ceramide and milk-derived ceramide.

[0068] In the lipid particles of the present invention, the blending amount of the neutral lipid is preferably 0 mol % or more and 55 mol % or less based on the total amount of the constituent lipid components.

[0069] <Lipids with non-ionic hydrophilic polymer chains> The lipid particles 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 particles can be obtained. Examples of nonionic hydrophilic polymers include, but are not limited to, 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 constituent units. Of 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 (polyethylene glycol will also be referred to as PEG hereinafter) is particularly preferred.

[0070] The lipid having a nonionic hydrophilic polymer chain is not particularly limited, but includes PEG-modified phosphoethanolamine, diacylglycerol PEG derivative, monoacylglycerol PEG derivative, dialkylglycerol PEG derivative, cholesterol PEG derivative, ceramide PEG derivative, etc. Among these, monoacylglycerol PEG or diacylglycerol PEG is preferred. 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. The nonionic hydrophilic polymer chain may be branched and may have a substituent such as a hydroxymethyl group.

[0071] In the lipid particles of the present invention, the amount of lipid having a nonionic hydrophilic polymer chain is preferably 0.25 mol % to 12 mol %, more preferably 0.5 mol % to 6 mol %, and even more preferably 1 mol % to 3 mol %, based on the total amount of lipid.

[0072] <Nucleic acid> The lipid particles of the present invention may contain nucleic acids. Examples of nucleic acids include plasmids, single-stranded DNA, double-stranded DNA, siRNA (small interfering RNA), miRNA (micro RNA), mRNA, antisense oligonucleotides (also known as ASO), ribozymes, aptamers, saRNA, and sgRNA, and any of these may be contained. Furthermore, modified nucleic acids may be contained. RNA is particularly preferred as the nucleic acid, and RNA having 5 to 20,000 bases is preferred. In the lipid particles of the present invention, the mass ratio of lipid to nucleic acid is preferably 2-1000, more preferably 3-500, even more preferably 5-200, and particularly preferably 5-100.

[0073] <Method of manufacturing lipid particles> The method for producing the lipid particles of the present invention will now be described. The method for producing lipid particles is not limited, but lipid particles can be produced by dissolving all or some of the oil-soluble components constituting the lipid particles 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 micromixer may be used for mixing, or emulsification may be performed using an emulsifier such as a homogenizer, an ultrasonic emulsifier, a high-pressure injection emulsifier, or the like. Alternatively, the lipid-containing solution can be dried under reduced pressure using an evaporator or spray-dried using a spray dryer to prepare a dried mixture containing lipids, and this mixture can then be added to an aqueous solvent and emulsified using the emulsifier described above.

[0074] An example of a method for producing lipid particles containing nucleic acids is Step (a) of dissolving components of lipid particles containing the compound of the present invention in an organic solvent to obtain an oil phase; a step (b) of mixing the oil phase obtained in the step (a) with an aqueous phase containing nucleic acids; (c) diluting the mixture containing the oil phase and the aqueous phase obtained in step (b) to obtain a dispersion of nucleic acid-lipid particles; a step (d) of removing the organic solvent from the dispersion of nucleic acid-lipid particles obtained in the step (c); The method includes the steps of:

[0075] In step (a), the components of lipid particles containing the compound of the present invention are dissolved in an organic solvent (an alcohol such as ethanol, or an ester). 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.

[0076] In step (b), the aqueous phase can be obtained by dissolving nucleic acids (e.g., siRNA, mRNA, antisense nucleic acids, etc.) in water or a buffer solution. Components such as antioxidants can be added as needed. The mixing ratio (volume ratio) of the aqueous phase to the oil phase is preferably 5:1 to 1:1, more preferably 4:1 to 2:1.

[0077] In step (b), the mixture can be diluted with water or a buffer solution (such as phosphate buffered saline (PBS)).

[0078] In step (d), the method for removing the organic solvent from the nucleic acid-lipid particle dispersion is not particularly limited, and any common method can be used. For example, the organic solvent can be removed by dialysis using a solution such as phosphate-buffered saline or sucrose-Tris buffer.

[0079] The lipid particles can be subjected to sizing as needed. The sizing method is not particularly limited, but the particle size can be reduced using an extruder or the like. Furthermore, the dispersion containing the lipid particles of the present invention can be frozen or freeze-dried by a common method.

[0080] <About lipid particles> In the present invention, lipid particles refer to particles composed of lipids, and include compositions having any structure selected from lipid aggregates in which lipids are aggregated, micelles, and liposomes, but the structure of the lipid particles is not limited to these as long as the composition contains lipids. Liposomes have a lipid bilayer structure, have an aqueous phase inside, and include liposomes with a single bilayer membrane and multilayer liposomes with multiple layers stacked on top of each other. Either type of liposome may be included in the present invention.

[0081] The morphology of lipid particles can be confirmed by electron microscopy or structural analysis using X-rays. For example, cryo-transmission electron microscopy (CryoTEM) can be used to determine whether the lipid particles have a lipid bilayer structure (lamellar structure) and an inner water layer, like liposomes, or whether they have an electron-dense core inside the particle packed with lipids and other components. Small-angle X-ray scattering (SAXS) measurements can also be used to determine whether the lipid particles have a lipid bilayer structure (lamellar structure).

[0082] 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 a general method (e.g., dynamic light scattering method, laser diffraction method, etc.).

[0083] <Use of lipid particles> As an example of the use of lipid particles in the present invention, nucleic acid (e.g., RNA) can be introduced into cells by introducing lipid particles containing nucleic acid into cells. Furthermore, when the lipid particles of the present invention contain nucleic acid having pharmaceutical uses, the lipid particles can be administered to a living body as a nucleic acid drug.

[0084] When the lipid particles of the present invention are used as nucleic acid drugs, the lipid particles of the present invention can be administered to a living body either alone or mixed with a pharmaceutically acceptable administration vehicle (e.g., physiological saline or phosphate buffer). The concentration of the lipid particles in the mixture with the pharmaceutically acceptable carrier is not particularly limited and can generally be 0.05% by mass to 90% by mass. In addition, the nucleic acid drug containing the lipid particles of the present invention may also contain other pharmaceutically acceptable additives, such as a pH-adjusting buffer or an osmotic pressure adjuster.

[0085] The administration route of the nucleic acid drug containing the lipid particles of the present invention is not particularly limited, and can be administered by any method. Administration methods include oral administration and 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, colonic administration, buccal administration, nasal administration, intracisternal administration, inhalation, etc.). Parenteral administration is preferred, and the preferred administration methods are intravenous injection, subcutaneous injection, intradermal injection, or intramuscular injection. The nucleic acid drug containing the lipid particles of the present invention can also be administered by direct injection into the diseased site.

[0086] The dosage form of the lipid particles of the present invention is not particularly limited, but when administered orally, the lipid particles of the present invention can be combined with an appropriate excipient and used in the form of tablets, troches, capsules, pills, suspensions, syrups, etc. Furthermore, preparations suitable for parenteral administration can contain additives such as antioxidants, buffers, bacteriostatic agents, and isotonic sterile injections, suspending agents, solubilizing agents, thickening agents, stabilizers, or preservatives, as appropriate.

[0087] <Nucleic acid delivery carrier> The lipid particles of the present invention are capable of retaining nucleic acids at a high encapsulation rate, and are therefore extremely useful as nucleic acid delivery carriers. Using a nucleic acid delivery carrier utilizing the present invention, for example, the resulting lipid particles can be mixed with nucleic acids and transfected in vitro or in vivo, thereby introducing nucleic acids into cells. Furthermore, the nucleic acid delivery carrier utilizing the present invention is also useful as a nucleic acid delivery carrier for nucleic acid medicines. That is, the lipid particles of the present invention are useful as compositions for nucleic acid delivery in vitro or in vivo (preferably in vivo).

[0088] The present invention will now be described with reference to examples, but the present invention is not limited to these examples. [Example]

[0089] Unless otherwise specified, purification by column chromatography was performed using an automatic purification system ISOLERA (Biotage), a medium-pressure fractionation and purification system Purif-espoir-2 (Shoko Science Co., Ltd.), or a medium-pressure liquid chromatograph YFLC W-prep 2XY (Yamazen Corporation). Unless otherwise specified, the carrier used in silica gel column chromatography was Chromatorex Q-Pack SI 50 (Fuji Silysia Chemical Ltd.), or Hi-Flash Column W001, W002, W003, W004, or W005 (Yamazen Corporation). NH silica gel used was Chromatorex Q-Pack NH 60 (Fuji Silysia Chemical Ltd.). NMR spectra were measured using tetramethylsilane as an internal standard with a Bruker AV300 (manufactured by Bruker), a Bruker AV400 (manufactured by Bruker), or an AVNEO400 (manufactured by Bruker), and all δ values ​​are shown in ppm. MS spectra were measured using an ACQUITY SQD LC / MS System (Waters). clogP was calculated using ChemDraw Professional Version: 19.1.0.8 (PerkinElmer).

[0090] [Example 1] (1) [ka] To a mixture of potassium monoethyl malonate (60.1 g) and acetonitrile (400 mL), triethylamine (75.0 mL) and anhydrous magnesium chloride (40.0 g) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, heptanoyl chloride (25.0 g) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent from the reaction mixture was evaporated under reduced pressure, and toluene (200 mL) was added. After evaporation under reduced pressure, toluene (100 mL) was added. 15% aqueous hydrochloric acid (250 mL) was added dropwise to the resulting residue under ice cooling, and the organic layer was separated and washed with 15% aqueous hydrochloric acid (76 mL), followed by water (75 mL). Toluene (100 mL) was added, and the mixture was evaporated under reduced pressure to give ethyl 3-oxononanoate (35.2 g). 1 H-NMR(CDCl3)δ: 4.20 (2H, q, J=8.0Hz), 3.43 (2H, s), 2.53 (2H, t, J=8.0Hz), 1.65-1.52 (2H, m), 1.26-1.21 (9H, m), 0.88 (3H, t, 8.0Hz).

[0091] (2) [ka] A solution of ethyl 3-oxononanoate (15.0 g) in ethanol (10 mL) was added to a 20% sodium ethoxide-ethanol solution (32 mL), followed by dropwise addition of ethyl 8-bromooctanoate (18.9 g) and stirring at 90°C for 4 hours. The reaction mixture was cooled to room temperature, and then 33% aqueous sodium hydroxide (22.5 mL) was added and stirred at room temperature for 1 hour. 15% aqueous hydrochloric acid (48 mL) was added to the reaction mixture and stirred at 60°C for 30 minutes. The reaction mixture was cooled to 40°C, and the organic layer was separated and the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the resulting residue, and the organic layer was separated and the solvent was evaporated under reduced pressure. Hexane was added to the resulting residue, and the solid was collected by filtration, washed with hexane, and dried under reduced pressure to give 10-oxohexadecanoic acid (9.1 g). 1 H-NMR(CDCl3)δ: 2.45-2.28 (6H, m), 1.71-1.47 (6H, m), 1.40-1.20 (14H, m), 0.88 (3H, t, J=8.0Hz).

[0092] (3) [ka] To a mixture of 10-oxohexadecanoic acid (2.0 g), 2-hexyl-1-decanol (1.8 g), and toluene (20 mL), p-toluenesulfonic acid (0.07 g) was added and stirred for 3 hours at 130° C. After the reaction mixture was cooled to room temperature, a 5% aqueous solution of sodium bicarbonate was added, and the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-hexyldecyl 10-oxohexadecanoate (3.7 g). 1 H-NMR(CDCl3)δ:3.97 (2H, d, J=5.6Hz), 2.38 (4H, t, J=7.6Hz), 2.29 (2H, t, J=7.6Hz), 1.65-1.50 (7H, m), 1.35-1.20 (38H, m), 0.92-0.83 (9H, m).

[0093] (4) [ka] To a mixture of 2-hexyldecyl 10-oxohexadecanoate (3.7 g) and toluene (18 mL), sodium borohydride (0.42 g) was added, and then methanol (3.7 mL) was added dropwise under ice-cooling and the mixture was stirred at the same temperature for 3 hours. 30% aqueous hydrochloric acid (18 mL) was added dropwise to the reaction mixture under ice-cooling, and the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2-hexyldecyl 10-hydroxyhexadecanoate (3.5 g). 1 H-NMR(CDCl3)δ:3.97 (2H, d, J=6.0Hz), 3.61-3.54 (1H, m), 2.30 (2H, t, J=7.6Hz), 1.65-1.56 (3H, m), 1.48-1.22 (46H, m), 0.92-0.83 (9H, m).

[0094] (5) [ka] To a mixture of 2-hexyldecyl 10-hydroxyhexadecanoate (3.6 g), triethylamine (3.1 mL), and tetrahydrofuran (36 mL), 4-nitrophenyl chloroformate (2.21 g) was added and stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to yield 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate (4.5 g) as a colorless oil. 1 H-NMR(CDCl3)δ:8.28 (2H, dd, J=7.2Hz, 2.1Hz), 7.39 (2H, dd, J=7.2Hz, 2.1Hz), 4.86-4.76 (1H, m), 3.97 (2H, d, J=5.7Hz), 2.30 (2H, t, J=7.2Hz), 1.74-1.20 (49H, m), 0.92-0.85 (9H, m).

[0095] (6) [ka] Potassium carbonate (7.9 g) was added to a mixture of 2,2'-azanediylbis(ethan-1-ol) (2.0 g), 2-bromo-N,N-diethylethan-1-amine hydrobromide (7.4 g), and ethanol (40 mL), and the mixture was stirred under reflux for 8 hours. The reaction mixture was cooled to room temperature, and the insoluble materials were removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol) (2.3 g) as a pale yellow oil. 1 H-NMR(CDCl3)δ:3.58 (4H, t, J=5.4Hz), 2.70 (4H, t, J=5.4Hz), 2.67-2.48 (8H, m), 1.04 (6H, t, J=7.5Hz). MS m / z(M+H):205.

[0096] (7) [ka] To a mixture of 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate (2.00 g), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol) (1.85 g), triethylamine (1.27 mL), and tetrahydrofuran (20 mL), 4-dimethylaminopyridine (1.11 mg) was added and stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to obtain a colorless oily substance, bis(2-hexyldecyl) 16-(2-(diethylamino)ethyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate (197 mg). 1 H-NMR(CDCl3)δ: 4.71-4.59 (2H, m), 4.21-4.08 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.6Hz), 2.71-2.44 (8H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (14H, m), 1.35-1.20 (84H, m), 1.10-0.96 (6H, m), 0.92-0.84 (18H, m). MS m / z(M+H):1251. clogP:30.3764

[0097] [Example 2] [ka] A colorless oily substance, bis(2-butyloctyl) 16-(2-(diethylamino)ethyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate, was obtained in the same manner as in Example 1, except that 2-butyl-1-octanol was used instead of 2-hexyl-1-decanol. 1 H-NMR(CDCl3)δ: 4.72-4.58 (2H, m), 4.21-4.08 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.6Hz), 2.73-2.43 (8H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (14H, m), 1.36-1.20 (68H, m), 1.10-0.96 (6H, m), 0.92-0.84 (18H, m). MS m / z(M+H):1139. clogP:26.1444

[0098] [Example 3] (1) [ka] To a mixture of 2,2'-azanediylbis(ethan-1-ol) (2.5 g), 3-chloro-N,N-diethylpropan-1-amine (4.6 g), and ethanol (25 mL), potassium carbonate (4.3 g) was added and the mixture was stirred under reflux for 6 hours. After the reaction mixture was cooled to room temperature, insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 2,2'-((3-(diethylamino)propyl)azanediyl)bis(ethan-1-ol) (2.9 g) as a pale yellow oil. 1H-NMR(CDCl3)δ: 3.62 (4H, t, J=5.2Hz), 2.26 (2H, t, J=6.0Hz), 2.61-2.49 (10H, m), 1.68-1.60 (2H, m), 1.04 (6H, t, J=7.2Hz). MS m / z(M+H):219.

[0099] (2) [ka] A colorless oily substance, bis(2-butyloctyl)16-(3-(diethylamino)propyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate, was obtained in the same manner as in Example 1, except that 2-butyl-1-octanol was used instead of 2-hexyl-1-decanol, and 2,2'-((3-(diethylamino)propyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 4.72-4.60 (2H, m), 4.23-4.07 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.81 (4H, t, J=6.6Hz), 2.72-2.37 (8H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (16H, m), 1.35-1.20 (68H, m), 1.00 (6H, t, J=7.2Hz), 0.90-0.85 (18H, m). MS m / z(M+H): 1153. clogP: 26.389

[0100] [Example 4] [ka] A colorless oily substance, bis(3-pentyloctyl)16-(2-(diethylamino)ethyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate, was obtained in the same manner as in Example 1, except that 3-pentyloctan-1-ol was used instead of 2-hexyl-1-decanol. 1 H-NMR(CDCl3)δ: 4.72-4.58 (2H, m), 4.21-4.11 (4H, m), 3.97 (4H, t, J=7.2Hz), 2.84 (4H, t, J=6.6Hz), 2.71-2.64 (2H, m), 2.56-2.46 (6H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (16H, m), 1.36-1.20 (70H, m), 1.01 (6H, t, J=7.2Hz), 0.92-0.84 (18H, m). MS m / z(M+H):1167.

[0101] [Example 5] [ka] A colorless oily substance, bis(2-pentylheptyl)16-(2-(diethylamino)ethyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate, was obtained in the same manner as in Example 1, except that 2-pentylheptan-1-ol was used instead of 2-hexyl-1-decanol. 1H-NMR(CDCl3)δ: 4.72-4.58 (2H, m), 4.21-4.08 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.6Hz), 2.71-2.64 (2H, m), 2.56-2.46 (6H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (14H, m), 1.36-1.20 (68H, m), 1.01 (6H, t, J=7.2Hz), 0.92-0.84 (18H, m). MS m / z(M+H):1139. clogP:26.1444

[0102] [Example 6] [ka] A colorless oily substance, bis(2-hexyloctyl)16-(2-(diethylamino)ethyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate, was obtained in the same manner as in Example 1, except that 2-hexyloctan-1-ol was used instead of 2-hexyl-1-decanol. 1 H-NMR(CDCl3)δ: 4.72-4.58 (2H, m), 4.21-4.08 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.6Hz), 2.71-2.64 (2H, m), 2.56-2.46 (6H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (14H, m), 1.36-1.20 (76H, m), 1.01 (6H, t, J=7.2Hz), 0.92-0.84 (18H, m). MS m / z(M+H):1195. clogP: 28.2604

[0103] [Example 7] (1) [ka] A mixture of 10-methoxy-10-oxodecanoic acid (47.6 g), thionyl chloride (47.6 mL), and N,N-dimethylformamide (0.1 mL) was stirred under reflux for 1 hour. The solvent was evaporated under reduced pressure to give methyl 10-chloro-10-oxodecanoate (59.7 g) as a brown oil. 1 H-NMR(CDCl3)δ:3.67 (3H, s), 2.88 (2H, t, J=7.2Hz), 2.30 (2H, t, J=7.2Hz), 1.75-1.57 (4H, m), 1.38-1.25 (8H, m).

[0104] (2) [ka] To a suspension of zinc(II) chloride (13.6 g) in tetrahydrofuran (300 mL), 1.0 mol / L pentylmagnesium bromide-tetrahydrofuran solution (200 mL) was added dropwise at -78 °C. The mixture was warmed to 0 °C and stirred at the same temperature for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.9 g) was added to the reaction mixture under ice cooling, and then methyl 10-chloro-10-oxodecanoate (24.9 g) was added dropwise at the same temperature. The mixture was stirred at the same temperature for 1 hour. 1.0 mol / L aqueous hydrochloric acid (100 mL), hexane (100 mL), and ethyl acetate (100 mL) were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain methyl 10-oxopentadecanoate (19.8 g) as a white solid. 1 H-NMR(CDCl3)δ:3.67 (3H, s), 2.38 (4H, t, J=7.2Hz), 2.30 (2H, t, 7.2Hz), 1.65-1.49 (6H, m), 1.35-1.20 (12H, m), 0.88 (3H, t, J=7.2Hz).

[0105] (3) [ka] To a mixture of methyl 10-oxopentadecanoate (5.3 g) and 2-hexyldecan-1-ol (7.1 g), tetraisopropyl orthotitanate (0.55 g) was added and stirred at 110° C. for 2 hours. After the reaction mixture was cooled to room temperature, water (0.5 mL) was added, followed by stirring at room temperature for 15 minutes. The mixture was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-hexyldecyl 10-oxopentadecanoate (9.2 g) as a colorless oil. 1 H-NMR(CDCl3)δ:3.97 (2H, d, J=5.6Hz), 2.38 (4H, t, J=7.6Hz), 2.29 (2H, t, J=7.6Hz), 1.65-1.50 (7H, m), 1.35-1.20 (36H, m), 0.92-0.83 (9H, m).

[0106] To a mixture of 2-hexyldecyl 10-oxopentadecanoate (9.2 g), methanol (36 mL), and tetrahydrofuran (36 mL) was added sodium borohydride (1.0 g) under ice-cooling and stirred at the same temperature for 1 hour. Water (80 mL), 1.0 mol / L aqueous hydrochloric acid (35 mL), and hexane (40 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed with saturated aqueous sodium chloride (20 mL) and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to yield 2-hexyldecyl 10-hydroxypentadecanoate (7.2 g) as a colorless oil. 1 H-NMR(CDCl3)δ:3.97 (2H, d, J=6.0Hz), 3.61-3.54 (1H, m), 2.30 (2H, t, J=7.6Hz), 1.65-1.56 (3H, m), 1.48-1.22 (44H, m), 0.92-0.83 (9H, m).

[0107] To a mixture of 2-hexyldecyl 10-hydroxypentadecanoate (2.1 g), triethylamine (2.4 mL), and tetrahydrofuran (21 mL), 4-nitrophenyl chloroformate (1.8 g) was added and stirred at room temperature for 4 hours. Water (60 mL) and hexane (60 mL) were added to the reaction mixture, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to yield 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)pentadecanoate (2.7 g) as a colorless oil. 1 H-NMR(CDCl3)δ:8.28 (2H, dd, J=7.2Hz, 2.1Hz), 7.39 (2H, dd, J=7.2Hz, 2.1Hz), 4.86-4.76 (1H, m), 3.97 (2H, d, J=5.7Hz), 2.30 (2H, t, J=7.2Hz), 1.74-1.20 (47H, m), 0.92-0.85 (9H, m).

[0108] To a mixture of 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)pentadecanoate (2.00 g), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol) (1.89 g), triethylamine (1.29 mL), and tetrahydrofuran (10 mL), 4-dimethylaminopyridine (1.13 g) was added and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol-ethyl acetate) and silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to obtain a colorless oily substance, bis(2-hexyldecyl) 16-(2-(diethylamino)ethyl)-12,20-dioxo-10,22-dipentyl-11,13,19,21-tetraoxa-16-azahentriacontanedioate (0.12 g). 1H-NMR(CDCl3)δ: 4.72-4.58 (2H, m), 4.21-4.08 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.6Hz), 2.71-2.64 (2H, m), 2.56-2.46 (6H, m), 2.29 (4H, t, J=7.8Hz), 1.65-1.50 (14H, m), 1.36-1.20 (80H, m), 1.01 (6H, t, J=7.2Hz), 0.92-0.84 (18H, m). MS m / z(M+H):1223. clogP: 29.3184

[0109] [Example 8] (1) [ka] To a solution of glutaric anhydride (27.3 g) in tetrahydrofuran (273 mL), 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution (200 mL) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, 2 mol / L aqueous hydrochloric acid (240 mL) was added under ice cooling, followed by ethyl acetate (270 mL). The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane), and then hexane (10 mL) was added. The solid was collected by filtration, washed with hexane, and dried under reduced pressure to yield 5-oxoundecanoic acid (16.0 g) as a white solid. 1 H-NMR(CDCl3)δ:2.50 (2H, t, J=7.2Hz), 2.40 (4H, t, J=7.2Hz), 2.02-1.80 (2H, m), 1.63-1.48 (2H, m), 1.37-1.20 (6H, m), 0.88 (3H, t, J=6.6Hz).

[0110] (2) [ka] To a mixture of 5-oxoundecanoic acid (3.0 g), 2-butyloctan-1-ol (2.5 g), and toluene (6.0 mL), p-toluenesulfonic acid (0.14 g) was added and stirred for 2 hours at 100° C. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2-butyloctyl 5-oxoundecanoate (5.0 g) as a colorless oil. 1 H-NMR(CDCl3)δ:3.97 (2H, d, J=5.1Hz), 2.47 (2H, t, J=7.2Hz), 2.39 (2H, t, J=7.2Hz), 2.33 (2H, t, J=7.2Hz), 1.95-1.83 (2H, m), 1.66-1.49 (3H, m), 1.36-1.20 (22H, m), 0.92-0.82 (9H, m).

[0111] To a mixture of 2-butyloctyl 5-oxoundecanoate (7.3 g), toluene (30 mL), and methanol (30 mL), sodium borohydride (0.90 g) was added under ice-cooling and stirred at the same temperature for 1 hour. Water (30 mL), 2.0 mol / L aqueous hydrochloric acid (30 mL), and ethyl acetate (30 mL) were added to the reaction mixture under ice-cooling, and the organic layer was separated. After washing with saturated aqueous sodium chloride and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to yield 2-butyloctyl 5-hydroxyundecanoate (6.9 g) as a colorless oil. 1 H-NMR(CDCl3)δ:3.97 (2H, d, J=5.7Hz), 3.65-3.53 (1H, m), 2.35 (2H, t, J=7.2Hz), 1.87-1.20 (32H, m), 0.92-0.84 (9H, m).

[0112] (3) [ka] To a mixture of 2-butyloctyl 5-hydroxyundecanoate (1.62 g), triethylamine (2.38 mL), and tetrahydrofuran (16 mL), 4-nitrophenyl chloroformate (1.71 g) was added and stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2-butyloctyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoate (1.99 g) as a colorless oil. 1 H-NMR(CDCl3)δ:8.28 (2H, d, J=9.3Hz), 7.39 (2H, d, J=9.3Hz), 4.88-4.77 (1H, m), 3.99 (2H, d, J=6.0Hz), 2.41-2.31 (2H, m), 1.80-1.48 (7H, m), 1.44-1.20 (24H, m), 0.92-0.83 (9H, m).

[0113] (4) [ka] A colorless oily substance, bis(2-butyloctyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 1, except that 2-butyloctyl 5-(((4-nitrophenoxy)carbonyl)oxy)undecanoate was used instead of 2-hexyldecyl 10-(((4-nitrophenoxy)carbonyl)oxy)hexadecanoate. 1H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):999. clogP:20.8544

[0114] [Example 9] [ka] In Example 8, a colorless oily substance, bis(2-hexyldecyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 1, except that 2-hexyl-1-decanol was used instead of 2-butyl-1-octanol. 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (64H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):1111. clogP:25.0864

[0115] [Example 10] (1) [ka] A colorless oily substance, 2-pentylheptyl 5-hydroxyundecanoate, was obtained in the same manner as in Example 8(1) and Example 8(2), except that 2-pentyl-1-heptanol was used instead of 2-butyl-1-octanol. 1 H-NMR(CDCl3)δ: 3.98 (2H, d, J=6.0Hz), 3.63-3.57 (1H, m), 2.41-2.28 (2H, m), 1.84-1.22 (32H, m), 0.88 (9H, t, J=7.2Hz).

[0116] (2) [ka] To a solution of 2-pentylheptyl 5-hydroxyundecanoate (0.50 g) in tetrahydrofuran (5.0 mL), 1,1'-carbonyldiimidazole (0.33 g) was added and stirred at room temperature for 30 hours. Water (10 mL) and hexane (20 mL) were added to the reaction mixture, and the organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-oxo-1-((2-pentylheptyl)oxy)undecan-5-yl 1H-imidazole-1-carboxylate (0.64 g) as a pale yellow oil. 1 H-NMR(CDCl3)δ: 8.14-8.12 (1H, m), 7.43-7.41 (1H, m), 7.08-7.06 (1H, m), 5.11-5.04 (1H, m), 3.97 (2H, d, J=5.6Hz), 2.38-2.32 (2H, m), 1.80-1.54 (7H, m), 1.40-1.22 (24H, m), 0.91-0.85 (9H, m).

[0117] (3) [ka] To a mixture of 1-oxo-1-((2-pentylheptyl)oxy)undecan-5-yl 1H-imidazole-1-carboxylate (0.50 g), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol) (0.11 g), and acetonitrile (2.5 mL), potassium carbonate (0.33 g) was added and stirred at 80°C for 2 hours. After cooling the reaction mixture to room temperature, ethyl acetate (3 mL), hexane (3 mL), water (3 mL), and methanol (1 mL) were added, and the organic layer was separated. The mixture was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to obtain bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate (0.24 g) as a colorless oil. 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):999. clogP:20.8544

[0118] [Example 11] (1) [ka] A colorless oily substance, 2,2'-((2-(dimethylamino)ethyl)azanediyl)bis(ethan-1-ol), was obtained in the same manner as in Example 1(6), except that 2,2'-((2-(dimethylamino)ethyl)azanediyl)bis(ethan-1-ol) hydrochloride was used instead of 2-bromo-N,N-diethylethan-1-amine hydrobromide. 1 H-NMR(CDCl3)δ: 3.57 (4H, t, J=5.2Hz), 2.71 (4H, t, J=5.2Hz), 2.64 (2H, t, J=5.2Hz), 2.41 (2H, t, J=5.2Hz), 2.61 (6H, s). MS m / z(M+H): 177.

[0119] (2) [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(dimethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that 2,2'-((2-(dimethylamino)ethyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.85 (4H, t, J=6.4Hz), 2.77-2.65 (2H, m), 2.46-2.19 (12H, m), 1.73-1.50 (14H, m), 1.33-1.20 (48H, m), 0.91-0.84 (18H, m). MS m / z(M+H):970. clogP:19.7964

[0120] [Example 12] (1) [ka] A colorless oily substance, 2,2'-((2-(dimethylamino)ethyl)azanediyl)bis(ethan-1-ol), was obtained in the same manner as in Example 1(6), except that N-(2-bromoethyl)-N-propylpropan-1-amine hydrobromide was used instead of 2-bromo-N,N-diethylethan-1-amine hydrobromide. 1 H-NMR(CDCl3)δ: 3.58 (4H, t, J=5.4Hz), 2.70 (4H, t, J=5.4Hz), 2.67-2.62 (2H, m), 2.54-2.48 (2H, m), 2.45-2.38 (4H, m), 1.57-1.43 (4H, m), 0.88 (6H, t, J=7.2Hz). MS m / z(M+H):233.

[0121] (2) [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(dipropylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that 2,2'-((2-(dimethylamino)ethyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.83 (4H, t, J=6.4Hz), 2.69-2.62 (2H, m), 2.52-2.47 (2H, m), 2.39-2.29 (8H, m), 1.74-1.49 (14H, m), 1.49-1.37 (4H, m), 1.36-1.20 (48H, m), 0.91-0.84 (24H, m). MS m / z(M+H):1027. clogP:21.9124

[0122] [Example 13] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that 2,2'-((3-(diethylamino)propyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.80 (4H, t, J=6.4Hz), 2.61-2.45 (6H, m), 2.44-2.37 (2H, m), 2.32 (4H, t, J=7.2Hz), 1.74-1.49 (16H, m), 1.35-1.21 (48H, m), 1.00 (6H, t, J=7.2Hz), 0.91-0.85 (18H, m). MS m / z(M+H):1013. clogP:21.099

[0123] [Example 14] (1) [ka] Potassium carbonate (1.5 g) was added to a mixture of N1,N1-diethylbutane-1,4-diamine (0.51 g), 2-bromoethan-1-ol (1.1 g), and acetonitrile (5 mL), and the mixture was stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, the insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane, NH silica gel) to give 2,2'-((4-(diethylamino)butyl)azanediyl)bis(ethan-1-ol) (0.18 g) as a pale yellow oil. 1 H-NMR(CDCl3)δ: 3.62 (4H, t, J=5.2Hz), 2.65 (4H, t, J=5.2Hz), 2.57-2.49 (6H, m), 2.44-2.39 (2H, m), 1.53-1.43 (4H, m), 1.02 (6H, t, J=7.2Hz). MS m / z(M+H):233.

[0124] (2) [ka] A colorless oily substance, bis(2-pentylheptyl)11-(4-(diethylamino)butyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that 2,2'-((4-(diethylamino)butyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.80 (4H, t, J=6.4Hz), 2.58-2.47 (6H, m), 2.44-2.37 (2H, m), 2.32 (4H, t, J=7.2Hz), 1.74-1.49 (14H, m), 1.45-1.39 (4H, m), 1.35-1.21 (48H, m), 1.00 (6H, t, J=7.2Hz), 0.91-0.85 (18H, m). MS m / z(M+H):1027. clogP:20.68

[0125] [Example 15] (1) [ka] A pale yellow oily product, 3,3'-((2-(diethylamino)ethyl)azanediyl)bis(propan-1-ol), was obtained in the same manner as in Example 1(6), except that 3,3'-azanediylbis(propan-1-ol was used instead of 2,2'-azanediylbis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 3.74 (4H, t, J=5.2Hz), 2.61-2.51 (12H, m), 1.74-1.66 (4H, m), 1.04 (6H, t, J=7.2Hz). MS m / z(M+H):233.

[0126] (2) [ka] A colorless oily substance, bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-5,19-dihexyl-7,17-dioxo-6,8,16,18-tetraoxa-12-azatricosandioate, was obtained in the same manner as in Example 10, except that 3,3'-((2-(diethylamino)ethyl)azanediyl)bis(propan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.56-2.46 (12H, m), 2.32 (4H, t, J=7.2Hz), 1.83-1.75 (4H, m), 1.73-1.50 (14H, m), 1.35-1.21 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):1027. clogP:21.4444

[0127] [Example 16] (1) [ka] A pale yellow oily substance, 4,4'-((2-(diethylamino)ethyl)azanediyl)bis(butan-1-ol), was obtained in the same manner as in Example 1(6), except that 4,4'-azanediylbis(butan-1-ol) was used instead of 2,2'-azanediylbis(ethan-1-ol). 1 H-NMR(CDCl3)δ:3.62-3.58 (4H, m), 2.59-2.46 (12H, m), 1.66-1.59 (8H, m), 1.03 (6H, t, J=7.2Hz). MS m / z(M+H):261.

[0128] (2) [ka] A colorless oily substance, bis(2-pentylheptyl)13-(2-(diethylamino)ethyl)-5,21-dihexyl-7,19-dioxo-6,8,18,20-tetraoxa-13-azapentacosanedioate, was obtained in the same manner as in Example 10, except that 4,4'-((2-(diethylamino)ethyl)azanediyl)bis(butan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.60-2.41 (12H, m), 2.32 (4H, t, J=7.2Hz), 1.75-1.45 (22H, m), 1.35-1.21 (48H, m), 1.03 (6H, t, J=6.8Hz), 0.91-0.84 (18H, m). MS m / z(M+H):1055. clogP:20.9424

[0129] [Example 17] (1) [ka] A colorless oily product, ethyl 4-oxodecanoate, was obtained in the same manner as in Example 7(2), except that in Example 7(2), 1.0 mol / L pentylmagnesium bromide-tetrahydrofuran solution was replaced with 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution, and methyl 10-chloro-10-oxodecanoate was replaced with ethyl 4-chloro-4-oxobutanoate. 1H-NMR(CDCl3)δ: 4.13 (2H, q, J=6.8Hz), 2.72 (2H, t, J=7.2Hz), 2.57 (2H, t, J=7.2Hz), 2.45 (2H, t, J=7.2Hz), 1.62-1.51 (2H, m), 1.33-1.23 (9H, m), 0.88 (3H, t, J=6.8Hz).

[0130] (2) [ka] To a mixture of ethyl 4-oxodecanoate (2.0 g), tetrahydrofuran (4.0 mL), and ethanol (2.0 mL), 7.0 mol / L aqueous potassium hydroxide solution was added and stirred at 40°C for 45 minutes. After cooling the reaction mixture to room temperature, 20% aqueous potassium hydrogen sulfate solution (15 mL), ethyl acetate (10 mL), and water (10 mL) were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Hexane (6 mL) was added to the resulting residue under ice-cooling, and the solid was collected by filtration, washed with ice-cooled hexane, and dried under reduced pressure to give 4-oxodecanoic acid (1.5 g) as a white solid. 1 H-NMR(CDCl3)δ: 2.75-2.68 (2H, m), 2.66-2.61 (2H, m), 2.45 (2H, t, J=7.2Hz), 1.63-1.54 (2H, m), 1.34-1.23 (6H, m), 0.88 (3H, t, J=6.8Hz).

[0131] (3) [ka] A colorless oily product, 2-pentylheptyl 4-hydroxydecanoate, was obtained in the same manner as in Example 8(2), except that 4-oxoundecanoic acid was used instead of 5-oxoundecanoic acid and 2-pentylpentan-1-ol was used instead of 2-butyloctan-1-ol. 1H-NMR(CDCl3)δ: 3.97 (2H, d, J=6.0Hz), 3.65-3.58 (1H, m), 2.49-2.43 (2H, m), 1.89-1.56 (7H, m), 1.49-1.23 (22H, m), 0.89 (9H, t, J=6.8Hz).

[0132] (4) [ka] A colorless oily substance, bis(2-pentylheptyl)10-(2-(diethylamino)ethyl)-4,16-dihexyl-6,14-dioxo-5,7,13,15-tetraoxa-10-azanonadecandioate, was obtained in the same manner as in Example 10(2) and Example 10(3), except that 2-pentylheptyl 4-hydroxydecanoate was used instead of 2-pentylheptyl 5-hydroxyundecanoate in Example 10(2). 1 H-NMR(CDCl3)δ: 4.75-4.68 (2H, m), 4.23-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.71-2.64 (2H, m), 2.55-2.48 (6H, m), 2.45-2.29 (4H, m), 2.01-1.81 (4H, m), 1.67-1.48 (6H, m), 1.36-1.20 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):970. clogP:20.9884

[0133] [Example 18] [ka] A colorless oily substance, bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-6,18-dihexyl-8,16-dioxo-7,9,15,17-tetraoxa-12-azatricosane dioate, was obtained in the same manner as in Example 17, except that methyl 6-chloro-6-oxohexanoate was used instead of ethyl 4-chloro-4-oxobutanoate. 1 H-NMR(CDCl3)δ: 4.71-4.63 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.30 (4H, t, J=7.2Hz), 1.73-1.51 (14H, m), 1.46-1.22 (52H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):1027. clogP:21.9124

[0134] [Example 19] (1) [ka] A colorless oily substance, 2-pentylheptyl 5-hydroxyhexanoate, was obtained in the same manner as in Example 8(2), except that 5-oxohexanoic acid was used instead of 5-oxoundecanoic acid. 1 H-NMR(CDCl3)δ: 3.98 (2H, d, J=6.0Hz), 3.85-3.76 (1H, m), 2.41-2.86 (2H, m), 1.81-1.54 (3H, m), 1.51-1.43 (3H, m), 1.31-1.21 (16H, m), 1.20 (3H, d, J=6.0Hz), 0.89 (6H, t, J=6.8Hz)

[0135] (2) [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dimethyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10(2) and Example 10(3), except that 2-pentylheptyl 5-hydroxyhexanoate was used instead of 2-pentylheptyl 5-hydroxyundecanoate. 1 H-NMR(CDCl3)δ: 4.78-4.71 (2H, m), 4.21-4.10 (4H, m), 3.97 (4H, d, J=5.6Hz), 2.84 (4H, t, J=6.4Hz), 2.69-2.65 (2H, m), 2.55-2.49 (6H, m), 2.34-2.30 (4H, m), 1.75-1.56 (10H, m), 1.39-1.20 (38H, m), 1.01 (6H, t, J=7.2Hz), 0.90-0.86 (12H, m). MS m / z(M+H):858. clogP:15.5644

[0136] [Example 20] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-diethyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that a 1.0 mol / L ethylmagnesium bromide-tetrahydrofuran solution was used instead of the 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution used in Example 10. 1H-NMR(CDCl3)δ: 4.67-4.61 (2H, m), 4.22-4.10 (4H, m), 3.97 (4H, d, J=5.6Hz), 2.84 (4H, t, J=6.4Hz), 2.69-2.65 (2H, m), 2.55-2.49 (6H, m), 2.34-2.31 (4H, m), 1.74-1.55 (14H, m), 1.34-1.20 (32H, m), 1.01 (6H, t, J=7.2Hz), 0.94-0.87 (18H, m). MS m / z(M+H):886. clogP:16.6224

[0137] [Example 21] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-dipropyl-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that a 2.0 mol / L propylmagnesium bromide-tetrahydrofuran solution was used instead of the 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution used in Example 10. 1 H-NMR(CDCl3)δ: 4.74-4.67 (2H, m), 4.22-4.10 (4H, m), 3.97 (4H, d, J=5.6Hz), 2.83 (4H, t, J=6.4Hz), 2.69-2.65 (2H, m), 2.55-2.49 (6H, m), 2.34-2.30 (4H, m), 1.74-1.48 (14H, m), 1.43-1.20 (36H, m), 1.01 (6H, t, J=7.2Hz), 0.93-0.87 (18H, m). MS m / z(M+H):914. clogP:17.6804

[0138] [Example 22] [ka] A colorless oily substance, bis(2-pentylheptyl)5,17-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that a 2.0 mol / L butylmagnesium chloride-tetrahydrofuran solution was used instead of the 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution in Example 10. 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (40H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):942. clogP:18.7384

[0139] [Example 23] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-dipentyl-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that a 2.0 mol / L butylmagnesium chloride-tetrahydrofuran solution was used instead of the 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution in Example 10. 1H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.56-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (44H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):970. clogP:19.7964

[0140] [Example 24] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-diheptyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that a 1.0 mol / L heptylmagnesium bromide-tetrahydrofuran solution was used instead of the 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution used in Example 10. 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.56-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (52H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):1027. clogP:21.9124

[0141] [Example 25] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dioctyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that a 2.0 mol / L octylmagnesium bromide-diethyl ether solution was used instead of the 1.0 mol / L hexylmagnesium bromide-tetrahydrofuran solution in Example 10. 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.56-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (56H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):1055. clogP:22.9704

[0142] [Example 26] [ka] A colorless oily substance, bis(2-hexyloctyl)5,17-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 22, except that 2-hexyloctan-1-ol was used instead of 2-pentylheptan-1-ol. 1H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (4H, m), 3.97 (4H, d, J=6.0Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.32 (4H, t, J=7.2Hz), 1.73-1.50 (14H, m), 1.33-1.20 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.84 (18H, m). MS m / z(M+H):999. clogP:20.8544

[0143] [Example 27] [ka] A colorless oily substance, bis(2-((3r,5r,7r)-adamantan-1-yl)ethyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 10, except that 2-(1-adamantyl)ethanol was used instead of 2-pentylheptan-1-ol. 1 H-NMR(CDCl3)δ: 4.72-4.65 (2H, m), 4.22-4.09 (8H, m), 2.84 (4H, t, J=6.4Hz), 2.70-2.65 (2H, m), 2.55-2.48 (6H, m), 2.30 (4H, t, J=7.2Hz), 1.97-1.92 (6H, m), 1.74-1.48 (36H, m), 1.44-1.22 (20H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (6H, t, J=6.4Hz). MS m / z(M+H):986. clogP:19.1704

[0144] [Example 28] [ka] A colorless oily substance, bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-5,17-dipropyl-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 21, except that 2,2'-((3-(diethylamino)propyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1 H-NMR(CDCl3)δ: 4.73-4.67 (2H, m), 4.22-4.10 (4H, m), 3.97 (4H, d, J=5.6Hz), 2.80 (4H, t, J=6.4Hz), 2.58-2.47 (6H, m), 2.43-2.39 (2H, m), 2.34-2.30 (4H, m), 1.74-1.48 (16H, m), 1.43-1.20 (36H, m), 1.01 (6H, t, J=7.2Hz), 0.94-0.87 (18H, m). MS m / z(M+H):928. clogP:17.925

[0145] [Example 29] (1) [ka] Ethyl acrylate (24.0 mL) was added to a mixture of cyclohexane-1,3-dione (16.5 g), potassium carbonate (20.3 g), benzyltriethylammonium chloride (33.5 g), and dimethyl sulfoxide (165 mL) and stirred at 60°C for 4 hours. After cooling the reaction mixture to room temperature, N-acetyl-L-cysteine ​​(14.4 g) was added and stirred at room temperature for 1 hour. Ethyl acetate (165 mL) and 20% aqueous potassium hydrogen sulfate solution (330 mL) were added to the reaction mixture, and the organic layer was separated. The mixture was washed twice with 20% aqueous potassium hydrogen sulfate solution (100 mL), followed by water (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate (30 mL) and hexane (60 mL) were added to the resulting residue and stirred at room temperature for 20 minutes. The solid matter was collected by filtration, washed with a 33% ethyl acetate-hexane solution, and then dried under reduced pressure to obtain a pale yellow solid of ethyl 3-(2,6-dioxocyclohexyl)propanoate (20.2 g). 1 H-NMR(CDCl3)δ: 9.57 (1H, s), 4.18 (2H, q, J=7.2Hz), 2.58-2.44 (6H, m), 2.32 (2H, t, J=6.8Hz), 1.95-1.87 (2H, m), 1.27 (3H, t, J=6.8Hz). MS m / z(M+H):213.

[0146] Ethyl 3-(2,6-dioxocyclohexyl)propanoate (20.2 g) was added to 10% aqueous hydrochloric acid (200 mL) and stirred at 100°C for 4 hours. After cooling the reaction mixture to room temperature, ethyl acetate (200 mL) was added and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (50 mL). The organic layer and the extract were combined and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. Ethyl acetate (20 mL) and hexane (40 mL) were added to the resulting residue, and the solid was collected by filtration, washed with a 33% ethyl acetate-hexane solution, and dried under reduced pressure to give 5-oxononanedioic acid (9.1 g) as a pale yellow solid. 1H-NMR(CDCl3)δ: 2.43 (4H, t, J=7.2Hz), 2.19 (4H, t, J=7.2Hz), 1.66 (4H, quin, J=7.2Hz). MS m / z(M-H):201.

[0147] (2) [ka] To a mixture of 5-oxononanedioic acid (0.500 g), heptan-1-ol (0.517 g), and toluene (1.0 mL), p-toluenesulfonic acid (0.023 g) was added and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and then purified by silica gel column chromatography (ethyl acetate-hexane) to obtain diheptyl 5-oxononanedioate (0.746 g) as a colorless oil. 1 H-NMR(CDCl3)δ: 4.06 (4H, d, J=6.8Hz), 2.47 (4H, t, J=7.2Hz), 2.32 (4H, t, J=7.2Hz), 1.93-1.85 (4H, m), 1.66-1.56 (4H, m), 1.36-1.24 (16H, m), 0.89 (6H, t, J=6.8Hz).

[0148] To a mixture of diheptyl 5-oxononanedioate (0.746 g), toluene (3.0 mL), and methanol (3.0 mL), sodium borohydride (0.085 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Water (3.0 mL), 1.0 mol / L aqueous hydrochloric acid (3.0 mL), and ethyl acetate were added to the reaction mixture under ice-cooling, and the organic layer was separated. After washing with saturated aqueous sodium chloride and drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to yield diheptyl 5-hydroxynonanedioate (0.656 g) as a colorless oil. 1H-NMR(CDCl3)δ: 4.06 (4H, d, J=6.8Hz), 3.65-3.56 (1H, m), 2.39-2.27 (4H, m), 1.83-1.39 (12H, m), 1.36-1.23 (16H, m), 0.88 (6H, t, J=6.8Hz).

[0149] To a solution of diheptyl 5-hydroxynonanedioate (0.656 g) in tetrahydrofuran (4.0 mL), 1,1'-carbonyldiimidazole (0.398 g) was added and stirred at room temperature for 3 hours. Water (4 mL) and hexane (4 mL) were added to the reaction mixture, and the organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give diheptyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate (0.82 g) as a pale yellow oil. 1 H-NMR(CDCl3)δ: 8.14-8.12 (1H, m), 7.43-7.41 (1H, m), 7.08-7.06 (1H, m), 5.12-5.05 (1H, m), 4.06 (4H, d, J=6.4Hz), 2.35 (4H, t, J=6.4Hz), 1.80-1.54 (12H, m), 1.35-1.23 (16H, m), 0.88 (6H, t, J=7.2Hz).

[0150] (3) [ka] To a mixture of diheptyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate (0.82 g), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol) (0.17 g), and acetonitrile (4.0 mL), potassium carbonate (0.45 g) was added and stirred at 80°C for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate (4 mL) and water (4 mL) were added, the organic layer was separated, and the solvent was evaporated under reduced pressure. To the resulting residue, ethyl acetate (4 mL), hexane (4 mL), and water (4 mL) were added, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to give diheptyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(heptyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate (0.39 g). 1 H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 4.05 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.72-1.54 (24H, m), 1.36-1.24 (32H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1059. clogP:16.9164

[0151] [Example 30] [ka] A colorless oily substance, bis(2-hexyloctyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-((2-hexyloctyl)oxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that 2-hexyloctan-1-ol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.75-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 3.96 (8H, d, J=5.6Hz), 2.83 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.73-1.56 (20H, m), 1.36-1.24 (80H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (24H, t, J=6.8Hz). MS m / z(M+H):1451. clogP: 31.2084

[0152] [Example 31] [ka] A colorless oily substance, dipentyl 11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-bis(4-oxo-4-(pentyloxy)butyl)-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that pentan-1-ol was used instead of heptan-1-ol. 1H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 4.05 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.72-1.54 (24H, m), 1.36-1.24 (16H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):946. clogP:12.6844

[0153] [Example 32] [ka] A colorless oily substance, dihexyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that hexane-1-ol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 4.05 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.72-1.54 (24H, m), 1.36-1.24 (24H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1002. clogP:14.8004

[0154] [Example 33] [ka] A colorless oily substance, dioctyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(octyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that octan-1-ol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 4.05 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.72-1.54 (24H, m), 1.36-1.24 (40H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1115. clogP:19.0324

[0155] [Example 34] [ka] A colorless oily substance, dinonyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(nonyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that nonan-1-ol was used instead of heptan-1-ol. 1H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 4.05 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.72-1.54 (24H, m), 1.36-1.24 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1171. clogP:21.1484

[0156] [Example 35] [ka] A colorless oily substance, didecyl 5,17-bis(4-(decyloxy)-4-oxobutyl)-11-(2-(diethylamino)ethyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that decan-1-ol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.15 (4H, t, J=6.0Hz), 4.05 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.34-2.28 (8H, m), 1.72-1.54 (24H, m), 1.36-1.24 (56H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1227. clogP:23.2644

[0157] [Example 36] (1) [ka] To a mixture of dihexyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate (0.691 g), 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol) (0.234 g), and acetonitrile (3.0 mL), potassium carbonate (0.339 g) was added and stirred at 80°C for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, ethyl acetate (4.0 mL) and water (4.0 mL) were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to give dihexyl 5-(((2-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)ethoxy)carbonyl)oxy)nonanedioate (0.212 g). 1 H-NMR(CDCl3)δ: 4.73-4.66 (1H, m), 4.20 (2H, t, J=6.0Hz), 4.06 (4H, t, J=6.8Hz), 3.54 (2H, t, J=5.2Hz), 2.88 (2H, t, J=6.2Hz), 2.71-2.66 (4H, m), 2.58-2.47 (6H, m), 2.33-2.29 (4H, m), 1.74-1.55 (13H, m), 1.36-1.27 (12H, m), 1.03 (6H, t, J=7.0Hz), 0.91-0.87 (6H, m). MS m / z(M+H):604.

[0158] (2) [ka] To a mixture of dihexyl 5-(((2-((2-(diethylamino)ethyl)(2-hydroxyethyl)amino)ethoxy)carbonyl)oxy)nonanedioate (0.106 g), dipentyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate (0.093 g), and acetonitrile (1.0 mL), potassium carbonate (0.830 g) was added and stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate (4 mL) and water (4 mL) were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol-ethyl acetate-hexane) to give 1-hexyl 21-pentyl 11-(2-(diethylamino)ethyl)-5-(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-17-(4-oxo-4-(pentyloxy)butyl)-6,8,14,16-tetraoxa-11-azahenicosanedioate (0.110 g). 1 H-NMR(CDCl3)δ: 4.73-4.66 (2H, m), 4.15 (4H, t, J=6.8Hz), 4.05 (8H, t, J=6.6Hz), 2.83 (4H, t, J=6.4Hz), 2.69-2.65 (2H, m), 2.54-2.49 (6H, m), 2.33-2.29 (8H, m), 1.74-1.55 (24H, m), 1.38-1.25 (20H, m), 1.01 (6H, t, J=7.2Hz), 0.93-0.87 (12H, m). MS m / z(M+H):974. clogP:13.7424

[0159] [Example 37] [ka] A colorless oily product, 1-heptyl 21-hexyl 11-(2-(diethylamino)ethyl)-5-(4-(heptyloxy)-4-oxobutyl)-17-(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 36, except that diheptyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate was used instead of dipentyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate in Example 36. 1 H-NMR(CDCl3)δ: 4.73-4.66 (2H, m), 4.16 (4H, t, J=6.8Hz), 4.05 (8H, t, J=6.6Hz), 2.83 (4H, t, J=6.0Hz), 2.70-2.66 (2H, m), 2.55-2.49 (6H, m), 2.33-2.29 (8H, m), 1.73-1.56 (24H, m), 1.38-1.23 (28H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.86 (12H, m). MS m / z(M+H):1030. clogP:15.8584

[0160] [Example 38] [ka] A colorless oily substance, diheptyl 11-(3-(diethylamino)propyl)-5,17-bis(4-(heptyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29, except that 2,2'-((3-(diethylamino)propyl)azanediyl)bis(ethan-1-ol) was used instead of 2,2'-((2-(diethylamino)ethyl)azanediyl)bis(ethan-1-ol). 1H-NMR(CDCl3)δ: 4.73-4.66 (2H, m), 4.15 (4H, t, J=6.8Hz), 4.05 (8H, t, J=6.6Hz), 2.80 (4H, t, J=6.4Hz), 2.58-2.47 (6H, m), 2.42-2.39 (2H, m), 2.33-2.29 (8H, m), 1.74-1.57 (26H, m), 1.35-1.21 (32H, m), 1.00 (6H, t, J=7.2Hz), 0.90-0.86 (12H, m). MS m / z(M+H):1073. clogP:17.161

[0161] [Example 39] (1) [ka] To a mixture of diethyl 4-oxoheptanedioate (5.0 g), tetrahydrofuran (10 mL), and ethanol (10 mL), 20% aqueous potassium hydroxide (14 g) was added and stirred at room temperature for 30 minutes. To the reaction mixture, 30% aqueous hydrochloric acid (10 mL) and ethyl acetate (10 mL) were added, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure to give 4-oxoheptanedioic acid (4.3 g) as a pale yellow solid. 1 H-NMR(CDCl3)δ: 2.82-2.74 (4H, m), 2.68-2.58 (4H, m). MS m / z(M-H):173.

[0162] (2) [ka] A colorless oily substance, diheptyl 10-(2-(diethylamino)ethyl)-4,16-bis(3-(heptyloxy)-3-oxopropyl)-6,14-dioxo-5,7,13,15-tetraoxa-10-azanonadecandioate, was obtained in the same manner as in Example 29(2) and Example 29(3), except that 4-oxoheptanedioic acid was used instead of 5-oxononanedioic acid. 1 H-NMR(CDCl3)δ: 4.80-4.73 (2H, m), 4.16 (4H, t, J=6.0Hz), 4.06 (8H, t, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.55-2.48 (6H, m), 2.44-2.31 (8H, m), 2.00-1.85 (8H, m), 1.66-1.56 (8H, m), 1.36-1.24 (32H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1002. clogP:17.1844

[0163] [Example 40] (1) [ka] Potassium carbonate (9.4 g) was added to a mixture of octane-1-thiol (5.0 g), 2-bromoethan-1-ol (4.7 g), and acetonitrile (25 mL) and stirred at 60°C for 4 hours. After cooling the reaction mixture to room temperature, water (25 mL) and hexane (25 mL) were added. The organic layer was separated and washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2-(octylthio)ethan-1-ol (6.1 g). 1H-NMR(CDCl3)δ: 3.72 (2H, q, J=6.0Hz), 2.73 (2H, t, J=6.0Hz), 2.52 (2H, t, J=7.2Hz), 2.23 (1H, t, J=6.0Hz), 1.63-1.54 (2H, m), 1.43-1.21 (10H, m), 0.88 (3H, t, J=6.8Hz).

[0164] (2) [ka] A colorless oily substance, bis(2-(octylthio)ethyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-(2-(octylthio)ethoxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29(2) and Example 29(3), except that 2-(octylthio)ethan-1-ol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.74-4.66 (2H, m), 4.21 (8H, t, J=6.8Hz), 4.16 (4H, t, J=6.4Hz), 2.84 (4H, t, J=6.4Hz), 2.75-2.65 (10H, m), 2.57-2.48 (14H, m), 2.36-2.31 (8H, m), 1.72-1.54 (16H, m), 1.42-1.23 (48H, m), 1.01 (6H, t, J=7.2Hz), 0.88 (12H, t, J=6.8Hz). MS m / z(M+H):1354. clogP:21.954

[0165] [Example 41] [ka] A colorless oily substance, bis(cyclohexylmethyl) 5,17-bis(4-(cyclohexylmethoxy)-4-oxobutyl)-11-(2-(diethylamino)ethyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanediioate, was obtained in the same manner as in Example 29, except that cyclohexylmethanol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.73-4.66 (2H, m), 4.16 (4H, t, J=6.4Hz), 3.87 (8H, d, J=6.8Hz), 2.84 (4H, t, J=6.4Hz), 2.70-2.64 (2H, m), 2.57-2.46 (6H, m), 2.34-2.30 (8H, m), 1.76-1.55 (40H, m), 1.30-0.90 (26H, m). MS m / z(M+H):1050. clogP:14.8204

[0166] [Example 42] [ka] A colorless oily substance, 1-hexyl 21-octyl 11-(2-(diethylamino)ethyl)-5-(4-(hexyloxy)-4-oxobutyl)-17-(4-(octyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 36(2), except that dioctyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate was used instead of dipentyl 5-((1H-imidazole-1-carbonyl)oxy)nonanedioate in Example 36(2). 1H-NMR(CDCl3)δ: 4.73-4.66 (2H, m), 4.16 (4H, t, J=6.4Hz), 4.07-4.03 (8H, m), 2.84 (4H, t, J=6.4Hz), 2.70-2.66 (2H, m), 2.56-2.50 (6H, m), 2.33-2.29 (8H, m), 1.73-1.54 (24H, m), 1.37-1.21 (32H, m), 1.02 (6H, t, J=7.2Hz), 0.91-0.86 (12H, m). MS m / z(M+H):1059. clogP:16.9164

[0167] [Example 43] (1) [ka] To a mixture of 2-mercaptoethanol (3.0 g), potassium hydroxide (2.6 g), and ethanol (100 mL), 1-bromohexane (5.2 g) was added and stirred at room temperature for 2 hours. The solvent was then removed under reduced pressure. Ethyl acetate (150 mL) and water (200 mL) were added to the resulting residue, and the organic layer was separated and washed with water (100 mL) and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give 2-(hexylthio)ethan-1-ol (6.2 g). 1 H-NMR(CDCl3)δ: 3.72 (2H, dt, J=6.0, 6.0Hz), 2.73 (2H, t, J=6.0Hz), 2.52 (2H, t, J=7.6Hz), 2.22-2.15 (1H, m), 1.63-1.53 ​​(2H, m), 1.42-1.22 (6H, m), 0.89 (3H, t, J=6.8Hz).

[0168] (2) [ka] A colorless oily substance, bis(2-(hexylthio)ethyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-(2-(hexylthio)ethoxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29(2) and Example 29(3), except that 2-(hexylthio)ethan-1-ol was used instead of heptan-1-ol. 1 H-NMR(CDCl3)δ: 4.72-4.66 (2H, m), 4.21 (8H, t, J=7.0Hz), 4.16 (4H, t, J=6.2Hz), 2.84 (4H, t, J=6.4Hz), 2.73 (8H, t, J=6.8Hz), 2.69-2.65 (2H, m), 2.57-2.49 (14H, m), 2.36-2.32 (8H, m), 1.75-1.54 (24H, m), 1.42-1.23 (24H, m), 1.01 (6H, t, J=7.2Hz), 0.91-0.87 (12H, m). MS m / z(M+H):1242. clogP:17.722

[0169] [Example 44] (1) [ka] To a solution of 8-bromooctan-1-ol (5.0 g) in N-methylpyrrolidone (25 mL), 70% aqueous sodium hydrogen sulfide solution (13.4 g) was added under ice cooling and stirred at room temperature for 1 hour. Water (100 mL), ethyl acetate (50 mL), and hexane (50 mL) were added to the reaction mixture, and the organic layer was separated and washed with water (100 mL) and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 8-mercaptooctan-1-ol (3.8 g). 1H-NMR(CDCl3)δ: 3.68-3.61 (2H, m), 2.53 (2H, dt, J=7.6, 7.6Hz), 1.71-1.53 ​​(5H, m), 1.42-1.20 (9H, m).

[0170] To a mixture of 8-mercaptooctan-1-ol (1.9 g), potassium hydroxide (0.72 g), and ethanol (60 mL), methyl p-toluenesulfonate (2.2 g) was added and stirred at room temperature for 1 hour. The solvent was then evaporated under reduced pressure. Ethyl acetate (150 mL) and water (100 mL) were added to the resulting residue, and the organic layer was separated and washed with water (100 mL) and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 8-(methylthio)octan-1-ol (1.3 g). 1 H-NMR(CDCl3)δ: 3.67-3.62 (2H, m), 2.49 (2H, t, J=7.4Hz), 2.10 (3H, s), 1.63-1.53 ​​(4H, m), 1.42-1.20 (9H, m).

[0171] (2) [ka] A colorless oily substance, bis(8-(methylthio)octyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-((8-(methylthio)octyl)oxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate, was obtained in the same manner as in Example 29(2) and Example 29(3), except that 8-(methylthio)octan-1-ol was used instead of heptan-1-ol. 11H-NMR (CDCl3) δ: 4.72 - 4.66 (2H, m), 4.16 (4H, t, J = 6.4 Hz), 4.05 (8H, t, J = 6.6 Hz), 2.84 (4H, t, J = 6.4 Hz), 2.69 - 2.65 (2H, m), 2.55 - 2.46 (14H, m), 2.33 - 2.29 (8H, m), 2.10 (12H, s), 1.72 - 1.56 (32H, m), 1.42 - 1.31 (32H, m), 1.01 (6H, t, J = 7.0 Hz). MS m / z (M + H): 1298. clogP: 17.5084

[0172] The structures of the compounds of Comparative Example 1 and Comparative Example 2 are shown below. [Chemical formula]

[0173] [Chemical formula]

[0174] Test Example 1: Preparation of mRNA-encapsulating lipid particles and measurement of reporter protein expression rate in mice <Preparation of EPO mRNA-encapsulating lipid particles>[ The compounds shown 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-

[0175] Neutral lipids used were 1,2-distearoyl-sn-glycero-3-phosphocholine (product name: COATSOME(R) MC-8080; NOF corporation) (hereinafter referred to as DSPC), or L-α-dioleoyl phosphatidylethanolamine (hereinafter referred to as DOPE) (product name: COATSOME(R) ME-8181; NOF corporation), or 1,2-dioleoyl-sn-glycero-3-phosphocholine (hereinafter referred to as DOPC) (product name: COATSOME(R) MC-8181; NOF corporation).

[0176] EPO mRNA (product name: CleanCap EPO mRNA (5moU); TriLink) was diluted with 50 mmol / L citric acid buffer at pH 4 so that the weight ratio of total lipid concentration to mRNA concentration was about 16:1 to 64:1 to obtain an aqueous phase. Subsequently, using NanoAssemblr (Precision NanoSystems), the aqueous phase and the oil phase were mixed so that the volume ratio of the aqueous phase to the oil phase was aqueous phase:oil phase = 3:1, and the mixture was diluted 1.5-fold with phosphate buffered saline (PBS) to obtain a dispersion of mRNA-lipid particles. This dispersion was dialyzed using a dialysis cassette (Slide-A-Lyzer G2, MWCO: 10 kD, Thermo Fisher Scientific) against a 10% sucrose aqueous solution to remove ethanol, and lipid particles encapsulating EPO mRNA were obtained.

[0177] <Measurement of particle size> The particle size of the mRNA-encapsulating lipid particles was measured by diluting the lipid particle dispersion 10-fold with phosphate buffered saline (PBS) and using a zeta potential and particle size measurement system ELS-Z2 (Otsuka Electronics). The results are shown in Table 1.

[0178] <Evaluation of encapsulation efficiency of mRNA> (Quantification of total mRNA concentration) To 30 - 60 μL of lipid particles retaining mRNA, 15 - 30 μL of 3 mol / L sodium acetate aqueous solution and 4.5 - 9 μL of glycogen were added, and then 0.75 - 1.5 mL of ethanol was added to dissolve the lipids and precipitate only the mRNA. Subsequently, centrifugation was performed to remove the supernatant. After air - drying for 15 minutes or more, water was added for redissolution, and the total mRNA concentration was quantified by measuring the concentration using a NanoDrop NF1000 (Thermo Fisher Scientific).

[0179] (Quantification of mRNA concentration in the outer aqueous phase) Quantification was performed according to the protocol using the Quant - iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific). First, the 20×TE buffer contained in the above - mentioned kit was diluted with water to obtain 1×TE buffer. Here, TE indicates Tris / EDTA (ethylenediaminetetraacetic acid). To quantify only the mRNA in the outer aqueous phase, the lipid particle dispersion retaining mRNA was diluted 10,000 - fold with 1×TE buffer. 100 μL of the lipid particle dispersion diluted 10,000 - fold was placed in a 96 - well plate, and then 100 μL of RiboGreen reagent (the reagent contained in the above - mentioned Quanti - iT Ribogreen RNA Assay Kit) diluted 2,000 - fold with 1×TE buffer was added to the sample. The fluorescence (excitation wavelength: 485 nm, emission wavelength: 535 nm) was measured using a plate reader InfiniteF200 (TECAN) to quantify the mRNA concentration in the outer aqueous phase.

[0180] (Calculation of encapsulation efficiency) Using the quantification results of the total mRNA concentration and the mRNA concentration in the outer aqueous phase obtained in the above - mentioned steps, the mRNA encapsulation efficiency of the mRNA - lipid particles was calculated according to the following formula. The results are shown in Table 1. mRNA encapsulation efficiency (%)=(total mRNA concentration - mRNA concentration in the outer aqueous phase)÷total mRNA concentration×100

[0181] <Measurement of EPO enzyme activity> C57BL / 6J mice were intravenously administered with the dispersion of mRNA lipid particles prepared in <Preparation of EPO mRNA-encapsulating lipid particles> so that the mRNA dosage was 0.1 mg / kg. Blood was collected from the posterior vena cava 20 to 24 hours after administration to obtain plasma. Using the obtained plasma, the human EPO enzyme activity was quantified using ab119522 Erythropoietin (EPO) Human Elisa Kit (Abcam). The quantified values were described as the relative EPO protein amount when Comparative Example 1 was set as 1. The results are shown in Table 1.

[0182]

Table 1

[0183] Compared with the nucleic acid-lipid composition of the comparative example, the nucleic acid-lipid composition of the present invention was shown to have a high EPO protein expression rate.

[0184] Test Example 2: Preparation of mRNA-encapsulating lipid particles and measurement of reporter protein expression rate in mice <Preparation of FLuc mRNA-encapsulating lipid particles> The compounds, neutral lipids, cholesterol (product name: Cholesterol HP; Nippon Seika Co., Ltd.) described in Table 2, and 1,2-dimyristoyl-rac-glycero-3-(methylpolyoxyethylene 2000) (hereinafter, DMG-PEG2000) were dissolved in ethanol at the molar ratios shown in Table 2 so that the total lipid concentration was 20 mmol / L to obtain an oil phase.

[0185] For the neutral lipid, in the case of Comparative Example 1, 1,2-distearoyl-sn-glycero-3-phosphocholine (product name: COATSOME(R)MC-8080; NOF corporation) was used, and in cases other than Comparative Example 1, L-α-dioleoyl phosphatidylethanolamine (product name: COATSOME(R)MC-8181; NOF corporation) was used.

[0186] FLuc mRNA (Product name: CleanCap FLuc mRNA (5moU); TriLink) was diluted with 50 mmol / L citric acid buffer at pH 4 so that the weight ratio of total lipid concentration to mRNA concentration was about 19:1 to 64:1 to obtain an aqueous phase. Subsequently, NanoAssemblr (Precision NanoSystems) was used to mix them so that the volume ratio of the aqueous phase to the oil phase was aqueous phase: oil phase = 3:1, and the mixture was diluted 1.5-fold with phosphate buffered saline (PBS) to obtain a dispersion of mRNA lipid particles. This dispersion was dialyzed using a dialysis cassette (Slide-A-Lyzer G2, MWCO: 10 kD, Thermo Fisher Scientific) against a 10% sucrose aqueous solution to remove ethanol, and lipid particles encapsulating FLuc mRNA were obtained.

[0187] [[ID=z3]] <Measurement of particle size> The particle size of the lipid particles encapsulating mRNA was measured for the lipid particle dispersion by diluting it 10-fold with phosphate buffered saline (PBS) and using a zeta potential and particle size measurement system ELS-Z2 (Otsuka Electronics). The results are shown in Table 2.

[0188] <Evaluation of mRNA encapsulation efficiency> (Quantification of total mRNA concentration) To 30 - 60 μL of lipid particles retaining mRNA, 15 - 30 μL of 3 mol / L sodium acetate aqueous solution and 4.5 - 9 μL of glycogen were added, and then 0.75 - 1.5 mL of ethanol was added to dissolve the lipid and precipitate only mRNA. Then, centrifugation was performed to remove the supernatant. After air drying for 15 minutes or more, water was added for redissolution, and the total mRNA concentration was quantified by measuring the concentration using a NanoDrop NF1000 (Thermo Fisher Scientific).

[0189] (Quantification of mRNA concentration in the external aqueous phase) Quantification was performed according to the protocol using the Quant-iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific). First, the 20×TE buffer included in the above kit was diluted with water to obtain a 1×TE buffer. Here, TE indicates Tris / EDTA (ethylenediaminetetraacetic acid). To quantify only the mRNA in the outer aqueous phase, the lipid particle dispersion containing mRNA was diluted 10,000-fold with 1×TE buffer. 100 μL of the lipid particle dispersion diluted 10,000-fold was placed in a 96-well plate, and then 100 μL of the RiboGreen reagent (the reagent included in the above-mentioned Quanti-iT Ribogreen RNA Assay Kit) diluted 2,000-fold with 1×TE buffer was added to the sample. The mRNA concentration in the outer aqueous phase was quantified by measuring fluorescence (excitation wavelength: 485 nm, emission wavelength: 535 nm) using a plate reader, Infinit EF200 (TECAN).

[0190] (Calculation of encapsulation efficiency) Using the quantification results of the total mRNA concentration and the mRNA concentration in the outer aqueous phase obtained in the above steps, the mRNA encapsulation efficiency of the mRNA lipid particles was calculated according to the following formula. The results are shown in Table 2. mRNA encapsulation efficiency (%) = (total mRNA concentration - mRNA concentration in the outer aqueous phase) ÷ total mRNA concentration × 100

[0191] <Luciferase luminescence measurement> ICR mice were administered a single dose of the dispersion of mRNA lipid particles prepared in <Preparation of Lipid Particles Encapsulating FLuc mRNA> as an mRNA dose of 1 μg intramuscularly into the rectus femoris muscle from the dorsal side. 50 minutes after administration, 150 mg / kg of D-luciferin potassium (FUJIFILM Wako Pure Chemical Corporation) was administered intraperitoneally, and 6 hours after administration under isoflurane gas anesthesia, luminescence was measured using an IVIS Imaging System (PerkinElmer) in the prone position. An ROI was set so that all of the lower limbs on the administered side were included, and the luminescence amount (Photone / Sec) was quantified using Living Image Software (PerkinElmer). Luciferase [P / S] in Table 2 indicates Photons / sec (light intensity).

[0192] The results are shown in Table 2.

[0193]

Table 2

[0194] The nucleic acid-lipid composition of the present invention was shown to have a high reporter protein expression rate.

[0195] [[ID=!9]] (PTEN Antisense Oligonucleotide Information) PTEN (Phosphatase and Tensin Homolog Deleted from Chromosome 10) is an enzyme that catalyzes the dephosphorylation reaction of phosphatidylinositol 3,4,5-trisphosphate, which is an inositol phospholipid. An antisense oligonucleotide nucleic acid (PTEN ASO) against the PTEN protein was purchased from Hokkaido System Science Co., Ltd. It is a phosphodiester bond of an oligonucleotide consisting of 20 bases, and the sequence is described below. 5(m)^t(m)^g(m)^5(m)^t(m)^a^g^5c^5c^t^5c^t^g^g^a^t(m)^t(m)^t(m)^g(m)^a(m)[[ID=!7]] It should be noted that there seems to be a formatting issue with the tags in the original text where and are not properly formatted in the input. I have translated them as they are but this might be a mistake in the original text. Also, the "!9" in the translated text for is a result of trying to maintain the integrity of the input while highlighting this potential error.Here, the lowercase letters (a, g, t) represent adenine, guanine, and thymidine, respectively, and (m) represents 2'MOE modification. 5(m) = 2'-MOE 5-Me cytosine t(m) = 2'-MOE thymidine g(m) = 2'-MOE guanine a(m) = 2'-MOE adenine, 5c = 5-methyl-d cytosine, and ^ represents phosphorothioate. 2'-MOE indicates 2'-O-methoxyethyl.

[0196] (Preparation of PTEN ASO-LNP) The first lipid, phospholipid, cholesterol, and polyethylene glycol lipid (PEG lipid) shown in Table 3 were dissolved in ethanol at the molar ratios shown in Table 3 so that the total lipid concentration was 20 mmol / L, to obtain an oil phase.

[0197] The neutral lipid used was DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine, product name: COATSOME MC-8080; NOF Corporation). The cholesterol used was cholesterol (product name: Cholesterol HP; Nippon Fine Chemical Co., Ltd.). The PEG lipid used was monostearyl PEG (product name: Polyethylene Glycol Monostearate (4E.O.), Fujifilm Wako Pure Chemical Industries, Ltd.).

[0198] The structure of monostearyl PEG (also referred to as monoPEG) is shown below. [ka]

[0199] PTEN ASO (5 mg) was dissolved in 1 mL of sterilized water and diluted with 10 mmol / L acetate buffer at pH 4 to obtain an aqueous phase with a nucleic acid concentration of 54.6 μmol / L. Subsequently, using a syringe pump, the aqueous phase and the oil phase were mixed with a micromixer (see Japanese Patent Publication No. 5288254) such that the volume ratio of the aqueous phase to the oil phase was 3:1, and the mixture was diluted 2-fold with phosphate buffered saline (PBS) to obtain a dispersion of nucleic acid-lipid particles.

[0200] The molar ratios of the first lipid, phospholipid, sterol, and PEG lipid in the lipid composition, and the mass ratio of the nucleic acid to the total lipid during mixing are also shown in Table 3.

[0201] [Table 3]

[0202] <Measurement of particle size> The particle size and polydispersity index of the lipid particles were measured for a lipid particle dispersion by diluting 10-fold with phosphate buffered saline (PBS) and using a zeta potential / particle size measurement system ELS-Z2 (Otsuka Electronics Co., Ltd.). The measurement results are shown in Table 3.

[0203] <Evaluation of encapsulation efficiency of PTEN ASO> (Quantification of total nucleic acid concentration) To 60 μL of lipid particles retaining nucleic acid, 30 μL of 3 mol / L aqueous sodium acetate solution and 9 μL of glycogen were added, and then 1.5 mL of ethanol was added to dissolve the lipid and precipitate only the nucleic acid. Thereafter, centrifugation was performed to remove the supernatant. After air-drying for 15 minutes or longer, water was added for redissolution, and the total nucleic acid concentration was quantified by measuring the concentration using a NanoDrop ND1000 (Thermo Fisher Scientific).

[0204] (Quantification of nucleic acid concentration in the external aqueous phase) Quantification was performed using the Quant-iT RiboGreen RNA Assay Kit (Thermo Fisher Scientific) according to the protocol. First, the 20×TE buffer included in the above kit was diluted with water to obtain 1×TE buffer. Note that TE indicates Tris / EDTA (ethylenediaminetetraacetic acid). To quantify only the nucleic acids in the outer aqueous phase, the lipid particle dispersion containing nucleic acids was diluted 10,000-fold with 1×TE buffer.

[0205] 100 μL of the lipid particle dispersion diluted 10,000-fold was placed in a 96-well plate. Subsequently, 100 μL of the RiboGreen reagent (the reagent included in the above Quanti-iT Ribogreen RNA Assay Kit) diluted 2,000-fold with 1×TE buffer was added to the sample, and the fluorescence (excitation wavelength: 485 nm, emission wavelength: 535 nm) was measured using a plate reader Infinite F200 (TECAN) to quantify the nucleic acid concentration in the outer aqueous phase.

[0206] (Calculation of encapsulation efficiency) Using the quantification results of the total nucleic acid concentration and the nucleic acid concentration in the outer aqueous phase obtained in the above steps, the nucleic acid encapsulation efficiency of the nucleic acid-lipid particles was calculated according to the following formula. Nucleic acid encapsulation efficiency (%) = (total nucleic acid concentration - nucleic acid concentration in the outer aqueous phase) ÷ total nucleic acid concentration × 100 The calculation results are shown in Table 3.

[0207] <PTEN mRNA knockdown evaluation in vitro> (Cells used for evaluation) [[ID=2I]] In in vitro tests using A431 cells (American Type Culture Collection), a mixture of E-MEM (gibco), FBS (fetal bovine serum) (gibco), Penicillin-streptomycin (gibco), and NEAA (Non-Essential Amino Acid) (FUJIFILM Wako Pure Chemical Corporation) at a ratio of 88:10:1:1 was used as the culture medium.

[0208] In in vitro studies using SH-SY5Y cells (American Type Culture Collection), a mixture of E-MEM (Gibco), Ham's F12 (Gibco), FBS (Gibco), Penicillin-streptomycin (Gibco), and NEAA (Fujifilm Wako Pure Chemical Industries) in a ratio of 41.5:41.5:15:1:1 was used as the culture medium.

[0209] (PTEN mRNA quantification by PCR) PTEN protein mRNA measurement was performed using TaqMan® Fast Advanced Cells-to-CT. TM The protocol of the kit (Thermo Fisher Scientific) was followed. A dispersion of nucleic acid-lipid particles, naked ASO, or PBS, prepared to a final ASO concentration of 500 nmol / L, was added to A431 cells or SH-SY5Y cells. After 24 hours of exposure at 37°C and 5% CO2, the culture supernatant was removed and the cells were washed once with 4°C PBS. After removing the PBS, lysis solution was added at 50 μL / well and allowed to stand at room temperature for 5 minutes to obtain cell lysates. The cell lysates were analyzed using TaqMan® Fast Advanced Cells-to-CT. TM Reverse transcription and PCR reactions were performed using the PCR kit (Thermo Fisher Scientific), and PCR reaction reagents Hs02621230_s1, FAM / MGB (Thermo Fisher Scientific), and Human GAPDH Endogenous Control, VIC® / MGB (Thermo Fisher Scientific).

[0210] The PTEN mRNA value for each sample was calculated using the ΔΔCt method. Specifically, the ΔCt value for each sample was calculated by subtracting the GAPDH Ct value from the PTEN Ct value. The average ΔCt value for the PBS-treated group was subtracted from the calculated ΔCt value to calculate the ddCt value. Each ΔΔCt value was calculated relative to the naked ASO used as a comparison, and this was used as the PTEN mRNA relative value. The calculation results are shown in Table 4.

[0211] [Table 4]

Claims

1. A compound represented by the following formula (1) or a salt thereof: 【Chemical 1】 During the ceremony, R １ and R ２ each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R ３ represents a hydrocarbon group having 2 to 8 carbon atoms, and R １ , R ２ and R ３ The hydrocarbon group represented by is —OH, COOH, and —NR ５１ R ５２ and optionally substituted with one or more substituents selected from R ４ represents a hydrocarbon group having 1 to 8 carbon atoms, R ５ and R ６ are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ where R ５ and R ６ are both hydrocarbon groups having 1 to 8 carbon atoms, R ７ is -R １０ -L ２ -R １１ -L ３ -R １２ indicates, R ５１ and R ５２ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, L １ , L ２ , and L ３ each independently represents —OC(O)O—, —C(O)O—, —OC(O)—, or —O—. R ８ represents a hydrocarbon group having 1 to 12 carbon atoms, R ９ represents a hydrocarbon group having 1 to 24 carbon atoms, R １０ represents a hydrocarbon group having 1 to 8 carbon atoms, R １１ represents a hydrocarbon group having 1 to 24 carbon atoms, R １２ represents a hydrocarbon group having 1 to 24 carbon atoms, R ９ , and R １２ The hydrocarbon group represented by is an aryl group or -S-R ５８ R 58 represents a hydrocarbon group having 1 to 12 carbon atoms; R １１ The hydrocarbon group represented by is —OC(O)O—R ５３ , -C(O)O-R ５４ or —OC(O)—R ５５ R 53 , R 54 , and R 55 each independently represent a hydrocarbon group having 1 to 24 carbon atoms; the hydrocarbon group represented by R 53 , R 54 , and R 55 may be substituted with —S—R 58 , R 58 representing a hydrocarbon group having 1 to 12 carbon atoms; The above hydrocarbon group represents a chain alkyl group, alkenyl group or alkynyl group for a monovalent group, and a chain alkylene group, alkenylene group or alkynylene group for a divalent group.

2. R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms; R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, and R １ , R ２ and R ３ The hydrocarbon group represented by may be substituted with —OH, R ４ represents a hydrocarbon group having 1 to 8 carbon atoms, R ５ and R ６ are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ where R ５ and R ６ are both hydrocarbon groups having 1 to 8 carbon atoms, R ７ But, -R １０ -L ２ -R １１ -L ３ -R １２ indicates, L １ , and L ３ each independently represents —C(O)O— or —OC(O)—. L ２ represents —OC(O)O—, —C(O)O—, or —OC(O)—. R ８ represents a hydrocarbon group having 1 to 8 carbon atoms, R ９ represents a hydrocarbon group having 1 to 16 carbon atoms, R １０ represents a hydrocarbon group having 1 to 8 carbon atoms, R １１ represents a hydrocarbon group having 1 to 9 carbon atoms, R １２ represents a hydrocarbon group having 1 to 16 carbon atoms, R ９ , and R １２ The hydrocarbon group represented by is an aryl group or -S-R ５８ may be substituted with R ５８ represents a hydrocarbon group having 1 to 8 carbon atoms, R １１ The hydrocarbon group represented by is —C(O)O—R ５５ , or —OC(O)—R ５６ may be substituted with R ５５ , and R ５６ each independently represents a hydrocarbon group having 1 to 16 carbon atoms, R ５５ , and R ５６ The hydrocarbon group represented by is —S—R ５８ and R ５８ The definition of is as above, The compound according to claim 1 or a salt thereof.

3. The compound or salt thereof according to claim 1, which is a compound represented by the following formula (1-1) or a salt thereof: 【Chemistry 2】 During the ceremony, R １ and R ２ each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R ３ represents a hydrocarbon group having 2 to 8 carbon atoms, and R １ , R ２ and R ３ The hydrocarbon group represented by is —OH, COOH, or —NR ５１ R ５２ may be substituted with R ４ represents a hydrocarbon group having 1 to 8 carbon atoms, R ５ and R ６ are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ where R ５ and R ６ are both hydrocarbon groups having 1 to 8 carbon atoms, L １ represents —OC(O)O—, —C(O)O—, —OC(O)—, or —O—; R ８ represents a hydrocarbon group having 1 to 12 carbon atoms, R ９ represents a hydrocarbon group having 1 to 24 carbon atoms, and R ９ The hydrocarbon group represented by is an aryl group or -S-R ５８ and R ５８ represents a hydrocarbon group having 1 to 12 carbon atoms, R ５１ and R ５２ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R １３ represents a hydrocarbon group having 1 to 8 carbon atoms, L ４ represents —OC(O)O—, —C(O)O—, —OC(O)—, or —O—; R １４ is -R １５ -L ５ -R １６ indicates R １５ represents a hydrocarbon group having 1 to 24 carbon atoms, and L ５ represents —OC(O)O—, —C(O)O—, —OC(O)—, or —O—, and R １６ represents a hydrocarbon group having 1 to 24 carbon atoms, R １５ The hydrocarbon group having 1 to 24 carbon atoms represented by is —OC(O)O—R ５３ , -C(O)O-R ５４ , or —OC(O)—R ５５ may be substituted with R １６ The hydrocarbon group having 1 to 24 carbon atoms represented by is an aryl group having 6 to 20 carbon atoms or -S-R ５８ may be substituted with R ５３ , R ５４ , R ５５ each independently represents a hydrocarbon group having 1 to 24 carbon atoms, R ５３ , R ５４ , R ５５ The hydrocarbon group represented by is —S—R ５８ and R ５８ The definition of is as above.

4. In formula (1-1), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms; R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, and R １ , R ２ and R ３ The hydrocarbon group represented by may be substituted with —OH, R ４ represents a hydrocarbon group having 1 to 8 carbon atoms, R ５ and R ６ are each independently a hydrocarbon group having 1 to 8 carbon atoms, or -R ８ -L １ -R ９ where R ５ and R ６ are both hydrocarbon groups having 1 to 8 carbon atoms, L １ represents —C(O)O— or —OC(O)—, R ８ represents a hydrocarbon group having 1 to 8 carbon atoms, R ９ represents a hydrocarbon group having 1 to 18 carbon atoms, and R ９ The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, or -S-R ５８ may be substituted with R ５８ represents a hydrocarbon group having 1 to 8 carbon atoms, R １３ represents a hydrocarbon group having 1 to 8 carbon atoms, R １４ is -R １５ -L ５ -R １６ indicates R １５ represents a hydrocarbon group having 1 to 18 carbon atoms; L ５ represents -OC(O)O-, and R １６ represents a hydrocarbon group having 1 to 18 carbon atoms, R １５ The hydrocarbon group having 1 to 18 carbon atoms represented by is —C(O)O—R ５４ , or —OC(O)—R ５５ may be substituted with R ５４ , and R ５５ each independently represents a hydrocarbon group having 1 to 16 carbon atoms; R ５４ , and R ５５ The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or -S-R ５８ and R ５８ is defined as above, R １６ The hydrocarbon group having 1 to 18 carbon atoms represented by is an aryl group or -S-R ５８ and R ５８ The definition of is as above, The compound according to claim 3 or a salt thereof.

5. The compound or salt thereof according to claim 1, which is a compound represented by the following formula (1-2) or a salt thereof: 【Chemistry 3】 During the ceremony, R １ and R ２ each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R ３ represents a hydrocarbon group having 2 to 8 carbon atoms, and R １ , R ２ and R ３ The hydrocarbon group represented by is —OH, COOH, or —NR ５１ R ５２ may be substituted with R ４ and R ８ each independently represents a hydrocarbon having 1 to 8 carbon atoms, R ２１ and R ２２ each independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ２３ and R ２４ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, R ２５ and R ２６ each independently represents a hydrocarbon group having 1 to 24 carbon atoms, L ２１ and L ２２ each independently represents —OC(O)O—, —C(O)O—, —OC(O)—, or —O—, R ２５ and R ２６ The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, or -S-R ５８ may be substituted with R ５７ is -OH, COOH, -NR ５１ R ５２ , -OC(O)OR ５３ , -C(O)O-R ５４ , —OC(O)—R ５５ , -O-R ５６ indicates, R ５１ and R ５２ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ５３ , R ５４ , R ５５ and R ５６ each independently represents a hydrocarbon group having 1 to 18 carbon atoms, R ５８ represents a hydrocarbon group having 1 to 12 carbon atoms.

6. In formula (1-2), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms; R １ and R ２ The hydrocarbon group represented by may be substituted with —OH, R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, R ４ and R ８ each independently represents a hydrocarbon having 1 to 8 carbon atoms, R ２１ and R ２２ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ２３ and R ２４ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ２５ and R ２６ each independently represents a hydrocarbon group having 1 to 16 carbon atoms, L ２１ and L ２２ each independently represents —C(O)O— or —OC(O)—; The compound according to claim 5 or a salt thereof.

7. In formula (1-2), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, R ４ and R ８ each independently represents a hydrocarbon having 1 to 8 carbon atoms, R ２１ and R ２２ each independently represents a hydrocarbon group having 1 to 6 carbon atoms, R ２３ and R ２４ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ２５ and R ２６ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, L ２１ and L ２２ each independently represents —C(O)O— or —OC(O)—; The compound according to claim 5 or a salt thereof.

8. The compound or salt thereof according to claim 1, which is a compound represented by the following formula (1-3) or a salt thereof: 【Chemistry 4】 During the ceremony, R １ and R ２ each independently represents a hydrocarbon group having 1 to 18 carbon atoms; R ３ represents a hydrocarbon group having 2 to 8 carbon atoms, and R １ , R ２ and R ３ The hydrocarbon group represented by is —OH, COOH, or —NR ５１ R ５２ may be substituted with R ４ and R ８ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ３１ , R ３２ , R ３３ , and R ３４ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, R ３５ , R ３６ , R ３７ , and R ３８ each independently represents a hydrocarbon group having 1 to 24 carbon atoms, L ３１ , L ３２ , L ３３ , and L ３４ each independently represents —OC(O)O—, —C(O)O—, —OC(O)—, or —O—, R ３５ , R ３６ , R ３７ , and R ３８ The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms or an S—R ５８ may be substituted with R ５１ and R ５２ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ５８ represents a hydrocarbon group having 1 to 12 carbon atoms.

9. In formula (1-3), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms; R １ and R ２ The hydrocarbon group represented by may be substituted with —OH, R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, R ４ and R ８ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ３１ , R ３２ , R ３３ , and R ３４ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ３５ , R ３６ , R ３７ , and R ３８ each independently represents a hydrocarbon group having 1 to 16 carbon atoms, L ３１ , L ３２ , L ３３ , and L ３４ each independently represents —C(O)O— or —OC(O)—, R ３５ , R ３６ , R ３７ , and R ３８ The hydrocarbon group represented by is an aryl group having 6 to 20 carbon atoms, or S—R ５８ may be substituted with R ５８ represents a hydrocarbon group having 1 to 8 carbon atoms; The compound according to claim 8 or a salt thereof.

10. In formula (1-3), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, R ４ and R ８ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ３１ , R ３２ , R ３３ , and R ３４ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３５ , R ３６ , R ３７ , and R ３８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, L ３１ , L ３２ , L ３３ , and L ３４ each independently represents —C(O)O— or —OC(O)—, R ３５ , R ３６ , R ３７ , and R ３８ The hydrocarbon group represented by is —S—R ５８ may be substituted with R ５８ represents a hydrocarbon group having 1 to 8 carbon atoms; The compound according to claim 8 or a salt thereof.

11. In formula (1-3), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, R ４ and R ８ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ３１ , R ３２ , R ３３ , and R ３４ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３５ , R ３６ , R ３７ , and R ３８ are each independently -S-R ５８ represents a hydrocarbon group having 1 to 12 carbon atoms substituted with R ５８ represents a hydrocarbon group having 1 to 8 carbon atoms, L ３１ , L ３２ , L ３３ , and L ３４ each independently represents —C(O)O— or —OC(O)—; The compound according to claim 8 or a salt thereof.

12. In formula (1-3), R １ and R ２ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３ represents a hydrocarbon group having 2 to 4 carbon atoms, R ４ and R ８ each independently represents a hydrocarbon group having 1 to 8 carbon atoms, R ３１ , R ３２ , R ３３ , and R ３４ each independently represents a hydrocarbon group having 1 to 3 carbon atoms, R ３５ , R ３６ , R ３７ , and R ３８ each independently represents a hydrocarbon group having 1 to 12 carbon atoms, L ３１ , L ３２ , L ３３ , and L ３４ each independently represents —C(O)O— or —OC(O)—; The compound according to claim 8 or a salt thereof.

13. A compound or a salt thereof described below: Bis(2-butyloctyl) 16-(3-(diethylamino)propyl)-10,22-dihexyl-12,20-dioxo-11,13,19,21-tetraoxa-16-azahentriacontanedioate; 【Chemistry 5】 Bis(2-butyloctyl) 11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 6】 Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 7】 Bis(2-pentylheptyl)11-(2-(dimethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 8】 Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 9】 Bis(2-pentylheptyl)11-(4-(diethylamino)butyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 10】 Bis(2-pentylheptyl)12-(2-(diethylamino)ethyl)-5,19-dihexyl-7,17-dioxo-6,8,16,18-tetraoxa-12-azatricosane dioate; 【Chemistry 11】 Bis(2-pentylheptyl)13-(2-(diethylamino)ethyl)-5,21-dihexyl-7,19-dioxo-6,8,18,20-tetraoxa-13-azapentacosane dioate; 【Chemistry 12】 Bis(2-pentylheptyl)10-(2-(diethylamino)ethyl)-4,16-dihexyl-6,14-dioxo-5,7,13,15-tetraoxa-10-azanonadecanedioate; 【Chemistry 13】 Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-dimethyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 14】 Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-diethyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 15】 Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-dipropyl-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 16】 Bis(2-pentylheptyl)5,17-dibutyl-11-(2-(diethylamino)ethyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 17】 Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-7,15-dioxo-5,17-dipentyl-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 18】 Bis(2-pentylheptyl)11-(2-(diethylamino)ethyl)-5,17-diheptyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 19】 Bis(2-((3r,5r,7r)-adamantan-1-yl)ethyl)11-(2-(diethylamino)ethyl)-5,17-dihexyl-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 20】 Bis(2-pentylheptyl)11-(3-(diethylamino)propyl)-7,15-dioxo-5,17-dipropyl-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical 21】 Diheptyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(heptyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical Formula 22】 Dihexyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical 23】 Dioctyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(octyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 24】 Dinonyl 11-(2-(diethylamino)ethyl)-5,17-bis(4-(nonyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 25】 1-heptyl 21-hexyl 11-(2-(diethylamino)ethyl)-5-(4-(heptyloxy)-4-oxobutyl)-17-(4-(hexyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical 26】 Diheptyl 11-(3-(diethylamino)propyl)-5,17-bis(4-(heptyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical 27】 Diheptyl 10-(2-(diethylamino)ethyl)-4,16-bis(3-(heptyloxy)-3-oxopropyl)-6,14-dioxo-5,7,13,15-tetraoxa-10-azanonadecanedioate; 【Chemical Formula 28】 1-Hexyl 21-octyl 11-(2-(diethylamino)ethyl)-5-(4-(hexyloxy)-4-oxobutyl)-17-(4-(octyloxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical 29】 Bis(2-(hexylthio)ethyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-(2-(hexylthio)ethoxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemistry 30】 Bis(8-(methylthio)octyl)11-(2-(diethylamino)ethyl)-5,17-bis(4-((8-(methylthio)octyl)oxy)-4-oxobutyl)-7,15-dioxo-6,8,14,16-tetraoxa-11-azahenicosanedioate; 【Chemical 31】

14. A lipid particle comprising the compound according to any one of claims 1 to 13 or a salt thereof and a lipid.

15. The lipid particle according to claim 14, wherein the lipid is at least one type of lipid selected from the group consisting of sterols and lipids having nonionic hydrophilic polymer chains.

16. The lipid particle of claim 14 or 15, further comprising a neutral lipid.

17. 17. The lipid particle of claim 14, further comprising a nucleic acid.

18. The lipid particle of claim 17 , wherein the nucleic acid comprises a nucleic acid having 50 or more bases.

19. A pharmaceutical composition comprising the lipid particles according to any one of claims 14 to 18 as an active ingredient.

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