Nitrogen-containing chain compound and composition thereof

Abstract

The invention discloses a nitrogen-containing chain compound and a composition thereof. Specifically disclosed is a nitrogen-containing chain compound represented by formula I or II or a pharmaceutically acceptable salt thereof. The composition containing the nitrogen-containing chain compound can realize lung targeting delivery of nucleic acid. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a nitrogen-containing chain compound and a composition thereof. Background Art

[0002] Nucleic acids have shown great advantages in vaccines, with the characteristics of short R&D cycle and significant preventive effect (over 95%). At present, clinical trials are underway for nucleic acid drugs in the treatment of rare diseases, tumors, viral diseases, cardiovascular diseases, and metabolic diseases. In recent years, nucleic acid drugs have made breakthrough progress in the field of infectious diseases and tumor treatment in a short period of time. In addition, since the R&D cycle of nucleic acid drugs is shorter than that of traditional drugs, it has also brought hope to patients with rare diseases and is expected to prolong the lives of such patients. However, naked RNA is a negatively charged hydrophilic macromolecule. Due to the electrostatic repulsion of the cell membrane, it is difficult to enter the cell and is easily rapidly degraded by ubiquitous RNA enzymes. Therefore, a suitable delivery carrier is needed to enter the cell and bring it to the target treatment site. How to efficiently and safely deliver nucleic acid drugs to specific target cells and protect them from degradation has become a key issue in this research field.

[0003] At present, liver-targeted nucleic acid delivery materials have been confirmed by a large number of studies, but extrahepatic nucleic acid delivery is still an unresolved problem. A few studies have shown that extrahepatic delivery can be achieved through lipid nanoparticles. For example, the SORT theory proposes that cationic lipids with permanent positive charges, such as DOTAP, can be incorporated into lipid nanoparticles to achieve lung-targeted delivery; and anionic lipids with permanent negative charges, such as 18BMP, can be incorporated to achieve spleen-targeted delivery. Summary of the invention

[0004] The present invention aims to provide a new ionizable lipid compound to provide a new solution for extrahepatic nucleic acid delivery. To solve the above technical problems, the present invention provides a nitrogen-containing chain compound and a composition thereof. Specifically, a nitrogen-containing chain compound or a pharmaceutically acceptable salt thereof as shown in formula I or II is provided, and a composition containing the above nitrogen-containing chain compound can achieve lung-targeted delivery of nucleic acids. The technical solution of the present invention is as follows:

[0005] The present invention provides a nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof;

[0006]

[0007] Wherein, R is C1-C6 alkylene, R 1 is hydrogen or C1-C4 alkyl;

[0008] R 3 is C1-C6 alkylene;

[0009] R2 is hydrogen or C1-C4 alkyl;

[0010] X, Y, Z and W are independently C1-C2 alkylene;

[0011] T, M, Q and S are independently The a end is connected to X, Y, Z or W;

[0012] A, B, C and D are independently C1-C 20 alkyl;

[0013] In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When is hydrogen, R is

[0014] In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When it is C1-C4 alkyl, R is

[0015] In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When is hydrogen, R is

[0016] In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When it is C1-C4 alkyl, R is

[0017] In the nitrogen-containing chain compound shown in Formula II, when T, M, Q and S are the same and are When R is

[0018] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I or II, the definitions of some groups can be as described below, and the definitions of other groups can be as described in any other embodiment (hereinafter referred to as "a preferred embodiment"): in R, the C1-C6 alkylene is a C2-C4 alkylene, preferably a straight-chain alkylene, for example

[0019] In a preferred embodiment, R 3 In the above, the C1-C6 alkylene group is a C2-C4 alkylene group, preferably a straight chain alkylene group, for example

[0020] In a preferred embodiment, R1 In the above, the C1-C4 alkyl group is a methyl group.

[0021] In a preferred embodiment, R 2 In the above, the C1-C4 alkyl group is a methyl group.

[0022] In a preferred embodiment, in X, Y, Z and W, the C1-C2 alkylene group is a methylene group or an ethylene group.

[0023] In a preferred embodiment, among A, B, C and D, C1-C 20 The alkyl group is C4-C 20 Alkyl, preferably straight chain alkyl, such as

[0024] In a preferred embodiment, R is C3-C6 alkylene, Best

[0025] In a preferred embodiment, R is Best

[0026] More preferred

[0027] In a preferred embodiment, R 2 is hydrogen or methyl; preferably hydrogen.

[0028] In a preferred embodiment, R is C3-C6 alkylene, R 2 is hydrogen; or R is C2-C6 alkylene, R 2 It is a C1-C4 alkyl group.

[0029] In a preferred embodiment, R is R 2 is hydrogen; or, R is R 2 It is a C1-C4 alkyl group.

[0030] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, X, Y and Z are the same.

[0031] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, Y and Z are the same, and X is different from Y and Z.

[0032] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, X and Y are the same, and Z is different from X and Y.

[0033] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, T, M and Q are the same.

[0034] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, M and Q are the same, and T is different from M and Q.

[0035] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, T and M are the same, and Q is different from T and M.

[0036] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, A, B and C are

[0037] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, A and B are the same, and C is different from A and B.

[0038] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, B and C are the same, and A is different from B and C.

[0039] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula II, X, Y, Z and W are the same.

[0040] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula II, T, M, Q and S are the same.

[0041] In a preferred embodiment, in the nitrogen-containing chain compound shown in Formula II, A, B, C and D are the same.

[0042] In a preferred embodiment, the nitrogen-containing chain compound as shown in formula I is a nitrogen-containing chain compound as shown in formula I-1, I-2, I-3, I-4, I-5 or I-6:

[0043]

[0044] Preferably, it is a nitrogen-containing chain compound as shown in Formula I-1, I-2, I-3 or I-4; more preferably, it is a nitrogen-containing chain compound as shown in Formula I-1 or I-2; most preferably, it is a nitrogen-containing chain compound as shown in Formula I-1.

[0045] In a preferred embodiment, the nitrogen-containing chain compound as shown in formula II is a nitrogen-containing chain compound as shown in formula II-1:

[0046]

[0047] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best

[0048] R 2 is hydrogen or C1-C4 alkyl;

[0049] X, Y and Z are the same;

[0050] T, M and Q are the same;

[0051] A, B and C are the same;

[0052] X, Y and Z are independently methylene;

[0053] T, M and Q are independently

[0054] A, B and C are independently C4-C 20 alkyl.

[0055] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl;

[0056] X, Y and Z are the same;

[0057] T, M and Q are the same;

[0058] A, B and C are the same;

[0059] X, Y and Z are independently ethylene;

[0060] T, M and Q are independently The a end is connected to X, Y or Z;

[0061] A, B and C are independently C4-C 20 alkyl.

[0062] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen;

[0063] Y and Z are the same, but X is different from Y and Z;

[0064] M and Q are the same, T is different from M and Q;

[0065] A and B are the same, C is different from A and B;

[0066] Y and Z are independently methylene; X is ethylene;

[0067] M and Q are independently T is The a end is connected to X, Y or Z;

[0068] A, B and C are independently C4-C 20 alkyl.

[0069] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen;

[0070] X and Y are the same, but Z is different from X and Y;

[0071] T and M are the same, Q is different from T and M;

[0072] B and C are the same, and A is different from B and C;

[0073] X and Y are independently methylene; Z is ethylene;

[0074] T and M are independently Q is The a end is connected to X, Y or Z;

[0075] A, B and C are independently C4-C 20 alkyl.

[0076] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen;

[0077] Y and Z are the same, but X is different from Y and Z;

[0078] M and Q are the same, T is different from M and Q;

[0079] A and B are the same, C is different from A and B;

[0080] Y and Z are independently ethylene; X is methylene;

[0081] M and Q are independently The a terminal is connected to X, Y or Z; T is A, B and C are independently C4-C 20 alkyl.

[0082] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen;

[0083] X and Y are the same, but Z is different from X and Y;

[0084] T and M are the same, Q is different from T and M;

[0085] B and C are the same, and A is different from B and C;

[0086] X and Y are independently ethylene; Z is methylene;

[0087] T and M are independently The a terminal is connected to X, Y or Z; Q is A, B and C are independently C4-C 20 alkyl.

[0088] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula II, R is a C2-C6 alkylene group,

[0089]

[0090] X, Y, Z and W are the same;

[0091] T, M, Q and S are the same;

[0092] A, B, C and D are the same;

[0093] X, Y, Z and W are independently methylene;

[0094] T, M, Q and S are independently A, B, C and D are independently C4-C 20 alkyl.

[0095] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, R is

[0096] Best R 2 is hydrogen or methyl;

[0097] X, Y and Z are the same;

[0098] T, M and Q are the same;

[0099] A, B and C are the same;

[0100] X, Y and Z are independently methylene;

[0101] T, M and Q are independently

[0102] A, B and C are independently C4-C 20 alkyl.

[0103] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, R is

[0104] Best R 2 is hydrogen or methyl;

[0105] X, Y and Z are the same;

[0106] T, M and Q are the same;

[0107] A, B and C are the same;

[0108] X, Y and Z are independently ethylene;

[0109] T, M and Q are independently The a end is connected to X, Y or Z;

[0110] A, B and C are independently C4-C 20 alkyl.

[0111] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, R is

[0112] Best More preferred

[0113] R 2 is hydrogen or methyl; preferably hydrogen;

[0114] Y and Z are the same, but X is different from Y and Z;

[0115] M and Q are the same, T is different from M and Q;

[0116] A and B are the same, C is different from A and B;

[0117] Y and Z are independently methylene; X is ethylene;

[0118] M and Q are independently T is The a end is connected to X, Y or Z;

[0119] A, B and C are independently C4-C 20alkyl.

[0120] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, R is

[0121] Best More preferred

[0122] R 2 is hydrogen or methyl; preferably hydrogen;

[0123] X and Y are the same, but Z is different from X and Y;

[0124] T and M are the same, Q is different from T and M;

[0125] B and C are the same, and A is different from B and C;

[0126] X and Y are independently methylene; Z is ethylene;

[0127] T and M are independently Q is The a end is connected to X, Y or Z;

[0128] A, B and C are independently C4-C 20 alkyl.

[0129] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, R is

[0130] Best More preferred

[0131] R 2 is hydrogen or methyl; preferably hydrogen;

[0132] Y and Z are the same, but X is different from Y and Z;

[0133] M and Q are the same, T is different from M and Q;

[0134] A and B are the same, C is different from A and B;

[0135] Y and Z are independently ethylene; X is methylene;

[0136] M and Q are independently The a terminal is connected to X, Y or Z; T is A, B and C are independently C4-C 20 alkyl.

[0137] In a preferred embodiment, in the nitrogen-containing chain compound as shown in formula I, R is

[0138] Best More preferred

[0139] R 2 is hydrogen or methyl; preferably hydrogen;

[0140] X and Y are the same, but Z is different from X and Y;

[0141] T and M are the same, Q is different from T and M;

[0142] B and C are the same, and A is different from B and C;

[0143] X and Y are independently ethylene; Z is methylene;

[0144] T and M are independently The a terminal is connected to X, Y or Z; Q is

[0145] A, B and C are independently C4-C 20 alkyl.

[0146] In a preferred embodiment, in the nitrogen-containing chain compound as shown in Formula II, R is

[0147] X, Y, Z and W are the same;

[0148] T, M, Q and S are the same;

[0149] A, B, C and D are the same;

[0150] X, Y, Z and W are independently methylene;

[0151] T, M, Q and S are independently

[0152] A, B, C and D are independently C4-C 20 alkyl.

[0153] In a preferred embodiment, the nitrogen-containing chain compound as shown in Formula I or II satisfies the following conditions (1), (2), (3), (4), (5) or (6), preferably satisfies the following conditions (1), (2), (3), (4) or (5), more preferably satisfies the following conditions (1), (2), (3) or (4), more preferably satisfies the following conditions (1), (2) or (3), more preferably satisfies the following conditions (1) or (2), and most preferably satisfies the following condition (1):

[0154] (1) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is hydrogen;

[0155] (2) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is hydrogen;

[0156] Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is a C1-C4 alkyl group;

[0157] Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-2, I-3 or I-4, and R is R 2 is hydrogen;

[0158] (3) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-3 or I-4, and R is R 2 is hydrogen or C1-C4 alkyl;

[0159] Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-5 or I-6, and R is R 2 is hydrogen;

[0160] (4) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is a C1-C4 alkyl group;

[0161] Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-5 or I-6, and R is R 2 is hydrogen or C1-C4 alkyl;

[0162] Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula II-1, and R is

[0163] (5) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-2, and R is R 2 is hydrogen;

[0164] Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-2, and R is R 2 is a C1-C4 alkyl group;

[0165] (6) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula II-1, and R is .

[0166] In a preferred embodiment, the nitrogen-containing chain compound as shown in Formula I or II is a nitrogen-containing chain compound as shown in Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13:

[0167]

[0168]

[0169] Wherein G and E are each independently C6-C 20 Straight chain alkyl.

[0170] In a preferred embodiment, the nitrogen-containing chain compound as shown in Formula I or II is any of the following compounds:

[0171]

[0172] ,

[0173]

[0174] ,

[0175]

[0176] ,

[0177]

[0178]

[0179] ,

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187] 、

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] 、

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205] 、

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] 、

[0214]

[0215]

[0216]

[0217] 、

[0218]

[0219]

[0220]

[0221]

[0222] 、

[0223]

[0224]

[0225]

[0226]

[0227] 、

[0228]

[0229]

[0230]

[0231]

[0232]

[0233] or

[0234]

[0235] Among them, A1 represents The structure of the fragment is A2 means The structure of the fragment is A3 means The structure of the fragment is A5 means The structure of the fragment is A6 means The structure of the fragment is A7 indicates The structure of the fragment is A14 indicates The structure of the fragment is A20 means The structure of the fragment is A30 means The structure of the fragment is

[0236] C6 represents C6 straight chain alkyl; C8 represents C8 straight chain alkyl; 10 Represents C 10 Straight chain alkyl; C 12 Represents C 12 Straight chain alkyl; C 14 Represents C 14 Straight chain alkyl; C 16 Represents C 16 Straight chain alkyl; C 18 Represents C 18 Straight chain alkyl; C 20 Represents C 20 Straight chain alkyl.

[0237] In a preferred embodiment, the nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof is a nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof for preparing a delivery system, and the delivery system is a system for delivering therapeutic agents and / or preventive agents to the lungs; the therapeutic agent and / or preventive agent is one or two or more nucleic acids.

[0238] In a preferred embodiment, the delivery is lung-targeted delivery.

[0239] In a preferred embodiment, the nucleic acid may be a conventional nucleic acid in the art, such as single-stranded deoxyribonucleic acid (DNA), double-stranded DNA, small interfering RNA (siRNA), asymmetric double-stranded small interfering RNA (aiRNA), microRNA (miRNA), small hairpin RNA (shRNA), circular RNA (circRNA), transfer RNA (tRNA), messenger RNA (mRNA) and other forms of nucleic acid molecules known in the art, preferably mRNA, more preferably firefly luciferase (Fluc) mRNA.

[0240] In a preferred embodiment, the nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof is a nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof as a pharmaceutical excipient, and the functions of the pharmaceutical excipient include nucleic acid encapsulation, lung-targeted delivery, cell uptake promotion or lysosomal escape promotion.

[0241] In a preferred embodiment, the pharmaceutical excipient is a pharmaceutical excipient in a drug for treating and / or preventing a disease, and the disease is a lung-related disease.

[0242] The present invention provides a lipid carrier, which includes a substance X, wherein the substance X is the nitrogen-containing chain compound shown in Formula I or II or a pharmaceutically acceptable salt thereof.

[0243] In a preferred embodiment, the lipid carrier further comprises phospholipids.

[0244] In a preferred embodiment, the phospholipid may be a conventional phospholipid in the art, which is an amphiphilic auxiliary molecule that helps the fusion of lipid particles and cell membranes. The phospholipid may be a phospholipid molecule having an electrically charged polar end and a non-polar end of a fatty chain, such as dioleoylphosphatidylethanolamine (DOPE).

[0245] In a preferred embodiment, the lipid carrier further comprises sterol.

[0246] In a preferred embodiment, the sterol may be a conventional sterol in the art, including animal, plant or fungus sterols. The sterol is selected from one or more of cholesterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatine, ursolic acid and α-tocopherol, such as cholesterol.

[0247] In a preferred embodiment, the lipid carrier further comprises PEG lipid (lipid modified with polyethylene glycol).

[0248] In a preferred embodiment, the PEG lipid may be a lipid molecule having a polyethylene glycol-modified hydrophilic end, such as PEG-modified dimyristoylglycerol (DMG-PEG2000).

[0249] In a preferred embodiment, in the lipid carrier, the molar ratio of the substance X to the phospholipid is 2 to 10:1, preferably 2 to 8:1, for example 5:1.

[0250] In a preferred embodiment, in the lipid carrier, the molar ratio of the substance X to sterol is 1 to 4:1, preferably 1 to 2:1, for example 1.3:1.

[0251] In a preferred embodiment, in the lipid carrier, the molar ratio of the substance X to the PEG lipid is 20-40:1, preferably 25-35:1, for example 33:1.

[0252] In a preferred embodiment, the lipid carrier consists of the substance X, the phospholipid, the PEG lipid and the sterol.

[0253] In a preferred embodiment, the lipid carrier is composed of the substance X, DOPE, DMG-PEG2000 and cholesterol; the molar ratio of the substance X, DOPE, cholesterol and DMG-PEG2000 is 50:10:38.5:1.5.

[0254] In a preferred embodiment, the lipid carrier is a lipid carrier for preparing a delivery system or a drug for treating and / or preventing a disease, the disease is a lung-related disease, and the delivery system is as described above.

[0255] The present invention provides a lipid nanoparticle, which comprises a therapeutic agent and / or a preventive agent and the above-mentioned lipid carrier, wherein the therapeutic agent and / or the preventive agent is one or two or more nucleic acids.

[0256] In a preferred embodiment, the nucleic acid may be a conventional nucleic acid in the art. The therapeutic agent and / or preventive agent may be single-stranded deoxyribonucleic acid (DNA), double-stranded DNA, small interfering RNA (siRNA), asymmetric double-stranded small interfering RNA (aiRNA), microRNA (miRNA), small hairpin RNA (shRNA), circular RNA (circRNA), transfer RNA (tRNA), messenger RNA (mRNA) and one or more of other forms of nucleic acid molecules known in the art, preferably mRNA, such as firefly luciferase (Fluc) mRNA.

[0257] In a preferred embodiment, in the lipid nanoparticles, the mass ratio of the lipid carrier to the therapeutic agent and / or preventive agent is 10 to 40:1, preferably 20 to 30:1.

[0258] In a preferred embodiment, the particle size (average particle size) of the lipid nanoparticles may be 50 to 1200 nm, preferably 70 to 260 nm.

[0259] In a preferred embodiment, in the lipid nanoparticles, the lipid carrier encapsulates the therapeutic agent and / or preventive agent.

[0260] In a preferred embodiment, the lipid nanoparticles are composed of the lipid carrier and the therapeutic agent and / or preventive agent.

[0261] In a preferred embodiment, the lipid nanoparticles are composed of the substance X, the phospholipid, the PEG lipid, the sterol and the therapeutic agent and / or preventive agent.

[0262] In a preferred embodiment, the lipid nanoparticles are composed of the lipid carrier and firefly luciferase mRNA; the mass ratio of the lipid carrier to the firefly luciferase mRNA is 20:1; the lipid carrier is composed of the substance X, DOPE, DMG-PEG2000, cholesterol and firefly luciferase mRNA; the molar ratio of the substance X, DOPE, cholesterol and DMG-PEG2000 is 50:10:38.5:1.5.

[0263] In a preferred embodiment, the lipid nanoparticles are lipid nanoparticles used to prepare a delivery system or a drug for treating and / or preventing a disease, the disease is a lung-related disease, and the delivery system is as described above.

[0264] In a preferred embodiment, the polydispersity index of the lipid nanoparticles is not higher than 1.00, such as not higher than 0.8.

[0265] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0266] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0267] In the structure fragment It means that the structural fragment is connected to the rest of the molecule through this site.

[0268] A "-" at the end of a group means that the group is attached to the rest of the molecule through that site.

[0269] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C1 to C 20 , C1~C6, C6~C 20 ) is a linear or branched, saturated, monovalent hydrocarbon group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0270] The term "alkylene" is a divalent group which is attached to the rest of the molecule by two single bonds and has the same definition as the term "alkyl".

[0271] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0272] The reagents and raw materials used in the present invention are commercially available.

[0273] The positive and progressive effect of the present invention is that a series of ionizable lipids with novel structures have been found to enable the substance A mentioned above to specifically target the lungs and treat related diseases. DETAILED DESCRIPTION

[0274] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0275] The meanings of the custom symbols in Examples 1-15 are as follows

[0276] A1 means The structure of the fragment is

[0277] A2 means The structure of the fragment is

[0278] A3 means The structure of the fragment is

[0279] A5 means The structure of the fragment is

[0280] A6 means The structure of the fragment is

[0281] A7 indicates The structure of the fragment is

[0282] A14 indicates The structure of the fragment is

[0283] A20 means The structure of the fragment is

[0284] A30 means The structure of the fragment is

[0285] C4 represents a C4 straight-chain alkyl group.

[0286] C6 represents a C6 straight-chain alkyl group.

[0287] C8 represents a C8 straight-chain alkyl group.

[0288] C 10 Represents C 10 Straight chain alkyl.

[0289] C 12 Represents C 12 Straight chain alkyl.

[0290] C 14 Represents C 14 Straight chain alkyl.

[0291] C 16 Represents C 16 Straight chain alkyl.

[0292] C 18 Represents C 18 Straight chain alkyl.

[0293] C 20 Represents C 20 Straight chain alkyl.

[0294] Reaction Formula I

[0295]

[0296] The ratio of the reaction raw materials amine compound to the alkylene oxide compound is between 1:3-1:3.9, preferably 1:3.15, and the reaction temperature is 101-140 degrees, preferably 115-125 degrees, with heating and stirring.

[0297] Example 1

[0298]

[0299] The reaction was carried out according to the general reaction formula I, with N,N-bis(3-aminopropyl)methylamine (200 mg, 1.38 mmol) and 1,2-epoxytetradecane (1.04 g, 4.35 mmol) as raw materials, the reaction mixture was heated to 120 degrees, and the reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents, and the pure product was obtained after recrystallization using methanol as solvent. The product was verified by mass spectrometry. Product: 172 mg, yield 16%. 1 H NMR (500 MHz, deuterated chloroform) δ 3.70–3.55 (m, 3H), 2.87–2.55 (m, 5H), 2.54–2.24 (m, 9H), 2.20 (t, J = 2.2 Hz, 3H), 1.67 (dtt, J = 38.7, 14.1, 7.2 Hz, 4H), 1.50–1.15 (m, 90H), 0.88 (t, J = 6.9 Hz, 9H). MALDI-TOF MS m / z of [M+H] + C 49 H 104 Calculated value of N3O3: 782.80; Measured value: 782.68.

[0300] According to the general reaction formula I, referring to the method of Example 1, only the type of amine raw material and / or the type of alkylene oxide raw material (the carbon chain length of group G is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 1, and the mass spectrometry characterization data of each compound are shown in the following table:

[0301]

[0302]

[0303] Reaction formula II

[0304]

[0305] The ratio of the reaction raw materials amine compound to the alkylene oxide compound is between 1:3-1:3.9, preferably 1:3.15, and the reaction temperature is 101-140 degrees, preferably 115-125 degrees, with heating and stirring.

[0306] Example 2

[0307]

[0308] The reaction was carried out according to the general formula II, with 3-methylaminopropylamine (50 mg, 0.57 mmol) and 1,2-epoxytetradecane (382 mg, 1.8 mmol) as raw materials, the reaction mixture was heated to 120 degrees, and the reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents, and the pure product was obtained after recrystallization using methanol as solvent. The product was verified by mass spectrometry. Product: 299 mg, yield 74%. MALDI-TOF MS m / z of [M+H] + C 49 H 104 Calculated value of N3O3: 725.75; Measured value: 725.83.

[0309] According to the general reaction formula II, referring to the method of Example 2, only the type of amine raw material and / or the type of alkylene oxide raw material (the carbon chain length of group G is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 2, and the mass spectrometry characterization data of each compound are shown in the following table:

[0310]

[0311]

[0312] Reaction Formula III

[0313]

[0314] The ratio of the reaction raw materials is between 1:3-1:3.9, preferably 1:3.15, and the reaction temperature is 101-140 degrees, preferably 115-125 degrees under heating and stirring.

[0315] Example 3

[0316]

[0317] The reaction was carried out according to the general reaction formula III, with N,N-bis(3-aminopropyl)methylamine (200 mg, 1.38 mmol) and tetradecyl acrylate (1.17 g, 4.35 mmol) as raw materials. The reaction mixture was heated to 120 degrees, and the reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using petroleum ether and ethyl acetate as eluents. The product was verified by mass spectrometry. Product: 495 mg, yield 38%. MALDI-TOF MS m / z of [M+H] + C 49 H 104 Calculated value of N3O3: 950.88; Measured value: 950.33.

[0318] According to the general reaction formula III, referring to the method of Example 3, only the type of amine raw material and / or the type of acrylate raw material (the carbon chain length of the group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 3, and the mass spectrometry characterization data of each compound are shown in the following table:

[0319]

[0320]

[0321]

[0322] Reaction Formula IV

[0323]

[0324] The ratio of the reaction raw materials is between 1:3-1:3.9, preferably 1:3.15, and the reaction temperature is 101-140 degrees, preferably 115-125 degrees under heating and stirring.

[0325] Example 4

[0326] The reaction was carried out according to the general reaction formula IV, with 3-methylaminopropylamine (100 mg, 1.13 mmol) and tetradecene acrylate (956 mg, 3.56 mmol) as raw materials. The reaction mixture was heated to 120 degrees, and the reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using petroleum ether and ethyl acetate as eluents. The product was verified by mass spectrometry. Product: 323 mg, yield 32%. MALDI-TOF MS m / z of [M+H] + C 49 H 104 Calculated value of N3O3: 893.48; Measured value: 893.86.

[0327] According to the general reaction formula IV, referring to the method of Example 4, only the type of amine raw material and / or the type of acrylate raw material (the carbon chain length of the group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 4, and the mass spectrometry characterization data of each compound are shown in the following table:

[0328]

[0329]

[0330] Reaction Formula V

[0331]

[0332] The ratio of the reaction raw materials is between 1:2:1-1:2.6:1.3:, preferably 1:2.1:1.05; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction temperature is 101-140 degrees, preferably 115-125 degrees under heating and stirring.

[0333] Example 5

[0334]

[0335] The reaction was carried out according to the general reaction formula V, with 1,2-bis(2-aminoethoxy)ethane (500mg, 3.37mmol) and 1,2-epoxyoctane (907mg, 7.08mmol) as raw materials, stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, hexadecyl acrylate (1.05g, 3.54mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry and nuclear magnetic resonance spectroscopy. Product: 268mg, yield 11.3%. 1 H NMR (500 MHz, deuterated chloroform) δ4.06 (d, J = 10.9 Hz, 2H), 3.71–3.47 (m, 10H), 3.14–2.25 (m, 12H), 1.61 (p, J = 6.9 Hz, 2H), 1.51–1.13 (m, 46H), 0.88 (t, J = 6.8 Hz, 9H). MALDI-TOF MS m / z of [M+H] + C 41 H 85 Calculated value of N2O6: 701.13; measured value: 701.21.

[0336] According to the general reaction formula V, referring to the method of Example 5, only one or more of the types of amine raw materials, the types of alkylene oxide raw materials (the carbon chain length of the group G is different) and the types of acrylate raw materials (the carbon chain length of the group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 5, and the mass spectrometry characterization data of each compound are shown in the following table:

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346] Reaction formula VI:

[0347]

[0348] The ratio of the reaction raw materials is between 1:1:2-1:1.3:2.6:, preferably 1:1.05:2.1; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction temperature is 101-140 degrees, preferably 115-125 degrees under heating and stirring.

[0349] Example 6

[0350]

[0351] The reaction was carried out according to the general reaction formula VI, with 1,2-bis(2-aminoethoxy)ethane (500mg, 3.37mmol) and hexadecyl acrylate (1.05g, 3.54mmol) as raw materials, stirred at room temperature, and monitored by TLC. After the reaction was complete, 1,2-epoxyoctadecane (907mg, 7.08mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents, and the product was verified by mass spectrometry and nuclear magnetic resonance spectroscopy. Product: 77mg, yield 3.3%. 1 H NMR (500 MHz, deuterated chloroform) δ 4.06 (t, J = 6.8 Hz, 2H), 3.82-3.41 (m, 10H), 3.04-2.73 (m, 6H), 2.67-2.42 (m, 5H), 2.39-2.24 (m, 1H), 1.62 (p, J = 7.0 Hz, 2H), 1.49-1.24 (m, 46H), 0.88 (t, J = 6.8 Hz, 9H). MALDI-TOF MS m / z of [M+H] + C 41 H 85 Calculated value of N2O6: 701.13; Measured value: 701.19.

[0352] According to the general reaction formula VI, referring to the method of Example 6, only one or more of the types of amine raw materials, alkylene oxide raw materials (the carbon chain length of group G is different) and acrylate raw materials (the carbon chain length of group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 6, and the mass spectrometry characterization data of each compound are shown in the following table:

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361] Reaction Formula VII

[0362]

[0363] The ratio of the reaction raw materials is between 1:2:1-1:2.6:1.3:, preferably 1:2.1:1.05; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction temperature is 101-140 degrees, preferably 115-125 degrees under heating and stirring.

[0364] Example 7

[0365]

[0366] The reaction was carried out according to the general formula VII, with N, N-bis (3-aminopropyl) methylamine (183mg, 1.26mmol) and octadecyl acrylate (860mg, 2.65mmol) as raw materials, stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, 1, 2-epoxy dodecane (243mg, 1.32mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry. Product: 107mg, yield 8.7%. MALDI-TOF MS m / z of [M+H] + calculated for C61 H 124 Calculated value of N3O5: 978.95; Measured value: 978.41.

[0367] According to the general reaction formula VII, referring to the method of Example 7, only one or more of the types of amine raw materials, alkylene oxide raw materials (the carbon chain length of the group G is different) and acrylate raw materials (the carbon chain length of the group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 7, and the mass spectrometry characterization data of each compound are shown in the following table:

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377] Reaction Formula VIII

[0378]

[0379] The ratio of the reaction raw materials is between 1:1:2-1:1.3:2.6:, preferably 1:1.05:2.1; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction temperature is 101-140 degrees, preferably heated and stirred at 115-125 degrees.

[0380] Example 8

[0381]

[0382] The reaction was carried out according to the general formula VIII, with N-methyl-2,2'-diaminodiethylamine (250mg, 2.13mmol) and 1,2-epoxydodecane (413mg, 2.24mmol) as raw materials, stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, 1.07g of acrylate (4.47mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry. Product: 450mg, yield 25%. MALDI-TOF MS m / z of [M+H] + calculated for C 47 H 95 N3O5, calculated value: 782.73; measured value: 782.69.

[0383] According to the general reaction formula VIII, referring to the method of Example 8, only one or more of the types of amine raw materials, alkylene oxide raw materials (the carbon chain length of group G is different) and acrylate raw materials (the carbon chain length of group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 8, and the mass spectrometry characterization data of each compound are shown in the following table:

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] Reaction Formula IX

[0393]

[0394] The ratio of the reaction raw materials is between 1:1:2-1:1.5:2.5:, preferably 1:1.05:2.1; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction temperature is 101-140 degrees, preferably 115-125 degrees under heating and stirring.

[0395] Example 9

[0396]

[0397] The reaction was carried out according to the general reaction formula IX, with 3-methylaminopropylamine (357 mg, 4.05 mmol) and dodecyl acrylate (1.02 g, 4.25 mmol) as raw materials, stirred at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed, 1,2-epoxydodecane (1.56 g, 8.5 mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry. Product: 320 mg, yield 11.3%. MALDI-TOF MS m / z of [M+H] + C 43 H 89 Calculated value of N2O4: 697.68; measured value: 697.62.

[0398] According to the general reaction formula IX, referring to the method of Example 9, only one or more of the types of amine raw materials, alkylene oxide raw materials (the carbon chain length of group G is different) and acrylate raw materials (the carbon chain length of group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 9, and the mass spectrometry characterization data of each compound are shown in the following table:

[0399]

[0400]

[0401]

[0402]

[0403]

[0404] Reaction Formula X

[0405]

[0406] The ratio of the reaction raw materials is between 1:1:1:1-1:1.5:1.5:1.5, preferably 1:1.05:1.05:1.05; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction temperature is 70-100 degrees, preferably heated and stirred at 90 degrees; the third step reaction is carried out with heating and stirring at 101-140 degrees, preferably at 115-125 degrees.

[0407] Example 10

[0408]

[0409] The reaction was carried out according to the general reaction formula X, with 3-methylaminopropylamine (200 mg, 2.27 mmol) and 1,2-epoxydodecane (772 mg, 2.38 mmol) as raw materials, stirred at room temperature, and the reaction progress was monitored by TLC; after the reaction was completed, acrylate (439 mg, 2.38 mmol) was added, and the reaction temperature was raised to 90 degrees, and the reaction progress was monitored by TLC; after the reaction was complete, 1,2-epoxydodecane (772 mg, 2.38 mmol) was added and the reaction temperature was raised to 120 degrees, and the reaction was monitored by TLC until the reaction was completed. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry. Product: 220 mg, yield 12.4%. MALDI-TOF MS m / z of [M+H] + C 49 H 100 Calculated value of N2O4: 781.77; measured value: 781.67.

[0410] According to the general reaction formula X, referring to the method of Example 10, only one or more of the types of amine raw materials, alkylene oxide raw materials (the carbon chain length of group G is different) and acrylate raw materials (the carbon chain length of group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 10, and the mass spectrometry characterization data of each compound are shown in the following table:

[0411]

[0412]

[0413]

[0414]

[0415] Reaction formula XI:

[0416]

[0417] The ratio of the reaction raw materials is between 1:2:1-1:2.5:1.5:, preferably 1:2.1:1.05; the first step of the reaction is first stirred at 20-50 degrees, preferably at 37 degrees for 12 hours, then the temperature is raised to 101-140 degrees, preferably 115-125 degrees, and the reaction is continued for 2 hours; the second step of the reaction temperature is 101-140 degrees, preferably 115-125 degrees, and heated and stirred.

[0418] Embodiment 11

[0419]

[0420] The reaction was carried out according to the general reaction formula XI, with N-methylethylenediamine (190 mg, 2.56 mmol) and octadecyl acrylate (1.74 g, 5.37 mmol) as raw materials. After stirring at room temperature for 12 hours, the temperature was raised to 120 degrees and the reaction was continued for 2 hours. After the reaction was completed by TLC monitoring, 1,2-epoxydodecane (494 mg, 2.68 mmol) was added to react at 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry. Product: 199 mg, yield 8.6%. MALDI-TOF MS m / z of [M+H] + C 57 H 114 Calculated value of N2O5: 907.87; measured value: 907.82.

[0421] According to the general reaction formula XI, referring to the method of Example 11, only one or more of the types of amine raw materials, alkylene oxide raw materials (the carbon chain length of the group G is different) and acrylate raw materials (the carbon chain length of the group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 11, and the mass spectrometry characterization data of each compound are shown in the following table:

[0422]

[0423]

[0424]

[0425]

[0426]

[0427] Reaction formula XII:

[0428]

[0429] The ratio of the reaction raw materials is between 1:1:1:1-1:1.3:1.3:1.3, preferably 1:1.05:1.05:1.05; the first step reaction is carried out with stirring at 20-50 degrees, preferably at 37 degrees; the second step reaction is heated and stirred at 101-140 degrees, preferably at 115-125 degrees; the third step reaction is heated and stirred at 101-140 degrees, preferably at 115-125 degrees.

[0430] Example 12

[0431]

[0432] The reaction was carried out according to the general formula XII, with 3-methylaminopropylamine (170 mg, 2.27 mmol) and octadecyl acrylate (773 mg, 2.38 mmol) as raw materials, stirred at room temperature for 12 hours, and the reaction was monitored by TLC after completion; 1,2-epoxyhexadecane (572 mg, 2.38 mmol) was added and the temperature was raised to 120 degrees to continue the reaction for 2 hours, and the reaction was monitored by TLC after completion; after the reaction was completed, octadecyl acrylate (773 mg, 2.38 mmol) was added to react at 120 degrees, and the reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents. The product was verified by mass spectrometry. Product: 206 mg, yield 9.3%. MALDI-TOF MS m / z of [M+H] + C 57 H 114 Calculated value of N2O5: 977.95; measured value: 977.86.

[0433] According to the general reaction formula XII, referring to the method of Example 12, only one or more of the types of amine raw materials, the types of alkylene oxide raw materials (the carbon chain length of the group G is different) and the types of acrylate raw materials (the carbon chain length of the group E is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 12, and the mass spectrometry characterization data of each compound are shown in the following table:

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] Reaction formula XIII:

[0440]

[0441] The ratio of the reaction raw materials is between 1:4-1:5.2, preferably 1:4.2; the reaction is carried out with stirring at 101-140 degrees, preferably heated and stirred at 115-125 degrees.

[0442] Example 13

[0443]

[0444] The reaction was carried out according to the general reaction formula XIII, with N, N-bis (3-aminopropyl) methylamine (200 mg, 1.38 mmol) and 1, 2-epoxytetradecane (614 mg, 2.9 mmol) as raw materials, stirred at room temperature for 24 hours, and the reaction progress was monitored by TLC. After the reaction was completed, 1, 2-epoxytetradecane (614 mg, 2.9 mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents, and the pure product was obtained after recrystallization using methanol as solvent. The product was verified by mass spectrometry and nuclear magnetic resonance spectroscopy. Product: 412 mg, yield 30.9%. 1 H NMR (500 MHz, deuterated chloroform) δ 3.75–3.54 (m, 4H), 2.83–2.20 (m, 19H), 1.83–1.54 (m, 4H), 1.50–1.18 (m, 88H), 0.88 (t, J = 6.9 Hz, 12H). MALDI-TOF MS m / z of [M+H] + C 63 H 132 Calculated value of N3O4: 995.017; Measured value: 995.193.

[0445] According to the general reaction formula XIII, referring to the method of Example 13, only the type of amine raw material and / or the type of alkylene oxide raw material (the carbon chain length of group G is different) in the reaction raw materials are changed to synthesize, and the obtained product structure is shown in Formula 13, and the mass spectrometry characterization data of each compound are shown in the following table:

[0446]

[0447]

[0448]

[0449] Embodiment 14

[0450]

[0451] The reaction was carried out according to the general formula XIII, with 1,4-bis(3-aminopropyl)piperazine (200 mg, 1 mmol) and 1,2-epoxytetradecane (424 mg, 2 mmol) as raw materials. After stirring at room temperature for 24 hours, the reaction progress was monitored by TLC. After the reaction was completed, 1,2-epoxytetradecane (424 mg, 2 mmol) was added and the temperature was raised to 120 degrees. The reaction progress was monitored by TLC until the reaction was complete. The crude product was separated by column chromatography using ethyl acetate, dichloromethane and methanol as eluents, and the pure product was obtained after recrystallization using methanol as solvent. The product was verified by mass spectrometry and nuclear magnetic resonance spectroscopy. Product: 367 mg, yield 34.9%. 1 H NMR (500 MHz, deuterated chloroform) δ 3.72–3.56 (m, 4H), 2.99–2.10 (m, 24H), 1.79–1.54 (m, 4H), 1.50–1.05 (m, 88H), 0.88 (t, J = 6.9 Hz, 12H). MALDI-TOF MS m / z of [M+H] + C 66 H 137 N4O4 calculated value: 1050.066; found value: 1050.060. The product is recorded as A3-4O14, where the group is defined as A30 and G is C 12 .

[0452] Effect Example 1

[0453] Preparation and detection of nanolipid particles (LNP preparations). The ionizable lipid compounds of Examples 1 to 4 were dissolved in ethanol with DOPE, cholesterol and DMG-PEG2000 at a molar ratio of 50:10:38.5:1.5 to prepare an ethanol lipid solution, and the luciferase RNA was dissolved in 10mM sodium citrate buffer solution (PH=3) and diluted to obtain an mRNA aqueous solution. The weight ratio of total lipid to mRNA was 20:1. The ethanol phase was manually and quickly injected into the aqueous phase at a volume ratio of 1:3, and then it was placed in cold PBS for dialysis for 2h.

[0454] The size and polydispersity index of lipid nanoparticles were determined by dynamic light scattering using Malvern Zetasizer Nano Zs. The test results are shown in the table below. The particle size (average particle size) of lipid nanoparticles is 50-1100nm, and most of them are 70-200nm. PDI is 0.1-0.8, and most of them are 0.1-0.3. Zeta potential in ddH2O is -10-25, and most of them are 2-22. Zeta potential in pbs is -16-5, and most of them are -6-5.

[0455]

[0456]

[0457]

[0458] Effect Example 2

[0459] The lipid nanoparticles prepared in Example 1 were systemically administered to 6-8 week old male ICR mice at a dose of 0.2 mg / kg by tail vein injection (Xipuer-BikaiShanghai), and an appropriate amount of 15 mg / mL luciferin potassium sodium solution was intraperitoneally injected into the mice 6 hours after administration. The mice were anesthetized and dislocated within 10 minutes to obtain the main organs of the mice for imaging in a living imager. The results of the luciferase expression test are shown in the following table. The higher the relative expression value of luciferase in the lung / liver, the better the lung specificity, ranging from 0 to 166, and the relative expression values ​​of most compounds were between 6 and 160:

[0460]

[0461]

[0462] Effect Example 3

[0463] Preparation and detection of nanolipid particles (LNP preparations). The ionizable lipid compounds of Examples 5 to 12 were dissolved in ethanol with DOPE, cholesterol and DMG-PEG2000 at a molar ratio of 50:10:38.5:1.5 to prepare an ethanol lipid solution, and the luciferase RNA was dissolved in 10mM sodium citrate buffer solution (PH=3) and diluted to obtain an mRNA aqueous solution. The weight ratio of total lipid to mRNA was 20:1. The ethanol phase was manually and quickly injected into the aqueous phase at a volume ratio of 1:3, and then it was placed in cold PBS for dialysis for 2h.

[0464] The size and polydispersity index of lipid nanoparticles were determined by dynamic light scattering using Malvern Zetasizer Nano Zs. The test results are shown in the table below. The particle size (average particle size) of lipid nanoparticles is 50-500nm, and most are 70-260nm. PDI is 0-0.7, and most are 0-0.4. The Zeta potential in ddH2O is -16-16, and most are 3-16. The Zeta potential in pbs is -9-5, and most are -3-4:

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499] Effect Example 4

[0500] The lipid nanoparticles prepared in Example 3 were systemically administered to 6-8 week old male ICR mice via tail vein injection (Xipuer-BikaiShanghai) at a dose of 0.2 mg / kg, and an appropriate amount of 15 mg / mL luciferin potassium sodium solution was intraperitoneally injected into the mice 6 hours after administration. The main organs of the mice were removed by anesthesia and disarticulation within 10 minutes and imaged in a living imager. The results of the luciferase expression test are shown in the following table. The higher the relative expression value of luciferase in the lung / liver, the better the lung specificity, ranging from 0 to 166, and most of them were 5 to 160:

[0501]

[0502]

[0503]

[0504] Effect Example 5

[0505] Preparation and detection of nanolipid particles (LNP preparations). The ionizable lipid compound of Example 13 was dissolved in ethanol with DOPE, cholesterol and DMG-PEG2000 at a molar ratio of 50:10:38.5:1.5 to prepare an ethanol lipid solution, and the luciferase RNA was dissolved in 10mM sodium citrate buffer solution (PH=3) and diluted to obtain an mRNA aqueous solution. The weight ratio of total lipid to mRNA was 20:1. The ethanol phase was manually and quickly injected into the aqueous phase at a volume ratio of 1:3, and then it was placed in cold PBS for dialysis for 2h.

[0506] The size and polydispersity index of lipid nanoparticles were determined by dynamic light scattering using Malvern Zetasizer Nano Zs. The test results are shown in the table below. The particle size (average particle size) of lipid nanoparticles can be 100-350nm, and most are 70-200nm. PDI is 0.1-0.6, and most are 0.1-0.3. The Zeta potential in ddH2O is -10-25, and most are 2-22. The Zeta potential in pbs is -16-5, and most are -6-5.

[0507]

[0508] Effect Example 6

[0509] The lipid nanoparticles prepared in Example 5 were systemically administered to 6-8 week old male ICR mice by tail vein injection (Xipuer-BikaiShanghai) at a dose of 0.2 mg / kg, and an appropriate amount of 15 mg / mL luciferin potassium sodium solution was intraperitoneally injected into the mice 6 hours after administration. The main organs of the mice were anesthetized and dislocated within 10 minutes and imaged in a living imager. The results of the luciferase expression test are shown in the following table. The higher the relative expression value of luciferase in the lung / liver, the better the lung specificity, ranging from 0 to 171, and most of them were 5 to 170.

[0510]

Claims

1. A nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof; in, R is C1-C6 alkylene, R 1 is hydrogen or C1-C4 alkyl; R 3 is C1-C6 alkylene; R 2 is hydrogen or C1-C4 alkyl; X, Y, Z and W are independently C1-C2 alkylene; T, M, Q and S are independently The a end is connected to X, Y, Z or W; A, B, C and D are independently C1-C 20 alkyl; In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When is hydrogen, R is In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When it is C1-C4 alkyl, R is In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When is hydrogen, R is In the nitrogen-containing chain compound shown in Formula I, when T, M and Q are the same and are R 2 When it is C1-C4 alkyl, R is In the nitrogen-containing chain compound shown in Formula II, when T, M, Q and S are the same and are When R is 2. The nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) In R, the C1-C6 alkylene group is a C2-C4 alkylene group, preferably a straight chain alkylene group, for example (2)R 3 In the above, the C1-C6 alkylene group is a C2-C4 alkylene group, preferably a straight chain alkylene group, for example (3)R 1 wherein the C1-C4 alkyl group is a methyl group; (4)R 2 wherein the C1-C4 alkyl group is a methyl group; (5) In X, Y, Z and W, the C1-C2 alkylene group is methylene or ethylene; (6) Among A, B, C and D, C1-C 20 The alkyl group is C4-C 20 Alkyl, preferably straight chain alkyl, such as 3. The nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) R is a C3-C6 alkylene group, Best (2)R 2 is hydrogen or methyl; preferably hydrogen; (3) In the nitrogen-containing chain compound as shown in Formula I, X, Y and Z are the same; (4) In the nitrogen-containing chain compound as shown in Formula I, T, M and Q are the same; (5) In the nitrogen-containing chain compound as shown in Formula I, A, B and C are the same; (6) In the nitrogen-containing chain compound of formula II, X, Y, Z and W are the same; (7) In the nitrogen-containing chain compound of formula II, T, M, Q and S are the same; (8) In the nitrogen-containing chain compound represented by formula II, A, B, C and D are the same.

4. The nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) R is Best More preferred (2) In the nitrogen-containing chain compound as shown in Formula I, Y and Z are the same, and X is different from Y and Z; (3) In the nitrogen-containing chain compound as shown in Formula I, M and Q are the same, and T is different from M and Q; (4) In the nitrogen-containing chain compound as shown in Formula I, A and B are the same, and C is different from A and B.

5. The nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) R is a C3-C6 alkylene group, R 2 is hydrogen; or R is C2-C6 alkylene, R 2 is a C1-C4 alkyl group; (2) In the nitrogen-containing chain compound as shown in Formula I, X and Y are the same, and Z is different from X and Y; (3) In the nitrogen-containing chain compound as shown in Formula I, T and M are the same, and Q is different from T and M; (4) In the nitrogen-containing chain compound as shown in Formula I, B and C are the same, and A is different from B and C.

6. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) The nitrogen-containing chain compound as shown in formula I is a nitrogen-containing chain compound as shown in formula I-1, I-2, I-3, I-4, I-5 or I-6: Preferably, it is a nitrogen-containing chain compound as shown in Formula I-1, I-2, I-3 or I-4; more preferably, it is a nitrogen-containing chain compound as shown in Formula I-1 or I-2; most preferably, it is a nitrogen-containing chain compound as shown in Formula I-1; (2) The nitrogen-containing chain compound as shown in formula II is a nitrogen-containing chain compound as shown in formula II-1:

7. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) In the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; X, Y and Z are the same; T, M and Q are the same; A, B and C are the same; X, Y and Z are independently methylene; T, M and Q are independently A, B and C are independently C4-C 20 alkyl; (2) In the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; X, Y and Z are the same; T, M and Q are the same; A, B and C are the same; X, Y and Z are independently ethylene; T, M and Q are independently The a end is connected to X, Y or Z; A, B and C are independently C4-C 20 alkyl; (3) In the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen; Y and Z are the same, but X is different from Y and Z; M and Q are the same, T is different from M and Q; A and B are the same, C is different from A and B; Y and Z are independently methylene; X is ethylene; M and Q are independently T is The a end is connected to X, Y or Z; A, B and C are independently C4-C 20 alkyl; (4) In the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen; X and Y are the same, but Z is different from X and Y; T and M are the same, Q is different from T and M; B and C are the same, and A is different from B and C; X and Y are independently methylene; Z is ethylene; T and M are independently Q is The a end is connected to X, Y or Z; A, B and C are independently C4-C 20 alkyl; (5) In the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen; Y and Z are the same, but X is different from Y and Z; M and Q are the same, T is different from M and Q; A and B are the same, C is different from A and B; Y and Z are independently ethylene; X is methylene; M and Q are independently The a terminal is connected to X, Y or Z; T is A, B and C are independently C4-C 20 alkyl; (6) In the nitrogen-containing chain compound as shown in Formula I, R is a C2-C6 alkylene group, Best R 2 is hydrogen or C1-C4 alkyl; preferably hydrogen; X and Y are the same, but Z is different from X and Y; T and M are the same, Q is different from T and M; B and C are the same, and A is different from B and C; X and Y are independently ethylene; Z is methylene; T and M are independently The a terminal is connected to X, Y or Z; Q is A, B and C are independently C4-C 20 alkyl; (7) In the nitrogen-containing chain compound as shown in formula II, R is a C2-C6 alkylene group, X, Y, Z and W are the same; T, M, Q and S are the same; A, B, C and D are the same; X, Y, Z and W are independently methylene; T, M, Q and S are independently A, B, C and D are independently C4-C 20 alkyl.

8. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies at least one of the following conditions: (1) In the nitrogen-containing chain compound as shown in formula I, R is Best R 2 is hydrogen or methyl; X, Y and Z are the same; T, M and Q are the same; A, B and C are the same; X, Y and Z are independently methylene; T, M and Q are independently A, B and C are independently C4-C 20 alkyl; (2) In the nitrogen-containing chain compound as shown in formula I, Best R 2 is hydrogen or methyl; X, Y and Z are the same; T, M and Q are the same; A, B and C are the same; X, Y and Z are independently ethylene; T, M and Q are independently The a end is connected to X, Y or Z; A, B and C are independently C4-C 20 alkyl; (3) In the nitrogen-containing chain compound as shown in formula I, R is Best More preferred R 2 is hydrogen or methyl; preferably hydrogen; Y and Z are the same, but X is different from Y and Z; M and Q are the same, T is different from M and Q; A and B are the same, C is different from A and B; Y and Z are independently methylene; X is ethylene; M and Q are independently T is The a end is connected to X, Y or Z; A, B and C are independently C4-C 20 alkyl; (4) In the nitrogen-containing chain compound as shown in Formula I, R is Best More preferred R 2 is hydrogen or methyl; preferably hydrogen; X and Y are the same, but Z is different from X and Y; T and M are the same, Q is different from T and M; B and C are the same, and A is different from B and C; X and Y are independently methylene; Z is ethylene; T and M are independently Q is The a end is connected to X, Y or Z; A, B and C are independently C4-C 20 alkyl; (5) In the nitrogen-containing chain compound as shown in Formula I, R is Best More preferred R 2 is hydrogen or methyl; preferably hydrogen; Y and Z are the same, but X is different from Y and Z; M and Q are the same, T is different from M and Q; A and B are the same, C is different from A and B; Y and Z are independently ethylene; X is methylene; M and Q are independently The a terminal is connected to X, Y or Z; T is A, B and C are independently C4-C 20 alkyl; (6) In the nitrogen-containing chain compound as shown in formula I, R is Best More preferred R 2 is hydrogen or methyl; preferably hydrogen; X and Y are the same, but Z is different from X and Y; T and M are the same, Q is different from T and M; B and C are the same, and A is different from B and C; X and Y are independently ethylene; Z is methylene; T and M are independently The a terminal is connected to X, Y or Z; Q is A, B and C are independently C4-C 20 alkyl; (7) In the nitrogen-containing chain compound as shown in formula II, R is X, Y, Z and W are the same; T, M, Q and S are the same; A, B, C and D are the same; X, Y, Z and W are independently methylene; T, M, Q and S are independently A, B, C and D are independently C4-C 20 alkyl.

9. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II satisfies the following conditions (1), (2), (3), (4), (5) or (6), preferably satisfies the following conditions (1), (2), (3), (4) or (5), more preferably satisfies the following conditions (1), (2), (3) or (4), more preferably satisfies the following conditions (1), (2) or (3), more preferably satisfies the following conditions (1) or (2), and most preferably satisfies the following condition (1): (1) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is hydrogen; (2) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is hydrogen; Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is or C1-C4 alkyl; Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-2, I-3 or I-4, and R is R 2 is hydrogen; (3) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-3 or I-4, and R is R 2 is hydrogen or C1-C4 alkyl; Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-5 or I-6, and R is R 2 is hydrogen; (4) The nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-1, and R is R 2 is a C1-C4 alkyl group; Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-5 or I-6, and R is R 2 is hydrogen or C1-C4 alkyl; Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula II-1, and R is (5) The nitrogen-containing chain compound as shown in Formula I or II is a nitrogen-containing chain compound as shown in Formula I-2, and R is R 2 is hydrogen; Or, the nitrogen-containing chain compound as shown in formula I or II is a nitrogen-containing chain compound as shown in formula I-2, and R is R 2 is a C1-C4 alkyl group; (6) The nitrogen-containing chain compound represented by formula I or II is a nitrogen-containing chain compound represented by formula II-1, wherein R is 10. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II is a nitrogen-containing chain compound as shown in Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13: Wherein G and E are each independently C6-C 20 Straight chain alkyl.

11. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II is any of the following compounds: Among them, A1 represents The structure of the fragment is A2 means The structure of the fragment is A3 means The structure of the fragment is A5 means The structure of the fragment is A6 means The structure of the fragment is A7 indicates The structure of the fragment is A14 indicates The structure of the fragment is A20 means The structure of the fragment is A30 means The structure of the fragment is C6 represents C6 straight chain alkyl; C8 represents C8 straight chain alkyl; 10 Represents C 10 Straight chain alkyl; C 12 Represents C 12 Straight chain alkyl; C 14 Represents C 14 Straight chain alkyl; C 16 Represents C 16 Straight chain alkyl; C 18 Represents C 18 Straight chain alkyl; C 20 Represents C 20 Straight chain alkyl.

12. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof is a nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof for preparing a delivery system, wherein the delivery system is a system for delivering a therapeutic agent and / or a preventive agent to the lung; the therapeutic agent and / or the preventive agent is one or two or more nucleic acids; The delivery is preferably lung-targeted delivery; The therapeutic agent and / or preventive agent is preferably one or more of single-stranded DNA, double-stranded DNA, siRNA, aiRNA, miRNA, shRNA, circRNA, tRNA and mRNA, preferably mRNA, such as FlucmRNA.

13. The nitrogen-containing chain compound of formula I or II or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof is a nitrogen-containing chain compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof as a pharmaceutical excipient, and the functions of the pharmaceutical excipient include nucleic acid encapsulation, lung-targeted delivery, cell uptake promotion or lysosomal escape promotion; The pharmaceutical excipient is preferably a pharmaceutical excipient in a drug for treating and / or preventing a disease, and the disease is a lung-related disease.

14. A lipid carrier comprising a substance X, wherein the substance X is a nitrogen-containing chain compound as shown in formula I or II according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. The lipid carrier according to claim 14, characterized in that It meets at least one of the following conditions: (1) The lipid carrier further comprises a phospholipid; the phospholipid is preferably a phospholipid molecule having an electric polar end and a non-polar end of a fatty chain, such as dioleoylphosphatidylethanolamine; (2) The lipid carrier further comprises a sterol; the sterol comprises an animal, plant or fungal sterol; the sterol is preferably selected from one or more of cholesterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatine, ursolic acid and α-tocopherol, such as cholesterol; (3) The lipid carrier further comprises PEG lipid; the PEG lipid is preferably a lipid molecule modified with a polyethylene glycol hydrophilic end, such as DMG-PEG2000.

16. The lipid carrier according to claim 14, characterized in that The lipid carrier satisfies at least one of the following conditions: (1) In the lipid carrier, the molar ratio of the substance X to the phospholipid is 2 to 10:1, preferably 2 to 8:1, for example 5:1; (2) In the lipid carrier, the molar ratio of the substance X to the sterol is 1 to 4:1, preferably 1 to 2:1, for example 1.3:1; (3) In the lipid carrier, the molar ratio of the substance X to the PEG lipid is 20-40:1, preferably 25-35:1, for example 33:

1.

17. The lipid carrier according to claim 14, wherein The lipid carrier is composed of the substance X, the phospholipid, the PEG lipid and the sterol; Preferably, the lipid carrier consists of the substance X, DOPE, DMG-PEG2000 and cholesterol; the molar ratio of the substance X, DOPE, cholesterol and DMG-PEG2000 is 50:10:38.5:1.

5.

18. The lipid carrier according to claim 14, wherein The lipid carrier is a lipid carrier for preparing a delivery system or a drug for treating and / or preventing a disease, wherein the disease is a lung-related disease, and the delivery system is as described in claim 12.

19. A lipid nanoparticle comprising a therapeutic agent and / or a preventive agent and a lipid carrier according to any one of claims 14 to 18, wherein the therapeutic agent and / or the preventive agent is one or two or more nucleic acids.

20. The lipid nanoparticle of claim 19, wherein The lipid nanoparticles satisfy at least one of the following conditions: The therapeutic agent and / or preventive agent is one or more of single-stranded DNA, double-stranded DNA, siRNA, aiRNA, miRNA, shRNA, circRNA, tRNA and mRNA, preferably mRNA, such as FlucmRNA; In the lipid nanoparticles, the mass ratio of the lipid carrier to the therapeutic agent and / or preventive agent is 10 to 40:1, preferably 20 to 30:1; The particle size of the lipid nanoparticles is 50 to 1200 nm, preferably 70 to 260 nm; In the lipid nanoparticles, the lipid carrier encapsulates the therapeutic agent and / or preventive agent.

21. The lipid nanoparticle of claim 19, wherein The lipid nanoparticles are composed of the lipid carrier and the therapeutic agent and / or preventive agent; Preferably, the lipid nanoparticles consist of the substance X, the phospholipid, the PEG lipid, the sterol and the therapeutic agent and / or preventive agent; More preferably, the lipid nanoparticles are composed of the lipid carrier and firefly luciferase mRNA; the mass ratio of the lipid carrier to the firefly luciferase mRNA is 20:1; the lipid carrier is composed of the substance X, DOPE, DMG-PEG2000, cholesterol and firefly luciferase mRNA; the molar ratio of the substance X, DOPE, cholesterol and DMG-PEG2000 is 50:10:38.5:1.

5.

22. The lipid nanoparticle of claim 19, wherein The lipid nanoparticles are lipid nanoparticles used to prepare a delivery system or to prepare a drug for treating and / or preventing a disease, wherein the disease is a lung-related disease, and the delivery system is as described in claim 11.

23. The lipid nanoparticle of claim 19, wherein The polydispersity index of the lipid nanoparticles is no higher than 1.00, such as no higher than 0.8.

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