WO2023179497A1 - Composé lipidique, support lipidique à base de composé lipidique, composition de nanoparticules lipidiques d'acide nucléique et formulation pharmaceutique - Google Patents

Composé lipidique, support lipidique à base de composé lipidique, composition de nanoparticules lipidiques d'acide nucléique et formulation pharmaceutique Download PDF

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WO2023179497A1
WO2023179497A1 PCT/CN2023/082278 CN2023082278W WO2023179497A1 WO 2023179497 A1 WO2023179497 A1 WO 2023179497A1 CN 2023082278 W CN2023082278 W CN 2023082278W WO 2023179497 A1 WO2023179497 A1 WO 2023179497A1
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alkyl
independently
group
heteroalkyl
lipid
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PCT/CN2023/082278
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Chinese (zh)
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黄珂
葛滨溪
高银佳
张楠
董兆芳
孙振华
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苏州科锐迈德生物医药科技有限公司
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Publication of WO2023179497A1 publication Critical patent/WO2023179497A1/fr

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    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
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    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
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    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
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    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Definitions

  • This invention requires an invention patent application submitted in China on March 21, 2022, titled "A lipid compound and a lipid carrier based on it, a nucleic acid lipid nanoparticle composition and a pharmaceutical preparation", with the application number 202210280492.9 priority, the entire contents of this patent application are incorporated herein by reference.
  • the invention belongs to the field of gene drug delivery, and specifically relates to a lipid compound and a lipid carrier based thereon, a nucleic acid lipid nanoparticle composition and a pharmaceutical preparation.
  • nucleic acid drugs can be used to prevent cancer, bacterial and viral infections, and treat diseases with genetic causes. Since nucleic acid drugs are easy to degrade and difficult to enter cells, they need to be encapsulated and delivered to target cells with the help of carriers. Therefore, the development of safe and efficient delivery carriers has become a prerequisite for the clinical application of gene therapy.
  • Lipid nanoparticles are currently a research hotspot in the field of non-viral gene vectors.
  • LNP is usually composed of four lipid compounds, namely cationic lipids, neutral lipids, sterols and amphipathic lipids. Among them, cationic lipids have the greatest impact on the performance of LNP, such as affecting the encapsulation rate of nucleic acid drugs, nucleic acid Drug delivery efficiency or cytotoxicity in the body, etc.
  • the present invention aims to provide a series of compounds that can be used to prepare lipid carriers alone or together with other lipid compounds to improve the delivery efficiency of nucleic acid drugs in the body and deliver nucleic acid drugs to organs that need to be enriched.
  • the present invention also provides lipid carriers comprising the above compounds.
  • the present invention also provides a nucleic acid lipid nanoparticle composition comprising the above compound or the above lipid carrier.
  • the present invention also provides pharmaceutical preparations comprising the above compound, or the above lipid carrier, or the above nucleic acid lipid nanoparticle composition.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrugs,
  • Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aromatic
  • the radical and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
  • Ra and Ra' are independently or,
  • Ra and Ra’ are connected to each other to form Z;
  • Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
  • Each R 1 is independently C 1- C 24 alkyl or C 2- C 24 alkenyl
  • Each R 2 is independently hydrogen or C 1- C 24 alkyl
  • Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
  • Each m is independently 0 or 1;
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof Examples of specific compounds.
  • the present invention provides a lipid carrier, which contains the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, and non-covalent complex. or prodrugs.
  • the present invention provides a nucleic acid lipid nanoparticle composition, which contains the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non- Covalent complexes or prodrugs, or lipid carriers as described above, as well as nucleic acid drugs.
  • the present invention provides a pharmaceutical preparation comprising the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or Prodrugs, or the above-mentioned lipid carrier, or the above-mentioned nucleic acid lipid nanoparticle composition, and pharmaceutically acceptable excipients, carriers and diluents.
  • the invention provides a series of compounds of formula (I) with novel structures.
  • the lipid carrier can be prepared alone or together with other lipid compounds.
  • the particle size is controllable, the distribution is uniform, and it has Monodisperse, with high encapsulation efficiency for negatively charged drugs.
  • it has a tertiary amine structure, it can exhibit different potentials at different pHs, and exhibit positive electricity when loading negatively charged drugs under acidic conditions, so that positively charged lipid carriers and negatively charged drugs attract each other; it can also be used It exhibits electroneutrality or electronegativity under neutral conditions in the body to avoid huge cellular toxicity.
  • Containing multiple degradable functional groups allows lipids to help release more nucleic acids in the body and achieve better expression effects; containing multiple degradable functional groups allows lipid metabolism to be faster.
  • the lipid carrier can also deliver nucleic acid drugs to organs that require enrichment.
  • the compound has a simple synthesis route, cheap and easily available raw materials, and has high market potential.
  • Figure 1 is an imaging diagram of mice injected intramuscularly with LNP@mRNA prepared from Compound 1 of the present invention.
  • Figure 2 is an anatomical imaging diagram of mice injected intramuscularly with LNP@mRNA prepared from Compound 1 of the present invention.
  • Figure 3 is an imaging diagram of mice injected intravenously with LNP@mRNA prepared from Compound 8 of the present invention.
  • Figure 4 is an anatomical imaging diagram of mice injected intravenously with LNP@mRNA prepared from Compound 8 of the present invention.
  • Figure 5 is an imaging diagram of mice injected intravenously with LNP@mRNA prepared from compound 58 of the present invention.
  • Figure 6 is an anatomical imaging diagram of mice injected intravenously with LNP@mRNA prepared from compound 58 of the present invention.
  • Figure 7 shows the metabolism of LNP@mRNA prepared from Compound 1 of the present invention and Dlin-MC3-DMA in mouse liver.
  • Figure 8 shows the metabolism of LNP@mRNA prepared from Compound 1 of the present invention and Dlin-MC3-DMA in mouse spleen.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention that is substantially non-toxic to organisms.
  • Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases. Such salts are also known as acid addition salts or Base addition salt.
  • Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • Common organic acids include (but are not limited to) trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, and tartaric acid.
  • Common inorganic bases include (but are not limited to) sodium hydroxide, potassium hydroxide, calcium hydroxide , barium hydroxide, etc.
  • Common organic bases include (but are not limited to) diethylamine, triethylamine, ethambutol, etc.
  • stereoisomer refers to having a vertical asymmetric plane due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), A stable isomer capable of rotating plane-polarized light. Since there are asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomerism, the present invention also includes these stereoisomers and their mixtures. Since the compounds of the present invention and their salts include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomeric and diastereomeric mixtures. Generally, these compounds can be prepared in the form of racemic mixtures.
  • stereoisomers that is, single enantiomers or diastereomers, or single stereoisomer enrichment (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%) mixtures.
  • Single stereoisomers of a compound are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing mixtures of enantiomeric products followed by isolation or resolution, e.g.
  • tautomers refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization chemical, amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • solvate refers to a substance formed by the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates, ethanolates, acetones, etc.
  • chelate refers to a complex with a cyclic structure obtained by the chelation of two or more ligands with the same metal ion to form a chelate ring.
  • non-covalent complex is formed by the interaction of a compound with another molecule without forming a covalent bond between the compound and the molecule. For example, recombination can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • prodrug refers to a derivative compound capable of providing, directly or indirectly, a compound of the invention when administered to a patient.
  • Particularly preferred derivative compounds or prodrugs are compounds that increase the bioavailability of the compounds of the invention when administered to a patient (e.g., compounds that are more readily absorbed into the bloodstream), or that enhance the delivery of the parent compound to the site of action (e.g., the lymphatic system).
  • all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.
  • each independently means that at least two groups (or ring systems) present in the structure with the same or similar value ranges can have the same or different meanings under specific circumstances.
  • the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.
  • the substituent Y can be either hydrogen, halogen, or hydroxyl, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
  • alkyl refers to a monovalent straight or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing no unsaturation, and connected to other moieties by a single bond, including (but Not limited to) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, etc.
  • C 1 -C 24 alkyl refers to an alkyl group containing 1 to 24 carbon atoms.
  • branched C 10 -C 15 alkyl refers to branched alkyl groups containing 10 to 15 carbon atoms, including (but not limited to) 1-butylhept-1-yl and 2-butyloctyl. -1-base etc.
  • alkylene refers to a divalent straight-chain or branched aliphatic group, which consists only of carbon atoms and hydrogen atoms, does not contain saturation, and is connected to other fragments through two single bonds, including (But not limited to) methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, etc.
  • C 1 -C 24 alkylene refers to an alkylene group containing 1 to 24 carbon atoms.
  • alkenyl refers to a monovalent linear or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, and connected to other moieties by a single bond, including (but Not limited to) vinyl, propenyl, allyl and other groups.
  • C 2 -C 24 alkenyl refers to an alkenyl group containing 2 to 24 carbon atoms.
  • alkenylene refers to a divalent straight-chain or branched aliphatic group, which consists only of carbon atoms and hydrogen atoms, contains at least one double bond, and is connected to other segments through two single bonds, including but not limited to) wait.
  • C 2 -C 24 alkenylene refers to an alkenylene group containing 2 to 24 carbon atoms.
  • alkynyl refers to a monovalent linear or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond, and connected to other moieties by a single bond, including (but Without limitation) groups such as ethynyl, propynyl, propargyl and 4-pentyn-1-yl.
  • C 2 -C 24 alkynyl refers to an alkynyl group containing 2 to 24 carbon atoms.
  • cycloalkyl refers to a monovalent monocyclic or polycyclic (such as fused, bridged or spirocyclic) aliphatic group consisting only of carbon atoms and hydrogen atoms and bonded to other atoms through a single bond. Fragment linkages include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 3 -C 24 alkyl refers to a cycloalkyl group containing 3 to 24 ring atoms.
  • heterocycloalkyl refers to a heterocycloalkyl group containing 3 to 24 ring atoms (or heteroatom groups).
  • aryl refers to a monovalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group consisting only of carbon atoms and hydrogen atoms and connected to other moieties by a single bond , including (but not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.
  • C 6 -C 10 aryl refers to an aryl group containing 6 to 10 ring atoms.
  • arylene refers to a divalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group, which consists only of carbon atoms and hydrogen atoms, and is bonded to other atoms through two single bonds. Fragment connection includes (but is not limited to) 1,4-phenylene, 1,4-naphthylene, 9,10-anthracenylene, 9,10-phenylene, etc.
  • C 6 -C 10 arylene refers to an arylene group containing 6 to 10 ring atoms.
  • pyrazolyl such as 1H -imidazol-1-yl
  • oxazolyl such as oxazol-2-yl
  • thiazolyl such as thiazol-4-yl
  • pyrazolylene such as 1,4-imidazolyl
  • oxazolyl such as 2,4-oxazolyl
  • thiazolyl such as 2,5-thiazolyl
  • hydroxy refers to the -OH group.
  • the invention provides compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof,
  • Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl or ,
  • Ra and Ra' are independently or,
  • Ra and Ra’ are connected to each other to form Z;
  • Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
  • Each R 1 is independently C 1- C 24 alkyl or C 2- C 24 alkenyl
  • Each R 2 is independently hydrogen or C 1- C 24 alkyl
  • Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
  • Each m is independently 0 or 1;
  • Ra and Ra' in formula (I) are each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 - C 12 heteroalkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from 1 to 3 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 - Group substitution of C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; preferably, Ra and Ra 'Each independently is C 1 -C 6
  • each Z in Formula (I) is independently C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 6 -C 10 arylene, or 5- 10-membered heteroarylene group; preferably, each Z is independently a C 1 -C 6 alkylene group or a C 1 -C 6 heteroalkylene group.
  • W in formula (I) is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cyclic Alkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from 1 to 3 each independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 ring Alkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl or C 1 -C 12 Heteroalkyl, said alkyl and hetero
  • each R 1 in formula (I) is independently C 3- C 24 alkyl or C 3- C 24 alkenyl; preferably, each R 1 is independently branched. C 3- C 24 alkyl or branched C 3- C 24 alkenyl.
  • each R 2 in formula (I) is independently hydrogen or C 1- C 6 alkyl; preferably, each R 2 is independently hydrogen or C 1- C 4 alkyl base.
  • each B 1 , B 2 , B 3 and B 4 in formula (I) is each independently C 1 -C 6 alkylene or C 2 -C 6 alkenylene; preferably , each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 4 alkylene group or a C 2 -C 4 alkenylene group.
  • a compound of Formula (I) has a structure shown in Formula (I-1) or Formula (I-1'):
  • Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, preferably C 1 -C 6 al
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl, preferably C 1 -C 6 alkyl;
  • R 1 is C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
  • B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-2) or Formula (I-2'):
  • Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, C 2 -C 12 alkyn
  • Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
  • Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-3) or Formula (I-3'):
  • Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group; preferably, each Z Each independently is C 1 -C 12 alkylene, preferably C 1 -C 6 alkylene;
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution;
  • W is C 1 -C 12 alkyl or C 1 -C 12 heteroalkyl, the alkyl and heteroalkyl groups
  • R 1 is C 1- C 24 alkyl or C 2- C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
  • B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-4) or Formula (I-4'):
  • Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl group substituted by a base, a 3-10 membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group; preferably, Ra and Ra' are each independently a
  • Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 6 alkylene or C 1 -C 6 heteroalkylene;
  • Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
  • Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-5) or Formula (I-5'):
  • Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene;
  • Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
  • Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • each Each is independently selected from the following clips:
  • each Z is independently selected from the following fragments:
  • X is selected from the following fragments:
  • the present invention provides a series of specific compounds falling within the scope of compounds of the general formula, including (but not limited to):
  • the invention provides a lipid carrier, which contains any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or Prodrugs.
  • This type of lipid carrier has high encapsulation efficiency for nucleic acid drugs, which greatly improves the delivery efficiency of nucleic acid drugs in the body.
  • the above-mentioned lipid carrier includes a first lipid compound and a second lipid compound, wherein the first lipid compound includes any of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, Tautomers, solvates, chelates, non-covalent complexes or prodrugs and optionally cationic lipids, the second lipid compound comprising anionic lipids, neutral lipids, sterols and amphiphiles One or a combination of two or more lipids.
  • the above-mentioned first lipid compound is any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent compound thereof. Complex or prodrug.
  • the above-mentioned first lipid compound is any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-common Valent complexes or combinations of prodrugs and cationic lipids.
  • the second lipid compound is a combination of neutral lipids, sterols, and amphipathic lipids.
  • the second lipid compound is a combination of anionic lipid, neutral lipid, sterol, and amphiphilic lipid.
  • the above-mentioned cationic lipids include (but are not limited to) one of DLinDMA, DODMA, DLin-MC2-MPZ, DLin-KC2-DMA, DOTAP, C12-200, DC-Chol and DOTMA or A combination of two or more is preferred, DLin-KC2-DMA and DOTAP.
  • the above-mentioned anionic lipids include (but are not limited to) phosphatidylserine, phosphatidylinositol, phospholipid One or a combination of two or more of acid, phosphatidylglycerol, DOPG, DOPS and dimyristoylphosphatidylglycerol, preferably DOPG and DOPS.
  • the above-mentioned neutral lipids include (but are not limited to) at least one of DOPE, DSPC, DPPC, DOPC, DPPG, POPC, POPE, DPPE, DMPE, DSPE and SOPE or its anionic or Lipids modified with cationic modifying groups are preferably DSPC.
  • the anionic or cationic modifying group is not limited.
  • the above-mentioned amphiphilic lipids include (but are not limited to) PEG-DMG, PEG-c-DMG, PEG-C14, PEG-c-DMA, PEG-DSPE, PEG-PE, PEG modified of ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, Tween-20, Tween-80, PEG-DPG, PEG-s-DMG, DAA, PEG-c-DOMG and GalNAc-PEG -One or a combination of two or more DSGs, preferably PEG-DMG and Tween-80.
  • the molar ratio of the first lipid compound, anionic lipid, neutral lipid, sterol and amphipathic lipid is (20 ⁇ 65): (0 ⁇ 20 ):(5 ⁇ 25):(25 ⁇ 55):(0.3 ⁇ 15);
  • the molar ratio can be 20:20:5:50:5, 30:5:25:30:10, 20: 5:5:55:15, 65:0:9.7:25:0.3, etc.;
  • any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers is (1 ⁇ 10):(0 ⁇ 10); exemplarily, the molar ratio can be 1: 1, 1:2, 1:5, 1:7.5, 1:10, 2:1, 5:1, 7.5:1, 10:1, etc.
  • the molar ratio of the first lipid compound, anionic lipid, neutral lipid, sterol and amphipathic lipid is (20 ⁇ 55): (0 ⁇ 13): (5 ⁇ 25): (25 ⁇ 51.5): (0.5 ⁇ 15); wherein, in the first lipid compound, any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, The molar ratio of tautomers, solvates, chelates, non-covalent complexes or prodrugs and cationic lipids is (3 ⁇ 4):(0 ⁇ 5).
  • the invention provides a nucleic acid nanoparticle composition, which contains any of the above compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, and non-covalent complexes thereof. drugs or prodrugs or the above-mentioned lipid carriers, as well as nucleic acid drugs.
  • the above-mentioned nucleic acid drugs include (but are not limited to) DNA, siRNA, mRNA, dsRNA, antisense nucleic acid, antisense oligonucleotide, microRNA, antisense microRNA, antagomir, microRNA inhibitor, microRNA One or a combination of two or more RNA activators and immunostimulatory nucleic acids.
  • the above-mentioned nucleic acid drug is combined with any of the above-mentioned compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or
  • the mass ratio of prodrugs is 1:(3 ⁇ 40).
  • the mass ratio of the above-mentioned nucleic acid drug and the above-mentioned lipid carrier is 1: (3-40).
  • the above mass ratio may be 1:3, 1:5, 1:10, 1:15, 1:20, 1:30, etc.
  • the present invention provides a pharmaceutical preparation, which contains any of the above compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or precursor thereof Drug, or the above-mentioned lipid carrier, or the above-mentioned nucleic acid lipid nanoparticle composition, and pharmaceutically acceptable excipients, carriers and diluents.
  • the particle size of the above-mentioned pharmaceutical preparation is 30-500nm; exemplarily, the particle size can be 30nm, 50nm, 100nm, 150nm, 250nm, 350nm, 500nm, etc.
  • the encapsulation rate of nucleic acid drugs in the above-mentioned pharmaceutical preparations is greater than 50%; for example, the encapsulation rate can be 55%, 60%, 65%, 70%, 75%, 79%, 80%, 85%, 89%, 90%, 93%, 95%, etc.
  • the "equivalent (eq)" ratio refers to the molar ratio of solvent or drug.
  • misappropriate amount means that the amount of solvent or drug added has a large adjustable range and has little impact on the synthesis result, and does not need to be specifically limited.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0 eq), stir for 10 minutes, then add 4-hydroxybutylacrylate (1.5eq), and stir at room temperature for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 2 Dissolve intermediate product 2 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.2eq), stir at room temperature for 16h after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), stir at room temperature for 16h after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add intermediate product 2 (1.5eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • Dissolve cystamine dihydrochloride (2.0eq) in an appropriate amount of methylene chloride, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.0eq), after addition, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 3 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.5eq) ), stir at room temperature for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.5eq) ), stir at room temperature for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 2 (1.0eq) in an appropriate amount of ethyl acetate, add 4M hydrochloric acid in ethyl acetate solution (6V), and stir at room temperature for 2 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • intermediate product 3 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
  • intermediate product 3 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of DMF, add intermediate product 2 (2.0eq) and potassium carbonate (3.0eq), and stir at 90°C for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • the results showed that the mRNA encapsulation efficiency of LNP@mRNA prepared from the compounds in the table above was greater than 80%, and the particle size of LNP@mRNA prepared by compounds 11, 15, 21, 38, and 59 together with the other three lipids was smaller. In addition, LNPs prepared from these compounds are negatively charged under neutral conditions and have good biological safety. It can be seen that the compound provided by the present invention has a high encapsulation efficiency for nucleic acid drugs, and can be used as a carrier to improve the delivery efficiency of nucleic acid drugs in the body.
  • FIG. 1 is an imaging image of mice injected intramuscularly with LNP@mRNA prepared from Compound 1.
  • Figure 2 is an anatomical image of mice injected intramuscularly with LNP@mRNA prepared from Compound 1. Combining Figures 1 and 2, it can be seen that the main components of mRNA are Expressed in muscle, liver and spleen.
  • Figure 3 is an imaging image of mice injected intravenously with LNP@mRNA prepared from Compound 8.
  • Figure 4 is an anatomical image of mice injected intravenously with LNP@mRNA prepared with Compound 8.
  • Figure 5 is an imaging image of mice injected intravenously with LNP@mRNA prepared from compound 58.
  • Figure 6 is an anatomical image of mice injected intravenously with LNP@mRNA prepared with compound 58. Combining Figures 5 and 6, it can be seen that the main components of mRNA are Expressed in the spleen and a small amount in the liver. Therefore, the above-mentioned lipid compound with a specific structure can be selected as a lipid carrier according to the organ in which the nucleic acid drug needs to be enriched.
  • MC3 cationic lipid DLin-MC3-DMA
  • DSPC disearoylphosphatidylcholine
  • PEG-DMG polyethylene glycol-dimyristate glyceryl ester
  • ethanol dissolve in ethanol (with lipid as the molar ratio of 50:38.5:10:1.5 (wherein, the equivalent of compound 1 or MC3 is 50, the equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5)
  • concentration is 24.4mg/mL
  • dissolve luciferase mRNA in 10mM citrate buffered saline solution with pH 4.0 drug concentration is 0.276mg/mL
  • the volume ratio of the two solutions is 1:3 ( Among them, the equivalent of the ethanol solution is 1 and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly
  • FIG. 7 shows the metabolism of LNP@mRNA prepared by Compound 1, MC3 and other three lipids in mouse liver. It can be seen that MC3 and LNP@mRNA reached the peak 6 hours after injection, and still maintained a high level after 48 hours. The lipid level of Compound 1 reached a peak at 2 hours after LNP@mRNA injection, and the peak value during the entire 48 hours was much lower than the lipid level of MC3. Therefore, it can be shown that Compound 1 has a higher concentration in the liver than MC3. Fast metabolic rate.
  • Figure 8 shows the metabolism of LNP@mRNA prepared by Compound 1, MC3 and other three lipids in the mouse spleen. It can be seen that MC3 reaches the peak 12 hours after LNP@mRNA injection and still maintains a high level 48 hours later. lipid levels, whereas compound 1 in The peak value was reached 2 hours after LNP@mRNA injection, and the peak value during the entire 48 hours was much lower than the lipid level of compound 1. Therefore, it can be seen that compound 1 has a faster metabolism in the spleen than MC3. Lipids are less concentrated in the liver and spleen, have faster metabolism, higher biosafety and less toxicity than cationic lipids already on the market.
  • Compound 55 was mixed with DOTAP ((2,3-dioleoylpropyl)trimethylammonium chloride), cholesterol, DSPC, and PEG-DMG at a molar ratio of 30:20:38.5:10:1.5 (wherein, compound 55 The equivalent of DOTAP is 30, the equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5) is dissolved in ethanol (based on the total weight of lipids, the concentration is 24.4 mg/mL) , dissolve luciferase mRNA in 50mM citrate buffered saline solution with pH 4.0 (drug concentration is 0.276mg/mL), the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1, and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly mix the two phases, and use dialysis or tangential flow technology to replace the buffer environment with PBS at pH 7.4 to prepare LNP@
  • Compound 56 was mixed with DOTAP, DOPS (dioleoylphosphatidylserine), cholesterol, DSPC, and PEG-DMG (total 15 mg) at a molar ratio of 20:25:15:25:5:10 (wherein, the equivalent of compound 56 is 20.
  • DOTAP 25
  • DOPS 15
  • cholesterol 25
  • DSPC 5
  • PEG-DMG 5
  • ethanol based on the total weight of lipids, the concentration is 24.4mg /mL
  • luciferase mRNA 5mg
  • 50mM citrate buffered saline solution with pH 4.0 drug concentration is 0.276mg/mL
  • the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1.
  • the equivalent of the aqueous solution is 3).
  • Compound 2 was mixed with DLin-KC2-DMA (CAS number: 1190197-97-7), DOPG (dioleoylphosphatidylglycerol), cholesterol, DSPC, and Tween-80 (total 30 mg) at a ratio of 15:5:3:51.5 :25:0.5 molar ratio (wherein, the equivalent of compound 2 is 15, the equivalent of DLin-KC2-DMA is 5, the equivalent of DOPG is 3, the equivalent of cholesterol is 51.5, the equivalent of DSPC is 25, and the equivalent of Tween-80 Equivalent to 0.5) was dissolved in ethanol (based on the total weight of lipids, the concentration was 24.4mg/mL), and luciferase mRNA (1mg) was dissolved in 50mM citrate buffered saline solution at pH 4.0 (drug concentration was 0.276mg /mL), the volume ratio of the two is 1:3 (where the equivalent of the ethanol solution is 1 and the equivalent of the aque

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Abstract

La présente invention appartient au domaine de l'administration de médicament génique, et concerne en particulier un composé lipidique, un support lipidique basé sur le composé lipidique, une composition de nanoparticules lipidiques d'acide nucléique et une formulation pharmaceutique. Le composé ayant la structure représentée dans la formule (I) peut préparer indépendamment un support lipidique, ou préparer conjointement un support lipidique avec d'autres composés lipidiques. Le support lipidique a une réactivité au pH, a une efficacité d'encapsulation élevée sur des médicaments à base d'acide nucléique, et est bénéfique pour améliorer l'efficacité d'administration in vivo de médicaments à base d'acide nucléique. De plus, le support lipidique peut également administrer un médicament à base d'acide nucléique à un organe nécessitant un enrichissement, et présente une bonne perspective d'application.
PCT/CN2023/082278 2022-03-21 2023-03-17 Composé lipidique, support lipidique à base de composé lipidique, composition de nanoparticules lipidiques d'acide nucléique et formulation pharmaceutique WO2023179497A1 (fr)

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