WO2023274265A1 - 苯酰胺类化合物及其用途 - Google Patents

苯酰胺类化合物及其用途 Download PDF

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Publication number
WO2023274265A1
WO2023274265A1 PCT/CN2022/102114 CN2022102114W WO2023274265A1 WO 2023274265 A1 WO2023274265 A1 WO 2023274265A1 CN 2022102114 W CN2022102114 W CN 2022102114W WO 2023274265 A1 WO2023274265 A1 WO 2023274265A1
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compound
salt
alkyl
alkenyl
formula
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English (en)
French (fr)
Inventor
祝令建
于秀招
蔡德勤
管忠俊
刘崇懿
姜军
黄建
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Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/003—Esters of saturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom

Definitions

  • the disclosure belongs to the field of medicine, and relates to benzamide compounds and applications thereof.
  • Nucleic acid-based drugs such as messenger RNA (mRNA), antisense oligonucleotides, small interfering RNA (siRNA), plasmids, etc., have broad application prospects. How to safely and effectively deliver them to target organs and target cells in vivo is a major constraint Problems of technological development.
  • mRNA messenger RNA
  • siRNA small interfering RNA
  • plasmids etc.
  • nucleic acid drug delivery system can be divided into two categories: viral vector system and non-viral system.
  • Liposome-mediated nucleic acid drug delivery is the main method belonging to the non-viral delivery system.
  • lipid nanoparticles have been demonstrated as delivery vehicles for nucleic acid drugs.
  • Lipid nanoparticles formed from cationic lipids and other co-lipids such as cholesterol, phospholipids, and PEGylated lipids encapsulate nucleic acids, protecting them from degradation and facilitating cellular uptake.
  • the delivery of liposomal nanoparticles for bioactive components has other advantages, such as good targeting, less side effects, good stability, and high transfection efficiency.
  • mRNA-based therapies such as vaccines, gene therapy, and protein replacement therapy
  • mRNA delivery systems there is a huge demand for mRNA delivery systems. Therefore, the development of efficient and safe mRNA delivery systems is effective for diseases based on mRNA and other nucleic acid drugs, including The treatment of diseases such as preventive diseases, genetic diseases and tumors is of great significance.
  • the disclosure provides the compound shown in formula I or its salt
  • M 1 to M 6 are each independently selected from a bond, -C(O)O-a1 and -OC(O)-a1, and a1 is a combination with R 1 , R 2 , R 3 , R 4 , R 5 or R 6 connected bonds, and M 1 to M 6 are not all -C(O)O-a1 or bonds;
  • R 1 to R 6 are each independently substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
  • R 7 are each independently hydrogen or substituted or unsubstituted C 1-6 alkyl
  • n 1, 2, 3, 4, 5, 6, 7 and 8;
  • n1 to n6 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • R 1 to R 6 are each independently unsubstituted alkyl or unsubstituted alkenyl.
  • R 1 to R 6 are each independently selected from C 4 -C 14 alkyl or C 4 -C 14 alkenyl.
  • R 1 is C 4 -C 14 alkyl (including but not limited to C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 1 is C 5 -C 12 alkyl.
  • R 2 is C 4 -C 14 alkyl (including but not limited to C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl).
  • R 2 is a C 5 -C 12 alkyl group.
  • R 3 is C 4 -C 14 alkyl (including but not limited to C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 3 is a C 5 -C 12 alkyl group.
  • R 4 is C 4 -C 14 alkyl (including but not limited to C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl).
  • R 4 is a C 5 -C 12 alkyl group.
  • R 5 is C 4 -C 14 alkyl (including but not limited to C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl). In other embodiments, in the compound represented by formula I or its salt, R 5 is C 5 -C 12 alkyl.
  • R 6 is C 4 -C 14 alkyl (including but not limited to C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 6 is a C 5 -C 12 alkyl group.
  • R 1 is C 4 -C 14 alkenyl (including but not limited to C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13 alkenyl, C 14 alkenyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 1 is C 5 -C 12 alkenyl.
  • R 2 is C 4 -C 14 alkenyl (including but not limited to C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13 alkenyl, C 14 alkenyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 2 is C 5 -C 12 alkenyl.
  • R 3 is C 4 -C 14 alkenyl (including but not limited to C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13 alkenyl, C 14 alkenyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 3 is C 5 -C 12 alkenyl.
  • R 4 is C 4 -C 14 alkenyl (including but not limited to C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13 alkenyl, C 14 alkenyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 4 is C 5 -C 12 alkenyl.
  • R 5 is C 4 -C 14 alkenyl (including but not limited to C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13 alkenyl, C 14 alkenyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 5 is C 5 -C 12 alkenyl.
  • R 6 is C 4 -C 14 alkenyl (including but not limited to C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl, C 9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13 alkenyl, C 14 alkenyl). In other embodiments, in the compound represented by formula I or a salt thereof, R 6 is C 5 -C 12 alkenyl.
  • R 5 is C 4 -C 14 alkenyl
  • R 6 is C 4 -C 14 alkenyl
  • R 3 is C 4 -C 14 alkenyl
  • R 4 is C 4 -C 14 alkenyl
  • R 1 is C 4 -C 14 alkenyl
  • R 2 is C 4 -C 14 alkenyl
  • R 1 is a C 4 -C 14 alkyl group
  • R 2 is a C 4 -C 14 alkyl group
  • R 3 is C 4 -C 14 alkyl
  • R 4 is C 4 -C 14 alkyl
  • R 5 is a C 4 -C 14 alkyl group
  • R 6 is a C 4 -C 14 alkyl group.
  • R 1 to R 6 are each independently C 4-15 alkyl or alkenyl.
  • R 1 to R 6 are each independently C 8-16 alkyl or alkenyl.
  • R 1 is C 4-15 alkyl or C 8-16 alkyl.
  • R 2 is C 4-15 alkyl or C 8-16 alkyl.
  • R 3 is C 4-15 alkyl or C 8-16 alkyl.
  • R 4 is C 4-15 alkyl or C 8-16 alkyl.
  • R 5 is C 4-15 alkyl or C 8-16 alkyl.
  • R 6 is C 4-15 alkyl or C 8-16 alkyl.
  • R 1 to R 6 are C 4-15 alkyl or C 8-16 alkyl.
  • R 1 is C 4-15 alkenyl or C 8-16 alkenyl.
  • R 2 is C 4-15 alkenyl or C 8-16 alkenyl.
  • R 3 is C 4-15 alkenyl or C 8-16 alkenyl.
  • R 4 is C 4-15 alkenyl or C 8-16 alkenyl.
  • R 5 is C 4-15 alkenyl or C 8-16 alkenyl.
  • R 6 is C 4-15 alkenyl or C 8-16 alkenyl.
  • R 1 to R 6 are C 4-15 alkenyl or C 8-16 alkenyl.
  • R 7 is hydrogen or optionally substituted C 1-3 alkyl. In some embodiments, in the compound represented by formula I or a salt thereof, R 7 is hydrogen, methyl or ethyl.
  • M 1 to M 6 in the compound represented by formula I or its salt are each independently -OC(O)-a1, and a1 is the combination of R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is connected to the bond.
  • M 1 and M 2 in the compound represented by formula I or a salt thereof are each independently -C(O)O-a1, and a1 is a bond connecting R 1 or R 2 .
  • M 1 , M 2 , M 3 , and M 4 in the compound represented by formula I or its salt are each independently -C(O)O-a1, and a1 is the same as R 1 , R 2 , R 3 or R 4 bonded.
  • M 1 , M 2 , M 3 and M 4 are bonds.
  • M 5 and M 6 are bonds in the compound represented by formula I or a salt thereof.
  • n1 to m3 in the compound represented by formula I or the salt thereof provided by some embodiments are each independently selected from 2, 3 and 4.
  • R 1 to R 6 are independently C 4 -C 14 alkyl or C 4 -C 14 alkenyl.
  • R 1 or R 2 are independently selected from
  • n1 to n6 in the compound represented by formula I or a salt thereof are each independently selected from 1, 2, 3, 4 and 5.
  • n1 to n6 in the compound represented by formula I or a salt thereof are 3 independently.
  • n1 to n6 in the compound represented by formula I or a salt thereof are 4 independently.
  • n1 to n6 in the compound represented by formula I or a salt thereof are 5 independently.
  • n1 to n6 are each independently selected from 6, 7, 8, 9 and 10.
  • n1 to n6 in the compound represented by formula I or a salt thereof are each independently 7.
  • n1 to n6 in the compound represented by formula I or a salt thereof are each independently 8.
  • n1 to n6 in the compound represented by formula I or a salt thereof are each independently 9.
  • the compound represented by formula I or its salt in the present disclosure is the compound represented by formula II or its salt
  • R 1 to R 7 , m1 to m3, n1 to n6 are as defined in the compound of formula I or a salt thereof.
  • n1 or n2 are each independently selected from 6, 7, 8, 9 and 10.
  • R 1 or R 2 are independently selected from
  • R 7 is independently hydrogen
  • n1 to m3 are independently selected from 2, 3 and 4.
  • the compound represented by formula I or its salt in the present disclosure is the compound represented by formula III or its salt
  • R 1 to R 7 , m1 to m3, n1 to n6 are as defined in the compound of formula I or a salt thereof.
  • R 7 is independently hydrogen
  • n1 to m3 are independently selected from 2, 3 and 4.
  • n1 to n6 in the compound represented by formula III or a salt thereof are each independently selected from 6, 7, 8, 9 and 10.
  • R 1 to R 6 are independently selected from
  • R 1 to R 6 are independently
  • Typical compounds shown in formula I or pharmaceutically acceptable salts thereof include but are not limited to:
  • the present disclosure also provides an isotopic substitution of the aforementioned compound or a salt thereof, preferably, the isotopic substitution is a deuterium atom substitution.
  • the present disclosure also provides a lipid particle comprising the aforementioned compound or a salt thereof, or an isotope substitution. Further, in some embodiments, the lipid particle further comprises an active agent, and the active agent is preferably an immunostimulatory oligonucleotide, siRNA, antisense oligonucleotide, mRNA, or a plasmid.
  • the active agent is preferably an immunostimulatory oligonucleotide, siRNA, antisense oligonucleotide, mRNA, or a plasmid.
  • the present disclosure also provides a pharmaceutical composition comprising the aforementioned lipid particles and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition.
  • the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients.
  • the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients.
  • the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients.
  • the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a use of the aforementioned compound or a salt thereof, or an isotope substitution, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition in the preparation of a medicament for inducing an immune response in a subject.
  • the present disclosure also provides the aforementioned compound or its salt, or isotope substitution, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases or disorders related to polypeptide overexpression the use of.
  • the present disclosure also provides the aforementioned compound or its salt, or isotope substitution, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or conditions related to insufficient expression of polypeptides the use of.
  • diseases or conditions described in the present disclosure include, but are not limited to, cancer, infection, autoimmune disease, neurodegenerative disease, and inflammation, such as COVID-19.
  • the present disclosure also provides a method for inducing an immune response in a subject, comprising administering to the patient the aforementioned compound or a salt thereof, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides a method for preventing and/or treating diseases or disorders related to polypeptide overexpression, comprising administering to the patient the aforementioned compound or its salt, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides a method for preventing and/or treating a disease or condition related to insufficient expression of a polypeptide, comprising administering to the patient the aforementioned compound or its salt, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition.
  • the present disclosure also provides the aforementioned compound or salt thereof, or the aforementioned lipid particle, or the aforementioned pharmaceutical composition for inducing an immune response in a subject.
  • the present disclosure also provides the aforementioned compounds or salts thereof, or the aforementioned lipid particles, or the aforementioned pharmaceutical compositions for preventing and/or treating diseases or disorders related to polypeptide overexpression.
  • the present disclosure also provides the aforementioned compounds or salts thereof, or the aforementioned lipid particles, or the aforementioned pharmaceutical compositions for preventing and/or treating diseases or conditions associated with insufficient expression of polypeptides.
  • Salts of compounds described in this disclosure include “acid” addition salts and “base” addition salts.
  • the compound salts also include salts formed by quaternization with basic groups (amino groups), and the quaternization reagents include linear or branched chlorinated hydrocarbons.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or or both with Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, agent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier.
  • an “effective amount” or “therapeutically effective amount” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • nucleic acid refers to polymers of deoxyribonucleotides (DNA), ribonucleotides (RNA) and modified forms thereof, either as individual fragments or as components of larger constructs, linear or branched Stranded, single-stranded, double-stranded, triple-stranded or hybrid forms thereof.
  • RNA ribonucleotides
  • a polynucleotide may include sense and antisense oligonucleotides or polynucleotide sequences of DNA or RNA.
  • the DNA or RNA molecule can be, for example, but not limited to: complementary DNA (cDNA), genomic DNA, synthetic DNA, recombinant DNA or a hybrid thereof, or an RNA molecule such as, for example, mRNA, shRNA, siRNA, miRNA, anti- Sense RNA and the like. Each possibility represents a separate embodiment of the invention.
  • the term also includes oligonucleotides comprising naturally occurring bases, sugars, and covalent internucleoside linkages, as well as oligonucleotides having non-naturally occurring portions that function like corresponding naturally occurring parts.
  • polypeptide polypeptide
  • peptide and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical analogs of the corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers.
  • leukocyte relates to white blood cells (WBC) produced and derived from pluripotent hematopoietic stem cells in the bone marrow.
  • WBC white blood cells
  • white blood cells have a nucleus, and based on their functional or physical properties, the types of white blood cells can be divided into five main types, including neutrophils, eosinophils, basophils, lymphocytes, and monocytes.
  • Alkyl refers to a saturated aliphatic hydrocarbon group including, but not limited to, straight and branched chain alkyl groups.
  • an alkyl group has 1-4 carbons, also known as C 1-4 alkyl.
  • an alkyl group has 10-22 carbons, also known as a C 10-22 alkyl.
  • an alkyl group has 4-22 carbons, also known as a C4-22 alkyl.
  • an alkyl group has 4-15 carbons, also known as a C 4-15 alkyl.
  • the alkyl group has 8-16 carbons, also known as C8-16 alkyl.
  • the alkyl group may be unsubstituted or replaced by one or more members selected from halogen, hydroxy, amino, oxo, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, Amino, alkylamino, dialkylamino, carboxyl, thio, and thioalkyl groups are substituted.
  • the alkyl group is a straight chain alkyl. In some embodiments, the alkyl group is a branched chain alkyl.
  • alkenyl means an unsaturated aliphatic hydrocarbon group and includes straight and branched chain alkenyl groups. In some embodiments, alkenyl groups have 1-4 carbons, also known as C 1-4 alkenyl. In some embodiments, alkenyl groups have 10-22 carbons, also known as C 10-22 alkenyl. In some embodiments, alkenyl groups have 4-22 carbons, also known as C4-22 alkenyl.
  • alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butenyl Alkenyl and Decenyl.
  • Alkenyl can be unsubstituted or replaced by one or more members selected from halogen, hydroxy, amino, oxo, alkoxycarbonyl, amido, alkylamido, dialkylamido, nitro, amino, Group substitution with alkylamino, dialkylamino, carboxy, thio and thioalkyl groups.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -NH2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • Figure 1 Comparison of intracellular mRNA luciferase expression after delivery of selected lipids (compounds 1-3 and comparative compounds 1 and 2).
  • Figure 2 Comparison of mRNA luciferase expression levels at injection sites in mice after delivery of selected lipids (compounds 1-3 and comparative compound 1).
  • Figure 3 Comparison of protein expression levels of growth factors injected intramuscularly in vivo after delivery of selected lipids (compounds 1, 3 and comparative compound 1).
  • Figure 4 Comparison of mRNA luciferase expression levels in the whole body of mice after delivery of selected lipids (compounds 1, 2 and comparative compound 1).
  • Figure 5 Comparison of mRNA luciferase expression levels in mouse lungs after delivery of selected lipids (compound 4 and comparative compound 1).
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • HPLC HPLC-based analytical chromatography
  • GAS15B DAD ultraviolet detector Water Vbridge C18 150*4.6mm 5um chromatographic column.
  • MS uses Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, Waters Xbridge C18 4.6*50mm, 5um chromatographic column, scanning in positive/negative ion mode, and the mass scanning range is 80-1200.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 silica gel plate, the specification of the thin-layer chromatography (TLC) silica gel plate is 0.2mm ⁇ 0.03mm, and the specification of the thin-layer chromatography separation and purification product is 0.4mm-0.5mm.
  • the flash column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or Changzhou Santai pre-packed pre-packed ultra-pure normal-phase silica gel column (40-63 ⁇ m, 60g, 24g, 40g, 120g or other specifications).
  • the known starting materials in this disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Bear Pharmaceutical and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • the nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Company.
  • Nitrogen atmosphere or hydrogenation atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • reaction solution was diluted with ethyl acetate, washed with water, and the aqueous phase was back-extracted with a small amount of ethyl acetate, the organic phases were combined, washed three times with water, washed once with saline, dried over sodium sulfate, concentrated by filtration, purified by flash column chromatography, and eluted System MeOH/DCM, MeOH%: 0%-5% (5min) ⁇ 5%-10% (10min) ⁇ 10%-15% (15min) to obtain 3.8 g of oil compound V2, yield 43.2%.
  • Compounds 1, 2, 3, 4 and comparative compounds 1, 2 were dissolved in ethanol solution, and mixed with DOPE, cholesterol, DMG-PEG solution dissolved in ethanol at a molar ratio of 20:30:40:0.75 to prepare ethanol lipid substance solution.
  • the mRNA encoding luciferase (GenBank: MN728548.1) was dissolved in citrate buffer to prepare an aqueous mRNA solution.
  • the ethanol lipid solution and mRNA aqueous solution were mixed by microfluidics, and the weight ratio of total lipid to mRNA was about 12-36:1 to prepare liposomes. Ethanol was dialyzed in PBS solution to obtain a liposome nanoparticle (LNP) preparation encapsulating luciferase-encoding mRNA.
  • LNP liposome nanoparticle
  • the nanometer size and polydispersity index (PDI) of liposomal nanoparticles were detected by dynamic light scattering using Malvern Zetasizer Nano ZS in 173° backscatter detection mode.
  • RNA Quantitative Detection Kit (purchased from Thermo Fisher Scientific, catalog number R11490) was used to determine the liposome encapsulation efficiency.
  • the pKa of the cations in the liposomal nanoparticles was determined using a fluorescence assay based on 6-(p-toluidine)-2-naphthalenesulfonic acid sodium salt (TNS).
  • TNS 6-(p-toluidine)-2-naphthalenesulfonic acid sodium salt
  • the lipid nanoparticles were respectively added into buffer solutions with different pHs, and after being thoroughly mixed, the fluorescence intensity at an excitation wavelength of 325 nm and an emission wavelength of 435 nm was detected at room temperature using a fluorescent microplate reader.
  • pKa is the pH value that produces half the maximum fluorescence intensity. See Table 1 for relevant data.
  • the liposome nanoparticles corresponding to comparative compounds 1 and 2 as a control, the mRNA expression efficiency at the in vitro cell level of the liposome nanoparticles corresponding to compounds 1-3 was detected.
  • HEK 293 cells were inoculated into the cell well plate and cultured overnight, and when the cell density reached above 80%, the liposome LNP solution encapsulating luciferase mRNA was added to the culture medium of the cell plate well. After 24 hours, the fluorescence intensity of the expressed luciferase protein was detected using a luciferase reporter gene detection kit (Promega) and a microplate reader. The fluorescence intensity value is the fluorescence value detected by the microplate reader. For each compound, at least three groups of LNPs were used to repeatedly calculate the average fluorescence value intensity and statistical difference, and the data are shown in Table 2 and Figure 1.
  • the lipid nanoparticles corresponding to compounds 1, 2 and 3 can deliver mRNA and express luciferase in cells better than comparative compound 1 and comparative compound 2.
  • a dose of 0.25 mg/kg was injected into the thigh muscle site of 6-8 week-old female BALB/c with luciferase-encapsulated mRNA liposomes. plastid nanoparticles.
  • the luciferase substrate was injected intraperitoneally into each mouse, and the fluorescence pictures of the mice were taken using the IVIS small animal optical in vivo imaging instrument (PerkinElme), and the fluorescence intensity at the injection site was counted.
  • the level of fluorescence intensity represents the level of expression of luciferase protein, which reflects the efficiency of liposome nanoparticle delivery of mRNA in vivo.
  • the fluorescence intensity in Table 3 and Figure 2 is the fluorescence intensity at the injection site of the mouse captured and counted by the IVIS small animal optical live imager. At least 3 groups of LNP corresponding to each compound were repeated to calculate the average fluorescence intensity.
  • the liposome nanoparticle corresponding to compound 1 As a control, the protein expression level of the liposome nanoparticle corresponding to compound 1 and 3 after intramuscular injection of mRNA was detected, that is, the delivery efficiency of intramuscular injection of mRNA in vivo. See Table 4 and Figure 3 for relevant data.
  • the fluorescence intensity in Figure 4 is the fluorescence intensity of the whole body of the mouse captured and counted by the IVIS small animal optical live imager.

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Abstract

提供了一种苯酰胺类化合物及其用途。具体而言，提供一种如式I所示化合物或其盐，其中R 1至R 7、M 1至M 6、m1至m3、n1至n6如本文中所定义。

Description

苯酰胺类化合物及其用途 技术领域
本公开属于医药领域，涉及苯酰胺类化合物及其用途。
背景技术
基于核酸类的药物，例如信使RNA(mRNA)、反义寡核苷酸、小干扰RNA(siRNA)、质粒等具有广阔的应用前景，如何安全有效地递送到体内靶器官和靶细胞是制约该技术发展的难题。
目前核酸药物递送系统可分为病毒载体系统和非病毒系统2大类，脂质体介导的核酸药物递送是属于非病毒递送系统的主要方法。
在基因治疗应用中，脂质纳米颗粒已经被证明可作为核酸药物的递送载体。由阳离子脂质和其他共脂质诸如胆固醇、磷脂和PEG化脂质形成的脂质纳米颗粒包封核酸，保护核酸免于降解并且促进细胞摄取。另外，脂质体纳米颗粒用于生物活性成分的递送具有其他优点，如靶向性好、副作用小、稳定性好和转染效率较高等。
随着基于mRNA的疗法，例如疫苗、基因治疗、蛋白替代疗法等领域快速发展，对于mRNA的递送系统提出了巨大的需求，因此开发高效、安全的mRNA递送系统对基于mRNA等核酸药物疾病，包括预防性疾病、遗传性疾病和肿瘤等疾病的治疗具有重要意义。
发明内容
本公开(The disclosure)提供了式I所示化合物或其盐
Figure PCTCN2022102114-appb-000001
其中，M 1至M 6各自独立地选自键、-C(O)O-a1和-OC(O)-a1，a1为与R 1、R 2、R 3、R 4、R 5或R 6连接的键，且M 1至M 6不全为-C(O)O-a1或键；
R 1至R 6各自独立地为取代或未被取代的烷基或取代或未被取代的烯基；
R 7各自独立地为氢或取代或未被取代的C 1-6烷基；
m1至m3各自独立地选自1、2、3、4、5、6、7和8；
n1至n6各自独立地选自0、1、2、3、4、5、6、7、8、9和10。
在一些实施方案中，式I所示化合物或其盐中R 1至R 6各自独立地为未被取代的烷基或未被取代的烯基。
在一些实施方案中，式I所示化合物或其盐中R 1至R 6各自独立地选自C 4-C 14烷基或C 4-C 14烯基。
在一些实施方案中，式I所示化合物或其盐中R 1为C 4-C 14烷基(包括但不限于C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基)。在另一些实施方案中，式I所示化合物或其盐中R 1为C 5-C 12烷基。
在一些实施方案中，式I所示化合物或其盐中R 2为C 4-C 14烷基(包括但不限于C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基)。
在另一些实施方案中，式I所示化合物或其盐中R 2为C 5-C 12烷基。
在一些实施方案中，式I所示化合物或其盐中R 3为C 4-C 14烷基(包括但不限于C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基)。在另一些实施方案中，式I所示化合物或其盐中R 3为C 5-C 12烷基。
在一些实施方案中，式I所示化合物或其盐中R 4为C 4-C 14烷基(包括但不限于C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基)。
在另一些实施方案中，式I所示化合物或其盐中R 4为C 5-C 12烷基。
在一些实施方案中，式I所示化合物或其盐中R 5为C 4-C 14烷基(包括但不限于C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基)。在另一些实施方案中，式I所示化合物或其盐中R 5为C 5-C 12烷基。
在一些实施方案中，式I所示化合物或其盐中R 6为C 4-C 14烷基(包括但不限于C 4烷基、C 5烷基、C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基)。在另一些实施方案中，式I所示化合物或其盐中R 6为C 5-C 12烷基。
另一些实施方案中，式I所示化合物或其盐中R 1为C 4-C 14烯基(包括但不限于C 4烯基、C 5烯基、C 6烯基、C 7烯基、C 8烯基、C 9烯基、C 10烯基、C 11烯基、C 12烯基、C 13烯基、C 14烯基)。在另一些实施方案中，式I所示化合物或其盐中R 1为C 5-C 12烯基。
在一些实施方案中，式I所示化合物或其盐中R 2为C 4-C 14烯基(包括但不限于C 4烯基、C 5烯基、C 6烯基、C 7烯基、C 8烯基、C 9烯基、C 10烯基、C 11烯基、C 12烯基、C 13烯基、C 14烯基)。在另一些实施方案中，式I所示化合物或其盐中R 2为C 5-C 12烯基。
在一些实施方案中，式I所示化合物或其盐中R 3为C 4-C 14烯基(包括但不限于C 4烯基、C 5烯基、C 6烯基、C 7烯基、C 8烯基、C 9烯基、C 10烯基、C 11烯基、C 12烯基、C 13烯基、C 14烯基)。在另一些实施方案中，式I所示化合物或其盐中R 3为C 5-C 12烯基。
在一些实施方案中，式I所示化合物或其盐中R 4为C 4-C 14烯基(包括但不限于C 4烯基、C 5烯基、C 6烯基、C 7烯基、C 8烯基、C 9烯基、C 10烯基、C 11烯基、C 12烯基、C 13烯基、C 14烯基)。在另一些实施方案中，式I所示化合物或其盐中R 4为C 5-C 12烯基。
在一些实施方案中，式I所示化合物或其盐中R 5为C 4-C 14烯基(包括但不限于C 4烯基、C 5烯基、C 6烯基、C 7烯基、C 8烯基、C 9烯基、C 10烯基、C 11烯基、C 12烯基、C 13烯基、C 14烯基)。在另一些实施方案中，式I所示化合物或其盐中R 5为C 5-C 12烯基。
在一些实施方案中，式I所示化合物或其盐中R 6为C 4-C 14烯基(包括但不限于C 4烯基、C 5烯基、C 6烯基、C 7烯基、C 8烯基、C 9烯基、C 10烯基、C 11烯基、C 12烯基、C 13烯基、C 14烯基)。在另一些实施方案中，式I所示化合物或其盐中R 6为C 5-C 12烯基。
进一步地，在一些实施方案中，式I所示化合物或其盐中R 5为C 4-C 14烯基，R 6为C 4-C 14烯基。
在一些实施方案中，式I所示化合物或其盐中R 3为C 4-C 14烯基，R 4为C 4-C 14烯基。
在一些实施方案中，式I所示化合物或其盐中R 1为C 4-C 14烯基，R 2为C 4-C 14烯基。
进一步地，在一些实施方案中，式I所示化合物或其盐中R 1为C 4-C 14烷基，R 2为C 4-C 14烷基。
在一些实施方案中，式I所示化合物或其盐中R 3为C 4-C 14烷基，R 4为C 4-C 14烷基。
在一些实施方案中，式I所示化合物或其盐中R 5为C 4-C 14烷基，R 6为C 4-C 14烷基。
另一方面，一些实施方案提供式I所示化合物或其盐中R 1至R 6各自独立为C 4-15烷基或烯基。另一些实施方案提供式I所示化合物或其盐中R 1至R 6各自独立为C 8-16烷基或烯基。
在一些实施方案中，式I所示化合物或其盐中R 1为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 2为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 3为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 4为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 5为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 6为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 1至R 6为C 4-15烷基或C 8-16烷基。
在一些实施方案中，式I所示化合物或其盐中R 1为C 4-15烯基或C 8-16烯基。
在一些实施方案中，式I所示化合物或其盐中R 2为C 4-15烯基或C 8-16烯基。
在一些实施方案中，式I所示化合物或其盐中R 3为C 4-15烯基或C 8-16烯基。
在一些实施方案中，式I所示化合物或其盐中R 4为C 4-15烯基或C 8-16烯基。
在一些实施方案中，式I所示化合物或其盐中R 5为C 4-15烯基或C 8-16烯基。
在一些实施方案中，式I所示化合物或其盐中R 6为C 4-15烯基或C 8-16烯基。
在一些实施方案中，式I所示化合物或其盐中R 1至R 6为C 4-15烯基或C 8-16烯基。
另一方面，一些实施方案提供的式I所示化合物或其盐中R 7为氢或任选取代的C 1-3烷基。在一些实施方案中，式I所示化合物或其盐中R 7为氢、甲基或乙基。
在一些实施方案中，式I所示化合物或其盐中M 1至M 6各自独立地为-OC(O)-a1，a1为与R 1、R 2、R 3、R 4、R 5或R 6连接的键。
在另一些实施方案中，式I所示化合物或其盐中M 1、M 2各自独立地为-C(O)O-a1，a1为与R 1或R 2连接的键。
在另一些实施方案中，式I所示化合物或其盐中M 1、M 2、M 3、M 4各自独立地为-C(O)O-a1，a1为与R 1、R 2、R 3或R 4连接的键。
另一方面，在一些实施方案中，式I所示化合物或其盐中M 1、M 2、M 3和M 4为键。
在另一些实施方案中，式I所示化合物或其盐中M 5和M 6为键。
进一步地，一些实施方案提供的式I所示化合物或其盐中m1至m3各自独立地选自2、3和4。
在一些实施方案中，式I所示化合物或其盐中R 1至R 6独立地为C 4-C 14烷基或C 4-C 14烯基。
在一些实施方案中，式I所示化合物或其盐中R 1或R 2独立地选自
Figure PCTCN2022102114-appb-000002
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地选自1、2、3、4和5。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地为3。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地为4。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地为5。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地选自6、7、8、9和10。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地为7。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地为8。
在一些实施方案中，式I所示化合物或其盐中n1至n6各自独立地为9。
另一方面，本公开式I所示化合物或其盐为式II所示化合物或其盐，
Figure PCTCN2022102114-appb-000003
其中R 1至R 7、m1至m3、n1至n6如式I化合物或其盐中定义。
在一些实施方案中，式I或式II所示化合物或其盐中n1或n2各自独立地选自6、7、8、9和10。
在一些实施方案中，式II所示化合物或其盐中R 1或R 2独立地选自
Figure PCTCN2022102114-appb-000004
在一些实施方案中，式I或II所示化合物或其盐中R 7独立地为氢。
在一些实施方案中，式II所示化合物或其盐中m1至m3独立地选自2、3和4。另一方面，本公开式I所示化合物或其盐为式III所示化合物或其盐
Figure PCTCN2022102114-appb-000005
其中R 1至R 7、m1至m3、n1至n6如式I化合物或其盐中定义。
在一些实施方案中，式III所示化合物或其盐中R 7独立地为氢。
在一些实施方案中，式III所示化合物或其盐中m1至m3独立地选自2、3和4。
在一些实施方案中，式III所示化合物或其盐中n1至n6各自独立地选自6、7、8、9和10。
在一些实施方案中，式III所示化合物或其盐中R 1至R 6独立地选自
Figure PCTCN2022102114-appb-000006
在一些实施方案中，式III所示化合物或其盐中R 1至R 6独立地为
Figure PCTCN2022102114-appb-000007
式I所示典型化合物或其可药用盐，包括但不限于：
Figure PCTCN2022102114-appb-000008
Figure PCTCN2022102114-appb-000009
Figure PCTCN2022102114-appb-000010
本公开还提供一种前述的化合物或其盐的同位素取代物，优选地，所述同位素取代物为氘原子取代物。
本公开中还提供一种脂质颗粒，其包含前述化合物或其盐，或同位素取代物。进一步地，在一些实施方案中，所述脂质颗粒进一步包含活性剂，所述活性剂优选免疫刺激性寡核苷酸、siRNA、反义寡核苷酸、mRNA、质粒。
本公开还提供药物组合物，其包含前述的脂质颗粒和药学上可接受的赋形剂。在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药 学上可接受的赋形剂。
本公开还提供一种前述的化合物或其盐，或同位素取代物，或前述脂质颗粒，或前述药物组合物在制备用于诱导受试者免疫反应的药物中的用途。
本公开还提供一种前述的化合物或其盐，或同位素取代物，或前述脂质颗粒，或前述药物组合物在制备用于预防和/或治疗与多肽过表达相关的疾病或病症的药物中的用途。
本公开还提供一种前述的化合物或其盐，或同位素取代物，或前述脂质颗粒，或前述药物组合物在制备用于预防和/或治疗与多肽表达不足相关的疾病或病症的药物中的用途。
在一些实施方案中，本公开所述疾病或病症包括但不限于：癌症、感染、自身免疫疾病、神经退行性疾病和炎症，例如新冠。
本公开还提供一种用于诱导受试者免疫反应的方法，包括向所述患者施用含有前述的化合物或其盐，或前述脂质颗粒，或前述药物组合物。
本公开还提供一种预防和/或治疗与多肽过表达相关的疾病或病症的方法，包括向所述患者施用含有前述的化合物或其盐，或前述脂质颗粒，或前述药物组合物。
本公开还提供一种预防和/或治疗与多肽表达不足相关的疾病或病症的方法，包括向所述患者施用含有前述的化合物或其盐，或前述脂质颗粒，或前述药物组合物。
另一方面，本公开还提供用于诱导受试者免疫反应的前述的化合物或其盐，或前述脂质颗粒，或前述药物组合物。
本公开还提供用于预防和/或治疗与多肽过表达相关的疾病或病症的前述的化合物或其盐，或前述脂质颗粒，或前述药物组合物。
本公开还提供用于预防和/或治疗与多肽表达不足相关的疾病或病症的前述的化合物或其盐，或前述脂质颗粒，或前述药物组合物。
本公开中所述化合物盐包括“酸”加成盐和“碱”加成盐。例如，通过与碱性基团(氨基)的酸-碱反应形成的盐，所述酸包括有机酸或无机酸。另外，所述化合物盐还包括通过与碱性基团(氨基)的季胺化形成的盐，所述季胺化试剂包括直链或支链式的氯代烃。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆 分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本公开所述化合物的化学结构中，键
Figure PCTCN2022102114-appb-000011
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022102114-appb-000012
可以为
Figure PCTCN2022102114-appb-000013
或
Figure PCTCN2022102114-appb-000014
或者同时包含
Figure PCTCN2022102114-appb-000015
和
Figure PCTCN2022102114-appb-000016
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022102114-appb-000017
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022102114-appb-000018
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至 少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
术语“核酸”、“核酸分子”、“寡核苷酸”、“多核苷酸”和“核苷酸”在本文中可以可互换地使用。该术语涉及脱氧核糖核苷酸(DNA)、核糖核苷酸(RNA)及其修饰的形式的聚合物，所述聚合物呈单独的片段或作为较大构建体的组分、直链或支链的、单链、双链、三链或其杂合体的形式。该术语还包括RNA/DNA杂合体。多核苷酸可以包括DNA或RNA的有义寡核苷酸和反义寡核苷酸(sense and antisense oligonucleotide)或多核苷酸序列。DNA或RNA分子可以是，例如，但不限于：互补DNA(cDNA)、基因组DNA、合成的DNA、重组DNA或其杂合体，或RNA分子，诸如，例如，mRNA、shRNA、siRNA、miRNA、反义RNA和类似物。每种可能性代表本发明的单独实施方案。该术语还包括包含天然存在的碱基、糖和共价的核苷间键的寡核苷酸，以及具有非天然存在的部分的寡核苷酸，所述非天然存在的部分的功能类似于相应的天然存在的部分。术语“多肽”、“肽”和“蛋白质”在本文中可互换地用于指氨基酸残基的聚合物。该术语应用于其中 一个或更多个氨基酸残基是相应的天然存在的氨基酸的人工化学类似物的氨基酸聚合物，以及应用于天然存在的氨基酸聚合物。
术语“白细胞”涉及产生自和源自骨髓中的多能造血干细胞的白细胞(WBC)。白细胞具有细胞核，并且基于功能特性或物理特性，白细胞的类型可以分为五种主要类型，包括中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、淋巴细胞和单核细胞。
“烷基”指饱和的脂族烃基团，包括但不限于直链和支链烷基基团。在一些实施方案中，烷基基团具有1-4个碳，也被称为C 1-4烷基。在一些实施方案中，烷基基团具有10-22个碳，也被称为C 10-22烷基。在一些实施方案中，烷基基团具有4-22个碳，也被称为C 4-22烷基。在一些实施方案中，烷基基团具有4-15个碳，也被称为C 4-15烷基。在一些实施方案中，烷基基团具有8-16个碳，也被称为C 8-16烷基。
烷基基团可以是未被取代的或被一个或更多个选自卤素、羟基、氨基、氧代、烷氧基羰基、酰氨基、烷基酰氨基、二烷基酰氨基、硝基、氨基、烷基氨基、二烷基氨基、羧基、硫代和硫代烷基的基团取代。在一些实施方案中，烷基基团为直链烷基。在一些实施方案中，烷基基团为支链烷基。
“烯基”指不饱和的脂族烃基团，包括直链和支链烯基基团。在一些实施方案中，烯基基团具有1-4个碳，也被称为C 1-4烯基。在一些实施方案中，烯基基团具有10-22个碳，也被称为C 10-22烯基。在一些实施方案中，烯基基团具有4-22个碳，也被称为C 4-22烯基。示例性的烯基基团包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、庚烯基、辛烯基、环己基-丁烯基和癸烯基。
烯基可以是未被取代的或被一个或更多个选自卤素、羟基、氨基、氧代、烷氧基羰基、酰氨基、烷基酰氨基、二烷基酰氨基、硝基、氨基、烷基氨基、二烷基氨基、羧基、硫代和硫代烷基的基团取代。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-NH 2。
术语“氧代”指＝O取代基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。
附图说明
图1：经选定脂质(化合物1-3与对比化合物1和2)递送后，细胞内mRNA荧光素酶表达量比较。
图2：经选定脂质(化合物1-3与对比化合物1)递送后，小鼠注射部位mRNA荧光素酶表达量比较。
图3：经选定脂质(化合物1、3与对比化合物1)递送后，体内肌肉注射生长因子蛋白表达量比较。
图4：经选定脂质(化合物1、2与对比化合物1)递送后，小鼠全身的mRNA荧光素酶表达量比较。
图5：经选定脂质(化合物4与对比化合物1)递送后，小鼠肺部的mRNA荧光素酶表达量比较。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(Methanol-d 4)，内标为四甲基硅烷(TMS)。
HPLC的测定使用Agilent1100高压液相色谱仪，GAS15B DAD紫外检测器，Water Vbridge C18 150*4.6mm 5um色谱柱。
MS的测定用Agilent6120三重四级杆质谱仪，G1315D DAD检测器，Waters Xbridge C18 4.6*50mm,5um色谱柱，以正/负离子模式扫描，质量扫描范围为80～1200。
薄层层析硅胶板使用烟台黄海HSGF254硅胶板，薄层色谱法(TLC)使用硅胶板采用规格是0.2mm±0.03mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60g，24g，40g，120g或其它规格)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)，毕得医药等公司。
实施例中无特殊说明，反应能够均在氮气氛下进行。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢气是由上海全浦科学仪器公司QPH-1L型氢气发生仪制得。
氮气氛或氢化氛通常抽真空，充入氮气或氢气，反复操作3次。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
二(辛烷-4-基)9,9'-((3-(3,5-双((3-(二(十二烷基氨基))丙基)氨基甲酰基)苯甲酰胺基)丙基)氮烷基二基)二壬酸酯
Figure PCTCN2022102114-appb-000019
化合物E的制备
Figure PCTCN2022102114-appb-000020
于氮气保护下，将化合物E1(13g,55mmol)和化合物E2(6.5g,50mmol)溶解于DCM(65mL)，加入DMAP(1.8g,15mmol)和EDCI(14.4g,75mmol)，室温下反应，TLC(EA/PE＝1/10)显示反应达到终点，将反应液与硅胶(100-200目)拌样浓缩，100-200目硅胶柱层析EA/PE＝1/30得14.14g油状物化合物E3，收 率：81.2％。
1H NMR(400MHz,CDCl 3)：δ4.92-4.83(m,1H),3.42-3.32(m,2H),2.30-2.23(m,2H),1.87-1.73(m,2H),1.63-1.18(m,20H),0.96-0.89(m,6H)。
于氮气保护下，将化合物E3(9.0g,25.8mmol)和化合物V2(1.8g,10.3mmol)溶解于DMF(18mL)中，加入K 2CO 3(3.56g,25.8mmol)，80℃反应,TLC(MeOH/DCM＝1/10)检测反应完全,乙酸乙酯(100mL)稀释，用水洗3次，硫酸钠干燥，过滤浓缩，硅胶柱纯化，MeOH/DCM体系，MeOH％：0％→15％，得到2.54g油状物化合物E4，产率34.6％。
1H NMR(400MHz,CDCl 3)：δ5.20(bs,1H),4.92-4.83(m,2H),3.47-3.32(m,2H),2.68-2.22(m,10H),1.87-1.39(m,46H),0.93-0.85(m,12H)。
将化合物E4(2.54g,3.58mmol)溶解于1,4-二氧六环(10mL)中，室温下加入4M HCl(10mL,40.0mmol)，室温下反应2小时，LCMS显示反应结束，浓缩至干，得2.15g粗品化合物E，产率88.5％。
MS m/z(ESI):611.5[M+1] +。
化合物V的制备
Figure PCTCN2022102114-appb-000021
于氮气保护下，将化合物V1(10.7g,42.9mmol)和化合物V3(3.0g,17.2mmol)溶解于DMF(30mL)中，加入碳酸钾(5.95g,43.1mmol)，80℃加热反应过夜，反应液用乙酸乙酯稀释，用水洗后，再用少量乙酸乙酯反萃水相，合并有机相，水洗3次，食盐水洗一次，硫酸钠干燥，过滤浓缩，快速柱层析纯化，洗脱体系MeOH/DCM，MeOH％：0％-5％(5min)→5％-10％(10min)→10％-15％(15min)得3.8克油状物化合物V2，产率43.2％。
1H NMR(400MHz,CDCl 3)：δ5.74(s,1H),3.25-3.09(m,2H),2.55-2.25(m,6H),1.69-1.54(m,2H),1.50-1.16(m,49H),0.88(t,6H)。
将化合物V2(2.0g,3.91mmol)溶解于1,4-二氧六环(18mL)中，室温下加入4M HCl(6mL,24.0mmol)，50℃下反应1.0～3.0小时，浓缩至干得1.92g粗品化合物V，所得粗品直接用于下一步。
MS m/z(ESI):411.5[M+1] +
步骤1：化合物1b的制备
Figure PCTCN2022102114-appb-000022
将化合物V(800mg,1.66mmol)和化合物1a(185mg,0.83mmol采用公知的方法“Tetrahedron Letters,2011,52(1),155-158”制备而得))溶解于DCM(8mL)中,加入EDCI(478mg,2.49mmol)，DMAP(101mg,0.83mmol)和三乙胺(340μL,2.49mmol)，反应于室温下搅拌过夜,乙酸乙酯稀释，水洗一次，硫酸钠干燥，过滤浓缩，快速柱层析纯化，洗脱体系MeOH/DCM，MeOH％：0％-10％(10min)→10％(5min)→10％-20％(10min)→20％-30％(10min)得340mg油状物化合物1b，产率40.8％。
1H NMR(400MHz,CDCl 3):δ8.98(s,2H),8.54(s,3H),3.94(s,3H),3.64-3.52(m,4H),2.75-2.60(m,4H),2.60-2.37(m,8H),1.93-1.68(m,4H),1.57-1.39(m,8H),1.37-1.03(m,72H),0.88(t,12H)。
步骤2：化合物1c的制备
Figure PCTCN2022102114-appb-000023
将化合物1b(340mg,0.337mmol)溶解于THF/MeOH(1/1，8mL)中,加入LiOH-H 2O(33.6mg,0.80mmol)，于50℃下加热反应完全,用稀盐酸和饱和碳酸氢钠溶液调节pH至7-8之间，并于室温放置过夜，浓缩，用三乙胺调节pH至11左右，再用大板纯化(MeOH/DCM＝1/5)得153g化合物1c，产率45.7％。
1H NMR(400MHz,CDCl 3):δ8.90(s,2H),8.57(s,1H),3.72-3.45(m,4H),3.11-2.40(m,12H),2.17-1.85(m,4H),1.71-1.46(m,8H),1.37-0.96(m,72H),0.86(t,12H)。
步骤3：化合物1的制备
Figure PCTCN2022102114-appb-000024
氮气保护下，将化合物1c(200mg,0.201mmol)溶解于THF(5mL)中，加入1滴DMF，加入SOCl 2(598mg,5.02mmol)，于室温34℃下加热反应3小时，减压蒸出溶剂，油泵抽干；粗品待用,氮气保护下，在另外一个瓶中称取化合物E(177mg,0.26mmol)，用无水二氯甲烷(3ml)溶解，加入三乙胺(202mg,2mmol)，将反应置于冰水浴中搅拌10～30分钟,，将前面得到的粗品一次性加入到该反应液中，自然升至室温反应过夜，反应液直接通过硅胶柱(300-400目，二氯甲烷/甲醇＝20:1-10:1)分离纯化，得到83mg油状化合物1，收率26％。
MS m/z(ESI):795.3[M/2+1] +。
1H NMR(400MHz,CDCl 3):δ8.70(s,3H),8.52(bs,3H),4.92-4.83(m,2H),3.62-3.52(m,6H),3.12-2.82(m,18H),2.30-2.23(m,4H),2.18-2.02(m,6H),1.77-1.43(m,24H),1.39-1.18(m,100H),0.93-0.85(m,24H)。
实施例2
辛-4-基9-((3-(3,5-双((3-(二(十二烷基氨基))丙基)氨基甲酰基)苯甲酰胺基)丙基)(十二烷基)氨基)壬酸酯
Figure PCTCN2022102114-appb-000025
步骤1：化合物2b的制备
Figure PCTCN2022102114-appb-000026
于氮气保护下，将化合物E3(2.5g,7.15mmol)和2a(12.4mg,71.5mmol)溶解于EtOH(10mL)中，室温(25-30℃)下反应24h，反应液用石油醚和水分层，再用水洗2次，硫酸钠干燥，过滤浓缩，快速柱层析层析，洗脱剂MeOH/DCM，MeOH：0％→25％，得1.7g油状化合物2b，产率53.8％。
MS m/z(ESI):443.4[M+1] +。
1H NMR(400MHz,CDCl 3)：δ5.20(bs,1H),4.92-4.83(m,1H),3.27-3.12(m,2H),2.70(t,2H),2.60(t,2H),2.27(t,2H),2.20(bs,1H),1.75-1.52(m,4H),1.51-1.42(m,15H),1.41-1.22(m,14H),0.93-0.85(m,6H)。
步骤2：化合物2c的制备
Figure PCTCN2022102114-appb-000027
于氮气保护下，将化合物V1(675mg,2.71mmol)和2b(1.0g,2.26mmol)溶解于DMF(4mL)中，加入碳酸钾(374mg,2.71mmol)，80℃加热反应过夜，反应液用乙酸乙酯稀释，用水洗后，再用少量乙酸乙酯反萃水相，合并有机相，水洗3次，食盐水洗一次，硫酸钠干燥，过滤浓缩，快速柱层析纯化，洗脱体系MeOH/DCM，MeOH％：0％→25％(30min)得0.92克油状化合物2c，产率66.7％。
1H NMR(400MHz,CDCl 3)：δ5.72(bs,1H),4.92-4.83(m,1H),3.27-3.12(m,2H),2.60-2.30(m,4H),2.27(t,2H),1.72-1.56(m,4H),1.51-1.22(m,51H),0.93-0.85(m,9H)。
步骤3：化合物2d的制备
Figure PCTCN2022102114-appb-000028
将化合物2c(0.92g,1.5mmol)溶解于1,4-二氧六环(2mL)中，HCl 4M in 1,4-二氧六环(2mL,8mmol)于室温下加入，室温(25-30℃)下反应，LCMS监测得反应基本完全，反应液直接浓缩并于油泵上抽2小时，所得粗品化合物2d直接用于下一步。
MS m/z(ESI):511.5[M+1] +。
步骤4：化合物2的制备
Figure PCTCN2022102114-appb-000029
将化合物1c(140mg,0.14mmol)和2d(107mg,0.18mmol)溶解于DCM(2mL)中，加入HATU(80mg,0.21mmol)和三乙胺(39μL,0.28mmol)，反应于室温下搅拌，TLC监测反应基本完全，乙酸乙酯稀释，用碳酸氢钠溶液洗一次，水洗两次，浓缩，制备板纯化，展开剂(MeOH/DCM＝1/5)/(EA/PE＝1/1)＝1.2/0.8，得113mg油状化合物2，产率54.1％。纯度：99.4％。
MS m/z(ESI):1488.9[M+1] +。
1H NMR(400MHz,CDCl 3):δ8.79-8.21(m,6H),4.97-4.82(m,1H),3.68-3.50(m,6H),2.91-2.41(m,18H),2.26(t,J＝7.4Hz,2H),1.94-1.71(m,6H),1.66-1.12(m,122H),0.96-0.81(m,21H)。
实施例3
2,2'-((3-(3,5-双((3-(二(十二烷基氨基))丙基)氨基甲酰基)苯甲酰胺基)丙基)氮烷基二基)二乙酸二壬酯
Figure PCTCN2022102114-appb-000030
步骤1：化合物3b的制备
Figure PCTCN2022102114-appb-000031
将化合物3a(1.0g,4.25mmol，1.0eq)和V3(0.32g，1.85mmol，2.3eq)溶于ACN(10mL)，然后依次加入碳酸钾(0.59g,1.85mmol,2.3eq)和KI(0.71g,1.85mmol,2.3eq，氮气保护下在75℃下搅拌4-10h，反应液减压浓缩除去溶剂，残留物加入EA(30ml)溶解后用饱和碳酸氢钠洗(20ml×2)、饱和食盐水(20mL)洗一次，用无水硫酸钠干燥，减压浓缩，用柱层析纯化(100-200目，PE/EA＝5:1)得到750mg化合物3b，收率37％。
MS m/z(ESI):543.5[M+1] +。
1H NMR(400MHz,CDCl 3):δ4.11-4.08(m,4H),3.50(s,4H),2.75(s,2H),1.64-1.61(m,8H),1.43(s,9H),1.30-1.26(m,25H),0.89-0.85(m,6H)。
步骤2：化合物3c的制备
Figure PCTCN2022102114-appb-000032
化合物3b(0.75g，1.38mmol,1.0eq)溶解于1,4-二氧六环(4mL)中，于室温下加入HCl 4M的1,4-二氧六环溶液(16ml)，搅拌反应，LCMS检测显示反应完成。直接减压浓缩至干得到659mg化合物3c，收率：100％。
MS m/z(ESI):443.4[M+1] +。
步骤3：化合物3的制备
Figure PCTCN2022102114-appb-000033
将化合物3c(0.66g，1.24mmol,1.3eq)和化合物1c(1.02g,0.96mmol，1.0eq)溶于DCM(20ml)中，然后依次加入HOBT(0.16g,1.15mmol,1.2eq)、EDCI(0.37g,1.91mmol,2.0eq)和DIEPA(0.62g，4.78mmol，5.0eq)，氮气保护下搅拌15～20h，反应液减压浓缩除去溶剂，残留物加入EA(30ml)溶解后用饱和碳酸氢钠洗(20ml×2)、饱和食盐水(20mL)洗一次，用无水硫酸钠干燥，减压浓缩，用反相柱层析纯化(H 2O/ACN，95％出产物)得到1.02g化合物3，收率77.78％，纯度：96.2％。
MS m/z(ESI):1420.9[M+1] +。
1H NMR(400MHz,CD3OD):δ8.49(s,3H),4.12-4.06(m,4H),3.63-3.48(m,9H),3.13-2.81(m,12H),2.01-1.97(m,6H),1.80-1.78(m,2H),1.63-1.58(m,12H),1.34-1.22(m,98H),0.91-0.87(m,18H)。
实施例4
((((苯-1,3,5-三羰基)三(氮烷基二基))三(丁烷-4,1-二基))三(氮烷基三基))六(己烷-6,1-二基)六(2-己基癸酸酯))
Figure PCTCN2022102114-appb-000034
步骤1：化合物4c的制备
于氮气保护下，将化合物4a(6.4g,35.3mmol)和4b(10.0g,39.0mmol)溶解于DCM(64mL)中，加入DMAP(1.3g,10.6mmol)和EDCI(10.2g,53.2mmol)，室温下反应，TLC(EA/PE＝1/10)显示反应完全，浓缩，纯化得8.9g油状化合物4c，产率：57.8％。
1H NMR(400MHz,CDCl 3):δ4.07(t,J＝6.6Hz,2H),3.40(t,J＝6.8Hz,2H),2.35-2.26(m,1H),1.93-1.81(m,2H),1.70-1.15(m,30H),0.87(t,J＝6.3Hz,6H)。
步骤2：化合物4e的制备
Figure PCTCN2022102114-appb-000035
于氮气保护下，将化合物4c(5.9g,14.1mmol)和4d(1.0g,5.7mmol)溶解于DMF(10mL)中，加入K 2CO 3(1.9g,13.7mmol)，80℃反应，TLC(MeOH/DCM＝1/10)检测基本反应完全，乙酸乙酯(100mL)稀释，用水洗，有机相硫酸钠干燥，过滤浓缩，纯化得0.96g油状化合物4e，产率19.3％。
1H NMR(400MHz,CDCl 3):δ5.00(s,1H),4.06(t,J＝6.7Hz,4H),3.18-3.04(m,2H),2.06-2.16(m,8H),1.72-1.52(m,12H),1.52-1.10(m,65H),0.87(t,J＝6.1Hz,12H)。
步骤3：化合物4f的制备
Figure PCTCN2022102114-appb-000036
室温下，将化合物4e(0.96g,1.1mmol)溶解于1,4-二氧六环(5mL)中，加入HCl(4M 1,4-二氧六环，5mL,20.0mmol)，室温下反应2～6小时，反应液直接浓缩至干，所得粗品直接用于下一步。
步骤4：化合物4的制备
Figure PCTCN2022102114-appb-000037
于氮气保护下，将粗品化合物4f(约1.1mmol)溶解于DCM(10mL)中，加入化合物4g(84mg,0.32mmol)，加入三乙胺(354μL,2.55mmol)，于室温下反应15～18小时，将反应液与硅胶(100-200目)拌样浓缩，200-300目硅胶柱层析(MeOH/DCM＝1/10)/(EA/PE＝1/1)＝3/1得到粗品670mg，取约320mg部分进一步大板纯化，展开剂为(MeOH/DCM＝1/5)/(EA/PE＝1/1)＝3/1，得202mg油状化合物4，两步收率26.0％。
1H NMR(400MHz,CDCl 3):δ8.40(s,3H),7.04(s,3H),4.04(t,J＝6.6Hz,12H),3.55-3.41(m,6H),2.62-2.36(m,18H),2.36-2.11(m,12H),1.74-1.50(m,36H),1.50-1.09(m,162H),0.87(t,J＝6.0Hz,36H)。
实施例5
N-(3-(3,5-双((3-(二(十二烷基氨基))丙基)氨基甲酰基)苯甲酰氨基)丙基)-N-十二烷基甘氨酸壬基酯
Figure PCTCN2022102114-appb-000038
步骤1：化合物5c的制备
Figure PCTCN2022102114-appb-000039
在25mL三口瓶中，依次加入化合物5a(1.3g,3.8mmol)，DMF(13mL)，化合物5b(1.0g,3.8mmol)和碳酸钾(524mg,3.8mmol)，氮气保护下置换三次，开启搅拌，加热内温110℃2h。取样LC-MS检测显示有目标产物的质谱峰，原料少量剩余。停止反应，将反应液降温到25℃，加入150mL的水，随后用EtOAc(60mL×3)萃取，有机相合并，依次水洗(60mL)，饱和食盐水洗(60mL)，无水硫酸钠(5g)干燥，过滤蒸干得到粗品。经过硅胶柱层析(PE/EA＝20/1-10/1-5/1)分离得到油状化合物5c(1.860g，收率：93.0％)。
Ms(ESI)：m/z 527.5[M+H] +。
步骤2：化合物5d的制备
Figure PCTCN2022102114-appb-000040
在25mL单口瓶中，依次加入化合物5c(1.7g,3.2mmol)，4N HCl(二氧六环中)(10mL)，氮气保护下置换一次，开启搅拌，室温23-26℃搅拌2h，取样LC-MS检测显示原料反应完毕。停止反应，减压浓缩得到白色固体化合物5d(1.8g,收率：111.6％)。
Ms(ESI)：m/z 427.4[M+H] +。
步骤3：化合物5的制备
Figure PCTCN2022102114-appb-000041
在100mL三口瓶中，依次加入化合物1c(2.0g,2.01mmol)，无水DCM(40mL)，化合物5d(1.2g,2.41mmol)和DIEA(2.1mL,12mmol)，氩气保护下置换三次，开启搅拌，冰水浴冷却到5℃。一次性加入HATU(917mg,2.41mmol)内温小于10℃搅拌30分钟，然后室温25-32℃搅拌19h，取样HPLC检测显示原料反应完毕，停止反应，加入50mL二氯甲烷稀释，一次用饱和碳酸氢钠溶液(30mL)和饱和食盐水洗，无水硫酸钠(5g)干燥，过滤蒸干得到粗品。经过200-300目的正相硅胶柱层析(PE/EtOH＝0％-60％)得到油状物，然后Pre-TLC(DCM/MeOH＝20/1)得到油状化合物5(526mg，收率：18.6％，HPLC纯度94.63％)。
MS m/z(ESI):1404.8[M+1] +。
1H NMR(400MHz,CDCl 3):δ8.47(s,3H),8.33(s,3H),4.10-4.02(t,2H),3.66-3.52(m,6H),3.32(s,2H),2.70-2.48(m,16H),1.74-1.43(m,18H),1.33-1.29(m,12H),1.27-1.14(m,90H),0.89-0.83(m,18H)。
对比实施例1
Figure PCTCN2022102114-appb-000042
对比化合物1
采用“Nano Lett.2015,15,8099-8107和WO2016187531A1”中方法制备而得。
对比实施例2
Figure PCTCN2022102114-appb-000043
对比化合物2
采用“WO2019099501A1”中方法制备而得。
测试例1：脂质颗粒组合物递送能力
1.1制备方法
分别将化合物1、2、3、4和对比化合物1、2溶于乙醇溶液，与溶于乙醇的DOPE、胆固醇、DMG-PEG溶液，以20：30：40：0.75的摩尔比混合配制乙醇脂 质溶液。将编码表达荧光素酶的mRNA(GenBank:MN728548.1)溶于柠檬酸盐缓冲液，配制mRNA水溶液。将乙醇脂质溶液和mRNA水溶液通过微流体混合，总脂质与mRNA的重量比约为12-36：1制备脂质体。在PBS溶液中透析去除乙醇，得到包封编码荧光素酶mRNA的脂质体纳米颗粒(LNP)制剂。
1.2脂质纳米颗粒组合物的表征
使用Malvern Zetasizer Nano ZS,以173°反向散射检测模式，利用动态光散射检测脂质体纳米颗粒的纳米尺寸和多分散系数(PDI)。
使用Quant-iT RiboGreen RNA Assay Kit RNA定量检测试剂盒(购于赛默飞世尔科技，货号R11490)，测定脂质体包封率。
使用基于6-(p-甲苯胺)-2-萘磺酸钠盐(TNS)的荧光分析，测定脂质体纳米颗粒中阳离子的pKa。配制150mM NaCl，10mM磷酸钠，10mM柠檬酸钠，10mM硼酸钠，pH 3-11.5不同pH的缓冲液。配制300μM TNS溶液，加入到缓冲液中。将脂质纳米颗粒分别加入到不同pH的缓冲液中，充分混合后，使用荧光酶标仪在室温下检测激发波长325nm，发射波长435nm的荧光强度。对荧光数据拟合分析，pKa为产生半数最大荧光强度的pH值。相关数据见表1。
表1
Figure PCTCN2022102114-appb-000044
1.3评估脂质颗粒组合物在细胞水平的mRNA表达效率
以对比化合物1和2对应的脂质体纳米颗粒为对照，检测化合物1-3对应的脂质体纳米颗粒的体外细胞水平的mRNA表达效率。
将HEK 293细胞接种到细胞孔板培养过夜，待细胞密度达到80％以上，将包封荧光素酶mRNA的脂质体LNP溶液加入到细胞板孔培养基中。24小时后，使用荧光素酶报告基因检测试剂盒(Promega)和酶标仪检测表达荧光素酶蛋白的荧光强度。荧光强度值即酶标仪检测到的荧光数值。每个化合物对应的LNP至少3组重复计算平均荧光值强度和统计学差异，数据见表2和图1。
图1中*即统计学0.01<P<0.05，表示组间具有统计学显著性差异，**即统计学P<0.01，***即统计学P<0.001表示极显著性差异。
表2
编号 平均荧光强度值
化合物1 6.47E+06
化合物2 4.09E+06
化合物3 4.58E+06
对比化合物1 3.38E+06
对比化合物2 2.61E+06
结论：如表2和图1所示荧光强度，化合物1、2和3对应的脂质纳米颗粒在细胞中递送mRNA表达荧光素酶表达量优于对比化合物1和对比化合物2。
1.4评估脂质颗粒组合物体内肌肉注射递送mRNA表达效率
为评估脂质体纳米颗粒在体内有效递送mRNA并表达相应编码的蛋白质，以0.25mg/kg的剂量对6-8周龄雌性BALB/c大腿肌肉部位注射包封有表达荧光素酶的mRNA脂质体纳米颗粒。6小时后，分别向每只小鼠腹腔注射荧光素酶底物，使用IVIS小动物光学活体成像仪器(PerkinElme)，拍摄小鼠的荧光图片，并统计注射部位的荧光强度。荧光强度的高低代表荧光素酶蛋白的表达量高低，即反应脂质体纳米颗粒体内递送mRNA的效率。表3和图2中荧光强度即IVIS小动物光学活体成像仪拍摄统计的小鼠注射部位的荧光强度。每个化合物对应的LNP至少3组重复计算平均荧光值强度。
以对比化合物1对应的脂质体纳米颗粒为对照，检测化合物1、2和3对应的脂质体纳米颗粒的体内肌肉注射mRNA递送效率。相关数据见表3和图2。
图2中*即统计学0.01<P<0.05，表示组间具有统计学显著性差异，**即统计学P<0.01，***即统计学P<0.001表示极显著性差异。
表3
编号 平均荧光强度值
化合物1 1.80E+08
化合物2 1.55E+08
化合物3 4.65E+07
对比化合物1 4.19E+07
结论：如表3和图2所示荧光强度，化合物1、2和3对应的脂质纳米颗粒体内肌肉注射递送mRNA，效果优于对比化合物1。
1.5评估脂质颗粒体内肌肉注射递送mRNA后的蛋白表达量
为评估脂质体纳米颗粒将mRNA在体内有效递送mRNA并表达相应编码的蛋白质，以0.05mg/kg的剂量对6-8周龄雌性BALB/c大腿肌肉部位注射包封有表达生长因子的mRNA(NCBI Reference Sequence:NM_000601.6)脂质体纳米颗粒。24小时后取注射部位肌肉，经研磨裂解后，使用ELISA试剂盒检测生长因子蛋白表达量(pg/mg)，即单位肌肉组织总蛋白量对应的生长因子蛋白量。每个化合物对应的LNP至少3组重复计算平均蛋白浓度。
以对比化合物1对应的脂质体纳米颗粒为对照，检测化合物1和3对应的脂 质体纳米颗粒的体内肌肉注射mRNA后的蛋白表达量，即mRNA体内肌肉注射的递送效率。相关数据见表4和图3。
图3中*即统计学0.01<P<0.05，表示组间具有统计学显著性差异，**即统计学P<0.01，***即统计学P<0.001表示极显著性差异。
表4
编号 平均蛋白表达量(pg/mg)
化合物1 121.4
化合物3 94.7
对比化合物1 43.6
结论：如表4和图3所示蛋白表达量，化合物1和3对应的LNP体内肌肉注射递送mRNA，蛋白表达量显著高于对比化合物1。
1.6评估脂质颗粒组合物体内尾静脉注射mRNA表达效率
为评估脂质体纳米颗粒将mRNA在体内有效递送mRNA并表达相应编码的蛋白质，以0.5mg/kg的剂量对6-8周龄雌性BALB/c尾静脉注射包封有表达荧光素酶的mRNA脂质体纳米颗粒。6小时后，分别向每只小鼠腹腔注射荧光素酶底物，使用IVIS小动物光学活体成像仪器(PerkinElme)，拍摄小鼠的荧光图片，并统计小鼠全身的荧光强度。荧光强度的高低代表荧光素酶蛋白的表达量高低，即反应脂质体纳米颗粒体内递送mRNA的效率。每个化合物对应的LNP至少3组重复计算平均荧光值强度，数据见表5和图4。
图4中荧光强度即IVIS小动物光学活体成像仪拍摄统计的小鼠全身的荧光强度。
以对比化合物1对应的脂质体纳米颗粒为对照，检测化合物1和2对应的脂质体纳米颗粒的体内尾静脉注射的mRNA递送效率。
图4中*即统计学0.01<P<0.05，表示组间具有统计学显著性差异，**即统计学P<0.01，***即统计学P<0.001表示极显著性差异。
表5
编号 平均荧光强度值
化合物1 7.47E+08
化合物2 9.69E+08
对比化合物1 3.98E+08
结论：如表5和图4所示荧光强度，化合物1和2对应的mRNA脂质纳米颗粒尾静脉注射，蛋白表达量显著优于对比化合物1。
1.7评估脂质颗粒组合物体内尾静脉注射mRNA肺部表达效率
为评估脂质体纳米颗粒将mRNA在肺部有效递送mRNA并表达相应编码的蛋白质，以0.5mg/kg的剂量对6-8周龄雌性BALB/c尾静脉注射包封有表达荧光素酶的mRNA脂质体纳米颗粒。6小时后，分别向每只小鼠腹腔注射荧光素酶底物 后，取小鼠肺部组织，使用IVIS小动物光学活体成像仪器(PerkinElme)，拍摄荧光图片，并统计荧光强度。荧光强度的高低代表荧光素酶蛋白的表达量高低，即反应脂质体纳米颗粒体内递送mRNA的效率。每个化合物对应的LNP至少3组重复计算平均荧光值强度，数据见表6和图5。
图5中*即统计学0.01<P<0.05，表示组间具有统计学显著性差异，**即统计学P<0.01，***即统计学P<0.001表示极显著性差异。
表6
编号 平均荧光强度值
化合物4 1.72E+06
对比化合物1 4.74E+05
结论：如表6和图5所示荧光强度，化合物4对应的mRNA脂质纳米颗粒尾静脉注射，肺部蛋白表达量显著优于对比化合物1。

Claims (21)

  1. 式I所示化合物或其盐
    Figure PCTCN2022102114-appb-100001
    其中，M 1至M 6各自独立地选自键、-C(O)O-a1和-OC(O)-a1，a1为与R 1、R 2、R 3、R 4、R 5或R 6连接的键，且M 1至M 6不全为-C(O)O-a1或键；
    R 1至R 6各自独立地为取代或未被取代的烷基或取代或未被取代的烯基；
    R 7各自独立地为氢或取代或未被取代的C 1-6烷基；
    m1至m3各自独立地选自1、2、3、4、5、6、7和8；
    n1至n6各自独立地选自0、1、2、3、4、5、6、7、8、9和10。
  2. 根据权利要求1所述的化合物或其盐，其中R 1至R 6各自独立地为未被取代的烷基或未被取代的烯基，优选C 4-C 14烷基或C 4-C 14烯基。
  3. 根据权利要求1或2所述的化合物或其盐，其中R 1为C 4-C 14烷基，优选C 5-C 12烷基。
  4. 根据权利要求1-3中任一项所述的化合物或其盐，其中R 2为C 4-C 14烷基，优选C 5-C 12烷基。
  5. 根据权利要求1-4中任一项所述的化合物或其盐，其中R 3为C 4-C 14烷基，优选C 5-C 12烷基；和/或R 4为C 4-C 14烷基，优选C 5-C 12烷基；和/或R 5为C 4-C 14烷基，优选C 5-C 12烷基；和/或R 6为C 4-C 14烷基，优选C 5-C 12烷基。
  6. 根据权利要求1-5中任一项所述的化合物或其盐，其中R 7为氢或任选取代的C 1-3烷基，优选氢、甲基或乙基。
  7. 根据权利要求1-6中任一项所述的化合物或其盐，其中M 1至M 6各自独立地为-OC(O)-a1，a1为连接R 1、R 2、R 3、R 4、R 5或R 6的键。
  8. 根据权利要求1-6中任一项所述的化合物或其盐，其中M 1和M 2各自独立地为-C(O)O-a1，a1为与R 1或R 2连接的键。
  9. 根据权利要求1-6中任一项所述的化合物或其盐，其中M 1、M 2、M 3和M 4各自独立地为-C(O)O-a1，a1为与R 1、R 2、R 3或R 4连接的键。
  10. 根据权利要求1-9中任一项所述的化合物或其盐，其中m1至m3各自独立地选自2、3和4。
  11. 根据权利要求1-10中任一项所述的化合物或其盐，其中n1至n6各自独立地选自6、7、8、9和10。
  12. 根据权利要求1或8所述的化合物或其盐，其中式I所示化合物或其盐为式II所示化合物或其盐，
    Figure PCTCN2022102114-appb-100002
    其中R 1至R 7、m1至m3、n1至n6如权利要求1中定义。
  13. 根据权利要求1或7所述的化合物或其盐，其中式I所示化合物或其盐为式III所示化合物或其盐，
    Figure PCTCN2022102114-appb-100003
    其中R 1至R 7、m1至m3、n1至n6如权利要求1中定义。
  14. 根据权利要求1所述的化合物或其盐，其中R 1和R 2各自独立地选自
    Figure PCTCN2022102114-appb-100004
  15. 式I所示化合物或其盐
    Figure PCTCN2022102114-appb-100005
    Figure PCTCN2022102114-appb-100006
    Figure PCTCN2022102114-appb-100007
  16. 一种根据权利要求1-15中任一项所述的化合物或其盐的同位素取代物，优选地，所述的同位素取代物为氘原子取代物。
  17. 一种脂质颗粒，其包含根据权利要求1-15中任一项所述的化合物或其盐，或根据权利要求16所述的同位素取代物，进一步包含活性剂，所述活性剂优选选自免疫刺激性寡核苷酸、siRNA、反义寡核苷酸、mRNA和质粒。
  18. 一种药物组合物，其包含根据权利要求17所述的脂质颗粒和药学上可接受的赋形剂。
  19. 根据权利要求1-15中任一项所述的化合物或其盐、或根据权利要求16所述的同位素取代物、或根据权利要求17所述的脂质颗粒、或根据权利要求18所述的药物组合物在制备用于诱导受试者免疫反应的药物中的用途。
  20. 根据权利要求1-15中任一项所述的化合物或其盐、或根据权利要求16所述的同位素取代物、或根据权利要求17所述的脂质颗粒、或根据权利要求18所述的药物组合物在制备用于预防和/或治疗与多肽过表达相关的疾病或病症的药物中的用途。
  21. 根据权利要求1-15任一项所述的化合物或其盐、或根据权利要求16所述的同位素取代物、或根据权利要求17所述的脂质颗粒、或根据权利要求18所述的药物组合物在制备用于预防和/或治疗与多肽表达不足相关的疾病或病症的药物中的用途。
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