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WO2023274265A1 - Composé benzamide et son utilisation - Google Patents

Composé benzamide et son utilisation 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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Prior art keywords
compound
salt
alkyl
alkenyl
formula
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Ceased
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PCT/CN2022/102114
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English (en)
Chinese (zh)
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
Original Assignee
Jiangsu Hengrui Pharmaceutical Co Ltd
Shanghai Shengdi Pharmaceutical Co Ltd
Shanghai Senhui Medicine Co Ltd
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Publication of WO2023274265A1 publication Critical patent/WO2023274265A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

L'invention concerne un composé benzamide et son utilisation. En particulier, l'invention concerne un composé représenté par la formule I ou un sel de celui-ci, R1 à R7, M1 à M6, m1 à m3 et n1 à n6 étant tels que définis dans la description.
PCT/CN2022/102114 2021-06-29 2022-06-29 Composé benzamide et son utilisation Ceased WO2023274265A1 (fr)

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