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WO2023272571A1 - Utilisation médicale d'un dérivé de 2,3-époxysuccinyle - Google Patents

Utilisation médicale d'un dérivé de 2,3-époxysuccinyle Download PDF

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Publication number
WO2023272571A1
WO2023272571A1 PCT/CN2021/103469 CN2021103469W WO2023272571A1 WO 2023272571 A1 WO2023272571 A1 WO 2023272571A1 CN 2021103469 W CN2021103469 W CN 2021103469W WO 2023272571 A1 WO2023272571 A1 WO 2023272571A1
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atom
alkyl
carbonyl
hydrogen
ethyl ester
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Chinese (zh)
Inventor
肖军海
秦成峰
李松
郭家林
钟武
邓永强
李晓峰
曹瑞源
张娜娜
李薇
郑志兵
李行舟
周辛波
樊士勇
肖典
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Academy of Military Medical Sciences AMMS of PLA
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Academy of Military Medical Sciences AMMS of PLA
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Priority to PCT/CN2021/103469 priority Critical patent/WO2023272571A1/fr
Publication of WO2023272571A1 publication Critical patent/WO2023272571A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to novel coronavirus nCoV-2019 inhibitors and their use in the preparation of drugs for treating COVID-2019, a disease caused by novel coronavirus nCoV-2019 infection, and pharmaceutical compositions containing them.
  • drugs for the treatment of COVID-2019 which are mainly potential drugs identified through drug repositioning in clinical research, including Chloroquine Phosphate (Chloroquine), Remdesivir (Remdesivir), Favipiravir (Favipiravir), Lopina
  • Chloroquine Phosphate Chloroquine
  • Remdesivir Remdesivir
  • Favipiravir Favipiravir
  • the targets of lopinavir and ritonavir include RdRp enzyme and protein integrase, and most of the specific mechanisms have yet to be confirmed.
  • the structures of the above-mentioned drugs are quite different, and the clinical efficacy is still unclear.
  • the present invention relates to a compound represented by formula I with inhibitory effect on novel coronavirus nCoV-2019, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, and its preparation for treating novel coronavirus Use of COVID-2019 medicines for diseases caused by nCoV-2019 infection and pharmaceutical compositions containing them.
  • the present invention provides the compound shown in formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt in the preparation for the treatment of viral infection Pneumonia caused by novel coronavirus 2019-nCoV infection, such as COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, low oxygen respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.), or in the preparation of drugs as novel coronavirus 2019-nCoV inhibitors, or in the preparation of drugs for inhibiting Use of novel coronavirus 2019-nCoV in a medicine for replicating or multiplying in cells (e.g. mammalian cells),
  • novel coronavirus 2019-nCoV infection such as COVID-2019
  • respiratory diseases including but not limited to simple infections such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, low oxygen respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc
  • R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;
  • R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from iso
  • R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;
  • Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;
  • R3, R4 are each independently selected from hydrogen,
  • the benzene ring is optionally monosubstituted by halogen, or, R3, R4 and the N atom directly connected to them form together
  • the present invention provides a pharmaceutical composition used in the preparation of pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to Simple infection such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.), or in the Use in the preparation of medicines as 2019 novel coronavirus (2019-nCoV) inhibitors, or in the preparation of medicines for inhibiting the replication or reproduction of 2019 novel coronavirus (2019-nCoV) in cells (such as mammalian cells) use,
  • 2019-nCoV infection COVID-2019 such as respiratory diseases, including but not limited to Simple infection such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.
  • 2019 novel coronavirus (2019-nCoV) inhibitors or in the preparation of medicines for inhibit
  • the pharmaceutical composition comprises the compound represented by formula 1, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt,
  • R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;
  • R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from iso
  • R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;
  • Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;
  • R3, R4 are each independently selected from hydrogen, Alternatively, R3, R4 and the N atom directly connected to them form together The benzene ring is optionally monosubstituted by halogen;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant
  • the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration.
  • the compound of formula 1 is selected from:
  • the present invention provides a method of treating and/or preventing disease in a mammal in need or inhibiting the replication or reproduction of 2019 novel coronavirus (2019-nCoV) in a mammal in need
  • a method comprising administering a therapeutically and/or preventively effective amount of a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof to a mammal in need
  • a pharmaceutical composition comprising a compound represented by formula 1, a racemate or an optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof in a therapeutically and/or preventively effective amount
  • R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;
  • R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from iso
  • R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;
  • Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;
  • R3, R4 are each independently selected from hydrogen, Alternatively, R3, R4 and the N atom directly connected to them form together The benzene ring is optionally monosubstituted by halogen;
  • pneumonia caused by viral infection such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple infections such as fever, cough and sore throat, pneumonia, Acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.);
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant
  • the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration.
  • the compound of formula 1 is selected from:
  • the present invention provides a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof or a compound represented by formula 1, its A pharmaceutical composition of a rotator or an optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, as a 2019 novel coronavirus (2019-nCoV) inhibitor, or for inhibiting a 2019 novel coronavirus (2019-nCoV) nCoV) replicates or reproduces in cells (such as mammalian cells), or it is used to treat pneumonia caused by viral infection, such as pneumonia caused by novel coronavirus 2019-nCoV infection COVID-2019 (such as respiratory diseases, including but not limited to simple sexual infections such as fever, cough and sore throat, pneumonia, acute or severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.)
  • R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;
  • R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from iso
  • R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;
  • Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;
  • R3, R4 are each independently selected from hydrogen, Alternatively, R3, R4 and the N atom directly connected to them form together The benzene ring is optionally monosubstituted by halogen;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant
  • the pharmaceutical composition is a tablet, capsule, aqueous solution or aqueous suspension for oral administration, or for topical ophthalmic administration.
  • its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof or comprises a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 is selected from:
  • the present invention provides a compound represented by formula 1, its racemate or optical isomer, its solvate, or a pharmaceutically acceptable salt thereof, for the preparation of treating, delaying or alleviating virus Infection-induced pneumonia drugs and uses of pharmaceutical compositions containing them,
  • R1 is selected from hydrogen or C1-C6 alkyl; preferably, R1 is selected from hydrogen or C1-C4 alkyl; more preferably, R1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl or tert-butyl; Most preferably, R1 is selected from hydrogen or ethyl;
  • R2 is selected from C1-C6 alkyl or C1-C6 alkyl containing S atom; preferably, R2 is selected from C3-C6 alkyl or C3-C6 alkyl containing S atom; more preferably, R2 is selected from n-propyl base, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, n-propyl containing S atom, isopropyl containing S atom, containing S Atom-containing n-butyl group, S-atom-containing isobutyl group, S-atom-containing tert-butyl group, S-atom-containing n-pentyl group, S-atom-containing isopentyl group, S-atom-containing neopentyl group or S-atom-containing Hexyl; most preferably R2 is selected from iso
  • R3, R4 are each independently selected from hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by R5, or, R3, R4 and the N atom directly connected to them together form a five-six membered saturated heterocyclic ring, so The five-six membered saturated heterocycle is optionally substituted by R5;
  • Each R5 is independently selected from unsubstituted benzene rings or benzene rings monosubstituted by halogen;
  • R3, R4 are each independently selected from hydrogen, Alternatively, R3, R4 and the N atom directly connected to them form together The phenyl ring is optionally monosubstituted with halogen.
  • the present invention relates to compounds represented by formula I, which have significant in vitro anti-nCoV-2019 virus-infected cells, and the EC50 of the preferred compounds are respectively 4.5 ⁇ M and 6.25 ⁇ M.
  • Another aspect of the present invention relates to a pharmaceutical composition, which contains the racemate or optical isomer of the compound of the present invention and at least one pharmaceutically acceptable carrier, which can be used for in vivo therapy and has biocompatibility.
  • the pharmaceutical composition can be prepared in various forms according to different administration routes.
  • the compound mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts, and the said pharmaceutical composition of the present invention can be used for preventing and/or treating pneumonia caused by novel coronavirus (nCoV-2019) infection ( COVID-2019) treatment.
  • the pharmaceutical composition involved in the present invention refers to comprising an effective dose of the compound of formula I of the present invention or a pharmaceutically acceptable salt or hydrate thereof and one or more suitable pharmaceutically acceptable carriers.
  • the pharmaceutical carriers here include but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerol, sorbic acid, potassium sorbate, saturated vegetable Partial glyceride mixtures of fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fibers Vegetable substances, macrogol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin.
  • compositions of the compounds of this invention can be administered in any of the following ways: oral, inhalation spray, rectal, nasal, buccal, topical, parenteral, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intravenous, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir.
  • the compounds of the present invention may be prepared in any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier that tablet uses generally comprises lactose and cornstarch, also can add lubricant such as magnesium stearate in addition.
  • Diluents used in capsule formulations generally include lactose and dried cornstarch.
  • Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral preparation forms.
  • the compound of the present invention When used locally, especially when treating the affected areas or organs that are easily accessible by local external application, such as eye, skin or lower intestinal neuropathy, the compound of the present invention can be made into different topical preparations according to different affected areas or organs
  • the format is specified as follows:
  • the compounds of the present invention When administered topically to the eye, the compounds of the present invention may be formulated as a micronized suspension or solution in the form of an isotonic sterile saline solution of pH with or without the addition of a preservative such as benzyl chloride. alkyl alkoxides.
  • the compound For ophthalmic use, the compound may also be formulated in the form of an ointment such as petrolatum ointment.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in suitable ointments, lotions or creams, wherein the active ingredients are suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil Oil, Sorbitan Monostearate, Tween 60, Cetyl Ester Wax, Cetyl Aryl Alcohol, 2-Octyldodecanol, Benzyl Alcohol and Water.
  • the compounds of the present invention can also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions.
  • the carrier and solvent that can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils such as mono- or diglycerides, may be employed as a solvent or suspending medium.
  • the dose and method of use of the compound of the present invention depend on many factors, including the patient's age, body weight, sex, natural health status, nutritional status, activity intensity of the compound, time of administration, metabolic rate, severity of the disease, and The subjective judgment of the treating physician.
  • the preferred dosage ranges from 0.01 to 100 mg/kg body weight/day, and the optimal dosage is 1 mg/kg-50 mg/kg body weight/day.
  • C1-C6 alkyl containing an S atom refers to a group formed after one C atom in the C1-C6 alkyl is replaced by an S atom, for example, "n-propane containing an S atom base” can be
  • C1-C6 alkyl refers to any straight chain or branched chain group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.
  • C1-C4 alkyl refers to any straight chain or branched chain group containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl base, tert-butyl, etc.
  • C1-C3 alkyl refers to any straight-chain or branched-chain group containing 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.
  • C3-C6 alkyl refers to any straight chain or branched chain group containing 3-6 carbon atoms, such as n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-amyl, n-hexyl, etc.
  • five-six-membered saturated heterocyclic ring refers to a 5- or 6-membered saturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur.
  • five- to six-membered ring saturated heterocycles include pyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, piperidine base, piperazinyl, morpholinyl, thiomorpholinyl, etc.
  • Non-limiting examples of six-membered ring saturated heterocyclic groups are, for example, pyranyl, piperidinyl, piperazinyl, morpholinyl, and the like.
  • the melting point of the compound was determined by RY-1 melting point apparatus, and the thermometer was not corrected.
  • the specific rotation was measured by a precision automatic polarimeter, Polar 3005 from OA Company, and the mass spectrum was measured by a Micromass ZabSpec high-resolution mass spectrometer (resolution 1000).
  • 1H NMR is measured by JNM-ECA-400 superconducting NMR instrument, working frequency 1H NMR 400MHz, 13C NMR 100MHz.
  • (+/-)-trans-epoxysuccinic acid (178 g, 1.35 mol) was dissolved in 2600 ml methanol. Add (234.9g, 1.35mol) L-arginine in 650ml water, heat to dissolve, then add dropwise in the methanol solution of (+/-)-trans-epoxysuccinic acid while stirring, finally will A large amount of insoluble material appeared. After the addition was complete, it was stirred overnight at room temperature. The precipitate was obtained by suction filtration, and the precipitate was washed with methanol/water (4:1) mixed solvent (1000ml) to obtain 201.2g of crude product. The crude product was recrystallized with about 3000ml of methanol water (2:1) to obtain 170.2g of (+)-trans-epoxysuccinic acid with a yield of 82.5%.
  • (+/-)-trans-epoxysuccinic acid (107.1g, 0.35mol) into 1050ml ethanol solution for suspension, stir, then add 95% concentrated sulfuric acid (102.9g, 1.05mol) dropwise After the addition was complete, the mixture was stirred at reflux for 4.5 hours. After the reaction, the solvent in the mixture was removed by rotary evaporation, and the residue in the bottle was poured into 200ml of ice water, and extracted 3 times with ethyl acetate (300ml*3).
  • the collected ester layer was washed with saturated brine (70ml*2), dried over anhydrous magnesium sulfate, filtered with suction, and the solvent in the solution was removed to obtain the crude intermediate 3 (13.1g), a colorless oil. No purification required, directly to the next step.
  • the EC50 of the drug was determined by CPE method and nucleic acid quantitative method. Drugs were formulated with 2% FBS in DMEM maintenance solution, 100, 50, 25, 12.5, 10, 6.25, 3.125 ⁇ M. Vero cells were inoculated into 96-well plates at a concentration of 10000/well one day in advance.
  • Discard the cell culture supernatant add 100 TCID50 novel coronavirus liquid, adsorb and culture at 37°C for 2 hours, discard the virus liquid, add different concentrations of drugs (200 ⁇ l/well) to each well, and use 4 replicate wells for each drug, and set up virus control and normal
  • the cell control group was cultured in a 5% CO 2 incubator at 37° C., and cytopathic changes (CPE) were observed every day. Two days after infection, 50 ⁇ l of cell supernatant was taken from each well to extract nucleic acid, and the viral load was detected by quantitative RT-PCR.
  • the new coronavirus is a Beijing isolate (2019-nCoV BetaCoV/Beijing/AMMS01/2020), which is kept by the biosafety level III laboratory of the Academy of Military Medical Sciences. All evaluations were completed in a biosafety level III laboratory. The results are shown in Table 1 and Table 2. The evaluation results of viral load showed that the EC50 of Example 8 and Example 9 were 6.25 ⁇ M and 4.5 ⁇ M, respectively.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé tel que représenté par la formule 1 qui a un effet inhibiteur sur le nouveau coronavirus 2019-nCoV ; un racémate ou un isomère optique de celui-ci, un solvate ou un sel pharmaceutiquement acceptable de celui-ci ; et son utilisation dans la préparation d'un médicament pour le traitement de la maladie COVID-2019 provoquée par une infection par le nouveau coronavirus 2019-nCoV, et dans une composition pharmaceutique le contenant. Dans la formule, R1 est indépendamment choisi parmi l'hydrogène ou l'éthyle ; R2 est choisi parmi un alkyle en C3-C6, ou un alkyle en C3-C6 contenant un atome de S ; R3 et R4 sont indépendamment choisis parmi un alkyle en C1-C6, et un alkyle en C1-C6 substitué par R5, R5 étant un cycle benzène qui est non substitué ou monosubstitué par halogène ; et R3 et R4 peuvent former un cycle hétérocyclique saturé à six chaînons, le cycle hétérocyclique saturé à six chaînons pouvant être monosubstitué par un cycle benzène.
PCT/CN2021/103469 2021-06-30 2021-06-30 Utilisation médicale d'un dérivé de 2,3-époxysuccinyle Ceased WO2023272571A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107151236A (zh) * 2016-03-03 2017-09-12 中国人民解放军军事医学科学院毒物药物研究所 一种2,3-环氧丁二酰衍生物及其制备方法和用途
WO2019022357A1 (fr) * 2017-07-28 2019-01-31 울산대학교 산학협력단 Composition pharmaceutique pour prévenir ou traiter le syndrome respiratoire du moyen-orient
CN113387909A (zh) * 2020-03-13 2021-09-14 中国人民解放军军事科学院军事医学研究院 2,3-环氧丁二酰衍生物的医药用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107151236A (zh) * 2016-03-03 2017-09-12 中国人民解放军军事医学科学院毒物药物研究所 一种2,3-环氧丁二酰衍生物及其制备方法和用途
WO2019022357A1 (fr) * 2017-07-28 2019-01-31 울산대학교 산학협력단 Composition pharmaceutique pour prévenir ou traiter le syndrome respiratoire du moyen-orient
CN113387909A (zh) * 2020-03-13 2021-09-14 中国人民解放军军事科学院军事医学研究院 2,3-环氧丁二酰衍生物的医药用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BUTTLE D J, SAKLATVALA J, TAMAI M, BARRETT A J: "Inhibition of interleukin 1-stimulated cartilage proteoglycan degradation by a lipophilic inactivator of cysteine endopeptidases", BIOCHEMICAL JOURNAL, vol. 281, no. 1, 1 January 1992 (1992-01-01), GB , pages 175 - 177, XP093020072, ISSN: 0264-6021, DOI: 10.1042/bj2810175 *
OU TIANLING, MOU HUIHUI, ZHANG LIZHOU, OJHA AMRITA, CHOE HYERYUN, FARZAN MICHAEL: "Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2", PLOS PATHOGENS, vol. 17, no. 1, 19 January 2021 (2021-01-19), pages 1 - 15, XP055825725, DOI: 10.1371/journal.ppat.1009212 *
XIN HU, JAIMEE R. COMPTON, DAGMAR H. LEARY, MARK A. OLSON, MICHAEL S. LEE, JONAH CHEUNG, WENJUAN YE, MARK FERRER, NOEL SOUTHALL, A: "Kinetic, Mutational, and Structural Studies of the Venezuelan Equine Encephalitis Virus Nonstructural Protein 2 Cysteine Protease", BIOCHEMISTRY, vol. 55, no. 21, 31 May 2016 (2016-05-31), pages 3007 - 3019, XP055567283, ISSN: 0006-2960, DOI: 10.1021/acs.biochem.5b00992 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12473314B2 (en) 2020-08-24 2025-11-18 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
US12208110B2 (en) 2020-10-16 2025-01-28 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

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