WO2023272571A1 - 2,3-环氧丁二酰衍生物的医药用途 - Google Patents
2,3-环氧丁二酰衍生物的医药用途 Download PDFInfo
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- 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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- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
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- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 1
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- LDFQMMUIJQDSAB-WDSKDSINSA-N diethyl (2s,3s)-oxirane-2,3-dicarboxylate Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)OCC LDFQMMUIJQDSAB-WDSKDSINSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
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- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
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- 230000003862 health status Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- PQPFFKCJENSZKL-UHFFFAOYSA-N pentan-3-amine Chemical compound CCC(N)CC PQPFFKCJENSZKL-UHFFFAOYSA-N 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
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- 239000001587 sorbitan monostearate Substances 0.000 description 1
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Classifications
-
- 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.
Abstract
一种式1所示具有新型冠状病毒2019-nCoV抑制作用的化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,及其在制备治疗新型冠状病毒2019-nCoV感染所致疾病COVID-2019药物及含有它们的药物组合物的用途。其中, R1独立地选自氢,或乙基; R2选自C3-C6烷基,或含有S原子的C3-C6烷基; R3,R4独立地选自C1-C6烷基,被R5取代的C1-C6烷基,其中R5为未取代或被卤素单取代的苯环,R3,R4可组成六元环饱和杂环,所述六元环饱和杂环可被苯环单取代。
Description
本发明涉及新型冠状病毒nCoV-2019抑制剂,及其在制备治疗新型冠状病毒nCoV-2019感染所致疾病COVID-2019药物及含有它们的药物组合物的用途。
2020年1月中旬,新型冠状病毒nCoV-2019的全基因组被我国科研工作者率先公布,这个全长29903的基因组(GenBank ID:MN908947.3)为药物作用靶标的选择提供了重要的信息。随着生物信息分析工作的进行,一系列潜在的作用靶标被提出来,包括S-spike蛋白、RdRp酶、Papain酶、3Cl蛋白酶等,但针对性的活性分子尚未见报道。目前有关于COVID-2019治疗药物,处于临床研究的主要是通过药物重定位确定的潜在药物,包括磷酸氯喹(Chloroquine)、瑞德西韦(Remdesivir)、法匹拉韦(Favipiravir)、洛匹那韦(lopinavir)和利托那韦(ritonavir),针对的靶标包括RdRp酶、蛋白整合酶,具体机制大多尚待确证。而上述药物的结构差别大,临床药效也尚不明确,因此新型冠状病毒nCoV-2019针对性抑制剂研究仍处于初始阶段,可借鉴的信息极少,很难有***的构效关系和共性结构指导高活性化合物的发现。
发明内容
本发明涉及具有新型冠状病毒nCoV-2019抑制作用的式I所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,及其在制备治疗新型冠状病毒nCoV-2019感染所致疾病COVID-2019药物及含有它们的药物组合物的用途。
为此,在本发明的第一方面,本发明提供了式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐在制备用于治疗病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)的药物中的用途,或者在制备作为新型冠状病毒2019-nCoV抑制剂的药物中的用途,或者在制备用于抑制新型冠状病毒2019-nCoV在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途,
其中,
R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;
R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或
R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5 所取代;
R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;
在本发明的第二方面,本发明提供了药物组合物在制备用于治疗病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)的药物中的用途,或者在制备作为2019新型冠状病毒(2019-nCoV)抑制剂的药物中的用途,或者在制备用于抑制2019新型冠状病毒(2019-nCoV)在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途,
其中所述药物组合物包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,
其中,
R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;
R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或
R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;
R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;
优选地,所述的药物组合物还包含药学上可接受的载体或辅料,优选地,所述药物组合物为用于口服的片剂、胶囊、水溶液或水悬浮液、用于眼部局部用药的微粉化悬浮液或溶液的制剂形式、用于皮肤局部用药的膏剂形式、软膏、洗剂或霜剂制剂形式、用于注射的无菌注射水或油悬浮液或无菌注射溶液。
在一些实施方案中,所述的式1化合物选自:
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸。
在本发明的第三方面,本发明提供了一种在有需要的哺乳动物中治疗和/或预防疾病的方法或者在有需要的哺乳动物中抑制2019新型冠状病毒(2019-nCoV)复制或繁殖的方法,所述方法包括给有需要的哺乳动物施用治疗和/或预防有效量的式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐物或治疗和/或预防有效量的包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的药物组合物,
其中,
R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;
R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原 子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或
R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;
R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;
其中所述的疾病包括病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等);
优选地,所述的药物组合物还包含药学上可接受的载体或辅料,优选地,所述药物组合物为用于口服的片剂、胶囊、水溶液或水悬浮液、用于眼部局部用药的微粉化悬浮液或溶液的制剂形式、用于皮肤局部用药的膏剂形式、软膏、洗剂或霜剂制剂形式、用于注射的无菌注射水或油悬浮液或无菌注射溶液。
在一些实施方案中,所述的式1化合物选自:
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸。
在本发明的第四方面,本发明提供了式1所示化合物,其消旋体或旋光异构体、其 溶剂化物、或其药学上可接受的盐或包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的药物组合物,其作为2019新型冠状病毒(2019-nCoV)抑制剂,或者用于抑制2019新型冠状病毒(2019-nCoV)在细胞(例如哺乳动物细胞)中复制或繁殖,或者用于治疗病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)
其中,
R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;
R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或
R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;
R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;
优选地,所述的药物组合物还包含药学上可接受的载体或辅料,优选地,所述药物组合物为用于口服的片剂、胶囊、水溶液或水悬浮液、用于眼部局部用药的微粉化悬浮液或溶液的制剂形式、用于皮肤局部用药的膏剂形式、软膏、洗剂或霜剂制剂形式、用于注射的无菌注射水或油悬浮液或无菌注射溶液。
在一些实施方案中,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的药物组合物,其中所述的式1化合物选自:
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥 珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸。
在本发明的第五方面,本发明提供了式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,用于制备治疗、延缓或减轻病毒感染所致肺炎药物及含有它们的药物组合物的用途,
其中,
R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;
R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或
R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;
R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;
在本发明的一个具体实施方案中,所述的式1化合物、其消旋体或旋光异构体、其溶剂化物、或其药学或生理学上可接受的盐,其中,所述化合物选自:
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸
(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
本发明涉及化合物式I所示化合物具有显著的体外抗nCoV-2019病毒感染细胞的活性,其中优选化合物的EC50分别为4.5μM、6.25μM。
本发明的另一个方面涉及药物组合物,其含有本发明化合物的消旋体或旋光异构体和至少一种药学上可接受的载体,其可用于体内治疗并具有生物相容性。所述药物组合物可以根据不同给药途径而制备成各种形式。本发明所提及的化合物也可以被制备成各种药学可接受的盐,本发明所说的药物组合物可以用于预防和/或治疗由于新型冠状病毒(nCoV-2019)感染造成的肺炎(COVID-2019)的治疗。
本发明涉及的药物组合物是指包括有效剂量的本发明式I化合物或其可药用盐或水合物和一种或多种适宜的可药用载体。这里的药用载体包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血白蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛脂。
本发明化合物的药物组合物可以以下面的任意方式施用:口服,喷雾吸入,直肠用药,鼻腔用药,颊部用药,局部用药,非肠道用药,如皮下,静脉,肌内,腹膜内,鞘内,心室内,胸骨内和颅内注射或输入,或借助一种外植储器用药。
当口服用药时,本发明化合物可制成任意口服可接受的制剂形式,包括但不限于片剂、胶囊、水溶液或水悬浮液。其中,片剂使用的载体一般包括乳糖和玉米淀粉,另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要,以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当局部用药时,特别是治疗局部外敷容易达到的患面或器官,如眼睛、皮肤或下肠道神经 性疾病时,可根据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式,具体说明如下:
当眼部局部施用时,本发明化合物可配制成一种微粉化悬浮液或溶液的制剂形式,所使用载体为等渗的一定pH的无菌盐水,其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用,也可将化合物制成膏剂形式如凡士林膏。
当皮肤局部施用时,本发明化合物可制成适当的软膏、洗剂或霜剂制剂形式,其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于:矿物油,液体凡士林,白凡士林,丙二醇,聚氧化乙烯,聚氧化丙烯,乳化蜡和水;洗剂或霜剂可使用的载体包括但不限于:矿物油,脱水山梨糖醇单硬脂酸酯,吐温60,十六烷酯蜡,十六碳烯芳醇,2-辛基十二烷醇,苄醇和水。
本发明化合物还可以无菌注射制剂形式用药,包括无菌注射水或油悬浮液或无菌注射溶液。其中,可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外,灭菌的非挥发油也可用作溶剂或悬浮介质,如单甘油酯或二甘油酯。
另外需要指出,本发明化合物的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.01~100mg/kg体重/天,其中最优剂量在1mg/kg-50mg/kg体重/天。
术语“C1-C6烷基”指的是任意的含有1-6个碳原子的直链或支链基团,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
术语“C1-C4烷基”指的是任意的含有1-4个碳原子的直链或支链基团,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。
术语“C1-C3烷基”指的是任意的含有1-3个碳原子的直链或支链基团,例如甲基、乙基、正丙基、异丙基等。
术语“C3-C6烷基”指的是任意的含有3-6个碳原子的直链或支链基团,例如正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、叔戊基、正己基等。
术语“五-六元环饱和杂环”指的是5元或6元饱和碳环,其中一个或多个碳原子被杂原子例如氮、氧和硫替代。五-六元环饱和杂环的非限制性实例包括吡喃基、吡咯烷基、咪唑烷基、吡唑烷基、噻唑烷基、四氢呋喃基、1,3-二氧戊环基、哌啶基、哌嗪基、吗啉基、硫吗啉基等。六元环饱和杂环基的非限制性实例是,例如吡喃基、哌啶基、哌嗪基、吗啉基等。
下面详细描述本发明的实施例,下面描述的实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。
下面将结合实施例进一步说明本发明的实质内容和有益效果。实施例仅用于说明本发明而非对本发明的限制。
化合物的熔点由RY-1熔点仪测定,温度计未较正。比旋光度由OA公司polar 3005型精密自动旋光仪测定,质谱由Micromass ZabSpec高分辨率质谱仪(分辨率1000)测定。1H NMR由JNM-ECA-400超导NMR仪测定,工作频率1H NMR 400MHz,13C NMR 100MHz。
中间体的制备
中间体1:(2S,3S)-环氧乙烷-2,3-二羧酸的制备
把(+/-)-反式-环氧琥珀酸(178g,1.35mol)溶到2600ml甲醇中。在650ml水中加入(234.9g,1.35mol)L-精氨酸,加热使溶解,然后在搅拌的同时逐滴加入到(+/-)-反式-环氧琥珀酸的甲醇溶液中,最后会有大量不溶物出现。加毕,室温下搅拌过夜。抽滤得到沉淀,用甲醇/水(4:1)混合溶剂(1000ml)冲洗沉淀,得到粗品201.2g。用甲醇水(2:1)约3000ml重结晶粗品得到(+)-反式-环氧琥珀酸170.2g,产率82.5%。
1H-NMR(400MHz,D
2O)1.54-2.02(4H,m),3.22(2H,t),3.48(2H,s),3.84(1H,t);[α]
D+54.7(c=1.00,H
20);EI-MS(m/z):[M+H]
+133.
中间体2:(2S,3S)-2,3-二乙酯基-环氧乙烷的制备
室温条件下,把(+/-)-反式-环氧琥珀酸(107.1g,0.35mol)加入到1050ml乙醇溶液中悬浮,搅拌,再逐滴加入95%浓硫酸(102.9g,1.05mol),加毕,搅拌回流混合物4.5小时。反应结束后,把混合物中的溶剂旋转蒸发除掉,给瓶中残渣倒入200ml冰水,用乙酸乙酯萃取3次(300ml*3)。合并萃取出的酯层,用饱和碳酸氢钠水溶液(200ml*2),饱和食盐水(200*2)连续洗涤,用无水硫酸镁干燥,抽滤,旋干,得到粗品,用色谱层析柱得到纯品,无色油状液体50.4g,产率76.6%。
1H-NMR(400MHz,CDCl
3)1.31(6H,t),3.66(2H,s),4.28(4H,dq);[α]
D+110.5(c=1.12,EtOH);EI-MS(m/z):[M+H]
+189.
中间体3:(2S,3S)-3-乙酯基-环氧乙烷-2-羧酸的制备
85%氢氧化钾(6.72g,0.1mol)加入到67ml乙醇中,配成氢氧化钾乙醇溶液。把中间体2(18.8g,0.1mol)加入到150ml乙醇中,搅拌,冰浴控温4-6℃,然后逐滴加入氢氧化钾乙醇溶液,加毕继续在4-6℃条件下搅拌1小时,之后升至室温搅拌4小时。反应结束后,把溶剂蒸发掉,加入50ml水,形成溶液,用乙酸乙酯(50ml*2)洗涤。分离出水层,冰浴,用6N盐酸酸化水层PH=2,用乙酸乙酯(70ml*3)萃取。收集酯层用饱和食盐水(70ml*2)洗涤,再用无水硫酸镁干燥,抽滤,再把溶液中的溶剂除掉,得到粗品中间体3(13.1g),无色油状物。不需纯化,直接下一步。
1H-NMR(400MHz,CDCl
3)1.27-1.31(3H,t),3.59-3.62(2H,s),4.23-4.25(2H,dq);EI-MS(m/z):[M+H]
+161.
中间体4:(2S,3S)-3-(4-硝基苯氧羰基)-环氧乙烷-2-羧酸乙酯的制备
取DCC(12.9g,0.0625mol)溶于乙酸乙酯(26ml),成为乙酸乙酯溶液。中间体3取10g和对硝基苯酚(8.69g,0.0625mol)溶于55ml乙酸乙酯溶液,将温度保持在4-5℃搅拌,缓慢滴入配好的DCC乙酸乙酯溶液,在低温反应3小时,升至室温反应1小时。反应完毕过滤残渣,有机层用乙酸乙酯(20ml)洗涤,乙酸乙酯再过滤,旋蒸溶剂,得到粗品,用乙酸乙酯-环己烷进行重结晶得到中间体4(14.1g,产率65.8%),其为黄色针状。
1H-NMR(400MHz,DMSO)1.26(3H,t),4.06(1H,d),4.08(1H,d),4.24(2H,q),7.58(2H,d),8.36(2H,d);[α]
D+114.8(c=1.00,AcOEt);EI-MS(m/z):[M+H]
+282.
实施例1 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸
1把DCC(10.32g,0.05mol)溶于20ml乙酸乙酯中,成乙酸乙酯溶液。把(12.49g,0.05mol)N-(叔丁氧羰基)-L-蛋氨酸、(4.36g,0.05mol)异戊胺和(6.76g,0.05mol)HOBt溶到35ml乙酸乙酯中,搅拌,冰浴3-8℃。然后逐滴加入前面配好的DCC乙酸乙酯溶液。保持3-8℃搅拌1.5小时,升至室温2.5小时。反应结束过滤掉杂质,用40ml乙酸乙酯洗涤沉淀,合并滤液,用5%盐酸(100ml)、饱和食盐水(100ml)、饱和碳酸氢钠(100ml)、饱和盐水(100ml)依次洗涤。有机层用无水硫酸镁干燥,旋蒸旋干得到粗品14.45g,产率96.1%。不需纯化直接下一步。
2将上一步粗品(18.5g,0.062mol)溶于65ml10%HCl-AcOEt溶液中,搅拌2.5小时。旋蒸溶剂,给残渣加50ml水,再用50ml乙酸乙酯洗涤,把水层用25%氢氧化钠碱化PH>10,乙酸乙酯(50ml*1,25ml*2)萃取。合并有机层用无水硫酸镁干燥,旋干。得粗品,直接下一步。
3上一步粗品(4.39g,0.32mol)和中间体3的(3g,0.32mol)、HOBt2.54g与30ml乙酸乙酯混合,冰浴下逐滴加入3.87gDCC与10ml乙酸乙酯的混合液,冰浴反应3小时。升至室温反应12小时。滤除不溶物,乙酸乙酯洗涤,依次用5%盐酸、饱和食盐水、饱和碳酸氢钠、饱和食盐水洗涤。无水硫酸镁干燥。减压旋干,得粗品,用无水乙醇重结晶得到化合物1。黄色针状粉末3.1g。产率42%
1H-NMR(400MHz,DMSO)0.86(6H,d)1.20-1.31(5H,m)1.54(1H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]
+
实施例2 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸
以己胺和中间体3为原料,操作同实施例1,得到化合物5白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(3H,t)1.17-1.35(11H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.90-3.20(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):375[M+H]
+.
实施例3 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸
以3-***和中间体3为原料,操作同实施例1,得到化合物8,黄色针状粉末。
1H-NMR(400MHz,DMSO)1.21-1.3(5H,m)1.50-1.88(4H,m)2.03(3H,s)2.42(2H,m)3.00-3.10(2H,m)3.61(1H,d)3.72(1H,d)4.16-4.17(2H,m)4.33-4.37(1H,m)7.17-7.27(5H,m)8.13(1H,t)8.63(1H,d)EI-MS(m/z):409[M+H]
+.
实施例4 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸
以4-苯基哌啶和中间体3为原料,操作同实施例1,得到化合物13,无色针状粉末。
1H-NMR(400MHz,DMSO)1.21(3H,t)1.50-1.90(6H,m)2.03(3H,s)2.42(2H,m)2.65(1H,t)2.75(2H,t)3.15(2H,t)3.60(1H,m)3.72(1H,d)4.12-4.15(2H,m)4.41-4.51(1H,m)7.10-7.38(5H,m)8.81(1H,d)EI-MS(m/z):435[M+H]
+.
实施例5 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸
以3-氟苯乙胺和中间体3为原料,操作同实施例1,得到化合物34,黄色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,t)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.70-2.75(2H,m)3.61-3.72(4H,m)4.16-4.17(2H,m)4.28-4.32(1H,m)7.05(3H,m)7.30(1H,m)8.17(1H,t)8.63(1H,d)EI-MS(m/z):413[M+H]
+.
实施例6 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸
以3-氨基戊烷和中间体3为原料,操作同实施例1,得到化合物39,白色针状粉末。
1H-NMR(400MHz,DMSO)0.86(6H,t)1.21-1.43(7H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)3.49-3.52(1H,m)3.59(1H,m)3.72(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.77(1H,t)8.63(1H,d)EI-MS(m/z):361[M+H]
+.
实施例7 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸
以4-苯基丁胺和中间体3为原料,操作同实施例1,得到化合物40,白色固体。
1H-NMR(400MHz,DMSO)1.21-1.3(3H,m)1.35-1.51(4H,m)1.79-1.88(2H,m)2.03(3H,s)2.42(2H,m)2.53(2H,t)3.00-3.10(2H,m)3.57(1H,d)3.67(1H,d)4.16-4.17(2H,m)4.27-4.28(1H,m)7.17-7.27(5H,m)8.06-8.09(1H,t)8.63(1H,d)EI-MS(m/z):423[M+H]
+.
实施例8 (2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
以异戊胺、N-(叔丁氧羰基)-L-亮氨酸和中间体3为原料,操作同实施例1,得到化合物40,白色固体。
1H-NMR(400MHz,DMSO)0.85-1.04(12H,m),1.32(3H,t,J=7Hz),1.41(2H,q,J=7Hz),1.47-1.76(4H,m),3.11-3.47(2H,m),3.48(1H,d,J=2Hz),3.69(1H,d,J=2Hz),4.27(2H,dq,J=7.2Hz),4.35-4.50(1H,m),6.16-6.30(1H,m),6.8(1H,d,J=8Hz)。 EI-MS(m/z):343[M+H]
+。
实施例9 (2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸
将(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸按中间体3的操作,得化合物,白色固体。
1H-NMR(400MHz,DMSO)0.85-1.04(12H,m),1.41(2H,q,J=7Hz),1.47-1.76(4H,m),3.11-3.47(2H,m),3.48(1H,d,J=2Hz),3.69(1H,d,J=2Hz),4.35-4.50(1H,m),6.16-6.30(1H,m),6.8(1H,d,J=8Hz)。EI-MS(m/z):314[M+H]
+。
实施例10 化合物对抗nCovV-2019冠状病毒感染的试验
采取CPE法和核酸定量法测定药物的EC50。用2%FBS的DMEM维持液将药物配制成、100、50、25、12.5、10、6.25、3.125μM。提前一天将Vero细胞以10000/孔浓度接种96孔板。弃细胞培养上清,加入100TCID50新型冠状病毒液,37℃吸附培养2小时,弃病毒液,每孔加入不同浓度的药物(200μl/孔),每个药物4复孔,并设立病毒对照和正常细胞对照组,放置37℃5%CO
2孵箱培养,每天观察细胞病变(CPE)。在感染后2天,每孔取50μl细胞上清提取核酸,用定量RT-PCR检测病毒载量。新型冠状病毒为北京分离株(2019-nCoV BetaCoV/Beijing/AMMS01/2020),由军事医学研究院生物安全III级实验室保存。全部评价在生物安全III级实验室内完成。结果如表1表2所示,病毒载量的评价结果表明实施例8、实施例9的EC50分别为6.25μM、4.5μM。
表1 化合物初筛结果
“×”表示药物对Vero细胞有毒性,“+”表示轻度细胞病变,
“++”表示中度细胞病变,“+++”表示完全细胞病变,“-”表示未病变
表2 化合物EC50的测定
“×”表示药物对Vero细胞有毒性,“+”表示轻度细胞病变,
“++”表示中度细胞病变,“+++”表示完全细胞病变,“-”表示未病变
以上所述的具体实施例,对本发明的目的、技术方案和有益效果进行了进一步详细说明,所应理解的是,以上所述仅为本发明的具体实施例而已,并不用于限定本发明的保护范围,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围。
Claims (7)
- 式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐在制备用于治疗病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)的药物中的用途,或者在制备作为新型冠状病毒2019-nCoV抑制剂的药物中的用途,或者在制备用于抑制新型冠状病毒2019-nCoV在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途,其中,R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;
- 药物组合物在制备用于治疗病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)的药物中的用途,或者在制备作为2019新型冠状病毒(2019-nCoV)抑制剂的药物中的用途,或者在制备用于抑制2019新型冠状病毒(2019-nCoV)在细胞(例 如哺乳动物细胞)中复制或繁殖的药物中的用途,其中所述药物组合物包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐,其中,R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;优选地,所述的药物组合物还包含药学上可接受的载体或辅料,优选地,所述药物组合物为用于口服的片剂、胶囊、水溶液或水悬浮液、用于眼部局部用药的微粉化悬浮液或溶液的制剂形式、用于皮肤局部用药的膏剂形式、软膏、洗剂或霜剂制剂形式、用于注射的无菌注射水或油悬浮液或无菌注射溶液。
- 根据权利要求1或2所述的用途,其中所述的式1化合物选自:(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧 琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸。
- 一种在有需要的哺乳动物中治疗和/或预防疾病的方法或者在有需要的哺乳动物中抑制2019新型冠状病毒(2019-nCoV)复制或繁殖的方法,所述方法包括给有需要的哺乳动物施用治疗和/或预防有效量的式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐物或治疗和/或预防有效量的包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的药物组合物,其中,R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;其中所述的疾病包括病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等);优选地,所述的药物组合物还包含药学上可接受的载体或辅料,优选地,所述药物组合物为用于口服的片剂、胶囊、水溶液或水悬浮液、用于眼部局部用药的微粉化悬浮液或溶液的制剂形式、用于皮肤局部用药的膏剂形式、软膏、洗剂或霜剂制剂形式、用于注射的无菌注射水或油悬浮液或无菌注射溶液。
- 根据权利要求4所述的方法,其中所述的式1化合物选自:(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸。
- 式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的药物组合物,其作为2019新型冠状病毒(2019-nCoV)抑制剂,或者用于抑制2019新型冠状病毒(2019-nCoV)在细胞(例如哺乳动物细胞)中复制或繁殖,或者用于治疗病毒感染所致肺炎、例如新型冠状病毒2019-nCoV感染所致肺炎COVID-2019(例如呼吸***疾病,包括但不限于单纯性感染如发热、咳嗽和咽痛等、肺炎、急性或严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)其中,R1选自氢或C1-C6烷基;优选地,R1选自氢或C1-C4烷基;更优选地,R1选自氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;最优选地,R1选自氢或乙基;R2选自C1-C6烷基或含有S原子的C1-C6烷基;优选地,R2选自C3-C6烷基或含有S原子的C3-C6烷基;更优选地,R2选自正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、己基、含有S原子的正丙基、含有S原子的异丙基、含有S原 子的正丁基、含有S原子的异丁基、含有S原子的叔丁基、含有S原子的正戊基、含有S原子的异戊基、含有S原子的新戊基或含有S原子的己基;最优选地,R2选自异丙基或R3、R4各自独立地选自氢、C1-C6烷基或被R5取代的C1-C6烷基,或者,R3、R4和与它们直接相连的N原子一起组成五-六元饱和杂环,所述五-六元饱和杂环任选地被R5所取代;R5各自独立地选自未取代的苯环或者被卤素单取代的苯环;优选地,所述的药物组合物还包含药学上可接受的载体或辅料,优选地,所述药物组合物为用于口服的片剂、胶囊、水溶液或水悬浮液、用于眼部局部用药的微粉化悬浮液或溶液的制剂形式、用于皮肤局部用药的膏剂形式、软膏、洗剂或霜剂制剂形式、用于注射的无菌注射水或油悬浮液或无菌注射溶液。
- 根据权利要求6所述的式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐或包含式1所示化合物,其消旋体或旋光异构体、其溶剂化物、或其药学上可接受的盐的药物组合物,其中所述的式1化合物选自:(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(异戊胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(己胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-苯并胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(苯基哌啶基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-氟苯乙胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(3-胺基戊烷基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲硫基-1-羰基-1-(4-苯基丁胺基)丁烷]甲酰胺基]环氧琥珀酸(2s,3s)-2-乙酯-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸(2s,3s)-3-[2-[(s)-4-甲基-1-羰基-1-(3-甲基丁胺基)戊烷]甲酰胺基]环氧琥珀酸。
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US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
Citations (3)
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 (ko) * | 2017-07-28 | 2019-01-31 | 울산대학교 산학협력단 | 중동호흡기 증후군의 예방 또는 치료용 약학조성물 |
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 |
-
2021
- 2021-06-30 WO PCT/CN2021/103469 patent/WO2023272571A1/zh unknown
Patent Citations (3)
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 (ko) * | 2017-07-28 | 2019-01-31 | 울산대학교 산학협력단 | 중동호흡기 증후군의 예방 또는 치료용 약학조성물 |
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)
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 (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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