WO2022199367A1 - Dithiocarbamate compound and preparation method therefor, pharmaceutical composition, and applications - Google Patents

Dithiocarbamate compound and preparation method therefor, pharmaceutical composition, and applications Download PDF

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WO2022199367A1
WO2022199367A1 PCT/CN2022/079468 CN2022079468W WO2022199367A1 WO 2022199367 A1 WO2022199367 A1 WO 2022199367A1 CN 2022079468 W CN2022079468 W CN 2022079468W WO 2022199367 A1 WO2022199367 A1 WO 2022199367A1
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aminodithiocarbamate
acid
pyridine
ethyl
methylene
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PCT/CN2022/079468
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French (fr)
Chinese (zh)
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尹玉新
李日东
宁显玲
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北京大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to an aminodithiocarboxylate compound, a preparation method, a pharmaceutical composition and an application thereof.
  • the novel coronavirus disease 2019 (COVID-19) is a global pandemic with the widest impact on human beings in the past 100 years. It has been declared by the World Health Organization as a International public health emergencies have brought major threats to human life and health.
  • the SARS-CoV-2 master protease (Mpro) plays a key role in the replication of the new coronavirus, and it has a specific cleavage site different from that of human proteases, so it is considered an ideal target for the development of anti-nCoV drugs. Due to the lack of safe and effective therapeutic drugs for COVID-19, it is of great significance to actively develop broad-spectrum anti-SARS-CoV-2 drugs.
  • the object of the present invention is to provide aminodithiocarbamate compounds and preparation methods, pharmaceutical compositions and applications thereof.
  • the aminodithiocarbamate compounds provided by the present invention have Mpro inhibitory activity and can be used for anti-(new) coronavirus .
  • the invention provides a kind of amino dithiocarboxylate compound, has the structure shown in formula I:
  • R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, thienyl, pyridyl, naphthyl or alkyl;
  • the heteroaryl is selected from quinolinyl, coumarin Sulphuryl, azaindolyl, 2H-1,4-benzoxazine-3(4H)-one or 3,4-dihydroquinolinone;
  • the substituted phenyl and substituted heteroaryl One or more substituents in the group are independently selected from halogen, methyl, methoxy, cyano, nitro, ethylenedioxy or phenyl;
  • R 2 is selected from hydrogen or methyl.
  • the alkyl group is a C1-C4 straight-chain alkyl group or a C3-C6 cycloalkyl group.
  • the alkyl group is a C1-C4 straight chain alkyl group and an ethyl group.
  • the C3-C6 cycloalkyl is cyclopropyl.
  • the halogen is fluorine or chlorine.
  • aminodithioformate compound is any one of the following compounds:
  • the present invention provides the preparation method of the aminodithiocarboxylate compound described in the above technical scheme, comprising the following steps:
  • 3-aminomethylpyridine and carbon disulfide are carried out an addition reaction, and the resulting product system is subjected to a nucleophilic substitution reaction with a compound having a structure shown in IV to obtain an aminodithiocarbamate compound having a structure shown in formula I;
  • R2 in formula II Said R2 in formula II , R1 in formula III, and R1 and R2 in formula IV are as defined in formula I.
  • the molar ratio of the compound having the structure shown in formula II to the compound having the structure shown in formula III is 1:1.
  • the sulfonylation reaction is carried out in the presence of a first basic catalyst and a first organic solvent.
  • the first basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine and potassium carbonate, and the first basic catalyst has the structure shown in formula II.
  • the molar ratio of the compounds is (2.8-3.2):1.
  • the first organic solvent comprises at least one of dichloromethane, tetrahydrofuran and N,N-dimethylformamide, and the dosage ratio of the first organic solvent to the compound having the structure shown in formula II is: (6-10) mL: 1 mmol.
  • the temperature of the sulfonylation reaction is 15-35° C., and the time is 10-15 h.
  • the molar ratio of the 3-aminomethylpyridine and carbon disulfide is 1:1.5.
  • the addition reaction is carried out in the presence of a second basic catalyst and a second organic solvent.
  • the second basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate and potassium phosphate, and the second basic catalyst is combined with 3-
  • the molar ratio of aminomethylpyridine is (1.8-2.2):1.
  • the second organic solvent comprises at least one of acetone, N,N-dimethylformamide and water, and the dosage ratio of the second organic solvent to 3-aminomethylpyridine is (10-20) mL: 1 mmol.
  • the temperature of the addition reaction is 15-35° C., and the time is 25-35 min.
  • the temperature of the nucleophilic substitution reaction is 25-80° C., and the time is 2-10 h.
  • the method further comprises: cooling the obtained product system after the nucleophilic substitution reaction to room temperature, filtering, concentrating the obtained filtrate, and separating the obtained residue by column chromatography to obtain the structure shown in formula I of amino dithiocarbamate compounds.
  • the eluent used in the column chromatography separation is a mixed reagent of ethyl acetate and petroleum ether, a mixed reagent of ethyl acetate and methanol, or ethyl acetate.
  • the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate and petroleum ether mixed reagent is (2-40):1.
  • the volume ratio of ethyl acetate to methanol in the ethyl acetate and methanol mixed reagent is (30-50):1.
  • the present invention provides pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solutions.
  • the pharmaceutically acceptable salt of the aminodithiocarbamate compound is a salt formed by the reaction of the aminodithiocarbamate compound with an inorganic acid or an organic acid
  • the inorganic acid is hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid, aminosulfonic acid or phosphoric acid
  • the organic acid is citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, Naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, Sal
  • the solvate of the aminodithioformate compound is methanolate, ethanolate or ethyl acetate.
  • the present invention provides a pharmaceutical composition, comprising active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients are the aminodithiocarboxylate compounds described in the above technical solution or the aminodithiocarboxylic acid described in the above technical solution A pharmaceutically acceptable salt, hydrate or solvate of the ester compound.
  • the content of the active ingredient is 0.1-99.9 wt %.
  • the pharmaceutically acceptable excipients are water, saline solution, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, magnesium carbonate, cyclic Dextrin, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides, diglycerides, At least one of pentaerythritol fatty acid ether, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the formulations of the pharmaceutical composition are capsules, tablets, aerosols, solutions, suspensions, sugar coatings, lozenges, syrups, emulsions, ointments, injections, powders, granules, pastes, Sustained release or foam.
  • the present invention provides the use of aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of Mpro inhibitors;
  • the aminodithiocarboxylate compound is the aminodithiocarboxylate compound described in the above technical solution;
  • the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are the pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solution ;
  • the pharmaceutical composition is the pharmaceutical composition described in the above technical solution.
  • the present invention provides aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of medicaments for preventing and/or treating coronavirus Applications;
  • the aminodithiocarboxylate compound is the aminodithiocarboxylate compound described in the above technical solution;
  • the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are the pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solution ;
  • the pharmaceutical composition is the pharmaceutical composition described in the above technical solution.
  • the coronavirus is a novel coronavirus.
  • the present invention provides a series of amino dithiocarbamate compounds, and the amino dithiocarbamate compounds provided by the present invention have Mpro inhibitory activity and can be used for anti-(new) coronavirus.
  • the results of the application examples show that the aminodithiocarbamate compounds provided by the present invention all have inhibitory effects on Mpro, and the inhibitory effect on Mpro is dose-dependent, wherein the aminodithiocarbamate compounds are at 10 ⁇ M.
  • the inhibition rate of Mpro under the condition of concentration is 35.5 ⁇ 97.5%.
  • the present invention provides aminodithiocarboxylate compounds, which have the structure shown in formula I:
  • R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, thienyl, pyridyl, naphthyl or alkyl;
  • the heteroaryl is selected from quinolinyl, coumarin Sulphuryl, azaindolyl, 2H-1,4-benzoxazine-3(4H)-one or 3,4-dihydroquinolinone;
  • the substituted phenyl and substituted heteroaryl One or more substituents in the group are independently selected from halogen, methyl, methoxy, cyano, nitro, ethylenedioxy or phenyl;
  • R 2 is selected from hydrogen or methyl.
  • the alkyl group is preferably a C1-C4 straight-chain alkyl group or a C3-C6 cycloalkyl group; the C1-C4 straight-chain alkyl group is preferably an ethyl group, and the C3-C6 cycloalkyl group is preferably Cyclopropyl.
  • the halogen is preferably fluorine or chlorine.
  • aminodithioformate compound is specifically any one of the following compounds:
  • the present invention provides the preparation method of the aminodithiocarboxylate compound described in the above technical scheme, comprising the following steps:
  • 3-aminomethylpyridine and carbon disulfide are subjected to an addition reaction, and the obtained product system is subjected to a nucleophilic substitution reaction with a compound having the structure shown in IV to obtain an aminodithiocarbamate compound having the structure shown in formula I.
  • the raw materials used are all commercially available commodities well known to those skilled in the art.
  • the compound having the structure shown in formula II is subjected to sulfonylation reaction with the compound having the structure shown in formula III to obtain the compound having the structure shown in formula IV.
  • the molar ratio of the compound having the structure represented by the formula II to the compound having the structure represented by the formula III is preferably 1:1.
  • the sulfonylation reaction is preferably carried out in the presence of a first basic catalyst and a first organic solvent.
  • the first basic catalyst preferably includes at least one of triethylamine, N,N-diisopropylethylamine, pyridine and potassium carbonate, more preferably N,N-diisopropyl Ethylamine; the molar ratio of the first basic catalyst to the compound having the structure represented by formula II is preferably (2.8-3.2):1, more preferably 3:1.
  • the first organic solvent preferably includes at least one of dichloromethane, tetrahydrofuran and N,N-dimethylformamide, more preferably dichloromethane; the first organic solvent is combined with the formula
  • the dosage ratio of the compound of the structure represented by II is preferably (6-10) mL:1 mmol, and more preferably 8 mL:1 mmol.
  • the temperature of the sulfonylation reaction is preferably 15-35°C, more preferably 20-25°C, and can be carried out at room temperature, that is, no additional heating or cooling is required.
  • the room temperature is specifically 25°C;
  • the time of the sulfonylation reaction is preferably 10-15 h, more preferably 12 h.
  • the obtained product system is preferably concentrated without further purification, and the obtained residue (containing the compound having the structure shown in formula IV) can be directly used for the subsequent reaction.
  • addition reaction of 3-aminomethylpyridine and carbon disulfide is carried out.
  • the molar ratio of the 3-aminomethylpyridine and carbon disulfide is preferably 1:1.5.
  • the addition reaction is preferably carried out in the presence of a second basic catalyst and a second organic solvent.
  • the second basic catalyst preferably includes at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate and potassium phosphate, more preferably potassium carbonate ;
  • the molar ratio of the second basic catalyst to 3-aminomethylpyridine is preferably (1.8-2.2):1, more preferably 2:1.
  • the second organic solvent preferably includes at least one of acetone, N,N-dimethylformamide and water, more preferably acetone;
  • the dosage ratio is preferably (10-20) mL:1 mmol, and more preferably 15 mL:1 mmol.
  • 3-aminomethylpyridine is preferably dissolved in the second organic solvent, and then the second basic catalyst and carbon disulfide are added to carry out the addition reaction.
  • the temperature of the addition reaction is preferably 15-35°C, more preferably 20-25°C, and can be carried out at room temperature; the time of the addition reaction is preferably 25-35min, more preferably for 30min.
  • the present invention preferably does not need to carry out any post-treatment, and directly mixes the product system obtained after the addition reaction with the residue obtained by concentration after the sulfonylation reaction to carry out a nucleophilic substitution reaction.
  • the temperature of the nucleophilic substitution reaction is preferably 25-80° C., more preferably 50-60° C.; and the time is preferably 2-10 h, more preferably 4-5 h.
  • the obtained product system is preferably cooled to room temperature, filtered, the filtrate is concentrated, and the residue is separated by column chromatography to obtain the aminodithiocarbamate compound having the structure shown in formula I.
  • the eluent used in the column chromatography separation is preferably selected adaptively according to the polarity of the target product.
  • the eluent can be a mixed reagent of ethyl acetate and petroleum ether, a mixture of ethyl acetate and methanol Reagent or ethyl acetate, wherein, in terms of volume ratio, the volume ratio of ethyl acetate and petroleum ether in the ethyl acetate and petroleum ether mixed reagent is preferably (2 ⁇ 40): 1, and the ethyl acetate and methanol
  • the volume ratio of ethyl acetate to methanol in the mixed reagent is preferably (30-50):1.
  • the pharmaceutically acceptable salt of the aminodithiocarbamate compound is specifically the salt formed by the reaction of the aminodithiocarbamate compound with an inorganic acid or an organic acid
  • the inorganic acid can be hydrochloric acid , hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid
  • the organic acid can be citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethyl acetate Sulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid,
  • the hydrate of the aminodithiocarbamate compound is not particularly limited.
  • the present invention does not specifically limit the solvate of the aminodithiocarboxylate compound, which may be methanolate, ethanolate or ethyl acetate in particular.
  • the present invention does not specifically limit the preparation methods of the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds, and methods well known to those skilled in the art can be used.
  • the present invention provides a pharmaceutical composition, comprising active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients are the aminodithiocarboxylate compounds described in the above technical solution or the aminodithiocarboxylic acid described in the above technical solution A pharmaceutically acceptable salt, hydrate or solvate of the ester compound.
  • the content of the active ingredient is preferably 0.1 to 99.9 wt %, more preferably 1 to 99 wt %.
  • the present invention does not specifically limit the types of the pharmaceutically acceptable adjuvants, and the types of pharmaceutically acceptable adjuvants well known to those skilled in the art can be used, specifically water, salt solution, polyethylene glycol, polyhydroxyethyl alcohol Oxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, magnesium carbonate, cyclodextrin, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid , at least one of cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides, diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the pharmaceutical composition can be prepared in any form, specifically, capsules, tablets, aerosols, solutions, suspensions, sugar coatings, lozenges, syrups, emulsions, ointments, Injections, powders, granules, pastes, sustained-release preparations or foam preparations are not particularly limited in the present invention.
  • the present invention provides the use of aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of Mpro inhibitors;
  • the dithiocarbamate compounds are the aminodithiocarbamate compounds described in the above technical scheme; the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are those described in the above technical scheme.
  • a pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound; the pharmaceutical composition is the pharmaceutical composition described in the above technical solution.
  • the present invention does not specifically limit the dosage form of the Mpro inhibitor.
  • the route of administration it can specifically be oral administration preparations, nasal administration preparations, pulmonary administration preparations, oral formulations, transdermal administration preparations, Formulations for parenteral, rectal, depot, intravenous, intraurethral, intramuscular, ocular or epidural.
  • the present invention provides aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of medicaments for preventing and/or treating coronavirus
  • the amino dithiocarboxylate compound is the amino dithiocarboxylate compound described in the above technical scheme; the pharmaceutically acceptable salt, hydrate, solvent of the amino dithiocarboxylate compound
  • the compound is a pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound described in the above technical solution;
  • the pharmaceutical composition is the pharmaceutical composition described in the above technical solution.
  • the present invention does not specifically limit the dosage form of the medicament for preventing or treating coronavirus, and the dosage form well known to those skilled in the art can be used.
  • the coronavirus is preferably a novel coronavirus.
  • 2-(quinoline-8-sulfonylamino) ethyl (pyridine-3-methylene) amino dithiocarbamate was prepared with reference to the method of Example 1, except that quinoline-8- Sulfonyl chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent was ethyl acetate; the total yield of the target product was 35%; the specific NMR data were as follows:
  • 2-(N-methylquinoline-8-sulfonylamino) ethyl (pyridine-3-methylene) amino dithiocarbamate was prepared with reference to the method of Example 1, except that 2 -Bromo-N-methylethylamine hydrobromide instead of 2-bromoethylamine hydrobromide, using quinoline-8-sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, eluent is ethyl acetate; the total yield of the target product is 48%; the NMR data are as follows:
  • the main protease (Mpro) inhibitory activity test was performed on the compounds prepared in Examples 1-29, including the following steps:
  • Example Inhibition rate% Example Inhibition rate% Example Inhibition rate% Example Inhibition rate% Example Inhibition rate% 1 16.0 11 62.7 twenty one 12.0 2 32.6 12 41.3 twenty two 16.8 3 2.7 13 41.6 twenty three 11.1 4 23.3 14 1.4 twenty four 2.1 5 46.0 15 11.8 25 17.6 6 52.5 16 7.5 26 8.2 7 31.0 17 8.9 27 1.5 8 19.4 18 13.4 28 87.3 9 30.6 19 16.7 29 77.3 10 13.5 20 93.8 / /
  • Example Inhibition rate% Example Inhibition rate% Example Inhibition rate% Example Inhibition rate% 1 55.0 11 82.7 twenty one 51.0 2 63.6 12 74.3 twenty two 66.8 3 43.7 13 81.6 twenty three 61.1 4 53.3 14 41.4 twenty four 42.1 5 66.0 15 51.8 25 68.6 6 72.5 16 47.5 26 48.2 7 74.0 17 48.9 27 35.5 8 53.4 18 63.4 28 95.3 9 61.6 19 76.7 29 93.6 10 53.5 20 97.5 / /

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and provides a dithiocarbamate compound and a preparation method therefor, a pharmaceutical composition, and applications. The dithiocarbamate compound provided in the present invention has Mpro inhibitory activity, and can be used in anti-(novel) coronavirus. As a result of an application example, the dithiocarbamate compound provided in the present invention has an inhibitory effect on the Mpro, and the inhibitory effect on the Mpro is dose-dependent, wherein the inhibition rate of the dithiocarbamate compound on the Mpro is 35.5-97.5% at a concentration of 10 μM.

Description

氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用Amino dithiocarbamate compound and its preparation method and pharmaceutical composition and application
本申请要求于2021年03月26日提交中国专利局、申请号为CN202110325241.3、发明名称为“氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application requires that the Chinese patent application with the application number CN202110325241.3 and the invention name "aminodithiocarbamate compounds and their preparation methods, pharmaceutical compositions and applications" be submitted to the China Patent Office on March 26, 2021. Priority, the entire contents of which are incorporated herein by reference.
技术领域technical field
本发明涉及药物化学技术领域，具体涉及氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用。The invention relates to the technical field of medicinal chemistry, in particular to an aminodithiocarboxylate compound, a preparation method, a pharmaceutical composition and an application thereof.
背景技术Background technique
新型冠状病毒肺炎(coronavirus disease 2019，COVID-19)是近百年来人类遭遇的影响范围最广的全球性大流行病，因其具有较高的传染性和死亡率，已被世界卫生组织宣布为国际突发公共卫生事件，给人类生命安全和健康带来了重大威胁。The novel coronavirus disease 2019 (COVID-19) is a global pandemic with the widest impact on human beings in the past 100 years. It has been declared by the World Health Organization as a International public health emergencies have brought major threats to human life and health.
SARS-CoV-2主蛋白酶(Mpro)在新型冠状病毒复制过程中起关键作用，同时其具有不同于人体蛋白酶的特异切割位点，因而被认为是开发抗新型冠状病毒药物的理想靶标。由于目前尚缺乏安全有效的COVID-19治疗药物，积极开发广谱抗SARS-CoV-2药物具有重要意义。The SARS-CoV-2 master protease (Mpro) plays a key role in the replication of the new coronavirus, and it has a specific cleavage site different from that of human proteases, so it is considered an ideal target for the development of anti-nCoV drugs. Due to the lack of safe and effective therapeutic drugs for COVID-19, it is of great significance to actively develop broad-spectrum anti-SARS-CoV-2 drugs.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供氨基二硫代甲酸酯类化合物及其制备方法和药物组合物及应用，本发明提供的氨基二硫代甲酸酯类化合物具有Mpro抑制活性，可用于抗(新型)冠状病毒。The object of the present invention is to provide aminodithiocarbamate compounds and preparation methods, pharmaceutical compositions and applications thereof. The aminodithiocarbamate compounds provided by the present invention have Mpro inhibitory activity and can be used for anti-(new) coronavirus .
为了实现上述发明目的，本发明提供以下技术方案：In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:
本发明提供了一种氨基二硫代甲酸酯类化合物，具有式I所示结构：The invention provides a kind of amino dithiocarboxylate compound, has the structure shown in formula I:
Figure PCTCN2022079468-appb-000001
Figure PCTCN2022079468-appb-000001
式I中，R 1选自取代或未取代的苯基、取代或未取代的杂芳基、噻吩基、吡啶基、萘基或烷基；所述杂芳基选自喹啉基、香豆素基、氮杂吲哚基、2H-1,4-苯并噁嗪-3(4H)-酮基或3,4-二氢喹啉酮基；所述取代的苯基和取代的杂芳基中一个或多个取代基独立地选自卤素、甲基、甲氧基、氰基、硝基、亚乙二氧基或苯基； In formula I, R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, thienyl, pyridyl, naphthyl or alkyl; the heteroaryl is selected from quinolinyl, coumarin Sulphuryl, azaindolyl, 2H-1,4-benzoxazine-3(4H)-one or 3,4-dihydroquinolinone; the substituted phenyl and substituted heteroaryl One or more substituents in the group are independently selected from halogen, methyl, methoxy, cyano, nitro, ethylenedioxy or phenyl;
R 2选自氢或甲基。 R 2 is selected from hydrogen or methyl.
优选地，所述烷基为C1～C4直链烷基或C3～C6环烷基。Preferably, the alkyl group is a C1-C4 straight-chain alkyl group or a C3-C6 cycloalkyl group.
优选地，所述烷基为C1～C4直链烷基为乙基。Preferably, the alkyl group is a C1-C4 straight chain alkyl group and an ethyl group.
优选地，所述C3～C6环烷基为环丙基。Preferably, the C3-C6 cycloalkyl is cyclopropyl.
优选地，所述卤素为氟或氯。Preferably, the halogen is fluorine or chlorine.
优选地，所述氨基二硫代甲酸酯类化合物为以下化合物中的任一种：Preferably, the aminodithioformate compound is any one of the following compounds:
2-((3-甲基喹啉)-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Methylquinoline)-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2-氧代-2H-苯并吡喃)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-oxo-2H-benzopyran)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(quinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2,3-二氢-1,4-苯并二噁英)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2,3-Dihydro-1,4-benzodioxin)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(pyridine-3-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-硝基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-nitrophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(噻吩-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(thiophene-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-Methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-氰基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-cyanophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(萘基-1-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Naphthyl-1-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(萘基-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Naphthyl-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-甲基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-methylphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(苯磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Benzenesulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((1,1'-二苯基)-4-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((1,1'-diphenyl)-4-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2,,5-二氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2,,5-Dichlorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Chlorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(乙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Ethylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(环丙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Cyclopropylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(1H-吡咯[2,3-b]吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(1H-pyrrole[2,3-b]pyridine-3-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)ethyl(pyridine-3-methylene)aminodi Thioformate;
2-((2-氧代-1,2,3,4-四氢喹啉)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-oxo-1,2,3,4-tetrahydroquinoline)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(N-甲基喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(N-Methylquinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((5-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((5-Chloro-2-fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯。2-((3-Chloro-2-fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate.
本发明提供了上述技术方案所述氨基二硫代甲酸酯类化合物的制备方法，包括以下步骤：The present invention provides the preparation method of the aminodithiocarboxylate compound described in the above technical scheme, comprising the following steps:
将具有式II所示结构的化合物与具有式III所示结构的化合物进行磺酰化反应，得到具有式IV所示结构的化合物；The compound having the structure shown in formula II is subjected to sulfonylation reaction with the compound having the structure shown in formula III to obtain the compound having the structure shown in formula IV;
Figure PCTCN2022079468-appb-000002
Figure PCTCN2022079468-appb-000002
将3-氨甲基吡啶和二硫化碳进行加成反应，将所得产物体系与具有IV所示结构的化合物进行亲核取代反应，得到具有式I所示结构的氨基二硫代甲酸酯类化合物；3-aminomethylpyridine and carbon disulfide are carried out an addition reaction, and the resulting product system is subjected to a nucleophilic substitution reaction with a compound having a structure shown in IV to obtain an aminodithiocarbamate compound having a structure shown in formula I;
所述式II中R 2、式III中R 1以及式IV中R 1和R 2如式I中所定义。 Said R2 in formula II , R1 in formula III, and R1 and R2 in formula IV are as defined in formula I.
优选地，所述具有式II所示结构的化合物与具有式III所示结构的化合物的摩尔比为1：1。Preferably, the molar ratio of the compound having the structure shown in formula II to the compound having the structure shown in formula III is 1:1.
优选地，所述磺酰化反应在第一碱性催化剂和第一有机溶剂存在条件下进行。Preferably, the sulfonylation reaction is carried out in the presence of a first basic catalyst and a first organic solvent.
优选地，所述第一碱性催化剂包括三乙胺、N,N-二异丙基乙胺、吡啶和碳酸钾中的至少一种，所述第一碱性催化剂与具有式II所示结构的化合物的摩尔比为(2.8～3.2)：1。Preferably, the first basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine and potassium carbonate, and the first basic catalyst has the structure shown in formula II. The molar ratio of the compounds is (2.8-3.2):1.
优选地，所述第一有机溶剂包括二氯甲烷、四氢呋喃和N,N-二甲基甲酰胺中的至少一种，所述第一有机溶剂与具有式II所示结构的化合物的用量比为(6～10)mL：1mmol。Preferably, the first organic solvent comprises at least one of dichloromethane, tetrahydrofuran and N,N-dimethylformamide, and the dosage ratio of the first organic solvent to the compound having the structure shown in formula II is: (6-10) mL: 1 mmol.
优选地，所述磺酰化反应的温度为15～35℃，时间为10～15h。Preferably, the temperature of the sulfonylation reaction is 15-35° C., and the time is 10-15 h.
优选地，所述3-氨甲基吡啶和二硫化碳的摩尔比为1：1.5。Preferably, the molar ratio of the 3-aminomethylpyridine and carbon disulfide is 1:1.5.
优选地，所述加成反应在第二碱性催化剂和第二有机溶剂存在条件下进行。Preferably, the addition reaction is carried out in the presence of a second basic catalyst and a second organic solvent.
优选地，所述第二碱性催化剂包括三乙胺、N,N-二异丙基乙胺、吡啶、碳酸钾、碳酸钠和磷酸钾中的至少一种，第二碱性催化剂与3-氨甲基吡啶的摩尔比为(1.8～2.2)：1。Preferably, the second basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate and potassium phosphate, and the second basic catalyst is combined with 3- The molar ratio of aminomethylpyridine is (1.8-2.2):1.
优选地，所述第二有机溶剂包括丙酮、N,N-二甲基甲酰胺和水中的至少一种，所述第二有机溶剂与3-氨甲基吡啶的用量比为(10～20)mL：1mmol。Preferably, the second organic solvent comprises at least one of acetone, N,N-dimethylformamide and water, and the dosage ratio of the second organic solvent to 3-aminomethylpyridine is (10-20) mL: 1 mmol.
优选地，所述加成反应的温度为15～35℃，时间为25～35min。Preferably, the temperature of the addition reaction is 15-35° C., and the time is 25-35 min.
优选地，所述亲核取代反应的温度为25～80℃，时间为2～10h。Preferably, the temperature of the nucleophilic substitution reaction is 25-80° C., and the time is 2-10 h.
优选地，所述亲核取代反应后还包括：将亲核取代反应后所得产物体系冷至室温，过滤，将所得滤液浓缩，将所得剩余物经柱层析分离，得到具有式I所示结构的氨基二硫代甲酸酯类化合物。Preferably, after the nucleophilic substitution reaction, the method further comprises: cooling the obtained product system after the nucleophilic substitution reaction to room temperature, filtering, concentrating the obtained filtrate, and separating the obtained residue by column chromatography to obtain the structure shown in formula I of amino dithiocarbamate compounds.
优选地，所述柱层析分离采用的洗脱剂为乙酸乙酯和石油醚混合试剂、乙酸乙酯和甲醇混合试剂或乙酸乙酯。Preferably, the eluent used in the column chromatography separation is a mixed reagent of ethyl acetate and petroleum ether, a mixed reagent of ethyl acetate and methanol, or ethyl acetate.
优选地，所述乙酸乙酯和石油醚混合试剂中乙酸乙酯与石油醚的体积比为(2～40)：1。Preferably, the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate and petroleum ether mixed reagent is (2-40):1.
优选地，所述乙酸乙酯和甲醇混合试剂中乙酸乙酯与甲醇的体积比为(30～50)：1。Preferably, the volume ratio of ethyl acetate to methanol in the ethyl acetate and methanol mixed reagent is (30-50):1.
本发明提供了上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物。The present invention provides pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solutions.
优选地，所述氨基二硫代甲酸酯类化合物的药学上可接受的盐为氨基二硫代甲酸酯类化合物与无机酸或有机酸反应形成的盐，所述无机酸为盐酸、氢溴酸、硫酸、硝酸、胺基磺酸或磷酸，所述有机酸为柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸或羟乙磺酸。Preferably, the pharmaceutically acceptable salt of the aminodithiocarbamate compound is a salt formed by the reaction of the aminodithiocarbamate compound with an inorganic acid or an organic acid, and the inorganic acid is hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid, aminosulfonic acid or phosphoric acid, the organic acid is citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, Naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, Salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid or isethionic acid.
优选地，所述氨基二硫代甲酸酯类化合物的溶剂化物为甲醇化物、乙醇化物或乙酸乙酯化物。Preferably, the solvate of the aminodithioformate compound is methanolate, ethanolate or ethyl acetate.
本发明提供了一种药物组合物，包括活性成分和药学上可接受的辅料，所述活性成分为上述技术方案所述氨基二硫代甲酸酯类化合物或上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物。The present invention provides a pharmaceutical composition, comprising active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients are the aminodithiocarboxylate compounds described in the above technical solution or the aminodithiocarboxylic acid described in the above technical solution A pharmaceutically acceptable salt, hydrate or solvate of the ester compound.
优选地，所述活性成分的含量为0.1～99.9wt％。Preferably, the content of the active ingredient is 0.1-99.9 wt %.
优选地，所述药学上可接受的辅料为水、盐溶液、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、碳酸镁、环糊精、直链淀粉、硬脂酸镁、滑石、琼脂、果胶、阿拉伯胶、硬脂酸、纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯、二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮中的至少一种。Preferably, the pharmaceutically acceptable excipients are water, saline solution, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, magnesium carbonate, cyclic Dextrin, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides, diglycerides, At least one of pentaerythritol fatty acid ether, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
优选地，所述药物组合物的制剂为胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂或泡沫剂。Preferably, the formulations of the pharmaceutical composition are capsules, tablets, aerosols, solutions, suspensions, sugar coatings, lozenges, syrups, emulsions, ointments, injections, powders, granules, pastes, Sustained release or foam.
本发明提供了氨基二硫代甲酸酯类化合物、氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物或药物组合物在制备Mpro抑制剂中的应用；The present invention provides the use of aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of Mpro inhibitors;
所述氨基二硫代甲酸酯类化合物为上述技术方案所述氨基二硫代甲酸酯类化合物；The aminodithiocarboxylate compound is the aminodithiocarboxylate compound described in the above technical solution;
所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物为上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物；The pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are the pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solution ;
所述药物组合物为上述技术方案所述药物组合物。The pharmaceutical composition is the pharmaceutical composition described in the above technical solution.
本发明提供了氨基二硫代甲酸酯类化合物、氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物或药物组合物在制备预防和/或治疗冠状病毒的药物中的应用；The present invention provides aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of medicaments for preventing and/or treating coronavirus Applications;
所述氨基二硫代甲酸酯类化合物为上述技术方案所述氨基二硫代甲酸酯类化合物；The aminodithiocarboxylate compound is the aminodithiocarboxylate compound described in the above technical solution;
所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物为上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物；The pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are the pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solution ;
所述药物组合物为上述技术方案所述药物组合物。The pharmaceutical composition is the pharmaceutical composition described in the above technical solution.
优选地，所述冠状病毒为新型冠状病毒。Preferably, the coronavirus is a novel coronavirus.
本发明提供了一系列氨基二硫代甲酸酯类化合物，本发明提供的氨基二硫代甲酸酯类化合物具有Mpro抑制活性，可用于抗(新型)冠状病毒。应用例的结果显示，本发明提供的氨基二硫代甲酸酯类化合物均对Mpro具有抑制作用，且对Mpro具有抑制作用呈剂量依赖性，其中，所述氨基二硫代甲酸酯类化合物在10μM浓度条件下对Mpro的抑制率为35.5～97.5％。The present invention provides a series of amino dithiocarbamate compounds, and the amino dithiocarbamate compounds provided by the present invention have Mpro inhibitory activity and can be used for anti-(new) coronavirus. The results of the application examples show that the aminodithiocarbamate compounds provided by the present invention all have inhibitory effects on Mpro, and the inhibitory effect on Mpro is dose-dependent, wherein the aminodithiocarbamate compounds are at 10 μM. The inhibition rate of Mpro under the condition of concentration is 35.5～97.5%.
具体实施方式Detailed ways
本发明提供了氨基二硫代甲酸酯类化合物，具有式I所示结构：The present invention provides aminodithiocarboxylate compounds, which have the structure shown in formula I:
Figure PCTCN2022079468-appb-000003
Figure PCTCN2022079468-appb-000003
式I中，R 1选自取代或未取代的苯基、取代或未取代的杂芳基、噻吩基、吡啶基、萘基或烷基；所述杂芳基选自喹啉基、香豆素基、氮杂吲哚基、2H-1,4-苯并噁嗪-3(4H)-酮基或3,4-二氢喹啉酮基；所述取代的苯基和取代的杂芳基中一个或多个取代基独立地选自卤素、甲基、甲氧基、氰基、硝基、亚乙二氧基或苯基； In formula I, R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, thienyl, pyridyl, naphthyl or alkyl; the heteroaryl is selected from quinolinyl, coumarin Sulphuryl, azaindolyl, 2H-1,4-benzoxazine-3(4H)-one or 3,4-dihydroquinolinone; the substituted phenyl and substituted heteroaryl One or more substituents in the group are independently selected from halogen, methyl, methoxy, cyano, nitro, ethylenedioxy or phenyl;
R 2选自氢或甲基。 R 2 is selected from hydrogen or methyl.
在本发明中，所述烷基优选为C1～C4直链烷基或C3～C6环烷基；所述C1～C4直链烷基优选为乙基，所述C3～C6环烷基优选为环丙基。In the present invention, the alkyl group is preferably a C1-C4 straight-chain alkyl group or a C3-C6 cycloalkyl group; the C1-C4 straight-chain alkyl group is preferably an ethyl group, and the C3-C6 cycloalkyl group is preferably Cyclopropyl.
在本发明中，所述卤素优选为氟或氯。In the present invention, the halogen is preferably fluorine or chlorine.
在本发明中，所述氨基二硫代甲酸酯类化合物具体为以下化合物中的任一种：In the present invention, the aminodithioformate compound is specifically any one of the following compounds:
2-((3-甲基喹啉)-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Methylquinoline)-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2-氧代-2H-苯并吡喃)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-oxo-2H-benzopyran)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(quinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2,3-二氢-1,4-苯并二噁英)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2,3-Dihydro-1,4-benzodioxin)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(pyridine-3-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-硝基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-nitrophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(噻吩-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(thiophene-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-Methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-氰基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-cyanophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(萘基-1-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Naphthyl-1-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(萘基-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Naphthyl-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((4-甲基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-methylphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(苯磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Benzenesulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((1,1'-二苯基)-4-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((1,1'-diphenyl)-4-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((2,,5-二氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2,,5-Dichlorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Chlorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(乙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Ethylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(环丙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Cyclopropylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(1H-吡咯[2,3-b]吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(1H-pyrrole[2,3-b]pyridine-3-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)ethyl(pyridine-3-methylene)aminodi Thioformate;
2-((2-氧代-1,2,3,4-四氢喹啉)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-oxo-1,2,3,4-tetrahydroquinoline)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-(N-甲基喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(N-Methylquinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((5-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((5-Chloro-2-fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
2-((3-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯。2-((3-Chloro-2-fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate.
本发明提供了上述技术方案所述氨基二硫代甲酸酯类化合物的制备方法，包括以下步骤：The present invention provides the preparation method of the aminodithiocarboxylate compound described in the above technical scheme, comprising the following steps:
将具有式II所示结构的化合物与具有式III所示结构的化合物进行磺酰化反应，得到具有式IV所示结构的化合物；The compound having the structure shown in formula II is subjected to sulfonylation reaction with the compound having the structure shown in formula III to obtain the compound having the structure shown in formula IV;
Figure PCTCN2022079468-appb-000004
Figure PCTCN2022079468-appb-000004
将3-氨甲基吡啶和二硫化碳进行加成反应，将所得产物体系与具有IV所示结构的化合物进行亲核取代反应，得到具有式I所示结构的氨基二硫代甲酸酯类化合物。3-aminomethylpyridine and carbon disulfide are subjected to an addition reaction, and the obtained product system is subjected to a nucleophilic substitution reaction with a compound having the structure shown in IV to obtain an aminodithiocarbamate compound having the structure shown in formula I.
在本发明中，若无特殊说明，所用原料均为本领域技术人员熟知的市售商品。In the present invention, unless otherwise specified, the raw materials used are all commercially available commodities well known to those skilled in the art.
本发明将具有式II所示结构的化合物与具有式III所示结构的化合物进行磺酰化反应，得到具有式IV所示结构的化合物。在本发明中，所述具有式II所示结构的化合物与具有式III所示结构的化合物的摩尔比优选为1：1。在本发明中，所述磺酰化反应优选在第一碱性催化剂和第一有机溶剂存在条件下进行。在本发明中，所述第一碱性催化剂优选包括三乙胺、N,N-二异丙基乙胺、吡啶和碳酸钾中的至少一种，更优选为N,N-二异丙基乙胺；所述第一碱性催化剂与具有式II所示结构的化合物的摩尔比优选为(2.8～3.2)：1，更优选为3：1。在本发明中，所述第一有机溶剂优选包括二氯甲烷、四氢呋喃和N,N-二甲基甲酰胺中的至少一种，更优选为二氯甲烷；所述第一有机溶剂与具有式II所示结构的化合物的用量比优选为(6～10)mL：1mmol，更优选为8mL：1mmol。本发明优选具有式II所示结构的化合物溶于第一有机溶剂中，在搅拌条件下加入第一碱性催化剂和具有式III所示结构的化合物进行磺酰化反应。在本发明中，所述磺酰化反应的温度优选为15～35℃，更优选为20～25℃，具体可以在室温条件下进行，即不需要额外的加热或降温，在本发明的实施例中，所述室温具体为25℃；所述磺酰化反应的时间优选为10～15h，更优选为12h。In the present invention, the compound having the structure shown in formula II is subjected to sulfonylation reaction with the compound having the structure shown in formula III to obtain the compound having the structure shown in formula IV. In the present invention, the molar ratio of the compound having the structure represented by the formula II to the compound having the structure represented by the formula III is preferably 1:1. In the present invention, the sulfonylation reaction is preferably carried out in the presence of a first basic catalyst and a first organic solvent. In the present invention, the first basic catalyst preferably includes at least one of triethylamine, N,N-diisopropylethylamine, pyridine and potassium carbonate, more preferably N,N-diisopropyl Ethylamine; the molar ratio of the first basic catalyst to the compound having the structure represented by formula II is preferably (2.8-3.2):1, more preferably 3:1. In the present invention, the first organic solvent preferably includes at least one of dichloromethane, tetrahydrofuran and N,N-dimethylformamide, more preferably dichloromethane; the first organic solvent is combined with the formula The dosage ratio of the compound of the structure represented by II is preferably (6-10) mL:1 mmol, and more preferably 8 mL:1 mmol. In the present invention, it is preferred that the compound having the structure shown in formula II is dissolved in the first organic solvent, and the first basic catalyst and the compound having the structure shown in formula III are added under stirring conditions to carry out the sulfonylation reaction. In the present invention, the temperature of the sulfonylation reaction is preferably 15-35°C, more preferably 20-25°C, and can be carried out at room temperature, that is, no additional heating or cooling is required. In the implementation of the present invention In an example, the room temperature is specifically 25°C; the time of the sulfonylation reaction is preferably 10-15 h, more preferably 12 h.
所述磺酰化反应后，本发明优选将所得产物体系浓缩，无需再进行进一步纯化，直接将所得剩余物(含具有式IV所示结构的化合物)用于后续反应即可。After the sulfonylation reaction, in the present invention, the obtained product system is preferably concentrated without further purification, and the obtained residue (containing the compound having the structure shown in formula IV) can be directly used for the subsequent reaction.
本发明将3-氨甲基吡啶和二硫化碳进行加成反应。在本发明中，所述3-氨甲基吡啶和二硫化碳的摩尔比优选为1：1.5。在本发明中，所述加成反应优选在第二碱性催化剂和第二有机溶剂存在条件下进行。在本发明中，所述第二碱性催化剂优选包括三乙胺、N,N-二异丙基乙胺、吡啶、碳酸钾、碳酸钠和磷酸钾中的至少一种，更优选为碳酸钾；所述第二碱性催化剂与3-氨甲基吡啶的摩尔比优选为(1.8～2.2)：1，更优选为2：1。在本发明中，所述第二有机溶剂优选包括丙酮、N,N-二甲基甲酰胺和水中的至少一种，更优选为丙酮；所述第二有机溶剂与3-氨甲基吡啶的用量比优选为(10～20)mL：1mmol，更优选为15mL：1mmol。本发明优选将3-氨甲基吡啶溶于第二有机溶剂中，之后加入第二碱性催化剂和二硫化碳进行加成反应。在本发明中，所述加成反应的温度优选为15～35℃，更优选为20～25℃，具体可以在室温条件下进行；所述加成反应的时间优选为25～35min，更优选为30min。In the present invention, addition reaction of 3-aminomethylpyridine and carbon disulfide is carried out. In the present invention, the molar ratio of the 3-aminomethylpyridine and carbon disulfide is preferably 1:1.5. In the present invention, the addition reaction is preferably carried out in the presence of a second basic catalyst and a second organic solvent. In the present invention, the second basic catalyst preferably includes at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate and potassium phosphate, more preferably potassium carbonate ; The molar ratio of the second basic catalyst to 3-aminomethylpyridine is preferably (1.8-2.2):1, more preferably 2:1. In the present invention, the second organic solvent preferably includes at least one of acetone, N,N-dimethylformamide and water, more preferably acetone; The dosage ratio is preferably (10-20) mL:1 mmol, and more preferably 15 mL:1 mmol. In the present invention, 3-aminomethylpyridine is preferably dissolved in the second organic solvent, and then the second basic catalyst and carbon disulfide are added to carry out the addition reaction. In the present invention, the temperature of the addition reaction is preferably 15-35°C, more preferably 20-25°C, and can be carried out at room temperature; the time of the addition reaction is preferably 25-35min, more preferably for 30min.
所述加成反应后，本发明优选无需进行任何后处理，直接将加成反应后所得产物体系与磺酰化反应后浓缩所得剩余物混合，进行亲核取代反应。在本发明中，所述亲核取代反应的温度优选为25～80℃，更优选为50～60℃；时间优选为2～10h，更优选为4～5h。After the addition reaction, the present invention preferably does not need to carry out any post-treatment, and directly mixes the product system obtained after the addition reaction with the residue obtained by concentration after the sulfonylation reaction to carry out a nucleophilic substitution reaction. In the present invention, the temperature of the nucleophilic substitution reaction is preferably 25-80° C., more preferably 50-60° C.; and the time is preferably 2-10 h, more preferably 4-5 h.
所述亲核取代反应后，本发明优选将所得产物体系冷至室温，过滤，滤液浓缩，剩余物经柱层析分离，得到具有式I所示结构的氨基二硫代甲酸酯类化合物。在本发明中，所述柱层析分离所用洗脱剂优选根据目标产物的极性进行适应性选择，具体的，洗脱剂可以为乙酸乙酯和石油醚混合试剂、乙酸乙酯和甲醇混合试剂或乙酸乙酯，其中，按体积比计，所述乙酸乙酯和石油醚混合试剂中乙酸乙酯与石油醚的体积比优选为(2～40)：1，所述乙酸乙酯和甲醇混合试剂中乙酸乙酯与甲醇的体积比优选为(30～50)：1。After the nucleophilic substitution reaction, in the present invention, the obtained product system is preferably cooled to room temperature, filtered, the filtrate is concentrated, and the residue is separated by column chromatography to obtain the aminodithiocarbamate compound having the structure shown in formula I. In the present invention, the eluent used in the column chromatography separation is preferably selected adaptively according to the polarity of the target product. Specifically, the eluent can be a mixed reagent of ethyl acetate and petroleum ether, a mixture of ethyl acetate and methanol Reagent or ethyl acetate, wherein, in terms of volume ratio, the volume ratio of ethyl acetate and petroleum ether in the ethyl acetate and petroleum ether mixed reagent is preferably (2～40): 1, and the ethyl acetate and methanol The volume ratio of ethyl acetate to methanol in the mixed reagent is preferably (30-50):1.
本发明提供了上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物。在本发明中，所述氨基二硫代甲酸酯类化合物的药学上可接受的盐具体为氨基二硫代甲酸酯类化合物与无机酸或有机酸反应形成的盐，所述无机酸可以为盐酸、氢溴酸、硫酸、硝酸、胺基磺酸或磷酸，有机酸可以为柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸或羟乙磺酸。本发明对所述氨基二硫代甲酸酯类化合物的水合物没有特殊限定。本发明对所述氨基二硫代甲酸酯类化合物的溶剂化物没有特殊限定，具体可以为甲醇化物、乙醇化物或乙酸乙酯化物。本发明对所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物和溶剂化物的制备方法没有特殊限定，采用本领域技术人员熟知的方法即可。The present invention provides pharmaceutically acceptable salts, hydrates or solvates of the aminodithiocarbamate compounds described in the above technical solutions. In the present invention, the pharmaceutically acceptable salt of the aminodithiocarbamate compound is specifically the salt formed by the reaction of the aminodithiocarbamate compound with an inorganic acid or an organic acid, and the inorganic acid can be hydrochloric acid , hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid, the organic acid can be citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethyl acetate Sulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, Benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, or isethionic acid. In the present invention, the hydrate of the aminodithiocarbamate compound is not particularly limited. The present invention does not specifically limit the solvate of the aminodithiocarboxylate compound, which may be methanolate, ethanolate or ethyl acetate in particular. The present invention does not specifically limit the preparation methods of the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds, and methods well known to those skilled in the art can be used.
本发明提供了一种药物组合物，包括活性成分和药学上可接受的辅料，所述活性成分为上述技术方案所述氨基二硫代甲酸酯类化合物或上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物。在本发明中，所述活性成分的含量优选为0.1～99.9wt％，更优选为1～99wt％。本发明对所述药学上可接受的辅料的种类没有特殊限定，采用本领域技术人员熟知种类的药学上可接受的辅料即可，具体可以为水、盐溶液、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、碳酸镁、环糊精、直链淀粉、硬脂酸镁、滑石、琼脂、果胶、阿拉伯胶、硬脂酸、纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘 油酯、二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮中的至少一种。The present invention provides a pharmaceutical composition, comprising active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients are the aminodithiocarboxylate compounds described in the above technical solution or the aminodithiocarboxylic acid described in the above technical solution A pharmaceutically acceptable salt, hydrate or solvate of the ester compound. In the present invention, the content of the active ingredient is preferably 0.1 to 99.9 wt %, more preferably 1 to 99 wt %. The present invention does not specifically limit the types of the pharmaceutically acceptable adjuvants, and the types of pharmaceutically acceptable adjuvants well known to those skilled in the art can be used, specifically water, salt solution, polyethylene glycol, polyhydroxyethyl alcohol Oxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, magnesium carbonate, cyclodextrin, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid , at least one of cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides, diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
在本发明中，所述药物组合物可以制成任何形式的制剂，具体可以为胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂或泡沫剂，本发明对此没有特殊限定。In the present invention, the pharmaceutical composition can be prepared in any form, specifically, capsules, tablets, aerosols, solutions, suspensions, sugar coatings, lozenges, syrups, emulsions, ointments, Injections, powders, granules, pastes, sustained-release preparations or foam preparations are not particularly limited in the present invention.
本发明提供了氨基二硫代甲酸酯类化合物、氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物或药物组合物在制备Mpro抑制剂中的应用；所述氨基二硫代甲酸酯类化合物为上述技术方案所述氨基二硫代甲酸酯类化合物；所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物为上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物；所述药物组合物为上述技术方案所述药物组合物。本发明对所述Mpro抑制剂的剂型没有特殊限定，根据给药途径，具体可以为口服给药制剂、鼻部给药制剂、肺部给药制剂、口腔含化制剂、经皮给药制剂、胃肠外给药制剂、直肠给药制剂、储库式给药制剂、静脉内给药制剂、尿道内给药制剂、肌内给药制剂、眼部给药制剂或硬膜外给药制剂。The present invention provides the use of aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of Mpro inhibitors; The dithiocarbamate compounds are the aminodithiocarbamate compounds described in the above technical scheme; the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are those described in the above technical scheme. A pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound; the pharmaceutical composition is the pharmaceutical composition described in the above technical solution. The present invention does not specifically limit the dosage form of the Mpro inhibitor. According to the route of administration, it can specifically be oral administration preparations, nasal administration preparations, pulmonary administration preparations, oral formulations, transdermal administration preparations, Formulations for parenteral, rectal, depot, intravenous, intraurethral, intramuscular, ocular or epidural.
本发明提供了氨基二硫代甲酸酯类化合物、氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物或药物组合物在制备预防和/或治疗冠状病毒的药物中的应用；所述氨基二硫代甲酸酯类化合物为上述技术方案所述氨基二硫代甲酸酯类化合物；所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物为上述技术方案所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物；所述药物组合物为上述技术方案所述药物组合物。本发明对所述预防或治疗冠状病毒的药物的剂型没有特殊限定，采用本领域技术人员熟知的剂型即可。The present invention provides aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of medicaments for preventing and/or treating coronavirus The amino dithiocarboxylate compound is the amino dithiocarboxylate compound described in the above technical scheme; the pharmaceutically acceptable salt, hydrate, solvent of the amino dithiocarboxylate compound The compound is a pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound described in the above technical solution; the pharmaceutical composition is the pharmaceutical composition described in the above technical solution. The present invention does not specifically limit the dosage form of the medicament for preventing or treating coronavirus, and the dosage form well known to those skilled in the art can be used.
在本发明中，所述冠状病毒优选为新型冠状病毒。In the present invention, the coronavirus is preferably a novel coronavirus.
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
实施例1Example 1
制备2-((3-甲基喹啉)-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，反应式如下所示：To prepare 2-((3-methylquinoline)-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the reaction formula is as follows:
Figure PCTCN2022079468-appb-000005
Figure PCTCN2022079468-appb-000005
将2-溴乙胺氢溴酸盐(0.21g,1mmol)溶于8mL二氯甲烷中，搅拌条件下加入N,N-二异丙基乙胺(DIEPA,0.39g,3mmol)和(3-甲基喹啉)-8-磺酰氯(0.24g,1mmol)，室温(25℃)条件下反应过夜；将所得产物体系浓缩，得到中间体；将3-氨甲基吡啶(0.11g,1mmol)溶于15mL丙酮中，加入碳酸钾(0.28g,2mmol)和二硫化碳(0.12g,1.5mmol)，室温条件下反应30min；向所得产物体系中加入上述中间体，60℃下反应4h；将所得产物体系冷至室温，过滤，滤液浓缩，剩余物经柱层析分离(洗脱剂为乙酸乙酯)，得到白色固体0.17g，即为2-((3-甲基喹啉)-8-磺酰氨基)乙基(吡啶 -3-亚甲基)氨基二硫代甲酸酯，总收率为39％；核磁数据具体如下：Dissolve 2-bromoethylamine hydrobromide (0.21 g, 1 mmol) in 8 mL of dichloromethane, add N,N-diisopropylethylamine (DIEPA, 0.39 g, 3 mmol) and (3- Methylquinoline)-8-sulfonyl chloride (0.24g, 1mmol), reacted at room temperature (25°C) overnight; the obtained product system was concentrated to obtain an intermediate; 3-aminomethylpyridine (0.11g, 1mmol) Dissolve in 15mL acetone, add potassium carbonate (0.28g, 2mmol) and carbon disulfide (0.12g, 1.5mmol), react at room temperature for 30min; add the above intermediate to the obtained product system, react at 60 ℃ for 4h; The system was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was separated by column chromatography (the eluent was ethyl acetate) to obtain 0.17 g of a white solid, which was 2-((3-methylquinoline)-8-sulfonic acid amido) ethyl (pyridine-3-methylene) amino dithiocarbamate, the total yield is 39%; NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.46(t,J＝4.8Hz,1H),8.94(d,J＝2.0Hz,1H),8.49(d,J＝6.8Hz,2H),8.29–8.26(m,2H),8.19(d,J＝8.4Hz,1H),7.71(t,J＝7.6Hz,1H),7.65(d,J＝8.0Hz,1H),7.46(t,J＝5.6Hz,1H),7.35(dd,J＝8.0,4.8Hz,1H),4.80(d,J＝5.6Hz,2H),3.25(t,J＝6.8Hz,2H),3.11(dd,J＝13.0,6.6Hz,2H),2.53(s,3H). 13C NMR(100MHz,DMSO-d 6)δ196.46,153.02,149.00,148.38,140.88,135.97,135.37,135.31,132.99,132.79,131.94,129.74,128.31,125.70,123.43,47.14,42.48,33.72,18.19。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.46 (t, J=4.8 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.49 (d, J=6.8 Hz, 2H), 8.29 –8.26(m, 2H), 8.19(d, J=8.4Hz, 1H), 7.71(t, J=7.6Hz, 1H), 7.65(d, J=8.0Hz, 1H), 7.46(t, J= 5.6Hz,1H),7.35(dd,J=8.0,4.8Hz,1H),4.80(d,J=5.6Hz,2H),3.25(t,J=6.8Hz,2H),3.11(dd,J= 13.0, 6.6Hz, 2H), 2.53(s, 3H). 13 C NMR (100MHz, DMSO-d 6 )δ196.46,153.02,149.00,148.38,140.88,135.97,135.37,135.31,132.99,132.79,131.94,129.79 128.31, 125.70, 123.43, 47.14, 42.48, 33.72, 18.19.
实施例2Example 2
制备2-((2-氧代-2H-苯并吡喃)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((2-oxo-2H-benzopyran)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000006
Figure PCTCN2022079468-appb-000006
参照实施例1的方法制备2-((2-氧代-2H-苯并吡喃)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(2-氧代-2H-苯并吡喃)-6-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝4：1；目标产物总收率为50％；核磁数据具体如下：2-((2-oxo-2H-benzopyran)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, different The point is only that (2-oxo-2H-benzopyran)-6-sulfonyl chloride is used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent is a mixture of ethyl acetate and petroleum ether Reagent, by volume ratio, ethyl acetate: petroleum ether=4:1; the total yield of the target product is 50%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.52(t,J＝5.6Hz,1H),8.49–8.47(m,2H),8.23–8.20(m,2H),8.05(t,J＝5.8Hz,1H),7.97(dd,J＝8.8,2.4Hz,1H),7.66(dt,J＝7.8,1.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.36(dd,J＝7.6,4.8Hz,1H),6.64(d,J＝9.6Hz,1H),4.81(d,J＝5.6Hz,2H),3.26(t,J＝6.8Hz,2H),3.06(dd,J＝13.0,6.2Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.48,159.29,155.62,149.06,148.44,143.63,136.44,135.48,132.80,129.60,127.46,123.49,118.90,117.63,47.22,42.05,33.84。 1 H NMR (400MHz, DMSO-d 6 )δ10.52(t, J=5.6Hz, 1H), 8.49-8.47(m, 2H), 8.23-8.20(m, 2H), 8.05(t, J=5.8 Hz,1H),7.97(dd,J=8.8,2.4Hz,1H),7.66(dt,J=7.8,1.8Hz,1H),7.60(d,J=8.8Hz,1H),7.36(dd,J ＝7.6,4.8Hz,1H),6.64(d,J＝9.6Hz,1H),4.81(d,J＝5.6Hz,2H),3.26(t,J＝6.8Hz,2H),3.06(dd,J =13.0, 6.2Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.48, 159.29, 155.62, 149.06, 148.44, 143.63, 136.44, 135.48, 132.80, 129.60, 127.46, 123.49, 117.290 42.05, 33.84.
实施例3Example 3
制备2-(喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(quinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000007
Figure PCTCN2022079468-appb-000007
参照实施例1的方法制备2-(喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用喹啉-8-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯；目标产物总收率为35％；核磁数据具体如下：2-(quinoline-8-sulfonylamino) ethyl (pyridine-3-methylene) amino dithiocarbamate was prepared with reference to the method of Example 1, except that quinoline-8- Sulfonyl chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent was ethyl acetate; the total yield of the target product was 35%; the specific NMR data were as follows:
1H NMR(400MHz,CDCl 3)δ9.18(t,J＝5.4Hz,1H),8.96(dd,J＝4.2,1.4Hz,1H),8.41–8.35(m,3H),8.26(dd,J＝8.4,1.4Hz,1H),8.06(dd,J＝8.2,1.2Hz,1H),7.65–7.59(m,2H),7.51(dd,J＝8.4,4.4Hz,1H),7.15(dd,J＝7.6,4.8Hz,1H),6.84(t,J＝6.0Hz,1H),4.81(d,J＝5.6Hz,2H),3.34(t,J＝6.4Hz,2H),3.18(t,J＝6.2Hz,2H). 13C NMR(100MHz,CDCl 3)δ197.40,151.44,149.14,148.49,142.98,137.09,136.24,135.39,133.65,132.55,131.07,128.74,125.67,123.60,122.42,47.89,42.91,34.86。 1 H NMR (400 MHz, CDCl 3 ) δ 9.18 (t, J=5.4 Hz, 1H), 8.96 (dd, J=4.2, 1.4 Hz, 1H), 8.41-8.35 (m, 3H), 8.26 (dd, J=8.4, 1.4Hz, 1H), 8.06 (dd, J=8.2, 1.2Hz, 1H), 7.65–7.59 (m, 2H), 7.51 (dd, J=8.4, 4.4Hz, 1H), 7.15 (dd , J＝7.6, 4.8Hz, 1H), 6.84(t, J＝6.0Hz, 1H), 4.81(d, J＝5.6Hz, 2H), 3.34(t, J＝6.4Hz, 2H), 3.18(t , J=6.2Hz, 2H). 13 C NMR (100MHz, CDCl 3 )δ197.40, 151.44, 149.14, 148.49, 142.98, 137.09, 136.24, 135.39, 133.65, 132.55, 131,.07, 128.74, 125.67, 128.60, 129.67, 128.60. 42.91, 34.86.
实施例4Example 4
制备2-((2,3-二氢-1,4-苯并二噁英)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((2,3-dihydro-1,4-benzodioxin)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows shown:
Figure PCTCN2022079468-appb-000008
Figure PCTCN2022079468-appb-000008
参照实施例1的方法制备2-((2,3-二氢-1,4-苯并二噁英)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(2,3-二氢-1,4-苯并二噁英)-6-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝10：1；目标产物总收率为46％；核磁数据具体如下：Prepare 2-((2,3-dihydro-1,4-benzodioxin)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodithiol with reference to the method of Example 1 formate, except that (2,3-dihydro-1,4-benzodioxin)-6-sulfonyl chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, washed The removing agent is a mixed reagent of ethyl acetate and petroleum ether. By volume ratio, ethyl acetate: petroleum ether=10:1; the total yield of the target product is 46%; the specific NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(t,J＝5.6Hz,1H),8.50–8.47(m,2H),7.76(t,J＝5.8Hz,1H),7.69–7.67(m,1H),7.37(dd,J＝7.6,4.8Hz,1H),7.27–7.24(m,2H),7.04–7.02(m,1H),4.82(d,J＝5.6Hz,2H),4.31(q,J＝4.8Hz,4H),3.24(t,J＝6.8Hz,2H),2.96(dd,J＝13.2,6.4Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ148.98(s),148.36(s),146.82(s),143.28(s),135.52(s),132.78(d,J＝13.8Hz),123.50(s),120.05(s),117.51(s),115.55(s),64.35(s),64.06(s),47.17(s),42.01(s),40.04(d,J＝21.0Hz),39.73(s),39.52(s),39.31(s),39.10(s),38.89(s),33.84(s)。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (t, J=5.6Hz, 1H), 8.50-8.47 (m, 2H), 7.76 (t, J=5.8Hz, 1H), 7.69-7.67 ( m, 1H), 7.37 (dd, J=7.6, 4.8Hz, 1H), 7.27–7.24 (m, 2H), 7.04–7.02 (m, 1H), 4.82 (d, J=5.6Hz, 2H), 4.31 (q, J=4.8Hz, 4H), 3.24 (t, J=6.8Hz, 2H), 2.96 (dd, J=13.2, 6.4Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ148. 98(s), 148.36(s), 146.82(s), 143.28(s), 135.52(s), 132.78(d, J=13.8Hz), 123.50(s), 120.05(s), 117.51(s), 115.55(s), 64.35(s), 64.06(s), 47.17(s), 42.01(s), 40.04(d, J=21.0Hz), 39.73(s), 39.52(s), 39.31(s), 39.10(s), 38.89(s), 33.84(s).
实施例5Example 5
制备2-(吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(pyridine-3-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000009
Figure PCTCN2022079468-appb-000009
参照实施例1的方法制备2-(吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用吡啶-3-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和甲醇混合试剂，按体积比计，乙酸乙酯：甲醇＝40：1；目标产物总收率为46％；核磁数据具体如下：2-(pyridine-3-sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that pyridine-3-sulfonyl chloride was used Instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and methanol, and by volume ratio, ethyl acetate:methanol=40:1; the total yield of the target product is 46% ; NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(t,J＝5.6Hz,1H),8.96(d,J＝2.0Hz,1H),8.82(dd,J＝5.0,1.4Hz,1H),8.50–8.47(m,2H),8.20–8.17(m,2H),7.69–7.62(m,2H),7.37(dd,J＝7.6,4.8Hz,1H),4.82(d,J＝5.6Hz,2H),3.26(t,J＝6.8Hz,2H),3.08(dd,J＝12.8,6.4Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.42,153.07,149.04,148.42,147.03,135.50,134.51,132.81,124.28,123.51,47.21,41.92,33.81。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.53 (t, J=5.6Hz, 1H), 8.96 (d, J=2.0Hz, 1H), 8.82 (dd, J=5.0, 1.4Hz, 1H) ,8.50-8.47(m,2H),8.20-8.17(m,2H),7.69-7.62(m,2H),7.37(dd,J=7.6,4.8Hz,1H),4.82(d,J=5.6Hz , 2H), 3.26 (t, J=6.8Hz, 2H), 3.08 (dd, J=12.8, 6.4Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.42, 153.07, 149.04, 148.42, 147.03 , 135.50, 134.51, 132.81, 124.28, 123.51, 47.21, 41.92, 33.81.
实施例6Example 6
制备2-((3-硝基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((3-nitrophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000010
Figure PCTCN2022079468-appb-000010
参照实施例1的方法制备2-((3-硝基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(3-硝基苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝5：1；目标产物总收率为41％；核磁数据具体如下：2-((3-nitrophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that (3 -nitrophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume ratio, ethyl acetate: petroleum ether=5: 1; The total yield of the target product is 41%; the NMR data are as follows:
1H NMR(400MHz,DMSO)δ10.51(t,J＝5.6Hz,1H),8.53(t,J＝2.0Hz,1H),8.49–8.47(m,3H),8.31(t,J＝5.6Hz,1H),8.23–8.21(m,1H),7.90(t,J＝8.0Hz,1H),7.66(dt,J＝7.8,1.8Hz,1H),7.36(dd,J＝7.6,4.8Hz,1H),4.80(d,J＝5.6Hz,2H),3.23(t,J＝6.8Hz,2H),3.08(dd,J＝13.0,6.2Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.34,149.02,148.41,147.90,142.12,135.48,132.77,132.55,131.30,127.10,123.49,121.39,47.18,41.92,38.89。 1 H NMR (400MHz, DMSO) δ 10.51 (t, J=5.6Hz, 1H), 8.53 (t, J=2.0Hz, 1H), 8.49-8.47 (m, 3H), 8.31 (t, J=5.6 Hz, 1H), 8.23–8.21 (m, 1H), 7.90 (t, J=8.0Hz, 1H), 7.66 (dt, J=7.8, 1.8Hz, 1H), 7.36 (dd, J=7.6, 4.8Hz) , 1H), 4.80(d, J=5.6Hz, 2H), 3.23(t, J=6.8Hz, 2H), 3.08(dd, J=13.0, 6.2Hz, 2H). 13 C NMR (100MHz, DMSO- d 6 ) δ196.34, 149.02, 148.41, 147.90, 142.12, 135.48, 132.77, 132.55, 131.30, 127.10, 123.49, 121.39, 47.18, 41.92, 38.89.
实施例7Example 7
制备2-(噻吩-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(thiophene-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000011
Figure PCTCN2022079468-appb-000011
参照实施例1的方法制备2-(噻吩-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用噻吩-2-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝3：1；目标产物总收率为48％；核磁数据具体如下：2-(thiophene-2-sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that thiophene-2-sulfonyl chloride was used Instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether. By volume, ethyl acetate: petroleum ether=3:1; the total yield of the target product is 48%; NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.52(s,1H),8.51–8.47(m,2H),8.08(d,J＝5.6Hz,1H),7.92(dd,J＝5.2,1.2Hz,1H),7.68(d,J＝7.6Hz,1H),7.60(d,J＝3.6Hz,1H),7.36(dd,J＝8.0,4.8Hz,1H),7.18(dd,J＝5.0,3.8Hz,1H),4.83(d,J＝5.6Hz,2H),3.29(t,J＝7.0Hz,2H),3.09(dd,J＝13.0,6.6Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.48,149.03,148.40,141.14,135.47,132.81,132.52,131.61,127.67,123.49,47.19,42.23,33.70。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.51-8.47 (m, 2H), 8.08 (d, J=5.6 Hz, 1H), 7.92 (dd, J=5.2, 1.2 Hz,1H),7.68(d,J=7.6Hz,1H),7.60(d,J=3.6Hz,1H),7.36(dd,J=8.0,4.8Hz,1H),7.18(dd,J=5.0 , 3.8Hz, 1H), 4.83 (d, J=5.6Hz, 2H), 3.29 (t, J=7.0Hz, 2H), 3.09 (dd, J=13.0, 6.6Hz, 2H). 13 C NMR (100MHz) ,DMSO-d 6 )δ196.48,149.03,148.40,141.14,135.47,132.81,132.52,131.61,127.67,123.49,47.19,42.23,33.70.
实施例8Example 8
制备2-((2-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((2-methoxyphenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000012
Figure PCTCN2022079468-appb-000012
参照实施例1的方法2-((2-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(2-甲氧基苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝5：1；目标产物总收率为42％；核磁数据具体如下：With reference to the method 2-((2-methoxyphenyl)sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate, the difference is only that (2 -Methoxyphenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume ratio, ethyl acetate: petroleum ether=5 : 1; the total yield of the target product is 42%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.49(t,J＝5.0Hz,1H),8.50–8.47(m,2H),7.73(d,J＝8.0Hz,1H),7.66(d,J＝7.6Hz,1H),7.62–7.58(m,1H),7.46(s,1H),7.36(dd,J＝7.6,4.8Hz,1H),7.21(d,J＝8.4Hz,1H),7.09–7.05(m,1H),4.81(d,J＝5.6Hz,2H),3.90(s,3H),3.24(t,J＝6.2Hz,2H),3.03(d,J＝6.0Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.60,156.26,149.05,148.41,135.47,134.50,132.85,129.42,127.67,123.50,120.06,112.77,56.07,47.16,42.14,33.76。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (t, J=5.0 Hz, 1H), 8.50-8.47 (m, 2H), 7.73 (d, J=8.0 Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.62–7.58 (m, 1H), 7.46 (s, 1H), 7.36 (dd, J=7.6, 4.8Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 7.09–7.05(m, 1H), 4.81(d, J=5.6Hz, 2H), 3.90(s, 3H), 3.24(t, J=6.2Hz, 2H), 3.03(d, J=6.0Hz, 2H) ). 13 C NMR (100MHz, DMSO-d 6 ) δ 196.60, 156.26, 149.05, 148.41, 135.47, 134.50, 132.85, 129.42, 127.67, 123.50, 120.06, 112.77, 56.07, 47.16, 42.14, 33.16.
实施例9Example 9
制备2-((2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((2-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000013
Figure PCTCN2022079468-appb-000013
参照实施例1的方法制备2-((2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(2-氟苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝4：1；目标产物总收率为33％；核磁数据具体如下：2-((2-Fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that (2- Fluorophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum ether=4:1; The total yield of the target product is 33%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.52(t,J＝5.2Hz,1H),8.50–8.47(m,2H),8.21(t,J＝5.4Hz,1H),7.82–7.78(m,1H),7.73–7.66(m,2H),7.46–7.35(m,3H),4.81(d,J＝5.2Hz,2H),3.26(t,J＝6.8Hz,2H),3.13(dd,J＝12.8,6.0Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.43,158.17(d,J＝252Hz),149.02,148.40,135.47,135.24(d,J＝8.0Hz),132.82,129.67,128.33(d,J＝14.0Hz),124.86,123.49,117.23(d,J＝21.0Hz),47.17,41.88,33.76。 1 H NMR (400MHz, DMSO-d 6 )δ10.52(t,J=5.2Hz,1H),8.50-8.47(m,2H),8.21(t,J=5.4Hz,1H),7.82-7.78( m, 1H), 7.73–7.66 (m, 2H), 7.46–7.35 (m, 3H), 4.81 (d, J=5.2Hz, 2H), 3.26 (t, J=6.8Hz, 2H), 3.13 (dd , J=12.8, 6.0Hz, 2H). 13 C NMR(100MHz, DMSO-d 6 )δ196.43, 158.17(d, J=252Hz), 149.02, 148.40, 135.47, 135.24(d, J=8.0Hz), 132.82 , 129.67, 128.33 (d, J=14.0Hz), 124.86, 123.49, 117.23 (d, J=21.0Hz), 47.17, 41.88, 33.76.
实施例10Example 10
制备2-((4-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((4-methoxyphenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000014
Figure PCTCN2022079468-appb-000014
参照实施例1的方法制备2-((4-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(4-甲氧基苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝5：1；目标产物总收率为45％；核磁数据具体如下：2-((4-methoxyphenyl)sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that ( 4-Methoxyphenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume ratio, ethyl acetate: petroleum ether= 5:1; the total yield of the target product is 45%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(t,J＝5.4Hz,1H),8.51–8.47(m,2H),7.76–7.72(m,3H),7.68–7.66(m,1H),7.36(dd,J＝7.6,4.8Hz,1H),7.13–7.09(m,2H),4.82(d,J＝5.6Hz,2H),3.83(s,3H),3.25(t,J＝6.8Hz,2H),2.97(dd,J＝13.0,6.6Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.54,162.14,149.05,148.43,135.46,132.82,132.01,128.65,123.49,114.34,55.62,47.19,42.03,33.83。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (t, J=5.4 Hz, 1H), 8.51-8.47 (m, 2H), 7.76-7.72 (m, 3H), 7.68-7.66 (m, 1H) ), 7.36(dd, J=7.6, 4.8Hz, 1H), 7.13–7.09(m, 2H), 4.82(d, J=5.6Hz, 2H), 3.83(s, 3H), 3.25(t, J= 6.8Hz, 2H), 2.97 (dd, J=13.0, 6.6Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.54, 162.14, 149.05, 148.43, 135.46, 132.82, 132.01, 128.65, 123.49, 114.34 , 55.62, 47.19, 42.03, 33.83.
实施例11Example 11
制备2-((4-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((4-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000015
Figure PCTCN2022079468-appb-000015
参照实施例1的方法制备2-((4-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(4-氟苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝4：1；目标产物总收率为41％。2-((4-Fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that (4- Fluorophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum ether=4:1; The total yield of the target product was 41%.
1H NMR(400MHz,DMSO-d 6)δ10.54(t,J＝5.4Hz,1H),8.52–8.48(m,2H),8.00(t,J＝5.6Hz,1H),7.88(dd,J＝8.8,5.2Hz,2H),7.68(d,J＝7.8Hz,1H),7.44(t,J＝8.8Hz,2H),7.37(dd,J＝8.0,4.8Hz,1H),4.84(d,J＝5.2Hz,2H),3.27(t,J＝7.0Hz,2H),3.04(dd,J＝13.0,6.6Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.50,164.13(d,J＝249Hz),149.08,148.44,136.81,135.49,132.83,129.53(d,J＝9.0Hz),123.50,116.36(d,J＝22.0Hz),47.22,42.01,33.83。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.54 (t, J=5.4Hz, 1H), 8.52-8.48 (m, 2H), 8.00 (t, J=5.6Hz, 1H), 7.88 (dd, J=8.8, 5.2Hz, 2H), 7.68(d, J=7.8Hz, 1H), 7.44(t, J=8.8Hz, 2H), 7.37(dd, J=8.0, 4.8Hz, 1H), 4.84( d, J=5.2Hz, 2H), 3.27 (t, J=7.0Hz, 2H), 3.04 (dd, J=13.0, 6.6Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.50, 164.13 (d, J=249Hz), 149.08, 148.44, 136.81, 135.49, 132.83, 129.53 (d, J=9.0Hz), 123.50, 116.36 (d, J=22.0Hz), 47.22, 42.01, 33.83.
实施例12Example 12
制备2-((3-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((3-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000016
Figure PCTCN2022079468-appb-000016
参照实施例1的方法制备2-((3-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(3-氟苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝4：1；目标产物总收率为44％；核磁数据具体如下：2-((3-Fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that (3- Fluorophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum ether=4:1; The total yield of the target product is 44%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.55(t,J＝5.4Hz,1H),8.51–8.48(m,2H),8.09(t,J＝5.6Hz,1H),7.68–7.65(m,3H),7.60(d,J＝7.6Hz,1H),7.55–7.51(m,1H),7.37(dd,J＝7.6,4.8Hz,1H),4.82(d,J＝5.6Hz,2H),3.26(t,J＝7.0Hz,2H),3.06(dd,J＝13.2,6.4Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.47,161.76(d,J＝246Hz), 149.07,148.44,142.62,135.48,132.81,131.65(d,J＝8.0Hz),123.50,122.75,119.63(d,J＝21.0Hz),113.54(d,J＝24.0Hz),47.21,42.00,33.81。 1 H NMR (400MHz, DMSO-d 6 )δ10.55(t,J=5.4Hz,1H),8.51-8.48(m,2H),8.09(t,J=5.6Hz,1H),7.68-7.65( m, 3H), 7.60 (d, J=7.6Hz, 1H), 7.55–7.51 (m, 1H), 7.37 (dd, J=7.6, 4.8Hz, 1H), 4.82 (d, J=5.6Hz, 2H) ), 3.26(t, J=7.0Hz, 2H), 3.06(dd, J=13.2, 6.4Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.47, 161.76(d, J=246Hz), 149.07, 148.44, 142.62, 135.48, 132.81, 131.65 (d, J=8.0Hz), 123.50, 122.75, 119.63 (d, J=21.0Hz), 113.54 (d, J=24.0Hz), 47.21, 42.00, 33.81.
实施例13Example 13
制备2-((4-氰基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((4-cyanophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000017
Figure PCTCN2022079468-appb-000017
参照实施例1的方法制备2-((4-氰基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(4-氰基苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝3：1；目标产物总收率为38％；核磁数据具体如下：2-((4-cyanophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that (4 -Cyanophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume ratio, ethyl acetate: petroleum ether=3: 1; the total yield of the target product is 38%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.55(t,J＝5.4Hz,1H),8.52–8.48(m,2H),8.27(t,J＝5.2Hz,1H),8.09(d,J＝8.0Hz,2H),7.98(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,1H),7.37(dd,J＝7.6,4.8Hz,1H),4.83(d,J＝5.2Hz,2H),3.26(t,J＝6.8Hz,2H),3.09(dd,J＝12.2,6.2Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.40,149.06,148.44,144.63,135.48,133.43,132.80,127.26,123.50,117.77,114.93,47.23,41.97,33.83。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.55 (t, J=5.4Hz, 1H), 8.52-8.48 (m, 2H), 8.27 (t, J=5.2Hz, 1H), 8.09 (d, J=8.0Hz, 2H), 7.98(d, J=8.0Hz, 2H), 7.68(d, J=8.0Hz, 1H), 7.37(dd, J=7.6, 4.8Hz, 1H), 4.83(d, J=5.2Hz, 2H), 3.26 (t, J=6.8Hz, 2H), 3.09 (dd, J=12.2, 6.2Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.40, 149.06, 148.44 , 144.63, 135.48, 133.43, 132.80, 127.26, 123.50, 117.77, 114.93, 47.23, 41.97, 33.83.
实施例14Example 14
制备2-((3-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((3-methoxyphenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000018
Figure PCTCN2022079468-appb-000018
参照实施例1的方法制备2-((3-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(3-甲氧基苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝2：1；目标产物总收率为43％；核磁数据具体如下：2-((3-methoxyphenyl)sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that ( 3-Methoxyphenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume ratio, ethyl acetate: petroleum ether= 2:1; the total yield of the target product is 43%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.98(t,J＝5.4Hz,1H),8.90(d,J＝7.2Hz,2H),8.52(d,J＝8.0Hz,1H),8.16–8.07(m,2H),7.52(t,J＝8.0Hz,1H),7.42–7.38(m,2H),7.21(dd,J＝8.4,2.0Hz,1H),5.01(d,J＝5.6Hz,2H),3.85(s,3H),3.30(t,J＝6.8Hz,2H),3.04(dd,J＝12.4,6.4Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ197.36,159.44,144.87,141.57,140.83,140.57,137.38,130.39,126.96,118.64,118.42,111.47,55.66,46.24,41.99,33.98。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.98 (t, J=5.4Hz, 1H), 8.90 (d, J=7.2Hz, 2H), 8.52 (d, J=8.0Hz, 1H), 8.16 –8.07(m,2H),7.52(t,J=8.0Hz,1H),7.42–7.38(m,2H),7.21(dd,J=8.4,2.0Hz,1H),5.01(d,J=5.6 Hz, 2H), 3.85(s, 3H), 3.30(t, J=6.8Hz, 2H), 3.04(dd, J=12.4, 6.4Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ197 .36, 159.44, 144.87, 141.57, 140.83, 140.57, 137.38, 130.39, 126.96, 118.64, 118.42, 111.47, 55.66, 46.24, 41.99, 33.98.
实施例15Example 15
制备2-(萘基-1-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：To prepare 2-(naphthyl-1-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000019
Figure PCTCN2022079468-appb-000019
参照实施例1的方法制备2-(萘基-1-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用萘基-1-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝4：1；目标产物总收率为38％；核磁数据具体如下：2-(naphthyl-1-sulfonamido) ethyl (pyridine-3-methylene) amino dithiocarbamate was prepared with reference to the method of Example 1, the difference was only that naphthyl-1- Sulfonyl chloride replaces (3-methylquinoline)-8-sulfonyl chloride, and the eluent is a mixed reagent of ethyl acetate and petroleum ether. By volume, ethyl acetate: petroleum ether=4:1; the total yield of the target product is The rate is 38%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.65(d,J＝8.0Hz,1H),8.50–8.47(m,2H),8.29(s,1H),8.23(d,J＝8.0Hz,1H),8.15(d,J＝7.2Hz,1H),8.10(d,J＝8.0Hz, 1H),7.75–7.62(m,4H),7.35(dd,J＝7.4,5.0Hz,1H),4.80(d,J＝5.2Hz,2H),3.20(t,J＝6.4Hz,2H),3.07(d,J＝6.0Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.43,149.04,148.41,135.44,133.88,133.77,132.81,128.94,128.51,127.84,127.49,126.83,124.68,124.52,123.47,47.17,41.9233.85。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.49(s, 1H), 8.65(d, J=8.0Hz, 1H), 8.50-8.47(m, 2H), 8.29(s, 1H), 8.23( d, J=8.0Hz, 1H), 8.15 (d, J=7.2Hz, 1H), 8.10 (d, J=8.0Hz, 1H), 7.75–7.62 (m, 4H), 7.35 (dd, J=7.4 , 5.0Hz, 1H), 4.80(d, J＝5.2Hz, 2H), 3.20(t, J＝6.4Hz, 2H), 3.07(d, J＝6.0Hz, 2H). 13 C NMR(100MHz, DMSO -d 6 )δ196.43,149.04,148.41,135.44,133.88,133.77,132.81,128.94,128.51,127.84,127.49,126.83,124.68,124.52,123.47,47.17,41.9233.85.
实施例16Example 16
制备2-(萘基-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(naphthyl-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000020
Figure PCTCN2022079468-appb-000020
参照实施例1的方法制备2-(萘基-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用萘基-2-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝3：1；目标产物总收率为43％；核磁数据具体如下：2-(naphthyl-2-sulfonamido) ethyl (pyridine-3-methylene) amino dithiocarbamate was prepared with reference to the method of Example 1, the difference was only that naphthyl-2- Sulfonyl chloride replaces (3-methylquinoline)-8-sulfonyl chloride, and the eluent is a mixed reagent of ethyl acetate and petroleum ether. By volume, ethyl acetate: petroleum ether=3:1; the total yield of the target product is The rate is 43%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.51–8.47(m,3H),8.18–8.13(m,2H),8.05(d,J＝7.2Hz,2H),7.85(d,J＝8.8Hz,1H),7.73–7.65(m,3H),7.35(dd,J＝7.8,5.0Hz,1H),4.81(d,J＝5.2Hz,2H),3.28(s,2H),3.08(s,2H). 13C NMR(100MHz,DMSO-d 6)δ196.48,149.06,148.42,137.41,135.45,134.15,132.79,131.72,129.40,129.19,128.68,127.81,127.55,127.40,123.47,122.21,47.19,42.08,33.87。 1 H NMR (400MHz, DMSO-d 6 )δ10.53(s, 1H), 8.51-8.47(m, 3H), 8.18-8.13(m, 2H), 8.05(d, J=7.2Hz, 2H), 7.85(d,J=8.8Hz,1H),7.73-7.65(m,3H),7.35(dd,J=7.8,5.0Hz,1H),4.81(d,J=5.2Hz,2H),3.28(s , 2H), 3.08(s, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.48, 149.06, 148.42, 137.41, 135.45, 134.15, 132.79, 131.72, 129.40, 129.19, 128.68, 127.81, 127.45 123.47, 122.21, 47.19, 42.08, 33.87.
实施例17Example 17
制备2-((4-甲基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((4-methylphenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000021
Figure PCTCN2022079468-appb-000021
参照实施例1的方法制备2-((4-甲基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(4-甲基苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯；目标产物总收率为41％；核磁数据具体如下：2-((4-methylphenyl)sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that (4 -methylphenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is ethyl acetate; the total yield of the target product is 41%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.54(s,1H),8.51–8.47(m,2H),7.84(d,J＝4.8Hz,1H),7.71–7.69(m,3H),7.40–7.35(m,3H),4.83(d,J＝5.2Hz,2H),3.26(d,J＝6.0Hz,2H),3.00(d,J＝5.6Hz,2H),2.38(s,3H). 13C NMR(100MHz,DMSO-d 6)δ196.54,149.07,148.44,142.69,137.53,135.48,132.83,129.64,126.53,123.50,47.21,42.06,33.89,20.98。 1 H NMR (400MHz, DMSO-d 6 )δ10.54(s, 1H), 8.51-8.47(m, 2H), 7.84(d, J=4.8Hz, 1H), 7.71-7.69(m, 3H), 7.40–7.35(m, 3H), 4.83(d, J=5.2Hz, 2H), 3.26(d, J=6.0Hz, 2H), 3.00(d, J=5.6Hz, 2H), 2.38(s, 3H ). 13 C NMR (100MHz, DMSO-d 6 ) δ 196.54, 149.07, 148.44, 142.69, 137.53, 135.48, 132.83, 129.64, 126.53, 123.50, 47.21, 42.06, 33.89, 20.98.
实施例18Example 18
制备2-(苯磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(benzenesulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000022
Figure PCTCN2022079468-appb-000022
参照实施例1的方法制备2-(苯磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用苯磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝40：1；目标产物总收率为54％；核磁数据具体如下：2-(benzenesulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that benzenesulfonyl chloride was used instead of (3-methyl) quinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum ether=40:1; the total yield of the target product is 54%; specific NMR data as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(t,J＝5.2Hz,1H),8.51–8.47(m,2H),7.93(t,J＝5.2Hz,1H),7.81(d,J＝8.0Hz,2H),7.68–7.57(m,4H),7.36(dd,J＝7.6,4.8Hz,1H),4.82(d,J＝5.6Hz,2H),3.25(t,J＝6.8Hz,2H),3.01(dd,J＝12.6,6.2Hz,2H). 13C  NMR(100MHz,DMSO-d 6)δ196.50,149.07,148.44,140.39,135.47,132.82,132.45,129.23,126.45,123.49,47.20,42.03,33.85。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (t, J=5.2 Hz, 1H), 8.51-8.47 (m, 2H), 7.93 (t, J=5.2 Hz, 1H), 7.81 (d, J=8.0Hz, 2H), 7.68–7.57 (m, 4H), 7.36 (dd, J=7.6, 4.8Hz, 1H), 4.82 (d, J=5.6Hz, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.01 (dd, J=12.6, 6.2 Hz, 2H). 13 C NMR (100 MHz, DMSO-d 6 )δ196.50, 149.07, 148.44, 140.39, 135.47, 132.82, 132.45, 129.23, 126.45, 123.49, 47.20, 42.03, 33.85.
实施例19Example 19
制备2-((1,1'-二苯基)-4-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((1,1'-diphenyl)-4-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000023
Figure PCTCN2022079468-appb-000023
参照实施例1的方法制备2-((1,1'-二苯基)-4-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(1,1'-二苯基)-4-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯；目标产物总收率为36％；核磁数据具体如下：2-((1,1'-diphenyl)-4-sulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, the difference was only In this case, (1,1'-diphenyl)-4-sulfonyl chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent was ethyl acetate; the total yield of the target product was 36%; The NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.52(d,J＝4.8Hz,1H),8.51–8.47(m,2H),7.97(t,J＝5.6Hz,1H),7.89(s,4H),7.74(d,J＝8.4Hz,2H),7.67(d,J＝8.0Hz,1H),7.52(t,J＝7.6Hz,2H),7.44(t,J＝7.2Hz,1H),7.35(dd,J＝8.0,4.8Hz,1H),4.82(d,J＝5.2Hz,2H),3.30(t,J＝6.8Hz,2H),3.07(dd,J＝13.0,6.6Hz,2H). 13C NMR(1000MHz,DMSO-d 6)δ196.51,149.05,148.42,143.93,139.15,138.53,135.44,132.80,129.10,128.46,127.41,127.16,127.06,123.46,47.20,42.07,33.91。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (d, J=4.8 Hz, 1H), 8.51-8.47 (m, 2H), 7.97 (t, J=5.6 Hz, 1H), 7.89 (s, 4H), 7.74(d, J＝8.4Hz, 2H), 7.67(d, J＝8.0Hz, 1H), 7.52(t, J＝7.6Hz, 2H), 7.44(t, J＝7.2Hz, 1H) ,7.35(dd,J＝8.0,4.8Hz,1H),4.82(d,J＝5.2Hz,2H),3.30(t,J＝6.8Hz,2H),3.07(dd,J＝13.0,6.6Hz, 2H). 13 C NMR (1000MHz, DMSO-d 6 ) δ 196.51, 149.05, 148.42, 143.93, 139.15, 138.53, 135.44, 132.80, 129.10, 128.46, 127.41, 127.16, 127.06, 123.46, 47.2
实施例20Example 20
2-((2,5-二氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：2-((2,5-Dichlorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000024
Figure PCTCN2022079468-appb-000024
参照实施例1的方法制备2-((2,5-二氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(2,5-二氯苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝2：1；目标产物总收率为41％；核磁数据具体如下：2-((2,5-dichlorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that the (2,5-dichlorophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum Ether=2:1; the total yield of the target product is 41%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(d,J＝5.2Hz,1H),8.52–8.49(m,2H),8.41(s,1H),7.96(s,1H),7.75–7.68(m,3H),7.39–7.36(m,1H),4.83(d,J＝5.2Hz,2H),3.25(d,J＝6.0Hz,2H),3.19(d,J＝5.6Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.39,149.08,148.43,139.47,135.51,133.71,133.51,132.83,132.16,129.96,129.54,123.50,47.23,41.92,33.60。 1 H NMR (400MHz, DMSO-d 6 )δ10.53(d, J=5.2Hz, 1H), 8.52-8.49(m, 2H), 8.41(s, 1H), 7.96(s, 1H), 7.75- 7.68 (m, 3H), 7.39–7.36 (m, 1H), 4.83 (d, J=5.2Hz, 2H), 3.25 (d, J=6.0Hz, 2H), 3.19 (d, J=5.6Hz, 2H) ). 13 C NMR (100MHz, DMSO-d 6 ) δ 196.39, 149.08, 148.43, 139.47, 135.51, 133.71, 133.51, 132.83, 132.16, 129.96, 129.54, 123.50, 47.23, 41.92, 33.60.
实施例21Example 21
制备2-((3-氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((3-chlorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000025
Figure PCTCN2022079468-appb-000025
参照实施例1的方法制备2-((3-氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(3-氯苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝10：1；目标产物总收率为37％；核磁数据具体如下：2-((3-chlorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that (3- Chlorophenyl)sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum ether=10:1; The total yield of the target product is 37%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),8.52–8.47(m,2H),8.10(d,J＝6.0Hz,1H),7.83–7.61(m,5H),7.38–7.35(m,1H),4.83(d,J＝2.0Hz,2H),3.28–3.23(m,2H),3.07–3.04(m,2H). 13C NMR(100MHz,DMSO-d 6)δ196.46,149.08,148.43,142.38,135.48,133.91,132.81,132.41,131.25,126.17,125.19,123.47,47.24,42.02,33.82。 1 H NMR (400MHz, DMSO-d 6 )δ10.55(s, 1H), 8.52-8.47(m, 2H), 8.10(d, J=6.0Hz, 1H), 7.83-7.61(m, 5H), 7.38–7.35 (m, 1H), 4.83 (d, J=2.0Hz, 2H), 3.28–3.23 (m, 2H), 3.07–3.04 (m, 2H). 13 C NMR (100MHz, DMSO-d 6 ) δ196.46, 149.08, 148.43, 142.38, 135.48, 133.91, 132.81, 132.41, 131.25, 126.17, 125.19, 123.47, 47.24, 42.02, 33.82.
实施例22Example 22
制备2-(乙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(ethylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000026
Figure PCTCN2022079468-appb-000026
参照实施例1的方法制备2-(乙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用乙基磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝10：1；目标产物总收率为46％，核磁数据具体如下：2-(Ethylsulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that ethylsulfonyl chloride was used instead of (3- Methylquinoline)-8-sulfonyl chloride, the eluent is a mixed reagent of ethyl acetate and petroleum ether, by volume, ethyl acetate: petroleum ether=10:1; the total yield of the target product is 46%, NMR The data is as follows:
1H NMR(400MHz,DMSO-d 6)δ10.57(t,J＝5.4Hz,1H),8.52–8.47(m,2H),7.70–7.68(m,1H),7.38–7.30(m,2H),4.85(d,J＝5.6Hz,2H),3.32(t,J＝6.8Hz,2H),3.18–3.17(m,2H),3.02(q,J＝7.4Hz,2H),1.18(t,J＝7.4Hz,3H). 13C NMR(100MHz,DMSO-d 6)δ196.69,149.07,148.44,135.49,132.85,123.51,47.21,45.56,34.34,8.10。 1 H NMR (400MHz, DMSO-d 6 )δ10.57(t, J=5.4Hz, 1H), 8.52-8.47(m, 2H), 7.70-7.68(m, 1H), 7.38-7.30(m, 2H) ), 4.85(d, J＝5.6Hz, 2H), 3.32(t, J＝6.8Hz, 2H), 3.18–3.17(m, 2H), 3.02(q, J＝7.4Hz, 2H), 1.18(t , J=7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 196.69, 149.07, 148.44, 135.49, 132.85, 123.51, 47.21, 45.56, 34.34, 8.10.
实施例23Example 23
制备2-(环丙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(cyclopropylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000027
Figure PCTCN2022079468-appb-000027
参照实施例1的方法制备2-(环丙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用环丙基磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯；目标产物总收率为39％；核磁数据具体如下：2-(Cyclopropylsulfonylamino)ethyl(pyridine-3-methylene)amino dithiocarbamate was prepared with reference to the method of Example 1, except that cyclopropylsulfonyl chloride was used instead of ( 3-methylquinoline)-8-sulfonyl chloride, the eluent is ethyl acetate; the total yield of the target product is 39%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.56(t,J＝5.4Hz,1H),8.52–8.48(m,2H),7.69(d,J＝8.0Hz,1H),7.39–7.33(m,2H),4.85(d,J＝5.6Hz,2H),3.35(t,J＝6.8Hz,2H),3.24(dd,J＝13.0,6.2Hz,2H),2.61–2.54(m,2H),0.94–0.90(m,4H). 13C NMR(100MHz,DMSO-d 6)δ196.71,149.08,148.44,135.50,132.86,123.51,47.21,41.98,34.34,29.46,4.76。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.56 (t, J=5.4Hz, 1H), 8.52-8.48 (m, 2H), 7.69 (d, J=8.0Hz, 1H), 7.39-7.33 ( m, 2H), 4.85 (d, J=5.6Hz, 2H), 3.35 (t, J=6.8Hz, 2H), 3.24 (dd, J=13.0, 6.2Hz, 2H), 2.61–2.54 (m, 2H) ), 0.94–0.90 (m, 4H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 196.71, 149.08, 148.44, 135.50, 132.86, 123.51, 47.21, 41.98, 34.34, 29.46, 4.76.
实施例24Example 24
制备2-(1H-吡咯[2,3-b]吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(1H-pyrrole[2,3-b]pyridine-3-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is shown below:
Figure PCTCN2022079468-appb-000028
Figure PCTCN2022079468-appb-000028
参照实施例1的方法制备2-(1H-吡咯[2,3-b]吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用1H-吡咯[2,3-b]吡啶-3-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和甲醇混合试剂，按体积比计，乙酸乙酯：甲醇＝30：1；目标产物总收率为41％；核磁数据具体如下：2-(1H-pyrrole[2,3-b]pyridine-3-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, with the exception of The only thing is that 1H-pyrrole[2,3-b]pyridine-3-sulfonyl chloride is used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent is a mixed reagent of ethyl acetate and methanol, according to the volume ratio In total, ethyl acetate: methanol = 30: 1; the total yield of the target product is 41%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ12.56(s,1H),10.48(s,1H),8.47(d,J＝9.2Hz,2H),8.37(d,J＝3.6Hz,1H),8.20(d,J＝7.6Hz,1H),8.05(s,1H),7.73(s,1H),7.65(d,J ＝7.6Hz,1H),7.37–7.34(m,1H),7.26(dd,J＝7.6,4.8Hz,1H),4.80(d,J＝5.2Hz,2H),3.22(t,J＝6.6Hz,2H),2.99(dd,J＝12.6,6.2Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.62,149.06,148.42,148.11,144.43,135.46,132.85,130.50,127.85,123.51,117.35,115.68,112.84,47.19,41.94,33.83。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.56(s, 1H), 10.48(s, 1H), 8.47(d, J=9.2Hz, 2H), 8.37(d, J=3.6Hz, 1H) ,8.20(d,J＝7.6Hz,1H),8.05(s,1H),7.73(s,1H),7.65(d,J＝7.6Hz,1H),7.37–7.34(m,1H),7.26( dd,J＝7.6,4.8Hz,1H),4.80(d,J＝5.2Hz,2H),3.22(t,J＝6.6Hz,2H),2.99(dd,J＝12.6,6.2Hz,2H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 196.62, 149.06, 148.42, 148.11, 144.43, 135.46, 132.85, 130.50, 127.85, 123.51, 117.35, 115.68, 112.84, 47.19, 41.94, 33.33.
实施例25Example 25
制备2-((3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)ethyl(pyridine-3-methylene)amino Dithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000029
Figure PCTCN2022079468-appb-000029
参照实施例1的方法制备2-((3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和甲醇混合试剂，按体积比计，乙酸乙酯：甲醇＝50：1；目标产物总收率为36％；核磁数据具体如下：2-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)ethyl(pyridine-3 -methylene)aminodithiocarbamate, except that 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonic acid was used Acid chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent was a mixed reagent of ethyl acetate and methanol. By volume ratio, ethyl acetate:methanol=50:1; the total yield of the target product was 36 %; NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),10.54(t,J＝5.2Hz,1H),8.52–8.48(m,2H),7.88(t,J＝5.8Hz,1H),7.69(d,J＝8.0Hz,1H),7.38–7.36(m,3H),7.12(d,J＝8.8Hz,1H),4.84(d,J＝5.6Hz,2H),4.70(s,2H),3.28(t,J＝6.8Hz,2H),3.02(dd,J＝12.8,6.4Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.56,164.32,149.09,148.46,146.21,135.53,133.98,132.86,127.55,123.53,121.92,116.61,114.25,66.72,47.25,42.10,33.87。 1 H NMR (400MHz, DMSO-d 6 )δ10.98(s,1H),10.54(t,J=5.2Hz,1H),8.52-8.48(m,2H),7.88(t,J=5.8Hz, 1H), 7.69(d, J＝8.0Hz, 1H), 7.38–7.36(m, 3H), 7.12(d, J＝8.8Hz, 1H), 4.84(d, J＝5.6Hz, 2H), 4.70( s, 2H), 3.28 (t, J=6.8Hz, 2H), 3.02 (dd, J=12.8, 6.4Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.56, 164.32, 149.09, 148.46, 146.21, 135.53, 133.98, 132.86, 127.55, 123.53, 121.92, 116.61, 114.25, 66.72, 47.25, 42.10, 33.87.
实施例26Example 26
制备2-((2-氧代-1,2,3,4-四氢喹啉)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((2-oxo-1,2,3,4-tetrahydroquinoline)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate, structural formula As follows:
Figure PCTCN2022079468-appb-000030
Figure PCTCN2022079468-appb-000030
参照实施例1的方法制备2-((2-氧代-1,2,3,4-四氢喹啉)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(2-氧代-1,2,3,4-四氢喹啉)-6-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和甲醇混合试剂，按体积比计，乙酸乙酯：甲醇＝30：1；目标产物总收率为43％；核磁数据具体如下：Prepare 2-((2-oxo-1,2,3,4-tetrahydroquinoline)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodisulfide with reference to the method of Example 1 Formate, except that (2-oxo-1,2,3,4-tetrahydroquinoline)-6-sulfonyl chloride is used instead of (3-methylquinoline)-8-sulfonyl chloride , the eluent is a mixed reagent of ethyl acetate and methanol, by volume ratio, ethyl acetate: methanol = 30: 1; the total yield of the target product is 43%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.55–10.45(m,2H),8.51–8.47(m,2H),7.75–7.67(m,2H),7.61–7.57(m,2H),7.36(dd,J＝7.6,4.8Hz,1H),6.98(d,J＝8.0Hz,1H),4.82(d,J＝5.2Hz,2H),3.25(t,J＝6.8Hz,2H),3.01–2.94(m,4H),2.51(d,J＝7.4Hz,2H). 13C NMR(100MHz,DMSO-d 6)δ196.57,170.34,149.04,148.42,141.91,135.48,133.17,132.83,126.30,126.13,124.13,123.50,115.03,47.19,42.04,33.86,29.86,24.51。 1 H NMR (400MHz, DMSO-d 6 )δ10.55-10.45(m,2H),8.51-8.47(m,2H),7.75-7.67(m,2H),7.61-7.57(m,2H),7.36 (dd,J＝7.6,4.8Hz,1H),6.98(d,J＝8.0Hz,1H),4.82(d,J＝5.2Hz,2H),3.25(t,J＝6.8Hz,2H),3.01 -2.94(m, 4H), 2.51(d, J=7.4Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 ) δ 196.57, 170.34, 149.04, 148.42, 141.91, 135.48, 133.17, 132.83, 126.30, 126.13 , 124.13, 123.50, 115.03, 47.19, 42.04, 33.86, 29.86, 24.51.
实施例27Example 27
制备2-(N-甲基喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-(N-methylquinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000031
Figure PCTCN2022079468-appb-000031
参照实施例1的方法制备2-(N-甲基喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二 硫代甲酸酯，不同之处仅在于，采用2-溴-N-甲基乙胺氢溴酸盐代替2-溴乙胺氢溴酸盐，采用喹啉-8-磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯；目标产物总收率为48％；核磁数据具体如下：2-(N-methylquinoline-8-sulfonylamino) ethyl (pyridine-3-methylene) amino dithiocarbamate was prepared with reference to the method of Example 1, except that 2 -Bromo-N-methylethylamine hydrobromide instead of 2-bromoethylamine hydrobromide, using quinoline-8-sulfonyl chloride instead of (3-methylquinoline)-8-sulfonyl chloride, eluent is ethyl acetate; the total yield of the target product is 48%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.56(t,J＝5.4Hz,1H),9.07(dd,J＝4.4,1.6Hz,1H),8.55–8.53(m,2H),8.49–8.48(m,1H),8.40–8.39(m,1H),8.30(d,J＝8.0Hz,1H),7.76(t,J＝7.8Hz,1H),7.71–7.68(m,2H),7.37(dd,J＝7.6,4.8Hz,1H),4.85(d,J＝5.6Hz,2H),3.60(t,J＝7.2Hz,2H),3.42–3.38(m,2H),2.93(s,3H). 13C NMR(100MHz,DMSO-d 6)δ196.61,151.28,149.03,148.40,143.20,136.86,136.30,135.43,133.90,132.83,132.72,128.68,125.72,123.47,122.42,49.56,47.20,35.18,32.54。 1 H NMR (400MHz, DMSO-d 6 ) δ 10.56 (t, J=5.4Hz, 1H), 9.07 (dd, J=4.4, 1.6Hz, 1H), 8.55-8.53 (m, 2H), 8.49- 8.48 (m, 1H), 8.40–8.39 (m, 1H), 8.30 (d, J=8.0Hz, 1H), 7.76 (t, J=7.8Hz, 1H), 7.71–7.68 (m, 2H), 7.37 (dd, J=7.6, 4.8Hz, 1H), 4.85 (d, J=5.6Hz, 2H), 3.60 (t, J=7.2Hz, 2H), 3.42–3.38 (m, 2H), 2.93 (s, 3H). 13 C NMR (100MHz, DMSO-d 6 )δ196.61,151.28,149.03,148.40,143.20,136.86,136.30,135.43,133.90,132.83,132.72,128.68,125.72,123.4,136.86,136.30,135.43,133.90,132.83,132.72,128.68,125.72,123.4,6.4,122 32.54.
实施例28Example 28
制备2-((5-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((5-chloro-2-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000032
Figure PCTCN2022079468-appb-000032
参照实施例1的方法制备2-((5-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(5-氯-2-氟苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝4：1；目标产物总收率为48％；核磁数据具体如下：2-((5-Chloro-2-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that, (5-chloro-2-fluorophenyl)sulfonyl chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent was a mixed reagent of ethyl acetate and petroleum ether. By volume, ethyl acetate : petroleum ether=4:1; the total yield of the target product is 48%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.97(s,1H),8.87(s,2H),8.54(s,1H),8.46(s,1H),8.05(s,1H),7.79(s,2H),7.55(s,1H),4.99(s,2H),3.29(s,2H),3.21(s,2H). 13C NMR(100MHz,DMSO)δ197.07,156.83(d,J＝252.0Hz),144.21,141.20,140.94,136.99,134.80(d,J＝8.0Hz),129.88(d,J＝16.0Hz),128.84,128.48(d,J＝3.0Hz),126.70,119.43(d,J＝23.0Hz),46.23,41.69,33.73。 1 H NMR (400MHz, DMSO-d 6 )δ10.97(s,1H), 8.87(s,2H), 8.54(s,1H), 8.46(s,1H), 8.05(s,1H), 7.79( s, 2H), 7.55(s, 1H), 4.99(s, 2H), 3.29(s, 2H), 3.21(s, 2H). 13 C NMR(100MHz, DMSO) δ197.07, 156.83(d, J=252.0 Hz), 144.21, 141.20, 140.94, 136.99, 134.80(d, J＝8.0Hz), 129.88(d, J＝16.0Hz), 128.84, 128.48(d, J＝3.0Hz), 126.70, 119.43(d, J = 23.0Hz), 46.23, 41.69, 33.73.
实施例29Example 29
制备2-((3-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，结构式如下所示：Preparation of 2-((3-chloro-2-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate, the structural formula is as follows:
Figure PCTCN2022079468-appb-000033
Figure PCTCN2022079468-appb-000033
参照实施例1的方法制备2-((3-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯，不同之处仅在于，采用(3-氯-2-氟苯基)磺酰氯代替(3-甲基喹啉)-8-磺酰氯，洗脱剂为乙酸乙酯和石油醚混合试剂，按体积比计，乙酸乙酯：石油醚＝3：1；目标产物总收率为40％；核磁数据具体如下：2-((3-Chloro-2-fluorophenyl)sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate was prepared with reference to the method of Example 1, except that, (3-chloro-2-fluorophenyl)sulfonyl chloride was used instead of (3-methylquinoline)-8-sulfonyl chloride, and the eluent was a mixed reagent of ethyl acetate and petroleum ether. By volume, ethyl acetate : petroleum ether=3:1; the total yield of the target product is 40%; the NMR data are as follows:
1H NMR(400MHz,DMSO-d 6)δ10.53(s,1H),8.50–8.43(m,3H),7.89–7.66(m,3H),7.39(d,J＝6.8Hz,2H),4.81(s,2H),3.26(s,2H),3.18(s,2H). 13C NMR(100MHz,DMSO-d 6)δ196.38,153.55(d,J＝253.0Hz),149.02,148.39,135.46,135.15,132.81,130.07(d,J＝13.0Hz),128.50,125.68(d,J＝4.0Hz),123.49,121.42(d,J＝18.0Hz),47.18,41.87,33.73。 1 H NMR (400MHz, DMSO-d 6 )δ10.53(s, 1H), 8.50-8.43(m, 3H), 7.89-7.66(m, 3H), 7.39(d, J=6.8Hz, 2H), 4.81(s, 2H), 3.26(s, 2H), 3.18(s, 2H). 13 C NMR (100MHz, DMSO-d 6 )δ196.38, 153.55(d, J=253.0Hz), 149.02, 148.39, 135.46, 135.15, 132.81, 130.07 (d, J=13.0Hz), 128.50, 125.68 (d, J=4.0Hz), 123.49, 121.42 (d, J=18.0Hz), 47.18, 41.87, 33.73.
应用例Application example
将实施例1～29制备的化合物进行主蛋白酶(Mpro)抑制活性测试，包括以下步骤：The main protease (Mpro) inhibitory activity test was performed on the compounds prepared in Examples 1-29, including the following steps:
将0.2μM Mpro和不同浓度化合物加入至缓冲溶液(50mM TrisHCl，pH＝7.5，1mM EDTA，0.001％Triton-100)中，室温同条件下孵育10min，加入20μM的底物 (GL Biochem)，通过酶标仪在激发光320nm和发射光405nm条件下记录荧光变化速率，根据荧光变化速率计算化合物的Mpro抑制率。其中，1μM浓度化合物测试结果如表1所示，10μM浓度化合物测试结果如表2所示所示。由表1和表2可知，本发明提供的氨基二硫代甲酸酯类化合物均对Mpro具有抑制作用，且对Mpro具有抑制作用呈剂量依赖性。0.2 μM Mpro and compounds of different concentrations were added to buffer solution (50 mM TrisHCl, pH=7.5, 1 mM EDTA, 0.001% Triton-100), incubated at room temperature for 10 min under the same conditions, and 20 μM of substrate (GL Biochem) was added, and the enzyme The fluorescence change rate was recorded under the condition of excitation light of 320nm and emission light of 405nm by the standard instrument, and the Mpro inhibition rate of the compound was calculated according to the fluorescence change rate. Among them, the test results of compounds with a concentration of 1 μM are shown in Table 1, and the test results of compounds with a concentration of 10 μM are shown in Table 2. It can be seen from Table 1 and Table 2 that the aminodithiocarbamate compounds provided by the present invention all have inhibitory effect on Mpro, and the inhibitory effect on Mpro is dose-dependent.
表1 1μM浓度化合物测试结果Table 1 1μM concentration compound test results
实施例Example 抑制率％Inhibition rate% 实施例Example 抑制率％Inhibition rate% 实施例Example 抑制率％Inhibition rate%
11 16.016.0 1111 62.762.7 21twenty one 12.012.0
22 32.632.6 1212 41.341.3 22twenty two 16.816.8
33 2.72.7 1313 41.641.6 23twenty three 11.111.1
44 23.323.3 1414 1.41.4 24twenty four 2.12.1
55 46.046.0 1515 11.811.8 2525 17.617.6
66 52.552.5 1616 7.57.5 2626 8.28.2
77 31.031.0 1717 8.98.9 2727 1.51.5
88 19.419.4 1818 13.413.4 2828 87.387.3
99 30.630.6 1919 16.716.7 2929 77.377.3
1010 13.513.5 2020 93.893.8 // //
表2 10μM浓度化合物测试结果Table 2 10μM concentration compound test results
实施例Example 抑制率％Inhibition rate% 实施例Example 抑制率％Inhibition rate% 实施例Example 抑制率％Inhibition rate%
11 55.055.0 1111 82.782.7 21twenty one 51.051.0
22 63.663.6 1212 74.374.3 22twenty two 66.866.8
33 43.743.7 1313 81.681.6 23twenty three 61.161.1
44 53.353.3 1414 41.441.4 24twenty four 42.142.1
55 66.066.0 1515 51.851.8 2525 68.668.6
66 72.572.5 1616 47.547.5 2626 48.248.2
77 74.074.0 1717 48.948.9 2727 35.535.5
88 53.453.4 1818 63.463.4 2828 95.395.3
99 61.661.6 1919 76.776.7 2929 93.693.6
1010 53.553.5 2020 97.597.5 // //
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.

Claims (32)

  1. 氨基二硫代甲酸酯类化合物，具有式I所示结构：Amino dithiocarbamate compounds have the structure shown in formula I:
    Figure PCTCN2022079468-appb-100001
    Figure PCTCN2022079468-appb-100001
    式I中，R 1选自取代或未取代的苯基、取代或未取代的杂芳基、噻吩基、吡啶基、萘基或烷基；所述杂芳基选自喹啉基、香豆素基、氮杂吲哚基、2H-1,4-苯并噁嗪-3(4H)-酮基或3,4-二氢喹啉酮基；所述取代的苯基和取代的杂芳基中一个或多个取代基独立地选自卤素、甲基、甲氧基、氰基、硝基、亚乙二氧基或苯基； In formula I, R 1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, thienyl, pyridyl, naphthyl or alkyl; the heteroaryl is selected from quinolinyl, coumarin Sulphuryl, azaindolyl, 2H-1,4-benzoxazine-3(4H)-one or 3,4-dihydroquinolinone; the substituted phenyl and substituted heteroaryl One or more substituents in the group are independently selected from halogen, methyl, methoxy, cyano, nitro, ethylenedioxy or phenyl;
    R 2选自氢或甲基。 R 2 is selected from hydrogen or methyl.
  2. 根据权利要求1所述的氨基二硫代甲酸酯类化合物，其特征在于，所述烷基为C1～C4直链烷基或C3～C6环烷基。The aminodithiocarbamate compound according to claim 1, wherein the alkyl group is a C1-C4 linear alkyl group or a C3-C6 cycloalkyl group.
  3. 根据权利要求2所述的氨基二硫代甲酸酯类化合物，其特征在于，所述C1～C4直链烷基为乙基。The aminodithiocarbamate compound according to claim 2, wherein the C1-C4 straight-chain alkyl group is an ethyl group.
  4. 根据权利要求2所述的氨基二硫代甲酸酯类化合物，其特征在于，所述C3～C6环烷基为环丙基。The aminodithiocarbamate compound according to claim 2, wherein the C3-C6 cycloalkyl group is a cyclopropyl group.
  5. 根据权利要求1所述的氨基二硫代甲酸酯类化合物，其特征在于，所述卤素为氟或氯。The aminodithiocarbamate compound according to claim 1, wherein the halogen is fluorine or chlorine.
  6. 根据权利要求1～5任一项所述的氨基二硫代甲酸酯类化合物，其特征在于，所述氨基二硫代甲酸酯类化合物为以下化合物中的任一种：The aminodithiocarbamate compound according to any one of claims 1 to 5, wherein the aminodithiocarbamate compound is any one of the following compounds:
    2-((3-甲基喹啉)-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Methylquinoline)-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((2-氧代-2H-苯并吡喃)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-oxo-2H-benzopyran)-6-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(quinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((2,3-二氢-1,4-苯并二噁英)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2,3-Dihydro-1,4-benzodioxin)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(pyridine-3-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((3-硝基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-nitrophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(噻吩-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(thiophene-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((2-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((4-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-Methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((4-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((3-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((4-氰基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-cyanophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((3-甲氧基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Methoxyphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(萘基-1-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Naphthyl-1-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(萘基-2-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Naphthyl-2-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((4-甲基苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((4-methylphenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(苯磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Benzenesulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((1,1'-二苯基)-4-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((1,1'-diphenyl)-4-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((2,,5-二氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2,,5-Dichlorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((3-氯苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-Chlorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(乙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Ethylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(环丙基磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(Cyclopropylsulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(1H-吡咯[2,3-b]吡啶-3-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(1H-pyrrole[2,3-b]pyridine-3-sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((3-氧代-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-sulfonamido)ethyl(pyridine-3-methylene)aminodi Thioformate;
    2-((2-氧代-1,2,3,4-四氢喹啉)-6-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((2-oxo-1,2,3,4-tetrahydroquinoline)-6-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-(N-甲基喹啉-8-磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-(N-Methylquinoline-8-sulfonylamino)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((5-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯；2-((5-Chloro-2-fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate;
    2-((3-氯-2-氟苯基)磺酰氨基)乙基(吡啶-3-亚甲基)氨基二硫代甲酸酯。2-((3-Chloro-2-fluorophenyl)sulfonamido)ethyl(pyridine-3-methylene)aminodithiocarbamate.
  7. 权利要求1～6任一项所述氨基二硫代甲酸酯类化合物的制备方法，包括以下步骤：The preparation method of the aminodithioformate compound according to any one of claims 1 to 6, comprising the following steps:
    将具有式II所示结构的化合物与具有式III所示结构的化合物进行磺酰化反应，得到具有式IV所示结构的化合物；The compound having the structure shown in formula II is subjected to sulfonylation reaction with the compound having the structure shown in formula III to obtain the compound having the structure shown in formula IV;
    Figure PCTCN2022079468-appb-100002
    Figure PCTCN2022079468-appb-100002
    将3-氨甲基吡啶和二硫化碳进行加成反应，将所得产物体系与具有IV所示结构的化合物进行亲核取代反应，得到具有式I所示结构的氨基二硫代甲酸酯类化合物；3-aminomethylpyridine and carbon disulfide are carried out an addition reaction, and the resulting product system is subjected to a nucleophilic substitution reaction with a compound having a structure shown in IV to obtain an aminodithiocarbamate compound having a structure shown in formula I;
    所述式II中R 2、式III中R 1以及式IV中R 1和R 2如式I中所定义。 Said R2 in formula II , R1 in formula III, and R1 and R2 in formula IV are as defined in formula I.
  8. 根据权利要求7所述的制备方法，其特征在于，所述具有式II所示结构的化合物与具有式III所示结构的化合物的摩尔比为1：1。The preparation method according to claim 7, wherein the molar ratio of the compound having the structure represented by formula II to the compound having the structure represented by formula III is 1:1.
  9. 根据权利要求7所述的制备方法，其特征在于，所述磺酰化反应在第一碱性催化剂和第一有机溶剂存在条件下进行。The preparation method according to claim 7, wherein the sulfonylation reaction is carried out in the presence of a first basic catalyst and a first organic solvent.
  10. 根据权利要求9所述的制备方法，其特征在于，所述第一碱性催化剂包括三乙胺、N,N-二异丙基乙胺、吡啶和碳酸钾中的至少一种，所述第一碱性催化剂与具有式II所示结构的化合物的摩尔比为(2.8～3.2)：1。The preparation method according to claim 9, wherein the first basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine and potassium carbonate, and the first basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine and potassium carbonate. The molar ratio of a basic catalyst to the compound having the structure represented by formula II is (2.8-3.2):1.
  11. 根据权利要求9所述的制备方法，其特征在于，所述第一有机溶剂包括二氯甲烷、四氢呋喃和N,N-二甲基甲酰胺中的至少一种，所述第一有机溶剂与具有式II所示结构的化合物的用量比为(6～10)mL：1mmol。The preparation method according to claim 9, wherein the first organic solvent comprises at least one of dichloromethane, tetrahydrofuran and N,N-dimethylformamide, and the first organic solvent is The dosage ratio of the compound represented by the formula II is (6-10) mL:1 mmol.
  12. 根据权利要求7～11任一项所述的制备方法，其特征在于，所述磺酰化反应的温度为15～35℃，时间为10～15h。The preparation method according to any one of claims 7-11, wherein the temperature of the sulfonylation reaction is 15-35°C, and the time is 10-15h.
  13. 根据权利要求7所述的制备方法，其特征在于，所述3-氨甲基吡啶和二硫化碳的摩尔比为1：1.5。The preparation method according to claim 7, wherein the molar ratio of the 3-aminomethylpyridine and carbon disulfide is 1:1.5.
  14. 根据权利要求7所述的制备方法，其特征在于，所述加成反应在第二碱性催化剂和第二有机溶剂存在条件下进行。The preparation method according to claim 7, wherein the addition reaction is carried out in the presence of a second basic catalyst and a second organic solvent.
  15. 根据权利要求14所述的制备方法，其特征在于，所述第二碱性催化剂包括三乙胺、N,N-二异丙基乙胺、吡啶、碳酸钾、碳酸钠和磷酸钾中的至少一种，第二碱性催化剂与3-氨甲基吡啶的摩尔比为(1.8～2.2)：1。The preparation method according to claim 14, wherein the second basic catalyst comprises at least one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate and potassium phosphate One, the molar ratio of the second basic catalyst to 3-aminomethylpyridine is (1.8-2.2):1.
  16. 根据权利要求14所述的制备方法，其特征在于，所述第二有机溶剂包括丙酮、N,N-二甲基甲酰胺和水中的至少一种，所述第二有机溶剂与3-氨甲基吡啶的用量比为(10～20)mL：1mmol。The preparation method according to claim 14, wherein the second organic solvent comprises at least one of acetone, N,N-dimethylformamide and water, and the second organic solvent and 3-aminomethane The dosage ratio of pyridine is (10-20) mL: 1 mmol.
  17. 根据权利要求7和13～16任一项所述的制备方法，其特征在于，所述加成反应的温度为15～35℃，时间为25～35min。The preparation method according to any one of claims 7 and 13-16, wherein the temperature of the addition reaction is 15-35°C, and the time is 25-35 min.
  18. 根据权利要求7所述的制备方法，其特征在于，所述亲核取代反应的温度为25～80℃，时间为2～10h。The preparation method according to claim 7, wherein the temperature of the nucleophilic substitution reaction is 25-80°C, and the time is 2-10 h.
  19. 根据权利要求7或18所述的制备方法，其特征在于，所述亲核取代反应后还包括：将亲核取代反应后所得产物体系冷至室温，过滤，将所得滤液浓缩，将所得剩余物经柱层析分离，得到具有式I所示结构的氨基二硫代甲酸酯类化合物。The preparation method according to claim 7 or 18, characterized in that, after the nucleophilic substitution reaction, the method further comprises: cooling the product system obtained after the nucleophilic substitution reaction to room temperature, filtering, concentrating the obtained filtrate, and removing the obtained residue After separation by column chromatography, aminodithiocarbamate compounds having the structure shown in formula I are obtained.
  20. 根据权利要求19所述的制备方法，其特征在于，所述柱层析分离采用的洗脱剂为乙酸乙酯和石油醚混合试剂、乙酸乙酯和甲醇混合试剂或乙酸乙酯。The preparation method according to claim 19, wherein the eluent used in the column chromatography separation is a mixed reagent of ethyl acetate and petroleum ether, a mixed reagent of ethyl acetate and methanol, or ethyl acetate.
  21. 根据权利要求20所述的制备方法，其特征在于，所述乙酸乙酯和石油醚混合试剂中乙酸乙酯与石油醚的体积比为(2～40)：1。The preparation method according to claim 20, wherein the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate and petroleum ether mixed reagent is (2-40):1.
  22. 根据权利要求20所述的制备方法，其特征在于，所述乙酸乙酯和甲醇混合试剂中乙酸乙酯与甲醇的体积比为(30～50)：1。The preparation method according to claim 20, wherein the volume ratio of ethyl acetate to methanol in the ethyl acetate and methanol mixed reagent is (30-50):1.
  23. 权利要求1～6任一项所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物。A pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound according to any one of claims 1 to 6.
  24. 根据权利要求23所述的氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物，其特征在于，所述氨基二硫代甲酸酯类化合物的药学上可接受的盐为氨基二硫代甲酸酯类化合物与无机酸或有机酸反应形成的盐，所述无机酸为盐酸、氢溴酸、硫酸、硝酸、胺基磺酸或磷酸，所述有机酸为柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸或羟乙磺酸。The pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound according to claim 23, wherein the pharmaceutically acceptable salt of the aminodithiocarbamate compound It is the salt formed by the reaction of aminodithioformate compound and inorganic acid or organic acid, the inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid or phosphoric acid, and the organic acid is citric acid, Tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, Succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetyl oxybenzoic acid or isethionic acid.
  25. 根据权利要求23所述的氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物，其特征在于，所述氨基二硫代甲酸酯类化合物的溶剂化物为甲醇化物、乙醇化物或乙酸乙酯化物。The pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound according to claim 23, wherein the solvate of the aminodithiocarbamate compound is methanolate, Ethanolate or ethyl acetate.
  26. 一种药物组合物，包括活性成分和药学上可接受的辅料，所述活性成分为权利要求1～6任一项所述氨基二硫代甲酸酯类化合物或权利要求23～25任一项所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物。A pharmaceutical composition, comprising an active ingredient and a pharmaceutically acceptable excipient, the active ingredient is the aminodithiocarbamate compound described in any one of claims 1 to 6 or any one of claims 23 to 25. A pharmaceutically acceptable salt, hydrate or solvate of the aminodithiocarbamate compound.
  27. 根据权利要求26所述的药物组合物，其特征在于，所述活性成分的含量为0.1～99.9wt％。The pharmaceutical composition according to claim 26, wherein the content of the active ingredient is 0.1-99.9 wt%.
  28. 根据权利要求26所述的药物组合物，其特征在于，所述药学上可接受的辅料为水、盐溶液、聚乙二醇、多羟基乙氧基化的蓖麻油、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、碳酸镁、环糊精、直链淀粉、硬脂酸镁、滑石、琼脂、果胶、阿拉伯胶、硬脂酸、纤维素低烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯、二甘油酯、季戊四醇脂肪酸醚、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮中的至少一种。The pharmaceutical composition according to claim 26, wherein the pharmaceutically acceptable adjuvant is water, saline solution, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin , lactose, terra alba, sucrose, magnesium carbonate, cyclodextrin, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, cellulose low alkyl ether, silicic acid, fatty acid, At least one of fatty acid amine, fatty acid monoglyceride, diglyceride, pentaerythritol fatty acid ether, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  29. 根据权利要求26所述的药物组合物，其特征在于，所述药物组合物的制剂为胶囊剂、片剂、气雾剂、溶液剂、悬浮剂、糖衣剂、锭剂、糖浆剂、乳剂、膏剂、注射剂、散剂、颗粒剂、糊剂、缓释剂或泡沫剂。The pharmaceutical composition according to claim 26, wherein the preparation of the pharmaceutical composition is capsule, tablet, aerosol, solution, suspension, sugar coating, lozenge, syrup, emulsion, Ointment, injection, powder, granule, paste, sustained release or foam.
  30. 氨基二硫代甲酸酯类化合物、氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物或药物组合物在制备Mpro抑制剂中的应用；Use of aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of Mpro inhibitors;
    所述氨基二硫代甲酸酯类化合物为权利要求1～6任一项所述氨基二硫代甲酸酯类化合物；The aminodithiocarbamate compound is the aminodithiocarbamate compound described in any one of claims 1 to 6;
    所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物为权利要求23～25任一项所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物；The pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds of any one of claims 23 to 25 Hydrates or solvates;
    所述药物组合物为权利要求27～29任一项所述药物组合物。The pharmaceutical composition is the pharmaceutical composition of any one of claims 27-29.
  31. 氨基二硫代甲酸酯类化合物、氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物或药物组合物在制备预防和/或治疗冠状病毒的药物中的应用；The use of aminodithiocarbamate compounds, pharmaceutically acceptable salts, hydrates, solvates or pharmaceutical compositions of aminodithiocarbamate compounds in the preparation of medicines for preventing and/or treating coronavirus;
    所述氨基二硫代甲酸酯类化合物为权利要求1～6任一项所述氨基二硫代甲酸酯类化合物；The aminodithiocarbamate compound is the aminodithiocarbamate compound described in any one of claims 1 to 6;
    所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物、溶剂化物为权利要求23～25任一项所述氨基二硫代甲酸酯类化合物的药学上可接受的盐、水合物或溶剂化物；The pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds are the pharmaceutically acceptable salts, hydrates and solvates of the aminodithiocarbamate compounds of any one of claims 23 to 25 Hydrates or solvates;
    所述药物组合物为权利要求27～29任一项所述药物组合物。The pharmaceutical composition is the pharmaceutical composition of any one of claims 27-29.
  32. 根据权利要求31所述的应用，其特征在于，所述冠状病毒为新型冠状病毒。The application according to claim 31, wherein the coronavirus is a novel coronavirus.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101899011A (en) * 2009-05-26 2010-12-01 北京大学 Dithiocarbamates compound, preparation method and application thereof
CN102234271A (en) * 2010-04-21 2011-11-09 北京大学 Aryl (alkyl) amino dithio formate compounds, and preparation method and application thereof
CN106146487A (en) * 2015-04-27 2016-11-23 北京大学 Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its production and use
CN106432208A (en) * 2015-08-10 2017-02-22 北京大学 (Aminosulfonyl)ethyl dithiocarbamate compounds, and preparation method and use thereof
CN113024514A (en) * 2021-03-26 2021-06-25 北京大学 Aminodithioformate compound, preparation method thereof, pharmaceutical composition and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101899011A (en) * 2009-05-26 2010-12-01 北京大学 Dithiocarbamates compound, preparation method and application thereof
CN102234271A (en) * 2010-04-21 2011-11-09 北京大学 Aryl (alkyl) amino dithio formate compounds, and preparation method and application thereof
CN106146487A (en) * 2015-04-27 2016-11-23 北京大学 Pyridylmethyl dithiocarbonic acid hetero-aromatic ring alkyl esters compound and its production and use
CN106432208A (en) * 2015-08-10 2017-02-22 北京大学 (Aminosulfonyl)ethyl dithiocarbamate compounds, and preparation method and use thereof
CN113024514A (en) * 2021-03-26 2021-06-25 北京大学 Aminodithioformate compound, preparation method thereof, pharmaceutical composition and application thereof

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