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CN101845052A - Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof - Google Patents

Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof Download PDF

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CN101845052A
CN101845052A CN 201010197730 CN201010197730A CN101845052A CN 101845052 A CN101845052 A CN 101845052A CN 201010197730 CN201010197730 CN 201010197730 CN 201010197730 A CN201010197730 A CN 201010197730A CN 101845052 A CN101845052 A CN 101845052A
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compound
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formula
cancer
pyridine
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CN101845052B (en
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刘登科
刘颖
刘冰妮
刘默
周云松
陈继方
侯佳佳
王平保
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention provides a nitrogen-containing heterocyclic ring thienopyridine ketone derivative with a structure as the first formula and salts thereof, which belong to the technical field of anti-malignant-tumor medicine, wherein R is a nitrogen-containing six-membered heterocyclic ring or a benzene nitrogen-containing six-membered heterocyclic ring. The invention also relates to the preparation method of the compound, and simultaneously discloses a medicine composition using the compound or pharmaceutically acceptable salts thereof as active ingredients, and the application thereof in the aspect that the compound or pharmaceutically acceptable salts as anti-malignant-tumor medicine.

Description

The nitrogenous heterocyclic Thienopyridinone derivatives of one class, Preparation Method And The Use
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have compound of anticarcinogenesis and preparation method thereof.
Background technology
Cancer is one of main killer of human health, and its mortality ratio ranked second the position in China position of ranking forefront in the world.According to World Health Organization statistics, global cancer mortality number in 2007 reaches 7,900,000 (account for all death tolls 13%), and lung cancer, cancer of the stomach, liver cancer, colorectal carcinoma and mammary cancer are the arch-criminals of annual most of cancer mortalities.In recent years, because the cancer risk factors such as abuse of urban air pollution, overweight or obesity, alcohol tobacco are on the rise, cause the sickness rate of cancer to rise year by year.In developing country, along with the reduction of transmissible disease death and child mortality, more people's life-time dilatations, the burden of cancer also increases thereupon.Pharmacological agent is one of main treatment means of cancer, and the searching of cancer therapy drug is the popular domain of scientists study always.At present being used for anticancer medicine clinically has hundreds of, prolong cancer patients's life effectively or improved cancer patients's life quality, but most drug is a cell toxicity medicament, selectivity is not high, when eliminating tumour cell, normal cell also there is major injury, cause the intensive toxic side effects, and have the resistance problem.In addition, existing chemicals is unsatisfactory to the result of treatment of most solid tumors.Therefore, seeking the new type anticancer medicine shoulders heavy responsibilities.
Summary of the invention
One object of the present invention is, discloses nitrogenous heterocyclic Thienopyridinone derivatives of a class and pharmaceutical salts thereof.
Another object of the present invention is that disclosing with nitrogenous heterocyclic Thienopyridinone derivatives of a class and salt thereof is the pharmaceutical composition of main active ingredient.
A further object of the present invention is, discloses the preparation method of nitrogenous heterocyclic Thienopyridinone derivatives of a class and salt thereof.
A further object of the invention is, nitrogenous heterocyclic Thienopyridinone derivatives of one class and pharmaceutical salts thereof are disclosed, as the application of medicine for resisting malignant tumors, particularly in the purposes that is used to prepare aspect treatment lung cancer, mammary cancer, liver cancer, the cancer of the stomach medicine.
The present invention is specifically related to the compound and the salt thereof of general formula I structure:
Figure GDA0000022231920000021
Wherein:
R is (a) nitrogenous hexa-member heterocycle;
(b) the nitrogenous hexa-member heterocycle of benzo.
The nitrogenous hexa-member heterocycle of nitrogenous hexa-member heterocycle of the present invention and benzo is specifically represented pyridine, quinoline etc.
The compound that the present invention relates to formula I structure, wherein part of compounds is:
I-15-(pyridine-2-base-methyl)-5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also;
I-25-(quinoline-2-base-methyl)-5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also.
The compound with formula I structure or its pharmacy acceptable salt among the present invention mean: the salt that The compounds of this invention is become with mineral acid, organic acid.Wherein particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts or the like.
The preparation route of formula I compound:
Figure GDA0000022231920000022
Wherein X is bromine or chlorine.
5,6,7,7a-tetramethylene sulfide also [3,2-c] the nitrogenous hexa-member heterocycle that replaces of pyridine-2 (4H)-ketone and brooethyl or chloromethyl or the nitrogenous hexa-member heterocycle of benzo be in methylene dichloride, trichloromethane, acetonitrile or toluene equal solvent, in the presence of acid binding agents such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide ,-10 ℃～105 ℃ reactions make formula I compound.
Reaction is made various intermediates or products therefrom be dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, dropping inorganic acid or organic acid solution are made pharmacy acceptable salt.
Specifically be that all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, the dripping hydrochloric acid diethyl ether solution is made hydrochloride to pH=2 under ice-water bath; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, and adding and wait a mole taurine, heated and stirred gets its taurate; Or all cpds is dissolved in a kind of among ether, DMF, acetone, methyl alcohol, ethanol, ethyl acetate or the DMSO, drips concentrated sulfuric acid solution down to pH=3, make vitriol in ice-water bath, or the like.
This compounds is effective for the treatment human malignancies.Although compound of the present invention can be without the direct administration of any preparation, described all cpds preferably uses with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (as vein, muscle administration) and oral administration.
The preparation of pharmaceutical compositions method of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in the scope of a broad.Usually, the weight range of active compound is 0.5%～90% (weight) of composition, and another preferred range is 0.5%-70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention all has the obvious suppression effect to tumour in external, body.
External antitumor action
(1) experimental technique:
Adopt classical cytotoxic activity vitro detection method mtt assay, detect the cell proliferation toxicity of invention compound the human tumor cells of vitro culture.
(2) experiment material:
Laboratory sample: nitrogenous heterocyclic Thienopyridinone derivatives is provided by contriver's self-control.Sample is with the DMSO hydrotropy during experiment, and serum-free DMEM substratum is diluted to desired concn, and sample segment solution is suspension.
Main agents: MTT, the packing of Amresco company, lot number: 04M0904; Complete DMEM substratum, Gibco company product, lot number: 1290007; Calf serum, Lanzhou people's marine life, lot number: 20060509; Trypsinase, the packing of Amresco company, lot number: 016B0604; Fluorouracil Injection, 0.25g/10mL (propping up), lot number: 0512022, Tianjin gold credit amino acid company limited.
Laboratory apparatus: Bechtop, Suzhou Decontamination Equipment Plant; CO 2Incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert 200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
Cell strain: lung cancer A-549 cell, liver cancer SMMC-7721 cell, mammary cancer MCF-7 cell, adenocarcinoma of stomach SGC-7901 cell, all available from Shanghai cell research institute of the Chinese Academy of Sciences.
(3) experimental procedure:
Cell cultures: tumor cell inoculation is containing 10% calf serum, in the DMEM nutrient solution of 100IU/mL penicillin G sodium salt and 100ug/mL Vetstrep, places 37 ℃, 100% relative humidity, contains 5%CO 2Incubator in, it is standby after 3 times to go down to posterity.
Mtt assay is measured: the cell in the vegetative period of taking the logarithm, behind 0.25% tryptic digestion (suspension cell need not digest), be suspended in the DMEM nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently, microscopically blood cell counts plate numeration viable cell with the glass dropper.(cell concn is adjusted into 6～10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ L 4Individual/mL), at 37 ℃, 100% relative humidity, contain 5%CO 2, 95% air incubator cultivate 24h after, every hole adds 10 μ L soups (final concentration is made as: 40 μ g/mL, 20 μ g/mL, 10 μ g/mL, 5 μ g/mL and five concentration of 2.5 μ g/mL).In addition, each concentration is established negative control (isoconcentration DMSO) and blank background (not adding cell), and each group is all established 6 multiple holes.Cultured continuously 24h again, every then hole adds the MTT solution 10 μ L of 5mg/mL, and after continuing to cultivate 4h, the careful suction removed supernatant liquor (suspension cell needs earlier centrifugally, inhales and removes supernatant).Every hole adds DMSO 100 μ L, puts micro oscillator concussion 5min so that crystallization is dissolved fully, and the single wavelength colorimetric of microplate reader 492nm is measured the OD value.Calculate inhibitory rate of cell growth as evaluation index with following method.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] * 100%.According to inhibitory rate of cell growth, calculate IC with the straight-line regression method 50Value.
(4) experimental result: see Table 1.
The IC of the tumour cell of table 1. pair vitro culture 50(μ g/mL)
(5) conclusion:
According to above-mentioned in vitro tests result, the compound that we have the general formula I structure as can be seen has stronger restraining effect to above-mentioned 4 kinds of human tumor cells.
Intravital antitumor action
(1) experiment material:
Sample: I-1 is provided by contriver's self-control.
Cell strain: liver cancer H22 cell, available from Shanghai cell research institute of the Chinese Academy of Sciences.
Positive control drug: endoxan, lot number: 07020121, Hengrui Medicine Co., Ltd., Jiangsu Prov..
Instrument: PB303-N type thousandth electronic balance, Mettler Toledo Inc. produces.
Animal: Kunming mouse, the SPF level, male and female half and half, body weight 18-22g purchases in Institute of Radiation Medicine, Chinese Academy of Medical Sciences, conformity certification number: SCXK (Tianjin) 2005-0001.
(2) experimental technique:
Get abdominal cavity inoculation knurl strain 9 days, tumor growth is good, the tangible tumor-bearing mice of abdominal tympanites, ascites is drawn in aseptic technique down, be made into the cancer cells suspension by physiological saline dilution in 1: 3, in all experiment mice right fore armpit subcutaneous vaccinations (0.2mL/ mouse), all operations is finished in 30min.To inoculate knurl liquid mouse next day by the body weight random packet, i.e. lotus knurl control group, endoxan group (25mg/kg), I-1 organizes (100mg/kg, 50mg/kg).The equal intraperitoneal injection of each administration group, once a day, control group gives with volume physiological saline.Mouse successive administration 10 days behind the last administration 24h, takes off cervical vertebra and puts to death, and peels off tumour, takes by weighing knurl and weighs, and calculates and respectively organizes heavy mean value of mouse tumor and inhibiting rate.
Inhibiting rate=[(the average knurl of the average knurl weight-experimental group of control group is heavy)/average knurl of control group is heavy] * 100%
(3) result:
Table 2. pair H22 tumor-bearing mice knurl heavily reaches the influence of inhibiting rate
Figure GDA0000022231920000061
Figure GDA0000022231920000062
(4) conclusion:
From above-mentioned animal vivo test result as can be seen, I-1 has certain restraining effect to the tumor growth of H22 tumor-bearing mice.During two dosage group intraperitoneal injections, inhibition rate of tumor growth all is better than positive control.
Embodiment
Below in conjunction with embodiment the present invention is described further, embodiment only is indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum ( 1H NMR, 13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Embodiment 1:
5-(pyridine-2-base-methyl)-5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-1) also
Figure GDA0000022231920000063
In the reaction flask that stirring, condenser, thermometer are housed, add 5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone 15.5g (0.1mol) also, with the 70mL acetonitrile it is dissolved, be cooled to-10 ℃ under stirring, add Anhydrous potassium carbonate 41.5g (0.3mol).2-(brooethyl) pyridine 17.2g (0.1mol) is added in the reaction system in batches, finish and be warming up to 45 ℃ of continuation reaction 6h (the flaggy demonstration reacts completely).Filter, filtrate solvent evaporated acetonitrile adds the 80mL methylene dichloride, with 3 * 80mL water washing reaction solution, divide and get dichloromethane layer, use the anhydrous sodium sulphate thorough drying, filter, methylene dichloride is to the greatest extent steamed in decompression, promptly gets light yellow wax shape product 14.3g (HPLC:98.1%), yield 58.1%.The Rf=0.51[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2]. 1H?NMR(DMSO-d6，400MHz)δ：3.072～3.101(t，2H)，3.578～3.607(t，2H)，4.248(s，2H)，4.284～4.301(t，1H)，4.617(s，2H)，6.577(s，1H)，7.530～7.561(m，1H)，7.836～7.855(d，1H)，7.982～8.025(m，1H)，8.692～8.703(d，1H)。MS，m/Z：246.0(M)。
Embodiment 2:
5-(quinoline-2-base-methyl)-5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone (Compound I-2) also
Figure GDA0000022231920000071
Add 5,6,7 in the reaction flask that stirring, condenser, thermometer are housed, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone 15.5g (0.1mol) also, with 80mL toluene it is dissolved, and is cooled to 0 ℃ under stirring, and adds triethylamine 30.4g (0.3mol).2-chloromethyl quinoline 17.8g (0.1mol) is added in the reaction system in batches, finish and be warming up to 100 ℃ of reaction 1h (the flaggy demonstration reacts completely).With 3 * 80mL water washing reaction solution, divide and get toluene layer, use the anhydrous sodium sulphate thorough drying, to filter, toluene is to the greatest extent steamed in decompression, promptly gets white wax shape product 17.8g (HPLC:97.8%), yield 60.3%.。The Rf=0.53[single-point, developping agent: v (sherwood oil): v (ethyl acetate)=1: 2].MS，m/Z：296.0(M)。
Embodiment 3:
Compound I-1 one-tenth hydrochloride: get I-1 solid product 2.0g, be dissolved in the 10mL anhydrous diethyl ether.Ice-water bath is cooled to 0 ℃, drip 25% hydrochloric acid diethyl ether solution to pH be 2, continue at stir about 1h under the ice-water bath.Filter, get white solid.
Embodiment 4:
Compound I-2 one-tenth taurate: get I-2 solid product 2.0g, be dissolved in the 15mL dehydrated alcohol.Be heated to the back adding that refluxes and wait a mole taurine, continue at the about 2h of stirring reaction down that refluxes.Reaction finishes, and leaves standstill 24h under room temperature.Filter, get white solid.
For the pharmaceutical composition of nitrogenous heterocyclic Thienopyridinone derivatives of the present invention is described more fully, following example of formulations is provided below, described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound and the salt thereof in the The compounds of this invention, preferably uses the compound described in the embodiment 1～4.
Embodiment 5:
Prepare hard gelatin capsule with following compositions:
Consumption/capsule
Compound I-1 75mg
Pregelatinized Starch 100mg
Poloxamer 4mg
Sodium starch glycolate 10mg
Magnesium Stearate 20mg
10% polyvidone ethanolic soln is an amount of
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Press recipe quantity with the mentioned component mixing, cross 60 mesh sieves three times, add an amount of 10% polyvidone ethanol (95%) solution system softwood, cross 18 mesh sieves and granulate, 40 ℃ of dryings are crossed the whole grain of 16 mesh sieves, are packed in the hard gelatin capsule.
Embodiment 6:
Prepare tablet with following compositions:
Consumption/sheet
Compound I-2 75mg
Starch 45mg
Microcrystalline Cellulose 40mg
Carboxymethyl starch sodium salt 4.5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Poloxamer 3mg
Preparation technology: supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 7:
The preparation of injection liquid:
The hydrochloride 45mg of Compound I-1
Propylene glycol 100mg
Polysorbate 80 is an amount of
Distilled water 300mL
Preparation method: get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic adjusting pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 8:
The preparation of injection lyophilized powder:
The taurate 50mg of Compound I-2
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-80%
Preparation method: get activeconstituents and add water for injection, regulate pH value to 4～8 with medicinal basic and make its dissolving.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals, promptly.

Claims (9)

1. the compound and the salt thereof that have formula I structure:
Figure FDA0000022231910000011
Wherein:
R is (a) nitrogenous hexa-member heterocycle;
(b) the nitrogenous hexa-member heterocycle of benzo.
2. the compound of Formula I described in claim 1, preferred following compound:
R is a pyridine, quinoline.
3. the compound of Formula I described in claim 2, represent following compound:
I-15-(pyridine-2-base-methyl)-5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also;
I-25-(quinoline-2-base-methyl)-5,6,7, the 7a-tetramethylene sulfide is [3,2-c] pyridines-2 (4H)-ketone also.
4. compound as claimed in claim 1, its pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
5. the salt of formula I compound as claimed in claim 4, preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate, amino acid salts.
6. the preparation method of claim 1 Chinese style I compound, it is characterized in that: 5,6,7,7a-tetramethylene sulfide also [3,2-c] the nitrogenous hexa-member heterocycle that replaces of pyridine-2 (4H)-ketone and monochloromethyl or the nitrogenous hexa-member heterocycle of benzo are in methylene dichloride, trichloromethane, acetonitrile or toluene, and in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide ,-10 ℃～105 ℃ reactions make formula I compound.
Figure FDA0000022231910000012
Wherein X is bromine or chlorine.
7. the pharmaceutical composition of an anti-malignant tumor, it comprises formula I compound or its salt and one or more pharmaceutical excipients for the treatment of significant quantity.
8. claim 1～5 Chinese style I compound and salt thereof are in the application that is used to prepare medicine for resisting malignant tumors.
9. application as claimed in claim 8 is in the purposes that is used to prepare aspect treatment lung cancer, liver cancer, mammary cancer, the cancer of the stomach medicine.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102127091A (en) * 2010-12-30 2011-07-20 天津药物研究院 Heterocyclic ring-containing schiff base compound
CN115073489A (en) * 2021-03-15 2022-09-20 同济大学 Thienopyridone compound, preparation method and antifungal drug

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CN1217186A (en) * 1991-09-09 1999-05-26 三共株式会社 Process for the preparation of pharmaceutical compositions containing hydropyridine derivatives as active ingredients

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CN1217186A (en) * 1991-09-09 1999-05-26 三共株式会社 Process for the preparation of pharmaceutical compositions containing hydropyridine derivatives as active ingredients

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102127091A (en) * 2010-12-30 2011-07-20 天津药物研究院 Heterocyclic ring-containing schiff base compound
CN102127091B (en) * 2010-12-30 2012-11-21 天津药物研究院 Heterocyclic ring-containing schiff base compound
CN115073489A (en) * 2021-03-15 2022-09-20 同济大学 Thienopyridone compound, preparation method and antifungal drug
CN115073489B (en) * 2021-03-15 2023-11-28 同济大学 A kind of thiophenepyridone compound, preparation method and an antifungal drug

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