CN108992450A - Cycloastragenol derivative is preparing the application in effect of anti hepatic fibrosis drug - Google Patents

Cycloastragenol derivative is preparing the application in effect of anti hepatic fibrosis drug Download PDF

Info

Publication number
CN108992450A
CN108992450A CN201810814217.4A CN201810814217A CN108992450A CN 108992450 A CN108992450 A CN 108992450A CN 201810814217 A CN201810814217 A CN 201810814217A CN 108992450 A CN108992450 A CN 108992450A
Authority
CN
China
Prior art keywords
cycloastragenol
derivative
preparation
hepatic fibrosis
application
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810814217.4A
Other languages
Chinese (zh)
Other versions
CN108992450B (en
Inventor
宋妍
陈广通
林海君
姜宝成
陈晨
李建林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yiwu Guoxin termite control Co.,Ltd.
Original Assignee
Nantong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nantong University filed Critical Nantong University
Priority to CN201810814217.4A priority Critical patent/CN108992450B/en
Publication of CN108992450A publication Critical patent/CN108992450A/en
Application granted granted Critical
Publication of CN108992450B publication Critical patent/CN108992450B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/004—Expansion of ring B by one atom, e.g. B homo steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids
    • C12P33/20—Preparation of steroids containing heterocyclic rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The invention discloses a kind of cycloastragenol derivative or its pharmaceutically can at salt and its prepare application in anti-hepatic fibrosis medicines.The present invention utilizes microbiological transformation technology, structural modification has successfully been carried out to cycloastragenol, obtain multiple new compounds, it is confirmed by Against Hepatic Fibrosis in Vitro test cell line, these compounds have preferable anti-hepatic fibrosis activity, it can be used as the active constituent of anti-hepatic fibrosis medicines, tool has been widely used.

Description

Cycloastragenol derivative is preparing the application in effect of anti hepatic fibrosis drug
Technical field
The present invention relates to field of medicaments, and in particular to application of the cycloastragenol derivative in preparation treatment liver disease drug, It more particularly relates to cycloastragenol derivative and prevents and treats the application in hepatic fibrosis medicines in preparation.
Background technique
Liver fibrosis refers to that liver cell necroses and when inflammatory stimulus, the pathology mistake of fibrous connective tissue hyperplasia in liver Journey.It is after various pathogenic factors lead to hepatic injury, hepatic stellate cells, which is activated to become, has very strong cellulation epimatrix energy The myofibroblastic-like cell of power, then collagen enzyme inhibitor generation increase, and collagenase activity also declines, and makes liver cell epimatrix Generation and degradation between proportional imbalance, eventually lead to Liver Collagen over-deposit become liver fibrosis.Liver fibrosis continues to dislike Change leads to cirrhosis even liver cancer, thus " hepatitis-liver fibrosis-cirrhosis-liver cancer " this chain be acknowledged as it is various slow Property hepatopathy leads to the common pathway of serious consequence.Research so far have confirmed liver fibrosis by it is appropriate treatment be can be inverse Turn, as long as can slow down or prevent the generation of liver fibrosis, so that it may mitigate or cure hepar damnification pathogenesis.Therefore, The treatment of anti-hepatic fibrosis is turned off the effective means of this chain, has far reaching significance to the research in hepatopathy field.Liver is starlike Cell is acknowledged as the main source cell of extracellular matrix at present, and the activation of hepatic stellate cells is that liver fibrosis is formed initially Key link.So inhibiting the activation of hepatic stellate cells is to treat the most effective approach of liver fibrosis.
Cycloastragenol is the internal metabolism aglycon of the principle active component Astragaloside IV of traditional Chinese medicine Radix Astragali, is had preferable Bioactivity.But cycloastragenol belongs to tetracyclic triterpenoid, lacks reactive group, reaction site is few, using routinizing Reaction method is learned to be difficult to prepare the derivative met the requirements.
Microorganism conversion is the enzymic catalytic reaction carried out using the enzyme system of organism autospecific, the type of reaction It is more, and there is High level of stereoselectivity and regioselectivity, become an important tool in organic synthesis.It is used for cycloastragenol Derivative preparation, great amount of samples can be provided for the follow-up study of the type compound.
Summary of the invention
The object of the present invention is to provide cycloastragenol derivative or its pharmaceutically can at salt preparation treat drug for liver disease Application in object, the hepatopathy is disease related with liver fibrosis, such as chronic hepatitis, cirrhosis or liver cancer.The drug is Anti-hepatic fibrosis medicines.The cycloastragenol derivative is the compound that structural formula is 1-6:
It is an object of the present invention to first public cycloastragenol new derivatives: compound 2 and 5.
The present invention also provides the preparation methods of above-mentioned cycloastragenol derivative, include the following steps:
1) cycloastragenol is added into culture medium for fermented and cultured microorganism, then carries out conversion culture, after removing mycelium Fermentation liquid is obtained, the microorganism is the bacterial strain that Mucor (Mucor) belongs to；
2) by the fermentation liquid after extracting, it is evaporated extract liquor, obtains conversion crude extract；
3) the conversion crude extract is collected using methylene chloride-methanol system with silica gel column chromatography and is merged component；
4) component is purified with reversed-phase high performance liquid chromatography, obtains product.
The concentration of cycloastragenol is 2-5000 μ g/mL in culture medium in above method step 1).
Extractant is conventional type organic solvent, ethyl acetate in above method step 2).
Above method step 3) preferably reversed-phase high performance liquid chromatography preparation condition is half preparation chromatographic column YMC ODS-A, 10.0I.D × 250mm, acetonitrile-water (55:45, V/V), flow velocity 2.0mL/min, Composition distribution are detected.
Document Advanced Synthesis&Catalysis 2015,357,1928 and Advanced Synthesis& Catalysis 2012,354,527 discloses the method for prepare compound 1,3,4 and 6.
The present invention experiments prove that, cycloastragenol derivative of the present invention have good anti-hepatic fibrosis activity, It can be used as the active constituent of anti-hepatic fibrosis medicines.
The active constituent of these anti-hepatic fibrosis medicines can be in the compound selected from cycloastragenol and structural formula 1-6 It is one or more of.
Can also be added in the drug using above compound as active constituent, when needs it is one or more pharmaceutically Acceptable carrier.The carrier includes the diluent of pharmaceutical field routine, excipient, filler, adhesive, wetting agent, collapses Agent, sorbefacient, surfactant, absorption carrier, lubricant etc. are solved, it can be according to the conventional method system of pharmaceutical field It is standby.
The present invention utilizes microbiological transformation technology, has successfully carried out structural modification to cycloastragenol, obtains a kind of new Cycloastragenol derivative, confirmed by interior animal experiment and Against Hepatic Fibrosis in Vitro test cell line, these compounds have Preferable anti-hepatic fibrosis activity, can be used as the active constituent of anti-hepatic fibrosis medicines, and tool has been widely used.
Detailed description of the invention
Fig. 1 is the HPLC map of compound 1-6 of the present invention.
Specific embodiment
The preparation of embodiment 1, the compound that structural formula is 1-6
The present invention uses microbial conversion process, using cycloastragenol as raw material, through everfermentation, extracting and developing, comes Prepare the compounds of this invention.The bacterial strain that Mucor (Mucor) belongs to can be purchased from Microbiological Culture Collection Administrative Center of the Chinese Academy of Sciences (CGMCC), potato culture is selected, is saved in being set in solid slope culture medium in 4 DEG C of refrigerators.
By taking Mucor racemosus Mucor racemosus AS 3.20 as an example, preparation structure formula be 1-6 compound process such as Under:
1) it ferments, convert and extracts
Mucor racemosus Mucor racemosus AS 3.20 is accessed 2 250mL triangular flasks (to train equipped with 100mL potato Support base) in, as seed liquor.At 160rpm on shaking table, 26 DEG C after shaken cultivation 1 day, it is in animated period to mycelia growth, is used Sterile pipette draws the seed liquor of 1mL, is added in 20 1000mL shaking flasks (equipped with 400mL potato culture).Oscillation After culture 1 day, 25mg cycloastragenol (0.2mL, 125mg/mL ethanol solution) is added in each shaking flask, shares the bottom 500mg Object.Continue conversion 7 days under the same terms, by filtering fermentation liquor, filters out mycelium, the isometric ethyl acetate extraction 3 of filtrate Secondary, extract liquor is concentrated to dryness, and obtains conversion product crude extract about 0.8g.
2) silica gel column purification
Gained crude extract is dissolved in a small amount of methanol, mixes with 1.0g column chromatography silica gel (200-300 mesh) and mixes sample, it is naturally dry It is dry, the chromatography capital equipped with 40g silica gel (200-300 mesh) is added to, with methylene chloride-dehydrated alcohol system gradient elution (50:1- 1:1), elution fraction is collected, using TLC analysis method (silica gel g thin-layer plate, methylene chloride-methanol (15:1) expansion, 10% sulphur Sour ethanol solution is spraying, heating colour developing) obtained similar elution fraction is merged.
3) reversed-phase high performance liquid chromatography purifies
Merge component to be purified with reversed-phase high performance liquid chromatography.Preparation condition is half preparation chromatographic column YMC ODS A-5 μm, 10.0 × 250mm, acetonitrile-water (55:45, V/V), flow velocity 2.0mL/min, differential detection.Obtain the compound that structural formula is 1-6 6 converted products, as shown in Figure 1.Its13C-NMR data are as shown in table 1.
Carbon modal data (the CDCl of 1. compound 1-6 of table3)
The above result shows that gained compound structure is correct.
The anti-hepatic fibrosis activity of 2 the compounds of this invention 1-6 of embodiment
1) experimental material
Instrument and reagent: CO2Incubator (Jouan IGO150)；Microplate reader (Bio-TEK ELx800)；Fluorescence is inverted aobvious Micro mirror (Olympus IX51)；MTT cell Proliferation and citotoxicity detection kit (green skies biotechnology research institute), RPM I1640 culture medium (Gibcol BRL), Rnase A, fetal calf serum, dimethyl sulfoxide (DMSO), trypsase (upper marine growth work Journey Co., Ltd).
Test cell strain: HSC-T6 cell strain is purchased from Chinese medicine section for the SD cultured rat hepatic stellate cells of SV40 transfection Institute of oncology of institute.
Test sample: compound 1-6, purity is 95% or more, and positive reference substance colchicin, each compound is with DMSO It is diluted after dissolution.
2) experimental method
Each test-compound is measured to the half inhibiting rate IC of HSC-T6 cell strain using mtt assay50Value: logarithmic growth phase HSC-T6 cell, with culture solution containing 1%DMEM adjustment cell concentration be 5 × 105/ mL, is inoculated in 96 well culture plates, at drug Every 100 μ L cell suspension of hole is added in reason group and cell controls group, and every group sets 3 multiple holes, and full culture medium is only added in blank control group, Every 100 μ L of hole, if 3 multiple holes.96 well culture plates are placed in 37 DEG C, 5%CO2After incubator culture for 24 hours, various concentration is added Given the test agent makes final concentration of 0.1-100 μM, continues to cultivate 72h.By mtt assay in microplate reader, the absorbance (A) of 450nm is measured Value calculates inhibiting rate [inhibiting rate=(1- experimental group A value/control group A value) × 100%].Experiment is repeated 3 times.Using SPSS 11.5 softwares make regression equation, calculate each given the test agent to the half-inhibitory concentration (IC of HSC-T6 cytosis 72h50)。
3) experimental result
According to mtt assay test result, the compounds of this invention 1-6 is calculated to the IC of above-mentioned cell50Value, the results are shown in Table 2.
Inhibiting effect of 2. test sample of table to HSC cell Proliferation
Compound HSC-T6IC50value(μM)
Colchicin 0.15
Compound 1 7.14
Compound 2 1.61
Compound 3 10.53
Compound 4 3.74
Compound 5 0.85
Compound 6 8.29
Cycloastragenol 31.46
The result shows that cycloastragenol and the compounds of this invention 1-6 of the invention have good anti-hepatic fibrosis activity, it can Using the active constituent as anti-hepatic fibrosis medicines.

Claims (10)

1. with following structural cycloastragenol derivative or its pharmaceutically can at salt preparation treatment liver disease drug in Using,
2. application as described in claim 1, it is characterised in that the hepatopathy is disease related with liver fibrosis.
3. application as claimed in claim 2, it is characterised in that the hepatopathy is chronic hepatitis, cirrhosis or liver cancer.
4. the application as described in one of claim 1-3 item, it is characterised in that the drug is anti-hepatic fibrosis medicines.
5. application as described in claim 1, it is characterised in that it is derivative that the drug contains cycloastragenol as described in claim 1 Object or its pharmaceutically can at one or more of salt and pharmaceutically acceptable carrier.
6. the preparation method of the cycloastragenol derivative with following structural,
Include the following steps:
1) cycloastragenol is added into culture medium for fermented and cultured microorganism, then carries out conversion culture, obtains after removing mycelium Fermentation liquid, the microorganism are the bacterial strain of mucor；
2) by the fermentation liquid after extracting, it is evaporated extract liquor, obtains conversion crude extract；
3) the conversion crude extract is collected using methylene chloride-methanol system with silica gel column chromatography and is merged component；
4) component is purified with reversed-phase high performance liquid chromatography, obtains product.
7. preparation method as claimed in claim 6, it is characterised in that the concentration of cycloastragenol is 2- in culture medium in step 1) 5000μg/mL。
8. preparation method as claimed in claim 6, it is characterised in that the microorganism is Mucor racemosus Mucor racemosusAS3.20。
9. preparation method as claimed in claim 6, it is characterised in that step 3) uses reversed-phase high performance liquid chromatography preparation condition It is detected for acetonitrile: water=55:45, flow velocity 2.0mL/min, Composition distribution.
10. a kind of cycloastragenol derivative, it is characterised in that have the following structure formula:
CN201810814217.4A 2018-07-23 2018-07-23 Application of cycloastragenol derivative in preparation of anti-hepatic fibrosis medicine Active CN108992450B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810814217.4A CN108992450B (en) 2018-07-23 2018-07-23 Application of cycloastragenol derivative in preparation of anti-hepatic fibrosis medicine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810814217.4A CN108992450B (en) 2018-07-23 2018-07-23 Application of cycloastragenol derivative in preparation of anti-hepatic fibrosis medicine

Publications (2)

Publication Number Publication Date
CN108992450A true CN108992450A (en) 2018-12-14
CN108992450B CN108992450B (en) 2020-01-14

Family

ID=64597003

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810814217.4A Active CN108992450B (en) 2018-07-23 2018-07-23 Application of cycloastragenol derivative in preparation of anti-hepatic fibrosis medicine

Country Status (1)

Country Link
CN (1) CN108992450B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109609581A (en) * 2018-12-28 2019-04-12 北京化工大学 A kind of method that microorganism mixed fermentation conversion degradation Astragaloside IV prepares cycloastragenol
CN109985043A (en) * 2019-03-18 2019-07-09 南通大学 Betula camphor and its derivative are with the application in effect of anti hepatic fibrosis drug

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1793132A (en) * 2006-01-12 2006-06-28 天津药物研究院 Derivative of cyclo membranousol kind and application thereof
CN101879170A (en) * 2010-07-14 2010-11-10 中国药科大学 Anti-tumor application of malonyl astragaloside I and aglycon thereof
CN105343109A (en) * 2015-11-23 2016-02-24 泰州永恒生物科技有限公司 Application of cycloastragenol in preparation of drugs for protecting liver and promoting liver injury restoration

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1793132A (en) * 2006-01-12 2006-06-28 天津药物研究院 Derivative of cyclo membranousol kind and application thereof
CN101879170A (en) * 2010-07-14 2010-11-10 中国药科大学 Anti-tumor application of malonyl astragaloside I and aglycon thereof
CN105343109A (en) * 2015-11-23 2016-02-24 泰州永恒生物科技有限公司 Application of cycloastragenol in preparation of drugs for protecting liver and promoting liver injury restoration

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIN-MIN FENG等: "Biocatalysis of Cycloastragenol by Syncephalastrum racemosum and Alternaria alternata to DiscoverAnti-Aging Derivatives", 《ADV.SYNTH. CATAL》 *
WEN-ZHI YANG等: "Biocatalysis of Cycloastragenol by Filamentous Fungi to Produce Unexpected Triterpenes", 《ADV.SYNTH.CATAL》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109609581A (en) * 2018-12-28 2019-04-12 北京化工大学 A kind of method that microorganism mixed fermentation conversion degradation Astragaloside IV prepares cycloastragenol
CN109985043A (en) * 2019-03-18 2019-07-09 南通大学 Betula camphor and its derivative are with the application in effect of anti hepatic fibrosis drug
CN109985043B (en) * 2019-03-18 2021-05-18 南通大学 Application of betulin and its derivatives in medicine with anti-hepatic fibrosis effect

Also Published As

Publication number Publication date
CN108992450B (en) 2020-01-14

Similar Documents

Publication Publication Date Title
Pavlov et al. Galanthamine production by Leucojum aestivum in vitro systems
CN105949265B (en) The preparation method of 20 (R) panaxatriol derivatives and application
CN102443027B (en) Fructosyl puerarin and preparation method and application thereof
Shubina et al. Pyridine nucleosides neopetrosides A and B from a marine Neopetrosia sp. sponge. Synthesis of neopetroside A and its β-riboside analogue
Bang et al. New aromatic compounds from the fruiting body of Sparassis crispa (Wulf.) and their inhibitory activities on proprotein convertase subtilisin/kexin type 9 mRNA expression
CN105017368B (en) Pananxadiol derivatives and preparation method and application
CN102766184B (en) Protopanoxadiol peroxide derivatives as well as preparation method and application thereof
Wang et al. Aldgamycins J–O, 16-membered macrolides with a branched octose unit from Streptomycetes sp. and their antibacterial activities
Eliwa et al. Biotransformation of papaverine and in silico docking studies of the metabolites on human phosphodiesterase 10a
CN108992450A (en) Cycloastragenol derivative is preparing the application in effect of anti hepatic fibrosis drug
CN109988217A (en) White birch 01 derivatives and the preparation method and application thereof
CN112142819B (en) Application of betulinic acid derivative in preparation of antitumor drugs
CN109985044B (en) Application of betulin and its derivatives in preparing antitumor drugs
CN108299467A (en) Indole carbazole Alkaloid with cytotoxic activity and preparation method, purposes
CN109985043A (en) Betula camphor and its derivative are with the application in effect of anti hepatic fibrosis drug
CN113134006B (en) Application of ursolic acid derivative in preparing antitumor drugs
CN104352505B (en) Applications of protopanaxatriol and derivatives thereof in preparation of medicines for treating hepatic disease
CN100448886C (en) Derivative of protopanoxatriol, prepn. method and application thereof
CN105853444B (en) Application of 20 (the R)-panaxatriol derivatives in preparation prevention or treatment liver disease drug
CN105030790B (en) Application of the Pananxadiol derivatives in prevention or treatment liver disease drug is prepared
Tian et al. Anti-mutagenicity of swertiamarin and its metabolite in incubated system of human intestinal flora
CN112022857B (en) Application of betulinic acid derivative in preparation of anti-liver-lesion medicine
CN104447931B (en) Protopanaxatriol's derivant and preparation method and application
CN106518873B (en) Matrine and Oxymatrine alkali derivant and the preparation method and application thereof
CN108676013B (en) Flavonol ketone compound with autophagy activation activity, preparation method and pharmaceutical application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20211012

Address after: 322001 first floor, No. 5, Jinger Road, Beiyuan street, Yiwu City, Jinhua City, Zhejiang Province

Patentee after: Yiwu Guoxin termite control Co.,Ltd.

Address before: 226019 Jiangsu Province, Nantong City Chongchuan District sik Road No. 9

Patentee before: NANTONG University

TR01 Transfer of patent right