CN107383048B - A kind of artemisinin derivatives, its synthesis and application - Google Patents
A kind of artemisinin derivatives, its synthesis and application Download PDFInfo
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Abstract
The present invention relates to pharmaceutical synthesis fields, specifically, being related to a kind of artemisinin derivatives, its synthesis and application, more specifically disclose a kind of artemisinin derivatives and preparation method thereof and the application in anti-tumor drug and inverase.Artemisinin derivatives of the present invention have structure shown in formula I, wherein R is other compounds residues.Preparation method is simple for artemisinin derivatives shown in formula I, and favorable reproducibility, environmental pollution is small, can be used for a large amount of preparations of compound shown in formula I.Compound shown in formula I of the present invention has apparent anti-tumor activity and HIV-resistant activity.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, specifically, being related to a kind of artemisinin derivatives, its synthesis and application.
Background technique
Sweet wormwood, belongs to composite family also known as artemisia annua (Artemisia annua L) is annual herb plant.Qinghaosu is for I
The sesquialter terpene lactone class antimalarial agent that state pharmacy worker extracts from Chinese medicine sweet wormwood in early 1970s, and in this structure
On the basis of again in succession synthesis, it is semi-synthetic go out a series of derivatives with antimalarial active, such as dihydroartemisinine, Artesunate, wormwood artemisia
Methyl ether, arteether etc..
The antimalarial active of qinghaosu and its derivative obtained it is universally acknowledged, have it is rapid-action, drug effect is high, toxic side effect is low
The advantages that.It meets the tendency of except extensively in addition to antimalarial treatments, artemisinin-based drug also has other multiple pharmacological effects, as anti-schistosome is made
With, anti-arrhythmia, relieving asthma, the effects of antiendotoxin, antiallergic action, lupus erythematosus, immunosupress.
With deepening continuously to qinghaosu and its derivatives active research, discloses such compound also and have and is certain
Antitumor action, it is inhibited for the growth of kinds of tumor cells.For example, Efferth etc. (Efferth T,
Olbrich A, Bauer R.), human tumor cell line influences anti-malaria medicaments Artesunate, arteether and Artemether
MRNA expression pattern (mRNA expression profiles for the response of human tumor cell
Lines to the antimalaral drugs artesunate, and artemether) biochemistry pharmacy (Biochem
Pharmacol.2002Aug15；64:617-23), Artesunate, arteether and Artemether are had studied to 55 kinds of tumour cells
Cytotoxicity, three kinds of compounds have inhibiting effect to the proliferation of 55 kinds of tumour cells as the result is shown, and Artesunate effect is aobvious
It writes, average 503nhibiting concentration IC50It is 12.3 μM, to including leukaemia, colon cancer, melanoma, prostate cancer, liver cancer, ovary
Kinds of tumor cells including cancer, breast cancer, cervical carcinoma, the low differentiation scaly epithelium rhinitis cancer of people etc. has selection lethal effect, green
Artemisic succinate has apparent cytotoxicity, 503nhibiting concentration (IC to leukaemia cell and rectum cancer cell50) it is respectively 1.11
± 0.56 and 2.13 ± 0.74 μM.
The document also analyzes Artesunate, arteether and Artemether effect front and back 464 pharmaceutical activity related gene (packet
Include drug resistant gene, DNA damage revision points, apoptosis gene, proliferation-associated genes, proto-oncogene, tumor suppressor gene and cell
The factor) express spectra, it is found that 208 genes are related to above-mentioned three kinds of sweet wormwood class Antitumor Activity of Drugs, relate generally to proliferation phase
Correlation gene, oncogene and tumor suppressor gene, as catalase, paddy cystine synzyme, thioredoxin peroxidase and
Reductase proteins etc. are changed in Liuyang.
AIDS (acquired immuno deficiency syndrome, AIDS) i.e. acquired immunodeficiency is comprehensive
Sign, AIDS is a kind of great infectious disease of harmfulness, is caused by aids infection viral (inhibition of HIV).HIV is a kind of to attack
The virus of human immune system is hit, there are two types of hypotype HIV-1 and HIV-2, variant is several for it.HIV is drenched by destroying the T of human body
Bar cell, and then cellular immunity and humoral immunity process are blocked, cause immune system to be paralysed, to cause various diseases in human body
Interior sprawling, eventually leads to AIDS.Since the variation of HIV is extremely rapid, it is difficult to specificity vaccine is produced, so far without effective treatment
Method causes great threat to human health.
For the present inventor after carrying out long-term a large amount of research to qinghaosu, design has synthesized a kind of artemisinin derivatives,
Through testing influence of the designed artemisinin derivative to activity of tumor cells using MTS method, the results showed that have antitumor work
Property.Simultaneously according to SFDA " the non-clinical pharmacodynamic study technological guidance principle (2006) of inverase ", using international experiment
Method detects the Anti-HIV-1 Active of designed artemisinin derivatives, the results showed that designed artemisine spreads out
Biology has external anti-HIV-1 effect, so as to complete the present invention.
Summary of the invention
It is an object of the present invention to provide a kind of artemisinin derivatives, the artemisinin derivatives have knot shown in formula I
Structure:
Wherein, R is other compounds residues.
Preferably, R is-OH ,-OMe ,-CnH2n、-OCnH2n+1、-OCnH2n、-OCnH2nOH、
One of.
The present invention also provides the preparation method of the artemisinin derivatives, described preparation method is simple, weight
Existing property is good, and environmental pollution is small, is suitable for industrialized production.
It is provided by the present invention the preparation method comprises the following steps: dihydroartemisinine and nucleopilic reagent are dissolved in organic solvent, in Lewis
0.5~2 hour is stirred under acid catalysis, at -40~10 DEG C, preferably -40~0 DEG C to get artemisinin derivatives shown in formula I,
Its synthetic reaction formula is as follows:
Provided by the present invention preparation method is simple, and favorable reproducibility, environmental pollution is small, is suitable for industrialized production, only
Dihydroartemisinine and nucleopilic reagent need to be dissolved in organic solvent, under Lewis acid catalysis, in -40~10 DEG C, preferably -40~0
It is stirred 0.5~2 hour at DEG C, can react to obtain artemisinin derivatives shown in formula I.
Nucleopilic reagent is also known as nucleophilic group, refers to the affinity having in significant structure to atomic nucleus, and the reagent to react.This hair
In the bright preparation method, the nucleopilic reagent is MeOH, TMSCnH2n, HOCnH2n+1、HOCnH2n、HOCnH2nOH、One of, wherein n=1~10.
In above-mentioned preparation method, the molar ratio of the dihydroartemisinine and nucleopilic reagent is 1:0.5~5.
Organic solvent refers to a kind of organic compound that can dissolve substance not soluble in water in solvent comprising carbon atom, packet
Include alkane, alkene, alcohol, aldehyde, amine, ester, ether, ketone, aromatic hydrocarbon, hydrogenate hydrocarbon, terpene hydrocarbon, halogenated hydrocarbons, heterocycle compound, nitrogenous chemical combination
The multiclass substance such as object and sulfur-containing compound, is in a liquid state at normal temperatures and pressures, has biggish volatility, molten in course of dissolution
No changes have been made for matter and the property of solvent.
Wherein, preferably, organic solvent described in preparation method of the present invention is methylene chloride, hexane, toluene, second
One of nitrile, dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethyl alcohol, t-butyl methyl ether or tetrahydrofuran.
Catalyst, which refers to, can improve chemical reaction rate, and the substance permanently sexually revised does not occur for this body structure.The present invention
The preparation method is with BF3OEt2、TMSOTf、AlCl3、ZnCl2, one of the Lewis acid such as MsCl be used as catalyst.
The molar ratio of the dihydroartemisinine and Lewis acid is 1:0.01~3.
In the present invention, whether completed with TLC detection reaction after agitation.
It after completion of stirring further include the process of post-processing in preparation method of the present invention.
Specifically, the post-processing are as follows: be slowly poured into water reaction solution and be quenched, be extracted with ethyl acetate, merge
Organic phase, with saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and solvent is removed in revolving and obtains crude product, through column layer
Analysis purifying obtains the artemisinin derivatives.
The present invention also provides the artemisinin derivatives to prepare the application in antitumor or inverase.
In the embodiment of the present invention, influence of the artemisinin derivative to activity of tumor cells shown in MTS method test formula I is utilized.
MTS method detects cell activity principle: MTS is a kind of completely new MTT analog, and full name is 3- (4,5-dimethylthiazol-
2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfopheny) -2H-tetrazolium, is a kind of yellow color
Dyestuff.Succinate dehydrogenase can be metabolized reduction MTS in living cells mitochondria, generate soluble formazan (Formazan) and change
The content for closing object , formazan can be measured at 490nm with microplate reader., formazan growing amount and living cells in general
Number is directly proportional, therefore the number of living cells can be deduced according to optical density OD value.
In the embodiment of the present invention, the tumour cell of test includes leukemia HL-60, lung cancer A-549, liver cancer SMMC-7721,
Breast cancer MCF-7 and colon cancer SW480.The results showed that under 40 μM, compound K PC-4000055, KPC-4000057,
KPC-4000058, KPC-4000059, KPC-4000061, KPC-4000062, KPC-4000063, KPC-DHA are to leukaemia
HL-60 Vitro Tumor Growth inhibiting rate is more than 70%；Compound K PC-4000055, KPC-4000057, KPC-4000058,
KPC-DHA is more than 60% to lung cancer A-549 tumor cell in vitro growth inhibition ratio, and KPC-4000058 is more than positive control
DDP；Compound K PC-4000055, KPC-4000057, KPC-4000058, KPC-DHA are to liver cancer SMMC-7721 Vitro Tumor
Inhibitory rate of cell growth is more than 80%；Compound K PC-4000055, KPC-4000057, KPC-4000058, KPC-4000062
It is more than 60% to breast cancer MCF-7 tumor cell in vitro growth inhibition ratio, and above positive control DDP；Compound K PC-
4000055, KPC-4000057, KPC-4000058 are more than 70% to colon cancer SW480 tumor cell in vitro growth inhibition ratio.
In the embodiment of the present invention, according to SFDA " the non-clinical pharmacodynamic study technological guidance principle (2006) of inverase ",
It is detected using Anti-HIV-1 Active of the international experimental method to drug.
HIV activity of the present invention includes: that (1) compound forms conjunction born of the same parents to HIV-1IIIB inducing host cell (C8166)
The inhibiting effect of body；(2) inhibiting effect (inhibiting effect that HIV-1p24 antigen generates) that compound replicates HIV-1IIIB；
(3) cytotoxic effect of the compound to host cell (C8166).
The results showed that being surveyed in 12 samples in the present invention, KPC-ART, KPC-ARM, KPC-4000056, KPC-
4000059, KPC-4000060, KPC-4000061, KPC-4000063 sample are smaller to the toxicity of C8166 cell, remaining sample
It is slightly larger to C8166 cytotoxicity；KPC-ART,KPC-ARM,KPC-4000055,KPC-4000057,KPC-4000059,KPC-
4000060, KPC-4000061, KPC-4000062 make be replicated with certain inhibition of the HIV-1IIIB in C8166 cell
With wherein KPC-4000057 antivirus action is most strong.The external anti-HIV-1 effect of remaining sample is weaker.
In conclusion artemisinin derivatives shown in formula I of the present invention have apparent antitumor and AntiHIV1 RT activity effect,
It is used as potential lead compound, is used in preparation treatment tumour and inverase.
Artemisine compounds shown in formula I can be used as active constituent and be used to prepare treatment and/or prevention respectively according to the present invention
Kind of cancer or HIV, the present invention also provide the method for treating and/or preventing above-mentioned disease, including give suffer from or be susceptible to it is above-mentioned
Artemisine compounds shown in the formula I of the invention of the effective therapeutic dose of the patient of disease.Artemisine compounds shown in above-mentioned formula I
Clinical dosage for patient must rely on treated main body, the concrete ways of administration, disease being treated seriousness and become
Change, and optimal dose is determined by the doctor for treating specific patient.
Reactive compound of the present invention can be used as unique anti-tumor drug and use, can also with it is one or more other anti-swollen
Tumor medicine is used in combination.Combination therapy by by each therapeutic component simultaneously, sequence or separate administration and realize.
The medicine for the treatment of tumour and HIV can be made in artemisine compounds shown in formula I with conventional auxiliary material combination
Object, including oral solution, granule, tablet, pill, powder, capsule and pill etc..
Qinghaosu of the present invention includes but is not limited to artemisinin derivatives shown in formula I, can also be blueness
Artemisin, dihydroartemisinine or Artemether.
The present invention also provides a kind of artemisinin derivatives preparation, the artemisinin derivatives preparation is to send out this
Oral preparation or ejection preparation is made in the bright artemisinin derivatives and pharmaceutically acceptable auxiliary material.
The oral preparation is tablet, oral solution, pill, capsule, granule, paste, pill, syrup, dissipates
Agent, electuary or tincture；The ejection preparation is powder-injection or injection.
Specifically, the artemisine preparation includes that (qinghaosu spreads out for the compound of the present invention of therapeutically effective amount
Biology) and pharmaceutically acceptable auxiliary material.Those skilled in the art can by the compound (artemisinin derivative) directly or
Connect addition and prepare pharmaceutically acceptable various common auxiliary materials required when different dosage forms, as filler, disintegrating agent, lubricant,
Common dosage forms such as tablet, capsule, injection, oral solution, granule, ball is made in traditional drug formulations method in adhesive etc.
Agent, powder and pill etc..Wherein, filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid；Disintegrating agent such as fine jade
Rouge, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates and sodium carbonate, low-substituted hydroxypropyl cellulose；Profit
Lubrication prescription such as talcum powder, calcium stearate, magnesium stearate, solid polyethylene glycol or Sodium Laurylsulfate；Adhesive such as carboxymethyl cellulose,
Alginates, gelatin, polyvinyl pyrrolidone, sucrose or Arabic gum.
After adopting the above technical scheme, compared with the prior art, the invention has the following beneficial effects:
The present invention provides a kind of new artemisinin derivatives, derivative through testing designed qinghaosu using MTS method
Influence of the object to activity of tumor cells, the results showed that there is anti-tumor activity.Simultaneously according to SFDA " the non-clinical medicine of inverase
Effect learns investigative technique guideline (2006) ", using international experimental method to the anti-of designed artemisinin derivatives
HIV-1 activity is detected, the results showed that designed artemisinin derivatives have external anti-HIV-1 effect.
Specific embodiment
The embodiment of the invention discloses a kind of artemisinin derivatives and the preparation method and application thereof.Those skilled in the art can
To use for reference present disclosure, it is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are to this
It is it will be apparent that they are considered as being included in the present invention for the technical staff of field.Product, method and application of the invention
Be described by preferred embodiment, related personnel obviously can not depart from the content of present invention, in spirit and scope it is right
Product as described herein, method and application is modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
For a further understanding of the present invention, the following describes the present invention in detail with reference to examples.
The preparation of embodiment 1:KPC-4000055
Dihydroartemisinine (300mg, 1.06mmol, 1.0eq) and n-octyl alcohol (331mmL, 2.11mmol, 2.0eq) are dissolved in
In the three-necked flask of one 10mL equipped with 5mL methylene chloride, nitrogen is replaced, -10 DEG C of dropwise addition boron trifluoride ether are cooled to
(53mmL, 422 μm of ol, 0.4eq), and 2h is stirred at this temperature.TLC (ethyl acetate: petroleum ether=2:8) display has been reacted
At.Reaction solution is slowly poured into water and is quenched, is extracted with ethyl acetate 3 times, merges organic phase, with saturated common salt water washing, nothing
Aqueous sodium persulfate dries, filters, and solvent is removed in revolving and obtains crude product, pure through column chromatography (ethyl acetate: petroleum ether=2:8)
Change obtains colourless oil liquid KPC-4000055 (320mg, yield 76%).
KPC-4000055:1H NMR (800MHz, CHLOROFORM-d) δ: 5.39 (s, 1H), 4.78 (d, J=3.3Hz,
1H), 3.83 (td, J=6.6,9.6Hz, 1H), 3.36 (td, J=6.4,9.6Hz, 1H), 2.65-2.56 (m, 1H), 2.37
(dt, J=4.0,14.1Hz, 1H), 2.09-1.98 (m, 1H), 1.83 (d, J=3.5Hz, 2H), 1.76-1.72 (m, 1H),
1.66-1.61 (m, 1H), 1.58-1.47 (m, 3H), 1.47-1.41 (m, 4H), 1.39-1.18 (m, 13H), 0.95 (d, J=
6.4Hz, 3H), 0.90 (d, J=7.3Hz, 3H), 0.88 (t, J=7.2Hz, 3H).
KPC-4000055:MS (ESI) m/z:419 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 2:KPC-4000056
Dihydroartemisinine (1.0g, 3.52mmol, 1.0eq) and 1,4- butanediol (3.11mL, 35.17mmol,
It 10.0eq) is dissolved in the three-necked flask of a 25mL equipped with 10mL methylene chloride, replaces nitrogen, be cooled to 5 DEG C of dropwise addition trifluoros
Change borate ether (442mmL, 3.52mmol, 1.0eq), and stirs 2h at this temperature.TLC (ethyl acetate: petroleum ether=4:6)
Display reaction is completed.Reaction solution is slowly poured into water and is quenched, is extracted with ethyl acetate 3 times, merges organic phase, uses saturated common salt
Water washing, anhydrous sodium sulfate dry, filter, and solvent is removed in revolving and obtains crude product, chromatograph (ethyl acetate: petroleum through column
Ether=4:6) purifying obtain white solid KPC-4000056 (1.1g, yield 88%).
KPC-4000056:1H NMR (800MHz, CHLOROFORM-d) δ: 5.39 (d, J=2.2Hz, 1H), 4.79
(br.s., 1H), 3.94-3.85 (m, 1H), 3.66 (br.s., 2H), 3.52-3.36 (m, 1H), 2.62 (d, J=2.9Hz,
1H),2.48-2.25(m,1H),2.08-1.99(m,1H),1.92-1.82(m,1H),1.81-1.73(m,2H),1.69-1.58
(m, 6H), 1.53-1.42 (m, 5H), 1.32 (dd, J=2.4,5.7Hz, 1H), 1.27-1.21 (m, 1H), 0.97-0.93 (m,
3H),0.91-0.89(m,3H)。
KPC-4000056:MS (ESI) m/z:379 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 3:KPC-4000057
Dihydroartemisinine (399mg, 1.40mmol, 1.0eq) and KPC-4000056 (500mg, 1.40mmol, 1.0eq)
It is dissolved in the three-necked flask of a 25mL equipped with 10mL methylene chloride, replaces nitrogen, be cooled to -20 DEG C of dropwise addition boron trifluoride second
Ether (178mmL, 1.40mmol, 1.0eq), and 2h is stirred at this temperature.TLC (ethyl acetate: petroleum ether=4:6) display is anti-
It should complete.Reaction solution is slowly poured into water and is quenched, is extracted with ethyl acetate 3 times, merges organic phase, is washed with saturated common salt
Wash, anhydrous sodium sulfate dries, filters, in revolving remove solvent obtain crude product, through column chromatography (ethyl acetate: petroleum ether=
4:6) purifying obtains white solid KPC-4000057 (650mg, yield 76%).
KPC-4000057:1H NMR (800MHz, CHLOROFORM-d) δ: 5.38 (s, 1H), 5.33 (s, 1H), 4.77
(d, J=3.4Hz, 1H), 4.41 (d, J=9.2Hz, 1H), 3.99 (td, J=5.8,9.5Hz, 1H), 3.88-3.82 (m, 1H),
3.48-3.33(m,2H),2.70-2.55(m,1H),2.44-2.33(m,3H),2.07-1.98(m,2H),1.93-1.85(m,
2H), 1.84-1.60 (m, 11H), 1.57 (s, 3H), 1.44 (d, J=3.1Hz, 6H), 1.34-1.22 (m, 6H), 0.95 (t, J
=5.9Hz, 6H), 0.90 (d, J=7.3Hz, 3H), 0.88 (d, J=7.2Hz, 3H).
KPC-4000057:MS (ESI) m/z:645 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 4:KPC-4000058
Dihydroartemisinine (1.0g, 3.52mmol, 1.0eq) is dissolved in three mouthfuls of a 25mL equipped with 10mL methylene chloride
In flask, nitrogen is replaced, -20 DEG C of dropwise addition boron trifluoride ether (44.2mmL, 0.35mmol, 0.1eq) are cooled to, and is warm herein
Degree is lower to stir 2h.TLC (ethyl acetate: petroleum ether=2:8) display reaction is completed.Reaction solution is slowly poured into water and is quenched, is used
Ethyl acetate extracts 3 times, merges organic phase, with saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and is removed in revolving
Solvent obtains crude product, obtains white solid KPC-4000058 through column chromatography (ethyl acetate: petroleum ether=1:9) purifying
(850mg, yield 90%).
KPC-4000058:1H NMR (800MHz, CHLOROFORM-d) δ: 5.84-5.77 (m, 1H), 5.41 (d, J=
2.3Hz, 1H), 5.02 (br.s., 1H), 4.73 (td, J=2.4,9.4Hz, 1H), 2.66-2.61 (m, 1H), 2.44 (dd, J=
2.3,4.6Hz,1H),2.39-2.31(m,2H),2.14-1.97(m,3H),1.92-1.84(m,2H),1.79-1.71(m,
2H),1.71-1.62(m,2H),1.56-1.44(m,4H),1.44-1.42(m,3H),1.39-1.36(m,3H),1.36-1.27
(m,3H),1.27-1.19(m,2H),1.01-0.92(m,10H),0.90-0.84(m,4H)。
KPC-4000058:MS (ESI) m/z:573 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 5:KPC-4000059
Dihydroartemisinine (10.0g, 35.17mmol, 1.0eq) and allyl trimethyl silane (16.77mL,
105.50mmol, 3.0eq) it is dissolved in the three-necked flask of a 250mL equipped with 100mL methylene chloride, replace nitrogen, cooling
Extremely -40 DEG C of dropwise addition boron trifluoride ether (4.42mL, 35.17mmol, 1.0eq), and 1h is stirred at this temperature, then rise to room
Temperature stirring 3h.TLC (ethyl acetate: petroleum ether=2:8) display reaction is completed.Reaction solution is slowly poured into water and is quenched, second is used
Acetoacetic ester extracts 3 times, merges organic phase, with saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and is removed in revolving molten
Agent obtains crude product, through column chromatography (ethyl acetate: petroleum ether=1:9) purifying obtain white solid KPC-4000059 (7.2g,
Yield 66%).
KPC-4000059:1H NMR (500MHz, CHLOROFORM-d) δ: 5.92 (d, J=6.7Hz, 1H), 5.32 (s,
1H), 5.18-5.01 (m, 2H), 4.29 (ddd, J=3.7,6.2,10.1Hz, 1H), 2.73-2.64 (m, 1H), 2.44-2.28
(m, 2H), 2.24-2.17 (m, 1H), 2.04 (s, 1H), 1.95-1.87 (m, 1H), 1.80 (dd, J=4.0,13.6Hz, 1H),
1.69-1.59 (m, 2H), 1.43 (d, J=6.6Hz, 1H), 1.41 (s, 3H), 1.34 (s, 1H), 1.40-1.14 (m, 3H),
0.96 (d, J=6.1Hz, 3H), 0.88 (d, J=7.5Hz, 3H).
KPC-4000059:MS (ESI) m/z:331 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 6:KPC-4000060
Dihydroartemisinine (1.0g, 3.52mmol, 1.0eq) is dissolved in three mouthfuls of a 25mL equipped with 10mL methylene chloride
In flask, nitrogen is replaced, is cooled to -20 DEG C of dropwise addition mesyl chlorides (272mmL, 3.52mmol, 1.0eq), and stir at this temperature
Mix 2h.Then triethylamine (974mmL, 7.04mmol, 2.0eq) is added, and is warmed to room temperature lower stirring 5h.TLC (ethyl acetate: stone
Oily ether=2:8) display reaction completion.Reaction solution is slowly poured into water and is quenched, is extracted with ethyl acetate 3 times, organic phase is merged,
With saturated common salt water washing, anhydrous sodium sulfate is dried, filtered, and solvent is removed in revolving and obtains crude product, chromatographs (acetic acid through column
Ethyl ester: petroleum ether=1:9) purifying obtain white solid KPC-4000060 (820mg, yield 88%).
KPC-4000060:1H NMR (500MHz, CHLOROFORM-d) δ: 6.19 (q, J=1.5Hz, 1H), 5.54 (s,
1H), 2.40 (ddd, J=4.0,13.3,14.6Hz, 1H), 2.12-2.00 (m, 2H), 1.95-1.88 (m, 1H), 1.71 (dd, J
=4.6,12.5Hz, 1H), 1.67 (d, J=3.2Hz, 1H), 1.59 (d, J=1.1Hz, 3H), 1.55 (s, 2H), 1.49-1.36
(m, 5H), 1.21-1.06 (m, 1H), 0.98 (d, J=6.0Hz, 3H).
KPC-4000060:MS (ESI) m/z:293 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 7:KPC-4000061
Dihydroartemisinine (10.0g, 35.17mmol, 1.0eq) and allyl alcohol (11.96mL, 175.84mmol, 5.0eq)
It is dissolved in the three-necked flask of a 250mL equipped with 100mL methylene chloride, replaces nitrogen, be cooled to -20 DEG C of dropwise addition boron trifluorides
Ether (4.42mL, 35.17mmol, 1.0eq), and 3h is stirred at this temperature.TLC (ethyl acetate: petroleum ether=2:8) display
Reaction is completed.Reaction solution is slowly poured into water and is quenched, is extracted with ethyl acetate 3 times, merges organic phase, is washed with saturated common salt
Wash, anhydrous sodium sulfate dries, filters, in revolving remove solvent obtain crude product, through column chromatography (ethyl acetate: petroleum ether=
1:9) purifying obtains white solid KPC-4000061 (8.6g, yield 75%).
KPC-4000061:1H NMR (500MHz, CHLOROFORM-d) δ: 5.96-5.79 (m, 1H), 5.40 (s, 1H),
5.26 (qd, J=1.8,17.2Hz, 1H), 5.13 (qd, J=1.6,10.5Hz, 1H), 4.83 (d, J=3.5Hz, 1H), 4.31
(tdd, J=1.7,4.8,13.5Hz, 1H), 3.99 (tdd, J=1.5,5.6,13.5Hz, 1H), 2.70-2.57 (m, 1H),
2.36 (ddd, J=4.0,13.6,14.5Hz, 1H), 2.09-1.98 (m, 1H), 1.92-1.72 (m, 3H), 1.66-1.60 (m,
1H), 1.53-1.44 (m, 2H), 1.43 (s, 3H), 1.39-1.29 (m, 1H), 1.27-1.20 (m, 1H), 0.94 (d, J=
6.4Hz, 3H), 0.92 (d, J=7.5Hz, 3H).
KPC-4000061:MS (ESI) m/z:347 [M+Na+]。
Structural formula is shown in Table 1.
The preparation of embodiment 8:KPC-4000062 and KPC-4000063
Dihydroartemisinine (1.0g, 3.52mmol, 1.0eq) and compound A (1.48g, 3.52mmol, 5.0eq) are dissolved in
In the three-necked flask of one 25mL equipped with 10mL methylene chloride, nitrogen is replaced, -20 DEG C of dropwise addition boron trifluoride ether are cooled to
(442mmL, 0.352mmol, 1.0eq), and 3h is stirred at this temperature.TLC (ethyl acetate: petroleum ether=4:6) display reaction
It completes.Reaction solution is slowly poured into water and is quenched, is extracted with ethyl acetate 3 times, organic phase is merged, with saturated common salt water washing,
Anhydrous sodium sulfate dries, filters, and solvent is removed in revolving and obtains crude product, chromatographs (ethyl acetate: petroleum ether=3:7) through column
Purifying obtains white solid KPC-4000062 (1.1g, yield 46%) and white solid KPC-4000063 (500mg, yield
21%).
KPC-4000062:1H NMR (400MHz, CHLOROFORM-d) δ: 5.37 (s, 1H), 5.20 (s, 1H), 5.10
(d, J=9.8Hz, 1H), 4.99 (dd, J=8.1,9.5Hz, 1H), 4.77 (d, J=3.3Hz, 1H), 4.50 (d, J=8.1Hz,
1H),4.30-4.11(m,2H),3.94-3.80(m,2H),3.74-3.64(m,1H),3.56-3.45(m,1H),3.41-3.32
(m, 1H), 2.68-2.56 (m, 1H), 2.37 (dt, J=3.9,14.0Hz, 1H), 2.09 (s, 3H), 2.04 (s, 3H), 2.03
(s, 3H), 2.01 (s, 3H), 1.87 (d, J=3.3Hz, 1H), 1.81-1.70 (m, 2H), 1.67-1.60 (m, 5H), 1.50-
1.42 (m, 5H), 1.25 (t, J=3.4Hz, 4H), 0.96 (d, J=6.2Hz, 3H), 0.89 (d, J=7.3Hz, 3H).
KPC-4000062:MS (ESI) m/z:710 [M+Na+].
Structural formula is shown in Table 1.
KPC-4000063:1H NMR (400MHz, CHLOROFORM-d) δ: 5.26 (s, 1H), 5.17-5.08 (m, 1H),
5.06-4.98 (m, 1H), 4.92 (dd, J=8.1,9.5Hz, 1H), 4.43 (d, J=8.1Hz, 1H), 4.34 (d, J=9.3Hz,
1H),4.24-4.03(m,2H),3.93-3.77(m,2H),3.67-3.56(m,1H),3.49-3.40(m,1H),3.33(td,J
=6.2,9.4Hz, 1H), 2.37-2.25 (m, 2H), 2.02 (s, 3H), 1.98 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H),
1.87-1.76(m,1H),1.72-1.55(m,5H),1.48-1.41(m,1H),1.36(s,3H),1.27-1.15(m,7H),
0.89 (d, J=6.0Hz, 3H), 0.80 (d, J=7.1Hz, 3H)
KPC-4000063:MS (ESI) m/z:710 [M+Na+].
Structural formula is shown in Table 1.
Compound made from above-described embodiment is shown in Table 1:
Compound made from table 1, embodiment 1-8
Embodiment 9: the external anti-HIV-1 effect experiment of the artemisinin derivative of class containing Formulas I
9.1 materials and method
9.1.1. drug and compound
Sample to be tested: sample to be tested is to apply compound made from a 1-8 and qinghaosu, dihydroartemisinine and Artemether,
Positive reference compound retrovir (3 '-Azido-3 '-deoxythymidine, AZT) is purchased from Sigma-aldrich.It is to be measured
Sample is dissolved in DMSO, and storage concentration is 50mM, 2-8 DEG C of preservation；AZT is dissolved in RPMI-1640 complete medium, storage
Concentration is 25mM, 0.22 μm of membrane filtration degerming, -20 DEG C of preservations after packing.
9.1.2. reagent and solution
Reagent: HEPES (N-2 (2-Hydroxyothyl) piperazine-N'- (2-ethanesufonic acid) (batch
Number: SLBF2383V), MTT (3, (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium
Bromide) (lot number: MKBG9627V), penicillin (Penicillin) (lot number: 018K06011), anti-igg Fc antibody (are criticized
Number: 083M4973), DMSO (lot number: RNBD5279) be purchased from Sigma-aldrich；Horseradish peroxidase-labeled goat-anti rabbit
(lot number: 120046) being KPL Products to IgG antibody；Skimmed milk power (lot number: 20150216B) is Inner Mongol Erie industry collection
Group's limited liability company's product；Beta -mercaptoethanol (lot number: 0787A20) is Shanghai Sheng Gong bioengineering Co., Ltd product；Sulphur
Sour streptomysin (Streptomycin sulfate) (lot number: 1183C462) is purchased from Amresco company；RPMI-1640 (lot number:
8113373) and fetal calf serum (FBS) (lot number: 1581729) is purchased from Invitrogen company；AntiHIV1 RT activity p24 monoclonal antibody and
Rabbit-anti HIV-1p24 polyclonal antibody is prepared by this laboratory.
Culture medium: RPMI-1640 complete medium, serum-free or contain 10% inactivated fetal bovine serum (FBS), 2mM L- paddy
Glutamine, 10mM HEPES, 50 μM of 2 mercapto ethanols, 100,000IU penicillin, 100 μ g/ml streptomysins.
9.1.3. laboratory apparatus
Centrifuge (manufacturer: Beckman Coulter, model: Allegra X-30), two stage biological safety cabinet (manufacturer:
Thermo, model: 1287), and CO2Cell incubator (manufacturer: Thermo, model: 3111), 2-8 DEG C of refrigerator (manufacturer: Haier,
Model: HYC-360), -20 DEG C of refrigerators (manufacturer: Haier, model: BCD-196E/D), -80 DEG C of refrigerator (manufacturers: Thermo, type
Number: 386L-86 DEG C), microplate reader (manufacturer: Bioteck, model: ELX800), inverted microscope (manufacturer: Nikon, model:
TS-100F)。
9.1.4. cell and virus
Cell: human T lymphocyte's C8166 cell comes from NIH；Cell is recovered according to a conventional method, passage: from liquid nitrogen
Recovery cell washes away frozen stock solution with RPMI-1640 culture medium, the complete medium 10ml containing 10%FBS is added, mixes, 37 DEG C
5%CO2Culture.A second generation is passed to cell every 3 days.First 1 day one second generation of biography is tested, cell used is made to be in logarithmic growth phase.
Virus: III B of experimental virus strain HIV-1 comes from NIH.Culture virus according to a conventional method, viral infection titration is by normal
Rule method carries out.It is viral to be sub-packed in cryopreservation tube, -80 DEG C of preservations in a small amount.
9.1.5.HIV-1 infectious titration
III B of HIV-1 is improved according to a conventional method to be titrated, and is summarized as follows: HIV-1 storage liquid is made 4 times on 96 orifice plates
Dilution, 10 gradients, 6 repeating holes of every gradient, while 6 hole of control wells is set.50 μ l of C8166 cell is added in every hole, and every hole is whole
Volume is 200 μ l, 37 DEG C, 5%CO2Culture.Fresh 100 μ l of RPMI-1640 complete medium is added within 3rd day, is being inverted within the 7th day
Whether the cytopathic effect (Cytopathic Effect, CPE) that HIV-1 is induced in the every hole of microscopically observation, have with every hole
The formation of plasomidum (Syncytium) determines；The titration of HIV-1 clinical separation strain detects HIV-1p24 Antigen Method using ELISA.
Using 2 times of negative control as Cutoff value, being higher than Cutoff value is positive (+), is negative (-) lower than Cutoff value.It presses
Reed&Muench method calculates the TCID50 (50%Tissue culture infection dose) of virus.
9.1.6. it captures p24 antigen ELISA method and measures HIV-1p24 antigen
200ng/ml 4 DEG C of plate overnights of anti-mouse IgG-Fc antibody；5% 4 DEG C of skimmed milk power sealing plate is stayed overnight；100 holes μ l/ are added
The anti-p24 monoclonal antibody (self-control) of mouse, 37 DEG C, 1 hour；Be added 100 holes μ l/ cracking infection cell culture supernatant, 37 DEG C, 2 hours；It is added
The 100 diluted rabbit-anti p24 of μ l/ hole 1:100 are mostly anti-, and 37 DEG C, 1 hour；The 100 diluted goat anti-rabbit iggs-of μ l/ hole 1:20000 are added
HRP, 37 DEG C, 1 hour；OPD substrate reactions liquid is added.After ten minutes, 2M sulfuric acid terminates reaction.Elx800ELISA instrument measures OD
Value measures wavelength 490nm, reference wavelength 630nm.Calculate drug to HIV-1 replicate expression p24 antigen inhibiting rate and
EC50 inhibits the drug concentration of 50%HIV-1p24 antigen presentation.
9.1.7. toxicity test of the sample to C8166 cell
4 × 105/ml C8166 cell suspension, 100 μ l is mixed from different drug solutions to be measured, if 6 dilutions, often
3 repeating holes of a dilution, while 6 the not cell control well of drug containing and 6 blank control wells are set.37 DEG C, 5%CO2
Culture 3 days, using MTT colorimetric determination cytotoxicity.ELx800 microplate reader measures OD value, and measurement wavelength is 570nm, reference wave
A length of 630nm.CC is calculated50It is worth (50%Cytotoxic Concentration), i.e. the normal T-lymphocytes to 50%
It is drug concentration when C8166 generates toxicity.
9.1.8. sample is to HIV-1ⅢBThe Inhibition test of cytopathogenic effect (CPE)
8 × 105/ml C8166 cell, 50 hole μ l/ is inoculated into 96 containing 100 μ l/ gradient pores doubling dilution drugs
In porocyte culture plates, the HIV-1 of 50 μ l is then addedIIIBDilute supernatant, the hole 1000TCID50/.If 6 dilutions, each
3 repeating holes of dilution, while the cell control well of 6 not drug containing is set.37 DEG C, 5%CO2Culture 3 days, inverted microscope
Under (100 ×) count plasomidum formation.EC50(50%Effectiveconcentration) is to inhibit Syncytium formation 50%
When compound concentration.
9.1.9. sample is to HIV-1ⅢBThe Inhibition test of virus replication in acute infection C8166 cell
By the C8166 cell and HIV-1 of 4 × 105/mlIIIB(virus infection amount and cytopathogenic effect Inhibition test phase
It is infected 2 hours at 37 DEG C together), the free virus of centrifugation removal, with PBS centrifuge washing 2 times.It is trained completely with RPMI-1640 again
Keynote cell concentration is supported to 4 × 105/ml.Take 100 μ l cell inoculations to 96 containing 100 μ l difference dilution untested compounds
On orifice plate, if 6 dilutions, 3 repeating holes of each dilution, while 6 the not cell control well of drug containing and 6 skies are set
White control wells.37 DEG C, 5%CO2Culture 3 days.Culture supernatant is collected, is cracked and is inactivated with final concentration 0.5%Triton X-100.It adopts
The inhibiting effect that HIV-1 is replicated with p24 antigen ELISA method detection drug is captured.
9.1.10. calculation formula
According to experimental result, dose response matched curve is drawn using Origin8.5, is calculated by Reed&Muench method
Sample inhibits 50% effective concentration (EC of virus50), 50% inhibits cell growth concentration (CC50) and Anti-HIV-1 Active treatment
Index TI value (Therapeutic index) are as follows: TI=CC50/EC50。
1, cell grows survival rate (%)=experimental port OD value/value × 100 control wells OD；
2, the inhibiting rate (%) of HIV-1 cytopathogenic effect=(1- experimental port plasomidum number/control wells plasomidum number) ×
100；
3, the inhibiting rate (%) of HIV-1p24 antigen presentation=(1- experimental port OD value/control wells OD value) × 100.
12 artemisinin derivatives such as table 2, KPC-400055 are to external anti-HIV-1 effect experiment result
The results showed that surveying in 12 samples at this, KPC-ART, KPC-ARM, KPC-4000056, KPC-
4000059, KPC-4000060, KPC-4000061, KPC-4000063 sample are smaller to the toxicity of C8166 cell, remaining sample
It is slightly larger to C8166 cytotoxicity；KPC-ART,KPC-ARM,KPC-4000055,KPC-4000057,KPC-4000059,KPC-
4000060, KPC-4000061, KPC-4000062 make be replicated with certain inhibition of the HIV-1IIIB in C8166 cell
With wherein KPC-4000057 antivirus action is most strong.The external anti-HIV-1 effect of remaining sample is weaker.
Embodiment 10: measurement of the artemisinin derivatives containing Formulas I to inhibition rate of tumor cell
Experimental method:
Inoculating cell: being made into individual cells suspension with the culture solution (DMEM or RMPI1640) containing 10% fetal calf serum,
With 3000~15000, every hole cell inoculation to 96 orifice plates, every pore volume 100ul, attached cell shifts to an earlier date 12~24 hours and is inoculated with
Culture.
Testing compound solution is added: compound is dissolved with DMSO, and compound is with 40uM concentration primary dcreening operation, every hole final volume
200ul, every kind of processing are all provided with 3 multiple holes.
Colour developing: after 37 degrees Celsius are cultivated 48 hours, attached cell abandons culture solution in hole, and every hole adds MTS solution 20ul and training
Nutrient solution 100ul；Suspension cell abandons 100ul culture supernatant, and every hole adds the MTS solution of 20ul；If 3 blank multiple holes (MTS solution
The mixed liquor of 20ul and culture solution 100ul), continue incubation 2~4 hours, measures absorbance value after the progress that reacts fully.
Colorimetric: selection 492nm wavelength, multi-function microplate reader (MULTISKAN FC) read each hole absorbance value, record knot
Fruit finally takes the average value of 3 results.
Positive reference compound: experiment is all provided with two positive compounds of cis-platinum (DDP) and taxol (Taxol) every time.
Measurement result (n=3) of 12 artemisinin derivatives such as table 3, KPC-400055 to inhibition rate of tumor cell
Note: 5 plants of discrepant compounds of cell activity have all repeated, as a result unanimously.
The results showed that under 40 μM, compound K PC-4000055, KPC-4000057, KPC-4000058, KPC-
4000059, KPC-4000061, KPC-4000062, KPC-4000063, KPC-DHA are to leukemia HL-60 Vitro Tumor Growth
Inhibiting rate is more than 70%；Compound K PC-4000055, KPC-4000057, KPC-4000058, KPC-DHA are to lung cancer A-549 body
Outer growth of tumour cell inhibiting rate is more than 60%, and KPC-4000058 is more than positive control DDP；Compound K PC-
4000055, KPC-4000057, KPC-4000058, KPC-DHA are to liver cancer SMMC-7721 tumor cell in vitro growth inhibition ratio
More than 80%；Compound K PC-4000055, KPC-4000057, KPC-4000058, KPC-4000062 are to breast cancer MCF-7 body
Outer growth of tumour cell inhibiting rate is more than 60%, and above positive control DDP；Compound K PC-4000055, KPC-
4000057, KPC-4000058 is more than 70% to colon cancer SW480 tumor cell in vitro growth inhibition ratio.
Embodiment 11: the preparation of the tablet containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative tablet shown in Formulas I.
Embodiment 12: the preparation of the oral solution containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative oral solution shown in Formulas I.
Embodiment 13: the preparation of the pill containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative pill shown in Formulas I.
Embodiment 14: the preparation of the capsule containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative capsule shown in Formulas I.
Embodiment 15: the preparation of the granule containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative granule shown in Formulas I.
Embodiment 16: the preparation of the paste containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative paste shown in Formulas I.
Embodiment 17: the preparation of the pill containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative pill shown in Formulas I.
Embodiment 18: the preparation of the syrup containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative syrup shown in Formulas I.
Embodiment 19: the preparation of the powder containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative powder shown in Formulas I.
Embodiment 20: the preparation of the electuary containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative electuary shown in Formulas I.
Embodiment 21: the preparation of the tincture containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative tincture shown in Formulas I.
Embodiment 22: the preparation of the powder-injection containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative powder-injection shown in Formulas I.
Embodiment 23: the preparation of the injection containing structure artemisinin derivative shown in Formulas I shown in the present invention
It takes and is mixed containing structure artemisinin derivative shown in Formulas I with customary adjuvant shown in the present invention, conventionally prepared
It obtains shown in the present invention containing structure artemisinin derivative injection shown in Formulas I.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (9)
1. a kind of artemisinin derivatives, which is characterized in that artemisinin derivatives have structure shown in formula I,
Wherein, R isWherein n=1~10.
2. a kind of preparation method of artemisinin derivatives described in claim 1, which is characterized in that the preparation method
Are as follows: dihydroartemisinine and nucleopilic reagent are dissolved in organic solvent, under Lewis acid catalysis, 0.5~2 is stirred at -40~10 DEG C
Hour, synthetic reaction formula was as follows to get artemisinin derivatives shown in formula I:
The nucleopilic reagent isWherein n=1~10.
3. preparation method according to claim 2, which is characterized in that under Lewis acid catalysis, stirred at -40~0 DEG C
0.5~2 hour.
4. preparation method according to claim 2 or 3, which is characterized in that the dihydroartemisinine and nucleopilic reagent
Molar ratio is 1:0.5~5.
5. preparation method according to claim 2 or 3, which is characterized in that the dihydroartemisinine and Lewis acid rub
You are than being 1:0.01~3.
6. a kind of artemisinin derivatives preparation, which is characterized in that the artemisinin derivatives preparation is by claim 1
Oral preparation or ejection preparation is made in the artemisinin derivatives and pharmaceutically acceptable auxiliary material.
7. artemisinin derivatives preparation according to claim 6, which is characterized in that the oral preparation be tablet,
Oral solution, pill, capsule, granule, paste, pill, syrup, powder, electuary or tincture；The ejection preparation is
Powder-injection or injection.
8. artemisinin derivatives preparation described in artemisinin derivatives described in claim 1 or claim 6 or 7 is being made
Application in standby antitumor or inverase.
9. application according to claim 8, which is characterized in that the tumour is leukaemia, breast cancer, liver cancer, colon
Cancer or lung cancer.
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Effective date of registration: 20191213 Address after: 314033 No. 340, Yun Hai Road, Jiaxing Economic Development Zone, Zhejiang, China Patentee after: Beck Norton (Zhejiang) Pharmaceutical Co., Ltd. Address before: 650106 Yunnan province Kunming city high and new technology industry development zone medicine road 166 Patentee before: Kun Yao Group Plc |