CN104557826A - Sesquiterpene lactone compound, pharmaceutical composition comprising sesquiterpene lactone compound, as well as preparation method and application of sesquiterpene lactone compound - Google Patents
Sesquiterpene lactone compound, pharmaceutical composition comprising sesquiterpene lactone compound, as well as preparation method and application of sesquiterpene lactone compound Download PDFInfo
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- CN104557826A CN104557826A CN201510002488.6A CN201510002488A CN104557826A CN 104557826 A CN104557826 A CN 104557826A CN 201510002488 A CN201510002488 A CN 201510002488A CN 104557826 A CN104557826 A CN 104557826A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
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Abstract
The invention relates to a sesquiterpene lactone compound, a pharmaceutical composition comprising the sesquiterpene lactone compound, a preparation method and the application of the sesquiterpene lactone compound, new sesquiterpene lactone 1 and new sesquiterpene lactone 2 separated from Inula Britannica, the preparation method for the new sesquiterpene lactone 1 and new sesquiterpene lactone 2, and the application of the new sesquiterpene lactone 1 and new sesquiterpene lactone 2 in preparation of an anti-tumor medicament. In-vitro anti-tumor activity screening shows that the compound disclosed by the invention has obvious activity on inhibiting the proliferation of tumor cells, can be made into clinically acceptable medicinal agents by combining with pharmaceutically acceptable carriers, and is used for treating cancer. The invention provides a lead compound for developing a new antitumor medicament, and has an important value on developing the resources of medicinal plants.
Description
Technical field
The invention belongs to medical art, be specifically related to be separated from Inula britannica obtain sesquiterpene lactones compound 1 and 2, containing its pharmaceutical composition and preparation method thereof and medical usage.
Background technology
Tumor is a kind of commonly encountered diseases, frequently-occurring disease, and wherein malignant tumor is a current harm humans the most serious healthy class disease.Chemotherapeutics also also produces toxic and side effects to human normal cell while killing cancerous cell, greatly limits its extensive use and the performance of curative effect.Researcher, by more and more paying close attention to the effective ingredient invested in natural plants, comprises China from plant, extracts the vinca, camptothecin (camptothecine, hydroxy camptothecin), the elemene that succeed; The KANGLAITE extracted from Semen Coicis core, polyporusum bellatus, celestial clever polysaccharide, astragalus polysaccharides and ginsenoside; The effective ingredient extracted from Chinese medicine Indigo Naturalis is effective to chronic leukemia; The harringtonine extracted from plant Folium et Ramulus Cephalotaxi and homoharringtonine have outstanding curative effect to acute acellular leukemia, at present in the world as clinical three line medicines.
Inula britannica is a kind of traditional Chinese herbal medicine, for the dry capitulum of Compositae Inulaplants Inula britannica, mainly be distributed in China, Korea S and Japan, this medicine records in Pharmacopoeia of People's Republic of China (version in 2010), nature and flavor are salty, warm, enter lung, kidney channel, there is the effect such as sending down the abnormal ascending QI preventing or arresting vomiting, expectorant row water.Cure mainly cough expectorant, the side of body lower distension, extensive abdominal edema, wind syndrome of ocular connectors due to invasion of pathogenic wind of decaptitating, let out dispersing wind and cold.The chemical composition of the Inula britannica of current report about has kind more than 40, mainly contain flavonoid, Sesquiterpene lactones and terpenoid, wherein prove that the composition great majority having pharmacologically active are sesquiterpene lactones compounds, mostly be chloroform extract, there is the effect such as antiinflammatory (suppressing iNOS and COX-2), anti-hepatitis, anti-liver injury, antitumor and cell toxicant, also effective in cure to diabetes.
Inventor, in Inula britannica acetic acid ethyl ester extract chemical constitution study process, is separated and obtains new sesquiterpene lactones compounds 1 and 2, do not have bibliographical information at present, do not have the active reporter of these two compounds.
Summary of the invention
The object of this invention is to provide a kind of extraction from Inula britannica and obtain sesquiterpene lactones compound 1 and 2, containing its pharmaceutical composition and preparation method thereof and the application in Tumor suppression.
Above-mentioned purpose of the present invention is achieved by technical scheme below:
There is the sesquiterpene lactones compound 1 and 2 of following structural formula
Pharmaceutical composition, the pharmaceutically acceptable carrier of compound according to claim 11 and 2 wherein containing treatment effective dose.
The preparation method of described compound 1 and 2: Inula britannica pulverizes rear merceration 24h under 95% ethanol room temperature, filter, merge extractive liquid, decompression recycling ethanol obtains crude extract, and the suspendible that adds water is even, be extracted with ethyl acetate 3 times, obtain ethyl acetate extract, extractum decolours after 95% ethanol elution through MCI, carry out rough segmentation with the chloroform-acetone gradient elution of silicagel column 10:0 → 1:1, merge identical flow point, obtain 6 part F1-F6; F1 is through Sephadex LH-20 column chromatography chloroform: obtain 5 fraction F1a-F1e through the methanol-water gradient elution of RP-18 column chromatography 25:75 → 100:0 after methanol=1:1 purification, gets F1d through silicagel column chloroform: through HPLC methanol after ethyl acetate=5:1 purification: water gradient 80:20 and 92:8 eluting are partly prepared into compound 1 and 2.
Described Inula britannica is racemosus Inula britannica or cotton wool Inula britannica.
The preparation method of described compound 2: narrow leaf Inula britannica pulverizes rear merceration 24h under 95% ethanol room temperature, filter, merge extractive liquid, decompression recycling ethanol obtains crude extract, is extracted with ethyl acetate 3 times successively, obtains ethyl acetate extract after the suspendible that adds water is even, extractum is through MCI variable concentrations methanol-water gradient elution, gradient is 20%, 40%, 60%, 80%, 100%, merges identical flow point, obtains 5 part F1-F5; Getting F4 through the chlorofonn-ethylacetate gradient elution of silicagel column 9:1 → 3:2 obtains 4 little portion F4a-F4d, gets F4c through Sephadex LH-20 column chromatography chloroform: through HPLC methanol after methanol=1:1 purification: water=82:18 is partly prepared into compound 1; Getting F5 through the petroleum ether-ethyl acetate gradient elution of silicagel column 9:1 → 2:3 obtains 3 fraction F5a-F5c, gets F5a through HPLC methanol: water=94:6 is prepared into compound 2.
The application of described compound 1 and 2 in preparation treatment cervical cancer or hepatocarcinoma or adenocarcinoma of lung medicine.
The application of described pharmaceutical composition in preparation treatment cervical cancer or hepatocarcinoma or adenocarcinoma of lung medicine.
When the compounds of this invention is used as medicine, directly can uses, or use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1-99.0%, is preferably the compounds of this invention of 0.5-90.0%, and all the other are acceptable on materia medica, nontoxic to humans and animals and pharmaceutically suitable carrier of inertia and/or excipient.
Described pharmaceutically suitable carrier or excipient are that one or more are selected from solid, semisolid and liquid diluent, filler and pharmaceutical preparation adjuvant.Pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention can oral administration and injection two kinds of form administrations.
Oral its solid available or liquid preparation, powder or tablet or sugar coated tablet or capsule or tincture or syrup or drop pill.
Inject its solid available or liquid preparation, injectable powder or injection of solution agent.
Accompanying drawing explanation
Fig. 1 is compound 1 and 2 structural formula.
Detailed description of the invention
Embodiment 1
Racemosus Inula britannica (5kg) pulverizes rear merceration 24h under 95% ethanol (3 × 15L) room temperature, filter, merge extractive liquid, decompression recycling ethanol obtains crude extract, and the suspendible that adds water is even, be extracted with ethyl acetate 3 times, obtain ethyl acetate extract (385mg), extractum decolours after 95% ethanol elution through MCI, carry out rough segmentation with the chloroform-acetone gradient elution of silicagel column 10:0 → 1:1, merge identical flow point, obtain 6 part F1-F6; F1 is through Sephadex LH-20 column chromatography chloroform: obtain 5 fraction F1a-F1e through the methanol-water gradient elution of RP-18 column chromatography 25:75 → 100:0 after methanol=1:1 purification, gets F1d through silicagel column chloroform: through HPLC methanol after ethyl acetate=5:1 purification: water gradient 80:20 and 92:8 eluting are partly prepared into compound 1(21mg) and 2(20mg);
Compound 1 structural identification: pale yellow powder; HR-ESIMS shows [M+H]
+for m/z 333.2035, can obtain molecular formula in conjunction with nuclear-magnetism is C
20h
28o
4, degree of unsaturation is 7;
1h NMR (CDCl
3, δ ppm, 600 MHz) and
13c NMR (CDCl
3, δ ppm, 150 MHz) and data are in table 1.Its planar structure and relative configuration can be determined in conjunction with DEPT, HSQC, HMBC, NOESY spectrum and this compounds nuclear magnetic data.
Table 1
1h NMR and
13c NMR signals assignment
Compound 2 structural identification: pale yellow powder; HR-ESIMS shows [M+H]
+for m/z 293.1918, can obtain molecular formula in conjunction with nuclear-magnetism is C
17h
24o
4, degree of unsaturation is 6;
1h NMR (CDCl
3, δ ppm, 600 MHz) and
13c NMR (CDCl
3,δ ppm, 150 MHz) data are in table 2.Its planar structure and relative configuration can be determined in conjunction with DEPT, HSQC, HMBC, NOESY spectrum and this compounds nuclear magnetic data.
Table 2
1h NMR and
13c NMR signals assignment
Embodiment 2
Cotton wool Inula britannica (5kg) pulverizes rear merceration 24h under 95% ethanol (3 × 15L) room temperature, filter, merge extractive liquid, decompression recycling ethanol obtains crude extract, and the suspendible that adds water is even, be extracted with ethyl acetate 3 times, obtain ethyl acetate extract (322mg), extractum decolours after 95% ethanol elution through MCI, carry out rough segmentation with the chloroform-acetone gradient elution of silicagel column 10:0 → 1:1, merge identical flow point, obtain 6 part F1-F6; F1 is through Sephadex LH-20 column chromatography chloroform: obtain 5 fraction F1a-F1e through the methanol-water gradient elution of RP-18 column chromatography 25:75 → 100:0 after methanol=1:1 purification, gets F1d through silicagel column chloroform: through HPLC methanol after ethyl acetate=5:1 purification: water gradient 80:20 and 92:8 eluting are partly prepared into compound 1(17mg) and 2(26mg).
Compound 1 and 2 structural identification is shown in embodiment 1.
Embodiment 3
Narrow leaf Inula britannica (5kg) pulverizes rear merceration 24h under 95% ethanol (3 × 15L) room temperature, filter, merge extractive liquid, decompression recycling ethanol obtains crude extract, is extracted with ethyl acetate 3 times successively, obtains ethyl acetate extract (350g) after the suspendible that adds water is even, extractum is through MCI variable concentrations methanol-water gradient elution, gradient is 20%, 40%, 60%, 80%, 100%, merges identical flow point, obtains 5 part F1-F5; Getting F4 through the chlorofonn-ethylacetate gradient elution of silicagel column 9:1 → 3:2 obtains 4 little portion F4a-F4d, gets F4c through Sephadex LH-20 column chromatography chloroform: through HPLC methanol after methanol=1:1 purification: water=82:18 is partly prepared into compound 1(19mg); Getting F5 through the petroleum ether-ethyl acetate gradient elution of silicagel column 9:1 → 2:3 obtains 3 fraction F5a-F5c, gets F5a through HPLC methanol: water=94:6 is partly prepared into compound 2(22mg);
Compound 2 structural identification is shown in embodiment 1 table 2.
Embodiment 4
Experiment material: DMEM culture medium, new-born calf serum, trypsin, MTT, DMSO, human A459 lung cancer cell line, hepatoma cell strain Hep G2, human cervical carcinoma cell lines Hela, CO
2incubator, superclean bench, microplate reader, inverted microscope, Tissue Culture Flask, 96 porocyte culture plates.
Experimental technique:
(1) culture medium preparation: GIBCO DMEM fluid medium, 4 DEG C of cold preservations are for subsequent use.
(2) the super new-born calf serum of calf serum deactivation: 200mL, after-40 DEG C of refrigerators take out, room temperature is melted, 56 DEG C of water-bath 30min.Be sub-packed in 15mL centrifuge tube after cooling ,-40 DEG C of refrigerator freezings are for subsequent use.
(3) complete culture solution: DMEM culture medium 95mL, adds 5mL deactivation new-born calf serum, mixing.
(4) sample stock solution: accurate measuring each sample extract 10. 0mg, adds in the 1.5mL centrifuge tube of sterilizing, adds 1mL DMSO and dissolves, freezing for subsequent use.
(5) pastille culture fluid: complete culture solution 1mL is added on sterilizing cillin bottle, adds each sample stock solution 20 μ L, is 200 μ g/mL medicinal liquid to be measured.
(6) 0.25% pancreatin: sterilizing D-Hanks buffer 100mL, adds pancreatin 0.25g, stir gently and make to dissolve completely, adjust ph to 7.2, degerming with 0.22 μm of degerming membrane filtration in aperture, be sub-packed in 15mL centrifuge tube, freezen protective is for subsequent use.
(7) MTT: be made into 5mg/mL solution with DMEM culture medium, 0.22 μm of degerming membrane filtration in aperture is degerming, and be sub-packed in 1.5mL centrifuge tube ,-40 DEG C of refrigerator freezings save backup.
(8) recovery of freeze-stored cell: take out freeze-stored cell cryopreservation tube in liquid nitrogen container, be added on rapidly vibration in 37 DEG C of warm water to make to melt completely, cryopreservation tube inner cell be transferred in the 15mL plastic centrifuge tube with cover of sterilizing, add 10mL complete culture solution, piping and druming is even, the centrifugal 10min of 1000 turns/min.Abandon supernatant, with 5mL complete culture solution re-suspended cell, cell suspension is proceeded to culture bottle, in 37 DEG C, 5%CO
2, full close humidity under cultivate.
(9) passage: wash twice with sterilizing D-hanks liquid after at the bottom of cell covers with bottle, add 0.25% trypsin digestion and cell 2 minutes, outwell trypsin, after jog cell can come off completely, after adding complete culture solution 15mL, dispel cell with pipet, be sub-packed in 3 new Tissue Culture Flasks, or after adjustment cell concentration, add 96 well culture plates, continue to cultivate.
(10) drug treating and result measure: get one bottle, the cell just covered with, collecting cell after trypsinization, even with pipet piping and druming, get two cell suspension Trypan Blues, in counted under microscope number of viable cells, and determine dead cell number <5%, otherwise give it up.With complete culture solution adjustment cell number to 1 × 10
5individual cell/mL.In 96 porocyte culture plates, every hole adds 100 μ L cell suspension, and culture plate is placed in CO
2cultivate 24h in incubator, in every hole, add the complete culture solution of 100 μ L containing variable concentrations sample after taking out culture plate, obtain the drug solution of variable concentrations.Each concentration establishes 4 parallel holes, and separately establish 4 porocytes to add not pastille complete culture solution and make negative control hole, the complete culture solution that 4 porocytes add containing 5-fluorouracil (5-FU) makes positive control, and 5-fluorouracil final concentration is 20 μ g/mL.After adding medicine, culture plate vibrates mixing on microwell plate agitator, is placed in CO
2continue in incubator to cultivate 48h.Take out culture plate, every hole adds the MTT liquid of 10 μ L 5mg/mL, vibration mixing, continues to cultivate 4h.Discard culture fluid in every hole, the DMSO adding 150 μ L dissolves formazan crystallization, and vibration makes to dissolve completely.Measure each hole absorbance in microplate reader, measure wavelength 570nm, reference wavelength 630nm.
Experimental result:
The different sample of table 3 is to the half-inhibition concentration (IC of human cervical carcinoma cell lines Hela
50)
The different sample of table 4 is to the half-inhibition concentration (IC of hepatoma cell strain Hep G2
50)
The different sample of table 5 is to the half-inhibition concentration (IC50) of lung adenocarcinoma cells A549
Can find out that the propagation of the compounds of this invention 1 and 2 pairs of human cervical carcinoma cells, hepatoma carcinoma cell and lung adenocarcinoma cells has stronger inhibitory action by above-mentioned experimental result.
Embodiment 5
Compound 1 and/or 2 is obtained, the conventional tablet form the filler on itself and pharmaceutics meaning, disintegrating agent or capsule by embodiment 1 or 2 or 3 method; Or the slow releasing tablet that itself and filler and hydroxypropyl methylcellulose formed or capsule; The wherein optional lactose of filler, microcrystalline Cellulose, dextrin, starch, calcium phosphate; Disintegrating agent can select hyprolose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose; Also optionally binding agent, lubricant or wetting agent is added.
Such as according to weight ratio, the sesquiterpene lactones compound in the present invention 1 part, lactose or microcrystalline Cellulose 0.05 ~ 0.2, hyprolose or carboxymethyl starch sodium 0.05 ~ 0.2; Or, the sesquiterpene lactones compound in the present invention 1 part, lactose or microcrystalline Cellulose 0.03 ~ 0.08, hydroxypropyl methylcellulose K4M 0.15 ~ 0.4.Described medicine more preferably formula is: according to weight ratio, the sesquiterpene lactones compound in the present invention 1 part, lactose or microcrystalline Cellulose 0.08 ~ 0.12, hyprolose or carboxymethyl starch sodium 0.08 ~ 0.12; Or, the sesquiterpene lactones compound in the present invention 1 part, lactose or microcrystalline Cellulose 0. 05 ~ 0.07, hydroxypropyl methylcellulose K4M 0.2 ~ 0.3.
Embodiment 6
Obtain compound 1 and/or 2 by embodiment 1 or 2 or 3 method, by its routinely oral liquid method for making make oral liquid.
Embodiment 7
Obtain compound 1 and/or 2 by embodiment 1 or 2 or 3 method, it is mixed with 20% polyoxyl castor oil, is dissolved in the water of phosphoric acid potassium dihydrogen, dipotassium hydrogen phosphate, Nipagin ester and sodium carboxymethyl cellulose, the suspension type injection made.After the sesquiterpene lactones compound that also method of embodiment 1 can be obtained respectively dissolves with a small amount of DMSO, inject routinely with water, fine straining, injection is made in embedding, sterilizing.
Embodiment 8
Obtain compound 1 and/or 2 by embodiment 1 or 2 or 3 method, after it is dissolved with a small amount of DMSO, be dissolved in sterile water for injection, be stirred to dissolve, filter with aseptic suction funnel, more aseptic fine straining, in subpackage and ampoule, the injectable powder of aseptic sealing by fusing after frozen drying.
Claims (7)
1. there is the sesquiterpene lactones compound 1 and 2 of following structural formula
。
2. pharmaceutical composition, the pharmaceutically acceptable carrier of compound according to claim 11 and 2 wherein containing treatment effective dose.
3. the preparation method of compound 1 and 2 described in claim 1, it is characterized in that: Inula britannica pulverizes rear merceration 24h under 95% ethanol room temperature, filters, merge extractive liquid, decompression recycling ethanol obtains crude extract, the suspendible that adds water is even, is extracted with ethyl acetate 3 times, obtains ethyl acetate extract, extractum decolours after 95% ethanol elution through MCI, carry out rough segmentation with the chloroform-acetone gradient elution of silicagel column 10:0 → 1:1, merge identical flow point, obtain 6 part F1-F6; F1 is through Sephadex LH-20 column chromatography chloroform: obtain 5 fraction F1a-F1e through the methanol-water gradient elution of RP-18 column chromatography 25:75 → 100:0 after methanol=1:1 purification, gets F1d through silicagel column chloroform: through HPLC methanol after ethyl acetate=5:1 purification: water gradient 80:20 and 92:8 eluting are partly prepared into compound 1 and 2.
4. the preparation method of compound 1 and 2 according to claim 3, is characterized in that: described Inula britannica is racemosus Inula britannica or cotton wool Inula britannica.
5. the preparation method of compound 2 according to claim 1, it is characterized in that: narrow leaf Inula britannica pulverizes rear merceration 24h under 95% ethanol room temperature, filter, merge extractive liquid, decompression recycling ethanol obtains crude extract, 3 times are extracted with ethyl acetate successively after the suspendible that adds water is even, obtain ethyl acetate extract, extractum is through MCI variable concentrations methanol-water gradient elution, and gradient is 20%, 40%, 60%, 80%, 100%, merge identical flow point, obtain 5 part F1-F5; Getting F4 through the chlorofonn-ethylacetate gradient elution of silicagel column 9:1 → 3:2 obtains 4 little portion F4a-F4d, gets F4c through Sephadex LH-20 column chromatography chloroform: through HPLC methanol after methanol=1:1 purification: water=82:18 is partly prepared into compound 1; Getting F5 through the petroleum ether-ethyl acetate gradient elution of silicagel column 9:1 → 2:3 obtains 3 fraction F5a-F5c, gets F5a through HPLC methanol: water=94:6 is prepared into compound 2.
6. the application of compound 1 and 2 according to claim 1 in preparation treatment cervical cancer or hepatocarcinoma or adenocarcinoma of lung medicine.
7. the application of pharmaceutical composition according to claim 2 in preparation treatment cervical cancer or hepatocarcinoma or adenocarcinoma of lung medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111635380A (en) * | 2020-06-17 | 2020-09-08 | 中国科学院昆明植物研究所 | Sesquiterpene in mugwort, pharmaceutical composition thereof, preparation method and application thereof |
| CN111704594A (en) * | 2020-06-17 | 2020-09-25 | 中国科学院昆明植物研究所 | Artemisia polyantha lactone A-S and Artemisia polyantha element A-G as well as pharmaceutical composition and application thereof |
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| CN1445221A (en) * | 2002-05-28 | 2003-10-01 | 河北医科大学 | Pharmaceutical application of derivant of benzofuran-ketone |
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| CN101186598A (en) * | 2007-12-11 | 2008-05-28 | 河北医科大学 | 1-oxy-acetyl inula Britannica lactone derivative, preparation method thereof and application of the same in preparing cancer-curing medicine |
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2015
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| CN1445221A (en) * | 2002-05-28 | 2003-10-01 | 河北医科大学 | Pharmaceutical application of derivant of benzofuran-ketone |
| CN101125141A (en) * | 2007-08-10 | 2008-02-20 | 河北医科大学 | Anticancer medicine composition and its application in preparing anticancer medicine |
| CN101186598A (en) * | 2007-12-11 | 2008-05-28 | 河北医科大学 | 1-oxy-acetyl inula Britannica lactone derivative, preparation method thereof and application of the same in preparing cancer-curing medicine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111635380A (en) * | 2020-06-17 | 2020-09-08 | 中国科学院昆明植物研究所 | Sesquiterpene in mugwort, pharmaceutical composition thereof, preparation method and application thereof |
| CN111704594A (en) * | 2020-06-17 | 2020-09-25 | 中国科学院昆明植物研究所 | Artemisia polyantha lactone A-S and Artemisia polyantha element A-G as well as pharmaceutical composition and application thereof |
| CN111635380B (en) * | 2020-06-17 | 2022-05-13 | 中国科学院昆明植物研究所 | Sesquiterpene in mugwort, pharmaceutical composition thereof, preparation method and application thereof |
| CN111704594B (en) * | 2020-06-17 | 2022-05-17 | 中国科学院昆明植物研究所 | Artemisia polyanthrene lactone A-S and Artemisia polyanthrin A-G as well as pharmaceutical composition and application thereof |
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| CN104557826B (en) | 2016-03-16 |
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