WO2001023384A1 - Agents antitumoraux - Google Patents

Agents antitumoraux Download PDF

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Publication number
WO2001023384A1
WO2001023384A1 PCT/JP2000/006655 JP0006655W WO0123384A1 WO 2001023384 A1 WO2001023384 A1 WO 2001023384A1 JP 0006655 W JP0006655 W JP 0006655W WO 0123384 A1 WO0123384 A1 WO 0123384A1
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WO
WIPO (PCT)
Prior art keywords
compound
cancer
antitumor
extract
present
Prior art date
Application number
PCT/JP2000/006655
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English (en)
Japanese (ja)
Inventor
Keiji Wakabayashi
Hajime Komatsu
Original Assignee
Japan As Represented By Director General Of Agency Of National Cancer Center
The Organization For Pharmaceutical Safety And Research
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 Japan As Represented By Director General Of Agency Of National Cancer Center, The Organization For Pharmaceutical Safety And Research filed Critical Japan As Represented By Director General Of Agency Of National Cancer Center
Priority to JP2001526536A priority Critical patent/JP4769959B2/ja
Priority to AU74460/00A priority patent/AU7446000A/en
Publication of WO2001023384A1 publication Critical patent/WO2001023384A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an antitumor agent and a novel phenanthroindrididine alkyloid compound having a cancer cytotoxic activity.
  • An object of the present invention is to provide an antitumor agent containing an insect-derived natural ingredient as an active ingredient.
  • an object of the present invention is to provide a novel compound having an insect-derived cancer cytotoxic activity, and a medicament containing the compound as an active ingredient.
  • the present inventors have conducted intensive studies to detect useful substances from natural products.
  • the extract of Ideopsis (Ideopsis) belonging to the family Amarantidae, which feeds on Tylophora tanakae, a potato family plant has been found.
  • a remarkable cancer cytotoxic activity at a dilution of 100,000.Furthermore by purifying the fractions of the extract, a novel compound having a cancer cytotoxic activity, fenanthroindolizidine alkyloid, was obtained.
  • the compounds constituting the present invention are clearly derived from insects, Specifically, the present invention relates to the following antitumor agents, novel compounds having antitumor activity, and pharmaceutical compositions containing the compounds as active ingredients.
  • An antitumor agent comprising, as an active ingredient, a phenanthroindolizidine alkyloid compound represented by the following general formula (1).
  • a pharmaceutical composition c containing the compound according to [2] as a main component The present invention also relates to the use of the compound represented by the general formula (1) in the production of an antitumor agent. Alternatively, the present invention relates to the use of a compound represented by the general formula (1) in the treatment of a tumor. Furthermore, the present invention relates to the use of 3-demethyltyloforinine represented by the structural formula (1) in the production of a pharmaceutical composition.
  • the compound used as an active ingredient in the antitumor agent of the present invention is an organic solvent extract of Ryukyu Asagi Madara of the family Paragonidae.
  • a production method using Ryukyu Asagi Madara pupas as a starting material is shown below.
  • Ryukyu Asagi cod pupae are ground or powdered prior to extraction.
  • Ultrasonic treatment or the like can be used for pulverization.
  • This is extracted with an organic solvent such as methanol.
  • the extraction method may be a commonly used method, for example, a method of immersing a crushed Ryukyu Asagida pupa in an organic solvent for a long time, heating and stirring at a temperature below the boiling point of the organic solvent, and performing extraction.
  • the obtained extract is concentrated under reduced pressure to obtain an organic solvent extract.
  • the organic solvent extract is dissolved in water, extracted with a hydrophobic organic solvent such as hexane and defatted.
  • the aqueous layer is made acidic (pH 2) by adding concentrated hydrochloric acid, and washed with an organic solvent such as ethyl acetate. Further, the aqueous layer is made basic (pH 9) with aqueous ammonia and extracted with an organic solvent such as ethyl acetate.
  • hydrophobic organic solvent used in the degreasing step examples include hydrocarbons such as pentane, hexane, heptane, and cyclohexane.
  • Organic solvents used in the extraction step include lower fatty acid esters such as methyl acetate, ethyl acetate, and butyl acetate; lower alcohols such as methanol, ethanol, and isopropanol; and methyl ether, ethyl ether, tetrahydrazine, and dioxane.
  • ком ⁇ онентs such as acetone and methyl ethyl ketone, or aromatic hydrocarbons such as toluene and benzene, or halogenated hydrocarbons such as dichloromethane and chloroform.
  • a solvent and a mixed solvent of a hydrophilic solvent and a hydrophobic solvent can also be used.
  • the target compound is contained in this basic fraction. From the fraction extracted with the organic solvent, the compound is separated and purified by high performance liquid chromatography (hereinafter abbreviated as HPLC).
  • HPLC high performance liquid chromatography
  • a reversed-phase chromatography filler such as 0DS, octyl, phenyl, and cyanoprobe, and an adsorption chromatography filler such as silica gel
  • the conditions that can be used general conditions using 0DS as a carrier and a water-soluble organic solvent such as acetonitrile, methanol, tetrahydrofuran and water, or a mixed solvent of a buffer solution can be used. It is preferable to use a mixed solvent.
  • the fraction of the column containing the target compound can be further purified by repeating preparative HPLC using a 0DS column and aqueous acetonitrile. In this way, the compound described as the general formula of claim 1 which finally gives a single peak in the analysis by HPLC can be isolated.
  • the HPLC profile of each compound is as shown in the examples.
  • a compound having an antitumor activity revealed by the present invention can also be chemically synthesized based on its structural information.
  • diarylhexahydroindolizines (3) have been synthesized through the reaction of benzoylacetic acid (1) derived from phenylalanine with topiroline (2).
  • This compound has been reported to be a biosynthetic precursor for tylophorin (R. B. Herbert, et al., J. Chem. Soc. Perkin I, 1984, 825-831 .; R. B. Herbert, et al., J. Chem. Soc. Chem. Co., 1977, 955-956 .;
  • Equation (2) shows a series of synthesis steps.
  • R, Rl, and R2 each represent a hydroxyl group or a methoxy group bonded to one or more substitutable positions
  • R3 represents a hydroxyl group or a hydrogen atom.
  • the cancer cytotoxic activity of the present compound obtained by the above method can be measured by a known method.
  • the cytotoxic effect can be measured by WST-1 assay (manufactured by Dojindo Co., Ltd.) using human gastric cancer cells TMK-1.
  • WST-1 assay manufactured by Dojindo Co., Ltd.
  • the cytotoxic activity of the antitumor agent provided by the present invention can be evaluated.
  • the cytotoxic effect of the antitumor agent of the present invention is comparable to, for example, Taxol, a cancer chemotherapeutic agent currently in practical use. That is, it can be said that the antitumor activity of the antitumor agent of the present invention is extremely excellent.
  • the compounds that could be confirmed to have antitumor activity in the present invention showed efficacy on a wide range of tumor cells. Therefore, these compounds can be expected as antitumor agents having a broad action spectrum.
  • the present invention relates to a novel 3-demethyltylophorinine represented by the formula (1). Furthermore, the present invention relates to a pharmaceutical composition containing 3-demethyltyrofurinine as an active ingredient (1)
  • the compound found to have antitumor activity in the present invention can be made into an antitumor agent or a pharmaceutical composition by using a known formulation technique. That is, an antitumor agent or a pharmaceutical composition can be obtained by blending these compounds with a pharmaceutically acceptable excipient.
  • the compounds of the present invention can be administered to animals and humans as they are or together with conventional pharmaceutical carriers.
  • the administration form is not particularly limited, and is appropriately selected and used as needed. Specific examples include oral preparations such as tablets, capsules, granules, fine granules and powders, and parenteral preparations such as injections and suppositories.
  • Oral preparations are manufactured according to a conventional method using excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
  • excipients such as starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, and inorganic salts.
  • binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used.
  • the compounds of the present invention can also be administered as suspensions, emulsions, syrups, and elixirs. These various forms may contain flavoring agents and coloring agents.
  • Parenteral preparations are manufactured according to the usual methods, and are generally used as diluents such as distilled water for injection, physiological saline, aqueous solution of pudose, vegetable oil for injection, sesame oil, laccase oil, soybean oil, corn oil, propylene glycol, and polyethylene glycol. Etc. can be used. If necessary, bactericides, preservatives and stabilizers may be added.
  • Other parenteral preparations include liquid preparations for external use, ointments such as ointments, suppositories for rectal administration, and the like, and are produced according to a conventional method.
  • the content of the active ingredient in the antitumor agent or the pharmaceutical composition according to the present invention can be appropriately adjusted so as to give a required dose by a selected administration route. .
  • the usual dosage is 0.01 g to lmg, preferably 0.01 g to 0.1 mg, more preferably 0.1 g to 0.1 mg / kg of body weight. 0 lm can be indicated.
  • the final dose is appropriately adjusted in consideration of the weight, age, sex, symptoms, etc. of the patient to be administered.
  • FIG. 1 is a diagram showing the steps of obtaining extracts from Ryukyu Asagi Madara pupae, and the ratio of cancer cytotoxic activity of each extract.
  • FIG. 2 is a view showing an HPLC profile of a basic fraction of an extract from Ryukyu Asagi Madara pupae, an adult, and a turmoulinka.
  • the horizontal axis represents the retention time (minutes), and the vertical axis represents the HPLC signal (absorbance at 254 nm).
  • the Ryukyu Asagi Madara pupa used was collected from Ishigaki Island and purchased from Hiroshima Mikado Co., Ltd.
  • Five Ryukyu Asagi Madara pupae (2.8 g) were homogenized, sonicated three times for 20 minutes at room temperature, and extracted with methanol (40 ml). The solution was concentrated under reduced pressure to obtain 0.2 g of a methanol extract. The residue was dissolved in water and extracted with n-hexane. Subsequently, concentrated hydrochloric acid was added to the aqueous layer (pH 2), and the mixture was extracted with 10 ml of ethyl acetate.
  • the aqueous layer was made alkaline (pH 9) with aqueous ammonia and extracted three times with ethyl acetate.
  • the cancer cytotoxic activity was examined.
  • TMK-1 human gastric cancer cell TMK-1 was used.
  • Cells in a confluent state were collected after trypsinization and diluted to 5 ⁇ 10 4 cells / ml in Eagle's medium (Gibco BRL, Gaithersburg, MD) containing 10% fetal calf serum. 100 1 of the cell suspension was dispensed into gels on a 96-well plate and diluted extract samples were added.
  • the IC5 ⁇ ) value of the methanol extract was 107 ng / ml. 87% of the cancer cytotoxic activity was enriched in the basic fraction.
  • Isolated compound A (wherein X is a hydrogen atom in the formula of the general formula (1) described in the claims; hereinafter abbreviated as compound A); In the formula of the general formula (1), X is a methoxy group; hereinafter, abbreviated as compound B) has a cancer cytotoxic activity of IC 5 .
  • the values were 0.5 and 0.7 ng / ml, respectively.
  • each fraction was evaluated for cancer cytotoxicity.
  • the basic fraction showing the cancer cytotoxic activity was analyzed on a 0DS column (Shiseido Capsell Pak C18, 4.6 ⁇ 250) with a gradient solvent system of acetonitrile in 20 mM potassium dihydrogen phosphate buffer. Separated by HPLC on Shiseido Co., Ltd. (linear gradient of 10 to 25% from 0 to 80 minutes) (flow rate: 1 ml / min, UV: 254 im). Significant cancer cytotoxicity was observed in the fraction with a retention time of 30-34 minutes (Peak I) and 34-38 minutes (Peak I I).
  • the respective cancer cytotoxic activities corresponding to peaks I and II were 34 and 34%, respectively, of the total cancer cytotoxicity by HPLC hair ply.
  • sonication was performed three times for 20 minutes at room temperature and extracted with 200 ml of methanol.
  • the methanol extract was treated with n-hexane, acid, and base as described above.
  • the basic fraction 38.7 nig was purified by HPLC on the same gradient solvent system.
  • Compounds A (2.2 mg) and B (3.7 mg) were isolated by selecting peaks I and a fraction containing II in the HPLC profile (FIG. 2).
  • FIG. 1 shows the extraction process and the ratio of the cancer cytotoxic activity of each extract.
  • Compound A was isolated as fine, colorless crystals, and was estimated to have a phenolic hydroxyl group by TLC test using iron (II) chloride.
  • the UV spectrum of Compound A showed the absorbance of 259, 285, and 314 dishes attributable to the phenanthroindolizidine scaffold.
  • Compound A cation EI-MS showed a molecular ion peak at m / z 365 (M) +.
  • the m / z 296 (M-69) + fragment ion peak generated by the retro Diels Alder reaction which is characteristic of the phenanthroindolizidine alkaloids, and the m / z 70 reference peak corresponding to the pyrrolidine ring It was observed.
  • Compound A was determined to be 3-demethyltyrofurinine (3,14-dihydroxy-6, 7-dimethylthioxyphenanthroindo 1 izidine) having the following structural formula (1). This compound is a new compound.
  • Compound B was isolated as pale yellow fine crystals, and was estimated to have a phenolic hydroxyl group by TLC test using iron (II) chloride.
  • the UV spectrum of Compound B showed absorbance at 261 and 319 nm and was very similar to Compound A.
  • Compound B cation EI-MS showed a molecular ion peak at m / z 395 (M) + .
  • an m / z 326 (M-69) + fragment ion peak and an m / z 70 reference peak were observed. These fragments characterized the phenanthroindolizidine skeleton and suggested the presence of a C-14 hydroxyl group.
  • the physicochemical and spectral properties of the compound of the present invention are as follows.
  • A549 lung cancer cell line
  • DLD-1 colonal cancer cell line
  • K556 leukemia cell line
  • Hela cervical cancer cell line was obtained from RIKEN Cell Bank (Tsukuba, Japan).
  • IC 5 when compound A was used as test compound were 0.4 for A549 (lung cancer cell line), 0.5 for DLD-1 (colorectal cancer cell line), 0.8 for Hela (cervical cancer cell line), and 0.4 for K562 (leukemia cell line). Indicated.
  • IC 5 of compound B. (ng / ml) values were 0.5 for A549 cancer cells, 0.8 for DLD-1, 1.0 for Hela, and 0.5 for K562.
  • the present invention has provided a novel antitumor agent containing, as an active ingredient, a compound derived from an insect, for which an attempt has not been made to search for an antitumor compound.
  • the present invention is novel in that it has found an antitumor activity in a new structure, and has great significance in reporting a new structure in which antitumor activity can be expected.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des agents antitumoraux contenant comme ingrédient actif des alcaloïdes phénan-throindolizidines représentés par la formule (1), d'origine Ideopsis similis. X représente hydrogène ou méthoxy CH3O.
PCT/JP2000/006655 1999-09-27 2000-09-27 Agents antitumoraux WO2001023384A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2001526536A JP4769959B2 (ja) 1999-09-27 2000-09-27 抗腫瘍剤
AU74460/00A AU7446000A (en) 1999-09-27 2000-09-27 Antitumor agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP27337099 1999-09-27
JP11/273370 1999-09-27

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WO2001023384A1 true WO2001023384A1 (fr) 2001-04-05

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005530691A (ja) * 2002-02-15 2005-10-13 エール ユニヴァーシティ 新規なチロインジシンとその関連プロセス、薬学的組成物および方法
EP1604990A1 (fr) * 2004-06-11 2005-12-14 National Health Research Institutes Alkaloides de Phenanthroindolizidine
EP1968975A2 (fr) * 2006-01-05 2008-09-17 The University of North Carolina at Chapel Hill Analogues de tylophorine utilisés comme agents antitumoraux
WO2010047126A1 (fr) 2008-10-23 2010-04-29 株式会社ヤクルト本社 DÉRIVÉ DE PHÉNANTHROINDOLIZIDINE ET INHIBITEUR DE NFκB LE CONTENANT EN TANT QUE PRINCIPE ACTIF
WO2010047127A1 (fr) 2008-10-23 2010-04-29 株式会社ヤクルト本社 COMPOSÉ DE PHÉNANTHROINDOLIZIDINE ET INHIBITEUR DE NFκB LE CONTENANT EN TANT QUE PRINCIPE ACTIF
CN101189968B (zh) * 2006-11-23 2011-06-01 南开大学 菲并吲哚里西啶和菲并喹喏里西啶衍生物及其盐在农药上的应用
CN103446211A (zh) * 2013-09-24 2013-12-18 兰州理工大学 一种牛心朴子总生物碱及其制备方法和应用
JP2014512400A (ja) * 2011-04-29 2014-05-22 インダストリアル テクノロジー リサーチ インスティテュート 関節炎治療用のキナンクム属植物抽出物およびそれに含まれる有効成分
CN103880839A (zh) * 2009-03-03 2014-06-25 中国医学科学院药物研究所 13a-(S)去氧娃儿藤宁衍生物、其药物组合物与用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ABE FUMIKO ET AL.: "Further investigation of phenanthroindolizidine alkaloids from tylophora tanakae", CHEM. PHARM. BULL., vol. 46, no. 5, 1998, pages 767 - 769, XP002935110 *
HERBERT R.B. ET AL.: "Biosynthesis of phenanthroindolizidine alkaloids: Incorporation of 2-pyrrolidin-2-ylacetophenone and benzoylacetic acid and derivatives", J. CHEM. SOC. PERKIN TRANS. I, 1984, pages 825 - 831, XP002935112 *
NARASIMHA RAO K. ET AL.: "Thymidylate synthase activity in leukocytes from patients with chronic myelocytic leukemia and acute lymphocytic leukemia and its inhibition by phenanthroindolizidine alkaloids pergularinine and tylophorinidine", CANCER LETT., vol. 128, no. 2, 1998, pages 183 - 188, XP002935111 *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005530691A (ja) * 2002-02-15 2005-10-13 エール ユニヴァーシティ 新規なチロインジシンとその関連プロセス、薬学的組成物および方法
EP1604990A1 (fr) * 2004-06-11 2005-12-14 National Health Research Institutes Alkaloides de Phenanthroindolizidine
US7332502B2 (en) 2004-06-11 2008-02-19 National Health Research Institutes Phenanthroindolizidine alkaloids
US7652027B2 (en) 2004-06-11 2010-01-26 National Health Research Institutes Phenanthroindolizidine alkaloids
EP1968975A2 (fr) * 2006-01-05 2008-09-17 The University of North Carolina at Chapel Hill Analogues de tylophorine utilisés comme agents antitumoraux
EP1968975A4 (fr) * 2006-01-05 2009-03-25 Univ North Carolina Analogues de tylophorine utilisés comme agents antitumoraux
US8188089B2 (en) 2006-01-05 2012-05-29 The University Of North Carolina At Chapel Hill Tylophorine analogs as antitumor agents
CN101189968B (zh) * 2006-11-23 2011-06-01 南开大学 菲并吲哚里西啶和菲并喹喏里西啶衍生物及其盐在农药上的应用
KR20110081199A (ko) * 2008-10-23 2011-07-13 가부시끼가이샤 야구르트혼샤 페난트로인돌리지딘 화합물 및 이것을 유효 성분으로 하는 ＮＦκＢ 저해제
US9174979B2 (en) 2008-10-23 2015-11-03 Kabushiki Kaisha Yakult Honsha Phenanthroindolizidine compound and NFκB inhibitor containing same as active ingredient
WO2010047127A1 (fr) 2008-10-23 2010-04-29 株式会社ヤクルト本社 COMPOSÉ DE PHÉNANTHROINDOLIZIDINE ET INHIBITEUR DE NFκB LE CONTENANT EN TANT QUE PRINCIPE ACTIF
WO2010047126A1 (fr) 2008-10-23 2010-04-29 株式会社ヤクルト本社 DÉRIVÉ DE PHÉNANTHROINDOLIZIDINE ET INHIBITEUR DE NFκB LE CONTENANT EN TANT QUE PRINCIPE ACTIF
US8569327B2 (en) 2008-10-23 2013-10-29 Kabushiki Kaisha Yakult Honsha Phenanthroindolizidine derivative and NFκB inhibitor containing same as active ingredient
KR101708512B1 (ko) 2008-10-23 2017-02-20 가부시키가이샤 야쿠르트 혼샤 페난트로인돌리지딘 유도체 및 이것을 유효 성분으로 하는 ＮＦκＢ 저해제
KR101708511B1 (ko) 2008-10-23 2017-02-20 가부시키가이샤 야쿠르트 혼샤 페난트로인돌리지딘 화합물 및 이것을 유효 성분으로 하는 ＮＦκＢ 저해제
KR20110079661A (ko) * 2008-10-23 2011-07-07 가부시끼가이샤 야구르트혼샤 페난트로인돌리지딘 유도체 및 이것을 유효 성분으로 하는 ＮＦκＢ 저해제
JP5583590B2 (ja) * 2008-10-23 2014-09-03 株式会社ヤクルト本社 フェナンスロインドリジジン化合物及びこれを有効成分とするＮＦκＢ阻害剤
CN102186850B (zh) * 2008-10-23 2014-10-29 株式会社益力多本社 菲骈吲哚里西定衍生物和将其作为有效成分的NFκB抑制剂
CN103880839A (zh) * 2009-03-03 2014-06-25 中国医学科学院药物研究所 13a-(S)去氧娃儿藤宁衍生物、其药物组合物与用途
US9549958B2 (en) 2011-04-29 2017-01-24 Industrial Technology Research Institute Extracts of Cynanchum sp. and active ingredients contained therein in use of arthritis treatment
JP2014512400A (ja) * 2011-04-29 2014-05-22 インダストリアル テクノロジー リサーチ インスティテュート 関節炎治療用のキナンクム属植物抽出物およびそれに含まれる有効成分
CN103446211A (zh) * 2013-09-24 2013-12-18 兰州理工大学 一种牛心朴子总生物碱及其制备方法和应用

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AU7446000A (en) 2001-04-30

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