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WO1999005135A1 - Composes polyophenoliques et medicaments a base de tels composes - Google Patents

Composes polyophenoliques et medicaments a base de tels composes Download PDF

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Publication number
WO1999005135A1
WO1999005135A1 PCT/JP1998/003272 JP9803272W WO9905135A1 WO 1999005135 A1 WO1999005135 A1 WO 1999005135A1 JP 9803272 W JP9803272 W JP 9803272W WO 9905135 A1 WO9905135 A1 WO 9905135A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
present
topoisomerase
compounds
Prior art date
Application number
PCT/JP1998/003272
Other languages
English (en)
Japanese (ja)
Inventor
Hiroshi Nozaki
Munekazu Iinuma
Masashi Yamada
Yukie Suma
Original Assignee
Meiji Milk Products Co., Ltd.
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 Meiji Milk Products Co., Ltd. filed Critical Meiji Milk Products Co., Ltd.
Publication of WO1999005135A1 publication Critical patent/WO1999005135A1/fr

Links

Classifications

    • 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
    • C07D307/93—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 condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel plant-derived polyfuninol compound and a medicament represented by an antitumor agent containing the same.
  • plants are known to contain various physiologically active substances.
  • alloids such as vinplastin and pinklistin, corsemide of a cohachytin analog, camptothecin derivative CPT-1 It is known that 1st class has an antitumor effect.
  • An object of the present invention is to provide a novel plant-derived compound useful as a medicament. Disclosure of the invention
  • the present inventors focused on topoisomerase II, and aimed at finding a drug that exerts an antitumor effect by acting on the topoisomerase II to inhibit the distribution (M phase) of DNA whose replication has been completed.
  • topoisomerase II Upon searching for plant extract components, they found that three types of polyphenol compounds isolated from a plant of the family Calyptaceae had an excellent inhibitory activity against topoisomerase II and were useful as an antitumor agent, and completed the present invention.
  • the present invention provides compounds nepalencinol A, B and C represented by the following formula, or salts thereof.
  • the present invention also provides a medicine containing the above compound or a salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or a salt thereof, and a pharmaceutically acceptable carrier.
  • the above-mentioned compound of the present invention can be obtained by extracting and isolating from the plant of the family Acalyptaceae.
  • the plants used in the family Calarigaceae include bearded balsam (Kobresia), beetle (Mal tif ol ia), balsam (Morrowi i), balsam (Fol iosi ssima), balsam (Thunbergi i) (Reini i), and kenyu ganefu (Ci 1 iato-morginata).
  • the extraction site is not particularly limited, and one or two or more sites (hereinafter, referred to as “the original material”) among the fruits, pericarp, bark, root bark, leaves, root materials, and the like of these plants are used.
  • the extraction method is not particularly limited, either, and the extraction can be performed by extracting from these raw materials with a solvent and isolating.
  • the drug substance is cut into small pieces, dried and pulverized, extracted with an organic solvent such as benzene, ethyl acetate, methanol, and acetone, and concentrated under reduced pressure to obtain an extract.
  • the extract can be purified by recrystallization, silica gel column chromatography, etc. to isolate the components.
  • it can be used in the middle of the above extraction operation, for example, in the stage of extraction extract.
  • the compound of the present invention or a salt thereof is useful as an antitumor agent because it exhibits an excellent inhibitory activity against topoisomerase II.
  • the medicament of the present invention can be administered either orally or parenterally (intramuscularly, subcutaneously, intravenously, suppositories, etc.).
  • parenterally intramuscularly, subcutaneously, intravenously, suppositories, etc.
  • the compound of the present invention or a salt thereof and various pharmaceutically acceptable carriers can be blended to prepare a pharmaceutical composition.
  • excipients When preparing oral preparations, excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. are added, and then tablets, coated tablets, and granules are prepared in a conventional manner.
  • Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbitol, microcrystalline cellulose, and the like.
  • Shellac hydroxypropylcellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like.
  • Disintegrators include, for example, starch, agar, gelatin powder, crystalline cellulose, carbonated calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc.
  • Lubricants include, for example, magnesium stearate, talc, polyethylene Glycols, silica, hydrogenated vegetable oils, etc. are permitted to be added to pharmaceuticals as coloring agents, but flavoring agents such as cocoa powder, heart-strength, aromatic acid, heart-strength oil, dragon brain, cinnamon powder Are used. Of course, these tablets can be sugar-coated, gelatin-coated, and optionally coated as needed.
  • a pH adjuster, a buffer, a stabilizing agent, a preservative, and the like are added as necessary, and a subcutaneous, intramuscular, or intravenous injection is prepared by a conventional method.
  • the injection may be prepared as a solid preparation by freeze-drying or the like after storage of the solution in a container, and may be prepared at the time of use.
  • One dose may be stored in a container, or multiple doses may be stored in the same container.
  • the dose of the medicament of the present invention is usually from 0.01 to 100 mg / day, preferably from 0.1 to 100 mg / day for an adult in the case of human as nepalencinol A, B or C. .
  • the dosage is usually 0.1 mg / kg of the animal to be treated.
  • the range is from 0.1 to 100 mg, preferably from 0.1 to 100 mg. This daily dose
  • the balmwort (Kobresia) of the family Amarantidae was washed with water, air-dried, pulverized, and extracted with methanol.
  • the solvent is distilled off from the methanol extract under reduced pressure, and the obtained residue is fractionated into n-hexane, ethyl acetate and butanol-soluble parts.
  • the obtained ethyl acetate-soluble part is Kieselgel 60 (Merck).
  • the mixture was subjected to silica gel column chromatography packed with, and then subjected to ODS medium pressure ram chromatography and preparative column chromatography to obtain nepalencinol A7Omg.
  • Topoisomerase 11 (Top GEN, Inc) was diluted with Nuclear extration buffer to 0.75 unit /.
  • the reaction amount of the enzyme was quantified by digitizing the band density of the agarose gel using the Macros (Gel Plotting Macros) attached to the NIH Image Computer.
  • the minicircle DNA band was loaded into a computer, quantified and calculated to obtain the residual activity rate (%). Table 1 shows the results.
  • the compound of the present invention exhibits excellent topoisomerase II inhibitory activity and is useful as an antitumor agent.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Furan Compounds (AREA)

Abstract

La présente invention concerne, d'une part des néparensinols A, B et C, et d'autre part des médicaments où ces néparensinols interviennent comme principe actif. Ces composés, de par leur action inhibitrice vis-à-vis de la topoisomérase II, conviennent particulièrement comme agents antinéoplastiques.
PCT/JP1998/003272 1997-07-22 1998-07-22 Composes polyophenoliques et medicaments a base de tels composes WO1999005135A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9195779A JPH1135569A (ja) 1997-07-22 1997-07-22 ポリフェノール化合物及びこれを含有する医薬
JP9/195779 1997-07-22

Publications (1)

Publication Number Publication Date
WO1999005135A1 true WO1999005135A1 (fr) 1999-02-04

Family

ID=16346833

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/003272 WO1999005135A1 (fr) 1997-07-22 1998-07-22 Composes polyophenoliques et medicaments a base de tels composes

Country Status (2)

Country Link
JP (1) JPH1135569A (fr)
WO (1) WO1999005135A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8143408B2 (en) 2007-04-23 2012-03-27 Astrazeneca Ab N-(8-heteroaryltetrahydronaphtalene-2yl) or N-(5-heteroarylchromane-3-yl) carboxamide derivatives for the treatment of pain

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009107928A (ja) * 2006-02-27 2009-05-21 Meiji Milk Prod Co Ltd パウ・フェロから単離された新規化合物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KAWABATA J., ET AL.: "KOBOPHENOL A, A UNIQUE TETRASTILBENE FROM CAREX KOBOMUGI OHWI (CYPERACEAE).", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 30., no. 29., 1 January 1989 (1989-01-01), GB, pages 3785 - 3788., XP002912921, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(01)80655-9 *
KULANTHAIVEL P., ET AL.: "NATURALLY OCCURRING PROTEIN KINASE C INHIBITORS; II. ISOLATION OF OLIGOMERIC STILBENES FROM CARAGANA SINICA.", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 61., no. 01., 1 January 1995 (1995-01-01), JP, pages 41 - 44., XP002912920, ISSN: 0009-2363 *
OHYAMA M., ET AL.: "PHENOLIC COMPOUNDS ISOLATED FROM THE ROOTS OF SOPHORA STENOPHYLLA.", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 46., no. 04., 1 April 1998 (1998-04-01), JP, pages 663 - 668., XP002912918, ISSN: 0009-2363 *
OSHIMA Y., ET AL.: "AMPELOPSINS D, E, H AND CIS-AMPELOPSIN E, OLIGOSTILBENES FROM AMPELOPSIS BREVIPEDUNCULATA VAR. HANCEI ROOTS.", PHYTOCHEMISTRY, PERGAMON PRESS, GB, vol. 33., no. 01., 1 January 1993 (1993-01-01), GB, pages 179 - 182., XP002912919, ISSN: 0031-9422, DOI: 10.1016/0031-9422(93)85418-Q *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8143408B2 (en) 2007-04-23 2012-03-27 Astrazeneca Ab N-(8-heteroaryltetrahydronaphtalene-2yl) or N-(5-heteroarylchromane-3-yl) carboxamide derivatives for the treatment of pain

Also Published As

Publication number Publication date
JPH1135569A (ja) 1999-02-09

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