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WO2006025251A1 - Substances physiologiquement actives de biselide a, biselide b, et biselide c, processus de production, et utilisations - Google Patents

Substances physiologiquement actives de biselide a, biselide b, et biselide c, processus de production, et utilisations Download PDF

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Publication number
WO2006025251A1
WO2006025251A1 PCT/JP2005/015422 JP2005015422W WO2006025251A1 WO 2006025251 A1 WO2006025251 A1 WO 2006025251A1 JP 2005015422 W JP2005015422 W JP 2005015422W WO 2006025251 A1 WO2006025251 A1 WO 2006025251A1
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WO
WIPO (PCT)
Prior art keywords
biselide
biceride
pharmacologically acceptable
acceptable salt
physiologically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2005/015422
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English (en)
Japanese (ja)
Inventor
Hideo Kigoshi
Kiyotake Suenaga
Toshiaki Teruya
Kazuteru Fukasawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Kayaku Co Ltd
Original Assignee
Nippon Kayaku 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 Nippon Kayaku Co Ltd filed Critical Nippon Kayaku Co Ltd
Publication of WO2006025251A1 publication Critical patent/WO2006025251A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • 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 a novel biceride derivative useful as a pharmaceutical, particularly a cell growth inhibitor.
  • Non-Patent Document 1 as an anticancer agent, adriamycin, cisplatin, taquinol, vincristine and the like are known. However, many multidrug-resistant cancers that are resistant to these anticancer agents are also recognized, which is a therapeutic problem.
  • Patent Document 1 describes the growth inhibitory effect on cancer cells of a tridecanolide derivative isolated from marine organisms as a substance that inhibits cell division of sea urchin fertilized eggs. It has not been known whether it has a direct growth inhibitory effect on human cancer cells, especially solid cancers, and it has become a clinical problem! It was unknown.
  • Patent Document 1 Japanese Unexamined Patent Publication No. 2000-229977
  • Non-Patent Document 1 Shigeru Tsukagoshi, Transition of Cancer Chemotherapy, Cancer and Chemotherapy 26 Supplement 1, p. 23- 31 (1999)
  • An object of the present invention is to provide a novel cell growth inhibitor useful as a pharmaceutical, particularly as an anticancer agent.
  • Biceride C or a pharmacologically acceptable salt thereof, represented by
  • Biceride A a physiologically active substance represented by the following formula (III)
  • a bioactive substance biceride B represented by: or a bioactive substance biceride C according to (1), or a pharmacologically acceptable salt thereof, as an active ingredient,
  • bioactive substance bicelide A or biselide B having the following physical properties or the bicelide C described in (2) or a pharmacologically acceptable salt thereof is used as an active ingredient.
  • Biceride A, biceride B, or biceride C of the present invention, or a pharmacologically acceptable salt thereof, exhibits a cell growth inhibitory action, and is a chemical against cancer that exhibits anticancer agents, particularly multidrug resistance. It can be used as a therapeutic agent.
  • Biselide A, Biselide B, or Biselide C (hereinafter referred to as Biselides! /, U) of the present invention each have the above physical properties, and the above formula (1), formula ( ⁇ ), It is represented by formula (III).
  • Biselide A has a structure in which the primary hydroxyl group of Biselide C is converted to a acetoxy group, and
  • Biselide B has a carboxyl group of Biselide A converted to an ester group.
  • the bicerides of the present invention can be collected from marine animals that produce the bicerides.
  • Examples of marine animals that produce bicerides include squirts that are a kind of marine protozoa, preferably squirts of the family Didemnidae.
  • Bicerides are usually collected by methods such as adsorption chromatography, gel filtration chromatography, thin layer chromatography, high performance liquid chromatography. These can be isolated purely by combining them appropriately or by repeating them as necessary.
  • the pharmacologically acceptable salt is not particularly limited as long as it is a salt that can be usually taken.
  • the bicelides or pharmacologically acceptable salts of the present invention are used as pharmaceuticals, they may be used alone or mixed with pharmaceutically acceptable additives such as carriers, excipients, diluents, solubilizers and the like. It can be safely administered orally or parenterally (systemic administration, topical administration, etc.) in the form of powders, granules, tablets, caplets, capsules, injections, suppositories, ointments and the like.
  • the content of the compound of the present invention or a pharmaceutically acceptable salt in the preparation varies depending on the preparation, but is preferably 0.1 to LOO% by weight.
  • the dosage varies depending on the route of administration, the age of the patient, and the actual symptoms to be prevented or treated, but when administered orally to an adult, for example, the active ingredient is 1 to 0.01 mg to 2000 mg, preferably 0.01 mg to The dose can be 800 mg and can be divided into 1 to several times a day.
  • bicerides or their pharmacologically acceptable salts are adversely affected, various pharmaceutical additives used for pharmaceuticals, that is, carriers and other auxiliaries such as stabilizers, preservatives, Soothing agents, emulsifiers and the like may be used in the formulation.
  • the content of bicerides or their pharmacologically acceptable salts can be varied widely depending on the preparation form, etc., and is generally 0.01 to 100% (weight), preferably 0.1 to Contains 70% (by weight).
  • Drugs containing bicerides or pharmacologically acceptable salts thereof as active ingredients are preferably cell growth inhibitors or multidrug resistant cancer cell growth inhibitors, gastric cancer, lung cancer, colon cancer, spleen It is used as an anticancer agent used for cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, brain tumor, leukemia, etc., or an anticancer agent used for multidrug resistant cancer.
  • a 90% methanol extract (1.5 g) was subjected to silica gel column chromatography (silica gel 15. Og). After adsorption, the column was washed with 75 mL of Kuroguchi Form, and then the elution and separation of Chloform Form Z-Methanol was carried out sequentially with 75 mL of 20Z1 solution, 75 mL of ⁇ solution, 75 mL of 5Zl solution, 75 mL of 2Zl solution, and 200 mL of lZl solution to obtain 6 fractions. It was. The second elution fraction (536. 8 mg) was further subjected to ODS silica gel column chromatography using Cosmosil 75C18-OPN (10. Og). Separation with methanol Z hydraulic power S 60Z40 solution 30mL, 80,20 solution 30mL, 80/20 solution 30mL, and methanol 200mL gave 4 fractions.
  • the obtained second elution fraction (27. Omg) was subjected to high performance liquid chromatography using a Develosil ODS—HG-5 ( ⁇ 20 mm ⁇ 250 mm) column. Methanol Z water Z trifluoroacetic acid (70Z30Z0.1) was used as the solvent, and the flow rate was 5. OmL.
  • the eluate was detected by UV215 nm absorption. By purification three times, 1.2 mg of Biselide A (elution time 18.5 minutes) and 160 g of Biselide B (elution time 24.5 minutes) were obtained.
  • O-silica gel column chromatography using Cosmosil 75C18-OPN (33. Og) was performed using n-butanol extract (1.8 g). Methanol Z water was separated with 60Z40 solution 100mL, 80Z20 solution 100mL, 80,20 solution 100mL, and methanol 200mL to obtain 4 fractions.
  • the obtained first elution fraction (301.5 mg) was further subjected to ODS silica gel column chromatography using Cosmosil 75 C18-OPN (6. Og). Three fractions were obtained by separation by methanol / water 20/80 liquid 30mL, 80/20 liquid 30mL, and methanol / lOOmL.
  • the second elution fraction (80.4 mg) was obtained from Develosil ODS—HG— 5 ( Separation was performed by high performance liquid chromatography using a ⁇ 20 mm ⁇ 250 mm column. Methanol Z water Z trifluoroacetic acid (55Z45Z0.1) solution was used as the solvent, and the flow rate was 5. OmL Z min. The eluate was detected by UV215nm absorption. Purification was performed 5 times to obtain 1.9 mg of Viceride C (elution time 30.1 minutes).
  • RPMI1640 medium manufactured by Iwakine soil
  • 10% fetal calf serum manufactured by Moregate
  • MDA-MB-231 ATCC
  • human lung cancer cell NCI-H460 A TCC
  • the IC value is the cell strength without treatment with the drug. Absorbance obtained: C, the cell force without cell addition.
  • log (drug concentration) is the X axis
  • the growth inhibition rate at each drug concentration is the Y axis
  • the Y axis value is
  • biceride A, biselide B, and biselide C exhibited a cell growth inhibitory action on mammalian cancer cells.
  • Human breast cancer cell MDA MB-231, human lung cancer cell HOP 18 (ATCC), human lung cancer cell NCI—H460, or RPMI1640 medium (manufactured by Iwakine) supplemented with 10% fetal bovine serum (manufactured by Moregate) Human colon cancer cells DLD-1 (National Institutes of Health) at 37 ° C, 5% CO
  • MDA-MB-231 and NCI-H460 were seeded in the same number as in Experiment 1, HOP18 was seeded at 5000 per well, and DLD-1 was seeded at 2000 per well in a 96-well plate and cultured for 1 day.
  • Biceride C or adriamycin was added. After further culturing for 3 days, the cells were fixed with methanol and stained with methylene blue dye. After dyeing, the dye was extracted with 0.3% hydrochloric acid, the absorbance at 660 nm was measured, the IC value was determined by the above method, and the value is shown in Table 2.
  • mouse lymphocytic leukemia cell P388 (cancer research institute) or its adriamycin resistant strain P388ZADR (cancer research institute) was obtained at 37 ° C, 5% Cultured under CO. After seeding these cells in a 96-well plate and culturing for 1 day
  • Biceride A, Biceride B or Adriamycin were added. After further culturing for 2 days, 0.16 mg / mL WST-1 (Dojindo Laboratories) and 3.3 ⁇ g / mL 1-methoxy-5-methyl phenazinium methylsulfate (Dojindo Laboratories) ) was added to the culture and cultured for 4 hours. The value obtained by subtracting the absorbance at 660 nm from the absorbance at 450 nm was determined, and the IC value was determined by the above method. The values are shown in Table 2.
  • biselide A and biselide C have a cell growth inhibitory effect on mammalian cancer cells, and are also sensitive to multidrug resistant cancer cells (P388ZADR).
  • the cell growth inhibitory effect was almost the same.

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

Abstract

[PROBLÈMES] Cette invention concerne un nouvel agent anticancéreux efficace contre les cellules cancéreuses multiples pharmacorésistantes. [MOYEN DE RÉSOLUTION DES PROBLÈMES] Cette invention a pour objet une substance active de biselide C, représentée par la formule suivante (I): (I) ou un sel pharmaceutiquement acceptable de cette substance.
PCT/JP2005/015422 2004-09-01 2005-08-25 Substances physiologiquement actives de biselide a, biselide b, et biselide c, processus de production, et utilisations Ceased WO2006025251A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004254312A JP2006069947A (ja) 2004-09-01 2004-09-01 生理活性物質ビセライドａ、ビセライドｂ及びビセライドｃ、それらの製造法並びにそれらの用途
JP2004-254312 2004-09-01

Publications (1)

Publication Number Publication Date
WO2006025251A1 true WO2006025251A1 (fr) 2006-03-09

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Application Number Title Priority Date Filing Date
PCT/JP2005/015422 Ceased WO2006025251A1 (fr) 2004-09-01 2005-08-25 Substances physiologiquement actives de biselide a, biselide b, et biselide c, processus de production, et utilisations

Country Status (2)

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JP (1) JP2006069947A (fr)
WO (1) WO2006025251A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5555118A (en) * 1978-10-18 1980-04-22 Grelan Pharmaceut Co Ltd Anti-tumor substance and its preparation
JP2000229977A (ja) * 1999-02-09 2000-08-22 Sagami Chem Res Center トリデカノリド誘導体及び抗癌剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5555118A (en) * 1978-10-18 1980-04-22 Grelan Pharmaceut Co Ltd Anti-tumor substance and its preparation
JP2000229977A (ja) * 1999-02-09 2000-08-22 Sagami Chem Res Center トリデカノリド誘導体及び抗癌剤

Also Published As

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