WO1998029404A1 - Derive de benzopyranne obtenu a partir de propolis - Google Patents

Derive de benzopyranne obtenu a partir de propolis Download PDF

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Publication number
WO1998029404A1
WO1998029404A1 PCT/JP1996/003860 JP9603860W WO9829404A1 WO 1998029404 A1 WO1998029404 A1 WO 1998029404A1 JP 9603860 W JP9603860 W JP 9603860W WO 9829404 A1 WO9829404 A1 WO 9829404A1
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WO
WIPO (PCT)
Prior art keywords
solvent
derivative represented
extract
salt
benzovirane
Prior art date
Application number
PCT/JP1996/003860
Other languages
English (en)
Japanese (ja)
Inventor
Tetsuya Matsuno
Yasuyuki Matsumoto
Junji Morikawa
Masahiro Saito
Original Assignee
Eiken Kagaku Kabushiki Kaisha
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
Priority to JP7329583A priority Critical patent/JPH09143179A/ja
Application filed by Eiken Kagaku Kabushiki Kaisha filed Critical Eiken Kagaku Kabushiki Kaisha
Priority to PCT/JP1996/003860 priority patent/WO1998029404A1/fr
Priority to AU11526/97A priority patent/AU1152697A/en
Publication of WO1998029404A1 publication Critical patent/WO1998029404A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • 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 provides a compound represented by the following chemical formula (I):
  • Antineoplastic agents used to treat cancer are broadly classified into chemotherapeutic agents and immunotherapy agents.
  • Chemotherapeutic agents are used not only for unresectable cancers, but also in combination with surgery, given before and after surgery.
  • cancer chemotherapeutics include alkylating agents (nitrogen mustards, ethyleneimines, sulfonic esters, etc.), antimetabolites (folate antagonists, pyrimidine antagonists, etc.), plant fission toxins (colsemi) , Vinblastine, etc.), antibiotics (sarcomycin, carcinophylline, mitomycin, etc.), hormonal agents (adrenocortical steroids, male hormones, female hormones, etc.), and porphyrin complex salts (morphophilin, copp) etc. Used on the floor.
  • chemotherapeutic agents are often cytotoxic substances and not only attack cancer cells, but also act on normal cells, and generally have strong side effects. For example, side effects such as vomiting, nausea, anorexia, malaise, neuropathy, myelopathy (leukopenia), hair loss, and stomatitis may be seen. Therefore, caution is required for long-term administration.
  • Immunotherapeutic agents are mainly immunostimulants, which increase the immunity to cause immune response cells to recognize cancer cells as foreign and treat them. However, immunostimulants have few side effects, but generally have mild antitumor effects and are often used as adjuvant therapy.
  • antitumor agents have advantages and disadvantages. Therefore, development of an antitumor agent which has high antitumor activity, has few side effects, and can be administered for a long time has been desired. In addition, since antitumor agents are generally expensive, it is also desirable that they be supplied at low cost in order to reduce the economic burden on patients.
  • Propolis which is used as a folk remedy, is a resinous substance that is a mixture of vegetation collected by bees and saliva, honey, pollen, etc., and has a pharmacological action such as antibacterial action and anti-inflammatory action. It has been known. It is also known that drinking propolis as a dietary supplement has an antitumor effect, and attempts have been made to extract and purify an antitumor active substance from propolis (Japanese Patent Application Laid-Open No. 5-58943, Japanese Patent Application Laid-Open No. Heisei 5-58943). -271031, No. 7-330596), anti-tumor effect has been recognized in the extract. Disclosure of the invention
  • the present inventors conducted extraction and purification from propolis in order to find a novel physiologically active substance having an antitumor effect, and obtained a compound of the formula (I)
  • the present invention provides a novel benzovirane derivative, and provides an antitumor agent containing the same as a main component. Further, the present invention provides a method for producing a benzopyran derivative from propolis.
  • a pharmaceutical composition comprising, as an active ingredient, a benzovirane derivative represented by the above formula (I) or a salt thereof;
  • a pharmaceutical composition for treating or preventing a tumor comprising a benzopyran derivative represented by the above formula (I) or a salt thereof as an active ingredient;
  • the salts of the benzopyran derivative in the above [1] to [5] include pharmaceutically acceptable salts.
  • the column used in step (2) is for high performance liquid chromatography, and a commercially available 0DS silica gel column can be used for the reversed phase column.
  • the ODS 80TM column manufactured by Tosoichi
  • the column used in step (3) is for high-performance liquid chromatography, and a commercially available Inertsil-based column can be used as the adsorption column.
  • SIL columns manufactured by L-Science are preferred.
  • the column used in step (4) is a high-performance liquid
  • a commercially available GPC column can be used as a molecular sieve column for mouth chromatography, and in this application, a Shodex GPC-H2000 column (manufactured by Showa Denko KK) equilibrated with a chromatophore form is particularly preferred.
  • the benzopyran derivative of the present invention has an antitumor cell effect on tumor cells as shown in the examples, it is possible to obtain an extremely effective antitumor effect, that is, an effect of treating or preventing a tumor by administering it in various modes. It is thought to show.
  • the method of administering the compound may be parenteral or oral, and the composition administered may include a therapeutically effective amount of the compound and a pharmacologically acceptable diluent, stabilizer, or excipient. Etc. are contained.
  • the administration form include intravenous injection, subcutaneous injection, intramuscular injection, parenteral administration such as suppositories and ointments, and oral administration using tablets, powders, capsules, granules and the like.
  • propolis extracts are known to have antibacterial, antioxidant, anti-inflammatory, virus growth inhibitory, macrophage activating, antitumor, and hair-growth effects (Japanese Patent Laid-Open No. 5-271031, These effects can also be expected from the benzopyran derivative of the present invention extracted from propolis. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a diagram showing a mass spectrum of a benzopyran derivative.
  • FIG. 2 is a diagram showing a 1 H-NMR spectrum of a benzopyran derivative. BEST MODE FOR CARRYING OUT THE INVENTION
  • propolis 100 g was mixed with 10 volumes of 99.5% ethanol, and the mixture was stirred at room temperature using a magnetic mixer. The resulting suspension was filtered under reduced pressure to obtain an ethanol extract of propolis. Next, the solvent of the obtained ethanol extract was removed by evaporation using a rotary evaporator, and about 30 g of the obtained residue was dispersed in a mixture of water and ethyl acetate (1: 1), and the upper ethyl acetate layer was separated. An ethyl acetate extract of propolis was obtained.
  • the solvent of the obtained ethyl acetate extract was evaporated and removed on a rotary evaporator, and about 20 g of the obtained residue was dispersed in 99.5% methanol.Insoluble matters were removed by low-speed centrifugation, and methanol extraction of propolis was performed. A liquid was obtained.
  • the sample extract obtained in step 1 is injected into an ODS column for high-performance liquid chromatography and an ODS 80 TM column (manufactured by Tosoh I) equilibrated with 70% methanol, and the 70% Gradient elution with a 100% methanol concentration gradient was performed. Fractions with a 90-95% methanol concentration were collected.
  • the fractions having a methanol concentration of 90 to 95% obtained in Step 2 were collected into one, and the solvent was removed by evaporation on a rotary evaporator to obtain about 2 g of a residue.
  • the obtained residue was dissolved in a gel form, and the obtained solution was injected into an Inertsil series column for high-performance liquid chromatography and an Inertsil SIL column (manufactured by GL Sciences) equilibrated with the gel form. The minutes were dispensed.
  • Step 4 The fractions obtained in step 3 were collected into one, and the solvent was removed by evaporation on a rotary evaporator to obtain about 50 mg of a residue. Next, the obtained residue was dissolved in black-mouthed form, and the resulting solution was injected into a GPC column for high-performance liquid mouth chromatography, Shodex GPC-H2000 column (manufactured by Showa Denko KK), equilibrated with black-mouthed form. The main fraction was collected.
  • step 4 The fractions obtained in step 4 were collected into one, and the solvent was removed by evaporation on a rotary evaporator to obtain about 15 mg of a colorless needle-like crystalline substance.
  • the physical properties shown in Example 2 of the acicular crystal material confirmed that it was 3- [2-dimethyl-8- (3-methyl-2-butenyl) benzopyran] -6-propionic acid. did.
  • This benzopyran derivative is insoluble in water, solubilized by alkali, and does not dissolve by acid. It is slightly soluble in methanol, ethanol, acetone and ether, soluble in acetonitrile, readily soluble in chloroform, ethyl acetate and dimethylformamide, and insoluble in n-hexane and petroleum ether.
  • the benzopyran derivative of the present invention is represented by the formula (I): molecular formula: C 19 H 22 0 3, molecular weight: 298.38) and was the boss.
  • Example 1 Using the benzovirane derivative obtained in Example 1 as a test substance, a cell damage activity test on tumor cells was performed as follows.
  • test substance 0.1 ⁇ l appropriately diluted with MEM medium containing 10% fetal bovine serum and 2 mM glumin was added, and then trypsin-treated human liver cancer HuH 13 shares (J. CELLULAR PHYSIOL., VO L 148, 290-294, 1991) was prepared at 3 ⁇ 10 4 cells / ml with the above-mentioned culture solution and dispensed in 0.05 ml increments.
  • the plate was cultured in a 5% CO2 incubator at 37 ° (after 72 hours, the culture supernatant was removed, and 0.1 ml of a culture solution containing 0.02% neutral red was added to each well.
  • Cells were stained by culturing for 1 hour in a carbon dioxide incubator at C. After removing the culture supernatant, the residue was washed once with physiological saline, and then the dye was washed with 0.01N normal hydrochloric acid / 30% ethanol. After extraction, the absorbance at 550 nm was measured using a microplate reader 1.
  • tissue culture anti-cancer drug sensitivity test Histoculture Drug Response assay, HDRA
  • HDRA tissue culture Drug Response assay
  • Compound (I) 150 ⁇ g / mis APC 150 ⁇ g / ml, MMC 2 g / ml, 5-FU300 zg / mis ADM 15 // mls DDP 20 ⁇ g in RPMI 1640 medium containing 20% fetal serum / m1 was added thereto, and 1 ml was dispensed into a 24-well plate, and a collagen gel of about 1 cm square was allowed to stand therein. About 10 mg of tumor tissue collected from two gastric cancer patients was accurately measured and placed on the collagen gel, and the plate was cultured in a 5% CO 2 incubator at 37 ° C. for 7 days.
  • the benzopyran derivative (3- [2-dimethyl-18- (3-methyl-12-butenyl) benzovirane] _6-probenoitic acid) of the present invention exhibits antitumor activity and can be used as an antitumor agent. In addition, it can be expected as an antitumor agent with high safety and few side effects.

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  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Treatment Of Liquids With Adsorbents In General (AREA)
  • Extraction Or Liquid Replacement (AREA)

Abstract

L'invention concerne un acide 3-[2-diméthyl-8-(3-méthyl-2-butényl)benzopyranne]-6-acrylique, représenté par la formule chimique (I), ainsi que des agents antitumoraux contenant ledit composé et ses sels en tant que principe actif.
PCT/JP1996/003860 1995-11-24 1996-12-27 Derive de benzopyranne obtenu a partir de propolis WO1998029404A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7329583A JPH09143179A (ja) 1995-11-24 1995-11-24 プロポリス由来のベンゾピラン誘導体
PCT/JP1996/003860 WO1998029404A1 (fr) 1995-11-24 1996-12-27 Derive de benzopyranne obtenu a partir de propolis
AU11526/97A AU1152697A (en) 1996-12-27 1996-12-27 Benzopyran derivative originating in propolis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7329583A JPH09143179A (ja) 1995-11-24 1995-11-24 プロポリス由来のベンゾピラン誘導体
PCT/JP1996/003860 WO1998029404A1 (fr) 1995-11-24 1996-12-27 Derive de benzopyranne obtenu a partir de propolis

Publications (1)

Publication Number Publication Date
WO1998029404A1 true WO1998029404A1 (fr) 1998-07-09

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PCT/JP1996/003860 WO1998029404A1 (fr) 1995-11-24 1996-12-27 Derive de benzopyranne obtenu a partir de propolis

Country Status (2)

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JP (1) JPH09143179A (fr)
WO (1) WO1998029404A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060359A1 (fr) * 1998-09-28 2001-08-23 Mikako Hirota Activite physiologique d'un derive de benzopyrane issu de la propolis

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006213609A (ja) * 2005-02-01 2006-08-17 Iwate Univ 免疫担当細胞の活性化剤、これを用いたネコ免疫不全ウイルス感染の予防方法ならびにネコ免疫不全ウイルスの駆逐方法および癌発生の予防方法ならびに癌の駆逐方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0558943A (ja) * 1991-08-29 1993-03-09 Kyowa Hakko Kogyo Co Ltd プロポリス由来新生理活性物質
JPH05271031A (ja) * 1991-07-03 1993-10-19 Nippon Puroporisu Kk プロポリス抽出物の製造方法
JPH07330596A (ja) * 1994-06-01 1995-12-19 Eiken Chem Co Ltd 抗腫瘍剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05271031A (ja) * 1991-07-03 1993-10-19 Nippon Puroporisu Kk プロポリス抽出物の製造方法
JPH0558943A (ja) * 1991-08-29 1993-03-09 Kyowa Hakko Kogyo Co Ltd プロポリス由来新生理活性物質
JPH07330596A (ja) * 1994-06-01 1995-12-19 Eiken Chem Co Ltd 抗腫瘍剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 101, Abstract No. 226818, (1984); & PHYTOCHEMISTRY, 23(5), (1984), p. 1135-7. *
CHEMICAL ABSTRACTS, Vol. 71, Abstract No. 120483, (1969); & AUST. J. CHEM., 22(10), (1969), p. 2175-85. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060359A1 (fr) * 1998-09-28 2001-08-23 Mikako Hirota Activite physiologique d'un derive de benzopyrane issu de la propolis

Also Published As

Publication number Publication date
JPH09143179A (ja) 1997-06-03

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