WO1994018190A1 - Compose de depsidone - Google Patents

Compose de depsidone Download PDF

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Publication number
WO1994018190A1
WO1994018190A1 PCT/JP1994/000179 JP9400179W WO9418190A1 WO 1994018190 A1 WO1994018190 A1 WO 1994018190A1 JP 9400179 W JP9400179 W JP 9400179W WO 9418190 A1 WO9418190 A1 WO 9418190A1
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WO
WIPO (PCT)
Prior art keywords
medium
culture
yellow
compound
cells
Prior art date
Application number
PCT/JP1994/000179
Other languages
English (en)
Japanese (ja)
Inventor
Zengxiang Chen
Bi Mei HE
Tomoko Akama
Takuya Hamaguchi
Ikuyo Taneoka
Akira Kawashima
Kazunori Hanada
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Sichuan Industrial Institute Of Antibiotic Of State Pharmaceutical Administration
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 Taisho Pharmaceutical Co., Ltd., Sichuan Industrial Institute Of Antibiotic Of State Pharmaceutical Administration filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU59796/94A priority Critical patent/AU5979694A/en
Publication of WO1994018190A1 publication Critical patent/WO1994018190A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • C07D321/12—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms

Definitions

  • the present invention relates to a novel depsidone-based compound having an action of promoting the uptake of low-density lipoprotein (LDL) from blood into the liver.
  • LDL low-density lipoprotein
  • Hyperlipidemia is a known factor linked to atherosclerotic disease and has been proven to be a risk factor for E-cardiac disease. Therefore, blood lipid-lowering agents are effective for these conditions, and various drug powers have been discovered so far. Because of the inability to completely control blood lipids in clinical practice, there is a need for the development of new lipid-lowering agents.
  • An object of the present invention is to provide a debsidone compound having an action of promoting LDL uptake from blood into the liver. Disclosure of the invention
  • HEPATOMA G2 cultured cells hereinafter abbreviated as HEPG2
  • HEPG2 human liver cancer
  • MC-142 (Hereinafter referred to as MC-142).
  • the strain producing the novel substance MC-142 of the present invention is a strain newly isolated from the soil collected by the present inventors, and has the name of microorganism rPenicillium purpurogenum TF-03.
  • This strain grows well on potato-glucose agar medium, oatmeal agar medium, YpSS agar medium, etc., and has extremely good spore formation. Observation under a microscope of colonies formed by this strain on a malt dextran agar medium at 25 ° C for 7 days reveals that the hyphae have septum, are highly branched, and have a white to bright yellow color. Present. The conidium-forming cells diverge from the tip of the conidiophores that have diverged from the aerial hyphae or the basal hyphae into a bicyclic unisymmetrical shape via the metre, respectively.
  • Conidia It forms a chain of conidia, and has a morphological force called Penicilli, which is characteristic of Benicillium.
  • Conidiophores have septum, surface is smooth, diameter is 2.0 ⁇ 4.0m, length is 40 ⁇ 270m.
  • Metri is 9.0-13.0 m X 2.0-3.2 ⁇ m, and Fearide 10.0-13.0 ( ⁇ 20.) ⁇ ⁇ X 1.8-2.8 zm.
  • Conidia are elliptical to subspherical, rarely spherical, and the surface is smooth to slightly rough, with a size of 2.4 to 3.2 (4.0) 11 1.8 to 3.0 izm.
  • Table 1 shows the results of macroscopic observation when cultured at 25 ° C for 14 days on various media.
  • the color display quoted the system color name of the Japan Standards Association and the JIS color name book (1985).
  • This strain grows in a sub-mouth liquid medium with a pH of 6.0 at a temperature in the range of 14 to 39 ° C, and the optimum temperature is 28 to 35 ° C.
  • the strain grows in YpsS liquid medium at 26 ° C in the range of ⁇ 2 to 8, and the optimum pH is 6 to 8.
  • the production of MC-142 is carried out by cultivating Penicillium purpurogenum TF-0374 in a medium containing various nutrients under aerobic conditions in accordance with the production of general fermentation products.
  • the medium is mainly a liquid medium and consists of a carbon source, a nitrogen source, and inorganic salts. If necessary, it can be added with bisamines, precursors, and defoamers.
  • the pH is adjusted to around 6.
  • the carbon source for example, glucose, maltose, dextrin, glycerin, starch or the like is used alone or as a mixture.
  • the nitrogen source for example, yeast exo-peptone, meat extract, soy flour, corn liquor, urea, ammonium salt or the like is used alone or in combination.
  • the inorganic salt for example, potassium phosphate, magnesium sulfate, sodium chloride, calcium carbonate and the like are used alone or in combination.
  • Adekinol, a silicon compound, or the like can be used.
  • the culture method is suitable for aerobic cultivation such as shaking culture and aeration and stirring culture, and is performed at pH 4-8, 25-30 ° C for 2-3 days, preferably at pH 6-7, 26-28 ° C. Incubate for 2 days.
  • the MC-142 produced by this culture can be isolated according to a general method for collecting fermentation products.
  • MC-142 is extracted from the cells separated by centrifugation or filtration with an organic solvent such as a lower alcohol or acetone, and the extract is concentrated with Mil to remove the organic solvent.
  • the solution is dissolved in a water-insoluble organic solvent such as benzene, benzene, orifice, and concentrated under reduced pressure to form a syrup.
  • This syrup is again dissolved in an organic solvent such as ethyl acetate, benzene, black form, acetone, methanol, etc., and column chromatography using silica gel, high-performance liquid chromatography filled with silica gel 0DS for reverse phase distribution.
  • MC-142 can be purified and isolated by subjecting it to a gel filtration power and a ram chromatograph.
  • the target substance of the present invention, MC-142, obtained by the above purification was analyzed for its elemental analysis value, molecular weight, ultraviolet absorption spectrum, 1H-NMR spectrum, 13C-NMR spectrum, etc.
  • the structural formula was determined from the results.
  • MC-142 The physicochemical properties of MC-142 are as follows.
  • FIG. 2 shows the result of measurement at 400 MHz in CDC13.
  • FIG. 3 shows the results of measurement at 100 MHz in DC13.
  • Purpurogenum TF-0374 strain was inoculated and cultured with shaking at 26 ° C for 72 hours. Then 50
  • a medium having the same composition as the seed culture was placed in 30 L and 120 L, respectively, and after sterilization, 0.3 L and 1.2 L of the seed culture were inoculated at 26 ° C. The cells were cultured with aeration and stirring for 48 hours.
  • L.Omg of MC-142 obtained in the example was dissolved in ethanol and used to obtain the target concentration.
  • LPDS Dulbecco's modified single-glue medium containing 10% ribonucleic acid tindeficient serum
  • the compound of the present invention (MC-142) has an excellent LDL uptake promoting activity in the liver, and thus can provide a drug useful as a lipid-lowering agent.
  • the method of administration of MC-142 is oral administration.
  • the dosage form can be selected from tablets, granules, powders, capsules, syrups, and suspending agents.
  • conventional excipients eg, microcrystalline cellulose, starch, lactose, mannitol, etc.
  • binders eg, hydroxypropyl cellulose, polyvinyl virolidone, etc.
  • a powder eg, magnesium stearate, talc, etc.
  • a disintegrant eg, calcium carboxymethylcellulose
  • the dose of MC-142 is 100 to 50 Omg for treating adults, and is administered once or several times a day. This dosage can be adjusted appropriately according to the patient's age, weight and condition.
  • FIG. 1 shows the infrared absorption spectrum of MC-142 measured with a KBr tablet.
  • FIG. 2 shows the 1H-NMR spectrum of MC-142 measured in CDC 13 at 400 MHz.
  • FIG. 3 shows the 13C-NMR spectrum of MC-142 in CDC13 measured at 10 MHZ.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé d'obtention d'un composé favorisant le passage de LDL du sang dans le foie, composé représenté par la formule (1).
PCT/JP1994/000179 1993-02-08 1994-02-07 Compose de depsidone WO1994018190A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59796/94A AU5979694A (en) 1993-02-08 1994-02-07 Depsidone compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1995793 1993-02-08
JP5/19957 1993-02-08

Publications (1)

Publication Number Publication Date
WO1994018190A1 true WO1994018190A1 (fr) 1994-08-18

Family

ID=12013682

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/000179 WO1994018190A1 (fr) 1993-02-08 1994-02-07 Compose de depsidone

Country Status (2)

Country Link
AU (1) AU5979694A (fr)
WO (1) WO1994018190A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004039453A3 (fr) * 2002-10-31 2004-08-05 Bayer Healthcare Ag Derives de 7h-dibenzo[b,g][1,5]dioxocine-5-one et leur utilisation
CN103242348A (zh) * 2013-05-22 2013-08-14 中国人民解放军军事医学科学院毒物药物研究所 吲哚啉二酮哌嗪类螺环化合物及其制备方法和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0352884A (ja) * 1989-07-20 1991-03-07 Kitasato Inst:The Ｆｏ―６０８ａ物質およびその製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0352884A (ja) * 1989-07-20 1991-03-07 Kitasato Inst:The Ｆｏ―６０８ａ物質およびその製造法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 114(23), Abstract No. 225301w, (1991). *
CHEMICAL ABSTRACTS, 115(7), Abstract No. 68099n, (1991). *
CHEMICAL ABSTRACTS, 115(7), Abstract No. 71214b, (1991). *
CHEMICAL ABSTRACTS, 115(7), Abstract No. 71215c, (1991). *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004039453A3 (fr) * 2002-10-31 2004-08-05 Bayer Healthcare Ag Derives de 7h-dibenzo[b,g][1,5]dioxocine-5-one et leur utilisation
JP2006508938A (ja) * 2002-10-31 2006-03-16 バイエル・ヘルスケア・アクチェンゲゼルシャフト ７Ｈ−ジベンゾ［ｂ，ｇ］［１，５］ジオキソシン−５−オン誘導体およびそれらの使用
CN103242348A (zh) * 2013-05-22 2013-08-14 中国人民解放军军事医学科学院毒物药物研究所 吲哚啉二酮哌嗪类螺环化合物及其制备方法和用途
CN103242348B (zh) * 2013-05-22 2016-01-06 中国人民解放军军事医学科学院毒物药物研究所 吲哚啉二酮哌嗪类螺环化合物及其制备方法和用途

Also Published As

Publication number Publication date
AU5979694A (en) 1994-08-29

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