WO1997038005A1 - Nouvel antibiotique, procede de preparation et composition medicamenteuse contenant cet antibiotique - Google Patents

Nouvel antibiotique, procede de preparation et composition medicamenteuse contenant cet antibiotique Download PDF

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Publication number
WO1997038005A1
WO1997038005A1 PCT/JP1997/001221 JP9701221W WO9738005A1 WO 1997038005 A1 WO1997038005 A1 WO 1997038005A1 JP 9701221 W JP9701221 W JP 9701221W WO 9738005 A1 WO9738005 A1 WO 9738005A1
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WO
WIPO (PCT)
Prior art keywords
substance
cholesterol
culture
same
test
Prior art date
Application number
PCT/JP1997/001221
Other languages
English (en)
Japanese (ja)
Inventor
Kenzo Harimaya
Yoshikazu Sato
Fukio Konno
Toru Sasaki
Mina Kanda
Noriko Chiba
Takashi Mikawa
Original Assignee
Meiji Seika Kaisha, Ltd.
Mitsubishi Chemical Corporation
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 Seika Kaisha, Ltd., Mitsubishi Chemical Corporation filed Critical Meiji Seika Kaisha, Ltd.
Publication of WO1997038005A1 publication Critical patent/WO1997038005A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • 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
    • C12P33/00—Preparation of steroids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the false side thread is thread-like, has partition walls, and is colorless.
  • Ascospores are arranged in one row above the asci and two rows below.
  • the shape is elliptical, the size is 15.6 to 18.4 9.3 to 10.
  • O ⁇ m one cell, colorless and smooth.
  • the above-mentioned bacteria are cultured in a medium containing nutrients that can be used by ordinary microorganisms.
  • a nutrient source glucose, water syrup, dextrin, sucrose, starch, sugar, animal and vegetable oils and the like can be used.
  • a nitrogen source soybean flour, wheat germ, corn steep 'liquor, cottonseed kashiwa, meat extract, peptone, yeast extract, ammonium sulfate, sodium nitrate, urea and the like can be used.
  • Organic and inorganic substances can be added as appropriate to support the growth of bacteria and promote the production of MK 6059 substance.
  • Example 1 Culture of Erythodorosis incubinus L1227 strain Glucose 5.0%, soybean flour 1.0%, meat extract 0.4%, peptone 0.4%, yeast powder 0.1%, NaCl 0.1% A seed medium (pH 7.0) containing 25% and CaCO 3 0.5% was dispensed into 10 20 Om 1 Erlenmeyer flasks each with 4 Om 1 and autoclaved for 121 and 20 minutes.
  • the active fraction was collected and concentrated to dryness under reduced pressure to obtain 304 mg of an oily substance.
  • This oily substance was dissolved in a small amount of methanol, placed on a 800 ml column of Sephadex LH-20 (Pharmacia) filled with methanol, and developed with methanol.
  • This oily substance is dissolved in a small amount of methanol and filled with methanol. (Manufactured by TOSOH CORPORATION) Placed on a 1 L tower and developed with methanol. The active substance eluted in fractions No. 45-48 in 10 ml fractions. The active fractions were collected and concentrated to dryness under reduced pressure to obtain crude MK 6059 substance. Dissolve 162 mg of this crude MK 6059 substance in a small amount of methanol and place it in a 20 ml column of Cosmoseal 75 C18-0PN (manufactured by Nacalai Tesque) filled with 60% methanol, and add 60% methanol 250m 1-100% methanol 250ml A gradient elution was performed. The active substance eluted in fractions No. 37-42 in the 5 g fraction.
  • mice After completion of oral administration 4 days later, the mice were fasted, the test drug was orally administered the next day again, blood was collected 4 hours later, serum was separated, and serum lipids were quantified. The liver was taken out immediately after blood collection, and its weight was measured. The results are shown in Table 3 as values per 10 g of mouse body weight.
  • Table 3 Effect of continuous administration (5 days) of MK 6059 substance on serum lipids of normal mice Serum lipid (mgl3 ⁇ 4) Liver weight treatment Tch TG g / 10g bw Control 131.6 ⁇ 10.6 159.6 Sat 4.5 0.45 Sat 0.01 605 ⁇ 117.2 Sat 6.1 120.1 ⁇ 11. ⁇ 0.43 Sat 0.02 lOOrag / kg.po, 5days
  • Serum total cholesterol (Tch) was quantified using a cholesterol C-Test Co. (Wako Pure Chemical Industries) and triglyceride (TG) using a triglyceride G-Test Co. (Wako Pure Chemical Industries) kit. .
  • the drug dose is 1 Omg / kg, 3 Omg / k N 10 Omg / k cholestira for MK 6005 substance Min was 400 mg / kg and 80 mg / kg, and the control group received 0.5% CMC.
  • Table 5 shows the results. Table 5 Effect of MK 6059 substance on cholesterol-loaded hamster serum lipids Serum lipids (mg / dl)
  • MK 6059 substance For the MK 6059 substance, administration of 30 mg Zkg and 100 mg kg significantly reduced the total cholesterol level as compared to the control group. For cholestyramine, administration of 400 mg / kg also significantly reduced the total cholesterol level compared to the control group, but required a higher dose than the MK6059 substance. Cholesterol absorption inhibition test in 5 pharmacological test examples As shown in the above pharmacological test results, the MK 6059 substance has a marked cholesterol lowering effect in various animals, and the point of action of this pharmacological action should be clarified. In addition, a cholesterol absorption inhibition test was performed in rats.
  • test substance was suspended in 0.5% CMC in a rat (about 6 animals per group) weighing approximately 240 g, which had been preliminarily reared on a diet containing 1% cholesterol. It was orally administered once daily in the evening for 10 days. After the continuous oral administration for 10 days, the test was started 1 day after fasting. 1 The test substance was administered to the rat on the 1st day, and then 30 minutes later, [ 3 H] -cholesterol (Chemical No. 1) was used as a tracer. One 0.5 ml mouse was given a single intravenous injection in the tail vein, and 2 mI [ 14 C] -cholesterol (a first chemical) was given a single oral gavage in the stomach.
  • the MK 659 substance is useful as a new type of lipid lowering agent.
  • the MK609 substance has an effect of lowering serum cholesterol or triglyceride, and is expected to be applied as a therapeutic drug for hyperlipidemia.
  • INDUSTRIAL APPLICABILITY The MK609 substance of the present invention is expected to be used as an antifungal agent and a hyperlipidemic agent as shown in Examples.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Mycology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Cette invention concerne un agent antifongique et antilipémique qui comprend la substance MK6059 correspondant à la formule générale (I). Cette substance est préparée en cultivant un brin de MK6059 appartenant au genre Ellisiodothis dans un milieu nutritif traditionnel pour microbes. On soumet ensuite le système obtenu à une extraction par solvant, à un échange ionique, à une chromatographie sur gel de silice, à une chromatographie de filtration sur gel, ou analogue, ceci de manière à isoler la substance voulue.
PCT/JP1997/001221 1996-04-10 1997-04-09 Nouvel antibiotique, procede de preparation et composition medicamenteuse contenant cet antibiotique WO1997038005A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8862896 1996-04-10
JP8/88628 1996-04-10

Publications (1)

Publication Number Publication Date
WO1997038005A1 true WO1997038005A1 (fr) 1997-10-16

Family

ID=13948081

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/001221 WO1997038005A1 (fr) 1996-04-10 1997-04-09 Nouvel antibiotique, procede de preparation et composition medicamenteuse contenant cet antibiotique

Country Status (1)

Country Link
WO (1) WO1997038005A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521169A (en) * 1994-01-14 1996-05-28 Bristol-Myers Squibb Company Ascosteroside and analogs thereof useful in antifungal compositions for methods of treating infections and inhibition of fungal growth
WO1996035432A1 (fr) * 1995-05-09 1996-11-14 Merck & Co., Inc. Agents antifongiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521169A (en) * 1994-01-14 1996-05-28 Bristol-Myers Squibb Company Ascosteroside and analogs thereof useful in antifungal compositions for methods of treating infections and inhibition of fungal growth
WO1996035432A1 (fr) * 1995-05-09 1996-11-14 Merck & Co., Inc. Agents antifongiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. ANTIBIOT., Vol. 49, No. 6, (June 1996), J.A. GORMAN et al., "Ascosteroside, a New Antifungal Agent from Ascotricha Amphitricha I. Taxonomy, Fermentation and Biological Activities". *
J. ANTIBIOT., Vol. 49, No. 6, (June 1996), J.E. LEET et al., "Ascosteroside, a New Antifungal Agent from Ascotricha Amphitricha II. Isolation and Structure Elucidation". *

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