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WO1999063102A1 - COMPOSE(S) ANTIDIABETIQUE ACTIF WF19353 ET PROCEDE DE PREPARATION DE CES COMPOSES PAR FERMENTATION COMPRENANT L'UTILISATION D'UN CHAMPIGNON DE L'ESPECE $i(HELICOMYCES) - Google Patents

COMPOSE(S) ANTIDIABETIQUE ACTIF WF19353 ET PROCEDE DE PREPARATION DE CES COMPOSES PAR FERMENTATION COMPRENANT L'UTILISATION D'UN CHAMPIGNON DE L'ESPECE $i(HELICOMYCES) Download PDF

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Publication number
WO1999063102A1
WO1999063102A1 PCT/JP1999/002708 JP9902708W WO9963102A1 WO 1999063102 A1 WO1999063102 A1 WO 1999063102A1 JP 9902708 W JP9902708 W JP 9902708W WO 9963102 A1 WO9963102 A1 WO 9963102A1
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WIPO (PCT)
Prior art keywords
substance
methanol
reaction
exchangeable
max
Prior art date
Application number
PCT/JP1999/002708
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English (en)
Inventor
Yoshihiro Ohtsu
Toshihiro Shibata
Michizane Hashimoto
Yasuhisa Tsurumi
Shigehiro Takase
Motohiro Hino
Original Assignee
Fujisawa Pharmaceutical 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 Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP54687799A priority Critical patent/JP2002509445A/ja
Publication of WO1999063102A1 publication Critical patent/WO1999063102A1/fr

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    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/02Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using fungi
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00Microorganisms, 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
    • C12N1/14Fungi; Culture media therefor
    • C12N1/145Fungal isolates
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12RINDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00Microorganisms ; Processes using microorganisms
    • C12R2001/645Fungi ; Processes using fungi

Definitions

  • the present invention relates to new bioactive compounds, hereinafter entitled WF19353 substances which are useful as a medicament.
  • the present invention relates to new bioactive compounds, WF19353 substances.
  • WF19353 substances which have the inhibitory activity against gluconeogenesis, to a process for preparation thereof, to a pharmaceutical composition comprising the same, which are useful as antidiabetic or antiobesic agents, and to a use thereof as a medicament.
  • one object of this invention is to provide the novel compounds, WF19353 substances which are of use for treating and preventing diabetes, obesity and the like.
  • Another object of this invention is to provide a process for production of the WF19353 substances by fermentation of a WF19353 substances- producing strain belonging to the genus Helicomyces in a nutrient medium.
  • a further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, the WF19353 substances.
  • Still further object of this invention is to provide a use of the WF19353 substances for treating and preventing diabetes, obesity and the like.
  • the WF19353 substances comprise 4 components, which are referred to as WF19353F substance, WF19353B substance, WF19353A substance and WF19353D substance, respectively, and, in this specification, the expression "WF19353 substance” refers to one of the WF19353 substances.
  • the WF19353 substances can be produced by fermentation of the WF19353 substances-producing strain belonging to the genus Helicomyces such as Helicomyces sp. No. 19353 in a nutrient medium.
  • the production of the WF19353 substances is not limited to the use of the particular organism described herein, which is given for the illustrative purpose only.
  • This invention also includes the use of any mutants which are capable of producing the WF19353 substances including natural mutants as well as artificial mutants which can be produced from the described organism by conventional means such as irradiation of X- ray, ultra-violet radiation, treatment with N-methyl-N'-nitro-N- nitrosoguanidine, 2-aminopurine, and the like.
  • the fungal strain No.19353 was originally isolated from a decayed leaf sample, collected at Kawauchi-mura, Futaba-gun, Fukushima-ken, Japan. This organism grew restrictedly on various culture media, and formed dark brown colonies. On the Miura's LCA medium (Miura, K. and M. Kudo: Trans. My col. Soc. Japan, 11:116-118, 1970), the strain produced helical conidia from vegetative hyphae. The conidia were hyaline, multicellular, coiled and planate. Teleomorph was not observed. Its mycological characteristics were as follows.
  • Conidia were borne on sessile denticles of vegetative and aerial hyphae, or on short lateral branches. Conidiogenous cells were acrogenous or intercalary, monoblastic or polyblastic, pale brown, smooth, cylindrical, and denticulate. The denticles were 2-5 x 1-2 ⁇ m in size. Conidia were holoblastic, solitary, hyaline, smooth, helical, coiled 2-3 times in two dimensions, planate, and 13-18(-25) ⁇ m in diameter. They were sometimes uncoiled and formed filamentous shapes. Conidial filaments were 5-12 septate and 1-2 ⁇ m thick.
  • Chlamydospores were formed intercalary, solitary but aggregated at old cultures, pale brown, smooth, subglobose to pyriform, and 5-9 ⁇ m in diameter. Vegetative hyphae were smooth, septate, pale brown and branched. The hyphal cells were cylindrical and 2-4 ⁇ m in width.
  • Strain No.19353 was able to grow at the temperature range from 5 to 31 °C, with the growth optimum at 24 to 27°C. These temperature data were determined on potato dextrose agar (made by NISSUI).
  • Potato dextrose G Restrictedly, 1.5-2.5 cm agar (Difco 0013)
  • S Circular, convex, felty, radiately sulcate or wrinkly, partly hygroscopic, formed no anamorph, brownish gray (6F2) to grayish brown (6F3), and white to yellowish white
  • Czapek's solution G Very restrictedly, 1.0-1.5 cm agar S: Circular, submerged, thin, plane, formed no anamorph, yellowish gray (4B2) to grayish yellow (4C3)
  • Corn meal agar G Restrictedly, 1.5-2.5 cm (Difco 0386)
  • S Circular, thin, plane, submerged, hygroscopic, formed no anamorph, dark gray (1F1) at the center, and brownish gray (4F2) to olive brown (4F3) at the margin
  • MY20 agar* G Very restrictedly, 0.5-1.0 cm
  • Oatmeal agar G Very restrictedly, 1.0-1.5 cm
  • G growth, measuring colony size in diameter S : colony surface
  • the WF19353 substances are produced when the WF19353 substances- producing strain belonging to the genus Helicomyces is grown in a nutrient medium containing sources of assimilable carbon and nitrogen under aerobic conditions (e. g. shaking culture, submerged culture, etc.).
  • the preferred sources of carbon in the nutrient medium are carbohydrates such as glucose, sucrose, starch, fructose or glycerin, or the like.
  • the preferred sources of nitrogen are peanut powder, yeast extract, peptone, gluten meal, cotton seed flour, soybean powder, soybean meal, corn steep liquor, dried yeast, wheat germ, etc., as well as inorganic and organic nitrogen compounds such as ammonium salts (e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.), urea or amino acid, or the like.
  • ammonium salts e. g. ammonium nitrate, ammonium sulfate, ammonium phosphate, etc.
  • urea or amino acid or the like.
  • the carbon and nitrogen sources though advantageously employed in combination, need not to be used in their pure form because less pure materials, which contain traces of growth factors and considerable quantities of mineral nutrients, are also suitable for use.
  • medium mineral salts such as sodium or calcium carbonate, sodium or potassium phosphate, sodium or potassium chloride, sodium or potassium iodide, magnesium salts, copper salts, zinc salts, iron salts, or cobalt salts, or the like.
  • a defoaming agent such as liquid paraffin, fatty oil, plant oil, mineral oil, silicone or the like may be added.
  • Agitation and aeration of the culture mixture may be accomplished in a variety of ways, such as agitation by a propeller or similar mechanical agitation equipment, by revolving or shaking the fermenter, and the like.
  • the fermentation is usually conducted at a temperature between about 10°C and 40 °C, preferably 20 °C to 35 °C, for a period of about 24 hours to 120 hours, which may be varied according to fermentation conditions and scales.
  • the culture broth is then subjected for recovery of the WF19353 substances to various procedures conventionally used for recovery and purification of biological active substance, for instance, solvent extraction with an appropriate solvent or a mixture of some solvents, chromatography or recrystallization from an appropriate solvent or a mixture thereof.
  • the WF19353F substance as obtained has the following physico-chemical properties:
  • Soluble methanol, acetic acid
  • the WF19353B substance as obtained has the following physico-chemical properties:
  • Soluble methanol, acetic acid
  • HPLC High Performance Liquid Chromatography
  • the WF19353A substance as obtained has the following physico-chemical properties:
  • Soluble methanol, dimethyl sulfoxide, acetic acid Slightly soluble: water Insoluble: ethyl acetate, n-hexane Color reaction:
  • the WF19353D substance as obtained has the following physico- chemical properties:
  • Soluble methanol, dimethylsulf oxide, acetic acid Slightly soluble: water Insoluble: ethyl acetate, n-hexane Color reaction:
  • the WF19353 substances possesses pharmacological activities such as the inhibitory activity against gluconeogenesis, and the like, and therefore are useful for the treatment and prevention of diabetes, obesity and the like.
  • the WF19353 substances may be useful for various diseases because of its useful pharmaceutical activity such as the inhibitory activity against gluconeogenesis, and so on.
  • Hepatocytes were prepared from 24 hours starved male Wistar rat (150- 200g) by the collagenase perfusion technique. Cells were cultured in
  • glucose produced into the medium was determined enzymatically.
  • Gluconeogenesis rate was performed as glucose value derived from pyruvate.
  • WF19353 A substance 0.21 ⁇ g/ml
  • the pharmaceutical composition of this invention can be used in the form of pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the WF19353 substance, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral administrations.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, injections, ointments, liniments, eye drops, lotion, gel, cream, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening, solubilizing and coloring agents and perfumes may be used.
  • the composition for applying the composition to human, it is preferable to apply it by intravenous, intramuscular, topical or oral administration.
  • the dosage of therapeutically effective amount of the WF19353 substance varies from and also depends upon the age and condition of each individual patient to be treated, in the case of individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01 - 10 mg of the WF19353 substance per kg weight of human being, in the case of intramuscular administration, a daily dose of 0.1 - 10 mg of the WF19353 substance per kg weight of human being, in case of oral administration, a daily dose of 0.5 - 50 mg of the WF19353 substance per kg weight of human being is generally given for treating.
  • the following examples are given for the purpose of illustrating the present invention.
  • Example 1 Fermentation of strain WF19353 for the production of the WF19353F substance and the WF19353B substance:
  • a loopful of the slant culture (strain WF19353) was inoculated into 30ml of sterilized seed medium consisting of sucrose 4%, glucose 1%, soluble starch
  • Etsu Chemical Co., Ltd. 0.05% in each of six 100ml Erlenmeyer flasks.
  • the flasks were incubated at 25 °C for 5 days on a rotary shaker (220 rpm, 5.1 cm-throw) and then inoculated (5%) into 160ml of the same sterilized seed medium in each of sixteen 500ml Erlenmeyer flasks. And the flasks were incubated at 25 °C for 2 days on a rotary shaker (220 rpm, 5.1 cm-throw).
  • the resultant seed culture was inoculated (3%) into 20 liters of sterilized production medium in each of four 30-liter jar fermenters .
  • the production medium was composed of glucose 1%, modified starch 6%, cotton seed flour 1%, soybean flour 1%, KH 2 P0 4 1.6%, Na 2 HP0 4 12H 2 0 1.2%, Adekanol
  • the fermentation was carried out at 25 ⁇ C for 5 days under aeration of 20 liters/minute and agitation of 250 rpm.
  • the culture broth was filtrated with an aid of diatomaceous earth. And then, 50 liters of methanol was added to the mycelium obtained thus and the mixture was allowed to stand for about 2 hours with stirring at room temperature. The resultant mixture was filtrated with an aid of diatomaceous earth.
  • the filtrate was diluted with an equal volume of water and passed through a column (5 liters) of DIAION HP20 (Mitsubishi Chemical Co., Ltd.) packed with water. The column was washed with 50% aqueous methanol (15 liters) and then eluted with methanol (20 liters). The eluate was concentrated in vacuo to an aqueous solution (2 liters) and 3 liters of water was added to the solution.
  • This solution was passed through a column (2 litters) of YMC-GEL (ODS-AM120-S50, YMC Co., Ltd.) packed with water.
  • the column was eluted with 20% aqueous acetonitrile (13 liters) and then 25% aqueous acetonitrile (7.5 liters). The elution was monitored by analytical HPLC indicated below2). Fractions containing the WF19353F substance and the WF19353B substance were combined respectively.
  • the portion corresponding to the WF19353F substance was diluted with an equal volume of water and passed through a column (2 liters) of YMC-
  • the column was washed with water and eluted with 95% aqueous methanol.
  • the eluate was concentrated in vacuo to dryness and dissolved in small amount of methanol.
  • About twice amount of ethyl acetate was added to the solution and allowed to stand at 4°C for about 12 hours to yield 478 mg of the WF19353F substance as a powder.
  • the portion corresponding to the WF19353B substance was diluted with an equal volume of water and passed through a column (2 liters) of YMC- GEL (ODS-AM 120-S50) packed with water. The column was eluted with 35% aqueous methanol containing 0.1% trifluoroacetic acid (11 liters). The portion corresponding to the WF19353B substance was diluted with an equal volume of water and passed through a column (1 liter) of YMC-GEL (ODS-
  • strain WF19353 Fermentation of strain WF19353 for the production of the WF19353A substance and the WF19353D substance: A loopful of the slant culture (strain WF19353) was inoculated into 30 ml of sterilized seed medium consisting of sucrose 4%, glucose 1%, soluble starch 2%, cotton seed flour 3%, soybean flour 1.5%, KH 2 P0 4 1%, CaC0 3 0.2%, Adekanol LG-109 (Asahi Denka Co., Ltd.) 0.05% and Silicone KM-70 (Shin-Etsu Chemical Co., Ltd.) 0.05% in each of six 100 ml Erlenmeyer flasks.
  • the flasks were incubated at 25 °C for 5 days on a rotary shaker (220 rpm, 5.1 cm-throw) and then inoculated (5%) into 160 ml of the same sterilized seed medium in each of sixteen 500 ml Erlenmeyer flasks. And the flasks were incubated at 25 °C for 2 days on a rotary shaker (220 rpm, 5.1 cm-throw). The resultant seed culture was inoculated (3%) into 20 liters of sterilized production medium in each of four 30-liter jar fermenters.
  • the production medium was composed of glucose 1%, modified starch 6%, cotton seed flour 1%, soybean flour 1%, KH 2 P0 4 1.6%, Na 2 HP0 4 -12H 2 0 1.2%, Adekanol LG- 109 0.05% and Silicone KM-70 0.05%.
  • the fermentation was carried out at 25°C for 5 days under aeration of 20 liters/minute and agitation of 250 rpm.
  • Retention time WF19353D 7.0 min
  • the portion corresponding to the WF19353A substance was diluted with an equal volume of water and passed through a column (350 ml) of YMC- GEL (ODS-AM 120-S50) packed with water.
  • the column was washed with 25% aqueous acetonitrile (1 liters) and eluted with 30% aqueous acetonitrile
  • the portion corresponding to the WF19353A substance was diluted with an equal volume of water and passed through a column (30 ml) of YMC GEL (ODS-AM120-S50) packed with water. The column was washed with water and eluted with 95% aqueous methanol. The eluate was concentrated in vacuo to dryness and given the crude powder.
  • the portion corresponding to the WF19353D substance was diluted with an equal volume of water and passed through a column (180 ml) of YMC- GEL (ODS-AM 120-S50) packed with water.
  • the column was washed with water (540 ml) and 25% aqueous acetonitrile (540 ml) and then eluted with 30% aqueous acetonitrile.
  • trifluoroacetic acid was added to the portion corresponding to the WF19353D substance (Final concentration was 0.2%.).
  • the solution was diluted with an equal volume of water and passed through a column (38 ml) of YMC-GEL (ODS-AM 120-S50) packed with water.
  • the column was washed with water and 25% aqueous methanol containing 0.1% trifluoroacetic acid. Then it was eluted with 40% methanol containing 0.1% trifluoroacetic acid.
  • the portion corresponding to the WF19353D substance was diluted with an equal volume of water and passed through a column (5 ml) of YMC GEL (ODS-AM120-S50) packed with water. The column was washed with water and eluted with 95% aqueous methanol. The eluate was concentrated in vacuo to dryness, and given the 4.8 mg of WF19353D substance as a white powder.
  • Fig.l and Fig.2 show ⁇ -NMR spectrum and 13 C-NMR spectrum, respectively, of WF19353F substance in DMSO-d6.
  • Fig.3 and Fig.4 show ⁇ -NMR spectrum and 13 C-NMR spectrum, respectively, of WF19353B substance in DMSO-d6.
  • Fig.5 and Fig.6 show ⁇ -NMR spectrum and 13 C-

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  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne de nouveaux composés bioactifs WF19353, qui ont une activité inhibitrice de la glucogenèse. L'invention concerne également un procédé permettant de préparer ces composés par fermentation d'une couche productrice de WF19353 appartenant à l'espèce Helicomyces dans un milieu nutritif et de récupérer les composés WF19353. L'invention concerne également une composition pharmaceutique contenant le(s) composé(s) et vecteur(s) WF19353, l'utilisation du(des) composé(s) WF19353 pour la préparation d'un médicament destiné au traitement ou à la prévention du diabète ou de l'obésité chez l'homme ou l'animal.
PCT/JP1999/002708 1998-05-29 1999-05-21 COMPOSE(S) ANTIDIABETIQUE ACTIF WF19353 ET PROCEDE DE PREPARATION DE CES COMPOSES PAR FERMENTATION COMPRENANT L'UTILISATION D'UN CHAMPIGNON DE L'ESPECE $i(HELICOMYCES) WO1999063102A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP54687799A JP2002509445A (ja) 1998-05-29 1999-05-21 新規化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPP3803A AUPP380398A0 (en) 1998-05-29 1998-05-29 Novel compounds
AUPP3803 1998-05-29

Publications (1)

Publication Number Publication Date
WO1999063102A1 true WO1999063102A1 (fr) 1999-12-09

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PCT/JP1999/002708 WO1999063102A1 (fr) 1998-05-29 1999-05-21 COMPOSE(S) ANTIDIABETIQUE ACTIF WF19353 ET PROCEDE DE PREPARATION DE CES COMPOSES PAR FERMENTATION COMPRENANT L'UTILISATION D'UN CHAMPIGNON DE L'ESPECE $i(HELICOMYCES)

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JP (1) JP2002509445A (fr)
AU (1) AUPP380398A0 (fr)
WO (1) WO1999063102A1 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No relevant documents disclosed *

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Publication number Publication date
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AUPP380398A0 (en) 1998-06-25

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