WO2002020816A1 - Nouveau compose f-15949 - Google Patents

Nouveau compose f-15949 Download PDF

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Publication number
WO2002020816A1
WO2002020816A1 PCT/JP2001/007589 JP0107589W WO0220816A1 WO 2002020816 A1 WO2002020816 A1 WO 2002020816A1 JP 0107589 W JP0107589 W JP 0107589W WO 0220816 A1 WO0220816 A1 WO 0220816A1
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Prior art keywords
measured
methanol
spectrum
ppm
salt
Prior art date
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PCT/JP2001/007589
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English (en)
Japanese (ja)
Inventor
Toshio Takatsu
Tatsuya Yano
Shiho Kozuma
Yasunori Ono
Original Assignee
Sankyo Company, Limited
Ohnuki, Takashi
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Application filed by Sankyo Company, Limited, Ohnuki, Takashi filed Critical Sankyo Company, Limited
Priority to AU2001282599A priority Critical patent/AU2001282599A1/en
Publication of WO2002020816A1 publication Critical patent/WO2002020816A1/fr

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    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
    • C12P7/6436—Fatty acid esters
    • C12P7/6445—Glycerides
    • C12P7/6463—Glycerides obtained from glyceride producing microorganisms, e.g. single cell oil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Definitions

  • the present invention relates to a compound having antifungal activity or a salt thereof, a method for producing the compound, a medicament containing the compound as an active ingredient, an antifungal agent containing the compound as an active ingredient, and a microorganism producing the compound. Etc.
  • antifungal compounds currently used in clinical practice include amphotericin B, flucytosine, and azole compounds. Many of these compounds have become problematic in terms of cytotoxicity and emergence of resistant bacteria.
  • Echinocandin (Nyfe 1 er, R. and K eller — Schierlein, W., H) produced by the genus Aspergillus (A spergi 11 us), etc. elv. C hi m.
  • the inventors conducted intensive searches to find novel compounds having antifungal activity As a result, a novel compound was found in a fungal culture, and it was confirmed that the compound had antifungal activity. Thus, the present invention was completed.
  • the present invention provides a compound having an antifungal activity or a salt thereof, a method for producing the compound, a medicament containing the compound as an active ingredient, an antifungal agent containing the compound as an active ingredient, and production of the compound.
  • the purpose of the present invention is to provide microorganisms and the like that perform the treatment.
  • R represents an alkyl group having 1 to 6 carbon atoms or a hydrogen atom.
  • Solubility Soluble in methanol and acetone, insoluble in water and normal hexane
  • Solubility Soluble in methanol and acetone, insoluble in water and normal hexane
  • UV absorption spectrum The ultraviolet absorption spectrum measured in methanol shows the following maximum absorption: 2336 nm ( ⁇ 79-70)
  • Solubility Soluble in methanol and acetone, insoluble in water and normal hexane
  • the nuclear magnetic resonance spectrum measured at 74 ppm, is as follows: '.
  • 13C- nuclear magnetic resonance spectrum measured in heavy methanol at 49.O ppm in heavy methanol is shown below:
  • a medicament comprising the compound according to any one of (1) to (6) or a salt thereof as an active ingredient
  • An antifungal composition comprising the compound according to any one of (1) to (6) or a salt thereof as an active ingredient.
  • Haplographium 'Heliosef Rum' Lao 'and de Hog H aplographiumhelioceph al um V asant Rao & de Hoog
  • S ANK 2 689 9 FE RM BP— 7 2 4 3) 1 2
  • a method for preventing or treating mycosis comprising using the compound or the salt thereof according to any one of (6) to (6).
  • the compound described in any one of the above (1) to (6) is generically referred to as a substance F-15949.
  • the straight-chain or branched-chain alkyl having 1 to 6 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, t-butyl, isopentyl, and isobutyl.
  • a hexyl group and the like can be exemplified.
  • a compound represented by the above formula (1) represented by the general formula (I) and R i in the general formula represents a hydrogen atom or the compound described in the above (3) is represented by F-15949.
  • —1 is a compound represented by the general formula (I) of the above (1), wherein R i is a methyl group or the compound of the above (4).
  • 9 4 9 4 referred to as c as described above straight ⁇ compounds showing a branched chain alkyl group having the general formula Ri has 1 to 6 carbon atoms represented and in said general formula (I) is, according to conventional methods It can be synthesized by reacting F-15949-1 or F-15949-4 with various alkylating agents and the like.
  • the compound described in the above (5) or (6) is referred to as F-15949-12.
  • F—1 5 9 4 9—1, F—1 5 9 4 9—2 and F—1 5 949—4 are represented by the following general formula (III)
  • the F-15949 substance can be converted to a salt according to a conventional method.
  • Salts of F—15949 substances can be used for pharmaceutical or non-pharmaceutical applications.
  • Salts of the F15949 substance used in medicine are not particularly limited as long as they are pharmacologically acceptable.
  • examples include sodium salts, potassium salts, ammonium salts and the like. it can.
  • the salt of the F-15949 substance used for non-pharmaceutical uses (for example, as a synthetic intermediate) is not particularly limited.
  • Alkali metal salts such as tritium salts and calcium salts, alkaline earth metal salts such as calcium salts, barium salts and magnesium salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts, Metal salts such as cobalt salts; inorganic salts such as ammonium salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, and N-methyldal.
  • inorganic salts such as ammonium salts, tert-octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, and N-methyldal.
  • Kamin salt Guanidine salt, Getylamine salt, Triethylamine salt, Dicyclohexylamine salt, N, N 'Dibenzinoleethylenediamine salt, Salt, pro force in salt, diethanolamine salt, N- benzyl Hue phenethyl Rua Min salts, piperidines Rajin Salts, organic amine salts such as tetramethylammonium salt, tris (hydroxymethyl) amino methane salt; and amino acids such as glycine, lysine, arginine, ordin, and asparagine. Salts and the like can be mentioned.
  • the F-159499 substance can be converted into an ester according to a conventional method.
  • the ester of the F-159499 substance include an ester formed of an alkyl group having 1 to 6 carbon atoms.
  • Such esters include, for example, methyl ester, ethyl ester, propyl ester, isopropyl ether, butyl ester, isobutyl ester, s_butyl ester, t-butynoleestenol, pentynoleestenol, isopentinole
  • Examples include esdenole and neopentinole ester.
  • the F-159949 substance has various isomers.
  • these isomers and mixtures of these isomers are all represented by a single formula.
  • isomers thereof and c also includes Te base that is also advised mixtures of these isomers, F- 1 5 94 9 substances and their salts, it may become solvates.
  • water may be absorbed when left in the air or recrystallized to form adsorbed water or form a hydrate. Such a solvate is also included in the present invention.
  • the present invention also includes all of so-called prodrugs, which are metabolized in the living body and converted into F-15949 substances.
  • the F-15949 substance is present in a fungal culture that produces the F-159499 substance.
  • Examples of the F—15949 substance-producing bacterium include fungi belonging to the genus Haplographium.
  • the haplopro- gram “Helicosepharum Lao” and “De” are used.
  • Hog Hap 1 ographlumheliocephalum Vasant Rao & de Hoog
  • more preferably haplography film 'Heliosefalum' Rao 'and'de'hog S ANK 268 899 (F ERM BP-7243) strain ( Hereinafter, it is simply referred to as “S ANK 26 89 9 shares.”)
  • S 'ANK 26 8 9 9 share, 1 9 July 1998, has been separated from the soil that was collected in the pine forest of Shimane Prefecture c
  • the bacteriological properties of the S ANK 26 89 9 strain are described below.
  • the composition of the medium used for culturing the bacteria is as shown below.
  • PDA medium Nissipotedextrox agar 39 g
  • WSH medium Improved Weitz manandSilva-Hutner medium
  • CMA medium Corn meal agar medium
  • the flora is flat, consisting of a thin mycelium, colorless, white at all edges, without exudate and odor. It produces sparse conidia in the center. The back is colorless.
  • the flora is flat, consists of a thick hyphal layer, colorless, white at all edges, without exudate and phlegm. The back is colorless.
  • the flora is flat, consisting of a thin mycelium, colorless, wool-like in the center, light yellow (2A3) at all edges, without exudate and smell. The back was colorless.
  • the micromorphology of the S ANK 2 689 9 strain was as follows.
  • the bristles are elongate, smooth and smooth, 4440-650 / im in length, 4-6 ⁇ m in width at the base, tapering to the top and dark.
  • the conidium is 45 to 105 ⁇ m in length and 4 to 6 ⁇ m in width and stands upright from the hypha, straight or slightly bent, solitary, smooth, with septum, near the base It becomes dark on thick walls and colorless on thin walls towards the top.
  • the conidium-forming cells are multibudding, forming primary metres at the top of the conidiophores, Form conidia or secondary metres.
  • the primary metrology is 5 to 9 m in length and 3.5 to 5 / m in width. Thin wall ⁇ Smooth and colorless. Secondary metres are colorless and form conidia.
  • Conidia are 6 to 9 / m in length and 2 to 3 m in width, are aerobically linked with or without branching, are single-celled, smooth and thin-walled. Conidia are cylindrical to oblong, rarely slightly bent, have flat emergent roots at both ends, and are colorless.
  • the strain was compared with the strains described in recent literature.
  • the strain was found to be Zucconi & Pagano Coneerningthegenericli mits ⁇ nHap 1 ographiu m., Mycotaxon 66, 11 (1993), and Rao & de Hoogeworcritical Hyphomycetes from India.Stud.Myco 1., 28, 56 (19986) Has been matched with the haplography game 'Heliosef Alm. Lao and de Hog. Therefore, this strain was identified as haplografium 'Heliosefalum-Lao' and de hog, and transferred to haplografum 'Loseofalum.
  • Lao-and-de-hog S ANK2698 It was named 9 strains. This strain was established on July 26, 2000 at 1-1-1 Higashi, Tsukuba City, Ibaraki Prefecture, Japan 1 The 6th National Institute of Advanced Industrial Science and Technology (AIST) International Depositary with the Faculty of Engineering, Biotechnology and Industrial Technology Research Institute) and given the deposit number FE RM BP—.
  • fungi are susceptible to mutation in the natural world or by artificial manipulation (for example, ultraviolet irradiation, irradiation, chemical treatment, etc.), and the SANK 26899 strain of the present invention is used. Is also presumed to be prone to such mutations.
  • the SANK26889 strain includes all its mutants.
  • mutants also include those obtained by genetic methods, for example, recombination, transduction, transformation, and the like. That is, SANK 28699 strains that produce F-15949 substances, their mutant strains, and all strains that are not clearly distinguished from them are S ANK 28699 strains. Is included.
  • the F_15949 substance can be produced by culturing a bacterium producing the substance.
  • F— 1 5 9 4 9 It can be performed using a medium such as that used for production of the product.
  • Such media contain carbon and nitrogen sources and inorganic salts that can be assimilated by microorganisms.
  • Carbon sources include, for example, glucose, fructose, maltose, sucrose, mannitol, glycerin, dextrin, oats, rye, corn starch, potatoes, corn flour, soybean oil, cottonseed oil, Molasses, citric acid, tartaric acid and the like can be mentioned. These carbon sources can be contained in the medium alone or in combination of two or more.
  • the amount of the carbon source contained in the medium depends on other components in the medium, but is usually 1 to 10% by weight of the medium.
  • Nitrogen sources include, for example, soybean flour, bran, peanut flour, cottonseed powder, casein hydrolyzate, pharmamine, corn steep liquor, peptone, meat extract, yeast, yeast extract, malt extract, and sodium nitrate Examples thereof include lithium, ammonium nitrate, and ammonium sulfate. These nitrogen sources can be contained in the medium alone or in combination of two or more.
  • the amount of nitrogen source to be contained in the culture medium depends on other components in the culture medium, but is usually 0.2 to 6% by weight of the culture medium.
  • the carbon source and the nitrogen source need not be of high purity, but may be of low purity. Low purity carbon and nitrogen sources may contain trace amounts of growth factors, vitamins, inorganic nutrients, and the like. '
  • the inorganic salt is not particularly limited as long as an ion can be obtained.
  • examples thereof include a sodium salt, a potassium salt, a magnesium salt, an ammonium salt, a calcium salt, a phosphate, and a sulfate. , Hydrochloride, carbonate and the like.
  • vitamin B1 which can be assimilated by the F ⁇ 15949 substance-producing bacteria, vitamins such as biotin, cell growth promoting substances such as thiamine, metal salts such as manganese and molybdenum, etc. May also be included in the medium as needed.
  • an antifoaming agent such as silicon oil, polyalkylene glycol ether, vegetable oil, animal oil, or a surfactant may be contained in the medium. It is preferable that the pH of the medium used for the culture of the F-15949 substance producing bacterium is pH 4.0 to 6.5. '''
  • the upper limit of the culture temperature of the F-159 4 9 substance-producing bacterium is 23 to 37 ° C, the lower limit is 15 to 18 ° C, and the preferred range is 18 to 30 ° C.
  • the temperature is more preferably 18 ° C to 23 ° C.
  • the culture method is not particularly limited as long as it is a method usually used for culturing microorganisms, and examples thereof include a culture method using a solid medium, a stirring culture method, a shaking culture method, and an aeration culture method.
  • the stirring culture method, the shaking culture method, and the aeration culture method are preferable, and the shaking culture method is more preferable.
  • the aeration and stirring culture method is most suitable for industrial production.
  • the following is an example of the culture of the F-15949 substance producing bacterium.
  • Seed culture is performed by shaking at 20 to 23 ° C for several days in an Erlenmeyer flask containing the liquid medium as described above. Seed culture is divided into two or more stages, if necessary, and scaled up in stages. The obtained seed culture is used for main culture.
  • the main culture is basically performed under the same conditions as the seed culture. That is, the seed culture is inoculated into the main culture medium, and cultured with shaking at a constant temperature for several days.
  • the medium is prepared in a jar fermenter or tank. Sterilize the medium at 121 ° C for 20 minutes, cool, and inoculate the seed culture. Culture is performed at 20 ° C by aeration and stirring.
  • the amount of F-15949 substance in the culture solution can be measured by high performance liquid chromatography (HPL) analysis.
  • HPL high performance liquid chromatography
  • the F-15949 substance can be extracted from the obtained culture, the cells contained therein and / or the culture supernatant thereof. Centrifugation or filtration using diatomaceous earth as a filter aid can be used to separate cells and other solids from the culture supernatant. Can be used.
  • the physical and chemical properties of the compound can be used for the extraction of F-155949.
  • the F-15949 substance present in the culture filtrate or culture supernatant is an organic solvent that is immiscible with water under acidic or neutral conditions, such as ethyl acetate, chloroform, chloride, methylene chloride. , Butanol, and a mixed solvent of two or more thereof.
  • the F-15949 substance present in the cells is extracted from the cells using 50 to 90% aqueous acetone or methanol, and the organic solvent is distilled off. Extraction can be carried out in the same manner as when it is present in a liquid or culture supernatant.
  • the F-15949 substance present in the whole culture is 20 to 80%, preferably 40 to 60%, more preferably 50 to 50% acetone or methanol in the whole culture. % Can be added and extracted. After completion of the extraction, diatomaceous earth is filtered as a filter aid, and the resulting soluble matter can be extracted in the same manner as in the culture filtrate or culture supernatant. Purification to isolate the F-15949 substance from the above extract is performed by adsorption chromatography, ion exchange chromatography, partition chromatography, reverse phase chromatography, HPLC, etc. This can be done by any means.
  • Adsorption chromatography involves contacting the above-mentioned extract containing the F-15949 substance with an adsorbent and adsorbing and removing the foreign substances, or adsorbing the F-15949 substances and contaminating them. After removing the substance, the elution is performed by eluting the F-15949 substance.
  • the adsorbent include activated carbon, Amberlite XAD-2, XAD-4 (hereinafter, manufactured by Rohm and Haas), Diaion HP-10, HP-20, and CH P—20 P; HP—50; Sepabeads SP—207 (manufactured by Mitsubishi Chemical Corporation).
  • the solvent used to elute the adsorbed F-15949 substance include methanol water, acetone water, and butanol water.
  • Ion-exchange chromatography uses the fact that F-15949 acts as an acidic substance. That is, the above-mentioned extract containing the F-15949 substance is brought into contact with an anion exchange carrier to adsorb the F-15949 substance to the carrier, and after removing impurities, the solvent-based F— 1 5 9 4 by changing ionic strength, pH, etc. Elute 9 substances.
  • anion exchange carriers examples include DEAE-cellulose (Brown), DEAE-Sephadex, DEAE-Sepharose, QAE-Sephadex (above, manufactured by Pharmacia's Fine 'Chemicals), DEAE-G Opal C (manufactured by Tohsoichi Co., Ltd.), Duo Light A-2 (manufactured by Diamond 'Shamrock' Chemical), Amber Light IRA-68 (manufactured by Rohm & Norse) And Dowex 1X4, 21K, and SBR-P (manufactured by Dow Chemical Company).
  • DEAE-cellulose Brown
  • DEAE-Sephadex DEAE-Sepharose
  • QAE-Sephadex above, manufactured by Pharmacia's Fine 'Chemicals
  • DEAE-G Opal C manufactured by Tohsoichi Co., Ltd.
  • Duo Light A-2 manufactured by Diamond 'Shamrock' Chemical
  • Amber Light IRA-68 manufactured by Rohm & Nor
  • Carriers used for distribution chromatography include, for example, silica gel, TS ⁇ gelt Yopearl HW-40F (manufactured by Tosoichi Co., Ltd.), and Sephadex LH-20 (manufactured by Amersham Pharmacia). And the like.
  • Examples of the carrier used for the reverse phase chromatography include Cosmo Seal 140C18 (manufactured by Nacalai Tester Co., Ltd.).
  • Columns used for HPLC include, for example, Shodex Asahi Pack C8P50-4E (manufactured by Showa Denko KK), YMC Pack OD S-AM (manufactured by IMC Corporation), capsules Reverse-phase columns such as Pack C 8 UG 1220 (manufactured by Shiseido Co., Ltd.) and Gasil ODS (manufactured by Sensyu Kagaku Co., Ltd.).
  • These purification means can be used alone or in appropriate combination to isolate the F-15949 substance. If necessary, the same purification procedure may be repeated.
  • a method suitable for purification such as column chromatography, batch chromatography, thin-layer chromatography, etc., can be selected.
  • the F-15949 substance or its salt has an antifungal effect and is therefore useful as a prophylactic or therapeutic agent for fungal infections.
  • F-155949 or a salt thereof When F-155949 or a salt thereof is used as a prophylactic or therapeutic agent for fungal infection, it can be administered in various forms.
  • the dosage form depends on the formulation, age, sex, disease and the like. For example, tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules, capsules and the like are orally administered. Injections are administered intravenously, intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered rectally.
  • Formulations containing various substances as active ingredients are formed according to standard methods. It can be produced using known auxiliaries usually used in the field of pharmaceutical preparations such as agents, binders, disintegrants, lubricants, dissolving agents, flavoring agents, coating agents and the like.
  • auxiliaries usually used in the field of pharmaceutical preparations such as agents, binders, disintegrants, lubricants, dissolving agents, flavoring agents, coating agents and the like.
  • widely known carriers in the art can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, carbonated calcium, kaolin, crystalline cellulose, and the like.
  • excipients such as silicic acid, water, ethanol, propanol, simple syrup, dextrose solution, starch solution, gelatin solution, carboxymethyl cenorellose, shellac, methinoresenorelose, potassium phosphate, polyvinylinolepyrrolidone, etc.
  • Disintegrators such as lactose, sucrose, stealine, cacao batata , Decay inhibitor such as hydrogenated oil, quaternary ammonium base, absorption enhancer such as sodium lauryl sulfate, humectant such as glycerin and starch, starch, lactose, kaolin, bentonite, colloid
  • Adsorbents such as silica, lubricating agents such as purified talc, stearate, powdered boric acid, polyethylene glycol and the like can be mentioned. Tablets can be made into tablets coated with a usual coating, if necessary, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film
  • a wide variety of carriers known in the art can be used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc. And binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.
  • the liquid and suspensions are preferably sterilized and isotonic with blood.
  • these liquids, emulsions and suspensions they should be used as diluents.
  • Those widely known in the field can be widely used, and examples thereof include water, ethyl alcohol, propylene glycol, epoxidized isostearyl alcohol, poloxysylated isostearyl alcohol, and polyoxetylene sorbitan fatty acid esters. it can. They may contain sufficient amounts of salt, sugar, or glycerin to maintain isotonicity.
  • Solubilizer buffer, soothing sugar, Coloring agents, preservatives, flavoring agents, flavoring agents, sweetening agents, and other agents may be included.
  • a normal liquid sampling agent such as glucose or amino acid, or as an emulsion with polyoxyethylene sorbitan fatty acid esters and the like.
  • the amount of the F-1,5,949 substance contained in the above-mentioned pharmaceutical preparation is not particularly limited, but the upper limit is 30 to 70% by weight, the lower limit is 1% by weight, and the preferable range is 1 to 3%. 0% by weight. .
  • the dosage of a pharmaceutical preparation containing F-15949-substance depends on the symptoms, age, body weight, administration method, dosage form, etc., but is usually administered to adults daily.
  • the amount of 9 material the upper limit is 2 0 to 2 0 0 0 mg
  • the lower limit is 0.0 0 1 to 0. lm g
  • the preferred range is 0.0 1 to 2 0 0 mg
  • the number of doses of pharmaceutical preparations containing F-155949 is once every few days, once a day, or several times a day.
  • Example 1 Culture of F—1 5 9 4 9 substance producing bacteria
  • Antifoam agent 1 0.1 ml
  • An HPLC column (capsule pack C 8 UG 12 0: diameter: 200 ⁇ l) was previously prepared by equilibrating the acetone solution (300 ⁇ l) with 72% acetonitrile water containing 0.04% trifluoroacetic acid.
  • mm X length 250 mm: manufactured by Shiseido Co., Ltd. and developed at a flow rate of 13. O ml / min with the solvent system used for equilibration.
  • the ultraviolet absorption of the active fraction was detected at a wavelength of 240 nm, and a peak eluted at a retention time of 25 to 26 minutes was collected.
  • concentration under reduced pressure to m 1 the suspension was suspended in 2 O ml of water and freeze-dried to obtain 10 mg of F-159, 49-1 as a colorless powder. Isolation of 5 9 4 9—2
  • F-155949-2 in this example was monitored by HPLC under the following conditions.
  • F-1 595 49-4 in the present embodiment was monitored by monitoring HPLC under the following conditions.
  • F-15949-1 and F-15949-4 exhibited growth inhibitory activity against various fungi.
  • the antifungal activity of F-15949-2 can be confirmed and confirmed by the method of this example.
  • novel compound F-15949 or the salt thereof provided by the present invention has an excellent antifungal activity and is useful as a preventive or therapeutic agent for various fungal infections.

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Abstract

L'invention concerne des nouveaux composés représentés par la formule générale suivante (I) ou des sels correspondants (I), dans laquelle R1 représente C1-16 ou de l'hydrogène, des nouveaux composés représentés par la formule générale suivante (II) ou des sels correspondants (II). Cette invention concerne également un procédé de production de ces composés au moyen d'un micro-organisme appartenant au genre ∫i⊃Haplographium∫/i⊃, etc. Du fait de leur excellent effet antifongique, on utilise ces composés comme produits préventifs ou remèdes à diverses infections fongiques.
PCT/JP2001/007589 2000-09-06 2001-09-03 Nouveau compose f-15949 WO2002020816A1 (fr)

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AU2001282599A AU2001282599A1 (en) 2000-09-06 2001-09-03 Novel compound f-15949

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JP2000269772 2000-09-06
JP2000-269772 2000-09-06

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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUZANNE M.M. ET AL.: "Khafrefungin, a novel inhibitor of sphingolipid synthesis", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 272, no. 51, 1997, pages 32709 - 32714, XP001055056 *

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