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WO2006059400A1 - Antibiotics fki-2140, method of producing the same and strain producing the same - Google Patents

Antibiotics fki-2140, method of producing the same and strain producing the same Download PDF

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Publication number
WO2006059400A1
WO2006059400A1 PCT/JP2004/018443 JP2004018443W WO2006059400A1 WO 2006059400 A1 WO2006059400 A1 WO 2006059400A1 JP 2004018443 W JP2004018443 W JP 2004018443W WO 2006059400 A1 WO2006059400 A1 WO 2006059400A1
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WIPO (PCT)
Prior art keywords
substance
antibiotic
fki
absorption spectrum
producing
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Ceased
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PCT/JP2004/018443
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French (fr)
Japanese (ja)
Inventor
Hiroshi Tomoda
Rokuro Masuma
Satoshi Omura
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Kitasato Institute
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Kitasato Institute
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Priority to PCT/JP2004/018443 priority Critical patent/WO2006059400A1/en
Publication of WO2006059400A1 publication Critical patent/WO2006059400A1/en
Anticipated expiration legal-status Critical
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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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings

Definitions

  • the present invention relates to an antibiotic FK 1-2140 useful as an animal drug, agricultural chemical or pharmaceutical product having growth inhibitory activity against, for example, microorganisms, nematodes and arthropods, a method for producing the same, and a strain.
  • the antibiotic FK 1 -2 1 40 is FK I-1 40 A 1 or A 2 substance (stereoisomer of FK I-2 140 A1 substance; hereinafter referred to as A 1 substance stereoisomer), and / Or FK 1 -2140 B substance, and Z or FK I-2 1 40 C substance, and / or FK 1 -2 1 40 D substance, and or FK 1 -21 40 E substance, and Z or FK 1 -2 1 40 F substance and Z or FK I-2 1 40 G 1 or G 2 substance (stereoisomer of FK I 2 1 40 G 1 substance; hereinafter referred to as G 1 stereoisomer) is there.
  • antibiotics produced by microorganisms have been discovered so far. Among them, some antibiotics such as penicillin, streptomycin, amphotericin B, Thai mouth shin, monensin, ivernuctin, blasticidin S, polyoxin have been put to practical use in the fields of pharmaceuticals, veterinary drugs and agricultural chemicals. It is also well known that mitomycin (, bleomycin, doxorubicin, aclarubicin, adriamycin, etc. are put to practical use as anticancer agents in the pharmaceutical field (Yoshio Ueno, Satoshi Omura, “Microbial Drug Chemistry, Revised”). 3rd edition, "1 79-245, Nanedo, 1 995).
  • An object of the present invention is an antibiotic FK useful as a veterinary or agrochemical, pharmaceutical product having growth inhibitory activity against microorganisms, nematodes, arthropods, etc. that can solve various problems such as toxicity, side effects and tolerance. It provides 1-2140, its production method and strains.
  • the present inventors have continued to search for metabolites produced by microorganisms, and as a result, microorganisms, nematodes, and so on in the culture of FK1-2140 strain newly isolated from soil. It was found that substances having growth inhibitory activity against arthropods were produced. Subsequently, the active substance was separated and purified from the culture, and as a result, the following formula [I or]!
  • Antibiotic FK I-2140 G 1 or G 2 (stereoisomer of G 1), and these substances are collectively called antibiotic FK I-2140.
  • FK 1 -2140 B substance represented by: and / or the following formula [IV]]
  • FK 1 -2140 C substance represented by: and / or the following formula [V]
  • FK 1 -2140 D substance represented by: and / or the following formula [VI]
  • An antibiotic FK 1 -2140 comprising FK 1 -2 140 G 1 or G 2 substance (stereoisomer of G 1 substance) represented by the formula:
  • the present invention further includes formulas [I] to [! X] FK I— 21 4 OA 1 or A 2 substance (stereoisomer of A 1 substance), and / or FK 1-2 1 40 B substance, and Z or FK 1 -21 40 C substance , And Pino or FK 1 -2 1 40 D substance, and Z or FK 1 -21 40 E substance, and ⁇ or FK 1 -2140 F substance, and or FK I-21 40 0 1 or 0 2 substance (G
  • the present invention provides an antibiotic FK 1-21 40 exhibiting growth inhibitory activity against arthropods, which comprises one stereoisomer) as an active ingredient.
  • the present invention further belongs to a filamentous fungus and has the formulas [I] to [!
  • FK I-21 40 A1 or A 2 substance (stereoisomer of A 1 substance), and / or FK 1 -2 1 40 B substance, and or FK 1 -21 40 C3 ⁇ 4 quality, and / or FK 1—21 40 D substance, and Z or FK 1 -2 1 40 E substance, and Z or FK I—2 1 40 F substance, and or FK I—2 1 40 G 1 or G 2 (G 1 substance
  • Microorganisms capable of producing (stereoisomers) are cultured in a medium, and FK I-21 40A1 or A2 substance, and / or FK1-21 40B substance, and / or FK I-21 40 are contained in the culture.
  • Substance C and / or FK 1-21 40 D Substance and / or FK 1 -21 40 E Substance and Z or FK 1 -21 40 F Substance and / or FK I-21 40 G 1 or G 2 Accumulate substances from the culture, FK I-21 40A 1 or A2 substance, and / or FK 1-21-240 B substance, and or FK 1-21 40 C substance, and Z or FK I-21 21 D Substance, and Z or FK 1 -2 1 40 E substance, and Z or FK 1 -21 40 F substance, and or FK I -2 1 40 G 1 or G 2 substances are collected.
  • the production method of antibiotic FK 1 -2 1 40 is provided.
  • the present invention further relates to a microorganism belonging to a filamentous fungus and capable of producing the antibiotic FK 1-21 40, Penicillium sp. (Penici 1 1 i urn s p.) FKI-21 40 (FERM ABP-1 0 1 65) or a variant thereof, which provides a method for producing the antibiotic FK 1-2140.
  • the present invention further relates to Penicillum sp. FK I—2 140 (FERM ABP— 1 0 1) which belongs to filamentous fungi and has the ability to produce the antibiotic FK 1-21 40. 65).
  • the bacteriological properties of the FK1-2140 strain of the present invention are as follows.
  • This strain grew well on lapec yeast extract agar medium, 25% glycerin, nitrate agar medium, wort agar medium, Miura agar medium, etc., and conidia were well established on various agar mediums.
  • Penicillus is formed at the tip of the conidia pattern.
  • Penicillus is a single wheeler, composed of 3 to 10 phialides.
  • the phialide was an ampoule type with a size of 8 to 12 X 2.0 to 3.5 / m.
  • Fia mouth-type conidia are formed from the tip of the phialide and become chained as the culture time elapses.
  • the conidia are spherical to subspherical, grayish green in size, 2.8 to 3.0 X 2. 7 to 3.0 m, and have a streaky surface.
  • Table 1 Medium Growth condition on medium Colony surface Colony back surface Color of soluble pigment (co-alpha diameter) Wapek Yeast extract agar medium
  • the optimal growth conditions for this strain are pH 3-7 and temperature 16.8-8-32.3 ° C.
  • the growth range of this strain is pH 2-8, temperature 1 1.5-5-3 5. 6 ° C.
  • this strain belongs to the genus Penicillium (Penici 1 1 i urn). It was identified as one strain belonging to it and named Benicillium 'SP FK I—2 1 4 0. This strain is named Penicillium 'SP FK I-21 40 (Penici 1 1 i urn s p. FK I-21 40) and is based on the Budapest Treaty on the International Approval of Deposit of Microorganisms in Patent Procedures.
  • Preferred examples of the FK 1-21 40 substance-producing bacterium used in the present invention include the aforementioned Penicillium sp. (Penici 1 1 iurn s p.) FK I-2 140 strain.
  • fungi are generally susceptible to mutations in mycological characteristics and are not constant, and are naturally or commonly used UV irradiation or mutant derivatives such as N-methyl-N'-nitro- It is a well-known fact that mutations are caused by artificial mutation means using N-nitrosoguanidine, ethyl methanesulfonate, etc., and such artificial mutants as well as natural mutants belong to filamentous fungi.
  • Formula [I] ⁇ [! Any strain having the ability to produce the antibiotic FK 1 -2 1 40 represented by X] can be used in the present invention.
  • an antibiotic FK1-21-240-producing bacterium belonging to the filamentous fungus is cultured in a medium and separated from the culture. Separation. Performed by purification.
  • Nutrient sources suitable for production of the antibiotic FK 1-2140 of the present invention may be those that can be used as a nutrient source for filamentous fungi.
  • peptone for example, commercially available peptone, meat extract, corn's steeple liquor, cottonseed powder, peanut powder, soy flour, yeast extract, NZ—amine, casein hydrate, soda nitrate, ammonium nitrate, ammonium sulfate Nitrogen sources such as glycerin, starch, glucose, galactose, mannose, etc., or carbon sources such as fat, and inorganic salts such as salt, phosphate, calcium carbonate, magnesium sulfate, etc. alone or in combination Can be used.
  • Nitrogen sources such as glycerin, starch, glucose, galactose, mannose, etc.
  • carbon sources such as fat
  • inorganic salts such as salt, phosphate, calcium carbonate, magnesium sulfate, etc. alone or in combination Can be used.
  • metal salts and animal oils, vegetable oils and mineral oils can be added as antifoaming agents as necessary. Any of these may be used as long as they are useful for the production of the antibiotic FK I-2 140 using the producing bacteria, and all known filamentous fungal culture materials can be used. Liquid culture and stationary culture are preferred for mass culture of antibiotic FK I-21 40, and the culture temperature can be applied within the range in which the producing bacteria can grow and antibiotic FK 1-2140 can be produced. Culturing can be carried out by appropriately selecting according to the properties of the antibiotic FK I-2 140 substance producing bacteria using the conditions described above.
  • Antibiotic FK I-2 140 can be extracted from the culture medium with a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • known methods used for collecting fat-soluble substances such as adsorption chromatography, gel filtration chromatography, scraping from thin layer chromatography, centrifugal countercurrent distribution chromatography, high performance liquid chromatography It can be collected purely by appropriately combining or repeating the first class.
  • Infrared absorption spectrum Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 2. imax 3426, 29 1 0, 1 683, 1 606, 1 508, 1 247, 1 027, 759 cm 1 showing characteristic absorption maxima,
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in black mouth form, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water and n-hexane.
  • UV absorption spectrum UV absorption spectrum measured in ethanol Is as shown in Fig. 3; imax 208, 226, and 250 nm, showing special absorption maxima.
  • Red external absorption spectrum Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 4; imax 3253, 2925, 1 702, 1 608, 1 502, 1 253 , 1 033, shows a Japanese ⁇ absorption maximum at 8 1 1 cm 1,
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in chloroform, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in black mouth form, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water, n-hexane,
  • UV absorption spectrum The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 7, showing characteristic absorption maxima near imax 220, 279, and 324 nm.
  • Infrared absorption spectrum Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 8, imax 3268, 2964, 1 689, 1 608, 1 509, 1 378, 1 257, 1 08 1, 1 033, 806 cm 1 showing characteristic absorption maxima,
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in black mouth form, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,
  • Red external absorption spectrum Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 10, imax 3428, 2937, 1 687, 1 6 1 0, 1 5 1 1 378, 1 257, 1 072, 825, 67 l cm 1 showing characteristic absorption maxima,
  • Solubility in solvents Soluble in black mouth form, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane, (9) Color reaction: Brown with sulfuric acid.
  • Infrared absorption spectrum Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 12. imax 2937, 1 687, 1 600, 1 25
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in black mouth form, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water, n-hexane, (9) Color reaction: Brown with sulfuric acid.
  • Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 14, imax 3426, 2925, 1 689, 1 60 8, 1 46 1, 1 26 1, 1 093, 1 03 1, 806 cm—showing a special absorption maximum at 1 ,
  • Solubility in solvents Soluble in formaldehyde, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,
  • UV absorption spectrum measured in ethanol is as shown in Fig. 15; absorption characteristic around imax 218, 284, 295, 326 nm Showing maximum,
  • Red external absorption spectrum Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 16; imax 3421, 2962, 2857, 1700, 1604, 1 26 1, 1 0 97, 1 033, 806 cm—shows characteristic absorption maxima in 1 ,
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in chloroform, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water, n-hexane,
  • Infrared absorption spectrum measured by the KBr tablet method is as shown in Fig. 18. ⁇ & ⁇ 3409, 2925, 2859, 1 69 7, 1 604, 1 259 , 1 shows the 099, 1 035, 806 cm JP ⁇ absorption electrode size to 1,
  • s is a single line
  • d is a double line
  • t is a triple line
  • q is a quadruple line
  • Solubility in solvents Soluble in black mouth form, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,
  • FK I—21 40 A 1 substance, FK I—21 40 A 2 substance, FK 1 -21 40 B substance, FK I—2 1 40 C substance, FK I—21 40 D substance, FK 1 ⁇ 2 1 40 E substance, FK I— 21 40 F substance, FK I-2 1 40 G 1 substance and FK 1— 2 1 40 G 2 substance have been described in detail for various physicochemical properties. No compound has been reported so far and the antibiotic FK 1 -21 4 0 was determined to be a novel substance.
  • the antibiotic FK I — 2140 of the present invention exhibits growth inhibitory activity against arthropods, such as insecticides. Can be used as a medicine.
  • Arthropods are generic names for organisms that have nodes in their bodies and that cover and protect the body with a substance called chitin, and include organisms such as centipedes, ticks, spiders, rikiji and shrimp.
  • FIG. 1 is an ultraviolet absorption spectrum of the FK 1 -21 40 A 1 substance of the present invention.
  • FIG. 2 is an infrared absorption spectrum of the FK I 1 2 140 A 1 substance of the present invention.
  • FIG. 3 is an ultraviolet absorption spectrum of the FK I-2 1 40 A 2 substance of the present invention.
  • FIG. 4 is an infrared absorption spectrum of the FK I 2 1 4 OA 2 substance of the present invention.
  • FIG. 5 is an ultraviolet absorption spectrum of the FK I-2 1 40 0 B substance of the present invention.
  • FIG. 6 is an infrared absorption spectrum of the FK I 1 2 1 4 0 B substance of the present invention.
  • FIG. 7 is an ultraviolet absorption spectrum of the FK I-2 1 40 C material of the present invention.
  • FIG. 8 shows the infrared absorption spectrum of the FK I-2 140 C material of the present invention.
  • FIG. 9 is an ultraviolet absorption spectrum of the FK I 2 1 4 0 D substance of the present invention.
  • FIG. 10 shows the infrared absorption spectrum of the FK I-2 140D material of the present invention.
  • Fig. 11 shows the ultraviolet absorption spectrum of the FK I-2 1 40 E substance of the present invention.
  • Fig. 12 shows the infrared absorption spectrum of the FK I-2 1 40 E substance of the present invention.
  • Figure 13 shows the UV absorption spectrum of the FK I-2 1 40 F substance of the present invention.
  • Fig. 14 shows the infrared absorption spectrum of FK I-2 1 40 F substance of the present invention.
  • Figure 15 shows the ultraviolet absorption spectrum of the FK I ⁇ 2 1 40 G 1 substance of the present invention.
  • Fig. 6 shows the infrared absorption spectrum of the FK I-2 1 40 G 1 substance of the present invention.
  • Fig. 7 shows the ultraviolet absorption spectrum of the FK I ⁇ 2 1 40 G 2 substance of the present invention.
  • Fig. 8 shows the infrared absorption spectrum of the FK I ⁇ 2 1 40 G 2 substance
  • Benicillium sp. FK I—2 1 40 strain (FE RM A BP— 1 0 1 65) cultured on agar slant medium, glucose 2.0%, polypeptone (Nippon Pharmaceutical Co., Ltd., Japan) 0.5%, Yeast extract (Oriental Yeast Co., Ltd., Japan) 0.2%, agar 0.1%, potassium dihydrogen phosphate 0.1%, magnesium sulfate heptahydrate 0.05% liquid medium (pH 5.7)
  • a platinum loop was inoculated into a 500 ml 1-volume Erlenmeyer flask containing 100 ml of 1) and cultured with shaking at 27 ° C for 3 days.
  • Seed culture it As a liquid, Glucose 1.0%, Soluble starch 2.0%, Soybean oil 2.0%, Pharmamedia (Iwaki, Japan) 1.0%, Meat extract (Kyokuto Pharmaceutical, Japan) ) 60 ml of 500 ml triangular flasks containing 100 ml of liquid medium consisting of 0.5%, calcium carbonate 0.3%, magnesium sulfate heptahydrate 0.1%, agar 0.1% 1 ml each was inoculated and cultured with shaking at 27 ° C for 3 days. This was transferred in 20 Oml portions into 30 1 L roux flasks and incubated at 27 ° C for 1 day.
  • FK I-21 40 Crude substance I was subjected to high performance liquid chromatography (CAP CELL PAK C 1 8. 020 X 25 Omm, Shiseido, Japan), and 50% acetonitrile was used as the mobile phase to separate the peaks. By concentration under reduced pressure, 4.9 mg of FK I—21 40 C substance, 9.8 mg of FKI—21 40 D substance, 2.2 mg of FK I—21 40 E substance, 4.8 mg of FKI—21 40 F substance could be isolated, and 97.5 mg of FK I—2 1 40A1 substance, FK I—2 1 4 OA 2 substance, and FK I—21 40 B substance were obtained.
  • microorganisms belonging to filamentous fungi and capable of producing antibiotic FK 1-21 40 are cultured in a medium, and antibiotic FK I-2 140 substance is accumulated in the culture, and the culture is performed.
  • Antibiotic FK I-2140 collected from foods is useful as an animal medicine or pesticide because it has growth inhibitory activity against arthropods, and is expected to be effective as a medicine.

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Abstract

A microorganism (Penicillium sp. FKI-2140, FERM ABP-10165), which belongs to fungi and is capable of producing antibiotics FKI-2140 (FKI-2140A1 or A2, and/or FKI-2140B, and/or FKI-2140C, and/or FKI-2140D, and/or FKI-2140E, and/or FKI-2140F, and/or FKI-2140G1 or G2), is cultured in a medium to thereby accumulate the antibiotics FKI-2140 in the culture medium. Then the antibiotics FKI-2140 are collected from the culture medium. Because of having a growth inhibitory effect on arthropods, the obtained substances are expected as usable as animal drugs, pesticides and drugs.

Description

明細書 抗生物質 FK 1 -2 140及びその製造法並びに菌株  Description Antibiotic FK 1 -2 140, production method thereof and strain

技術分野 Technical field

本発明は、 例えば微生物、 線虫、 節足動物に対して生育阻害活性を有する動 物薬、 農薬あるいは医薬品として有用な抗生物質 FK 1 -21 40及びその製造 法並びに菌株に関する。  The present invention relates to an antibiotic FK 1-2140 useful as an animal drug, agricultural chemical or pharmaceutical product having growth inhibitory activity against, for example, microorganisms, nematodes and arthropods, a method for producing the same, and a strain.

本発明において抗生物質 FK 1 -2 1 40とは FK I - 1 40 A 1又は A 2物質 （FK I - 2 1 40A1物質の立体異性体；以下、 A 1物質の立体異性体 という） 、 及び/又は FK 1 -2140 B物質、 及び Z又は FK I - 2 1 40 C 物質、 及び/又は FK 1 -2 1 40 D物質、 及び 又は FK 1 -21 40 E物質 、 及び Z又は FK 1 -2 1 40 F物質、 及び Z又は FK I - 2 1 40 G 1又は G 2物質 （FK I 2 1 40 G 1物質の立体異性体；以下、 G 1物質の立体異性体 という） を総称したものである。  In the present invention, the antibiotic FK 1 -2 1 40 is FK I-1 40 A 1 or A 2 substance (stereoisomer of FK I-2 140 A1 substance; hereinafter referred to as A 1 substance stereoisomer), and / Or FK 1 -2140 B substance, and Z or FK I-2 1 40 C substance, and / or FK 1 -2 1 40 D substance, and or FK 1 -21 40 E substance, and Z or FK 1 -2 1 40 F substance and Z or FK I-2 1 40 G 1 or G 2 substance (stereoisomer of FK I 2 1 40 G 1 substance; hereinafter referred to as G 1 stereoisomer) is there.

背景技術 Background art

従来から微生物の生産する抗生物質は、 これまでに数多く発見されており、 それらの内で幾つかの抗生物質たとえば、 ペニシリン、 ストレプトマイシン、 ァ ムホテリシン B、 タイ口シン、 モネンシン、 ィベルヌクチン、 ブラスチシジン S 、 ポリオキシン、 等が医薬品、 動物薬および農薬の分野で実用化されている。 そ してまた、 マイトマイシン ( 、 ブレオマイシン、 ドキソルビシン、 アクラルビシ ン、 アドリアマイシン、 等が医薬の分野で抗癌剤として実用化されていることは 周知の通りである （上野芳夫、 大村智編 「微生物薬品化学、 改訂第 3版」 第 1 7 9〜 245頁、 南江堂、 1 995年） 。  Many antibiotics produced by microorganisms have been discovered so far. Among them, some antibiotics such as penicillin, streptomycin, amphotericin B, Thai mouth shin, monensin, ivernuctin, blasticidin S, polyoxin Have been put to practical use in the fields of pharmaceuticals, veterinary drugs and agricultural chemicals. It is also well known that mitomycin (, bleomycin, doxorubicin, aclarubicin, adriamycin, etc. are put to practical use as anticancer agents in the pharmaceutical field (Yoshio Ueno, Satoshi Omura, “Microbial Drug Chemistry, Revised”). 3rd edition, "1 79-245, Nanedo, 1 995).

しかしながら、 これらの抗生物質は一方では、 毒性、 副作用および耐性等の 種々の点において解決しなければならない多くの問題を抱えており、 したがって 、 これらの問題点を解消し得る新規な抗生物質の開発が強く望まれているのが現 状である。 However, these antibiotics, on the other hand, have many problems that must be solved in various respects such as toxicity, side effects and tolerance, and therefore, development of new antibiotics that can solve these problems Is strongly desired Is.

発明の開示 Disclosure of the invention

本発明者らは、 毒性、 副作用および耐性等の種々の問題点を解消し得る新規 な抗生物質を得るために、 微生物の培養物中から抗生物質の探索を続けた結果、 糸状菌に属する F K I— 2140菌株の生産する F K I— 2140物質が微生物 、 線虫、 節足動物に対して生育阻害活性を示すことを見出した。  In order to obtain a novel antibiotic capable of solving various problems such as toxicity, side effects and resistance, the present inventors have continued to search for antibiotics in the culture of microorganisms. As a result, FKI belonging to filamentous fungi — FKI produced by 2140 strain— 2140 substances were found to exhibit growth inhibitory activity against microorganisms, nematodes and arthropods.

本発明の目的は毒性、 副作用および耐性等の種々の問題点を解消し得る微生 物、 線虫、 節足動物等に対する生育阻害活性を有する動物薬あるいは農薬、 医薬 品として有用な抗生物質 FK 1— 2140及びその製造法並びに菌株を提供する ものである。  An object of the present invention is an antibiotic FK useful as a veterinary or agrochemical, pharmaceutical product having growth inhibitory activity against microorganisms, nematodes, arthropods, etc. that can solve various problems such as toxicity, side effects and tolerance. It provides 1-2140, its production method and strains.

上記の目的を実現するために本発明者らは、 微生物の産生する代謝産物につ いて探索を続けた結果、 新たに土壌から分離した FK 1— 2140菌株の培養物 中に、 微生物、 線虫、 節足動物に対して生育阻害活性を有する物質が生産されて いることを見出した。 次いで、 該培養物から活性物質を分離、 精製した結果、 後 記の式 [ I又は]！] で表される FK I - 214 OA 1又は A2物質、 及び 又は 式 [III] で表される FK 1 -2140 B物質、 及び/又は式 [IV] で表される F K I - 2140 C物質、 及び Z又は式 [V] で表される FK 1 -2140 D物質 、 及び 又は式 [VI] で表される FK 1 -2140 E物質、 及び/又は式 [W] で表される FK 1 -21 40 F物質、 及び Z又は式 [ϋ又は] X] で表される FK In order to achieve the above object, the present inventors have continued to search for metabolites produced by microorganisms, and as a result, microorganisms, nematodes, and so on in the culture of FK1-2140 strain newly isolated from soil. It was found that substances having growth inhibitory activity against arthropods were produced. Subsequently, the active substance was separated and purified from the culture, and as a result, the following formula [I or]! FK I-214 OA 1 or A2 substance represented by the above formula, and / or FK 1 -2140 B substance represented by the formula [III], and / or FKI-2140 C substance represented by the formula [IV], and Substance FK 1 -2140 D represented by Z or formula [V] and / or substance FK 1 -2140 E represented by formula [VI] and / or FK 1 -21 40 represented by formula [W] F substance represented by F substance, and Z or formula [ϋ or] X]

I - 2140 G 1又は G 2物質をそれぞれ見出した。 I-2140 G 1 or G 2 substances were found respectively.

これらの式 [I] 〜 [！ X] で表される物質は従来まったく知られていないこ とから、 本物質をそれぞれ抗生物質 FK 1 -2140八1又は八2 (A 1物質の 立体異性体） 、 抗生物質 FK I— 2140 Β、 抗生物質 FK I— 2140 C、 抗 生物質 FK I— 2140 D、 抗生物質 FK I - 2140 E、 抗生物質 FK I一 2 These formulas [I] ~ [! Since the substance represented by X] has not been known at all, this substance was classified as antibiotic FK 1 -2140 8 1 or 8 2 (stereoisomer of A 1 substance) and antibiotic FK I— 2140 Antibiotic FK I—2140 C, Antibiotic FK I—2140 D, Antibiotic FK I-2140 E, Antibiotic FK I 1 2

140 F、 抗生物質 FK I - 2140 G 1又は G 2物質 （G 1物質の立体異性体 ) と称し、 これらの物質を抗生物質 FK I— 2140と総称することにした。 140 F, Antibiotic FK I-2140 G 1 or G 2 (stereoisomer of G 1), and these substances are collectively called antibiotic FK I-2140.

本発明はかかる知見に基づいて完成されたものでり、 下記式 [I又は H] [I又は ]

Figure imgf000004_0001
The present invention has been completed based on such findings, and has the following formula [I or H] [I or]
Figure imgf000004_0001

で表される FK I— 2140 A 1又は A 2物質 （A 1物質の立体異性体） 、 及び Z又は下記式 [ ] FK I-2140 A 1 or A 2 substance (stereoisomer of A 1 substance), and Z or the following formula []

Figure imgf000004_0002
Figure imgf000004_0002

で表される FK 1 -2140 B物質、 及び/又は下記式 [IV] ]FK 1 -2140 B substance represented by: and / or the following formula [IV]]

Figure imgf000004_0003
Figure imgf000004_0003

で表される FK 1 -2140 C物質、 及び/又は下記式 [V] FK 1 -2140 C substance represented by: and / or the following formula [V]

Figure imgf000004_0004
Figure imgf000004_0004

で表される FK 1 -2140 D物質、 及び/又は下記式 [VI]

Figure imgf000005_0001
FK 1 -2140 D substance represented by: and / or the following formula [VI]
Figure imgf000005_0001

Figure imgf000005_0002
Figure imgf000005_0002

Figure imgf000005_0003
で表される FK 1 -2 140 G 1又は G 2物質 （G 1物質の立体異性体） からな る抗生物質 FK 1 -2140を提供するものである。
Figure imgf000005_0003
An antibiotic FK 1 -2140 comprising FK 1 -2 140 G 1 or G 2 substance (stereoisomer of G 1 substance) represented by the formula:

本発明は更に、 前述の式 [I] 〜 [！ X] で示される FK I— 21 4 OA 1又 は A 2物質 （A 1物質の立体異性体） 、 及び/又は FK 1 - 2 1 40 B物質、 及 び Z又は FK 1 -21 40 C物質、 及ぴノ又は FK 1 -2 1 40 D物質、 及び Z 又は FK 1 -21 40 E物質、 及びノ又は FK 1 -2140 F物質、 及び 又は FK I - 21 40〇 1又は〇2物質 （G 1物質の立体異性体） を有効成分とする 節足動物に対して生育阻害活性を示す抗生物質 FK 1 -21 40を提供するもの である。 本発明は更に、 糸状菌に属し、 前述の式 [I] 〜 [！ X] で表される FK I - 21 40 A1又は A 2物質 （A 1物質の立体異性体） 、 及び 又は FK 1 -2 1 40 B物質、 及び 又は FK 1 -21 40 C¾質、 及び 又は FK 1— 21 40 D物質、 及び Z又は FK 1 -2 1 40 E物質、 及び Z又は FK I— 2 1 40 F物 質、 及び 又は FK I— 2 1 40 G 1又は G 2 (G 1物質の立体異性体） を生産 する能力を有する微生物を培地で培養し、 培養物中に FK I— 21 40A1又は A 2物質、 及び/又は FK 1 -21 40 B物質、 及び/又は FK I - 21 40 C 物質、 及び/又は FK 1 - 2 1 40 D物質、 及び/又は FK 1 -21 40 E物質 、 及び Z又は FK 1 -21 40 F物質、 及び/又は FK I - 21 40 G 1又は G 2物質を蓄積せしめ、 該培養物から FK I - 21 40A 1又は A2物質、 及び, 又は FK 1 -2 1 40 B物質、 及び 又は FK 1 -21 40 C物質、 及び Z又は FK I - 21 40 D部質、 及び Z又は FK 1 -2 1 40 E物質、 及び Z又は FK 1 -21 40 F物質、 及び 又は FK I - 2 1 40 G 1又は G 2物質を採取する 抗生物質 FK 1 -2 1 40の製造法を提供するものである。 The present invention further includes formulas [I] to [! X] FK I— 21 4 OA 1 or A 2 substance (stereoisomer of A 1 substance), and / or FK 1-2 1 40 B substance, and Z or FK 1 -21 40 C substance , And Pino or FK 1 -2 1 40 D substance, and Z or FK 1 -21 40 E substance, and ノ or FK 1 -2140 F substance, and or FK I-21 40 0 1 or 0 2 substance (G The present invention provides an antibiotic FK 1-21 40 exhibiting growth inhibitory activity against arthropods, which comprises one stereoisomer) as an active ingredient. The present invention further belongs to a filamentous fungus and has the formulas [I] to [! X] FK I-21 40 A1 or A 2 substance (stereoisomer of A 1 substance), and / or FK 1 -2 1 40 B substance, and or FK 1 -21 40 C¾ quality, and / or FK 1—21 40 D substance, and Z or FK 1 -2 1 40 E substance, and Z or FK I—2 1 40 F substance, and or FK I—2 1 40 G 1 or G 2 (G 1 substance Microorganisms capable of producing (stereoisomers) are cultured in a medium, and FK I-21 40A1 or A2 substance, and / or FK1-21 40B substance, and / or FK I-21 40 are contained in the culture. Substance C and / or FK 1-21 40 D Substance and / or FK 1 -21 40 E Substance and Z or FK 1 -21 40 F Substance and / or FK I-21 40 G 1 or G 2 Accumulate substances from the culture, FK I-21 40A 1 or A2 substance, and / or FK 1-21-240 B substance, and or FK 1-21 40 C substance, and Z or FK I-21 21 D Substance, and Z or FK 1 -2 1 40 E substance, and Z or FK 1 -21 40 F substance, and or FK I -2 1 40 G 1 or G 2 substances are collected. The production method of antibiotic FK 1 -2 1 40 is provided.

本発明は更に、 糸状菌に属し、 抗生物質 FK 1— 21 40を生産する能力を 有する微生物がぺニシリウム 'エスピー (P e n i c i 1 1 i urn s p. ) F K I - 21 40 (FERM ABP- 1 0 1 65) またはその変異株である抗生 物質 FK 1 - 2 1 40の製造法を提供するものである。  The present invention further relates to a microorganism belonging to a filamentous fungus and capable of producing the antibiotic FK 1-21 40, Penicillium sp. (Penici 1 1 i urn s p.) FKI-21 40 (FERM ABP-1 0 1 65) or a variant thereof, which provides a method for producing the antibiotic FK 1-2140.

本発明は更に、 糸状菌に属し、 抗生物質 FK 1 -21 40を生産する能力を 有するぺニシリゥム 'エスピー （Pen i c i 1 1 i urn s p. ) FK I— 2 140 (FERM ABP— 1 0 1 65) を提供するものである。  The present invention further relates to Penicillum sp. FK I—2 140 (FERM ABP— 1 0 1) which belongs to filamentous fungi and has the ability to produce the antibiotic FK 1-21 40. 65).

前記の式 [I] 〜 [！ X] で表される本発明の FK I— 2 1 4 OA 1又は A 2 物質 （A 1物質の立体異性体） 、 及び Z又は FK I -21 40 B物質、 及びノ又 は FK I— 21 40 C物質、 及び 又は FK 1 -2140 D物質、 及び 又は F K I - 21 40 E物質、 及ぴ 又は FK 1 -2 1 40 F物質、 及び Z又は FK I - 21 40 G 1又は G 2物質 （G 1物質の立体異性体） を生産する能力を有する 微生物 （以下 「FK I - 2 1 40物質生産菌」 と称する） は、 糸状菌に属するが 、 本発明の物質生産能を有するものであればよく、 特に制限されることはない。 本発明の抗生物質 FK I— 2 1 4 0を生産するために使用される菌株の好適な一 例としては、 本発明者らによつて沖繮県の土壌より新たに分離された糸状菌 F K 1 - 2 1 4 0株が挙げられる。 The above formulas [I] to [! X] FK I— 2 1 4 OA 1 or A 2 substance (stereoisomer of A 1 substance), and Z or FK I-21 40 B substance, and No or FK I—21 40 C substance, and or FK 1 -2140 D substance, and or FKI-21 40 E substance, and or FK 1 -2 1 40 F substance, and Z or FK I-21 40 G 1 or G 2 substance (G Microorganisms that have the ability to produce (stereoisomers of one substance) (hereinafter referred to as “FK I-2 140 substance producing bacteria”) belong to filamentous fungi. Any material may be used as long as it has the substance-producing ability of the present invention, and is not particularly limited. As a suitable example of the strain used for producing the antibiotic FK I-2 1 40 of the present invention, filamentous fungus FK newly isolated from the soil of Okinoshima Prefecture by the present inventors is used. 1-2 1 4 0 strains.

本発明の FK 1— 2 1 4 0菌株の菌学的性状を示すと以下のとおりである。 The bacteriological properties of the FK1-2140 strain of the present invention are as follows.

1. 形態的特徴 1. Morphological features

本菌株は、 ッァペック ·イーストエキス寒天培地、 25 %グリセリン，硝酸 塩寒天培地、 麦芽汁寒天培地、 三浦寒天培地などで良好に生育し、 各種寒天培地 で分生子の着生は良好であつた。  This strain grew well on lapec yeast extract agar medium, 25% glycerin, nitrate agar medium, wort agar medium, Miura agar medium, etc., and conidia were well established on various agar mediums.

ッァぺック ·ィーストエキス寒天培地に生育したコロニーを顕微鏡で観察す ると、 菌糸は無色で隔壁を有しており、 分生子柄 （3 0〜75 X 0. 8〜2. 5 m) は気菌糸より直立して生じ、 分岐することはなかった。 分生子柄の先端に はぺニシルスが形成される。 ぺニシルスは単輪生で、 3〜1 0本のフィアライド が群生して構成される。 フィアライドはアンプル型で、 大きさ 8〜1 2 X 2. 0 〜3. 5 /mであった。 フィアライドの先端からフィァ口型分生子が形成され、 培養時間の経過とともに連鎖状となる。 分生子は、 球形から亜球形、 灰緑色、 大 きさ 2. 8〜3. 0 X 2. 7〜3. 0 mで、 表面は筋状である。  When the colonies grown on the toppek extract extract were observed with a microscope, the mycelium was colorless and had a septum, and a conidial pattern (30 to 75 x 0.8 to 2.5 m) Occurred upright from the aerial hyphae and never branched. Penicillus is formed at the tip of the conidia pattern. Penicillus is a single wheeler, composed of 3 to 10 phialides. The phialide was an ampoule type with a size of 8 to 12 X 2.0 to 3.5 / m. Fia mouth-type conidia are formed from the tip of the phialide and become chained as the culture time elapses. The conidia are spherical to subspherical, grayish green in size, 2.8 to 3.0 X 2. 7 to 3.0 m, and have a streaky surface.

2. 各種培地上での培養性状  2. Culture characteristics on various media

各種寒天培地上で、 25で、 7日間培養した場合の肉眼的観察結果は下記の 第 1表に示す通りであった。  The results of macroscopic observation when cultured for 7 days at 25 on various agar media were as shown in Table 1 below.

第 1表 培地 培地上の生育状態 コロニー表面 コロニー裏面 可溶性色素 (コ αニーの直径） の色調 の色調 ッァペック ·ィ一ストエキス寒天培地  Table 1 Medium Growth condition on medium Colony surface Colony back surface Color of soluble pigment (co-alpha diameter) Wapek Yeast extract agar medium

良好 （2 7〜2 9mm) 羊毛状〜ビロード状 灰緑色 薄黄褐色 薄茶褐色 しわ状 周辺 白色 Good (2 7 ~ 2 9mm) Wool-like to velvety Gray-green Light yellowish brown Light brown Brown Wrinkled Surrounding White

周辺平滑  Perimeter smoothing

25 %グリセリン ·硝酸塩寒天培地 25% glycerin nitrate agar

抑制的 （ 1 1〜 1 3 mm)  Inhibitory (1 1 to 1 3 mm)

羊毛状〜ビロード状 灰緑色 薄黄褐色 なし  Wooly-velvet gray-green light tan None

ややしわ状 周辺 白色  Slightly wrinkled around white

周辺平滑 麦芽汁寒天垮地  Surrounding smooth wort agar

良好 （2 8〜 3 0 mm)  Good (2 8-30 mm)

ビロード状 濃緑色 薄黄褐色 なし  Velvety dark green light tan none

周辺平滑 周辺 白色 三浦寒天培地  Surrounding smooth Surrounding white Miura agar medium

良好 （2 1〜2 3mm)  Good (2 1-2-3mm)

羊毛状〜ビロード状 薄灰緑色 薄灰緑色 なし  Wool-to-velvety Light gray green Light gray green None

周辺やや不規則 周辺 白色 . 生理的性状  Surrounding slightly irregular Surrounding white. Physiological properties

1 ) 最適生育条件  1) Optimal growth conditions

本菌株の最適生育条件は pH 3〜 7、 温度 1 6. 8〜32. 3°Cである。 The optimal growth conditions for this strain are pH 3-7 and temperature 16.8-8-32.3 ° C.

2) 生育の範囲 2) Range of growth

本菌株の生育範囲は pH2〜8、 温度 1 1. 5〜3 5. 6°Cである。 The growth range of this strain is pH 2-8, temperature 1 1.5-5-3 5. 6 ° C.

3) 好気性、 嫌気性の区別 3) Distinguishing between aerobic and anaerobic

好気性 微生物の国際寄託 Aerobic International deposit of microorganisms

上記 FK 1 - 2 1 40菌株の形態的特徴、 培養性状および生理的性状に基づ き、 既知菌種との比較を試みた結果、 本菌株はぺニシリウム (P e n i c i 1 1 i urn) 属に属する一菌株と同定し、 ベニシリゥム 'エスピー FK I— 2 1 4 0と命名した。 本菌株はぺニシリウム 'エスピー FK I— 21 40 (P e n i c i 1 1 i urn s p. FK I— 21 40) として、 特許手続上の微生物の寄託 の国際的承認に関するブタぺスト条約に基づき、 日本国茨城県つくば巿東 1丁目 1番地 1 中央第 6 (郵便番号 305 - 8566) [A I ST Ts ukub a Cen t r a l 6 i 1 - 1 , Η i g a s h i 1— c home T s u k υ b a—s h i, I b a r ak i -ken 305-85 66 Jap an] に所 在する独立行政法人産業技術総合研究所 特許生物寄託センター （I n t e r n a t i ona l Pa t e n t Or gan i sm De p o s i t a r y N a t i o n a 1 I n s t i t u t e o f Advan c e d I ndu s t r i a l S c i en c e and Te c hno l ogy) に平成 1 6年 （ 0 4) 1 1月 30日に寄託され、 受領番号 FERM ABP- 1 0 1 65が付与さ れた。  Based on the morphological characteristics, culture characteristics and physiological characteristics of the above FK 1-2 1 40 strain, as a result of a comparison with known bacterial species, this strain belongs to the genus Penicillium (Penici 1 1 i urn). It was identified as one strain belonging to it and named Benicillium 'SP FK I—2 1 4 0. This strain is named Penicillium 'SP FK I-21 40 (Penici 1 1 i urn s p. FK I-21 40) and is based on the Budapest Treaty on the International Approval of Deposit of Microorganisms in Patent Procedures. Kunibara Tsukuba 1-chome 1-chome 1 Central 6 (Zip 305-8566) (AI ST Ts ukub a Cen tral 6 i 1-1, Η igashi 1— c home T suk υ ba—shi, I bar ak i -ken 305-85 66 Jap an] National Institute of Advanced Industrial Science and Technology, Patent Biological Deposit Center (Internati onal l Patent Organ i sm De posita N ationa 1 I nstitute of Advan ced I ndu strial Sci en ce and Te c hno l ogy) was deposited on January 30th, 2004 and given the receipt number FERM ABP-1 0 1 65.

本発明で使用される FK 1 -21 40物質生産菌としては、 前述のベニシリ ゥム .エスピー （P e n i c i 1 1 i urn s p. ) FK I— 2 1 40菌株が好 ましい例として挙げられるが、 菌は一般的性状として菌学上の性状は極めて変異 し易く、 一定したものではなく、 自然的にあるいは通常行われる紫外線照射また は変異誘導体、.例えば N—メチル—N' —ニトロ— N—二トロソグァ二ジン、 ェ チルメタンスルホネート等を用いる人工的変異手段により変異することは周知の 事実であり、 このような人工変異株は勿論、 自然変異株も含め、 糸状菌に属し、 前記の式 [ I ] 〜 [！ X] で表される抗生物質 FK 1 -2 1 40を生産する能力を 有する菌株は、 すべて本発明に使用することができる。  Preferred examples of the FK 1-21 40 substance-producing bacterium used in the present invention include the aforementioned Penicillium sp. (Penici 1 1 iurn s p.) FK I-2 140 strain. However, fungi are generally susceptible to mutations in mycological characteristics and are not constant, and are naturally or commonly used UV irradiation or mutant derivatives such as N-methyl-N'-nitro- It is a well-known fact that mutations are caused by artificial mutation means using N-nitrosoguanidine, ethyl methanesulfonate, etc., and such artificial mutants as well as natural mutants belong to filamentous fungi. Formula [I] ~ [! Any strain having the ability to produce the antibiotic FK 1 -2 1 40 represented by X] can be used in the present invention.

本発明の抗生物質 FK 1 -2 1 40を製造するにあたっては、 先ず糸状菌に 属する抗生物質 FK 1 -2 1 40物質生産菌を培地に培養し、 その培養物から分 離. 精製することにより行われる。 本発明の抗生物質 FK 1 -2 1 40生産に適 した栄養源としては、 糸状菌の栄養源として使用し得るものであればよい。 例え ば、 市販のペプトン、 肉エキス、 コーン 'スチープ · リカー、 綿実粉、 落花生粉 、 大豆粉、 酵母エキス、 NZ—ァミン、 カゼインの水和物、 硝酸ソ一ダ、 硝酸ァ ンモニゥム、 硫酸アンモニゥム等の窒素源、 グリセリン、 澱粉、 グルコース、 ガ ラクト一ス、 マンノース等の炭水化物、 あるいは脂肪などの炭素源、 及び食塩、 リ ン酸塩、 炭酸カルシウム、 硫酸マグネシウム等の無機塩を単独あるいは組み合 わせて使用できる。 In producing the antibiotic FK1-2140 according to the present invention, first, an antibiotic FK1-21-240-producing bacterium belonging to the filamentous fungus is cultured in a medium and separated from the culture. Separation. Performed by purification. Nutrient sources suitable for production of the antibiotic FK 1-2140 of the present invention may be those that can be used as a nutrient source for filamentous fungi. For example, commercially available peptone, meat extract, corn's steeple liquor, cottonseed powder, peanut powder, soy flour, yeast extract, NZ—amine, casein hydrate, soda nitrate, ammonium nitrate, ammonium sulfate Nitrogen sources such as glycerin, starch, glucose, galactose, mannose, etc., or carbon sources such as fat, and inorganic salts such as salt, phosphate, calcium carbonate, magnesium sulfate, etc. alone or in combination Can be used.

その他必要に応じて微量の金属塩、 消泡剤として動物油、 植物油、 鉱物油な どを添加することもできる。 これらのものは生産菌を利用し抗生物質 FK I― 2 1 40の生産に役だつものであればよく、 公知の糸状菌の培養材料はすべて用い ることができる。 抗生物質 FK I— 21 40の大量培養には液体培養および静置 培養が好ましく、 培養温度は生産菌が発育し、 抗生物質 FK 1— 2 1 40を生産 できる範囲で適用できる。 培養は以上に述べた条件を使用する抗生物質 FK I - 2 1 40物質生産菌の性質に応じて適宜選択して行うことができる。  In addition, trace amounts of metal salts and animal oils, vegetable oils and mineral oils can be added as antifoaming agents as necessary. Any of these may be used as long as they are useful for the production of the antibiotic FK I-2 140 using the producing bacteria, and all known filamentous fungal culture materials can be used. Liquid culture and stationary culture are preferred for mass culture of antibiotic FK I-21 40, and the culture temperature can be applied within the range in which the producing bacteria can grow and antibiotic FK 1-2140 can be produced. Culturing can be carried out by appropriately selecting according to the properties of the antibiotic FK I-2 140 substance producing bacteria using the conditions described above.

抗生物質 FK I— 2 1 40は、 培養液よりクロ口ホルム、 酢酸ェチル等の水 不混和性の有機溶媒で抽出することができる。 上述の抽出法に加え、 脂溶性物質 の採取に用いられる公知の方法、 例えば吸着クロマトグラフィー、 ゲル濾過クロ マトグラフィー、 薄層クロマトグラフィ一よりのかき取り、 遠心向流分配クロマ トグラフィ一、 高速液体クロマトグラフィ一等を適宜組み合わせあるいは繰り返 すことによって純粋に採取することができる。  Antibiotic FK I-2 140 can be extracted from the culture medium with a water-immiscible organic solvent such as chloroform or ethyl acetate. In addition to the extraction methods described above, known methods used for collecting fat-soluble substances such as adsorption chromatography, gel filtration chromatography, scraping from thin layer chromatography, centrifugal countercurrent distribution chromatography, high performance liquid chromatography It can be collected purely by appropriately combining or repeating the first class.

理化学的性状 Physicochemical properties

次に、 本発明の抗生物質 FK 1 -2 1 40の理化学的性状について以下に説 明する。  Next, the physicochemical properties of the antibiotic FK 1-2140 according to the present invention will be described below.

[1] FK I— 21 40A 1物質  [1] FK I—21 40A 1 substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 286 (M + H、 高分解能高速原子衝撃質量分析による） 、 (3) 分子式 ： C1SH15N〇4 、 (2) Molecular weight: 286 (M + H, by high resolution fast atom bombardment mass spectrometry), (3) Molecular formula: C 1S H 15 N_〇 4,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 1図に示す通りであり、 ；imax208、 226、 250 nm付近に特徴的 な吸収極大を示す、  (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 1, showing characteristic absorption maxima near imax208, 226, and 250 nm.

(5) 赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 2図に示す通りであり、 imax 3426、 29 1 0、 1 683、 1 606 、 1 508、 1 247、 1 027、 759 c m 1に特徴的な吸収極大を示す、(5) Infrared absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 2. imax 3426, 29 1 0, 1 683, 1 606, 1 508, 1 247, 1 027, 759 cm 1 showing characteristic absorption maxima,

(6) プロトン核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （PP m)及びスピン結合定数 （Hz) を以下に示す、 (6) Proton nuclear magnetic resonance spectrum: chemical shift (PP m) and spin coupling constant (Hz) in deuterium form are shown below.

8. 07 (NH) 、 7. 68 ( 1 H)、 7. 30 ( 1 H)、 7. 21 ( 2 H) . 7. 20 ( 1 H) 、 6. 85 ( 1 H)、 6. 73 ( 2 H) 、 4. 72 ( 1 H)、 3. 71 (3H) 、  8.07 (NH), 7.68 (1H), 7.30 (1H), 7.21 (2H) 7.20 (1H), 6.85 (1H), 6.73 (2H), 4.72 (1H), 3.71 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: Chemical shift (ppm) in deuterated form is shown below.

1 70. 7 (s) . 1 59. 5 (s) , 1 33. 4 (s) . 1 3 1. 6 (s) , 1 30. 3 ( s ) . 1 29. 3 (d) 、 1 28. 4 (d) x2、 1 26. 5 (d ) 、 1 25. 3 (d) 、 1 1 6. 0 (d) 、 1 1 3. 9 (d) x 2、 77. 1 ( s) 、 75. 5 (d) 、 55. 3 (q) 、  1 70. 7 (s). 1 59. 5 (s), 1 33. 4 (s). 1 3 1. 6 (s), 1 30. 3 (s). 1 29. 3 (d), 1 28.4 (d) x2, 1 26.5 (d), 1 25.3 (d), 1 1 6.0 (d), 1 1 3.9 (d) x 2, 77.1 (s) , 75.5 (d), 55.3 (q),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

(8) 溶剤に対する溶解性： クロ口ホルム、 酢酸ェチル、 アセトン、 メタノー ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶。  (8) Solubility in solvents: Soluble in black mouth form, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water and n-hexane.

( 9 ) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: Brown with sulfuric acid.

[2] FK I - 2 1 40A2物質 （A1物質の立体異性体）  [2] FK I-2 1 40A2 substance (stereoisomer of A1 substance)

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 286 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 286 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3) 分子式 ： C16H15N〇4 、 (3) Molecular formula: C 16 H 15 N〇 4 ,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 3図に示す通りであり、 ；imax 208、 226、 250 nm付近に特徵的 な吸収極大を示す、 (4) UV absorption spectrum: UV absorption spectrum measured in ethanol Is as shown in Fig. 3; imax 208, 226, and 250 nm, showing special absorption maxima.

(5) 赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 4図に示す通りであり、 ；imax 3253、 2925、 1 702、 1 608 、 1 502、 1 253、 1 033、 8 1 1 c m 1に特徵的な吸収極大を示す、(5) Red external absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 4; imax 3253, 2925, 1 702, 1 608, 1 502, 1 253 , 1 033, shows a Japanese徵的absorption maximum at 8 1 1 cm 1,

(6) プロトン核磁気共鳴スぺクトル：重クロ口ホルム中の化学シフト （P P m) 及びスピン結合定数 （Hz) を以下に示す、 (6) Proton Nuclear Magnetic Resonance Spectrum: Chemical shift (P P m) and spin coupling constant (Hz) in deuterium form are shown below.

7. 70 (NH) 、 7. 48 (2H) 、 7. 29 ( 1 H) 、 6. 98 ( 2 H) 、 6. 97 ( 1 H) . 6. 86 ( 1 H) , 6. 78 ( 1 H) 、 4. 84 ( 1 H)、 3. 85 ( 3 H) 、  7.70 (NH), 7.48 (2H), 7.29 (1H), 6.98 (2H), 6.97 (1H), 6.86 (1H), 6.78 ( 1H), 4.84 (1H), 3.85 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す、 (7) 13 C nuclear magnetic resonance spectrum: chemical shift (ppm) in deuterium form is shown below.

1 70. 2 (s) . 1 59. 3 (s) , 1 35. 8 (s) , 1 32. 4 (s) , 1 30. 7 (d) 、 1 30. 5 (d) 、 1 27. 9 (d) x2、 127. 5 (s ) 、 1 24. 3 (d) 、 1 1 6. 1 (d) 、 1 1 4. 1 (d) X2、 76. 5 ( s) 、 73. 7 (d) 、 55. 4 (q)、  1 70. 2 (s). 1 59. 3 (s), 1 35. 8 (s), 1 32. 4 (s), 1 30.7 (d), 1 30.5 (d), 1 27 9 (d) x2, 127.5 (s), 1 24.3 (d), 1 1 6. 1 (d), 1 1 4.1 (d) X2, 76.5 (s), 73. 7 (d), 55.4 (q),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

( 8 ) 溶剤に対する溶解性： クロロホルム、 酢酸ェチル、 アセトン、 メタノ一 ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、  (8) Solubility in solvents: Soluble in chloroform, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,

( 9 ) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: Brown with sulfuric acid.

[3] FK I - 2 1 40 B物質  [3] FK I-2 1 40 B substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 384 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 384 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3)分子式 ： C2】H21N06 、 (3) Molecular formula: C 2 ] H 21 N 0 6 ,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 5図に示す通りであり、 imax226、 326、 357 nm付近に特徴的 な吸収極大を示す、 (5) 赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 6図に示す通りであり、 ；imax 3428、 2925、 1 621、 1 25 9 、 1 031、 806 cm 1に特徴的な吸収極大を示す、 (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 5. It shows characteristic absorption maxima near imax226, 326 and 357 nm. (5) Red external absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 6; imax 3428, 2925, 1 621, 1 259, 1 031, 806 A characteristic absorption maximum in cm 1

(6) プロトン核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （PP m) 及びスピン結合定数 （Hz) を以下に示す。  (6) Proton nuclear magnetic resonance spectrum: Chemical shift (PP m) and spin coupling constant (Hz) in heavy chloroform are shown below.

9. 45 (〇H)、 7. 80 (1 H) 、 7. 50 ( 1 H)、 7. 495 (NH) 、 7. 1 6 (2H)、 6. 84 (2H)、 6. 70 ( 1 H) , 6. 40 ( 1 H) 、 4. 6 1 (OH)、 3. 77 (3H)、 3. 72 ( 1 H) , 3. 62 ( 3 H) 、 2. 35 (3H)、  9.45 (〇H), 7.80 (1H), 7.50 (1H), 7.495 (NH), 7.16 (2H), 6.84 (2H), 6.70 ( 1 H), 6.40 (1 H), 4.6 1 (OH), 3.77 (3H), 3.72 (1 H), 3.62 (3 H), 2.35 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: Chemical shift (ppm) in deuterated form is shown below.

1 99. 4 (s) , 1 65. 4 (s) , 1 60. 5 (s) 、 1 57. 4 (s) , 1 38. 1 (d) 、 1 37. 5 (s) . 1 29. 7 (d) 、 1 28. 4 (d) 、 1 27. 8 (d) x2、 1 26. 8 (d) 、 1 1 9. 3 (s) 、 1 1 4. 5 (d ) X2、 1 1 1. 5 (s) 、 1 07. 6 (d) 、 84. 0 (d) 、 78. 7 (s )、 5 9. 1 (q)、 55. 4 (q)、 26. 9 (1;)、  1 99. 4 (s), 1 65. 4 (s), 1 60.5 (s), 1 57. 4 (s), 1 38. 1 (d), 1 37.5 (s). 1 29 7 (d), 1 28.4 (d), 1 27.8 (d) x2, 1 26.8 (d), 1 1 9.3 (s), 1 1 4.5 (d) X2, 1 1 1.5 (s), 1 07.6 (d), 84.0 (d), 78.7 (s), 5 9.1 (q), 55.4 (q), 26.9 ( 1;),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

(8) 溶剤に対する溶解性： クロ口ホルム、 酢酸ェチル、 アセトン、 メタノー ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、  (8) Solubility in solvents: Soluble in black mouth form, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water, n-hexane,

( 9 ) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: Brown with sulfuric acid.

[4] FK I - 21 40 C物質  [4] FK I-21 40 C substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 484 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 484 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3) 分子式 ： C27H33N〇7、 (3) Molecular formula: C 27 H 33 N_〇 7,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 7図に示す通りであり、 ；imax 220、 279、 324 nm付近に特徴的 な吸収極大を示す、 (5)赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 8図に示す通りであり、 imax 3268、 2964、 1 689、 1 608 、 1 509、 1 378、 1 257、 1 08 1、 1 033、 806 cm 1に特徴的 な吸収極大を示す、 (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 7, showing characteristic absorption maxima near imax 220, 279, and 324 nm. (5) Infrared absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 8, imax 3268, 2964, 1 689, 1 608, 1 509, 1 378, 1 257, 1 08 1, 1 033, 806 cm 1 showing characteristic absorption maxima,

(6) プロトン核磁気共鳴スぺクトル：重クロ口ホルム中の化学シフト （P P m) 及びスピン結合定数 （Hz) を以下に示す。  (6) Proton Nuclear Magnetic Resonance Spectrum: Chemical shift (P P m) and spin coupling constant (Hz) in deuterium form are shown below.

9. 1 3 (〇H) 、 7. 48 (NH) 、 7. 35 ( 1 H)、 7 1 6 (2H)、 9. 1 3 (〇H), 7.48 (NH), 7.35 (1H), 7 1 6 (2H),

6 8 1 (2H) 、 6. 77 (1 H) 、 6 32 ( 1 H) 6 24 (1 H)、 4 5 1 (OH) 、 3. 89 ( 1 H) 、 4 6 1 (OH) 3 76 (3H)、 3 68 ( 1 H) 、 3. 60 ( 3 H)、 2 1 8 (OH) 2 00 (1 H)、 1 8 6 ( 2 H) 、 1. 78 ( 1 H)、 1 4 1 (3H) 1 24 (3H) , 1 1 3 (3H) 、 6 8 1 (2H), 6. 77 (1 H), 6 32 (1 H) 6 24 (1 H), 4 5 1 (OH), 3.89 (1 H), 4 6 1 (OH) 3 76 (3H), 3 68 (1H), 3.60 (3H), 2 1 8 (OH) 2 00 (1 H), 1 8 6 (2H), 1.78 (1H), 1 4 1 (3H) 1 24 (3H), 1 1 3 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （PPm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: chemical shift (PPm) in heavy chloroform is shown below.

1 65. 5 (s) 、 1 6 0. 1 (s) . 1 55. 3 (s) ^ 1 35. 6 (d) 、 1 34. 3 (s) , 1 2 9. 0 (s) 、 1 27. 9 (d) X 2、 1 27. 8 (d ) . 1 21. 9 (s) . 1 1 4. 3 (d) X 2、 1 1 0. 8 (s) , 1 06. 9 1 65.5 (s), 1 6 0. 1 (s). 1 55. 3 (s) ^ 1 35.6 (d), 1 34.3 (s), 1 2 9. 0 (s), 1 27. 9 (d) X 2, 1 27. 8 (d). 1 21. 9 (s). 1 1 4. 3 (d) X 2, 1 1 0. 8 (s), 1 06. 9

(d) 、 85. 8 (d) 、 84. 3 (d) 、 83. 3 (s) 78. 1 (s) , 5 8. 9 (q) . 55. 4 (q) , 38. 5 (t) 、 27. 5 (q) , 26. 7(d), 85.8 (d), 84.3 (d), 83.3 (s) 78.1 (s), 5 8. 9 (q) .55.4 (q), 38.5 ( t), 27.5 (q), 26. 7

(q)、 26. 6 (t) . 24. 4 (q)、 (q), 26. 6 (t). 24. 4 (q),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

( 8 ) 溶剤に対する溶解性： クロ口ホルム、 酢酸ェチル、 アセトン、 メタノー ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、  (8) Solubility in solvents: Soluble in black mouth form, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,

( 9 ) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: Brown with sulfuric acid.

[5] FK I - 2 14 0 D物質  [5] FK I-2 14 0 D substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2)分子量 ： 4 8 4 (M + H、 高分解能高速原子衝撃質量分析による） 、 (3) 分子式 ： C27H33N07 、 (2) Molecular weight: 4 8 4 (M + H, by high resolution fast atom bombardment mass spectrometry), (3) Molecular formula: C 27 H 33 N0 7 ,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 9図に示す通りであり、 imax21 9、 279、 290、 324 nm付近 (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 9, imax21 9, 279, 290, around 324 nm

O  O

に特徴的な吸収極大を示す、 Shows a characteristic absorption maximum,

(5) 赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 1 0図に示す通りであり、 imax 3428、 2937、 1 687、 1 6 1 0、 1 5 1 し 1 378、 1 257、 1 072、 825、 67 l cm 1に特徴的 な吸収極大を示す、 (5) Red external absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 10, imax 3428, 2937, 1 687, 1 6 1 0, 1 5 1 1 378, 1 257, 1 072, 825, 67 l cm 1 showing characteristic absorption maxima,

(6) プロトン核磁気共鳴スぺクトル：重クロ口ホルム中の化学シフト （p p m) 及びスピン結合定数 （Hz) を以下に示す。  (6) Proton Nuclear Magnetic Resonance Spectrum: Chemical shift (p p m) and spin coupling constant (Hz) in deuterium form are shown below.

9. 1 6 (OH) 、 7. 7 5 (NH) 、 7. 3 5 ( 1 H) , 7. 1 8 (2H) 、 9. 1 6 (OH), 7. 75 (NH), 7. 3 5 (1 H), 7. 1 8 (2H),

6. 8 2 (2H) 、 6. 6 9 (1 H) 、 6. 3 5 ( 1 H) 、 6. 1 4 (1 H) 、6. 8 2 (2H), 6.69 (1H), 6.35 (1H), 6.14 (1H),

4. 6 0 (1 H) , 4. 5 6 (OH) 、 3. 7 6 (3H) 、 3. 7 1 (1 H) 、4. 6 0 (1 H), 4.5 6 (OH), 3.7 6 (3H), 3.7 1 (1 H),

3. 6 0 (3H) , 2. 0 3 (OH)、 1. 7 6 (1 H) 、 1. 6 9 (1 H) 、3.60 (3H), 2.03 (OH), 1.76 (1 H), 1.69 (1 H),

1. 5 2 (1 H) 、 1. 3 6 (1 H) 、 1. 3 4 (3H) , 0. 9 5 (3H) 、1. 5 2 (1 H), 1. 3 6 (1 H), 1. 3 4 (3H), 0.95 (3H),

0. 87 (3H) 、 0.87 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に '不一 9 0 (7) 13 C nuclear magnetic resonance spectrum: chemical shift (ppm) in heavy-mouthed form

1 65. 5 (s) , 1 60. 3 (s) , 1 5 5 . 2 (s) . 1 34. 4 (d) 、 1 65.5 (s), 1 60. 3 (s), 1 5 5 .2 (s). 1 34.4 (d),

1 33. 6 (s)、 1 28. 9 (s)、 1 2 7 . 8 (d) x 2 、 1 27 . 5 (d1 33.6 (s), 1 28.9 (s), 1 2 7.8 (d) x 2, 1 27.5 (d

) 、 1 2 3. 4 (d) 、 1 2 1. 6 (s) , 1 1 4. 3 (d) X 2、 1 1 0. 9), 1 2 3.4 (d), 1 2 1.6 (s), 1 1 4. 3 (d) X 2, 1 1 0. 9

(s) , 97. 0 (d) 、 84. 2 (d) 、 78. 7 (s)(s), 97.0 (d), 84.2 (d), 78.7 (s)

、 77. 1 (s) , 58. 8 (q) 、 55. 3 (q) 、 34. 1 (t) 、 34., 77.1 (s), 58.8 (q), 55.3 (q), 34.1 (t), 34.

1 (t) 、 3 1. 1 (q) 、 30. 4 ( t) 、 26. 2 (q) ^ 1 6. 7 (q) 、 但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 1 (t), 3 1.1 (q), 30.4 (t), 26.2 (q) ^ 1 6. 7 (q), where s is a single wire, d is a double wire, t is Triple line, q indicates quadruple line,

(8) 溶剤に対する溶解性： クロ口ホルム、 酢酸ェチル、 アセトン、 メタノ一 ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、 ( 9 ) 呈色反応：硫酸で褐色を呈する。 (8) Solubility in solvents: Soluble in black mouth form, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane, (9) Color reaction: Brown with sulfuric acid.

[6] F K I - 21 40 E物質  [6] F K I-21 40 E substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 382 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 382 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3) 分子式 ： C22H23N05 、 (3) Molecular formula: C 22 H 23 N0 5 ,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 1 1図に示す通りであり、 imax220、 280、 29 1、 330 n m付 近に特徴的な吸収極大を示す、  (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 11. The characteristic absorption maxima near imax220, 280, 291, and 330 nm are shown. Show,

(5)赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 1 2図に示す通りであり、 imax 2937、 1 687、 1 600、 1 25 (5) Infrared absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 12. imax 2937, 1 687, 1 600, 1 25

5、 1 1 74、 1 037 , 823 c m 1に特徵的な吸収極大を示す、 5, 1 1 74, 1 037, 823 cm 1 exhibit a special absorption maximum,

(6) プロトン核磁気共鳴スぺクトル：重クロ口ホルム中の化学シフト （P p m) 及びスピン結合定数 （Hz) を以下に示す。  (6) Proton nuclear magnetic resonance spectrum: Chemical shift (P pm) and spin coupling constant (Hz) in heavy chloroform are shown below.

9. 1 7 (〇H)、 7. 45 ( 1 H)、 7. 37 (NH)、 7. 1 7 (2H)、 9. 1 7 (〇H), 7.45 (1 H), 7.37 (NH), 7.17 (2H),

6. 84 (1 H)、 6. 82 ( 2 H)、 6. 80 ( 1 H)、 6. 34 ( 1 H)、 5. 06 ( 1 H) , 5. 02 ( 1 H)、 4. 56 (OH)、 3. 70 (3 H) , 1. 95 (3Η)、 6.84 (1H), 6.82 (2H), 6.80 (1H), 6.34 (1H), 5.06 (1H), 5.02 (1H), 4. 56 (OH), 3.70 (3 H), 1.95 (3Η),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: Chemical shift (ppm) in deuterated form is shown below.

1 65. 4 (s) , 1 60. 2 (s) 、 1 55. 6 (s) 、 1 42. 9 (s) , 1 34. 3 (s) 、 1 3 1. 2 (s) , 1 29. 1 (s) , 1 27. 9 ( d ) X 2、 1 27. 3 (d) 、 1 22. 6 (d) 、 1 22. 4 (s) 、 1 1 6. 7 ( t ) . 1 1 4. 4 (d) X 2, 1 1 0. 8 (s) , 1 07. 1 (s) , 84. 3 ( d)、 78. 8 (s)、 1 8. 7 (q)、  1 65.4 (s), 1 60.2 (s), 1 55.6 (s), 1 42.9 (s), 1 34.3 (s), 1 3 1.2 (s), 1 29.1 (s), 1 27.9 (d) X 2, 1 27.3 (d), 1 22.6 (d), 1 22.4 (s), 1 1 6.7 (t). 1 1 4.4 (d) X 2, 1 1 0.8 (s), 1 07. 1 (s), 84.3 (d), 78.8 (s), 18.7 (q),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

(8) 溶剤に対する溶解性： クロ口ホルム、 酢酸ェチル、 アセトン、 メタノー ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、 ( 9 ) 呈色反応：硫酸で褐色を呈する。 (8) Solubility in solvents: Soluble in black mouth form, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water, n-hexane, (9) Color reaction: Brown with sulfuric acid.

[6] FK I - 2 1 40 F物質  [6] FK I-2 1 40 F substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 466 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 466 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3) 分子式 ： C27H31N〇6 、 (3) Molecular formula: C 27 H 31 N_〇 6,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 1 3図に示す通りであり、 ；imax21 9、 279、 288、 323 nm付 近に特徴的な吸収極大を示す、  (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Figure 13; imax 219, 279, 288, 323 nm Showing,

(5)赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 1 4図に示す通りであり、 imax 3426、 2925、 1 689、 1 60 8、 1 46 1、 1 26 1、 1 093、 1 03 1、 806 c m—1に特徵的な吸収極 大を示す、 (5) Infrared absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 14, imax 3426, 2925, 1 689, 1 60 8, 1 46 1, 1 26 1, 1 093, 1 03 1, 806 cm—showing a special absorption maximum at 1 ,

(6) プロトン核磁気共鳴スぺクトル：重クロ口ホルム中の化学シフト （P P m ) 及びスピン結合定数 （H Z) を以下に示す , 0  (6) Proton Nuclear Magnetic Resonance Spectrum: Chemical shift (P P m) and spin coupling constant (H Z) in deuterium form are shown below, 0

9 . 1 0 (OH) 、 7. 44 (NH)、 7. 3 5 (1 H) , 7. 1 7 (2H) 、 9.10 (OH), 7.44 (NH), 7.35 (1 H), 7.17 (2H),

6 . 84 ( 1 H) 、 6. 82 (2H) 、 6. 3 3 (1 H) , 6. 3 1 (1 H) 、6.84 (1H), 6.82 (2H), 6.33 (1H), 6.31 (1H),

5 . 08 ( 1 H) 、 4. 82 (1 H)、 4. 5 3 (OH)、 4. 4 6 (1 H) ,5.08 (1 H), 4.82 (1 H), 4.5 3 (OH), 4.4 6 (1 H),

3 . 76 (3H) 、 3. 68 ( 1 H) 、 3. 6 0 (3H) . 2. 0 7 (1 H) 、3.76 (3H), 3.68 (1H), 3.60 (3H), 2.07 (1H),

2 . 03 ( 1 H) 、 1. 87 (1 H) 、 1. 7 9 ( 1 H) . 1. 7 5 (3H) 、2.03 (1H), 1.87 (1H), 1.79 (1H) 1.1.7 5 (3H),

1. 42 (3H)、 1. 42 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: Chemical shift (ppm) in deuterated form is shown below.

1 65. 5 (s) , 1 60. 3 (s) , 1 55. 2 (s) 1 34. 4 (d) . 1 33. 6 (s) , 1 28. 9 (s) 、 1 27. 8 (d) x2、 1 27. 5 (d ) , 1 23. 4 (d) 、 1 2 1. 6 (s) 、 1 1 4. 3 (d) x 2, 1 1 0. 9 (s) 、 1 06. 9 (d) 、 97. 0 (d) 、 84. 2 (d) 、 78. 7 (s) 、 77. 1 (s) 、 58. 8 (q) 、 55. 3 (q) 、 34. 1 (t) 、 34. 1 (t) 、 3 1. 1 (q) 、 30. 4 (t) 、 26. 2 ) 、 1 6. 7 (q) 、 但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 1 65.5 (s), 1 60. 3 (s), 1 55.2 (s) 1 34.4 (d). 1 33. 6 (s), 1 28.9 (s), 1 27. 8 (d) x2, 1 27.5 (d), 1 23.4 (d), 1 2 1.6 (s), 1 1 4.3 (d) x 2, 1 1 0.9 (s) , 1 06.9 (d), 97.0 (d), 84.2 (d), 78.7 (s), 77.1 (s), 58.8 (q), 55.3 (q) , 34.1 (t), 34. 1 (t), 3 1.1 (q), 30.4 (t), 26.2), 16.7 (q), where s is a single wire, d is a double wire, t is a triple wire Q indicates a quadruple line,

(8) 溶剤に対する溶解性： ク口口ホルム、 酢酸ェチル、 アセトン、 メタノー ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、  (8) Solubility in solvents: Soluble in formaldehyde, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,

(9) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: brown with sulfuric acid.

[7] FK I— 2 1 40G 1物質  [7] FK I— 2 1 40G 1 substance

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 450 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 450 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3) 分子式 ： C27H31N〇5 、 (3) Molecular formula: C 27 H 31 N 0 5 ,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 1 5図に示す通りであり、 ；imax 21 8、 284、 295、 326 nm付 近に特徴的な吸収極大を示す、  (4) UV absorption spectrum: UV absorption spectrum measured in ethanol is as shown in Fig. 15; absorption characteristic around imax 218, 284, 295, 326 nm Showing maximum,

(5) 赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 1 6図に示す通りであり、 ；imax 3421、 2962、 2857、 1 70 0、 1 604、 1 26 1、 1 0 97、 1 033、 806 cm— 1に特徴的な吸収極 大を示す、 (5) Red external absorption spectrum: Infrared absorption spectrum measured by KBr tablet method is as shown in Fig. 16; imax 3421, 2962, 2857, 1700, 1604, 1 26 1, 1 0 97, 1 033, 806 cm—shows characteristic absorption maxima in 1 ,

(6) プロトン核磁気共鳴スぺクトル：重クロ口ホルム中の化学シフト （p p m) 及びスピン結合定数 （Hz) を以下に示す。  (6) Proton Nuclear Magnetic Resonance Spectrum: Chemical shift (p p m) and spin coupling constant (Hz) in deuterium form are shown below.

7. 40 (NH) 、 7. 1 8 ( 2 H) 、 6. 90 ( 1 H) . 6. 78 ( 2 H) 、 6. 34 ( 1 H) 、 6. 28 ( 1 H)、 5. 44 ( 1 H) 、 5. 36 (OH) 、 4. 7 1 (1 H) 、 3. 80 (1 H)、 3. 74 ( 3 H) 、 3. 58 ( 3 H) 、 1. 69 ( 1 H) 、 1. 57 ( 1 H) 、 1. 56 ( 3 H) 、 1. 41 ( 3 H) 、 1. 40 (2H) 、 1. 3 1 (3H) 、  7.40 (NH), 7.18 (2H), 6.90 (1H), 6.78 (2H), 6.34 (1H), 6.28 (1H), 5. 44 (1H), 5.36 (OH), 4.71 (1H), 3.80 (1H), 3.74 (3H), 3.58 (3H), 1.69 ( 1H), 1.57 (1H), 1.56 (3H), 1.41 (3H), 1.40 (2H), 1.3 1 (3H),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: Chemical shift (ppm) in deuterated form is shown below.

1 67. 2 (s) , 1 59. 8 (s) , 1 52. 5 (s) 、 1 36. 2 (s) 1 33. 7 (s) 、 1 3 1. 9 (s) 、 1 28. 0 (d) 、 1 27. 5 (d) X 2、 1 23. 7 (d) 、 1 22. 2 (d) 、 1 1 8. 0 (s) , 1 1 4. 3 (s ) . 1 1 4. 2 (d) x 2、 1 08. 1 (s) 、 85. 1 (d) 、 80. 8 (s ) 、 78. 1 (s) . 59. 5 (q) , 55. 3 (q) . 4 1. l (t) 、 26 . 7 (q) 、 25. 6 (q) , 22. 2 (t) 、 1 7. 4 (q) 、 1 67. 2 (s), 1 59. 8 (s), 1 52.5 (s), 1 36.2 (s) 1 33.7 (s), 1 3 1.9 (s), 1 28 .0 (d), 1 27.5 (d) X 2, 1 23.7 (d), 1 22.2 (d), 1 1 8. 0 (s), 1 1 4. 3 (s). 1 1 4. 2 (d) x 2, 1 08. 1 (s), 85.1 (d), 80.8 (s), 78.1 (s) .59.5 (q), 55.3 (q) .4 1. l (t), 26. 7 (q), 25.6 (q), 22.2 (t), 17.4 (q),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

( 8 ) 溶剤に対する溶解性： クロロホルム、 酢酸ェチル、 アセトン、 メタノー ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、  (8) Solubility in solvents: Soluble in chloroform, ethyl acetate, acetone, methanol and acetonitrile. Insoluble in water, n-hexane,

( 9 ) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: Brown with sulfuric acid.

[8] FK I - 21 40 G 2物質 （G 1物質の立体異性体）  [8] FK I-21 40 G 2 substance (stereoisomer of G 1 substance)

( 1 ) 性状 ：淡黄色粉末、  (1) Property: pale yellow powder,

(2) 分子量 ： 450 (M + H、 高分解能高速原子衝撃質量分析による） 、 (2) Molecular weight: 450 (M + H, by high resolution fast atom bombardment mass spectrometry),

(3) 分子式 ： C27H31N05、 (3) Molecular formula: C 27 H 31 N0 5 ,

(4) 紫外部吸収スぺクトル：エタノール中で測定した紫外部吸収スぺクトル は第 1 7図に示す通りであり、 imax 2 1 8、 284、 295、 327 nm付 近に特徴的な吸収極大を示す、  (4) Ultraviolet absorption spectrum: The ultraviolet absorption spectrum measured in ethanol is as shown in Fig. 17. Absorption characteristic around imax 2 18, 284, 295 and 327 nm Showing maximum,

(5)赤外部吸収スぺクトル： KB r錠剤法で測定した赤外部吸収スぺクトル は第 1 8図に示す通りであり、 ληι&χ 3409、 2925、 2859、 1 69 7、 1 604、 1 259、 1 099、 1 035、 806 cm 1に特徵的な吸収極 大を示す、 (5) Infrared absorption spectrum: Infrared absorption spectrum measured by the KBr tablet method is as shown in Fig. 18. ληι & χ 3409, 2925, 2859, 1 69 7, 1 604, 1 259 , 1 shows the 099, 1 035, 806 cm JP徵的absorption electrode size to 1,

(6) プロトン核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （P P m) 及びスピン結合定数 （Hz) を以下に示す。  (6) Proton nuclear magnetic resonance spectrum: Chemical shifts (P P m) and spin coupling constants (Hz) in heavy chloroform are shown below.

7. 49 (NH)、 7. 1 9 ( 2 H)、 6. 93 ( 1 H)、 6. 79 ( 2 H)、 6. 36 ( 1 H)、 6. 3 1 ( 1 H)、 5. 50 ( 1 H)、 5. 22 (〇H)、 5. 04 (1 H)、 3. 83 ( 1 H)、 3. 77 ( 3 H)、 3. 58 ( 3 H)、 2. 09 (1 H)、 2. 0 1 (1 H)、 1. 67 ( 1 H)、 1. 66 ( 3 H)、 1. 62 (1 H)、 1. 57 (3H)、 0. 95 (3H)、  7.49 (NH), 7.19 (2H), 6.93 (1H), 6.79 (2H), 6.36 (1H), 6.31 (1H), 5 50 (1H), 5.22 (〇H), 5.04 (1H), 3.83 (1H), 3.77 (3H), 3.58 (3H), 2.09 (1 H), 2. 0 1 (1 H), 1.67 (1 H), 1.66 (3 H), 1.62 (1 H), 1.57 (3H), 0.95 (3H ),

(7) 13C核磁気共鳴スペクトル：重クロ口ホルム中の化学シフト （ppm) を以下に示す。 (7) 13 C nuclear magnetic resonance spectrum: chemical shift in deuterated form (ppm) Is shown below.

1 67. 4 (s) 、 1 59. 8 (s) , 1 52. 6 (s) 、 1 36. 2 (s) , 1 34. 1 (s) 1 32. 4 (s) 、 1 28. 4 (d) 、 1 27. 4 (d) x 2、 1 27. 1 (d) 、 1 23. 8 (d) 、 1 22. 5 (d) 、 1 1 8. 5 ( s ) . 1 1 4. 6 (s) , 1 1 3. 9 (d) x2、 1 08. 2 (s) 、 85. 0 ( d) 、 80. 5 (s) 、 78. 0 (s) 、 59. 7 (q) , 55. 4 (q) 、 4 1. 3 (t) . 25. 8 (q) , 25. 6 (q) , 23. 0 (t) 、 1 7. 7 ( q) 、  1 67.4 (s), 1 59.8 (s), 1 52.6 (s), 1 36.2 (s), 1 34.1 (s) 1 32. 4 (s), 1 28. 4 (d), 1 27.4 (d) x 2, 1 27.1 (d), 1 23.8 (d), 1 22.5 (d), 1 1 8.5 (s). 1 1 4.6 (s), 1 1 3.9 (d) x2, 1 08.2 (s), 85.0 (d), 80.5 (s), 78.0 (s), 59.7 ( q), 55.4 (q), 4 1.3 (t). 25. 8 (q), 25. 6 (q), 23.0 (t), 1 7. 7 (q),

但し、 sは一重線、 dは二重線、 tは三重線、 qは四重線を示す、 Where s is a single line, d is a double line, t is a triple line, q is a quadruple line,

(8) 溶剤に対する溶解性： クロ口ホルム、 酢酸ェチル、 アセトン、 メタノ一 ル、 ァセトニトリルに可溶。 水、 n—へキサンに難溶、  (8) Solubility in solvents: Soluble in black mouth form, ethyl acetate, acetone, methanol, and acetonitrile. Insoluble in water, n-hexane,

( 9 ) 呈色反応：硫酸で褐色を呈する。  (9) Color reaction: Brown with sulfuric acid.

以上の通り、 FK I— 21 40 A 1物質、 FK I— 21 40 A 2物質、 FK 1 -21 40 B物質、 FK I— 2 1 40 C物質、 FK I— 21 40 D物質、 FK 1 -2 1 40 E物質、 FK I— 21 40 F物質、 FK I - 2 1 40 G 1物質およ び FK 1— 2 1 40 G 2物質の各種理化学的性状について詳述したが、 このよう な性質に一致する化合物はこれまで報告されておらず、 抗生物質 FK 1 -21 4 0は新規物質であると決定した。  As described above, FK I—21 40 A 1 substance, FK I—21 40 A 2 substance, FK 1 -21 40 B substance, FK I—2 1 40 C substance, FK I—21 40 D substance, FK 1 − 2 1 40 E substance, FK I— 21 40 F substance, FK I-2 1 40 G 1 substance and FK 1— 2 1 40 G 2 substance have been described in detail for various physicochemical properties. No compound has been reported so far and the antibiotic FK 1 -21 4 0 was determined to be a novel substance.

抗節足動物活性 Anti-arthropod activity

次に、 本発明の抗生物質 FK 1 -21 40の抗節足動物活性について以下に べる。  Next, the antiarthropod activity of the antibiotic FK 1 -21 40 of the present invention will be described below.

96穴プレ一ト （コ一二ング社、 米国） に FK I - 21 4 OA 1物質、 FK 1 -21 40 A 2物質、 FK I— 21 40 B物質、 FK I— 21 40 C物質、 F K I - 2 1 40 D物質、 FK I— 2140 E物質、 FK I - 2 1 40 F物質、 F K I - 2 1 40 G 1物質及び FK 1 -21 40 G 2物質のメタノ一ル溶液を加え 、 真空ポンプ下でメタノールを留去した後、 検定用培地 （レシチン 0 1%、 炭酸水素ナトリウム 7. 5mM、 塩化カリウム 7. 5 m!V [、 塩化カルシウム二水 和物 7. 5 mM、 硫酸マグネシウム七水和物 7. 5mM) 250 1を加え、 1 5分間振とうした。 96 hole plate (Corning, USA) with FK I-21 4 OA 1 substance, FK 1 -21 40 A 2 substance, FK I— 21 40 B substance, FK I— 21 40 C substance, FKI -2 1 40 D substance, FK I— 2140 E substance, FK I-2 1 40 F substance, FKI-2 1 40 G 1 substance and FK 1 -21 40 G 2 substance methanol solution added, vacuum pump After distilling off methanol, assay medium (lecithin 0 1%, sodium bicarbonate 7.5 mM, potassium chloride 7.5 m! V [, calcium chloride dihydrate) (Sodium 7.5 mM, magnesium sulfate heptahydrate 7.5 mM) 250 1 was added and shaken for 15 minutes.

そこに緩衝液中 （トリス 20 mM、 塩化ナトリウム 440 mM、 塩化マグネ シゥム 23mM、 炭酸ナトリウム 1. 9mM、 硫酸マグネシウム 53mM、 塩化 カルシウム 1 OmM) で孵化させた節足動物^ Lr t em i a s a l i n aのノ —プリウス幼生を数匹含む緩衝液を 50 u 1加えて、 その様子を 2日後に顕微鏡 下で観察した結果を、 第 2表に示した。 Arthropods hatched in buffer (Tris 20 mM, Sodium chloride 440 mM, Magnesium chloride 23 mM, Sodium carbonate 1.9 mM, Magnesium sulfate 53 mM, Calcium chloride 1 OmM) ^ L rt em iasalina Table 2 shows the results of adding 50 u 1 of a buffer solution containing several Prius larvae and observing this state under a microscope two days later.

第 2表 抗生物質 抗節足動物活性 （ g /m 1 )  Table 2 Antibiotics Anti-arthropod activity (g / m 1)

FK I一 2 1 4 0 A 1 > 1 0 0 FK I 1 2 1 4 0 A 1> 1 0 0

FK I一 2 1 4 0 A 2 1 0 0  FK I 1 2 1 4 0 A 2 1 0 0

FK I一 2 1 4 0 B 5 0  FK I 1 2 1 4 0 B 5 0

FK I一 2 1 4 0 C 1 2 . 5  FK I 1 2 1 4 0 C 1 2.5

FK I一 2 1 4 0 D 6 • 2 5  FK I 1 2 1 4 0 D 6 • 2 5

FK I一 2 1 4 0 E 6 2 5  FK I 1 2 1 4 0 E 6 2 5

FK I一 2 1 4 0 F 0 1 9  FK I 1 2 1 4 0 F 0 1 9

FK I ― 2 1 4 0 G 1 6 • 2 5  FK I ― 2 1 4 0 G 1 6 • 2 5

FK I一 2 1 4 0 G 2 6 2 5 第 2表から明らかなように、 本発明の抗生物質 FK I _ 21 40は、 節足動 物に対して生育阻害活性を示し、 殺虫剤などの薬剤として使用し得る。 なお、 節 足動物とは体に節があり、 キチンと呼ばれる物質で体を覆い守っている生物の総 称で、 ムカデ、 ダニ、 クモ、 力二およびェビ等の生物を含む。  As can be seen from Table 2, the antibiotic FK I — 2140 of the present invention exhibits growth inhibitory activity against arthropods, such as insecticides. Can be used as a medicine. Arthropods are generic names for organisms that have nodes in their bodies and that cover and protect the body with a substance called chitin, and include organisms such as centipedes, ticks, spiders, rikiji and shrimp.

図面の簡単な説明 Brief Description of Drawings

第 1図は本発明の FK 1 -21 40 A 1物質の紫外部吸収スぺクトル。 第 2図は本発明の FK I一 2 140 A 1物質の赤外部吸収スぺクトル。 FIG. 1 is an ultraviolet absorption spectrum of the FK 1 -21 40 A 1 substance of the present invention. FIG. 2 is an infrared absorption spectrum of the FK I 1 2 140 A 1 substance of the present invention.

第 3図は本発明の FK I - 2 1 4 0 A 2物質の紫外部吸収スぺクトル。 第 4図は本発明の FK I一 2 1 4 OA 2物質の赤外部吸収スぺクトル。 第 5図は本発明の FK I - 2 1 4 0 B物質の紫外部吸収スぺクトル。  FIG. 3 is an ultraviolet absorption spectrum of the FK I-2 1 40 A 2 substance of the present invention. FIG. 4 is an infrared absorption spectrum of the FK I 2 1 4 OA 2 substance of the present invention. FIG. 5 is an ultraviolet absorption spectrum of the FK I-2 1 40 0 B substance of the present invention.

第 6図は本発明の FK I一 2 1 4 0 B物質の赤外部吸収スぺクトル。  FIG. 6 is an infrared absorption spectrum of the FK I 1 2 1 4 0 B substance of the present invention.

第 7図は本発明の FK I― 2 1 4 0 C物質の紫外部吸収スぺクトル。  FIG. 7 is an ultraviolet absorption spectrum of the FK I-2 1 40 C material of the present invention.

第 8図は本発明の FK I― 2 1 4 0 C物質の赤外部吸収スぺクトル。  FIG. 8 shows the infrared absorption spectrum of the FK I-2 140 C material of the present invention.

第 9図は本発明の FK I一 2 1 4 0 D物質の紫外部吸収スぺクトル。  FIG. 9 is an ultraviolet absorption spectrum of the FK I 2 1 4 0 D substance of the present invention.

第 1 0図は本発明の FK I ― 2 1 40 D物質の赤外部吸収スぺクトル。 第 1 1図は本発明の FK I ― 2 1 40 E物質の紫外部吸収スぺクトル。 第 1 2図は本発明の FK I ― 2 1 40 E物質の赤外部吸収スぺクトル。 第 1 3図は本発明の FK I ― 2 1 40 F物質の紫外部吸収スぺクトル。 第 1 4図は本発明の FK I ― 2 1 40 F物質の赤外部吸収スぺクトル。 第 1 5図は本発明の FK I ― 2 1 40 G 1物質の紫外部吸収スぺクトル 第 1 6図は本発明の FK I ― 2 1 40 G 1物質の赤外部吸収スぺクトル 第 1 7図は本発明の FK I ― 2 1 40 G 2物質の紫外部吸収スぺクトル 第 1 8図は本発明の FK I ― 2 1 40 G 2物質の赤外部吸収スぺクトル 発明を実施するための最良の形態  FIG. 10 shows the infrared absorption spectrum of the FK I-2 140D material of the present invention. Fig. 11 shows the ultraviolet absorption spectrum of the FK I-2 1 40 E substance of the present invention. Fig. 12 shows the infrared absorption spectrum of the FK I-2 1 40 E substance of the present invention. Figure 13 shows the UV absorption spectrum of the FK I-2 1 40 F substance of the present invention. Fig. 14 shows the infrared absorption spectrum of FK I-2 1 40 F substance of the present invention. Figure 15 shows the ultraviolet absorption spectrum of the FK I ― 2 1 40 G 1 substance of the present invention. Fig. 6 shows the infrared absorption spectrum of the FK I-2 1 40 G 1 substance of the present invention. Fig. 7 shows the ultraviolet absorption spectrum of the FK I ― 2 1 40 G 2 substance of the present invention. Fig. 8 shows the infrared absorption spectrum of the FK I ― 2 1 40 G 2 substance of the present invention. Best form for

次に、 実施例を挙げて本発明を説明するが、 本発明はこれのみに限定される ものでない。  Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

実施例 Example

寒天斜面培地で培養したベニシリゥム ·エスピー FK I— 2 1 40株 （FE RM A BP— 1 0 1 65) より、 グルコース 2. 0%、 ポリペプトン （日本製 薬社、 日本国） 0. 5%、 酵母エキス （オリエンタル酵母工業社、 日本国） 0. 2%、 寒天 0. 1 %、 リン酸二水素カリウム 0. 1 %、 硫酸マグネシウム七水和 物 0. 05%からなる液体培地 （pH5. 7) が 1 00m 1入った 500 m 1容 三角フラスコに 1白金耳接種し、 27 °Cで 3日間振とう培養した。 それを種培養 液として、 グルコ一ス 1. 0%、 可溶性澱粉 2. 0%、 大豆油 2. 0%、 ファー マメディア （イワキ社、 日本国） 1. 0%、 肉エキス （極東製薬工業社、 日本国 ) 0. 5%、 炭酸カルシウム 0. 3 %、 硫酸マグネシウム七水和物 0. 1 %、 寒 天 0. 1%からなる液体培地を 1 00 mlずつ分注した 500 ml容三角フラス コ 60本に 1 m 1ずつ接種し、 27 °Cで 3日間振とう培養し、 これを 1 L容ルー フラスコ 30本に 20 Omlずつ移し、 27°Cで 1 1日間静置培養した。 Benicillium sp. FK I—2 1 40 strain (FE RM A BP— 1 0 1 65) cultured on agar slant medium, glucose 2.0%, polypeptone (Nippon Pharmaceutical Co., Ltd., Japan) 0.5%, Yeast extract (Oriental Yeast Co., Ltd., Japan) 0.2%, agar 0.1%, potassium dihydrogen phosphate 0.1%, magnesium sulfate heptahydrate 0.05% liquid medium (pH 5.7) A platinum loop was inoculated into a 500 ml 1-volume Erlenmeyer flask containing 100 ml of 1) and cultured with shaking at 27 ° C for 3 days. Seed culture it As a liquid, Glucose 1.0%, Soluble starch 2.0%, Soybean oil 2.0%, Pharmamedia (Iwaki, Japan) 1.0%, Meat extract (Kyokuto Pharmaceutical, Japan) ) 60 ml of 500 ml triangular flasks containing 100 ml of liquid medium consisting of 0.5%, calcium carbonate 0.3%, magnesium sulfate heptahydrate 0.1%, agar 0.1% 1 ml each was inoculated and cultured with shaking at 27 ° C for 3 days. This was transferred in 20 Oml portions into 30 1 L roux flasks and incubated at 27 ° C for 1 day.

培養液に等量のァセトンを加え攪拌し、 ろ過後上澄みを減圧下ァセトンを留 去し、 これを酢酸ェチルで抽出した。 酢酸ェチル層は減圧濃縮下乾固し、 これを へキサン—ァセトニトリル （ 1 ： 1) で分配した後、 メタノール層を減圧濃縮下 乾固し、 1. 75 gの粗物質 Iを得、 これをへキサン—クロ口ホルムーアセトニ トリル （5 ： 1 ： 5) の二層系の下層を固定層および上層を移動層に用いた、 液 々分配クロマトグラフィー （三鬼社、 日本国） にかけ反転溶出にて溶出し、 減圧 濃縮することにより 97. 5mgの FK I— 21 40A 1物質、 FK I— 2 1 4 OA 2物質、 FK I— 21 40 B物質、 FK I - 21 40 C物質、 FK I— 21 40 D物質、 FK I - 2 1 40 E物質および FK 1 -2 1 40 F物質の粗物質 I と 3 1 0. lmgの FK I— 2 140G 1物質および FK I— 2140 G 2物質 の粗物質 Iを得た。  An equal amount of acetone was added to the culture solution and stirred. After filtration, the supernatant was removed from the supernatant under reduced pressure, and this was extracted with ethyl acetate. The ethyl acetate layer was evaporated to dryness under reduced pressure, and this was partitioned with hexane-acetonitrile (1: 1). The methanol layer was then evaporated to dryness under reduced pressure to obtain 1.75 g of crude substance I. Inverted elution by liquid-liquid partition chromatography (Mikisha, Japan) using hexane-black mouth formaceto acetonitrile (5: 1: 5) lower layer as fixed layer and upper layer as moving layer Elution and concentration under reduced pressure 97.5 mg FK I—21 40A 1 substance, FK I—2 1 4 OA 2 substance, FK I—21 40 B substance, FK I-21 21 C substance, FK I—21 40 D substance, FK I-2 1 40 E substance and FK 1 -2 1 40 F substance crude substance I and 3 1 0. lmg FK I— 2 140G 1 substance and FK I— 2140 G 2 substance crude substance I got.

FK I - 21 40粗物質 Iは高速液体クロマトグラフィー （CAP CELL PAK C 1 8. 020 X 25 Omm, 資生堂社、 日本国） にかけ、 50 %ァ セトニトリルを移動相としてピークを分取し、 それらを減圧濃縮することにより 、 4. 9mgの FK I— 21 40 C物質、 9. 8 m gの F K I— 21 40 D物質 、 2. 2mgの FK I— 21 40 E物質、 4. 8 m gの F K I— 21 40 F物質 を単離することができ、 97. 5mgの FK I— 2 1 40A1物質、 FK I— 2 1 4 OA 2物質、 FK I— 21 40 B物質の粗物質を得た。  FK I-21 40 Crude substance I was subjected to high performance liquid chromatography (CAP CELL PAK C 1 8. 020 X 25 Omm, Shiseido, Japan), and 50% acetonitrile was used as the mobile phase to separate the peaks. By concentration under reduced pressure, 4.9 mg of FK I—21 40 C substance, 9.8 mg of FKI—21 40 D substance, 2.2 mg of FK I—21 40 E substance, 4.8 mg of FKI—21 40 F substance could be isolated, and 97.5 mg of FK I—2 1 40A1 substance, FK I—2 1 4 OA 2 substance, and FK I—21 40 B substance were obtained.

これを再び高速液体クロマトグラフィー （CAPCELL PAK C 1 8 、 20 X 250 mm、 資生堂社、 日本国） にかけ、 30 %ァセトニトリルを移 動相としてピークを分取し、 それらを減圧濃縮することにより、 8. 7mgの F K I— 21 40A 1物質、 4. 0 mgの FK I _ 21 40 A 2物質、 0. 8mg の FK 1 -21 40 B物質を単離することができた。 粗物質 ITは高速液体クロマ トグラフィー （CAPCELL PAK C 1 8, 020 X 25 Omm, 資生堂 社、 日本国） にかけ、 50%ァセトニトリルを移動相としてピークを分取し、 そ れらを減圧濃縮することにより 3. Omgの FK I— 2140 G 1物質、 2. 0 mgの FK 1 -2 1 40 G 2物質を単離することができた。 This was again subjected to high-performance liquid chromatography (CAPCELL PAK C 1 8, 20 X 250 mm, Shiseido, Japan), and peaks were separated using 30% acetonitrile as the mobile phase and concentrated under reduced pressure. 7mg F 1 substance of KI-21 40A, 4.0 mg of FK I — 21 40 A 2 substance, 0.8 mg of FK 1 -21 40 B substance could be isolated. Crude material IT is subjected to high-performance liquid chromatography (CAPCELL PAK C 18 020 X 25 Omm, Shiseido, Japan), fractionated with 50% acetonitrile as the mobile phase, and concentrated under reduced pressure. According to the results, 3. Omg of FK I—2140 G 1 substance and 2.0 mg of FK 1 -2 1 40 G 2 substance could be isolated.

産業上の利用分野 Industrial application fields

以上説明したように、 糸状菌に属し、 抗生物質 FK 1 -21 40を生産する 能力を有する微生物を培地で培養し、 培養物中に抗生物質 FK I— 2 1 40物質 を蓄積せしめ、 該培養物から採取した抗生物質 FK I - 21 40は、 節足動物に 対する生育阻害活性を有することから動物薬あるいは農薬として有用であり、 医 薬品としての効果が期待される。  As described above, microorganisms belonging to filamentous fungi and capable of producing antibiotic FK 1-21 40 are cultured in a medium, and antibiotic FK I-2 140 substance is accumulated in the culture, and the culture is performed. Antibiotic FK I-2140 collected from foods is useful as an animal medicine or pesticide because it has growth inhibitory activity against arthropods, and is expected to be effective as a medicine.

Claims

請 求 の 範 囲 The scope of the claims 1. 下記式 1. Following formula [I又は]！]
Figure imgf000025_0001
で表される FK 1 -21 40 A 1物質又は FK I— 2 1 40 A 2物質 （ A 1物質 の立体異性体） 、 及び/又は下記式 [1Π]
Figure imgf000025_0002
で表される FK 1 -21 40 B物質、 及び/又は下記式 [W] [I or]! ]
Figure imgf000025_0001
FK 1 -21 40 A 1 substance or FK I— 2 1 40 A 2 substance (stereoisomer of A 1 substance), and / or the following formula [1 []
Figure imgf000025_0002
FK 1 -21 40 B substance represented by: and / or the following formula [W]
Figure imgf000025_0003
で表される FK 1 -21 40 C物質、 及び/又は下記式 [V]
Figure imgf000025_0003
FK 1 -21 40 C substance represented by: and / or the following formula [V]
Figure imgf000025_0004
で表される FK 1 -2140D物質、 及び/又は下記式 [VI]
Figure imgf000025_0004
FK 1 -2140D substance represented by: and / or the following formula [VI]
Figure imgf000026_0001
で表される FK 1 -2140 E物質、 及び/又は下記式 [I]
Figure imgf000026_0001
FK 1 -2140 E substance represented by: and / or the following formula [I]
Figure imgf000026_0002
で表される FK 1 -2140 F物質、 及び/又は下記式 [ϋ又は K]
Figure imgf000026_0002
FK 1 -2140 F substance represented by: and / or the following formula [ϋ or K] [1 [又は K]
Figure imgf000026_0003
で表される FK I - 2140 G 1物質又は FK I— 2140 G 2物質 （G 1物質 の立体異性体） からなる抗生物質 FK 1— 2140。 [1 [or K]
Figure imgf000026_0003
An antibiotic FK 1-2140 consisting of FK I-2140 G 1 substance or FK I-2140 G 2 substance (stereoisomer of G 1 substance) represented by 2. 請求の範囲 1記載の、 式 [I]〜 [！ X] で示される FK I - 214 OA 1物質又は A 2物質 （A 1物質の立体異性体） 、 及びノ又は FK I - 2140 B 物質、 及び又は FK 1 -2140 C物質、 及び/又は FK 1 -2140 D物質、 及び/又は FK 1 -2140 E物質、 及び/又は FK 1 -2140 F物質、 及び /又は FK I— 2140〇 1物質又は〇2物質 （G 1物質の立体異性体） を有効 成分とする節足動物に対して生育阻害活性を示す抗生物質 FK I— 2 1 40。 2. The formulas [I] to [! X] FK I-214 OA 1 substance or A 2 substance (stereoisomer of A 1 substance), and NO or FK I-2140 B substance, and / or FK 1 -2140 C substance, and / or FK 1 -2140 Substance D and / or FK 1 -2140 Substance E and / or FK 1 -2140 Substance F and / or FK I—2140 0 1 substance or 02 substance (stereoisomer of G 1 substance) Antibiotic FK I—2 1 40, which shows growth inhibitory activity against arthropods. 3. 糸状菌に属し、 請求の範囲 1記載の式 [I] 〜 [！ ] で表される FK I -2 1 40A 1物質又は A2物質 （A 1物質の立体異性体） 、 及び Z又は FK I - 1 40 B物質、 及び 又は FK 1 -2 140 C物質、 及び 又は FK I - 2 1 40 D物質、 及び Z又は FK 1 -21 40 E物質、 及び/又は FK 1 -21 4 0 F物質、 及び Z又は FK I - 21 40 G 1物質又は G 2物質 （G I物質の立体 異性体） を生産する能力を有する微生物を培地で培養し、 培養物中に FK I一 2 1 4 OA 1物質又は A 2物質、 及ぴ 又は FK 1— 21 40 B物質、 及び/又は FK I - 21 40 C物質、 及び 又は FK 1 - 21 40 D物質、 及び/又は FK 1 - 2 1 40 E物質、 及び Z又は FK 1 -21 40 F物質、 及び 又は FK I― 21 40 G 1物質又は G 2物質を蓄積せしめ、 該培養物から FK 1— 2 1 4 OA 1物質又は A 2物質、 及び/又は FK 1 -21 40 B物質、 及び/又は FK I― 2 1 40 C物質、 及び/又は FK 1 -2140 D物質、 及び/又は FK 1 -2 1 40 E物質、 及び/又は FK 1 -2 1 40 F物質及び/又は FK I - 2 1 40 G 1物質又は G 2物質を採取することを特徴とする抗生物質 FK I— 2 1 40の製 造法。 3. It belongs to a filamentous fungus, and the formulas [I] to [! ] FK I -2 1 40A 1 substance or A2 substance (stereoisomer of A 1 substance), and Z or FK I-1 40 B substance, and or FK 1 -2 140 C substance, and or FK I-2 1 40 D substance, and Z or FK 1 -21 40 E substance, and / or FK 1 -21 4 0 F substance, and Z or FK I-21 40 G 1 substance or G 2 substance (of GI substance Microorganisms capable of producing stereoisomers) are cultured in a medium, and FK I 2 1 4 OA 1 substance or A 2 substance, and or FK 1-21 40 B substance, and / or FK in the culture I-21 40 C substance, and / or FK 1-21 40 D substance, and / or FK 1-2 1 40 E substance, and Z or FK 1 -21 40 F substance, and or FK I-21 40 G 1 substance Or G 2 substance is accumulated and FK 1—2 1 4 OA 1 substance or A 2 substance, and / or FK 1 -21 40 B substance, and / or FK I—2 1 40 C substance, and / Or FK 1 -2140 D substance, and / or FK 1 -2 1 40 E substance, and / or FK 1- 2 1 40 F substance and / or FK I-2 1 40 G 1 substance or G 2 substance is collected. 4. 糸状菌に属し、 抗生物質 FK I -21 40を生産する能力を有する微生 物がぺニシリゥム .エスピー （Pen i c i l 1 i urn s p. ) FK I— 2 1 40 (FERM ABP- 1 0 1 65) またはその変異株である請求の範囲 3記 載の抗生物質 F K 1 -2 1 40の製造法。 4. A microorganism that belongs to the filamentous fungus and has the ability to produce the antibiotic FK I-21 40 is Penicillium sp. FK I— 2 1 40 1 65) or a method for producing the antibiotic FK 1 -2 140 described in claim 3 which is a mutant thereof. 5. 糸状菌に属し、 抗生物質 FK 1 -21 40を生産する能力を有するベニ シリウム 'エスピー （P en i c i 1 1 i urn s p. ) FK I— 2 1 40 (F ER ABP— 1 0 1 65) 。 5. Benicillium sp. (P en ici 1 1 i urn s p.) FK I— 2 1 40 (F ER ABP— 1 0 1 belonging to filamentous fungi and capable of producing antibiotic FK 1 -21 40 65).
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CN109810055A (en) * 2019-01-17 2019-05-28 广东轻工职业技术学院 A novel alkaloid compound derived from marine fungi and its application in the preparation of anti-lung cancer drugs

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009060015A1 (en) 2007-11-09 2009-05-14 Novartis Ag Dihydroquinolinones as ectoparasiticides
JP2011503029A (en) * 2007-11-09 2011-01-27 ノバルティス アーゲー Dihydroquinolinones as ectoparasite drugs
AU2008324224B2 (en) * 2007-11-09 2013-12-05 Elanco Tiergesundheit Ag Dihydroquinolinones as ectoparasiticides
US8648091B2 (en) 2007-11-09 2014-02-11 Novartis Ag Dihydroquinolinones as ectoparasiticides
WO2010128095A1 (en) * 2009-05-07 2010-11-11 Novartis Ag Ectoparasiticidal compositions
EP2248422A1 (en) 2009-05-08 2010-11-10 Novartis AG Ectoparasiticidal compositions
CN104886063A (en) * 2015-06-15 2015-09-09 牛赡光 Application of compound yaequinolone B
WO2017036128A1 (en) * 2015-09-06 2017-03-09 中国海洋大学 Alkaloid compound, preparation method thereof and use thereof as antiviral agent against herpes simplex virus type 1
US10639303B2 (en) 2015-09-06 2020-05-05 Ocean University Of China Alkaloids and their preparation and application as anti-HSV-1 agents
CN106554307A (en) * 2015-09-29 2017-04-05 于跃 A kind of preparation method of antiviral quinolinone alkaloid derivative derived from marine fungus
CN106554307B (en) * 2015-09-29 2019-09-27 扬州蓝色生物医药科技有限公司 A kind of preparation method of antiviral quinolinone alkaloid derivative derived from marine fungus
CN109776550A (en) * 2019-01-17 2019-05-21 广东轻工职业技术学院 A novel alkaloid compound derived from marine fungi and its application in the preparation of food preservatives
CN109810055A (en) * 2019-01-17 2019-05-28 广东轻工职业技术学院 A novel alkaloid compound derived from marine fungi and its application in the preparation of anti-lung cancer drugs
CN109776550B (en) * 2019-01-17 2021-08-10 广东轻工职业技术学院 Alkaloid compound derived from marine fungi and application thereof in preparation of food preservative

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