WO1983001952A1 - Physiologically active substance and process for its preparation - Google Patents

Physiologically active substance and process for its preparation Download PDF

Info

Publication number
WO1983001952A1
WO1983001952A1 PCT/JP1981/000355 JP8100355W WO8301952A1 WO 1983001952 A1 WO1983001952 A1 WO 1983001952A1 JP 8100355 W JP8100355 W JP 8100355W WO 8301952 A1 WO8301952 A1 WO 8301952A1
Authority
WO
WIPO (PCT)
Prior art keywords
active substance
culture
physiologically active
reaction
substance
Prior art date
Application number
PCT/JP1981/000355
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Ltd. Takeda Chemical Industries
Tsuneo Kanamaru
Susumu Shinagawa
Mitsuko Asai
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to PCT/JP1981/000355 priority Critical patent/WO1983001952A1/ja
Priority to US06/442,368 priority patent/US4521432A/en
Priority to CA000416173A priority patent/CA1190166A/en
Priority to JP57206810A priority patent/JPS5896049A/ja
Priority to DE8282110866T priority patent/DE3263167D1/de
Priority to EP82110866A priority patent/EP0080695B1/en
Publication of WO1983001952A1 publication Critical patent/WO1983001952A1/ja
Priority to US06/939,152 priority patent/US4767781A/en
Priority to US07/423,555 priority patent/US4948534A/en

Links

Classifications

    • 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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/66—Aspergillus

Definitions

  • the present invention relates to a novel physiologically active A-5859 having excellent fatty acid-decomposing a-adverse action, its 3 ⁇ 4, and a method for producing the same.
  • the present invention relates to a novel physiologically active substance FA-58'59, a salt thereof, and a method for producing the same.
  • the present invention relates to (1) a bioactive substance FA-585-9 and its soil 1 ⁇ 2) ⁇ a culture of a bioactive substance FA-585-9 producing bacterium belonging to the genus Mericella or Aspergillus in a medium. Then, a physiologically active substance FA-585-9 is added to the culture, and then the physiologically active substance FA-585-9 is collected.
  • bioactive substance FA-585-9 may be simply abbreviated as 8FA-585J.o
  • the present inventors searched for microbial metabolites for substances that inhibit the decomposition of fatty acids in order to develop new therapeutic drugs for uremic disease, and conducted extensive searches.
  • a substance that harms fatty acid degradation is found in a culture solution of an organism belonging to the genus Emelysera or Aspergillus, and by simply identifying this substance, the substance is a novel substance and excellent inhibition of fatty acid degradation. Found that it had an effect, and based on this, further studied, completed the present invention. Was.
  • the microorganism that can be used in the method of the present invention may be any microorganism that belongs to the genus Emerisella (; Bmerioella) or the genus Aspergillus and produces the bioactive substance PA-5859.
  • Nldulans ⁇ emerisella 'Yude, cis • pearl ⁇ larter ( ⁇ ⁇ nldulans var. Lata.), Melisse, ⁇ Lug rosa (r gulosa), Emelysera, -Dolans ( ⁇ ⁇ nldulans), Emelysera sublata ( ⁇ ⁇ sublata), Aspergillus, sp.
  • Emelysela force Dri Lineator IF 0 30851, Emelysela • Needlance Pearl Acrystarter IFO 30063, Emelysera.
  • ⁇ -Drans Baal 'Attaris Starter IFO 30844, Emelysera Kreis Tomita IF 0 30839, Emelysela, Needlance, Pearl ⁇ One-Dance IF 0 30872, Emelysela • Eudorans' Bur Larter IF 0 30847, Emelysera 'Lugrocer IF 0 8626, Emelysera' Le Groser IF 0 8
  • IFO 3085 0, IP 0 30851, IPO 30844, IFO 30839, IPO 30872, IFO 30847 .IFO 3091 3, IFG 30852, II * hi 30853 and IFO 30906 shares Deposited with the Institute for Fermentation Research (II * 0) and published in the Institute for Fermentation Osaka Research Communications jfilO, 1981 published by the Research Institute for Fermentation. I do.
  • Aspergillus ⁇ 704 strain is a fungus isolated and isolated from the field soil of Yamato-cho, Kawanishi-city, Iwate Prefecture, and has mycological properties under J3 ⁇ 4.
  • Oca. ⁇ D The area around is irregular and deep under the agar.
  • the aerial mycelia show a net-like expansion. It has a pale blue-green color with a yellow tint, and becomes pale brown as it gets older.
  • the number of conidial heads is small.
  • the color of the back is light brown or brown.
  • the growth was crazy, and the size of the mouth after 24 tJ, 2 weeks was 4.0-5.0 cm.
  • the area is flat, and the surroundings are thin and slightly tufted.
  • Aerial hyphae are sparse.
  • Conidium heads are very well formed and have a grayish yellow-green color.
  • the back has a light brown * yellowish brown color.
  • Conidium head The size is constant, but 75 is 75-100 / ⁇ in length, 20-40 / ⁇ in diameter, and is radial but gradually coarse * cylindrical.
  • Conidium pattern length 40-60 60 ⁇ , diameter 2.0-4.5 Wall surface is smooth, Colorless, slightly curved.
  • T ⁇ b Flask shape, flat top, diameter 4.5 ⁇ 7.5 ⁇
  • Emesella and Aspergillus can be mutated naturally or by mutagens as a general quality of the organism.
  • irradiation with radiation such as X-rays, gamma rays, ultraviolet rays, etc.
  • isolation of monospores treatment with various drugs or cultivation on media containing drugs, and many other methods obtained by mutation by other means
  • All mutants or naturally-occurring mutants having the property of producing FA-5589 can be used in the method of the present invention.
  • the culture medium used for fermentation in the method of the present invention may be a liquid medium or a solid medium, but may be a liquid medium or a solid medium. It is.
  • the medium is supplemented with assimilable carbon sources, digestible nitrogen sources, inorganic substances and macronutrients as appropriate.
  • carbon II include glucose, lactose, trisaccharide, malt II, dextrin, starch, glycerin, mannitol, sorbitol, oils and fats (eg, soybean oil).
  • sodium, potassium, calcium, magnesium containing salts, iron, manganese, zinc, cobalt, and nickel 4 metal salts, phosphoric acid, boric acid, etc. are used as appropriate.
  • amino acids eg, glutamic acid, aspartic acid, vanadin, lysine / parin, methamine, brolin, etc.
  • peptides eg, dipeptide, tripeptide, etc.
  • vitamins eg, Bi, B 2 , nicotinic acid, B 12, C, etc.
  • KakuShunrui eg, Bryn, kink spermidine and derivatives thereof
  • a medium or an organic acid, an alcohol, an agent or the like is added for the purpose of adjusting the pH of the medium, or an appropriate amount of an oil or a surfactant is added for the purpose of defoaming.
  • the means for culturing may be a static culturing, a shaking cultivation or a means of aeration and stirring culturing. Needless to say, it is desirable to use so-called deep aeration and stirring culture for large-scale treatment. Culture conditions are in the form of a medium ii ⁇ t ⁇ T ⁇ Naturally, it should be constant depending on the type of strain, culturing method, etc., but it is usually better to select them at a temperature of about X: ⁇ 37 and the initial PH of about 3 ⁇ S. In particular, it is desirable that the temperature during the mid-care period be about 23 to 323 ⁇ 4, and that the initial pfl be about 4 to 6.
  • the culturing period is also constant depending on the above conditions, but it is better to culture until the concentration of the physiologically active substance reaches the maximum.
  • the time required for this is about 1 to 8 days for ttfi in the case of shaking culture or aeration and stirring culture using a liquid medium.
  • Produced — 5859 is mainly present in the culture broth, so it is advantageous to separate the culture into the upper S solution and the cells by centrifugation or filtration, and then to purify the upper solution. . However, it is also possible to purify directly from L3 ⁇ 4 nutrients.
  • this FJL-5859 can be achieved by using the means normally used to collect metabolites produced by the organism. For example, after removing cells by centrifugal separation, a method is generally used in which effective substances are separated, collected, and purified from the resulting solution.
  • differences in solubility and solubility in four suitable solvents differences in removal methods and deposition rates from solutions, differences in various adsorption affinities, ion chromatography with ion exchangers, or reduction under reduced pressure, freeze drying, Crystallization, recrystallization, drying 4 Any of the methods may be used alone or in any combination, or may be used repeatedly.
  • OMPI For example, an aqueous solution of salt, vanadium chloride, sodium sulfate (ammonium sulfate) can be used.
  • an absorbing agent such as activated carbon
  • hydrophilic organic solvent systems include acetone, propyl ethyl ketone and methyl isobutyl ketone.
  • Any lower ketones, low-handling alcohols such as methanol, ethanol, isopropanol, propanol butanol, isobutanol, etc.
  • a mixed solution of a mixed solvent and water is exemplified. When water-soluble polymer substances are mixed, it is better to use a commonly used molecular sieve method to remove them. In other words, since this substance is a small molecule, for example, Sephadex G-10 [Pharma 'Fine Chemical
  • the carrier may be a strongly acidic cation resin, such as Amperlite IR-120, Dowex 50 (X2) [manufactured by Dow Chemical Company (USA)], Diayo.
  • Is obtained. — 5859 can be a pharmacologically acceptable clay.
  • the acid used for forming the salt include humic acid, nitric acid, oxalic acid, enzyme, succinic acid, citric acid, fumaric acid and the like.
  • 3420 (a), 3260 (sh) 3080 (m), 1660 (e), 1590 (e), 1485 (a), 1400 (e), 1325 (m), 1295 (a), 1145 (w), 1105 (Sale), 1060 (ir), 970 (m), 945 (m) e ⁇ ⁇ '
  • Soluble ethanol, methanol
  • 3400 (B, 3250 (a), 3190 (eh), 3045 (e), 2600 ⁇
  • Insoluble petroleum ether, hexane, getyl ether, benzene, tert.
  • Soluble ethanol, methanol
  • Envelope Greig'—Pack reaction, -Ndrin reagent, Sakaguchi reaction, Nitrich reagent, Ehr yich reagent
  • CH 3 is determined, and the substance is considered to be a novel compound.
  • the reaction was stopped by the addition of fee 70% perchloric acid 0 * 4 W, and the measurement of enzymatic activity by measuring the 14 C0 2.
  • the inhibitory activity of the compound FA-5859 was 17% at 2,50, 25% at 500 ⁇ z / l, and 1000 ⁇ /
  • F A-58559 or ⁇ of the present work is useful, for example, as a fatty acid decomposition inhibitor.
  • F A-589-fe can be used as a fatty acid-degrading agent, for example, for the treatment of diabetes in mammals (eg, mice, rats, humans). Administer about 0.2 * and 200 / kg as a daily dose of 59. Also, throw F A-5859 or its salt ⁇ ;
  • tablets, granules, capsules, tablets, and the like can be administered orally, and, for example, parenteral injections can be administered by conventional means.
  • I * A-585-99 of the present invention can be used as a biochemical reagent for elucidating the metabolism of fatty acids.
  • a cartin deficiency state can be reduced by one, so that the role of cartin in fatty acid oxidation can be further clarified.
  • the physiological role of mitochondria and peroxosomes in fatty acid hunting has been largely clarified; therefore, the incorporation of fatty acids into mitochondria;
  • the FA-585-59 of the present invention is also a useful substance as a synthetic intermediate for a compound exhibiting an advantageous fatty acid degradation inhibitory action.
  • Fig. 1 shows the infrared absorption spectrum of the physiologically active substance PA-589 obtained in Example 2 and Fig. 2 shows the biologically active substance FA-585 obtained in Example 2.
  • 9 represents the infrared absorption spectrum of the hydrochloride of No. 9.
  • Seed culture medium 500% from Q%, ⁇ W ⁇ l. 5%, Constraint Liquor 1.0%, Bolipeptone 0.5%, Yeast Extract 0.3% and Food 0.33 ⁇ 4, ⁇ 6.0 Was inoculated into a 7t 2 Tohsaka ro 7Tasco and cultured on a reciprocating shaker at 28 for 2 days.
  • Example 1 125 of the culture broth obtained in Example 1 was passed through a column of Amberlite IR 120 (H + type) (20), washed with water 40, and eluted with N-ammonia water 60. The eluate was compressed to a kill pressure of 30 to evaporate ammonia, passed through an activated carbon column for chromatography (30 £), washed with water 60, and eluted with 50% methanol water 90 £. The eluate was fractionated into 10 fractions, and the effective fractions ⁇ 5 to 6 were collected and reduced under reduced pressure to obtain 25.5 g of a syrupy crude substance.
  • Amberlite IR 120 H + type
  • Eme 9 sera christ minutar if 0 30839,
  • E main resellers one Doransu Pearl 'Doransu I ⁇ * 0 30872, E main Risepu Yudoransu Pearl Larter I i 1 0 30847, Emerisera Rugurosa IJ * 0 8626,
  • the 704 strain was inoculated into a two-volume slope flask that had been dispensed and sterilized with 500 W of the same seed culture medium as in Example 1 and cultured in a reciprocating shaking culture at 28 ° C for 2 days.
  • the solution 80 obtained in the example was treated and purified in the same manner as in the example ⁇ 2.
  • the syrup-free FA-5859 free product 3 • 15S obtained in the same manner as in the example 2 was dissolved in water 150 * After cooling, add N-hydrochloric acid 15 5 ⁇ , compress under reduced pressure, add ethanol 15 and leave to stand. The resulting crystals are recrystallized from water and ethanol to give colorless needle-like FA-5589 ⁇ 3 salts. , 3 S were obtained. m.p.214 tJ
  • the bioactive substance I * A-5859 has an excellent inhibitory effect on fatty acid degradation], and the bioactive substance 3CF A-5859 or its soil is used as a therapeutic agent for diabetes in mammals such as mice, rats, and humans.
  • the bioactive substance I 1 A-5859 is used as a biochemical reagent for elucidating the metabolism of fatty acids.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Emergency Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Obesity (AREA)
  • Microbiology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
PCT/JP1981/000355 1981-11-26 1981-11-26 Physiologically active substance and process for its preparation WO1983001952A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PCT/JP1981/000355 WO1983001952A1 (en) 1981-11-26 1981-11-26 Physiologically active substance and process for its preparation
US06/442,368 US4521432A (en) 1981-11-26 1982-11-17 Physiologically active substance FA-5859, its derivative, their production and use
CA000416173A CA1190166A (en) 1981-11-26 1982-11-23 Physiologically active substance fa-5859, its derivative, their production and use
JP57206810A JPS5896049A (ja) 1981-11-26 1982-11-24 生理活性物質ｆａ−５８５９，その誘導体，それらの製法および製剤
DE8282110866T DE3263167D1 (en) 1981-11-26 1982-11-24 Physiologically active substance fa-5859, its derivative; their production and antidiabetic agents containing said compounds
EP82110866A EP0080695B1 (en) 1981-11-26 1982-11-24 Physiologically active substance fa-5859, its derivative; their production and antidiabetic agents containing said compounds
US06/939,152 US4767781A (en) 1981-11-26 1986-12-08 Derivatives of beta-amino-gamma-trimethylammonio-butyrate and their production and use
US07/423,555 US4948534A (en) 1981-11-26 1989-10-16 Derivatives of β-amino-γ-trimethylammonio-butyrate and their production and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1981/000355 WO1983001952A1 (en) 1981-11-26 1981-11-26 Physiologically active substance and process for its preparation

Publications (1)

Publication Number Publication Date
WO1983001952A1 true WO1983001952A1 (en) 1983-06-09

Family

ID=13734327

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1981/000355 WO1983001952A1 (en) 1981-11-26 1981-11-26 Physiologically active substance and process for its preparation

Country Status (2)

Country Link
JP (1) JPS5896049A (enrdf_load_stackoverflow)
WO (1) WO1983001952A1 (enrdf_load_stackoverflow)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Tsuda Kyosuke, Nogami Hitoshi "Biseibutsu Yakuhin Kagaku" (Iyakuhin Kaihatsu Kiso Koza IV) (1971-5-1) Chijin Shokan Kabushiki Kaisha P. 357-364 *

Also Published As

Publication number Publication date
JPH0314300B2 (enrdf_load_stackoverflow) 1991-02-26
JPS5896049A (ja) 1983-06-07

Similar Documents

Publication Publication Date Title
JPH08175990A (ja) Ｐｉ３キナーゼ阻害剤とその製造法
JPS6316120B2 (enrdf_load_stackoverflow)
JPS6016236B2 (ja) 抗生物質ｃ―１５００３ ｐ―３の製造法
WO1983001952A1 (en) Physiologically active substance and process for its preparation
EP0846699A1 (en) Substance wf16616, process for production thereof, and use thereof
JPS6010720B2 (ja) 抗生物質ｃ―１５００３ ｐ―４の製造法
JPH07278041A (ja) 抗腫瘍性物質ｂｅ−２４８１１及びその製造法
JPH107557A (ja) 抗腫瘍性物質スピロラキシン
EP0504711B1 (en) Compound UCA1064-B
JPH10147594A (ja) 抗腫瘍性物質ｂｅ−４３５４７類
JP2803182B2 (ja) 抗腫瘍性物質ｂｅ―１２２３３
JP3458355B2 (ja) 抗生物質ｇｅ２２７０因子ａの生産を選択的に増加させる方法
JP2815166B2 (ja) 新規抗生物質ｍｋ１６８８物質ならびにその製造法
EP0333177A2 (en) FR-900493 substance, a process for its production and a pharmaceutical composition containing the same
US2965547A (en) Process for the production of l-6-diazo-5-oxonorleucine
KR820001433B1 (ko) 항생물질 c-15003 p-4의 제조법
JPH0429356B2 (enrdf_load_stackoverflow)
JPH09194497A (ja) 抗菌性物質ｂｅ−５３５９４類及びその製造法
KR970000591B1 (ko) 신균주 스트렙토마이세스 라벤도폴리아 DKRS 및 이를 이용한 아클라시노마이신 A, B, Y 및 아글리콘(Aglycone)의 제조방법
JPH0733395B2 (ja) 抗生物質ｔａｎ−９２８およびその製造法
JPH06298752A (ja) 抗腫瘍性物質ｂｅ−２６６６８及びその製造法
JPH05194571A (ja) 新規抗生物質ｎｋ３７４１８６ａ、ｎｋ３７４１８６ｂ、ｎｋ３７４１８６ｂ３及びｎｋ３７４１８６ｃ３、その製造法及びその用途
WO1984000539A1 (en) Deacetyl fa-5859 and process for its preparation
JPH0822236B2 (ja) 多環性キサントン系化合物の製造法
JP2000086627A (ja) 抗菌性物質ｂｅ−５４４７６及びその製造法

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): MC