• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A new compound which we refer to as Monacolin K, has the molecular formula C24H36O5 and has been found to have valuable antihypercholesteraemic activity. It can be produced by cultivating suitable micro-organisms from the genus Monascus, especially Monascus ruber strain 1005 (FERM 4822).
    公开号:SU969702A1
    申请号:SU802977031
    申请日:1980-09-12
    公开日:1982-10-30
    发明作者:Эндо Акира
    申请人:Санкио Компани Лимитед (Фирма)；
    IPC主号:
    专利说明:

    Growth on agar medium Saburo. (Sebourand) at 25 ° C is very fast: .1 the colony diameter reaches 6-6.5 cm 10 days after inoculation. The surface of the colony is very flat and the basal and aerial hyphae develop better, fj, than on a potato-jarKoKfio-agar medium. The number of glue stetation is very few. The surface of the colony can vary in color from reddish yellow to reddish brown, and the reverse side from reddish brown to dark brown. Growth on agar, on broth from oat flour, proceeds slowly: the diameter of the colony reaches 1.52 cm 10 days after the inoculation of the Colony is flat - The development of air hyphae and the formation of claistothecia is very weak. The surface and the reverse side of the colony may be dark red to reddish-brown non-color. Growth on the екаapek agar medium is very slow: the diameter of the colony reaches 1.6-1.8 cm after 10 days after inoculation. Growth rates on each of: reduced-media at essentially equal speeds at 25C. Morphological signs. Kleistotatsii spherical with a diameter of 30-60 μm, the walls of klekstotetii thin and membranous, their nols, ki have sepal walls and X1 of each soetoit hyphae with a diameter of 3.5-4.5 μm and a length of 15-70. um The bag consists of 8 spores, and it is approximately spherical, short and quickly disappearing. Ascospores are colorless and have an egg-like or oval shape, the size of 4-5Х4-7М surfaces is smooth. Conidia are colorless, spherical or pear-shaped in shape, size 6–9–6–11 µm, their bases are flat, the walls are relatively thick and smooth. Conidia are bound together by their foundations. Conidiophores are similar to vegetative hyphae and are branched or unbranched, with conidia forming on top. Mycelium is colorless and branched, has sepal walls, most of which are 3-5 µm in diameter. Based on the studied characteristics, all the considered microorganisms were identified as Monascus ruber strains. Getting Molakolin K. .Honascus ruber strain 1005 inoculates a liquid culture medium containing,% by volume: glucose 6, peptone 2.5, liquid after soaking 0.5 maize and ammonium chloride. Cultivation is continued under aerobic conditions at 28 ° C for 10 days. The resulting filtrate (.5) culture; 1 broth broth was adjusted to pH 3 by adding 6 n. hydrochloric acid, and then extracted equal; / volume of ethyl acetate. The solvent from the extract is distilled off under reduced pressure and the residue is dissolved in J.OO ml of benzene. The insoluble material is filtered off. The filtrate is washed twice, each time with 100 ml of a 5% w / v aqueous solution of sodium bicarbonate. Then 100 ml, 0.2 N are added to the washed filtrate. an aqueous solution of sodium hydroxide and the mixture is stirred at room temperature. After confirming the disappearance of Monacolin K from the benzene layer by TLC, the aqueous layer was separated, then the pH of the aqueous layer was adjusted to 3 with 6 n. hydrochloric acid and the resulting solution is extracted twice, each time with 100 ml of ethyl acetate. The extract was evaporated to dryness under reduced pressure, to give 260 mg of oil. The oil is dissolved in benzene, allowed to crystallize, and then recrystallized from an aqueous solution of acetone to obtain 87 kg of Monacolin K. colorless needles. Monacolin K has the following properties: Color and shape are colorless crystals. M.p. 157, (with decomposition). Elementary analysis,%: C 71,56; H 8.85; -O 19.59. Molecular weight 404 (according to mass spectrometry). Molecular formula. UV absorption spectrum (methanol), nm: maximum at 232, 238 and 246. Solubility. Soluble in lower alcohols (for example, methanol, ethanol, and propanol), acetone, chloroform, ethyl acetate, and benzene. Insoluble in petroleum ether and hexane. The specific rotation is frfjp. + 307.6 (s 1, methanol). Thin layer chromatography: Rf 0.47 5715 Kieselgel 60 Pr 54 silica gel (Merck & Co), 4: 1 mixture of methylene chloride acetone, detected as UV absorbing mass, 50% (v / v) sulfuric acid (color from pale red until reddish brown appears when heated) or iodine. The compound is neutral and insoluble in a neutral or acidic aqueous medium. It is converted to an acidic compound by treatment with alkali and can then be dissolved in water. This acidic compound can be extracted with ethyl acetate or chloroform at pH values corresponding to the acidic medium, and can be converted again to Monacolin K by distilling off the solvent. The study of physiological activity. The physiological activity of Monacline K was evaluated and quantified using the following in vivo and in vitro tests. In vivo test in rabbits. Monacolin's ability to reduce the level of cholesterol in rabbit blood is measured. Weight of used animals 2.5-3.0 kg. Directly before the experiment, blood is taken from the ear vein of each rabbit and the serum cholesterol level is measured by the conventional method. Then, the amount of Monacolin K is determined to be injected continuously for 1-5 days and the level of choles is measured. serine serum. The activity of Monacolin K or a culture medium containing Monacolin K is quantified on the basis of data on the cholesterol content obtained before and after the administration of Monacoline K. The decrease in blood cholesterol and rat liver levels. Vistar Imaniti cattle rats are used, each individual weighing about 300 g. Tests are carried out on groups / rats of 5 animals. 400 mg / kg of Triton WR-1339 are injected intravenously to each animal (trade name for the material with increased blood cholesterol levels) with the simultaneous administration of 10 mg / kg of Monacolin K. “intraperitoneally. 14 hours after the lipid-lowering effect of intraperitoneal administration, the rats are killed by exsanguination, blood is collected and the level of cholesterol in it is determined. As the test results show, the level of cholesterol in the blood decreases by 23.9% compared with the control group of animals. Reduced blood cholesterol levels in rabbits. Use experimental rabbits with a body weight of 2.7-2.9 kg. 1 mg / kg of monacolin K was orally administered to each rabbit twice a day ((morning and evening, J continuously for 5 days. Before administration and on the third and fifth day after administration, blood was collected from the ear vein and serum cholesterol was determined. As a result, it was found that the cholesterol content on the third and fifth day after the administration of Monacolin K was 15 and 29%, respectively, lower than before the administration of Monacolin K. In addition to the significant inhibitory effect on cholesterol biosynthesis, Monacolin K is characterized by a margin non-low toxicity. So, oral toxicity (LOyj,) Monacolin K for mice is 1 g / kg body weight or even greater. Comparison of the hypocholestermic effect of Monacolin K and its angshock ML-263 V during the development of rat tests the introduction of Triton WR-1339, it showed that Monacolin K was four to five times more active (see table). Acolin K and ML-236 B
    631 + 19 Control 490 + 16 Monacolin K (-22, 01 422 + 18 (-33.1% .Р 0.01 640 + 24 ML-236 В 512 + 18 (-18.9% .Р 0.02 408 + 15 (-35.3% .Р.0.001
    Mean + standard error for five rats;
      In parentheses are the percentage reduction, cholesterol compared with the control and the value of confidence. 4.14 + 0.1 3.861 + 165 3.40 + 0.11 4.020 + 178 (-17.5%. P 0.01) 3.19 + 0.14 3.856 + 231 (-22.8%. P -CO, 01) 4.00 + 0.12 3.756 + 220 4.003 + 187 3.43 + 0.01 (-16.72% .Р 0.01) 3.16 + 0.29 3.960 + 135 (-23 , 3%. P "0.01)
    权利要求:
    Claims (1)
    [1]
    1. Akira. Endo. MopasosP, and the new hypocholesteroleml agent that specifically inhibits 3-hydroxy-3-methyIqlutary1 coenzyme a reductase, - The Journal of antibiotics, 1980, V. 33, If Jy p.334.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU969702A1|1982-10-30|Monacoline exhibiting hypocholesteremic activity
    KR830002329B1|1983-10-22|Preparation of monacolin k.
    FI67231B|1984-10-31|FRAMEWORK FOR HYPOKOLESTEREMISK FOERENING
    NZ194445A|1984-07-06|Monacolin k salts and esters
    US3928572A|1975-12-23|Myriocin and process of preparation
    Umehara et al.1984|Studies on WF-5239, a new potent platelet aggregation inhibitor
    US3701787A|1972-10-31|Preparation of 5,6-dihydro-5-hydroxy-6-propenyl-2-pyrone by fermentation and derivatives thereof
    US4588822A|1986-05-13|Physiologically active substances SS 12538, their preparation and a novel microorganism producing same
    SU643085A3|1979-01-15|Method of obtaining s-11743/a antibiotic
    KR970002492B1|1997-03-05|Novel tripedtide derivatives
    US5770587A|1998-06-23|Antifungal agents
    JP2870763B2|1999-03-17|Antibacterial agent
    KR950004181B1|1995-04-27|Novel antibiotic vermisporin process for the production thereof and pharmaceutical composition comprising it as an active antibacterial agent
    US3318783A|1967-05-09|Antitumor agent m-6672 and method of preparation
    US3261751A|1966-07-19|Process of producing hamycin antibiotic and product produced
    JPH0585998A|1993-04-06|New compounds ca39-a and ca39-b, their use and production
    SU269821A1|OENTENTIO- -t, * "TYLE SECURITY 'EMBLEOTEKA
    US5712151A|1998-01-27|Antifungal agent
    US5702929A|1997-12-30|Antifungal agent
    JPH08165286A|1996-06-25|Antibiotic tetromycin a and b, and its production
    KR19990031527A|1999-05-06|Mt60109 | and phospholipase C activity inhibitory composition
    JPH08208644A|1996-08-13|New antibiotic substance cremimycin, its production and use
    DK165990B|1993-02-22|Hypocholesterolaemic agent monacolin K - produced by culturing Monascus strain
    JPH0632796A|1994-02-08|Benzanthracene derivative, antitumor agent containing the same derivative and production thereof
    JPH0892270A|1996-04-09|New physiologically active substance na14742, its production and use
    同族专利:
    公开号 | 公开日
    NZ192919A|1984-07-06|
    DK73080A|1980-08-21|
    SG6784G|1985-02-08|
    IE800321L|1980-08-20|
    DK149095B|1986-01-20|
    SU1158048A3|1985-05-23|
    BE881825A|1980-08-20|
    JPS5925599B2|1984-06-19|
    DK149095C|1986-06-16|
    HU182069B|1983-12-28|
    ATA92980A|1983-07-15|
    JPS55111790A|1980-08-28|
    AU532626B2|1983-10-06|
    NO800451L|1980-08-21|
    DD154494A5|1982-03-24|
    MX6314E|1985-04-01|
    FI800506A|1980-08-21|
    KR830002030A|1983-05-21|
    NL8001041A|1980-08-22|
    DE3006216C2|1985-10-31|
    ZA80962B|1981-03-25|
    PL124304B1|1983-01-31|
    PH15145A|1982-08-24|
    KR830002801B1|1983-12-16|
    NL191540C|1995-09-04|
    GB2046737A|1980-11-19|
    DE3006216A1|1980-09-04|
    IE49743B1|1985-12-11|
    NO153974B|1986-03-17|
    NL191540B|1995-05-01|
    DE3051175C2|1989-12-21|
    GB2046737B|1983-01-12|
    FI66427C|1984-10-10|
    FR2449685A1|1980-09-19|
    FR2449685B1|1985-06-28|
    NO153974C|1986-06-25|
    ES488796A0|1981-02-16|
    DK21889D0|1989-01-18|
    AT373915B|1984-03-12|
    ES8103171A1|1981-02-16|
    CA1129794A|1982-08-17|
    IT8067262D0|1980-02-20|
    PL222120A1|1980-10-20|
    SE453301B|1988-01-25|
    AU5567380A|1980-08-28|
    SE8001339L|1980-08-21|
    CH645890A5|1984-10-31|
    IT1175260B|1987-07-01|
    FI66427B|1984-06-29|
    DK21889A|1989-01-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS5612114B2|1974-06-07|1981-03-18|
    JPS55150898A|1979-05-11|1980-11-25|Sankyo Co Ltd|Preparation of a new physiologically active substance mb-530b|
    IL60219A|1979-06-15|1985-05-31|Merck & Co Inc|Hypocholesteremic fermentation products of the hmg-coa reductase inhibitor type,their preparation and pharmaceutical compositions containing them|JPS55150898A|1979-05-11|1980-11-25|Sankyo Co Ltd|Preparation of a new physiologically active substance mb-530b|
    US4231938A|1979-06-15|1980-11-04|Merck & Co., Inc.|Hypocholesteremic fermentation products and process of preparation|
    JPS5621594A|1979-07-27|1981-02-28|Sankyo Co Ltd|Mb-530b carboxylic acid metal salt and its preparation|
    AU548996B2|1980-02-04|1986-01-09|Merck & Co., Inc.|Tetrahydro-2h-pyran-2-one derivatives|
    PT72394B|1980-02-04|1982-09-06|Merck & Co Inc|Process for preparing dihydro and tetrahydromevinoline hypocholesterolimics|
    JPH0692381B2|1980-03-31|1994-11-16|三共株式会社|MB-530A derivative|
    JPS56142236A|1980-04-08|1981-11-06|Sankyo Co Ltd|Ml-236a and mb-530a derivative|
    MX7065E|1980-06-06|1987-04-10|Sankyo Co|A MICROBIOLOGICAL PROCEDURE FOR PREPARING DERIVATIVES OF ML-236B|
    JPH0371419B2|1981-08-27|1991-11-13|Sankyo Co|
    US4782084A|1987-06-29|1988-11-01|Merck & Co., Inc.|HMG-COA reductase inhibitors|
    US4997848A|1987-10-27|1991-03-05|Sankyo Company, Limited|Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition|
    CA2062023A1|1992-02-10|1993-08-11|Jagroop S. Dahiya|Novel fungal strains and use thereof in antibiotic production|
    JPH07504568A|1992-03-04|1995-05-25|
    NZ247617A|1992-05-15|1995-07-26|Sankyo Co|Octahydronaphthalene oxime derivatives and pharmaceutical compositions|
    HU210867B|1992-11-04|1995-10-30|Biogal Gyogyszergyar|Method for extraction and purification of mevinolin from culture medium|
    US6812007B1|1992-11-04|2004-11-02|Keri Vilmos|Process for the isolation and purification of mevinolin|
    SI9300303A|1993-06-08|1994-12-31|Krka Tovarna Zdravil|Process for isolation of hypolipemic effective substance|
    US5409820A|1993-08-06|1995-04-25|Apotex, Inc.|Process for the production of lovastatin using Coniothyrium fuckelii|
    US7238348B2|1996-09-30|2007-07-03|Beijing Peking University Wbl Corporation Ltd.|Method of treatment of osteoporosis with compositions of red rice fermentation products|
    US6046022A|1996-09-30|2000-04-04|Peking University|Methods and compositions employing red rice fermentation products|
    CZ300153B6|1998-03-20|2009-02-25|Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság|Metabolically controlled fermentation process when preparing lovastatin hydroxy acid|
    YU63602A|2000-02-24|2006-01-16|Biogal Gyogyszergyar Rt.|Method of purifying a fermentation broth|
    AU4183301A|2000-03-03|2001-09-17|Biogal Gyogyszergyar|A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities|
    KR20010095780A|2000-04-12|2001-11-07|나가오카 마사시|Embryo monascus|
    IN192861B|2000-06-30|2004-05-22|Ranbaxy Lab Ltd|
    WO2002064809A2|2001-02-09|2002-08-22|Unilever N.V.|Process for the preparation of one or more statins by fermentation|
    KR100379075B1|2002-03-07|2003-04-08|Jinis Biopharmaceuticals Co|Method for producing low cholesterol animal food product and food product therefrom|
    KR20020093147A|2002-05-30|2002-12-13|지니스생명공학 주식회사|Preventive and Dietary Supplement for adult chronic disease|
    KR100710500B1|2005-05-18|2007-04-24|고려대학교 산학협력단|Method for producing Monacolin K using Monascus sp|
    WO2010069593A1|2008-12-19|2010-06-24|Krka, D. D., Novo Mesto|Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates|
    EP2327682A1|2009-10-29|2011-06-01|KRKA, D.D., Novo Mesto|Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates|
    RO128803A0|2012-10-12|2013-09-30|Ion Gigel Fulga|Composition for the treatment or prevention of dyslipidemias|
    CN110331151A|2019-04-11|2019-10-15|北京工商大学|The construction method of purple Monascus mokH gene overexpression bacterial strain|
    CN111297938A|2020-03-11|2020-06-19|北京康立生医药技术开发有限公司|Method for detecting lovastatin in composition for assisting in reducing blood fat|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP54017856A|JPS5925599B2|1979-02-20|1979-02-20|
    [返回顶部]