GB2046737A - Antihypercholesteraemic Agent, Monacolin K, and Its Preparation - Google Patents
Antihypercholesteraemic Agent, Monacolin K, and Its Preparation Download PDFInfo
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- GB2046737A GB2046737A GB8005748A GB8005748A GB2046737A GB 2046737 A GB2046737 A GB 2046737A GB 8005748 A GB8005748 A GB 8005748A GB 8005748 A GB8005748 A GB 8005748A GB 2046737 A GB2046737 A GB 2046737A
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- Prior art keywords
- monacolin
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- antihypercholesteraemic
- monascus
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- 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
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
-
- 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
Abstract
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).
Description
SPECIFICATION
Antihypercholesteraemic Agent, Monacolin K, and its Preparation
The present invention relates to a new compound having antihypercholesteraemic activity and which we have named Monacolin K.
Monacolin K can be produced by cultivating various microorganisms of the genus Monascus.
Thus the present invention consists in a compound, Monacolin K, having the formula:
The invention further consists in a process for preparing an antihypercholesteraemic agent designated Monacolin K, which comprises cultivating a Monacolin K-producing microorganism of the genus Monascus in a culture medium therefor.
The invention still further consists in a pharmaceutical composition comprising
Monacolin K in admixture with a pharmaceutically acceptable carrier or diluent.
High blood cholesterol levels are recognized as being one of the main causes of cardiopathy, such as cardiac infarction or arteriosclerosis. As a result, considerable research has been undertaken with a view to discovering physiologically acceptable substances which are capable of inhibiting cholesterol biosynthesis and thus reducing blood cholesterol levels. One such compound is ML-236, which forms the subject of our United Kingdom Patent Specification No.
1,453,425. ML-236 is produced by cultivating
microorganisms of the genus Penicillium.
On investigating fungi of the genus Monascus,
it was found that these, particularly Monascus
ruber strain 1005 (FERM 4822), produced an
antihypercholesteraemic agent having
substantially better activity than that of ML-236.
This agent was named Monacolin K.
All microorganisms of the genus Monascus
which are capable of producing Monacolin K may
be employed in the process of the present
invention. Especially useful are strains of
Monascus ruber, particularly Monascus ruber
strain 1005 (FERM 4822).
Monascus ruber strain 1005 (FERM 4822) is a
newly isolated microorganism having the
following microbiological properties. It was
isolated from foodstuffs produced in Thailand and
deposited on 16 February 1 979 under the
accession No. FERM 4822 with the Fermentation
Research Institure, Agency of Industrial Science
and Technology, Ministry of International Trade
and Industry, Japan and under the accession No.
NRRL 12073 with the Agricultural Research
Service, Northern Regional Research Laboratory,
USA.
1. Growth
The growth on a potato-glucose-agar medium at 250C is fast and the diameter of the colony reaches 6-6.5 centimetres 10 days after inoculation. The colony is flat and a relatively thin basal layer of hyphae develops. Development of aerial hyphae is poor; the aerial hyphae are white and most of them are woolly. Many cleistothecia are formed on the basal layer of hyphae and turn reddish-brown on maturity. Both the surface and the reverse of the colony are brown to reddishbrown in colour.
The growth on Sabouraud's agar medium at 250C is very fast and the diameter of the colony reaches 6-6.5 centimetres 10 days after inoculation. The surface of the colony is very flat, and basal hyphae and aerial hyphae develop better than on potato-glucose-agar medium.
Cleistothecia counts are very few. The surface of the colony is reddish-yellow to reddish-brown in colour and the reverse is reddish-brown to dark brown.
The growth on oatmeal agar at 250C is slow and the diameter of the colony reaches 1.5-2 centimetres 10 days after inoculation. The colony is flat. Development of aerial hyphae and formation of cleistothecia are both very poor. Both the surface and the reverse of the colony are dark red to reddish-brown in colour.
The growth on Czapek's agar medium at 250C is very slow and the diameter of the colony reaches 1.6-1.8 centimetres 10 days after inoculation.
The rates af growth on each of the above media at 37OC are substantially equal to those at 250C.
2. Morphological Properties
The cleistothecia are spherical and 30-60 microns in diameter; their walls are thin and membranous; their stalks have septal walls and each consists of a hypha of diameter 3.5-4.5 microns and length 1 5-80 microns. The ascus consists of 8 spores and is nearly spherical and evanescent. The ascospores are colourless and ovoid or ellipsoid; they have a size of 4-5x4-7 microns; and their surfaces are smooth. The conidia are colourless and spherical or pyriform; their size is 6-9x6-1 1 microns; their bases are truncate and their walls are reiatively thick and smooth. The conidia are linked basipetally as a type of meristum arthrospore.The conidiophore is like a vegetative hypha and is branched or unbranched; the conidia being formed at the top.
The mycelia are colourless and branched and have septal walls; most of them have a diameter of 3-5 microns.
Based on the observations of its characteristics as reported above, this microorganism was identified as a strain of Monascus ruber van
Tieghem.
Microbiological properties of Monascus ruber have been reported in the following literature:
Takada, Transactions of the Micological Society of Japan, 9, 125-130 (1969) [Materials for the
Fungus Flora of Japan (7)]; and van Tieghem, Bull.
Soc. Botan. France,31,227 (1884). Ascospore generation of the strain has been reported by Cole et al in the Canadian Journal of Botany, 46, 987 (1968), "Conidium Ontogeny in hyphomycetes.
The imperfect state of Monascus ruber and its meristum arthrospores".
Although the use of Monascus ruber strain
1005 is hereafter specifically exemplified, it will be appreciated that any strains of the genus
Monascus, including varieties and mutants, which are capable of producing Monacolin K can be used in the process of the invention.
Monacolin K may be produced by cultivating the chosen microorganism in a culture broth under aerobic conditions, using the same techniques as are well known in the art for the cultivation of fungi and other microorganisms. For example, the Monacolin K-producing microorganism may first be cultivated on a suitable medium and then the produced microorganisms may be collected and inoculated into and cultivated on another culture medium to produce the desired Monacolin K; the culture media used for multiplication of the microorganism and for production of Monacolin K may be the same or different.
Any culture medium well known in the art for the cultivation of fungi may be employed, provided that it contains, as is well known, the necessary nutrient materials, especially an assimilable carbon source and an assimilable nitrogen source. Examples of suitable sources of assimilable carbon are glucose, maltose, dextrin, starch, lactose, sucrose and glycerine. Of these sources, glucose, glycerine and starch are particularly preferred for the production of
Monacolin K. Examples of suitable sources of assimilable nitrogen are peptone, meat extracts, yeast, yeast extract, soybean meal, peanut meal, corn steep liquor, rice bran and inorganic nitrogen sources. Of these nitrogen sources, peptone is particularly preferred. When producing Monacolin
K, an inorganic salt and/or a metal salt may, if necessary, be added to the culture medium.
Furthermore, if necessary, a minor amount of a heavy metal may also be added.
The microorganism is preferably cultivated under aerobic conditions using cultivation methods well known in the art, for example solid culture, shaken culture or culture under aeration and agitation. The microorganism will grow over a wide temperature range, e.g. from 7 to 400C, but, especially for the production of Monacolin K, the more preferred cultivation temperature is within the range from 20 to 350C.
During the cultivation of the microorganism, the production of Monacolin K may be monitored by sampling the culture medium and measuring the physiological activity of the Monacolin K in the culture medium by the test described hereafter. Cultivation may then be continued until a substantial accumulation of Monacolin K has been achieved in the culture medium, at which time the Monacolin K may be isolated and recovered from the culture broth by any suitable combination of isolation techniques chosen having regard to its physical and chemical properties.For example, any or all of the following isolation techniques may be employed: extraction of the liquor from the culture broth with a hydrophilic solvent (for example, diethyl ether, ethyl acetate, chloroform or benzene); extraction of the organism with a hydrophilic solvent (such as acetone or an alclhol); concentration; dissolution into a more polar solvent (e.g. acetone or an alcohol); removal of impurities with a less polar solvent (such as petroleum ether or hexane); gel filtration through a column of a material such as Sephadex (a trade name for a material available from Pharmacia, Co., Ltd., U.S.A.); absorptive chromatography with active carbon or silica gel; and so on. By using a suitable combination of these techniques, the desired
Monacolin K can be isolated from the culture broth as a pure substance.
Monacolin K was found to have the following properties:
1. Colour and form:
Colourless crystals.
2. Melting point: 1 57--1 59 OC (with decomposition).
3. Elemental analysis: C, 71.56%; H, 8.85%; 0, 19.59%.
4. Molecular weight:
404 (by mass spectrometry).
5. Molecular formula: C24H3605.
6. Ultraviolet absorption spectrum (methanol):
As shown in Figure 1 of the accompanying
drawings having maxima at 232, 238 and
246 my.
7. Infrared absorption spectrum (KBr):
As shown in Figure 2 of the accompanying
drawings.
8. Nuclear magnetic resonance spectrum (60
MHz proton):
As shown in Figure 3 of the accompanying
drawings in deuterated chloroform, using
tetramethylsilane as internal standard.
9. Nuclear magnetic resonance spectrum (13C):
As shown in Figure 4 of the accompanying
drawings, in deuterated methanol.
10. Solubility:
Soluble in lower alcohols (e.g. methanol,
ethanol and propanol), acetone, chloroform,
ethyl acetate and benzene. Insoluble in
petroleum ether and hexane.
11. Specific rotation: [t5=+307.6(c=1, methanol).
12. Thin layer chromatography:
Rf=0.47 [No. 571 5 Kieselgel 60F254 silica
gel)Merck & Co., Ltd.)developed by a 4:1
volume mixture of methylene chloride and
acetone, detectable as an ultraviolet
radiation-absorbing lump, 50% v/v sulphuric
acid (a pale red to reddish-brown colour
develops on heating) or with iodine].
The compound is neutral and is insoluble in neutral or acidic aqueous media. It is converted to an acidic substance upon treatment with an alkali and can then be dissolved in water. This acidic substance can be extracted with ethyl acetate or chloroform at an acid pH value and will revert to
Monacolin K on evaporation of the solvent.
The physiological activity of Monacolin K can be assayed and determined quantitatively by the following in vivo test.
In vivo test with rabbits
In this test, the ability of Monacolin K to reduce cholesterol levels in rabbit blood is measured. The animals employed should weigh from 2.5 to 3.0 kg. Immediately prior to starting the test, blood is collected from the vein in an ear of each rabbit and the cholesterol level in the blood serum is measured by a conventional method. A predetermined quantity of Monacolin K is then administered orally continuously for 1 to 5 days and the cholesterol level in the blood serum after administration is measured. The potency of the
Monacolin K or Monacolin K-containing culture medium can be determined quantitatively from the cholesterol values obtained prior to and after administration of Monacolin K.
We have demonstrated the ability of
Monacolin K to lower the blood and liver cholesterol levels by varous in vivo tests.
Reduction of blood cholesterol levels in rats
The animals used were rats of the Wistar
Imamichi strain, each having a body weight of about 300 g. The rests were conducted on groups of rats, each group consisting of 5 animals. Each animal was intraveneously injected with 400 mg/kg of Triton WR-1339 (a trade name for a material known to increase the blood cholesterol level) whilst simultaneously administering intraperitoneally 10 mg/kg of Monacolin K. 14 hours after intraperitoneal administration, the rats were sacrificed by bleeding and the blood was collected and its cholesterol level was determined by conventional means. As a resuit, it was established that blood cholesterol levels had been reduced, as compared with a control group of animals to which Triton WR-1339 alone had been administered, by 23.9%.
Reduction of blood cholesterol levels in rabbits
The test animals used were rabbits having a body weight of from 2.7 kg to 2.9 kg. Each rabbit was given orally 1 mg/kg of Monacolin K twice each day (morning and evening) continuously for 5 days. Prior to administration and at 3 and 5 days after administration, blood was collected from a vein in the ear and the cholesterol levels in the blood serum were determined. As a result it was found that the cholesterol levels at 3 and 5 days after administration of Monacolin K were 15% and 29%, respectively, lower than the level prior to administration of Monacolin K.
In addition to its valuable inhibitory effect on
the biosynthesis of cholesterol, Monacolin K has a
very low toxicity. Thus, the acute oral toxicity
(LD50) of Monacolin K in the mouse is 1 g/kg body
weight or more.
The Monacolin K may be administered orally or
parenterally in the form of a capsule, tablet,
injectable preparation or any other known
formulation, although we normally prefer to
administer it orally. The dose will vary, depending
upon the age and body weight of the patient and
the severity of the condition, but, in general, the
daily dose for an adult would be from 0.5 to 50
mg, either as a single dose or in 2 or 3 divided
doses. However, in view of the low toxicity of the
compound, higher doses may be employed if
required.
The invention is further illustrated by the
following non-limiting Example.
Example
Monascus ruber 1005 strain was inoculated
onto a liquid culture medium containing 6% w/v glucose,2.5% w/v peptone, 0.5% w/v corn steep
liquor and 0.5% w/v ammonium chloride.
Cultivation was continued under aerobic
conditions at a temperature of 280C for 10 days.
The resulting filtrate (5 litres) of the culture broth
was adjusted to a pH value of 3 by the addition of
6N hydrochloric acid and then extracted with an
equal volume of ethyl acetate. The solvent was
evaporated under reduced pressure from the
extract and the resulting residue was dissolved in
100 ml of benzene. Insolubles were filtered off.
The filtrate was washed twice, each time with
100 ml of a 5% w/v aqueous solution of sodium bicarbonate. 100 ml of a 0.2 N aqueous solution of sodium hydroxide were then added to the washed filtrate and the mixture was stirred at room temperature. After confirming the disappearance of Monacolin K from the benzene layer by thin layer chromatography, the aqueous layer was separated off. The pH value of the aqueous layer was then adjusted to 3 by addition of 6N hydrochloric acid and the resulting solution was extracted twice, each time with 100 ml of ethyl acetate. The extract was evaporated to dryness under reduced pressure, giving 260 mg of an oil. This oil was dissolved in benzene and allowed to crystallize and then recrystallized from an aqueous acetone solution to give 87 mg of colourless needles of Monacolin K having the properties heretofor described.
Claims (10)
1. A compound of formula:
2. A process for preparing an antihypercholesteraemic agent designated
Monacolin K, which comprises cultivating a
Monacolin K-producing microorganism of the
genus Monascus in a culture medium therefor.
3. A process according to Claim 2, in which
said microorganism is a strain of Monascus ruber.
4. A process according to Claim 3, in which
said strain is Monascus ruber strain 1005 (FERM
4822).
5. A process according to any one of Claims 2
to 4, in which cultivation is carried out at a
temperature of from 7 to 400C.
6. A process according to Claim 5, in which said temperature is from 20 to 350C.
7. A process according to Claim 2, substantially as hereinbefore described with reference to the foregoing Example.
8. Monacolin K when produced by a process according to any one of Claims 2 to 7.
9. A pharmaceutical composition comprising a compound according to Claim 1 or Claim 8 in admixture with a pharmaceutically acceptable carrier or diluent.
10. A composition according to Claim 9, in a form suitable for oral or parenteral administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX9203568A MX9203568A (en) | 1979-02-20 | 1992-06-26 | ANTI-HYPERCHOLESTEREMIC AGENT, MONACOLINE K, AND ITS PREPARATION. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP54017856A JPS5925599B2 (en) | 1979-02-20 | 1979-02-20 | New physiologically active substance monacolin K and its production method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2046737A true GB2046737A (en) | 1980-11-19 |
| GB2046737B GB2046737B (en) | 1983-01-12 |
Family
ID=11955290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8005748A Expired GB2046737B (en) | 1979-02-20 | 1980-02-20 | Antihypercholesteraemic agent monacolin k and its preparation |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS5925599B2 (en) |
| KR (1) | KR830002801B1 (en) |
| AT (1) | AT373915B (en) |
| AU (1) | AU532626B2 (en) |
| BE (1) | BE881825A (en) |
| CA (1) | CA1129794A (en) |
| CH (1) | CH645890A5 (en) |
| DD (1) | DD154494A5 (en) |
| DE (2) | DE3051175C2 (en) |
| DK (2) | DK149095C (en) |
| ES (1) | ES488796A0 (en) |
| FI (1) | FI66427C (en) |
| FR (1) | FR2449685B1 (en) |
| GB (1) | GB2046737B (en) |
| HU (1) | HU182069B (en) |
| IE (1) | IE49743B1 (en) |
| IT (1) | IT1175260B (en) |
| MX (1) | MX6314E (en) |
| NL (1) | NL191540C (en) |
| NO (1) | NO153974C (en) |
| NZ (1) | NZ192919A (en) |
| PH (1) | PH15145A (en) |
| PL (1) | PL124304B1 (en) |
| SE (1) | SE453301B (en) |
| SG (1) | SG6784G (en) |
| SU (2) | SU1158048A3 (en) |
| ZA (1) | ZA80962B (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4517373A (en) * | 1981-08-27 | 1985-05-14 | Sankyo Company, Limited | IsoMB-530B derivatives |
| EP0314435A2 (en) | 1987-10-27 | 1989-05-03 | Sankyo Company Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition, processes for their preparation and compositions containing them |
| EP0570245A2 (en) | 1992-05-15 | 1993-11-18 | Sankyo Company Limited | Octahydronaphthalene oxime derivatives for cholesterol biosynthesis inhibition, their preparation and use |
| US6387258B1 (en) | 2000-02-24 | 2002-05-14 | Biogal Gyogyszergyar Rt. | Method of purifying statins from a fermentation broth |
| WO2002063976A1 (en) * | 2001-02-09 | 2002-08-22 | Unilever N.V. | Food product comprising soy protein and statins |
| US6500651B1 (en) | 1998-03-20 | 2002-12-31 | Biogal Gyogyszergyar Rt. | Metabolic controlled fermentation procedure for the manufacture of lovastatin hydroxy acid |
| US6521762B2 (en) | 2000-03-03 | 2003-02-18 | BIOGAL Gyógyszergyar RT. | Process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities |
| US6632428B1 (en) | 1996-09-30 | 2003-10-14 | Peking University | Methods and compositions employing red rice fermentation products |
| US7238348B2 (en) | 1996-09-30 | 2007-07-03 | Beijing Peking University Wbl Corporation Ltd. | Method of treatment of osteoporosis with compositions of red rice fermentation products |
| EP2719288A1 (en) | 2012-10-12 | 2014-04-16 | Ion Gigel Fulga | Composition for the treatment or prevention of dyslipidaemias |
| US8715716B2 (en) | 2002-03-07 | 2014-05-06 | Jinis Biopharmaceuticals Co. | Methods for producing low cholesterol animal products using hypocholesterolemic feed supplements and products therefrom |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55150898A (en) * | 1979-05-11 | 1980-11-25 | Sankyo Co Ltd | Preparation of a new physiologically active substance mb-530b |
| US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| JPS5621594A (en) * | 1979-07-27 | 1981-02-28 | Sankyo Co Ltd | Mb-530b carboxylic acid metal salt and its preparation |
| AU548996B2 (en) * | 1980-02-04 | 1986-01-09 | Merck & Co., Inc. | Tetrahydro-2h-pyran-2-one derivatives |
| PT72394B (en) * | 1980-02-04 | 1982-09-06 | Merck & Co Inc | Process for preparing dihydro and tetrahydromevinoline hypocholesterolimics |
| JPH0692381B2 (en) * | 1980-03-31 | 1994-11-16 | 三共株式会社 | MB-530A derivative |
| JPS56142236A (en) | 1980-04-08 | 1981-11-06 | Sankyo Co Ltd | Ml-236a and mb-530a derivative |
| MX7065E (en) * | 1980-06-06 | 1987-04-10 | Sankyo Co | A MICROBIOLOGICAL PROCEDURE FOR PREPARING DERIVATIVES OF ML-236B |
| US4782084A (en) * | 1987-06-29 | 1988-11-01 | Merck & Co., Inc. | HMG-COA reductase inhibitors |
| CA2062023A1 (en) | 1992-02-10 | 1993-08-11 | Jagroop S. Dahiya | Novel fungal strains and use thereof in antibiotic production |
| JPH07504568A (en) * | 1992-03-04 | 1995-05-25 | 藤沢薬品工業株式会社 | Tetralin derivatives as HMG-CoA reductase inhibitors |
| HU210867B (en) * | 1992-11-04 | 1995-10-30 | Biogal Gyogyszergyar | Method for extraction and purification of mevinolin from culture medium |
| US6812007B1 (en) * | 1992-11-04 | 2004-11-02 | Keri Vilmos | Process for the isolation and purification of mevinolin |
| SI9300303A (en) * | 1993-06-08 | 1994-12-31 | Krka Tovarna Zdravil | Process for isolation of hypolipemic effective substance |
| US5409820A (en) * | 1993-08-06 | 1995-04-25 | Apotex, Inc. | Process for the production of lovastatin using Coniothyrium fuckelii |
| KR20010095780A (en) * | 2000-04-12 | 2001-11-07 | 나가오카 마사시 | Embryo monascus |
| IN192861B (en) | 2000-06-30 | 2004-05-22 | Ranbaxy Lab Ltd | |
| KR20020093147A (en) * | 2002-05-30 | 2002-12-13 | 지니스생명공학 주식회사 | Preventive and Dietary Supplement for adult chronic disease |
| KR100710500B1 (en) | 2005-05-18 | 2007-04-24 | 고려대학교 산학협력단 | Method for producing Monacolin K using Monascus sp |
| SI2373609T1 (en) | 2008-12-19 | 2013-12-31 | Krka, D.D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| EP2327682A1 (en) | 2009-10-29 | 2011-06-01 | KRKA, D.D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| CN110331151A (en) * | 2019-04-11 | 2019-10-15 | 北京工商大学 | The construction method of purple Monascus mokH gene overexpression bacterial strain |
| CN111297938A (en) * | 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5612114B2 (en) * | 1974-06-07 | 1981-03-18 | ||
| JPS55150898A (en) * | 1979-05-11 | 1980-11-25 | Sankyo Co Ltd | Preparation of a new physiologically active substance mb-530b |
| IL60219A (en) * | 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 |
-
1979
- 1979-02-20 JP JP54017856A patent/JPS5925599B2/en not_active Expired
-
1980
- 1980-02-19 KR KR1019800000654A patent/KR830002801B1/en active
- 1980-02-19 CA CA345,983A patent/CA1129794A/en not_active Expired
- 1980-02-19 IE IE321/80A patent/IE49743B1/en not_active IP Right Cessation
- 1980-02-19 AU AU55673/80A patent/AU532626B2/en not_active Expired
- 1980-02-20 DE DE3051175A patent/DE3051175C2/de not_active Expired
- 1980-02-20 NO NO800451A patent/NO153974C/en unknown
- 1980-02-20 MX MX808652U patent/MX6314E/en unknown
- 1980-02-20 DK DK73080A patent/DK149095C/en not_active IP Right Cessation
- 1980-02-20 SU SU802887300A patent/SU1158048A3/en active
- 1980-02-20 PH PH23668A patent/PH15145A/en unknown
- 1980-02-20 ES ES488796A patent/ES488796A0/en active Granted
- 1980-02-20 FI FI800506A patent/FI66427C/en not_active IP Right Cessation
- 1980-02-20 DD DD80219159A patent/DD154494A5/en unknown
- 1980-02-20 IT IT67262/80A patent/IT1175260B/en active
- 1980-02-20 HU HU80397A patent/HU182069B/en unknown
- 1980-02-20 BE BE0/199476A patent/BE881825A/en not_active IP Right Cessation
- 1980-02-20 NZ NZ192919A patent/NZ192919A/en unknown
- 1980-02-20 FR FR8003662A patent/FR2449685B1/en not_active Expired
- 1980-02-20 PL PL1980222120A patent/PL124304B1/en unknown
- 1980-02-20 SE SE8001339A patent/SE453301B/en not_active IP Right Cessation
- 1980-02-20 AT AT0092980A patent/AT373915B/en not_active IP Right Cessation
- 1980-02-20 GB GB8005748A patent/GB2046737B/en not_active Expired
- 1980-02-20 DE DE3006216A patent/DE3006216C2/en not_active Expired
- 1980-02-20 CH CH136680A patent/CH645890A5/en not_active IP Right Cessation
- 1980-02-20 NL NL8001041A patent/NL191540C/en not_active IP Right Cessation
- 1980-02-20 ZA ZA00800962A patent/ZA80962B/en unknown
- 1980-09-12 SU SU802977031A patent/SU969702A1/en active
-
1984
- 1984-01-24 SG SG67/84A patent/SG6784G/en unknown
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1989
- 1989-01-18 DK DK021889A patent/DK21889D0/en not_active Application Discontinuation
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4517373A (en) * | 1981-08-27 | 1985-05-14 | Sankyo Company, Limited | IsoMB-530B derivatives |
| EP0314435A2 (en) | 1987-10-27 | 1989-05-03 | Sankyo Company Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition, processes for their preparation and compositions containing them |
| US4997848A (en) * | 1987-10-27 | 1991-03-05 | Sankyo Company, Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition |
| US5403860A (en) * | 1987-10-27 | 1995-04-04 | Sankyo Company, Limited | Octahydronaphthalene oxime compounds for cholesterol synthesis inhibition |
| US5658942A (en) * | 1987-10-27 | 1997-08-19 | Sankyo Company, Limited | Octahydronaphthalene oxime compounds for cholesterol synthesis inhibition |
| EP0570245A2 (en) | 1992-05-15 | 1993-11-18 | Sankyo Company Limited | Octahydronaphthalene oxime derivatives for cholesterol biosynthesis inhibition, their preparation and use |
| US7238348B2 (en) | 1996-09-30 | 2007-07-03 | Beijing Peking University Wbl Corporation Ltd. | Method of treatment of osteoporosis with compositions of red rice fermentation products |
| US6632428B1 (en) | 1996-09-30 | 2003-10-14 | Peking University | Methods and compositions employing red rice fermentation products |
| US6500651B1 (en) | 1998-03-20 | 2002-12-31 | Biogal Gyogyszergyar Rt. | Metabolic controlled fermentation procedure for the manufacture of lovastatin hydroxy acid |
| US6387258B1 (en) | 2000-02-24 | 2002-05-14 | Biogal Gyogyszergyar Rt. | Method of purifying statins from a fermentation broth |
| US6521762B2 (en) | 2000-03-03 | 2003-02-18 | BIOGAL Gyógyszergyar RT. | Process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities |
| WO2002063976A1 (en) * | 2001-02-09 | 2002-08-22 | Unilever N.V. | Food product comprising soy protein and statins |
| US6849281B2 (en) | 2001-02-09 | 2005-02-01 | Unilever Bestfoods, North America, A Division Of Conopco, Inc. | Food product suitable for reducing low density lipoprotein cholesterol levels |
| CN100456962C (en) * | 2001-02-09 | 2009-02-04 | 荷兰联合利华有限公司 | Food product comprising soy protein and statins |
| US8715716B2 (en) | 2002-03-07 | 2014-05-06 | Jinis Biopharmaceuticals Co. | Methods for producing low cholesterol animal products using hypocholesterolemic feed supplements and products therefrom |
| EP2719288A1 (en) | 2012-10-12 | 2014-04-16 | Ion Gigel Fulga | Composition for the treatment or prevention of dyslipidaemias |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 727 | Application made for amendment of specification (sect. 27/1977) | ||
| 727A | Application for amendment of specification now open to opposition (sect. 27/1977) | ||
| 727B | Case decided by the comptroller ** specification amended (sect. 27/1977) | ||
| SP | Amendment (slips) printed | ||
| PE20 | Patent expired after termination of 20 years |
Effective date: 20000219 |