KR830002801B1 - Process for preparing antihypercholesteramic agent monacolink and its preparation - Google Patents
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Abstract
Description
제1도는 본 발명에 따른 모나콜린K의 자외선 스펙트럼.1 is an ultraviolet spectrum of Monacholine K according to the present invention.
제2도는 본 발명에 따른 모나콜린K의 적외선 스펙트럼.2 is an infrared spectrum of Monacholine K according to the present invention.
제3도는 내부표준으로서 테트라메틸실란을 사용하는 중수소클로로포름 중에서 60MHz 양성자를 사용하여 본 발명에 따른 모나콜린K의 핵자기 공명스펙트럼.3 is a nuclear magnetic resonance spectrum of monacoline K according to the present invention using 60 MHz protons in deuterium chloroform using tetramethylsilane as an internal standard.
제4도는 중소소메탄올 중에서 Bc를 사용하여 본 발명에 따른 모나클린K의 핵자기 공명스펙트럼.4 is a nuclear magnetic resonance spectrum of Monacrine K according to the present invention using Bc in small and medium methanol.
본 발명 모나스쿠스(monascus)속에 속하는 미생물에 의해 생성되며, 고(高) 콜레스테롤 혈증 치료작용을 갖는 신규한 화합물의 제조방법에 관한 것이다.The present invention relates to a method for producing a novel compound produced by a microorganism belonging to the genus Monascus, and having a high cholesterol treatment.
지방 과혈증, 특히 고 콜레스테롤 혈증은 심근경색증이나 또는 동맥경화증 등과 같은 심장병의 주원인증의 하나로 알려지고 있기 때문에, 혈중의 지방질, 특히 콜레스테롤 함량의 감소능을 갖는 화합물을 개발하기 위하여 상당한 노력이 행해져 왔다. 그중에서도 한가지 화합물이 영국특허 명세서 제 1,453,425호에 기술되어 있으며, 이 화합물은 페니실륨 속에 속하는 미생물로부터 단리시킨 것으로 ML-236으로 명명되고 있다.Since hyperlipidemia, particularly hypercholesterolemia, is known as one of the main causes of heart disease, such as myocardial infarction or arteriosclerosis, considerable efforts have been made to develop compounds that have the ability to reduce blood fat, especially cholesterol content. . One such compound is described in British Patent No. 1,453,425, which is named ML-236 as isolated from microorganisms belonging to the genus Penicillium.
본 발명자들은 미생물들을 계통적으로 배양 연구한 결과, 모나스쿠스속과 균류, 보다 상세하게는 모나스쿠스 터버(monascus rubber) 1005균류를 배양하여 얻을 수 있는 모나콜린K로 명명한 신규 화합물을 발견해 내었다.As a result of systematically studying the microorganisms, the inventors have discovered a new compound named Monacholine K that can be obtained by culturing the genus Monascus and fungi, and more specifically, the Monascus rubber 1005 fungus.
본 발명자들은 모나콜린K의 구조식을 발견하고, 이 화합물의 구조식은 영국특허 명세서 제 1,453,425호의 주제를 이루는 화합물 ML-236 B와 구조식은 유사하나, 모나콜린K는 ML-236B보다 2내지 5배의 놀라운 효과를 갖기 때문에, ML-236B 화합물에 비하여 상당히 소량을 투여하여도 콜레스테롤 함량을 동일량 감소시킬 수가 있다는 것을 발견하였다.We find the structural formula of monacoline K, which is similar in structure to that of compound ML-236 B, which is the subject of British Patent No. 1,453,425, but monacoline K is two to five times greater than ML-236B. Because of the surprising effect, it was found that even a small amount of administration compared to the ML-236B compound can reduce the cholesterol content by the same amount.
따라서, 본 발명의 목적은 하기 일반식으로 표시되며, 모나콜린K로 명명되는 신규한 화합물을 제공하는 것이며, 본 발명의 또 하나의 목적은 모나스쿠스 속에 속하는 미생물, 바람직하게는 모나스쿠스 러버 군주 가장 바람직하게는 모나스쿠스 러버 1005를 배양하여 모나콜린K를 제조하는 방법을 제공하는 것이다.Accordingly, an object of the present invention is to provide a novel compound represented by the following general formula, and designated as Monacholine K, and another object of the present invention is a microorganism belonging to the genus Monascus, preferably Monascus rubber monarch Preferably it provides a method for producing Monacoline K by culturing Monascus rubber 1005.
본 발명의 또 다른 목적은, 모나콜린K의 유효성분과 약학적으로 허용되는 담체 또는 회석제와를 혼합배합함을 특징으로 하는 약학 조성물을 제공하는 것이다.Still another object of the present invention is to provide a pharmaceutical composition comprising mixing and mixing an active ingredient of monacoline K with a pharmaceutically acceptable carrier or diluent.
본 발명에 따른 모나콜린K 생성군주는 타일란드에서 생산되는 식품중에서 단리시킨 물질로, 그 특징을 조사하여 모나스쿠스 러버라고 명명하여 일본국 통상산업성, 공업과학기술청 발효연구소에 기탁번호 제4822호로 기탁되었으며, 또한 미합중국 Agricultural Research Service, Northern Regional Research Lab-oratory에 기탁번호 제 12073호로 기탁되어 있다. 이 신규한 미생물의 세균학적 특성은 하기와 같다.Monacholine K-generating monarch according to the present invention is a substance isolated from food produced in Thailand, and investigated its characteristics and named as Monascus rubber and deposited in the Fermentation Research Institute of the Ministry of Commerce, Industry and Energy Deposited as US No. 12073 in the United States Agricultural Research Service, Northern Regional Research Lab-oratory. The bacteriological properties of this novel microorganism are as follows.
1. 생장1. Growth
이 미생물은 25℃의 감자-글루코오스-한천배지상에서 생장이 빨랐으며, 접종시킨 10일이 지난 후에 이군체의 직경은 6내지 6.5cm에 달했으며, 이 군체의 표면은 편평하였고, 상당히 얇은 기중군사층이 발생하였으며, 기중균사의 발육이 저조하였다.The microorganisms grew rapidly on potato-glucose-agar medium at 25 ° C. After 10 days of inoculation, the colonies ranged from 6 to 6.5 cm in diameter, and their surface was flat and fairly thin. This occurred, and the development of aerial hyphae was poor.
기중균사의 색상은 백색이었으며, 이들 기중균사체 대부분이 털이 많았다. 또 균사 기저충상에 많은 폐쇄포자낭과(閉鎖包子囊果)가 생성되었으며 , 숙성시에는 적갈색으로 변색되었다.The mycelia were white in color, and most of them were hairy. In addition, a lot of closed spore follicles were formed on the basal mycelia of the mycelia, and it turned reddish brown at aging.
균체의 표면과 이면은 모두 갈색 내지 적갈색이었다.Both the surface and the backside of the cells were brown to reddish brown.
또, 이 미생물은 25℃의 사보라우드(saboraud) 한천배지상에서 생장이 아주 빨랐으며, 접종시킨 10일이 지난 후에 이 균체의 직경은 6내지 6.5cm에 달했으며, 균체의 표면은 아주 편평하였고, 감자-글루코오스-한천 배지상에서의 경우보다도 기저균사 및 기중균사의 발육이 양호하였다. 폐쇄포자낭과는 극히 소수가 생성되었으며, 균체의 표면은 적황색 내지 적갈색이었고, 균체의 이면은 적갈색 내지 암갈색이었다. 또 25℃의 오우트미일 한천배지상에서의 생장은 느렸으며, 접종시킨 10일이 지난 후에 이 균체의 직경은 1.5내지 2cm에 달했으며, 균체의 표면은 편평하였고, 기중균사의 발육 및 폐쇄포자낭과 생성은 모두 극히 저조하였다. 균체의 표면과 이면의 색상은 모두 암갈색 내지 적갈색이었다. 또 25℃의 차백크(czapek's) 배지상에서의 생장속도는 아주 느렸으며, 접종시킨 10일이 지난후에 이 균체의 직경은 1.6내지 1.8cm에 달했다.The microorganism also grew very fast on saboraud agar medium at 25 ° C. After 10 days of inoculation, the microorganism had a diameter of 6 to 6.5 cm, and the surface of the microorganism was very flat. The growth of basal and aerial mycelium was better than that on -glucose-agar medium. Very few were produced from the occlusive spores, and the surface of the cells was reddish yellow to reddish brown, and the back surface of the cells was reddish brown to dark brown. The growth on oatmeal agar medium at 25 ° C was slow, and after 10 days of inoculation, the cell size ranged from 1.5 to 2cm, and the surface of the cell was flat, and the development of airborne hyphae and the formation of closed spores Were all extremely poor. The color of the surface and the backside of the cells was dark brown to reddish brown. The growth rate on the czapek's medium at 25 ° C was very slow, and after 10 days of inoculation, the cells reached a diameter of 1.6 to 1.8 cm.
전술한 각각의 배지상에 있어서 37℃에서의 생장속도는 25℃에서의 생장속도와 실질적으로 동일하였다.The growth rate at 37 ° C. on each medium described above was substantially the same as the growth rate at 25 ° C.
2. 형태학적 특징2. Morphological features
폐쇄포자낭과의 모임은 구형이고, 직경은 30내지 60미크론이며, 그 줄기는 격벽을 갖고, 각각의 줄기는 직경이 3.5내지 4.5미크론이고, 길이가 15내지 80미크론인 균사로 구성되어 있다. 또, 8개의 포자로 구성된 자낭은 그 모양이 구형이고, 이것은 점차로 없어진다.The collection of obstructed spores is spherical, 30 to 60 microns in diameter, the stems having a septum, and each stem is composed of mycelium from 3.5 to 4.5 microns in diameter and 15 to 80 microns in length. In addition, the sperma of eight spores is spherical in shape, which gradually disappears.
자낭자루의 색상은 무색이고, 그 모양은 달걀형이거나 또는 타원형이며, 이들은 4-5×4-7미크론의 크기를 갖고, 표면은 평활하다. 분생포자의 색상은 무색이고, 그 모양은 구형이거나 서양배형이며, 이들의 크기는 6-9×6-11 미크론이고, 이들의 밑면은 절단된 모양이며, 이들의 벽은 상당히 두껍고 평활하다. 분생포자들은 분 열조직 분절홀씨와 같이 하향적으로 고리가 연결된 형태를 이루고 있으며, 분생자 자루는 영양균사와같이 분기형이거나 또는 분기형을 이루고 있지 않고, 꼭대기에 분생포자를 형성하고 있다. 균사는 무색이고, 분기형이며, 적벽을 갖고 있는데 이들 균사의 직경은 대부분이 3내지 5미크론이다.The scapula is colorless, its shape is oval or elliptical, they are 4-5 × 4-7 microns in size and the surface is smooth. Conidia are colorless, spherical or western-shaped, their size is 6-9 × 6-11 microns, their undersides are cut and their walls are fairly thick and smooth. The conidia are formed in a downwardly connected form, such as a mitotic splitting hole, and the conidia bag is not branched or branched like nutrient hyphae, and forms conidia on the top. Mycelia are colorless, branched, and have red walls, most of which are 3 to 5 microns in diameter.
상기의 관찰결과로 부터 이 미생물은 모나스쿠스 러버반티겜(van Tiegheam) 균주로 확인되었다.From the above observations, the microorganism was identified as Monascus rubber van Tiegheam strain.
모나스쿠스러버의 생태학적 특징에 대해서는 van Tieghem, Bull. Soc. Botan. France, 31, 227(1884);Cole et at Canadian Journal of Botany, 46, 987(1968) and Takada Trans. Mycol. Soc. Japan, 9, 128(1969)에 상세하게 기재되어 있다.For ecological features of Monascus rubber, see van Tieghem, Bull. Soc. Botan. France, 31, 227 (1884); Cole et at Canadian Journal of Botany, 46, 987 (1968) and Takada Trans. Mycol. Soc. Japan, 9, 128 (1969).
모나콜린K는 균류 배양기술에 통상 이용되는 배양조건과 통일한 조건을 이용하여 산소성 조건하의 배양 육즙중에서 모나콜린K-생성 미생물을 배양시킴으로서 얻을 수 있다. 즉, 적당한 배양기상에서 이 미생물을 배양시킨 다음에, 미생물 집단을 또 다른 배양기상에 접종배양시킴으로서 목적하는 모나콜린K를 제조할 수 있다. 이 경우 모나콜린K의 제조용에 사용하는 배양기 조성물은 초기와 미생물 배양에 사용하는 조성물자 동일하거나 또는 다를 수도 있다.Monacholine K can be obtained by culturing monacoline K-producing microorganisms in culture broth under oxygenic conditions using the same conditions as those commonly used in fungal culture techniques. In other words, the desired monacoline K can be prepared by culturing the microorganisms in a suitable incubator and then inoculating and culturing the microbial population on another incubator. In this case, the incubator composition used for the preparation of monacoline K may be the same as or different from the composition used for the initial and microbial culture.
모나콜린K-생성 미생물, 특히 모나스쿠스 러버1005는 광범위한 온도, 이를테면 7내지 40℃의 범위에서 생장될 수 있는데 일반으로 모나콜린 K제조의 가장 바람직한 온도는 20내지 30℃의 범위이다.Monacoline K-producing microorganisms, in particular Monascus rubber 1005, can be grown over a wide range of temperatures, such as between 7 and 40 ° C. In general, the most preferred temperature for the production of monacoline K is in the range of 20 to 30 ° C.
본 미생물의 배양에 사용하는 배양기는 균류 및 기타 미생물의 배양시에 사용되는 공지의 영양물질을 함유하는데, 일반으로 이 배양기는 적어도 동화성 탄소원과 동화성 질소원을 함유한다. 동화성 탄소원과 바람직한 예로서는, 글루코오스, 말토오스, 덱스트린, 전분, 락토오스, 수크로오스. 글리세린 등이 있으며, 이들중에서도 글루코오스와 전분이모나콜린K의 제조에 특히 바람직하다.The incubator used for culturing the microorganism contains known nutrients used for culturing fungi and other microorganisms, and in general, the incubator contains at least an assimilable carbon source and an assimilable nitrogen source. Anabolic carbon sources and preferred examples are glucose, maltose, dextrin, starch, lactose and sucrose. Glycerin and the like, and among these, glucose and starch monacoline K are particularly preferable.
동화성 질소원의 바람직한 예로서는 펩톤, 육즙, 효모, 효모즙, 콩가루, 땅콩깻묵, 옥수수 침지액, 쌀겨무기질소원 등이 있으며, 이들중에서도 펩톤이 바람직하다.Preferred examples of the assimilable nitrogen source include peptone, gravy, yeast, yeast juice, soy flour, peanut jelly, corn steep liquor, rice arsenic nitrogen source, and among these, peptone is preferred.
모나콜린K를 제조할 목적으로 본 미생몰을 배양하는 경우에는 필요에 따라서 배양기중에 무기염 및 금속염을 혼입시킬 수가 있으며, 또 소량의 중금속을 혼입시킬 수도 있다. 바람직한 배양기의 조성예를 들면용성전분2%(중량/용적)%, 글루코오스1(중량/용적)%, 펩톤2(중량/용적)%및 한천 2(중량/용적)%로 조성된다.In the case of culturing the microorganisms for the purpose of producing monacoline K, inorganic salts and metal salts can be mixed in the incubator if necessary, and a small amount of heavy metals can also be mixed. Preferred compositions of the incubator are, for example, 2% (soluble / volume)% of starch, 1% (weight / volume) of glucose, 2% (weight / volume) of peptone 2, and 2% (weight / volume) of agar.
모나콜린K는 산소성 배양의 표준기술(이를테면, 고체배양, 진동배양 또는 통기 수반하의 교반배양)을 이용하여 산소성 분위기하에서 모나콜린K-생성 미생물을 배양하여 제조할 수가 있다.Monacholine K can be prepared by culturing monacoline K-producing microorganisms in an oxygenous atmosphere using standard techniques of oxygenous culturing (eg, solid culture, vibrating culture, or agitation with aeration).
배양도중이나 또는 배양기의 멸균시에 소포(消泡)가 요구될때에는 소포제(실리콘오일이나 또는 계면활성제)를 배지중에 혼입시킬 수가 있다.Antifoaming agents (silicone oils or surfactants) can be incorporated into the medium during the incubation or when antifoams are required during sterilization of the incubator.
모나콜린K의 생리학적 활성에 대해서는 토끼혈중에 있어서의 콜레스테를 함량의 저하능을 측정하는 하기의 실험에 의해 평가할 수가 있다. 본 실험에서는 중량이 2.5내지 3.Okg인 토끼를 사용해야 하며, 실험직전에 토끼귀의 동맥으로부터 피를 채취해서 통상의 방법에 의해 혈청중의 콜레스테롤 함량을 측정한다.The physiological activity of monacoline K can be evaluated by the following experiment which measures the ability of cholesterol to decrease in content in rabbit blood. In this experiment, a rabbit weighing 2.5 to 3.Okg should be used. Before the experiment, blood is drawn from the artery of the rabbit's ear, and the cholesterol content of serum is measured by a conventional method.
다음에 모나콜린K의 소정량을 1내지 5일간에 걸처서 간헐적으로 경구 투여하고, 투여한 후에 헐청중의 콜레스테룰 함량을 측정한다. 모나콜린K투여 전후에 있어서의 콜레스테룰 함량을 대비함으로서 모나콜벤 K의 역가를 측정할 수가 있다.Next, a prescribed amount of monacoline K is intermittently administered orally over 1 to 5 days, and after administration, the cholesterol content in the herb is measured. The titer of monacol ben K can be measured by comparing cholesterol content before and after monacoline K administration.
모나클린K 생성 미생물의 배양은 전술한 실험으로 측정하여 배양기중에 모나콜린K의 실질적인 양이 축적될때까지 계속 수행할 수 있는데, 이 단계에 이르면 물리적 성질을 이용한 바람직한 공지의 기술들을 병용하여 모나콜린K를 배양육즙으로주터 단리 및 회수할 수가 있다. 이를테면. 단리조작은 하기의 기술 즉, 디에틸에테르, 초산에틸, 클로로포름 또는 벤젠에 의한 추출방법, 보다 극성이 약한 용매(이를테면, 아세톤 또는 알코올)중에서의 용해방법, 보다 극성이 약한 용매(이를테면, 석유에테르 또는 헥산)중에서의 불순물의 제거방법, 세파덱스(미합중국 Pharmacia Co., LTD.제품의 상품명)등의 칼럼을 통한 겔 여과방법, 활성탄이나 실리카겔을 이용한 흡찰 크로마로그래피등 중의 일부 또는 모두를 이용할 수가 있다.Cultivation of monaclinic K-producing microorganisms can be carried out until the actual amount of monacoline K accumulates in the incubator as measured by the experiments described above. At this stage, monacoline K is used in combination with the known well-known techniques using physical properties. Can be isolated and recovered as culture broth. for example. Isolation is carried out by the following techniques: extraction with diethyl ether, ethyl acetate, chloroform or benzene, dissolution in a less polar solvent (such as acetone or alcohol), less polar solvent (such as petroleum ether). Or a method of removing impurities in hexane), gel filtration through a column such as Sephadex (trade name of Pharmacia Co., LTD.), Adsorption chromatography using activated carbon or silica gel, or the like. have.
전술한 기술방법등을 적절히 병용하여 배양육즙으로 부터 목적하는 모나콜린K를 순수한 물질로서 단리시킬 수가 있다.By appropriately using the above-described technical methods, the desired monacholine K can be isolated from the culture broth as a pure substance.
모나콜린K의 생리-화학적 특징은 하기와 같다.Physiological-chemical characteristics of monacoline K are as follows.
모나클린K는 융점이 157내지 159℃(분해)이며, 무색의 결정으로서 저급 알코올류(메탄을, 에탈올 및 프로판올), 아세톤 클로로포름, 초산에틸 및 벤젠중에 가용성이며 헥산 및 석유에테르 중에서는 불용성이다. 또 이물질은 중성을 나타내며, 중성이나 또는 산성의 수성매질중에서 불용성이나 알카리 처리를 행하여 산성물질로 전환시킨 다음에 수중에 용해지킬 수가 있다. 이 산성물길은 산성의 pH치에서 초산에틸 또는 클로로포름으로 추출할 다음, 용매를 중발시켜 모나콜린K로 환원시킬 수가 있다.Monaklin K has a melting point of 157 to 159 ° C (decomposition), a colorless crystal, soluble in lower alcohols (methane, ethanol and propanol), acetone chloroform, ethyl acetate and benzene, and insoluble in hexane and petroleum ether . In addition, foreign matters are neutral and can be dissolved in water after being converted to an acidic substance by performing an insoluble or alkaline treatment in a neutral or acidic aqueous medium. This acidic route can be extracted with ethyl acetate or chloroform at an acidic pH value and then reduced to monacoline K by neutralizing the solvent.
원소 분석치 분자식 .Elemental Analysis Molecular Formula.
C, 71.56%; H, 8.85%; 0, 19.59% C24H36O5 C, 71.56%; H, 8.85%; 0, 19.59% C 24 H 36 O 5
분자량. 비선광도Molecular Weight. Non-luminescence
404(질량 분석법에 의함) [α ]25 D=+307.6(c=1, 메란올)404 (by mass spectrometry) [α] 25 D = + 307.6 (c = 1, meranol)
실리카겔(merck & Co. LTD제품, NO. 7515 KieseIgeI 60 F254) 박층 크로마토그래피에 염화메틸렌과아세톤(4:1 용적비)과의 혼합물을 전개시키고. 50%(용적/용적) 황산(약하제 가열하면 담적색에서 적갈색으로 전개됨) 토는 요오드로 분무한 후 자외선 방사-흡수 램프를 사용하여 관찰하였더니 Rf치 0.7에서단일정이 나타났다. 새앙쥐에 있어서 모나콜린K의 급성 정투 독성 (LD50)은 체중 1㎏당 1g이상으로 저독성을 나타낸다.The mixture of methylene chloride and acetone (4: 1 volume ratio) was developed on silica gel (merck & Co. LTD, NO. 7515
본 발명자들은 여러가지의 생체내 실험을 통하여 모나콜린 K가 혈중의 콜레스테롤 함량을 저하시키는능력이 있다는 것을 실증하였다.The inventors have demonstrated through various in vivo experiments that monacoline K has the ability to lower blood cholesterol content.
쥐에 있어서 혈중 콜레스테롤 감소실험 :Blood cholesterol reduction in rats:
위스타르 이마미치(wistar imamichi)계 쥐를 실험동물로 사용하여 5마리의 쥐들로 구성되는 각각의 군에 대하여 실험을 행하였다.Wistar imamichi rats were used as experimental animals for each group consisting of five rats.
각각의 쥐에 Triton WR1339(혈중의 콜레스테롤 함량을 증가시키는 물질로 공지되어 있는 상품명)400mg/kg을 정맥내 주사함과 동시에, 모나콜린K. 10mg/kg을 복강내 투여 하였더니, 투여한 후 14시간이 지난뒤에 쥐들은 피를 흘리며 사망하였다.Each mouse was injected intravenously with 400 mg / kg of Triton WR1339 (a trade name known to increase blood cholesterol content). Intraperitoneally administered 10 mg / kg, the rats bleeding died 14 hours after administration.
통상의 방법에 의해 콜레스테롤 함량을 측정하였더니, Triton WR 1339만을 단독 투여한 또 다른 쥐들의군에 비하여 혈중의 콜레스테롤 함량이 23.9% 감소된 것이 입증되었다.Cholesterol content was measured by conventional methods, demonstrating a 23.9% reduction in blood cholesterol content as compared to another group of mice treated with Triton WR 1339 alone.
토끼에 있어서 혈중 클레스테롤 감소실험 :Blood Cholesterol Reduction in Rabbits:
체중 2.7kg내지 2.9kg의 토끼를 시험동물로 사용하여 각각의 토끼에 모나콜린K를 5일동안 연속적으로1일2회(조석으로)씩 1mg/kg을 경구투여하였다.Using rabbits of 2.7 kg to 2.9 kg body weight as test animals, each rabbit was orally administered 1 mg / kg of monacoline K twice daily for 5 days in the tidal phase.
투여하기 전과 투여한 후 3일 및 5일이 지난뒤에 토끼귀의 동맥으로부터 피를 채취해서 혈청중의 콜레스테롤을 측정한 결과, 모나콜린K를 투여한 후 3일 및 5일이 지난 뒤의 각각의 콜레스테롤 함량은 모나클린K를 투여하기 전의 함량보다 더 낮은 15% 및 29%이었다.Cholesterol was collected from rabbit arteries before and after 3 and 5 days of administration, and the serum cholesterol was measured.These cholesterol levels after 3 and 5 days after monacoline K were administered. The content was 15% and 29% lower than the content prior to the administration of Monaklin K.
따라서, 모나콜린 K는 고 콜레스테롤 혈중 치료제 또는 동맥 경화증 치료제로서 유용한 것이다.Thus, Monacholine K is useful as a treatment for high cholesterol blood or for treating atherosclerosis.
모나콜린K와 ML-236B를 비교하기 위하여, 모나콜린K와 동일물질인 하기식의 메리놀린(Mevinolin)을 비교하면 다음과 같다.In order to compare Monacholine K and ML-236B, the following formula merinoline (Mevinolin) of the same formula as Monacholine K is as follows.
ML-236B에 의한 콜레스테롤의 저하작용(12일간 투여)Lowering Cholesterol by ML-236B (12-day Administration)
상가에 대하여 모나콜린K(Mevinolin)의 효과는 하기표에 나타내있다.The effect of monacoline K (Mevinolin) on the mall is shown in the table below.
※ 소디움 메비놀리네이트(O) 또는 ML236B 소디움염(·)의 단독 경구투여후 쥐에 있어[14C] 아세테이트로부터의 콜레스테롤 합성의 급성 억제. 각 점은 같은 날에 분석된 대조와 비교하여 쥐 10마리에 있서의 억제율의 평균이다.Acute inhibition of cholesterol synthesis from acetate [ 14 C] in rats after oral administration of sodium mebinolinate (O) or ML236B sodium salt (·) alone. Each point is the average of inhibition rates in 10 rats compared to the control analyzed on the same day.
상기의 표로부터 모나콜린K의 효과가 ML-236B의 6배임을 알 수 있으며 ML-236B을 20mg/kg/일에서 12일간 투여한 때의 혈장콜레스테롤이 30.4% 저하하였으나 메비놀린을 8mg/kg/일에서 12일간 투여한 때의 혈장콜레스테롤의 저하율은 24.2% 이었으므로 메비놀린의 투여량은 적게하여도 될 것으로 기재되어 있다. 또한 모나콜린K의 사람에 대한 용법 및 용량에 대해서는 다음과 같다. 사람에 5,1550mg을 1일2회 7∼11일간 투여하고 7일 후의 혈청콜레스테롤의 저하율은 각각 14,25,24%이었음이 나타나 있으며 안전성과 그 효과가 나타나 있다.The above table shows that the effect of monacoline K is 6 times that of ML-236B. Plasma cholesterol decreased by 30.4% when ML-236B was administered at 20 mg / kg / day for 12 days, but 8 mg / kg / Since the rate of plasma cholesterol reduction when administered from days to 12 days was 24.2%, the dosage of mebinoline may be reduced. In addition, the usage and dosage of monacoline K in humans is as follows. In humans, 5,1550mg twice a day for 7-11 days, the decrease rate of serum cholesterol was 14,25,24% after 7 days, respectively, showing safety and its effects.
(placebo 에서는 저하율 4%)(4% reduction in placebo)
* 메비놀린 처리 후 총혈청 콜레스테롤중 바세린으로부터의 평균 백분율 변화* Average percentage change from petrolatum in total serum cholesterol after mevinolin treatment
○‥‥‥‥‥○ placebo; ●￣● 5mg b.i.d; ▲＿▲ 15mg b.i.d; ■＿■ 50mg b.i.d. 바아는 표준 편지를 나타낸다.○ ‥‥‥‥‥ ○ placebo; ￣ ● 5mg b.i.d; ▲ ＿ ▲ 15 mg b.i.d; ■ ＿ ■ 50mg b.i.d. Bars represent standard letters.
부작용에 대하여는 그 약효에 비하여 허용할 수 있음이 문헌(The American Society for Chemical Inve-stigation Inc, volume 69 April 1982, 918∼919)에 나타나 있다.Adverse reactions to the drug are acceptable in the literature (The American Society for Chemical Inve-stigation Inc, volume 69 April 1982, 918-919).
본 발명에 따른 화합물은 캡슐제, 정제, 주사제 또는 기타 공지되어 있는 제제형으로 하여 경구 또는 비경구적으로 투여할 수가 있으나, 경구투여하는 것이 바람직하다. 약용량은 환자의 나이, 체중 및 건강상태등에 관계되나. 일반으로 2일 용량은 성인의 경우에 1회량 또는 2내지 3회 분할량으로 하여 0.5 내지50mg이다.The compounds according to the invention can be administered orally or parenterally in capsules, tablets, injections or other known formulations, but are preferably administered orally. Dosage depends on the patient's age, weight and health condition. In general, the two-day dose is 0.5 to 50 mg in adults, divided into two or three divided doses.
그러나, 본 화할물은 저독성이기 때문에 필요에 따라서 약용량을 더 높여도 무관하다.However, because the compound is low toxicity, it is irrelevant to increase the dosage as needed.
하기에 실시예를 열거하여 본 발명을 보다 상세하게 서술하겠는데, 본 발명의 범위는 이 실시예만으로 한정되는 것은 아니다.Although an Example is given to the following and this invention is demonstrated in detail, the scope of the present invention is not limited only to this Example.
[실시예]EXAMPLE
글루코오스6(중량/용적)%, 펩톤 2.5(중량/용적)%, 옥수수 침지액 0.5(중량/용적)% 및 염화암모늄0.5(중량/용적)%를 함유하는 액상 배양기상에 모나스쿠스 러버 1005 균주를 접종한 후, 산소성 조건하의28℃의 온도에서 10일간 배양을 계속 행하였다. 생성되는 배양 육즙여액(5ℓ)에 6N염산을 첨가하여 pH를3으로 조정한 다음, 등용적의 초산에틸로 추출하였다. 추출액으로부터 용매를 감압 추출하여 생성되는 잔액을 10mI의 벤젠중에 용해시키고, 불용물을 여별하였다.Monascus rubber 1005 strain on a liquid incubator containing 6% glucose by weight, 2.5% by weight peptone, 0.5% by weight corn soak and 0.5% by weight ammonium chloride. After inoculation, the culture was continued for 10 days at a temperature of 28 ° C. under oxygenic conditions. 6N hydrochloric acid was added to the resulting culture broth filtrate (5 L) to adjust the pH to 3, and then extracted with an equal volume of ethyl acetate. The residue obtained by extracting the solvent from the extract under reduced pressure was dissolved in 10 ml of benzene, and the insolubles were filtered off.
여액을 1회에 5(중량/용적)%의 중탄산나트륨 수용액 100ml로 2회 세척하고, 세척한 여액에 0.2N수산화나트륨 수용액 100ml를 첨가시켜 생성되는 혼합물을 실온에서 교반하였다. 박충 크로마토그래피에 의해 벤젠충으로부터 모나콜린K가 없어진 것을 확인한 후에 수층을 여별하였다.The filtrate was washed two times with 100 ml of 5 (weight / volume)% aqueous sodium bicarbonate solution, and 100 ml of 0.2 N aqueous sodium hydroxide solution was added to the washed filtrate, and the resulting mixture was stirred at room temperature. After confirming that monacoline K disappeared from the benzeneworms by larva chromatography, the aqueous layer was filtered.
다음에 6N염산을 첨가하여 수층의 pH를 3으로 조정한 다음, 생성되는 용액을 1회에 100ml의 초산에 틸로 2회 추출을 행하고. 추출액을 감압하에 증발건고를 행하여 유상물질260mg을 얻었다. 이 유상물질을 벤젠중에 용해시키고 결정화 한 다음에 아세톤 수용액에서 재결정화 하였더니 전술한 특징을 갖는 무색 침상의모나콜린 K87mg이 얻어졌다.Next, 6N hydrochloric acid was added to adjust the pH of the aqueous layer to 3, and then the resulting solution was extracted twice with 100 ml of ethyl acetate once. The extract was evaporated to dryness under reduced pressure to give 260 mg of an oily substance. This oily substance was dissolved in benzene, crystallized and then recrystallized in acetone aqueous solution to give a colorless needle-shaped monacoline K87 mg having the characteristics described above.
Claims (1)
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 |
|---|---|
| KR830002030A KR830002030A (en) | 1983-05-21 |
| KR830002801B1 true KR830002801B1 (en) | 1983-12-16 |
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ID=11955290
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019800000654A KR830002801B1 (en) | 1979-02-20 | 1980-02-19 | Process for preparing antihypercholesteramic agent monacolink 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| 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 |
| JPS5835144A (en) * | 1981-08-27 | 1983-03-01 | Sankyo Co Ltd | Mb-530b derivative and its preparation |
| US4782084A (en) * | 1987-06-29 | 1988-11-01 | Merck & Co., Inc. | HMG-COA reductase inhibitors |
| US4997848A (en) * | 1987-10-27 | 1991-03-05 | Sankyo Company, Limited | Octahydronaphthalene oxime derivatives for cholesterol synthesis inhibition |
| 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 |
| ZA933359B (en) | 1992-05-15 | 1993-12-08 | Sankyo Co | Octahydronaphthalene oxime derivatives for cholesterol biosynthesis inhibition, their preparation and use |
| 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 |
| 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 |
| US6046022A (en) | 1996-09-30 | 2000-04-04 | Peking University | Methods and compositions employing red rice fermentation products |
| UA73074C2 (en) | 1998-03-20 | 2005-06-15 | Method of controlled fermentation for production of lovastatin as hydroxy-acid | |
| CZ20022779A3 (en) | 2000-02-24 | 2003-02-12 | Biogal Gyogyszergyar Rt. | Purification process of fermentation broth |
| WO2001066538A1 (en) | 2000-03-03 | 2001-09-13 | Biogal Gyogyszergyar Rt. | A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities |
| KR20010095780A (en) * | 2000-04-12 | 2001-11-07 | 나가오카 마사시 | Embryo monascus |
| IN192861B (en) | 2000-06-30 | 2004-05-22 | Ranbaxy Lab Ltd | |
| ATE356554T1 (en) * | 2001-02-09 | 2007-04-15 | Unilever Nv | FOODS CONTAINING SOY PROTEIN AND STATIN |
| KR100379075B1 (en) | 2002-03-07 | 2003-04-08 | Jinis Biopharmaceuticals Co | Method for producing low cholesterol animal food product and food product therefrom |
| 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 |
| RO128803A0 (en) | 2012-10-12 | 2013-09-30 | Ion Gigel Fulga | Composition for the treatment or prevention of dyslipidemias |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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
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1980
- 1980-02-19 KR KR1019800000654A patent/KR830002801B1/en active
- 1980-02-19 CA CA345,983A patent/CA1129794A/en not_active Expired
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- 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
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- 1980-02-20 NZ NZ192919A patent/NZ192919A/en unknown
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1984
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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