WO1997027314A1 - Processus de production d'analogues d'acide oleanolique par la culture de racine pileuse - Google Patents

Processus de production d'analogues d'acide oleanolique par la culture de racine pileuse Download PDF

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Publication number
WO1997027314A1
WO1997027314A1 PCT/JP1997/000127 JP9700127W WO9727314A1 WO 1997027314 A1 WO1997027314 A1 WO 1997027314A1 JP 9700127 W JP9700127 W JP 9700127W WO 9727314 A1 WO9727314 A1 WO 9727314A1
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Prior art keywords
oleanolic acid
plant
producing
hairy
hairy root
Prior art date
Application number
PCT/JP1997/000127
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English (en)
Japanese (ja)
Inventor
Kenji Katoh
Masami Matsumoto
Keiichiro Yasumi
Noboru Shirane
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Shionogi & Co., Ltd.
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Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU13196/97A priority Critical patent/AU1319697A/en
Publication of WO1997027314A1 publication Critical patent/WO1997027314A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • 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
    • C12P33/00—Preparation of steroids

Definitions

  • the present invention relates to a novel method for producing an oleanolic acid analog by hairy root culture. More specifically, the present invention relates to a method for culturing hairy roots induced by transformation with a plasmid capable of inducing hairy roots, The present invention relates to a novel method for producing analogs of oleanolic acid by collecting myricerol, 27-oxy-lactate fueroyl myricerol, myricerol, or 27-oxyl-yl phylloyl myrilone from glycerol.
  • Background art
  • Myricerol, 27-oxy-forced phenol oil myricerol, myricerone and 27-oxy-powered phenol oil myricerone, shown below, are useful as compounds that can be intermediates in the production of various compounds.
  • R 3 is hydrogen or a metabolic ester residue
  • R 4 is an optionally substituted aryl or an optionally substituted aromatic complex
  • one of X and Y is hydroxy and the other is Is hydrogen, or X and Y are oxo together, and Z is oxygen or two hydrogens.
  • R 3 is hydrogen or a metabolizable ester residue
  • R 6 is hydrogen or —R 6 —R 7
  • R 6 is —S 0 3 —, one CH 2 COO—, —COCOO— or
  • R 8 COO-(R 8 is lower alkylene or lower alkenylene) and R 7 is hydrogen or lower alkyl
  • Is very useful as an intermediate for producing the compound represented by Compounds (II) and (III) are known to be endothelin receptor antagonists (W092Z12991 and JP-A-7-53484), and various compounds caused by excessive secretion of endothelin are known. It is a compound useful as a therapeutic or prophylactic agent for diseases such as hypertension, cerebrovascular contraction, acute dysfunction, acute proliferative arrhythmia, acute myocardial infarction, intimal hyperplasia, and cerebral edema.
  • 27-hydroxyl phenol oil myricelone itself has a non-peptide endothelin receptor antagonist activity and exhibits an antihypertensive effect (FEBS letters, no. Vol., Pp. 411-44 (1992)).
  • 27-hydroxy phenol oil myricerol or 27-hydroxy phenol is extracted from the bark of milli ricacerifera (W092Z 12 9 9 1) or Merianthus. Extraction method from root bark of Comosath (Me lianthusc omo sus) (Journal of S outh African Chemical Institute, 1974) Vol. 27, pp. 131-136).
  • Myricerol and myricelone can be obtained by further alkaline hydrolysis of the thus obtained 27-hydroxyl fueroyl myricerol and 27-oxyl fueroyl mycelon, or by cod root bark, grape skin or It was obtained by a method of semi-synthetic production by chemically modifying oleanolic acid extracted from olive leaves as a raw material (Japanese Patent Application Laid-Open No. 7-316188).
  • the method of extracting from natural products has problems such as low yield and inconsistent content depending on the plant production area, and it has been difficult to supply a sufficient amount.
  • the method of semi-synthetic production from oleanolic acid was very difficult because it required about 10 steps of chemical reaction to synthesize mycelol or mycelone from oleanolic acid.
  • Methods for obtaining useful metabolites by hairy root cultivation include methods for producing tanshinones using tanzine in JP-A-2-231090, and lentils in JP-A-4-75595 and JP-A-4-177494.
  • a method for producing phyllosides by a family of family plants is described. Disclosure of the invention
  • the present inventors have conducted intensive studies with the aim of developing a new method for producing oleanolic acid analogs, and as a result, it has been found that the desired compound can be produced very easily in high yield by hairy root culture.
  • the present invention was completed.
  • the present invention provides a hairy root derived from a plant capable of producing an oleanolic acid derivative, which is transformed by a plasmid capable of leading the hairy root, and culturing the hairy root.
  • Another object of the present invention is to provide a method for producing an oleanolic acid derivative by collecting the oleanolic acid derivative from the obtained culture.
  • the present invention also provides a hairy root derived from a plant capable of producing an oleanolic acid analog, the hairy root being transformed by a plasmid capable of inducing a hairy root. .
  • the desired oleanolic acid analog can be obtained very simply and stably in high yield.
  • oleanolic acid analog refers to oleanolic acid, myricerol, 27-oxycaffeoyl myricerol, myriceron, 27-oxy-potassium fueoyl myricerone, and derivatives thereof.
  • the compounds to be obtained are included.
  • the “plant capable of producing an oleanolic acid analog” used in the present invention means an entire plant or a part thereof that produces the oleanolic acid analog.
  • Examples of a plant that produces the above-mentioned “oleanolic acid derivative” include, for example, Merianthus comomosus (Melianthuscomo sus) and Merianthus major (Me1ianthusmajor), and Bers ama abyssinica ), Millica such as White peach (My ricacerifera), Polygala such as Polygona japonica and Polygalasenega, and Astrobema A such as A stilbethunbergii.
  • the term "hairy root” refers to a differentiated or undifferentiated cultured tissue obtained by infecting a plant with bacteria and introducing a part of the plasmid retained by the bacteria into the plant. Means It is preferable that the undifferentiated culture has been sterilized by a method such as subculture in a medium containing an antibiotic.
  • plasmid capable of inducing hairy roots refers to the T-DNA region of Ri plasmid, which has all the necessary regions for hairy root formation. Any brasside that can be formed can be suitably used.
  • R i plasmid or recombinant plasmid of R i plasmid and T i brasmid can be mentioned.
  • Recombinant plasmid is the T-DNA region of Ri brasmid, which is the entire region required for hairy root formation transferred to the T-DNA region of Ti plasmid. Any one that has acquired the inductive ability can be used in the present invention.
  • hairy roots may be induced using the above-mentioned plant and the above-mentioned brasside by a commonly used method, and cultured and collected.
  • a sterile plant is prepared using the above plant by a conventional method.
  • the seeds, apical buds or stems of a plant are cut off, sterilized using a solution of sodium hypochlorite, ethanol, or the like, and then aseptically planted in a medium.
  • the medium used here is not limited in any way.
  • a synthetic medium or a medium containing an appropriate amount of nutrients such as a carbon source, a nitrogen source, inorganic ions and vitamins, and commonly used in plant tissue culture * is used. Any of natural media can be suitably used.
  • Examples of the carbon source include glucose, sucrose, maltose, invert sugar, and the like. One or more of these may be appropriately selected in consideration of plant assimilation. Select and use them in combination.
  • Nitrogen sources include, for example, ammonium ions (eg, ammonium nitrate, ammonium sulfate, etc.), nitrate ions (eg, potassium nitrate, ammonium nitrate, etc.), amino acids (eg, glycine, glutamine, glutamic acid), protein decomposition products such as peptone, and meat.
  • ammonium ions eg, ammonium nitrate, ammonium sulfate, etc.
  • nitrate ions eg, potassium nitrate, ammonium nitrate, etc.
  • amino acids eg, glycine, glutamine, glutamic acid
  • protein decomposition products such as peptone
  • meat include inorganic nitrogen compounds or organic nitrogen compounds such as extracts and yeast extracts. One or more of these may be appropriately selected and used from the viewpoint of plant assimilation.
  • inorganic ion examples include inorganic salts composed of cations such as potassium ion, calcium ion, magnesium ion, and iron ion and anions such as sulfate ion, phosphate ion, citrate ion, and chloride ion, for example, magnesium sulfate, Potassium phosphate, potassium nitrate, calcium carbonate, ferric chloride and the like are listed.
  • vitamins include thiamine, pyridoxine, nicotinamide, inositol and the like. One or more of these may be appropriately selected and used.
  • the medium include the Murashige and Skoog's medium, the Nitche and Nitce * s medium, or a modified medium thereof.
  • glucose sucrose
  • plant hormones such as auxin and cytokinin can be used alone or in an appropriate combination of two or more.
  • These media may be adjusted to pH 5 to 7, preferably around pH 5.7, and sterilized by a generally used method.
  • sterilization method include, for example, a method of applying an autoclave, or using an aseptic filter to filter under an aseptic environment.
  • the germ-free bacteria produced by the above method are inoculated with bacteria having a plasmid capable of inducing hairy roots.
  • the bacteria used here are not particularly limited, and any bacteria having the above-mentioned plasmid can be suitably used.
  • Agrobacterium rhizogenes (Ag robacteri um rhizogenes), Agrobacterium um tume faciens, Ri plasmid or recombinant plasmid is introduced into the cells, and preferably Agrobacterium umme faciens.
  • Murizogenes is preferred.
  • Agrobacterium rhizogenes which is a strain that produces an abnormal amino acid of the mykimopine type, is preferred because of its high hairy root induction efficiency.
  • Agrobacterium umme faciliens incorporating Ri Brasmid or recombinant plasmid into cells is described in Plant Physiology (P 1 ant Physio 1 ogy, 1994, Vol. 104, No. 801). -80 p. 2) can be used to introduce Ri brasmid or recombinant plasmid into cells.
  • the inoculation may be performed by a commonly used known method. For example, a method in which bacteria are attached to a sessile needle or the like and pierced into a sterile plant, a method in which a sterile plant is damaged and a bacterium is applied thereto, a method in which a bacterial suspension is dropped or sprayed on the wound, and a cultivation of bacteria There is a method of immersing a sterile plant in a liquid or a bacterium-containing liquid.
  • Hairy roots are formed when the plant inoculated with bacteria is allowed to stand on a suitable medium for about 1 to 6 weeks, preferably in the dark, and the culture temperature varies depending on the plant species. : ⁇ 30, preferably about 25 and ⁇ 28.
  • the medium used here is not particularly limited, and the same medium as described above can be used.
  • the hairy root obtained by the above method is sterilized according to a usual method.
  • a method of cutting out the tip including the growth point of plant tissue and culturing it several times, or using an antibiotic (cefotaxime, carpenicillin, etc.) with a final concentration of 0.5 mgZm 1 to 1 mgZm 1 A method of cultivating hairy roots cut out on a medium may be used.
  • the medium used here is the same as described above except for the case where an antibiotic is added, and is not particularly limited.
  • the culturing may be carried out under conditions of about 20 "C to about 30, preferably about 25" C to about 28X: preferably in a dark place.
  • those having a high growth rate and those having a large number of branches are selected, and are selected from about 20 to about 30 X :, preferably about 25 to about 25.
  • the medium used here is the same as above.
  • the oleanolic acid derivative is extracted from the hairy roots after the above culture by a commonly used extraction method.
  • the immersion liquid is first immersed in the solvent, the immersion liquid is filtered, and the solvent in the obtained extract is distilled off.
  • immersion in a solvent may be performed directly, or once a drying step such as freeze-drying is performed, immersion in the solvent may be performed.
  • the solvent may be any of water, a polar organic solvent and a non-polar solvent, but is preferably a solvent such as methanol or ethyl acetate. Methanol is particularly preferred because of its high extraction efficiency.
  • Any of the generally used methods can be suitably used for distilling off the solvent.
  • a method such as decompression can be used, and distillation by an evaporator is particularly preferable.
  • the obtained residue is purified and recrystallized by a commonly used method to obtain the desired compound.
  • the purification method include column chromatography, high-performance liquid chromatography, and the like.
  • a method of purifying with a column such as silica gel is preferable.
  • the solvent used for recrystallization may be alcohol (methanol, ethanol, etc.), benzene or a mixture thereof, and a 1: 1 mixture of ethanol and benzene is particularly preferred.
  • the oleanolic acid derivatives obtained by the method of the present invention are useful as various pharmaceuticals and intermediates for producing the same.
  • the oleanolic acid analog When used as a pharmaceutical or an intermediate for producing the same, it may be converted to a salt that can be formed as necessary.
  • salts that can be formed include salts with alkali metals (such as sodium, potassium and lithium), alkaline earth metals (such as calcium and magnesium), ammonium and organic bases (such as triethylamine and pyridine). I can do it. These salts can be formed by a commonly used method.
  • the compound obtained by hairy root culture * is 27-oxy-caffeoylmycerol
  • it is subjected to a hydrolysis reaction and a selective oxidation reaction at the 3-position to obtain mycelone.
  • 27-oxy-caffeoylmilycetone is obtained by hairy root ginger, it is hydrolyzed, and if myricerol is obtained, it is subjected to a selective oxidation reaction at the 3-position. Obtain myriceron.
  • R 5 is hydrogen or a R 6 - is R 7
  • R 6 is - S 0 3 -, - CH 2 COO-, one COCOO- or a COR 8 COO-
  • R 8 is a lower alkylene or lower Alkenylene
  • R 7 is hydrogen or lower alkyl
  • R 9 is t-butoxycarbonyl or hydrogen.
  • Murashige-Skoog medium (1900 mg of potassium sulfate, 50 mg of ammonium nitrate, 150 mg of agglomerated calcium 2) Hydrate 440 mg, magnesium sulfate heptahydrate 37 Omg, dipotassium hydrogen phosphate 17 Omg, ferrous sulfate heptahydrate 27.8 mg, ethylenediaminetetrahydroacetic acid disodium 37.3 mg , Manganese sulfate tetrahydrate 22.3 mg, zinc sulfate heptahydrate 8.6 mg, boric acid 6.2 mg, potassium iodide 0.83 mg, sodium molybdate dihydrate 0.25 mg , Copper sulfate pentahydrate 0.02 5 mg, cobalt chloride hexahydrate 0.02 5 mg 00ml).
  • Agrobacterium rhizogenes IFO 144554 was inoculated into the upper hypocotyl part of the obtained sterile seedling using a stalked needle, and 2 to 4 weeks later, the hairy root generated from the inoculated site was cut off.
  • the cells were inoculated in Murashige-Skoog medium solidified with 0.2% dielan gum, and cultured in the dark at 25 for 20 days. Then, the cells were transferred to Murashige-Skoog medium solidified with 0.2% dielan gum containing cefotaxime (O.C.O.SnigZm1), and subcultured * every week with a medium containing the same antibiotics. ⁇ 8 times repeated to get rid of hairy roots,
  • Murashige-Skoog's modified medium is used in the Murashige-Skoog mineral medium for 1 000 ml.
  • thiamine hydrochloride 0.5 mg of pyridoxine hydrochloride, 0.5 mg of nicotinic acid, 10 Omg of myo-inositol,
  • nicotinic acid 10 Omg of myo-inositol
  • Add 30 g of sucrose and 2.0 g of gellan gum then add distilled water to make up to 1 000 ml, adjust the pH to around 5.8, and dispense 40 ml in 1 000 m 1 Meyer.
  • the autoclave was sterilized for 15 minutes.
  • Hairy roots (40 g) of Merianthus comosas two weeks after the start of culture were extracted by immersing twice in methanol (80 ml) twice for three days.
  • the extract and 16 Oml of hexane were mixed, and liquid-liquid distribution was carried out in a separating funnel to remove the hexane fraction and remove low-polar substances such as lipids.
  • the remaining methanol fraction was concentrated under reduced pressure by an evaporator and evaporated to dryness, and then 100 ml each of ethyl ethyl phosphate and water were added thereto, followed by liquid-liquid distribution in a separating funnel. After removing the aqueous layer, the ethyl acetate layer was dried under reduced pressure to obtain a crude extract.
  • the crude extract was dissolved in a mixed solvent of chloroform and methanol (95: 5) to obtain a crude extract, which was then subjected to column chromatography (si1icagel 60, 230 # 400 mesh, Merck). The extract was added. First, elution was performed with a mixed solvent of chloroform and methanol (95: 5), and then elution was performed with a mixed solvent of chloroform and methanol (8: 2). After collecting and concentrating the yellow fraction, a part thereof was purified by high performance liquid chromatography to obtain about 17 mg (yield: about 1% of fresh weight) of a target compound.
  • the high-performance liquid chromatography column uses Deve 1 osi 1 ODS-HG-5 (20 mm x 250 mm) and a flow rate of 10 ml using a mixture of acetonitrile and water (8: 2). / min, temperature 20t: Purification was performed while monitoring with UV 330
  • Compound (III) was synthesized in the same manner as in JP-A-7-53484 and JP-A-7-3161888.
  • the mother liquor was chromatographed on ODS silica gel and eluted with a mixture of methanol-water (85:15).
  • the precipitated crystals were collected and recrystallized from methanol together with the above crystals to obtain 13.5 g of myristerol.
  • a solution of mycerol (10.19 g, 21.55 mmo 1) obtained in the first step in pyridine solution (80 ml) was placed in a nitrogen atmosphere at room temperature under anhydrous nitrogen (80 ml, 0.1 ml). 86 mo 1) was added dropwise over 10 minutes. After stirring for 3.5 hours in the room, the mixture was cooled to Ot: and methanol (69 m; 1.70 mO 1) was added dropwise over 5 minutes. After stirring at room temperature for 30 minutes, the mixture was poured into a mixture of ice-concentrated hydrochloric acid (90 ml), water (200 ml), and methylene hydride (400 ml).
  • an oleanolic acid derivative can be produced very easily and in a high yield as compared with the conventional method.
  • the obtained oleanolic acid analogs are very useful as various pharmaceuticals or intermediates for their production.

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Abstract

Cette invention concerne un processus de production d'analogues d'acide oléanolique, lequel processus consiste à induire et à cultiver des racines pileuses provenant de plantes capables de former des analogues d'acide oléanoliques tel que du myricérol, du 27-hydroxy-caffeoylmyricérol, du myricérone ou du 27-hydroxy-caffeoylmyricérone. Ce processus fait appel à des plasmides, tel qu'un plasmide Ri, capables d'induire des racines pileuses et d'absorber, dans le milieu de culture, les analogues d'acide oléanolique ainsi obtenus.
PCT/JP1997/000127 1996-01-23 1997-01-22 Processus de production d'analogues d'acide oleanolique par la culture de racine pileuse WO1997027314A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13196/97A AU1319697A (en) 1996-01-23 1997-01-22 Process for producing oleanolic acid analogs by culturing hairy root

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5828696 1996-01-23
JP8/58286 1996-01-23

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WO1997027314A1 true WO1997027314A1 (fr) 1997-07-31

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080643A1 (fr) * 2002-03-22 2003-10-02 Shionogi & Co., Ltd. Procede de production de derives de triterpenes
ES2217978A1 (es) * 2003-04-30 2004-11-01 Consejo Sup. Investig. Cientificas Utilizacion del acido oleanolico como agente vasodilatador y restaurador de la disfuncion endotelial.
WO2005054177A1 (fr) 2003-12-01 2005-06-16 Novartis Ag Amides de l'acide delta-amino-gamma-hydroxy-omega-aryl- alkanoique en tant qu'inhibiteurs de la renine
WO2005090285A1 (fr) * 2004-03-24 2005-09-29 Shionogi & Co., Ltd. Nouveau cristal de derive de triterpene
WO2006077801A1 (fr) * 2005-01-18 2006-07-27 Shionogi & Co., Ltd. Preparation d’un derive de myricerone
EP1915993A1 (fr) 2000-11-17 2008-04-30 Novartis AG Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP1977741A2 (fr) 2004-03-17 2008-10-08 Novartis AG Utilisation d'inhibiteurs de la rénine en thérapie
CN101016328B (zh) * 2007-02-09 2010-09-29 江苏久吾高科技股份有限公司 一种分离纯化熊果酸、齐墩果酸的方法
WO2011116115A1 (fr) 2010-03-16 2011-09-22 Novartis Ag Composition d'aliskiren comprenant un acide gras à chaîne moyenne et procédé de fabrication correspondant

Citations (2)

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Publication number Priority date Publication date Assignee Title
JPH01269500A (ja) * 1988-04-22 1989-10-26 Rikagaku Kenkyusho 植物培養細胞によるブラシノステロイドの製造方法
JPH0753484A (ja) * 1993-06-11 1995-02-28 Shionogi & Co Ltd トリテルペン誘導体およびそれを含有するエンドセリンレセプター拮抗剤

Patent Citations (2)

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JPH01269500A (ja) * 1988-04-22 1989-10-26 Rikagaku Kenkyusho 植物培養細胞によるブラシノステロイドの製造方法
JPH0753484A (ja) * 1993-06-11 1995-02-28 Shionogi & Co Ltd トリテルペン誘導体およびそれを含有するエンドセリンレセプター拮抗剤

Non-Patent Citations (1)

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Title
J. S. AFR. CHEM. INST., Vol. 27, No. 3, (1974), KOEKEMOER J. et al., "Chemistry of Milianthus Comosus. VI. Structure of a New Triterpenoid Acid from the Root Bark". *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1915993A1 (fr) 2000-11-17 2008-04-30 Novartis AG Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP1930000A1 (fr) 2000-11-17 2008-06-11 Novartis AG Combinaison de composés organiques
KR100900177B1 (ko) * 2002-03-22 2009-06-02 시오노기세이야쿠가부시키가이샤 트리테르펜 유도체의 제조 방법
WO2003080643A1 (fr) * 2002-03-22 2003-10-02 Shionogi & Co., Ltd. Procede de production de derives de triterpenes
US7223882B2 (en) 2002-03-22 2007-05-29 Shionogi & Co., Ltd. Process for producing triterpene derivative
CN1310940C (zh) * 2002-03-22 2007-04-18 盐野义制药株式会社 三萜衍生物的制备方法
WO2004096203A1 (fr) * 2003-04-30 2004-11-11 Consejo Superior De Investigaciones Cientificas Utilisation d'acide oleanolique en tant qu'agent de vasodilatation et de restauration du dysfonctionnement endothelial
ES2217978A1 (es) * 2003-04-30 2004-11-01 Consejo Sup. Investig. Cientificas Utilizacion del acido oleanolico como agente vasodilatador y restaurador de la disfuncion endotelial.
WO2005054177A1 (fr) 2003-12-01 2005-06-16 Novartis Ag Amides de l'acide delta-amino-gamma-hydroxy-omega-aryl- alkanoique en tant qu'inhibiteurs de la renine
EP1977741A2 (fr) 2004-03-17 2008-10-08 Novartis AG Utilisation d'inhibiteurs de la rénine en thérapie
WO2005090285A1 (fr) * 2004-03-24 2005-09-29 Shionogi & Co., Ltd. Nouveau cristal de derive de triterpene
US7612225B2 (en) 2004-03-24 2009-11-03 Shionogi & Co., Ltd. Crystal of triterpene derivative
JP4707115B2 (ja) * 2004-03-24 2011-06-22 塩野義製薬株式会社 トリテルペン誘導体の新規結晶
WO2006077801A1 (fr) * 2005-01-18 2006-07-27 Shionogi & Co., Ltd. Preparation d’un derive de myricerone
JPWO2006077801A1 (ja) * 2005-01-18 2008-06-19 塩野義製薬株式会社 ミリセロン誘導体の製造方法
CN101016328B (zh) * 2007-02-09 2010-09-29 江苏久吾高科技股份有限公司 一种分离纯化熊果酸、齐墩果酸的方法
WO2011116115A1 (fr) 2010-03-16 2011-09-22 Novartis Ag Composition d'aliskiren comprenant un acide gras à chaîne moyenne et procédé de fabrication correspondant

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