WO1997043434A1 - Nouvelle substance active sur le plan physiologique et son procede de preparation - Google Patents

Nouvelle substance active sur le plan physiologique et son procede de preparation Download PDF

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Publication number
WO1997043434A1
WO1997043434A1 PCT/JP1997/001612 JP9701612W WO9743434A1 WO 1997043434 A1 WO1997043434 A1 WO 1997043434A1 JP 9701612 W JP9701612 W JP 9701612W WO 9743434 A1 WO9743434 A1 WO 9743434A1
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Prior art keywords
active substance
physiologically active
producing
novel physiologically
culture
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PCT/JP1997/001612
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English (en)
Japanese (ja)
Inventor
Kazuhiko Kurosawa
Kousaku Takahashi
Kyouko Matsubara
Masayuki Okue
Naohiro Washida
Kanji Higashio
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Snow Brand Milk Products Co., Ltd.
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Priority to JP54073497A priority Critical patent/JP3851661B2/ja
Publication of WO1997043434A1 publication Critical patent/WO1997043434A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid

Definitions

  • the present invention relates to novel nitrophenyl pyrone system of the physiologically active substance, c further relates to a method for producing a microorganism and novel physiologically active substance that is used to produce and manufacture the same, the present invention provides such novel physiologically Pharmaceuticals containing an active substance as an active ingredient, in particular, inhibitors of immune rejection due to organ transplantation, etc., therapeutic agents for autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, uveitis, allergies such as atopic dermatitis —Regarding therapeutic agents for diseases, antibacterial agents for infections caused by various microorganisms, or agents for overcoming anticancer drug resistance.
  • an active substance as an active ingredient
  • therapeutic agents for autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, uveitis
  • allergies such as atopic dermatitis —Regarding therapeutic agents for diseases, antibacterial agents for infections caused by various
  • Immunosuppressants are effective in the prevention and treatment of diseases and conditions that require a reduced immune response. Prevent transplant rejection, for example, kidney, liver, bone marrow, heart and corneal transplantation, or treat autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, uveitis, or allergic diseases such as atopic dermatitis It is indicated as a therapeutic agent for many immune diseases. Since the US Food and Drug Administration (USFDA) approved cyclosporine in 1983, immunosuppressants have been actively developed, and drugs such as Prograf and Spanidine have been put into practical use. It has a high reputation in the field.
  • USFDA US Food and Drug Administration
  • an object of the present invention is to provide a novel nitrophenylpyrone-based physiologically active substance, a microorganism used for producing and producing the novel physiologically active substance, and a method for producing the novel physiologically active substance.
  • a novel bioactive substance having an immunosuppressive activity, an antiallergic activity, an antibacterial activity and an effect of overcoming anticancer drug resistance and having few side effects, a microorganism used for producing and producing the bioactive substance, and a culture of the microorganism It is another object of the present invention to provide a method for producing the physiologically active substance by obtaining the physiologically active substance.
  • an object of the present invention is to provide a medicament for preventing or treating various diseases by utilizing the above-mentioned physiological activities.
  • the present invention relates to a novel physiologically active substance represented by the following formula (1) and a pharmacologically acceptable salt thereof.
  • the present invention also relates to a microorganism belonging to Streptomyces, which can be used for producing and producing a novel physiologically active substance represented by the formula (I).
  • microorganisms include, specifically, the soil of Okinawa Island by the present inventors. And S. streptomyces spectabil (s) SN F4435 strain (FERM BP-5915).
  • the present invention relates to a method for producing a novel bioactive substance, comprising culturing the microorganism, producing the novel bioactive substance in a culture, and collecting this.
  • the present invention relates to a method for producing a novel bioactive substance by synthetic chemistry by culturing the microorganism, producing an analog Spectinabin in the culture, and closing the tetraene moiety.
  • the present invention relates to a medicament comprising a novel physiologically active substance represented by the above formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the medicament of the present invention is used as a therapeutic agent for immune rejection or autoimmune disease due to organ transplantation, a therapeutic agent for allergic disease, an antibacterial agent for infectious disease, or an agent for overcoming anticancer drug resistance.
  • the physiologically active substance of the present invention is a novel nitrophenylpyrone-based compound, and in view of its activity, an inhibitor of immune rejection by organ transplantation or the like, systemic erythematosus, rheumatoid arthritis, uveitis, etc. It is useful as a therapeutic agent for autoimmune diseases, a therapeutic agent for allergic diseases such as atopic dermatitis, an antibacterial agent for infectious diseases caused by various microorganisms, or a drug for overcoming anticancer drug resistance.
  • FIG. 1 shows an ultraviolet absorption spectrum of compound SNF4435C of the present invention in methanol (1S gZml).
  • FIG. 2 shows an infrared absorption spectrum of the compound of the present invention SNF4435C with a potassium bromide tablet.
  • FIG. 3 shows a 500 MHz NMR spectrum (TMS standard) of a compound of the present invention SNF4435C in a double-mouthed form solution.
  • FIG. 4 shows a 125 MHz 13 C NMR spectrum of the compound of the present invention SNF 4435C in a heavy-mouthed form solution (based on heavy-mouthed form).
  • FIG. 5 shows an ultraviolet absorption spectrum of compound SNF4435D of the present invention in methanol (18.0 g Zml).
  • FIG. 6 shows an infrared absorption spectrum of a compound of the present invention SNF4435D with a lithium bromide tablet.
  • FIG. 7 shows a 500 MHz NMR spectrum (based on TMS) of the compound of the present invention SNF4435D in a double-mouthed form solution.
  • FIG. 8 shows a 125 MHz 13 C NMR spectrum (based on double-mouthed form) of a compound of the present invention S NF4435D in a heavy chloroform solution.
  • the novel physiologically active substance of the present invention (hereinafter, referred to as the compound of the present invention) can be obtained by culturing a microorganism.
  • the microorganism to be used is not particularly limited as long as it is a bacterium that produces the compound of the present invention, but is preferably a bacterium belonging to the genus Streptomyces (Streptomyces sp.), Particularly preferably Streptomyces ′ (Strep tomyces_spectabi 1 is) Strain SN F4435 can be mentioned.
  • This Streptomyces scutabilis SNF4435 strain is a strain isolated from soil collected from Oki Jiphonjima Island by the present inventors, and has a deposit number of FERM P.R. -Deposited on February 27, 1996 as 15476, then transferred from this original deposit to a deposit under the Budapest Treaty, and given the accession number FERM BP-5915.
  • Isolation of Streptomyces spectabili ⁇ SNF 4435 strain is carried out by the method usually used for the isolation of actinomycetes from the soil of Okijima Island, for example, Goodfellow, M .; Actinomycetologica Vol. 2, No. .1 13-29 (1988) It can be easily implemented by the method.
  • Aerial hyphae settle down in the stomach, and pseudo-ringy branching is slightly observed, but no division of the hyphae is observed.
  • Aerial hyphae have a reddish or rarely white hue, and a chain of more than 10 spores is formed, forming a flexible linear shape.
  • the surface of the spores is almost smooth and cylindrical with a size of about 0.4X0.8 mm. No special organs such as sclerotia, spores, zoospores, etc. are found.
  • Table 1 shows the results of culturing at 27 ° C for 14 days on various agar plate media.
  • the description of the colors was based on the JIS Color Name Book (JIS Z 8102 compliant, Japan Standards Association, April 15, 1993, 1st edition, 3rd printing).
  • peptone yeast' iron agar medium In a 27 ° C culture using tryptone 'yeast' broth medium, peptone yeast 'iron agar medium or tyrosine agar medium, only peptone yeast' iron agar medium 'was cultured. Was.
  • the mycological properties of SNF 4435 strain are that the aerial hyphae are linear and do not form spores, but there are slight pseudoringy branches. At the tip of the aerial mycelium It links about 10 spores and its surface is smooth. In various media, the color of the aerial mycelium changes from pink to red.
  • melanin-like pigment is produced on peptone, yeast, and iron agar medium, and starch has a moderate hydrolytic property and moderate protein degradation ability o
  • the 2,6-diaminopimelic acid contained in the cell wall was of the LL-type. Based on these properties, the SNF4435 strain is considered to belong to the genus Streptomyces, and is described in "Bergey's Manual of Determinative Bacteriology", 8th ed., And ISP Report "International Journal of Systematic Bacteriology", Volume 18, 69, 279 (1968), 19, 391 (1969) 22 and 265 (1972), Streptomyces and Streptomyces spectabilis are closely related.Therefore, the SNF4435 strain and Streptomyces sp. (Streptomyces spectabilis IFO 13424) The results are shown in Table 2.
  • the microorganism used in the present invention may be irradiated with X-rays, ultraviolet rays, or the like, or treated with a mutagenic agent such as nitrite, N-methyl-N, -nitro-N-nitrosoguanine (NTG), transformation, transduction, or the like. It may be a microorganism mutated by a commonly used bacterial species conversion treatment method such as fusion.
  • the compound of the present invention is produced in a culture obtained by inoculating a nutrient source-containing medium that can be used by ordinary microorganisms with a bacterium producing the compound of the present invention and growing it, or producing the compound.
  • the target compound of the present invention can be produced by organic synthesis using a culture obtained by inoculating and growing the microorganisms used in the culture of the present invention. Any medium such as a synthetic medium, a semi-synthetic medium, and a natural medium can be used.
  • a carbon source glucose, glycerol, maltose, starch, sucrose, molasses, starch syrup or dextrin are used alone or as a mixture.
  • Nitrogen sources include soy flour, corn gluten meal, corn steep liquor, meat extract, yeast extract, cottonseed kashiwa, peptone, wheat germ, fish meal, urea and other organic nitrogen sources, ammonium sulfate, sodium nitrate, etc.
  • the inorganic nitrogen sources are used alone or as a mixture.
  • As the inorganic salt calcium carbonate, sodium chloride, potassium chloride, magnesium sulfate or various phosphates can be used.If necessary, heavy metals such as iron, copper, cobalt, molybdenum, manganese or zinc can be used. A trace amount of salt can also be added. When foaming during culture is remarkable, various antifoaming agents known as antifoaming agents may be appropriately added to the medium.
  • organic and inorganic substances useful for the production of the compound of the present invention, which are utilized by the producing bacteria, can be appropriately used.
  • the method for culturing the strain may be the same as the method for producing general microbial metabolites, and may be either solid culture or liquid culture.
  • any of stationary culture, stirring culture, shaking culture, and aeration culture may be performed.
  • Shaking culture or deep aeration stirring culture Nutrition is preferred.
  • the pH of the culture medium is preferably in the range of 4 to 8
  • the culture temperature is 22 to 37 ° C, preferably 25 to 30 ° C.
  • the culturing time is 48 to 168 hours, preferably 96 to 144 hours.
  • a separation means usually used for isolating a metabolite produced by a microorganism may be appropriately used. If necessary, synthetic chemistry means may be used as appropriate.
  • the compound of the present invention produced by culturing is usually accumulated both inside and outside the cells in the culture, it is often separated into cultured liquid and cells by means such as centrifugation and filtration.
  • Conventional separation methods from culture filtrates and cells such as dialysis, solvent extraction, methods utilizing the difference in solubility with impurities, ion-exchange resin or adsorption or partition chromatography, and gel filtration. Separation and purification can be performed alone or in an appropriate combination, and in some cases, repeated use.
  • the compound of the present invention which is collected using synthetic chemistry means, uses the above-described separation means for analogs (nitrophenylpyrone-based) of the compound of the present invention produced in a culture solution by culturing a microorganism.
  • the compound can be separated and purified, and can be produced by synthetic chemistry means, for example, a ring closure reaction using a catalyst.
  • synthetic chemistry means for example, a ring closure reaction using a catalyst.
  • the organic solvent used in the reaction include methanol, ethanol, tertiary butyl alcohol, tetrahydrofuran, dimethyl ether, ethylene glycol, dimethyl ether, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, dioxane, and the like.
  • Examples include methylene chloride, chloroform, dichloroethane, and acetonitrile.
  • the reaction temperature for the ring-closure reaction is usually from 20 to 400 ° C, and a higher or lower temperature can be selected as necessary.
  • the pressure during the ring closure reaction is usually 1 to 10 atm, and a higher or lower pressure can be selected as necessary.
  • Catalyst used for ring closure reaction examples thereof include aluminum chloride, tin chloride, boron fluoride, copper fluoborate and iodine.
  • the reaction time of the ring closure reaction is usually in the range of 30 minutes to 2 days, but a longer or shorter time can be selected as necessary.
  • Fig. 2 shows a reaction formula for closing the tetraene moiety of spectinapyrine in the present invention.
  • SNF4435C and SNF4435D are separated and purified by a method known in the field of synthetic organic chemistry, for example, a method using solvent extraction, recrystallization, chromatography, ion exchange resin, HP LC, etc. be able to.
  • SNF4435 has the same planar structure (see formula (I)) but has optical isomers, each of which is designated as SNF4435C or D. These optical isomers can be separated into their respective optical isomers by a conventional separation means such as liquid chromatography. When used as a medicament, the optical isomer may be used alone or in a racemic form.
  • Re KBr cm— 1 : 2950, 2850, 1670, 1600, 1520, 1350, 1255, 1165,
  • HP LC retention time 14.6 minutes
  • the novel physiologically active substance of the present invention when used as a medicine, it may be a pharmacologically acceptable salt.
  • Pharmaceutically acceptable salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, aluminum and other metal salts, and organic amines such as alkylamine salts and pyridine salts. Salt.
  • This compound or a pharmacologically acceptable salt thereof is safely orally and parenterally administered to humans and animals as a medicament.
  • Parenteral administration includes, for example, intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, transdermal administration, pulmonary administration, transmucosal administration, enteral administration, buccal administration, transmucosal administration, etc. These formulations are administered.
  • oral preparations include tablets (including sugar-coated tablets, coated tablets, and buccal tablets), powders, capsules (including soft capsules), granules (coated products, pills, troches, and liquids). , Or a pharmaceutically acceptable sustained release preparation thereof).
  • Liquid preparations for oral administration include suspensions, emulsions, syrups (including dry syrups), elixirs and the like.
  • compositions can be pharmacologically acceptable as preparations according to known pharmaceutical manufacturing methods.
  • Carriers, excipients, disintegrants, lubricants, coloring agents, and the like which are administered as pharmaceutical compositions.
  • the carriers used in these preparations include lactose, glucose, sucrose, mannitol, potato starch. , Maize starch, calcium carbonate, calcium phosphate, calcium sulfate, calcium cellulose, crystalline cellulose, canzo powder, gentian powder, etc.
  • binders include starch, tragacanth gum, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxypro.
  • Disintegrators such as pill cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like include, for example, starch, agar, gelatin powder, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium Lubricants such as crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, etc .; lubricating agents such as magnesium stearate, talc, hydrogenated vegetable oils, McGall, etc .; Can be used, respectively.
  • the novel physiologically active substance of the present invention when administered to a patient, it depends on conditions such as the degree of symptoms, age, health and weight of the patient, and is not particularly limited. Alternatively, it may be administered parenterally once or more times a day. Acute toxicity was hardly observed as shown in Example 6.
  • the dried soil lg obtained by heat-treating the soil collected at Okijima Island (60 ° C, 10 minutes) was suspended in 10 ml of sterilized water.
  • the suspension was diluted 10- to 3- fold and agar plates (ammonium sulfate 0.05%, monopotassium phosphate 0.05%, calcium chloride 0.01%, magnesium sulfate 0.01%, urea 0.01%, glucose 0.05%, soluble starch) 0.1%, chloramphenicol 0.008%, sulfuric acid first failure 0.0005%, manganese sulfate 0.000 16%, zinc sulfate heptahydrate 0.00014%, cobalt (II) chloride 0.0002%, agar 1.8%, PH6.0) (27, 10 days).
  • Example 2 120 L of the culture obtained in Example 1 (2) was centrifuged by continuous centrifugation (17,000 rpm, 20 L / h), and the obtained cells were extracted with 36 L of acetone. The acetone extract was concentrated under reduced pressure to remove acetone, and then extracted twice with an equal volume of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 70 g of a crude extract. This was dissolved in a small amount of hexane monoethyl acetate (7: 3) solvent, and applied to a 2 L silica gel column equilibrated with the same solvent.
  • the column was eluted with 6 L of hexane monoacetate (7: 3), then the compound of the present invention was eluted with hexane monoacetate (1: 1), and concentrated under reduced pressure to obtain 2.2 g of a yellow powder.
  • this powder was dissolved in a small amount of methanol and passed through an HPLC column (capsule pack C18—SG120, ⁇ 20 X 250 mm. Shiseido) equilibrated with 80% methanol aqueous solution at a flow rate of lOml / min. Eluted with the same solvent. Absorption at 220 nm was detected, and a detection peak of the compound SNF4435 of the present invention was collected.
  • SNF4435C The fraction with the largest absorption (retention time about 27 minutes) was designated SNF4435C, and the fraction with the largest absorption (retention time about 29 minutes) was designated SNF4435D.
  • SNF4435D The fraction with the largest absorption (retention time about 29 minutes) was designated SNF4435D.
  • Example 2 4 L of the culture obtained in Example 1 (2) was centrifuged (5000 rpm). Extracted with 2 L of acetone. The acetone extract was concentrated under reduced pressure to remove acetone, extracted twice with an equal amount of ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.5 g of a crude extract.
  • this powder was dissolved in a small amount of methanol and passed through an HP LC column (Power Cell Pack C18—S G120, ⁇ 20 X 250 mm, Shiseido) equilibrated with 80% methanol aqueous solution at a flow rate of 10 ml / min. Elution was performed, and the absorption at 220 nm was detected.
  • the peak of the compound of the present invention, SNF4435 was collected.
  • the fraction with the largest absorption (retention time about 27 minutes) was designated SNF4435C
  • the fraction with the next largest absorption was designated SNF4435D.
  • the spleen cells of male BALB / c mice were suspended in RPMI 1640 medium containing 10% fetal calf serum, and the compounds of the present invention, SNF 4435 C and SNF 4435D, were added at various concentrations, and mitogen (concanapalin A or (LPS) with or without 37 ° C, 5% 48 hours incubation under the conditions of 1 theta carbon dioxide concentration was determined intracellular up Write-rate of cell proliferation 3 .eta. thymidine as a reference. The results are shown in Table 3 (SNF4435C) and Table 4 (SNF4435D). In Tables 3 and 4, TZC represents the cell growth rate ((Mean soil SD) / Control).
  • the antimicrobial activity of the compounds of the present invention SNF 4435 C and SNF 4435 D against various microorganisms was observed by the size (diameter) of an inhibition circle by a paper disk method (diameter 8 mm).
  • the bioactive substances S NF4435C and S NF4435D were each measured by dissolving 100 g of methanol dissolved in methanol into a paper disk. Table 5 shows the results.
  • Baci Uus subti 1 is H17 Rec + 0 10
  • Bacillus subti 1 is M45 Rec ⁇ 0 10
  • the present invention provides a novel physiologically active substance, a microorganism used for producing and producing the physiologically active substance, and a method for producing the same. More specifically, a novel bioactive substance having an immunosuppressive activity, an antibacterial activity, and an effect of overcoming anticancer drug resistance, a microorganism used for producing the bioactive substance, and a bioactive substance obtained by using the microorganism to collect the bioactive substance A method for producing an active substance is provided.
  • the novel physiologically active substance according to the present invention is an inhibitor of immune rejection due to organ transplantation, etc.
  • a therapeutic agent for autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, uveitis
  • a therapeutic agent for allergic diseases such as atopic dermatitis I *
  • an antibacterial agent for infections caused by various microorganisms or a drug for overcoming anticancer drug resistance It is.

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Abstract

Nouvelle substance active sur le plan physiologique; micro-organisme à utiliser afin de préparer ladite substance; médicaments contenant ladite substance en tant qu'ingrédient actif. Nouvelle substance active SNF4435 sur le plan physiologique représentée par la formule suivante (I); souche de Streptomyces spectabilis SNF4435 isolée du sol dans l'île principale d'Okinawa; procédé consistant à mettre en culture ce micro-organisme dans un milieu de culture et à séparer ladite substance de la culture; procédé de préparation de ladite substance par synthèse chimique à partir de son analogue produit dans le milieu de culture. On peut utiliser ladite substance en tant que médicament immunodépresseur, par exemple, en tant qu'agent antibactérien contre des maladies auto-immunes, des maladies allergiques et des maladies infectieuses, ainsi qu'en tant qu'antagoniste contre la tolérance à des médicaments anti-cancer.
PCT/JP1997/001612 1996-05-14 1997-05-14 Nouvelle substance active sur le plan physiologique et son procede de preparation WO1997043434A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100358891C (zh) * 2002-02-25 2008-01-02 库多斯药物有限公司 可用作atm抑制剂的吡喃酮
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112126596B (zh) * 2020-08-20 2022-06-24 云南大学 一株具有抗病促生长作用的壮观链霉菌及其分离方法及应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012656A1 (fr) * 1991-12-23 1993-07-08 Michigan State University Procede de lutte contre les insectes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012656A1 (fr) * 1991-12-23 1993-07-08 Michigan State University Procede de lutte contre les insectes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON LETTERS, (1992), Vol. 33, No. 4, YASUHARU ISHIBASHI et al., "Total Synthesis of (+)-Isoaureothin: Determination of the Absolute Configurations of Aureothin, Isoaureothin and Spectinabilin", pages 512-524. *
TETRAHEDRON, (1976), Vol. 32, No. 2, K. KAKINUMA et al., "Spectinabilin, a New Nitrocontaining Metabolite Isolated from Streptomyces Spectabilis", pages 217-222. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100358891C (zh) * 2002-02-25 2008-01-02 库多斯药物有限公司 可用作atm抑制剂的吡喃酮
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

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