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WO2007007399A1 - Dérivé de thiazole - Google Patents

Dérivé de thiazole Download PDF

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Publication number
WO2007007399A1
WO2007007399A1 PCT/JP2005/012894 JP2005012894W WO2007007399A1 WO 2007007399 A1 WO2007007399 A1 WO 2007007399A1 JP 2005012894 W JP2005012894 W JP 2005012894W WO 2007007399 A1 WO2007007399 A1 WO 2007007399A1
Authority
WO
WIPO (PCT)
Prior art keywords
mrsa
formula
vre
wss2260
wss2258
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2005/012894
Other languages
English (en)
Japanese (ja)
Inventor
Yuriko Nozawa
Yi-Wen Chu
Jun-Ying Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Industrial Institute of Antibiotics
Taisho Pharmaceutical Co Ltd
Original Assignee
Sichuan Industrial Institute of Antibiotics
Taisho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Industrial Institute of Antibiotics, Taisho Pharmaceutical Co Ltd filed Critical Sichuan Industrial Institute of Antibiotics
Priority to PCT/JP2005/012894 priority Critical patent/WO2007007399A1/fr
Priority to CN2005800478205A priority patent/CN101400684B/zh
Publication of WO2007007399A1 publication Critical patent/WO2007007399A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/185—Heterocyclic compounds containing sulfur atoms as ring hetero atoms in the condensed system

Definitions

  • the present invention relates to a novel compound having anti-methicillin-resistant Staphylococcus aureus (hereinafter referred to as MRSA) activity and anti-vancomycin-resistant enterococci (VRE) activity.
  • MRSA anti-methicillin-resistant Staphylococcus aureus
  • VRE anti-vancomycin-resistant enterococci
  • MRSA has acquired resistance to ⁇ -ratata antibacterial agent, which is a treatment for Staphylococcus aureus, and was reported in the 1980s in Japan.
  • ⁇ -ratata antibacterial agent which is a treatment for Staphylococcus aureus
  • multi-drug resistant MRSA has become mainstream, and nosocomial infections have become a major problem in many hospitals.
  • a compound having anti-MRSA activity and having a skeleton or action mechanism different from that of existing drugs is useful as a new antibacterial drug.
  • VRE vancomycin-resistant enterococci
  • nosiheptide (Nosih tide) is known as a thiazole compound having an antibacterial action (Non-patent Document 1).
  • Non-Patent Document 1 K. Umemura et al. Bull. Chem. Soc. Jpn., 71, 1391-1396 (1998).
  • An object of the present invention is to provide a novel physiologically active substance having inhibitory activity against MRSA and VRE.
  • the present inventors isolated a large number of strains from soil and plants in order to achieve the above object, and as a result of various studies on the metabolites of the strains, As a result, the present invention was completed.
  • the present invention relates to a formula [0010] [Chemical 1]
  • R is a compound represented by the formula:
  • the compound of the group represented by is WSS2258, and the compound of R is an amino group is WSS2260.
  • the strains producing WSS2258 and WSS2260 were obtained by the present inventors from soil in Yunnan, China. It is an isolated actinomycete, and this strain was entrusted to the Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology on April 12, 2004, under the accession number FERM BP-10354.
  • the basic mycelium grows and branches well, but no fragmentation is seen. No aerial hyphae are formed, but shorter hyphae than the basic hyphae rise and form sporangia at the tip.
  • the sporangia are spherical and subspherical, the surface is wrinkled, and the size is about 4 10 x m. Also, the size of the spores released from the mature spore sac is about:! ⁇ 1.5 x m.
  • the following table 1 shows the results of macroscopic observation when cultured at 28 ° C for 3 weeks on various media.
  • the system color names from the Japanese Standards Association and JIS Color Name Book (1985) are used.
  • Table 2 shows the results of macroscopic observation when cultured at 30 ° C for 2 weeks on Prideham Gotleyve medium.
  • “+” indicates growth and “w” indicates weak growth.
  • Meso-diaminopimelic acid and glycine are detected from the cell wall of the bacterial cell component, and the cell wall type is type II. All microbial sugar components have arabinose detected and the sugar pattern is type D. It has MK9 (H) as the main menaquinone. The phospholipid pattern is saddle-shaped with only phosphatidylethanolamine (PE).
  • Production of WSS2258 and WSS2260 is generally carried out by culturing the TA0455 strain under aerobic conditions in a medium containing various nutrients, in the same manner as when producing general fermentation products.
  • a liquid medium is mainly used as a medium, which is composed of a carbon source, a nitrogen source, and an inorganic salt. Vitamins, precursors and antifoaming agents can be added as necessary, and the pH is adjusted to around 7.
  • a carbon source for example, glucose, sucrose, dextrin, glycerin, starch or the like is used alone or in combination.
  • nitrogen sources include meat extract, oatmeal, yeast Extract, soy flour, polypeptone, corn steep liquor, urea, ammonium salt, etc. are used alone or in combination.
  • the inorganic salt for example, monopotassium phosphate, magnesium sulfate, sodium chloride, calcium carbonate and the like are used alone or in combination.
  • Ade force knoll, silicon compound and the like can be used.
  • the culture method is suitable for aerobic culture such as shaking culture, aeration and agitation culture, pH 4-10, 25-35 ° C for 2-5 days, preferably PH 6-7, 25- Incubate at 28 ° C for 4 days.
  • the compound of the present invention can be obtained by purifying a fermentation product by a general method. That is, after culturing, a culture filtrate is obtained by centrifugation or filtration, adsorbed on a polystyrene resin such as Diamond HP-20 (trade name, manufactured by Mitsubishi Chemical Corporation), and then adsorbed with an organic solvent such as lower alcohol or acetone. Elute. The cells are extracted with an organic solvent such as lower alcohol or acetone. Next, the bacterial cell extract and the eluate from the adsorption resin were combined and concentrated under reduced pressure to remove the organic solvent, and then transferred to a water-insoluble organic solvent such as ethyl acetate, black mouth form, and n-butanol.
  • a culture filtrate is obtained by centrifugation or filtration, adsorbed on a polystyrene resin such as Diamond HP-20 (trade name, manufactured by Mitsubishi Chemical Corporation), and then adsorbed with an organic solvent such as lower alcohol or acetone. Elute.
  • the cells are extracted
  • This is concentrated to form a syrup.
  • This syrup is again dissolved in an organic solvent such as benzene, ethyl acetate, acetone, methanol, chloroform, etc., and silica gel column chromatography, gel filtration column chromatography, and column chromatography packed with ODS for reverse layer distribution.
  • an organic solvent such as benzene, ethyl acetate, acetone, methanol, chloroform, etc.
  • silica gel column chromatography, gel filtration column chromatography, and column chromatography packed with ODS for reverse layer distribution can be purified and isolated by being exposed to high performance liquid chromatography.
  • WSS2258 and WSS2260 obtained by the above method were determined by analysis of their molecular weight, ultraviolet absorption spectrum, ⁇ -NMR spectrum, 13 C_NMR spectrum, and the like.
  • Figure 2 shows the results measured at 125 MHz in deuterated dimethyl sulfoxide.
  • Figure 1 shows the results measured at 500 MHz in deuterated dimethyl sulfoxide.
  • Figure 2 shows the results measured at 125 MHz in deuterated dimethyl sulfoxide.
  • the compound of the present invention was found to have inhibitory activity against MRSA and VRE.
  • FIG. 1 shows a 1 H-NMR spectrum of WSS2258 measured at 500 MHz in deuterated dimethyl sulfoxide.
  • FIG. 2 shows the C-NMR spectrum of WSS2258 measured at 125 MHz in deuterated dimethyl sulfoxide.
  • FIG. 3 shows the 1 H-NMR spectrum of WSS2260 measured at 500 MHz in deuterated dimethyl sulfoxide.
  • FIG. 4 shows the 13 C-NMR spectrum of WSS2260 measured at 125 MHz in deuterated dimethyl sulfoxide.
  • n-butanol was added to 60 L of the obtained culture broth and stirred, and the cells were separated into cells and n-butanol extracted fractions by centrifugation. The n-butanol fraction was concentrated under reduced pressure to obtain 120.27 g of a brown oily substance.
  • Thin layer plate silica gel Merck F254 (manufactured by Merck)] was used for fractionation. The portions of Rf.0.62 to Rf.0.56 were scraped off, and the resulting silica gel was extracted with a mixed solvent of black mouth form monomethanol (1: 1) and concentrated to dryness under reduced pressure to obtain 69.3 mg of WSS2258. Similarly, remove the portion of Rf.0.06-0.37, extract the resulting silica gel with a mixed solvent of black mouth methanol (1: 1), concentrate under reduced pressure and dry to obtain 36.3 mg of WSS2260. It was.
  • vancomycin was dissolved in DMSO to a concentration of 10 mg / ml, and diluted with sterilized water to a target concentration.
  • the MIC measurement was performed by the following micro liquid dilution method.
  • linezolid was dissolved in DMSO to a concentration of 10 mg / m 1, and diluted with sterilized water to a target concentration was used. (Test species)
  • VRE owned by van (A), clinical isolate
  • the MIC measurement was performed by the following micro liquid dilution method.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Communicable Diseases (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés présentant une activité anti-MRSA et dont le squelette et le mécanisme d'action sont différents de ceux des médicaments existants, lesdits composés pouvant être employés en tant que nouveaux agents antimicrobiens. La vancomycine est couramment employée en tant que médicament contre les MRSA. Cependant, il existe depuis peu un besoin de trouver d'autres médicaments, dans la mesure où des entérocoques résistant à la vancomycine (VRE) et des souches bactériennes résistantes apparaissent. La présente invention décrit des dérivés de thiazole de formule : [dans la formule, R est le groupement de formule : ou un groupement amino] qui présentent une activité anti-MRSA et anti-VRE, et peuvent être employés en tant que médicaments.
PCT/JP2005/012894 2005-07-13 2005-07-13 Dérivé de thiazole Ceased WO2007007399A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP2005/012894 WO2007007399A1 (fr) 2005-07-13 2005-07-13 Dérivé de thiazole
CN2005800478205A CN101400684B (zh) 2005-07-13 2005-07-13 噻唑类化合物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2005/012894 WO2007007399A1 (fr) 2005-07-13 2005-07-13 Dérivé de thiazole

Publications (1)

Publication Number Publication Date
WO2007007399A1 true WO2007007399A1 (fr) 2007-01-18

Family

ID=37636807

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/012894 Ceased WO2007007399A1 (fr) 2005-07-13 2005-07-13 Dérivé de thiazole

Country Status (2)

Country Link
CN (1) CN101400684B (fr)
WO (1) WO2007007399A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074605A1 (fr) * 2007-12-12 2009-06-18 Novartis Ag Aminothiazoles et leurs utilisations
AU2012261611B2 (en) * 2007-12-12 2014-05-15 Novartis Ag Aminothiazoles and their uses

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101983964B (zh) * 2010-04-14 2013-08-14 中国医药集团总公司四川抗菌素工业研究所 一种具有抗菌和抗肿瘤活性的化合物、制备方法与用途
CN103304628B (zh) * 2013-06-06 2016-01-06 中国药科大学 诺西肽衍生物及其用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5439087A (en) * 1977-08-04 1979-03-24 Rhone Poulenc Ind Novel antibiotics and its preparation
JPS56127092A (en) * 1980-03-10 1981-10-05 Takeda Chem Ind Ltd Preparation of antibiotic substance

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5439087A (en) * 1977-08-04 1979-03-24 Rhone Poulenc Ind Novel antibiotics and its preparation
JPS56127092A (en) * 1980-03-10 1981-10-05 Takeda Chem Ind Ltd Preparation of antibiotic substance

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009074605A1 (fr) * 2007-12-12 2009-06-18 Novartis Ag Aminothiazoles et leurs utilisations
JP2011506394A (ja) * 2007-12-12 2011-03-03 ノバルティス アーゲー アミノチアゾール類およびその使用
US8426356B2 (en) 2007-12-12 2013-04-23 Novartis Ag Aminothiazoles and their uses
CN101945866B (zh) * 2007-12-12 2013-06-19 诺瓦提斯公司 氨基噻唑化合物及其用途
JP2013189468A (ja) * 2007-12-12 2013-09-26 Novartis Ag アミノチアゾール類およびその使用
AU2012261611B2 (en) * 2007-12-12 2014-05-15 Novartis Ag Aminothiazoles and their uses
EA020205B1 (ru) * 2007-12-12 2014-09-30 Новартис Аг Аминотиазолы, фармацевтические композиции на их основе и способы лечения бактериальной инфекции
US9492496B2 (en) 2007-12-12 2016-11-15 Novartis Ag Aminothiazoles and their uses

Also Published As

Publication number Publication date
CN101400684B (zh) 2011-06-15
CN101400684A (zh) 2009-04-01

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