• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1458340 Antibiotic compositions UPJOHN CO 24 March 1975 [17 April 1974] 12105/75 Heading A5B [Also in Division C2] Antibiotic compositions comprise a compound U43795 of formula I a salt, hydrate, zwitterion or acyl derivative thereof and a carrier therefor optionally with a further antimicrobial compound which if acid or base may form a salt with U43795.
    公开号:SU736875A3
    申请号:SU752124245
    申请日:1975-04-16
    公开日:1980-05-25
    发明作者:Гленн Мартин Давид；Джеймз Ханка Ладислав
    申请人:Тэ Апджон Компани (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to the field of medicine, in particular to the production of antibiotics. The method of obtaining antibiotics and-43,795, is not described in the patent and special literature. A method is proposed for obtaining a new antibiotic U-43,795, of the general formula m H CH-CH-CD cNH} that a culture of Streptomyces svlceus NRRZ5439 grows vgtsot in an iodine nutrient medium containing sources of carbon, nitrogen or protein material, followed by isolation of the target product is known by tricks. Carbon sources include glucose, brown sugar, sucrose, glycerin, starch, corn starch, lactose, dextrin, molasses, and nitrogen sources - liquid nocjje corn sticks, yeasts, autolyzed brewer's yeast, milk, soybean, cotton solids And corn flour, milk solids, kasei digestion on the pancreas, bard. animal peptone fluids meat and bone waste. The combination of these carbon and nitrogen sources is mainly used. The vegetative form of the microorganism is used for inoculation, not its spores. Vegetative graft material is obtained by inoculation of the soil. culture. o ivaceus NRRZ5439 in nutrient broth and transfer to the cut medium. The young inoculum vegetative material is transferred to a fermenter under aseptic conditions. The fermentation process is carried out at 20-32 ° C, the pH of the medium is 5.5-7.0, the optimum formation of the antibiotic is observed within .2-10 days. For the isolation and purification of O-43,795, a number of different methods can be applied, e.g. absorption, followed by elution with a solvent, column chromatography, partial chromatography, crystallization with separation, from the solvent. The antibiotic I-43,795 is isolated from the culture medium by filtration through diatomite (fW40). Transparent nutrient medium is filtered through chromatographic
    a column filled with styrene-type sulfonic acid resin. Column. washed, antibiotic eluted with base. The eluates of antibiotic action are mixed and concentrated.
    The resulting aqueous concentrate is filtered at a neutral pH through a column containing a weakly basic Popia | “new styrene type resin. A washing column from deionized water, 50% aqueous methanol, then eluted with acetic acid in 9% methanol. Active eluate fractions are mixed, then evaporated to dryness under reduced pressure.
    . The residue obtained is chromatographed on silk 1 gel 60 in the system methyl ethyl ketbn-acetone-water (65:20:15).
     Semi-Shshbt is a relatively pure antibiotic drug, 795.
    In the process of isolating the antibiotic, bioassays were performed using 6acWus subtJttS lU.
    PRI me R. Fermentation
    Soil strain of bacteria Slreptomyce
    sviceu WMRRZ5439 is inoculated into
    Erlenmeyer flasks {with a capacity of 500 mp with 100 ml of sterile medium containing: 25 g / l dextrose, 25 g / l Pharmamedic and up to 1 l of tap water; pH before sterilization of 7.2. The vaccine material is grown for 2 days at 28 ° C on a rotating vibration installation at 250 revolutions / m. The obtained graft material is inoculated in 500 ml Erlenmeyer flasks with a capacity of 500 ml of 100 ml of sterile fermentation medium of the following composition, g / l:
    Carbon2
    Corn starch
    : Soaked yeast 2.5 Kau S ou. 20 The fermentation medium also contains 1 ml of margarine from lard and up to 1 l of tap water, pH average. prior to sterilization, adjusted to 7.2 with 4N sodium hydroxide.
    Fermentation flasks are inoculated in a ratio of 5 ml of inoculum per 100 ml of enzyme.
    736875
    environment. It is then grown for 2-3 days with a rotating vibro. installation at 250 rpm
    Highlight. 250 l of fermentation medium is filtered through medium porosity diatomite. The obtained transparent nutrient medium is passed through a chromatographic column containing 25 liters of freshly regenerated Dowex50 X 16 (H) V at pH 7-8. The column is washed with 50 l of deionized water, 120 l of 1N are seduced, and 6 l of fractional material is collected. The active fractions are mixed and concentrated under reduced pressure to remove excess 5.
    Cleaning, Column with a weakly basic floor with a new styrene type resin,
    0Active aqueous concentrated eluate, Doitiex 50, obtained by the described method, pH 7-7.5 is passed through a column containing 4 liters of Amber ilc JR. 45 (OH). The column is then washed with 8 l of deionized water, 4 l of 50% aqueous methanol and 8 l of 90% aqueous methanol. Collect 2 L fractional product. The most active fractions determined by the subtitis test are mixed and evaporated to dryness under reduced pressure.
    Chromatography Silica gel is used in this process15 | 60, The reaction is carried out on residues 3R54 (OH) obtained by the method described. The active fractions obtained from column 3R 45 are evaporated to dryness; acetic acid washed with water. The residue obtained is suspended in 328 ml of water and evaporated up to 33 g of silica gel. The flask is then washed with 5 g of fresh silica gel. The homogeneous powder is chromatographed on a column of silica gel obtained by suspending 600 g. The silica gel in the system methyl ethyl ketone-acetone and water (65:20:15) is eluted with the first mixture (7200 ml) and 1200 ml are first collected. and then fractions 1-12 with 500 ml.
    The results are shown in the table.
    Taye continued (faces
    30 57 70 70 60 55 47 32 О Apply in the form of droplets, split as drops on a plate with jljtl- In the system methyl ethyl ketone-ac plate; Detection ningya fractions 3 and 4 are mixed and ynajpHvayut. under reduced pressure at 40c, the residue is triturated with methanol. Get 1, .37. G of pure U-43,795. Recrystallization from aqueous methanol is obtained analytically pure I-43,795 in the form of its crystalline hydrate. Water can be removed by drying. The obtained antibiotic U -43.795 is characterized by the following properties: NMR spectrum of a saturated solution of U-43.795 c) g O is determined by a VariatiX Z 100-15 spectrometer. The spectrum of 100 MHz clearly shows the presence of three non-replaceable protons. The methine proton at C-4 is visible at. as an apparent doublet at 5.34 with a linear separation of 8.2 Hz. The adjacent proton at C-5 is visible as an apparent doublet of doublets centered on nfjH 5.19 with a linear separation of 3.4 Hz and 8.2 Hz. The methin amino acid signal is an apparent doublet at 4.43 with a linear separation of 3.4 Hz, the IR spectrum of the newely rubbing of the U-43.795 partial hydrate was determined with a PerKin Efmer 421 spectrophotometer, the peaks were found at 3620, 3140, 2620 ,. 1660, 1640, - 1610 ,. 1585 1525; 1385, 1325, 1310, 1270, 1255 1180, 1135, 1110, 1075, 580, 9i5 800, 865, 805 and 705 cm, (5h. -Shoulder Ring dichroism - O shows water. / Q / l + 60,000 and / p / MOKSL-1 ppp / w / 2Q2 - 47,000,
    U -43,795 and -43,795 + AT - 125 aT-125
    权利要求:
    Claims (1)
    [1]
    ABA AT-125 e fraction 1-10 agel, yes (65:20:15) on silica gel. With those and -43.795, one zone is obtained after spraying the plate with ninhydrin solution. The plates show, in tetrahydrofuran-acetone-water (50:30:20),. The chemical structure of U -43,795 in crystalline form is established by diffraction {by X-rays: ptS, 45, 5R - (.-Amino-3-chloro-4-hydroxy-2-yzoxazolin-5-acetic acid. Mol, B, 212.59, Dissolved in water and slightly in methanol, QTHOCH, insoluble in ethyl acetate, ether, benzene and chloroform. Antibiotics -43,795, being an amphoteric compound, forms salts with acids, alkali metals (including ammonia), alkaline earth metals (including magnesium N aluminum ) and amines, and -43,795 is acylated with an appropriate galogen acid hydride or acid anhydride or a sulfenyl halide to form the corresponding bis-acyl derivative, where the 4-hydroxy acid and A-amino hydrogen are acylated, Antibiotic, and -43,795 active, against you, Pis and Sarcmo fuiea, mouse type 1210 leukemia, claims Preparation of an antibiotic of the general formula n "SI-CH-COg, characterized in that the culture of Strepfomyces swiceus NRRZ. 5439 is grown on medium containing:.-.---. ...,. - Sly sources raliye sopi, ui target methods. 73b875 ...... .., .-. ; .-. , carbon, nitrogen, mine-Sources of information, followed by highlighted in the examination of the product known iHutiHi-crobiq A e 9an "chemt) tberat) 4. 03. 1973, vot 3, pT 425-431.
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    同族专利:
    公开号 | 公开日
    AU7953875A|1976-09-30|
    US3944562A|1976-03-16|
    BE828040A|1975-10-17|
    FR2267779B1|1978-10-06|
    NL7504508A|1975-10-21|
    FR2267779A1|1975-11-14|
    ZA751855B|1976-02-25|
    CA1034524A|1978-07-11|
    DE2514984A1|1975-10-30|
    CH620243A5|1980-11-14|
    JPS50145589A|1975-11-21|
    GB1458340A|1976-12-15|
    SE7504413L|1975-10-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3856807A|1972-03-13|1974-12-24|Upjohn Co|L--{60 -amino-3-chloro-2-isoxazoline-5-acetic acid|ZA731225B|1972-03-13|1973-11-28|Upjohn Co|Composition of matter and process|
    US4275214A|1978-05-15|1981-06-23|The Upjohn Company|Substituted alkoxy carbonyl-3-oxo-α-phthalimido-5-isoxozolidineacetic acids|
    US4232164A|1978-05-15|1980-11-04|The Upjohn Company|Purification of AT-125|
    US4225720A|1978-05-15|1980-09-30|The Upjohn Company|Purification of AT-125|
    AU526380B2|1978-05-15|1983-01-06|Upjohn Company, The|2-isoxazoline-5-acetic acid derivatives|
    USRE31578E|1978-05-15|1984-05-01|The Upjohn Company|α amino-3-substituted-2-isoxazoline-5-acetic acids |
    DE3643012A1|1986-12-17|1988-06-30|Hoechst Ag|2,3-DISUBSTITUTED ISOXAZOLIDINE, METHOD FOR THE PRODUCTION THEREOF, THE CONTAINERS THEREOF AND THEIR USE|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/461,635|US3944562A|1974-04-17|1974-04-17|αS, 4S, 5R α-Amino-3-chloro-4-hydroxy-2-isoxazoline-5-acetic acid|
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