• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    The present invention provides antibiotic neplanocins of the general formula:- <IMAGE> wherein X is an NH2, -OH, -SH or -SCH3 group or a chlorine atom, R is a hydrogen atom or a protective group for the -OH group, and Z is a <IMAGE> group, in which Y is -O- or a valency bond and R is a hydrogen atom or a protective group for the -OH group, or Z is a group in which Y is -O- or a valency bond, and the physiologically- acceptable salts thereof. The present invention also provides processes for the production of these antibiotics and pharmaceutical compositions containing them.
    公开号:SU906388A3
    申请号:SU792763801
    申请日:1979-05-17
    公开日:1982-02-15
    发明作者:Отани Масару；Ягинума Сатоси；Цудзино Масатоси；Муто Наоки；Саито Тецу；Фудзии Тадасиро
    申请人:Тойо Дзозо Кабусики Кайся (Инофирма)；
    IPC主号:
    专利说明:

    3 A 11079 and is stored in a permanent collection at the Institute of Microbiological Industry and Technology in Japan, under the number FERM-P No. 4494.  Morphological signs.  On the medium, inorganic salt with krasmmal agar zri forms a curved and branched substrate mycelium with a diameter of 0.5–0.8 µm and not quite mature aerial mycelium.  The form of sporangium is cylindrical or bootshaped, the size is 5-15 liters and 25 microns.  Sporangiospores are in parallel chains with sporangia.  Sporangiospores have polar flagella and are in the form of sticks 0.5-1.0 1.0-2.0 µm in size.  Cultural features.  Wednesday Boxman number 1.  Growth is weak, the sporangium does not form, the substrate mycelium is colorless or bamboo, there is no soluble pigment.  .  Nutrient agar.  Growth is weak, there is no sporangium, substrate mycelium from light amber to light brown, soluble pigment golden brown.  Agars Emerson.  The growth is good, there is no potential, the substrate mycelium is light brown-camel, soluble pigment is pale golden brown.  Agar Bennett.  The growth is good, there is no dispute, the substrate mycelium is amber, the soluble pigment is pale golden brown.  Czapek's yeast agar.  The growth is good, the sporangium is small, there is no amber, rubellae, a soluble pigment is absent. Casein agar.  The growth is good, the sporangium is absent, the substrate mycelium from camel to light-conical color, soluble pigment clove-brown.  Saccharose nitrate agar.  Growth is weak, sporangium. a small, substrate mycelium of pearl is morning-pink, light yellow, there is no soluble pigment.  Glucose-aspartic agar.  Average height, small sporangia.  Substrate mycelium is bamboo, pearl-pink, there is no soluble pigment.  8 Glycerin-aspartic agar.  Growth is weak, there is no sporangium, the substrate mycelium is bamboo, pearl-roseau, there is no soluble pigment.  Tyrosine agar.  Growth is weak, there is no sporangium, substrate mycelium is light amber, there is no soluble pigment.  Agar with oat flour.  Growth is good, the sporangium is medium, substrate mycelium is amber, bright maize, there is no soluble pigment.  Yeast-Malt Agar.  Growth is good, sporangia is bad, substrate mycelium is topaz in color, soluble pigment is pale, Glucose-yeast agar.  Growth is good, the sporangium is absent, the substrate mycelium is light brown, the soluble pigment is golden brown.  Glycerin nitrate agar.  Growth is average, there is no sporangium, substrate mycelium is colorless-bamboo, there is no soluble pigment.  Physiological properties.  Well absorbs L-arabinose, D-acid, D-glucose, O-fructose, D-mannose, mannium L-rhamnose, sucrose, starch, salicin, galactose. u, glycerin, trehalose, maltose, cellobiose.  Does not assimilate inositol, ft-lactose, I raffinose, cellulose, L-sorbose, L-melibiosis, D-ribose, melesitosis, D-copbit, dulcite.  The optimal growth temperature is 10-45 ° C.  Unbound milk peptonizes and coagulates.  Cr-ahmal hydrolyzes.  Cellulose hydrolysis is negative.  Casein hydrolyzes.  .  Gelatin does not dilute.  I Tyrosine does not decompose.  Forms melanin of peptone, yeast, and iron-containing agar medium; on a tyrosine agar medium, melanin does not; It is formed.  Xanthine  hypoxanthine does not decompose.  Hydrogen sulfide does not emit.  Nitrates do not restore.  The antibiotic complex includes nonplanocins A, B, C, D and F.  Neplanocin A is a weak base and has the following physicochemical characteristics.  acetate, terrate, citrate or succinate.  Neplanocin C is a weak base and has the following characteristics.  Elementary analysis.  Found: carbon 47.59%, hydrogen 4.64%, nitrogen 25.50%.  Calculated: carbon 47.31%, water of the genus 4.66%, nitrogen 25.05%.  Molecular Weight 279 Molecular Form Melting point (with decomposition) o, 6 ml) Specific rotation, δ7%,).  UV absorption spectrum (16 JT / b in a A, E,, 9.  at pH) (2590 A,, at pH 10: D. 2630 A, Infrared Absorption Spectrum (KVg), Absorption Bands at 3450-3100 2920, 2740, 2680, 1680, 1630, 1600 1560, 1500, 1460, 1420, 1380, 1360 1330, 1300, 1240, 1200, 1170, 1100 1050, 1020, 960, 920, 900, 880, 83 780, 680 cm Spectrum of nuclear magnetic resonance (internal standard, in deuteririd Methyl sulfoxide, 100 M Soluble in water, dimethyl sulphide, dimethylformamide.  Insoluble in ethyl pate, chloroform, benzene and hexene.  Color reaction.  Positive: discoloration of potassium permanganate, periodate and Tol lense.  Negative: ferric chloride, ninhydrin, anisic aldehyde and Iolish.  Weak base.  Colorless lamellar crystals.  Rf value.  Lh-butanol :.  acetic acid: water-6: 1: 1,, 33; M-butanol: concentrated, ammonia:, 5: 2,, 19; n-propanol concentrated ammonia water 10: 1: 1,, 30, acetone: water 10: 1,, 43, ethyl acetate: methanol: water 10: 2: 1,, 27; chloroform: methanol: acetic acid 10 2: 1,, 20.  Structural formula J.  NONGS1-X / W OH OH.  Neplanocin C has the following biological properties, Suppressing the growth activity of pathogenic plant fungi: 100 Helminthosporium oryzae M 0306: 31.4 mm (zone of inhibition) Cladosporium herbarum M 4278: 14.0 mm (zone of suppression) Alternaria kikuchiana M 4588: 12.0 mm (zone of suppression) Acute toxicity.  LDjo: 55 mg / kg (intraperitoneally to mice).  Neplanocin C can be used in the form of a physiologically acceptable salt of a mineral acid or an organic acid, such as hydrochloride, acetate, tertrate citrate or succinate.  Antitumor activity.  Neplanocin C completely suppresses the growth of leukemic cells 1-5178U at a concentration of 0.8 GG / ml in vitro.  When intraperitoneal administration in doses of 10 mg / kg neplanocine C has a prolonging effect on life expectancy when infected with L-1210 leukemia, amounting to 131% of the control group.  Neplanocin D has the following physico-chemical characteristics.  Elementary analysis, C 49.70% i H 4.64%; N 21.20%. Molecular weight 264.  Molecular formula, melting point 236-237 ° C.   Specific rotation: pO-145 (, 6%, H, 0) o UV absorption spectrum in water Huto1X 2510 A, HLfcw 479; in acidic water: -yyj (. j) (, 2510 A, in alkaline water I  A, / 4 P {GTM A {, Infrared Absorption Spectrum (KBr).  Absorption bands at 3420-3120, 2940-2880, 168D, 1580, 1545, 1510, 1440, 1390, 1305, 1210, 1110, 1075 1040, 1000, 990, 975, 900, 845, 780 cm. Spectrum YH (internal standard in deuterium dimethylsulfoxide, 100 MHz), Soluble in water, dimethyl sulfoxide, dimethylformamide, acetic acid and pyridine.  It is insoluble in ethyl acetate, chloroform, benzene, and hexane.  Color reaction.  Positive: discolors potassium manganate and oxidizes periodate; Negative; 1shgidrin, felin ga and ferric chloride.  White needles.  Rf value.  and-butanol: acetic acid: in yes-6: 1: 1,, 27i N-butanol: concentrated ammonia: in yes-10: 0.5: 2,, 07; N-propanol: concentrated alcohol: water-10; : 1: 1,, 18, acetone: water-10: 1,, 33.  Structural formula TY) 4-V no-n, (1 / H he.  he.  Acute toxicity of nonplanocin 0.  With intraperitoneal administration of 100 mg / kg of neplanocine D in the amount of 100 mg / kg, there is no death.  Neplanocin B has the following physico-chemical characteristics.  Elementary analysis.  From 47.44% i H 4.63%; N 25.07%.  Molecular Weight 279.  Molecular formula.  Melting point 269-272С (with dilution) „24 Specific rotation. ) -3.5 (, 0%, dimethyl sulfoxide).  UV absorption spectrum in water: Yaug, A, E 330.4 in acidic water (one drop x / 2590 X, 7 0.1 n.  HC1); 10 in alkaline water (one drop of Xvyig 2630 A, 522.2 0.1 n.  NaOH) Infrared Absorption Spectrum (KBr).  Absorption bands at 3380, 3280, 3100, 2920, 2880, 2740, 1700, 1610, 1570, 1520, 1480, 1420, 1380, 1350, 1300, 1250, 1220, P70, P60, 1100, 1080, 1030, 1020, 980 , 970, 870, 840, 790, 730, 710 cm. NMR spectrum (internal standard DS in deuterium dimethyl sulfoxide, 100 MHz).  Soluble in water, dimethylsufoxide.  Insoluble in ethyl acetate, chloroform, benzene and sulfuric ether.  Color reaction.  Lightly put on: provides potassium permanganate.  Negative: ninhydrin, Molish and anisaldehyde.  Weak base.  White lamellar crystals.  Rf value.  N-butanol: acetic acid: water-6: 1: 1,, 42, I-butanol: concentrated ammonia: water-10: 0.5: 2,, Z7, N-propanol: concentrated ammonia: water-10 : 1: 1,, 41i acetone: water 10: 1: 1,, 48.  The structural formula W NONGS - | (0 Neplanocin F has the following physicochemical properties.  Elementary analysis.  C 48.74%, H 4.83%, N 25.71%, (contains crystallization water).  Molecular weight 263 molecule formula -.   Melting point 223 s (with decomposition). 21 Specific rotation.  6.6 (, 8).  UV absorption spectrum in water: X ax 2630 A, E - (, 7, Acidic water (one drop 2600 A, 527.1, n, HC O; in alkaline water (one drop O, 1 p -1 2630 A, , 8 H. NaOH).  Infrared absorption spectrum (KVg).  Absorption Bands at 3320, 3210, 2920, 1650, 1610, 1580, 1480, 1420, 1380, 1340, 1310, 1270, 1220, 1180, 1110, 1070, 1020, 980, 900, 840, 800, 730 cm-1 NMR Spectrum ( internal standard D; , in deuterium dimethyl sulfoxide, 100 MHz).  Solubility.  Soluble in water, dimethyl sulfose and acetic acid.  Insoluble in ethyl acetate, chlorine form, benzene and sulfuric ether.  Color reaction.  Positive: discolor ne.  manganate potassium.  Negative: ferric chloride, ninhydrin and felling.  Nature.  Weak base.  White needles.  Kf value.  N-butanol: acetic acid: water 6il: l,, 5r; N-butanol: concentrated ammonia. alcohol: water-10 0.5: 2,, 43, and-propanol: concentrated alcohol: water-10: 1: 1,, 59. ; acetone: water-10: 1,, 4 The structural formula of KHz tPgL BUT-Ng Neplanocine B and F have the following biological properties.  Acute toxicity.  Intraparenteral administration to mice of nonplanocin B or F in the amount of 100 mg / kg did not cause death.  Suppression of cell growth.  Neplanocin B in the amount of 0, and neplanocine F in the amount suppressed the growth of lymphoma cells in the case of intraperitoneal administration of not planocin B in the amount of 50 mg / kg, the drug has a prolonging effect on the life span - 142% of the control group.  Neplanocine has an antidepressant effect.  An antibiotic complex that includes a non-plate A. , B, C, D and F are obtained, for example, by inoculating strain Ampullariella A 11079 FERM-P No. 4494 in a suitable nutrient medium.  Microorganisms can be grown in various ways in an artificial medium or natural medium, liquid or solid culture.  In industrial production, a liquid medium is preferred. Digestible carbon sources, nitrogen sources, inorganic salts, and other substances can be used to make up the environment, and this medium is used for microorganisms that produce antibiotics, nonplanocillins.  As a carbon source, glucose, sucrose, glycerin, soluble starch and the like can be used.  Peptone, soybean powder, wheat extract, meat extract, rice bran, casein soda hydrolyzate, ammonium salt, etc can be used as a source of assimilable nitrogen. P.  Inorganic salts such as sodium chloride, phosphate (calcium, magnesium, iron or manganese) can also be used.  A BeitecTBO defoaming agent such as silicone oil or soybean oil may be added.  .  In the case of a bulk culture, a submerged aerated culture is preferably used.  In this case, the cultivation is carried out at the optimum temperature for the microorganisms, preferably 25-30 C.  Duration of cultivation depends on the applied conditions and is usually 2-4 days m.  The pH of the medium is neutral to slightly acid when grown.  This medium contains antibiotics-non-planar №1.  The isolation of nonplanocin antibiotics is carried out by standard isolation. or by separation of methods used to isolate products of microbial metabolism.  . Since nonplanocins are weak bases, blisters can be isolated by absorption with suitable adsorbents, followed by elution with a suitable solvent.  Active carbon, cation exchange resins, activated alumina or silica gel can be used as adsorbento.  The eluting solvents are chosen depending on the adsorbent used, for example, they can be water-miscible organic solvents, such as aqueous methanol, aqueous acetone or aqueous dioxane, or salt solutions, or acidic alkaline solutions.  In addition, non-planocins can be released and ochchats as substances of a slightly alkaline nature.  For example, antibiotics absorb cation-exchange. resin, such as Amberlite 1RP-50 or Dovek 50 and elute acceptable acidic, alkaline or saline.  A combination of an adsorbent and an ion exchange resin is used to isolate, elute and purify antibiotics.  For example, the culture filtrate is loaded into Amberlite 1R-120 cation exchange resin to absorb the antibiotic, elute with an alkaline solution, pH 3.7 with normal aqueous ammonia solution.  to obtain an active fraction, and after adjusting the pH to a neutral or weakly alkaline environment, antibiotics are adsorbed with activated carbon, followed by elution with 70% methanol.  The eluate is adsorbed with Amberlite 1RA-410 anion exchange resin and re-eluted with water to collect the active fractions.  The combined fractions are concentrated to obtain a crude product, which is then purified on silica gel.  Further purification is carried out by recrystallization.  Purity can be determined by a single melting point or a single spot on paper chromatography, thin layer chromatography, and paper electrophoresis at 2630 A of UV light.  Neplanocin A can also be obtained from Neplanocine D via derivatives of Neplanocine O.  To do this, the three hydroxyl groups in the cyclopentene ring of neplanocin D interact with benzoyl chloride.  The hydroxyl group in the adenine structure of neplanocin O is replaced by a marcapto group, for which the reaction is carried out, for example.  9 14 with a five-grained phosphorus, then a protecting group for the hydroxyl group is removed, resulting in a derivative of neplanocin D.  Methylation with its methyl iodide gives the derivative neplanocine O.  The derivative of neplanocin D is treated with methanol ammonia, the result is neplanocine A.  In addition, the three hydroxyl groups in the cyclopentene ring of neplanocin D are obtained by targeting.  This is achieved by reacting with acetic anhydride.  This compound is then converted to a derivative of neplancin D by reaction with thionyl chloride.  The derivative of neplanocin D can be converted to neplanocin A via a derivative of neplanocin D by treatment with a methanolic ammonia solution.  Example 1  A 500 ml flask is charged with 100 ml of an aqueous medium (pH 6.5) containing 2% glucose, 2% starch, 1% yeast extract, 1% casein hydrolyzate and 0.2% calcium carbonate.  The contents of the flask are sterilized for 15 minutes at 120 C.  B two flasks of this medium are seeded with one loop with a crop of species Ampultariella A 11079 FERM-P No. 4494 and shaken at 30 ° C.  After four days of culture; the medium is transferred to 20 liters of the same sterilized medium, which is in a fermentation tank, with a capacity of 30 liters and grown with stirring at 300 rpm and aeration at 20 liters / min for 48 hours.  The medium grown in this way is transferred to 200 liters of aqueous medium (pH 6.5 with 4% glucose, 1% nopoiiKa soybeans, 0.4% meat extract, 0.4% peptone, 0.1% yeast extract, 0, 25% sodium chloride and 0.1% calcium carbonate and immersed, with stirring, from 180 rpm and aeration 130 l / min for 40 hours.  The resulting broth (about 200 l) is filtered, and the mycelium is washed with water, Phi-trat and washing water and, as a result, approximately 140 l of clear filtrate is obtained (57 μg / ml in activity as neplanancin A).  Example 2  Obtained B example 1, the filtrate is passed through ko-.  59 A bottle of 20 L of Amberlite 1R-120 cation exchange resin (H type), where material is adsorbed, then the column is washed with 100 L of water.  Elution was carried out with a normal aqueous ammonia solution, pH 3.7.  The initial eluate (ZO l) discarded, 90 l subsequent. . . the eluate is collected, adjusted to pH 8 by the addition of 6 n.  hydrochloric acid, then passed through 4 l of activated carbon in a column, rinsed with water, eluted with 90 l of a 70% strength methanol solution.  The resulting eluate was concentrated under reduced pressure to give 1.5 L of concentrate.  The concentrate is introduced into a column filled with 10 liters of Amberlite 1RA-410 cation-exchange resin (Olf type) and eluted with water.  Adding 4 n.  hydrochloric acid regulate pH to 7.  The eluate is concentrated in vacuo, the material is precipitated upon cooling and filtered, yielding 4.8 g of crude non-planodin A (about 12% purity).  Untreated neplanocin A (41.8 g was dissolved in a small amount of water and introduced into a column (8.3–40 cm) filled with 2 liters of silica gel with a mixture of solvents — n-butanol: 28% aqueous ammonia:, 2: 1 and then eluted with the same mixture of solvents. Every 150 ml fractions, the active fractions correspond to the fraction nos. 24-52.  They are collected, concentrated in vacuo and incubated while cooling the shea.  The precipitate was filtered to give 2.6 g of crude crystalline neplanocin A (yield 32%).  Crude neplanocine A is dissolved in approximately 60 ml of hot water and the white needle crystals are incubated at room temperature. The needle crystals are filtered off to obtain 2.01 g of plankano A crystals (yield 25.2%). Example 3.  The filtrate (140 L, with an activity of 300 µg / ml as a blank) prepared in accordance with the same procedure as in Example 1, is passed through a column with 20 liters of Amberlite 1R-120 cation-exchange resin to adsorb the material and then washed with about 100 liters of water.  The elution is carried out with a normal aqueous ammonia solution pH 3.7, the initial eluate (20 L) is drained.  100 liters of the subsequent eluate are then collected, the pH is adjusted to 8 by the addition of concentrated hydrochloric acid, passed through a column of 4 liters of activated carbon, washed with water, eluted with 70 liters of 70% methyl alcohol solution.  The resulting eluate was concentrated under reduced pressure to give 1.5 L of concentrate.  The concentrate is dried at a temperature below O C, as a result.  , get 83.6 g of raw powder (purity 29.5%).   83 g of raw powder. dissolved in an aqueous saturated solution of y-butypic alcohol and introduced into a column of 8 cm, loaded with 2 l of silica gel with n-butyl alcohol, and then eluted with a mixture of solvents n-butanol: concentrated, aqueous ammonia: water-10: 0.2 :one.  Each fraction of 150 ml is separated.  The active fractions correspond to fractions No. 53-108, they are collected, concentrated and maintained at low temperature.  The precipitate was filtered to give 18.2 g of neplanocin C as a white crystalline substance (purity 96%, yield 41.6%).  The product is dissolved in hot water and cured at room temperature.  Colorless ibie-like crystals of neplanocin C precipitate.  Filtration gives pure neplanocine C.  Example 4  When prepared in accordance with the procedure of Example 1, 3.6 kg of activated carbon powder was added to the filtrate.  After stirring for 40 minutes, the activated carbon is filtered off and thoroughly rinsed. water, the elution is carried out with a 70% methanol solution.  40 l of the eluate is dried under vacuum to obtain 80 g of a crude powder containing neplanocin O. A column filled with 6 liters of silica gel with a mixture of solvents n-propanol: a concentrated aqueous ammonia: water-10: 1 solution, 80 g of raw powder are introduced and then elute it with the same mixture of solvents.  Fractionate each eluate.  Neplanocin D was found in fractions Nos. 20-37.  These active fractions are collected, concentrated in vacuo to 30 ml, and kept under cooling at 1-1w.  The precipitate is separated by filtration, resulting in 460 mg of crude crystalline planar O.
    +60 g of crude crystals are dissolved in 3 liters of hot water and injected onto a Sephadex G-15 column (1850 nl filled with water), then eluted with water. Each 100 ml of eluent is fractionated, fractions of eluate No. 15-16 (200 ml) are collected and concentrated under reduced pressure to 20 ml. The resulting concentrate is aged at room temperature. Obtain ml of precipitated neplanocin D in the form of white crystals,
    Example 5. 376 mg of nonplanocin D dissolved in 10 ml of anhydrous pyridine are thoroughly mixed at 55 ° C. 0.9 ml of benzoyl chloride is added dropwise to the solution and stirred for 2 hours at 60-65 ° C. The solution is kept at 40-45 ° C for 2 hours and then for 8 hours at room temperature. 10 ml of water are added with stirring and after 25 minutes it is dried under reduced pressure in an evaporator. The dried material is dissolved in 30 ml of chloroform, washed three times with 10 ml of 1N. hydrochloric acid and twice 1N. sodium bicarbonate solution, then washed twice with 20 ml of water, the chloroform layer is dehydrated with anhydrous magnesium sulfate and concentrated to obtain 747 ml of compound (|) pale pink (yield 91%
    Compound (I) has the following physicochemical characteristics oLj (, 6, methanol). Molecular formula Molecular weight 576 Mass spectrum), melting point 116-117 C. UV absorption spectrum 2320 X.,
    Rf value. Chloroform: methanol 10: 1,, 53.
    735 mg of compound (|) are thoroughly stirred, and 1.0736 g of phosphorus pentasulfide dissolved in 19 ml of pyridine, 0.18 ml of water is added dropwise to the mixture. After boiling under reflux for 4 hours with stirring, the reaction mixture is cooled and concentrated in vacuo. The result is a brown oily product. The oily product is poured into boiling water with stirring and stirred for an additional 30 minutes to obtain a yellowish material. . It is filtered to separate the precipitate, washed with a mixture of ethyl alcohol and sulfuric ether (1: 1), additionally washed with sulfuric ether and dried, the result is 561 mg of compound (II) (yield 74.3%) o
    Compound (II;) has the following physicochemical characteristics,
    , 9 (, 6, СНС1з), Molecular formula io &apos; e is the cool weight 592, Melting point 235-239 C (foam decomposition), UV. spectrum (in methanol) 2320 k, 858.5, 3230 A, 327.5. Rf is nothing. Chloroform: methanol 10 :, Rf 0.82,
    525 mg of compound (11) are dissolved in 31 ml of anhydrous methyl alcohol. 0.62 ml of freshly prepared 2N is added. a solution of sodium methylate in methanol and boil with stirring for 2 hours under reflux, resulting in the removal of benzoyl groups.
    After distillation, about 50 ml of methyl alcohol is added and the pH is adjusted to 7.5 by the addition of acetic acid. The solution was extracted twice with 20 ml of ethyl acetate and the aqueous layer was concentrated to give the derivative of neplanocin D (HI) in the form of needle crystals. Recrystallization from hot water was carried out to obtain 110 mg of the derivative of neplancin D (111) (yield 44.3%).
    The derivative of neplanocin O (ill) has the following physicochemical properties. Molecular formula S, Molecular weight 280 (mass spectrum). Melting point 260262 s (with decomposition). UV spectrum in water 2260 A, 6, 3240 A, 0. Rf value. Propanol: concentrated aqueous ammonia: water 10: 1: 1,, 21,
    Example 6, To a solution of 37 mg of a derivative of neplancin O (III) prepared according to Example 5, in 0.3 ml of 0.4N. Sodium hydroxide is added with 0.009 ml of methyl iodide and added at room temperature for 10 minutes. Then, 0.05 ml of 0.4N sodium hydroxide is added and 0.009 ml of methyl iodine is added, shaken again and held at room temperature. 10 ml of water is added to this solution, concentrated in vacuo to 2 ml and added to the column 1.4 to 49 cm, filled with Sephadex G-15. The elution is carried out with water and fractionated every 3 g of the eluate. The Sobirshot fractions Nos. 17-19 are concentrated and cooled to obtain 35 mg of the crisstax derivative of neplanactin D (IV), (90% yield). physical and chemical characteristics. 41, 7., 7, water) Molecular S 0. Molecular weight 294 (mass spectrum). Melting point 177-178 C. UV spectrum in water 2220 A, 8, 2880 1., b, 2950 A, 3, 2950, 7. Rf value. Propanol: concentrated aqueous ammonia solution: water 10: 1: 1. Rf 0.42. Example 7 Synthesis of non-A is carried out from a derivative of neplancin D (IV). 50 mg of the derivative of nonplanocin D (IV), prepared in accordance with the procedure of Example 6, dissolved in 1.5 ml of methanol ammonia solution (O saturation), are placed in a sealed tube and maintained at 146–148 ° C for 7 After removal of the solvent under reduced pressure, the residue was taken up in 3 ml of hot water, then cooled, to give 33 mg of neplanocin A as needles, (74% yield). Example 8. To 14g neplanat on D in 12 ml of anhydrous pyridine, add 1 ml of acetic anhydride and incubate at room temperature for 8 hours. Add 30 ml of n-hexane and cool in ice water to obtain 1 g of crystalline from dineni (2). 1 g of compound (2) is added to 25 ml of a solution, 0.8 ml of thionyl chloride and 0.4 ml of dimethylformam in chlorine form and heated under reflux for 3 hours at room temperature. Chloroform was distilled off under reduced pressure. The residue is poured into 100 ml of ice water with stirring. Extraction is carried out with 100 ml of chloroform, followed by sodium bicarbonate and water and sodium sulfate. After drying in vacuo, a derivative of neplanocin D (G) is obtained. Example 9. Synthesis of non-planar A from a derivative of neplanocin O (3). 35 ml of a saturated solution of ammonia in methyl alcohol is added to the derivative of planocin D (G) prepared in Example 8 and placed in a steel closed tube. The reaction mixture is cooled in vacuum and cooled to obtain a crystalline powder. which is subjected to chromatographic purification on silica gel. 286 mg of neplanocin A are obtained. Physical and chemical characteristics are identical to those corresponding to neplanocine A prepared in Example 7. Example 10. A filtrate (140 L, filled with Amberlite 1R-120 cation exchange resin) is passed through a column filled with 20 l. activity of about 50 µg / ml as (neplanocine u) when taken in accordance with the procedure of example 1, and then the column is washed with approximately 100 l of water. The elution of the adsorbed material is carried out with a normal aqueous solution of ammonia, pY 3.7. The initial eluate (as) drained, and the next 90 l s The yate is collected, the pH is adjusted to 8 by adding 6N hydrochloric acid, then loaded onto a column with 4 L of activated carbon, rinsed with water, eluted with 90 L of 70% aqueous methanol. In this way, the eluate is concentrated to obtain 500 ml of concentrate, (KI) is lowered to precipitate the material. The precipitate is collected and dried to give 5.1 L of crude nonplanocin B (purity approximately 60%, yield 44%). Example 11. Obtained in Example 10 neplanocin B (5.1 g) is injected in a column with 2 liters of silica gel (8.3 x 40 cm), filled together with a mixture of acetone and water (10: 0.5) . The subsequent zoning is carried out with the same solvent mixture, fractionated every 80 g, and fractions nos. 16-24 pooled. These active fractions are incubated at low temperature to precipitate non-planocin B as white plate-like crystals. 2.57 g of crystalline neplancin B are obtained (yield 32.8%). Example 12. The cultivation is carried out in accordance with
    权利要求:
    Claims (1)
    [1]
    Claim
    A method for producing an antibiotic complex including nonplanocins A in general form — where. X-1TH 2 IPs OH
    Z-HO-H 2 C or where ^ is -0- or valence bond, characterized in that the Ampul strain 1 ariel 1 a A 11079 FERM- No. 4494 is cultivated in a nutrient medium containing sources of carbon, nitrogen and an inorganic substance, the target product is isolated from the culture fluid and (or) it is divided into nonplanocins A, B, C, D and F.
    Priority by signs:
    05/25/78 - receipt unplanned on the A08/10/78 - receipt unplanning ί on the FROM01/29/79 - receipt unplanned on the D02/23/79 - receipt unplanned on the B and F
    ВНИИПИ Order 419/78 Circulation 504 Subscription
    Branch of PPP Patent, Uzhhorod) st. Project, 4
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    同族专利:
    公开号 | 公开日
    NL182231C|1988-02-01|
    SE7903672L|1979-11-26|
    GB2021582B|1982-10-20|
    IT1115245B|1986-02-03|
    GB2021582A|1979-12-05|
    CH641804A5|1984-03-15|
    HU192741B|1987-07-28|
    DK149313B|1986-04-28|
    DK177079A|1979-11-26|
    DE2917000C2|1985-10-03|
    DE2954197C2|1990-09-27|
    CA1128882A|1982-08-03|
    SE443576B|1986-03-03|
    NL182231B|1987-09-01|
    ES480384A1|1980-04-01|
    FR2426688B1|1982-03-12|
    MX5788E|1984-07-11|
    DE2917000A1|1979-11-29|
    IT7922957D0|1979-05-24|
    DK149313C|1986-10-20|
    FR2426688A1|1979-12-21|
    NL7903318A|1979-11-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE3148363A1|1980-12-12|1982-09-16|Toyo Jozo K.K., Shizuoka|NEPLANOCIN A DERIVATIVES|
    US4742064A|1985-09-10|1988-05-03|Regents Of The University Of Minnesota|Antiviral carbocyclic analogs of xylofuranosylpurines|
    ZA894534B|1988-06-20|1990-03-28|Merrell Dow Pharma|Novel neplanocin derivatives|
    US5145960A|1989-04-24|1992-09-08|E. R. Squibb & Sons, Inc.|Pyrimidinyl tetrahydrofurans|
    US5164520A|1989-04-24|1992-11-17|E. R. Squibb & Sons, Inc.|Intermediates for purinyl and pyrimidinyl tetrahydrofurans|
    NZ232993A|1989-04-24|1992-10-28|Squibb & Sons Inc|Purinyl and pyrimidinyl tetrahydrofurans|
    US5059690A|1990-03-01|1991-10-22|E. R. Squibb & Sons, Inc.|Purinyl tetrahydrofurans|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP53062899A|JPS6212227B2|1978-05-25|1978-05-25|
    JP53098027A|JPS6212228B2|1978-08-10|1978-08-10|
    JP54008205A|JPS6212226B2|1979-01-29|1979-01-29|
    JP54021201A|JPS6317078B2|1979-02-23|1979-02-23|
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