• 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:
    New semi-synthetic derivatives of 4''-erythromycin A and their preparation are described. The new compounds of the invention correspond to the formulae I and II in which the symbols have the meaning given in Claim 1. The compounds of formulae I and II, in which X and Y are a pair H, NH2, possess antibacterial properties and can be used as medicinal products. <IMAGE>
    公开号:SU927122A3
    申请号:SU782573754
    申请日:1978-02-03
    公开日:1982-05-07
    发明作者:Кристиан Сиаволино Фрэнк
    申请人:Пфайзер Инк(Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new derivatives of 4-deact * si-4-aminoerythromycin A or their salts., Having valuable pharmacological properties. .
    The purpose of the invention is to obtain new, useful compounds that expand the arsenal of means of exposure to a living organism, is achieved by synthesis of the latter, based on the known reaction of reductive amination P].
    where Rh and Rq ^ each are hydrogen or acetyl; R a is hydrogen, or R 0 and Rn together O
    -C - '1C - OH, a Rj- means s bond to the carbon atom to which R 4 is attached, or R d is oxygen, and Rj is hydrogen provided that if R (^ is hydrogen, then R $ ~ hydrogen, ® or their salts, which consists in the fact that the compound
    This goal is achieved according to the method of obtaining derivatives of .4-deoxy-4-aminoerythromycin A vol- ‘15
    where RR 5 have the indicated meanings, they are reacted with ammonium acetate 927122 in methanol or isopropanol, provided that when R l is acetyl, isopropanol is used at room temperature, followed by reduction with alkali metal cyanoborohydride or catalytic reduction using palladium on carbon or Raney nickel in hydrogen, and if necessary, when R and Rg together - t
    ABOUT
    II
    - With -, hydrolysis in water and diethyl ether.
    The desired product is isolated in the free state or in the form of a salt. 1
    Although it is necessary to use one mole of ammonium acetate per mole of ketone, it is preferable to use a ten-fold excess of it to ensure complete and rapid formation of the imine. 3 Such large excess quantities hardly affect the quality of the target product.
    As for the amount of reducing agent used per 2 mol of ketone, it is preferable to use about two moles of sodium cyanoborohydride per mole of ketone. The reaction time varies depending on the concentration, temperature, 3 at which the reaction is carried out, and the intrinsic viscosity of the reactants. At room temperature (the most preferred reaction temperature), the reaction is almost completely completed in 1 ~ 3 h. It is preferable to use isopropanol as a solvent for the reaction.
    When separating the desired derivatives of 4-deoxy-4-aminoerythromycin A 4 from non-basic, by-products or starting compounds, the main nature of the final product is used as an advantage. Accordingly, the aqueous solution product extra- 4 giruyut in the range of gradually increasing quantities pH, so that neutral or non-basic materials are extracted at lower pH, and the product ekstragi-: ruetsya at values of pH, exceeding
    5. The extraction solvent, either ethyl acetate or diethyl ether, is washed with brine and water, dried over sodium sulfate and, after removal of the solvent, the desired product is obtained. If necessary, it is possible to carry out further purification using column chromatography on silica gel in accordance with known methods.
    The reduction of imines can also be carried out using hydrogen and an appropriate hydrogenation catalyst.
    The latter can be used in various quantities, depending on how fast the reaction should be. Amounts of catalyst such as 10-200 wt.% Of the weight of compound 11 can be used quite effectively.
    The hydrogen gas pressure in the hydrogenation reactor also affects the reaction rate. To ensure a normal reaction time, it is preferable to use an initial pressure of 3.5 kg / cm. It is also preferred for convenience to carry out reduction at ambient temperature.
    The reaction time depends on numerous factors, including temperature, pressure, concentration and the characteristic viscosities of the reactants. If the reaction is carried out under the indicated conditions, then it is completed in 12-24 hours.
    Examples of acids that provide pharmaceutically acceptable salts are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic and aspartic acids.
    When compounds II are converted to amines using the described process, the formation of two epimeric amines is possible. In practice, it has been observed that both epimeric amines are present in the final product in various ratios depending on the chosen synthesis method. If the isolated product contains predominantly one of the epimers, then the specified epimer can be purified by recrystallization from a suitable solvent to obtain a product with a constant melting point.
    Although this mixture of epimers can be separated using known methods, for practical reasons, it is advantageous to use the mixture in the form in which it was isolated from the reaction. However, it is often beneficial to purify the epimer mixture with
    927 using at least one recrystallization from an appropriate solvent, and then clean using high pressure column chromatography, distribution between solvents or trituration in an appropriate solvent. The specified purification, if there is no need for separation of the epimers, leads to the removal of the starting compounds and unwanted by-products
    Both epimers of said compound have the same type of activity, i.e. are antibacterial agents. f 15
    New prbizvodnye -deoksi-4 April 11 -aminoeritromitsina A according to the invention exhibit in vitro activity against a variety of Gram-positive microorganisms such as Staphylococcus aureus and m Streptococcus aureus, and against certain Gram-negative microorganisms, such as spherical or ellipsoidal shape (cocci) . Their activity can easily be demonstrated in in vitro tests against various microorganisms in a cardiac extract as a medium using the usual double serial dilution technique. 3 (J Their in vitro activity makes them useful for external use in the form of ointments, creams, etc., for sterilization purposes, for example, items in the patient’s room, and as industrial antimicrobials, 35 for example, for treating water, mucous surfaces for the protection of paints and wood.
    In addition, many of the compounds of the invention and their acid addition salts are active against gram-positive and some gram-negative microorganisms, for example, PasfeureBba muBfocida and Neisseria sicca in vivo by oral and / or 45 parenteral administration or administration to animals and humans. Their in vivo activity is more limited in terms of the sensitivity of organisms and is determined using the usual 50 technique, which involves infection of mice of almost the same weight with a test organism and their corresponding treatment with oral or subcutaneous administration of test compounds.
    In practice, ten mice received intraperitoneal vaccinations of suitable
    6 diluted cultures containing approximately one to ten · LD 100 (lowest concentration of organisms, resulting in 100% death). At the same time, control tests are carried out in which mice are vaccinated with more highly diluted cultures, as a test for possible variations in the virulence of test organisms. The test compound is administered half an hour after inoculation and repeated after 4.24 and 48 hours. Surviving mice are incubated for 4 days after the last treatment and the number of surviving individuals is counted.
    When used in vivo, these new compounds can be taken orally or parenterally, for example, by subcutaneous and intramuscular injections in doses ranging from about 1 mg / kg to about 200 mg / kg live weight per day. A desired dosage is from about 5 mg / kg to about 100 mg / kg live weight per day, and a preferred range is a dosage range from about 5 mg / kg to about 50 mg / kg live weight per day.
    Suitable solvents for parenteral injection include aqueous media such as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueous media such as vegetable fatty oils (cottonseed oil, peanut oil, corn oil, sesame oil) , dimethyl sulfoxide and other non-aqueous solvents that do not affect the therapeutic efficacy of drugs and are not toxic in the volumes or proportions used (glycerin, propylene glycol, sorbitol) In addition, successfully Oguta be formulated for rapid preparation of solutions immediately before use. Such compositions may include liquid formulations. agents, for example propylene glycol, diethyl carbonate, glycerin, sorbitol, etc., buffering agents, hyaluronidase, local anesthetics and inorganic salts in order to impart the desired pharmaceutical properties. These compounds can also be combined with various pharmaceutically acceptable inert carriers, including solid diluents, aqueous media, non-toxic op7. 9271 Ganic solvents in the form of capsules, tablets, dry mixes, suspensions, solutions, elixirs and parenteral solutions or suspensions. These compounds are used in various pre- zirovkah 5, wherein the concentration level varies from about 0.5 to about 90% by weight of the total composition.
    PRI me R 1. 6.9 "semi-ketal
    11-acetyl-4 '- deoxy-4 |, -aminoerythro- 10 mycine A.
    To a stirred solution of 4.4 g of 6 ', 9 ~ of a half-ketal 11-acetyl ~ 4''-: deoxy-4- th- oxoerythromycin A and 4.38 g of ammonium acetate in 75 ml of methanol, 305 mg of 85% are added sodium cyanoborohydride. After stirring overnight at room temperature, the reaction mixture was poured into 300 ml of water, to which 20 ml of 250 ml of chloroform were then added, the pH of the aqueous layer was adjusted to 9.8, and the chloroform layer was separated. Then the aqueous Λ layer was again extracted with chloroform and the chloroform extracts were combined, 25 dried over sodium sulfate and concentrated to give a white foam. The remaining foam is dissolved in a stirred mixture of 125 ml of water and 125 h ml of fresh chloroform, and the pH of the mixture is adjusted to 30 dt to 4.5. Chloroform is separated and drained, the pH of the aqueous layer is adjusted to 5 »6, 7 and 8, and after setting each pH value, extraction is carried out with fresh chloroform. The extracts from aqueous phases with pH 6 and 7, volume ~ 35 are combined, washed with saturated saline and dried over sodium sulfate. After removal of solvent, 1.72 g of the expected product is obtained in the form of a white foam. The product is dissolved in a minimal amount of diethyl ether and then treated with hexane until cloudy.
    The crystalline 6.9 ~ semi-acetal of 11-acetyl-4-deoxy-4-aminoerythromycin A thus formed is filtered off and dried; yield 1.33 g, mp 204-206.5 ° C.
    NMR (S, CDCe 3 ): 3:31 (2H) s, 3.28 (1H) s, 2.31 (6H) s, 2.11 (3H) s and 1, 5 (3H) s. t
    Example .
    1. Complex 11-12-carbonate ester of 6,9-hemicetal 4-deoxy-4-aminoerythromycin A.
    A. To 189 g of 6,1-hemi-4-deoxy-4-oxoerythromycin A 11,12-carbonate ester in 1200 ml of 8 methanol are added 193 g of ammonium acetate at room temperature with stirring. After 5 minutes, the resulting solution was cooled to about -5 ° C and treated with 13.4 g of 85% sodium cyanoborohydride in 200 ml of methanol over a period of 45 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture was evaporated in vacuo to a volume of 800 ml and 1800 ml of water and 900 ml of chloroform were added to the stirred mixture.
    The pH is adjusted from 6.2 to 4.3 with 6 N hydrochloric acid and the chloroform layer is separated. Chloroform is combined with 1 L of water, and the pH is adjusted to 9.5. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure to obtain 17.4 g of a white foam. The residue was dissolved in a mixture of 1 L of water and 500 ml of ethyl acetate and the pH was adjusted to 5.5. The ethyl acetate layer was separated and the pH of the aqueous layer was adjusted sequentially to 5 "7 and 9" 5 3 and extracted after each pH was adjusted to 500 ml of fresh ethyl acetate. The ethyl acetate extract at pH 9.5 was dried over sodium sulfate and concentrated in vacuo to dryness, as a result of which 130 g were obtained. 120 g of the remaining foam were dissolved in a mixture of 1 L of water and 1 L of methylene chloride, and the pH of the aqueous layer was adjusted 4) 4, 4, 9 and 9.4 sequentially, moreover, after each establishment of pH, extraction is carried out with a fresh portion of 1 liter of methylene chloride. The methylene chloride extract at pH 9.4 was dried over sodium sulfate and concentrated under reduced pressure, whereby 32 g of product was obtained as a white foam. After crystallization from 250 ml of a mixture of acetone-water (1: 1 volume ratio), 28.5 g of crystalline epimers of 11,12-carbonate ester of 6,9-half-ketal of 4-deoxy-4-aminoerythromycin A are obtained.
    100 MHz NMR (S, CDCEij): 5.20 (1H) m, 3.37 (1.5H) s, 3.34 (1.5H) s, 2.3b (6n) s, 1, 66 (S ) s and 41 (characters) s.
    B. Separation of the epimers of 11,12-carbonate of 6.9 “half-ketal of 4-deoxy-4-aminoerythromycin A.
    On a high pressure liquid chromatography column, filled with silica gel GF 254, impregnated with:
    formamide, and eluted with chloroform, was placed 200 mg of 11,12-carbonate 6,9-hemiketal -deoksi 4-4 '1 -aminoeritromitsina Λ. Under pressure
    16.9 kg / cm * 4 (240 psi) at a rate of 4.76 cm 4 / min. 10 ml fractions were collected. The fractions from 14 to 21 and from 24 to 36 are collected.
    Fractions 14 to 21 are combined and concentrated to about 50 ml. Then, water (50 ml) was added to and the pH was adjusted to 9.0. The chloroform layer was separated, dried over sodium sulfate and concentrated, whereby 106 mg of a white foam was obtained. Ras - and tyranny with diethyl ether leads to the fact that the foam crystallizes. After stirring at room temperature for 1 h, a crystalline 11,12-carbonate ester of 6.9 ~ PO 3 (1 quetal of 4-dioxo-4-aminoerythromycin A was filtered and dried; yield 31.7 mg, mp 194- 19b ° C.
    100 MHz NMR (S, CDCEg): 5.24 (1H) d. 5.00 (1H) t, 3.40 (3H) s, 2.40 (6H) s,
    I, 66 (ZN) s and 1.40 (ZN) s.
    S. 8, g epimeric mixture of complex
    II, 12-carbonate ester of 6,9-half-ketal of 4 ”-deoxy-4” -aminoerythromycin A from Step A of Example 2 was dissolved in 50 ml of diethyl ether. The product is made to crystallize by scraping it with a glass rod. After 20 minutes of stirring, the crystalline product is filtered off and dried, resulting in 1.91 substances, so pl. 198.5200 ° C.
    100 MHz NMR (S, CDCe <j): 3.26 (3H) s, 2.30 (6H) s, 1, b1 (3H) s, 1.45 (3H) s.
    E5 G
    The NAR data indicate that the crystalline product is one epimer of the 11,12-carbonate ester of 4-deoxy-4 ”aminoerythromycin A and is identical to the ketone obtained in Example 3 B.
    II. 1 g of 11,12-carbonate epimer
    6.9 “half-ketal of 4” -deoxy-4 ”-aminoerythromycin A from Example 2 C was dissolved in 20 ml of acetone and heated in a steam bath until a point was reached. boiling. 25 ml of water are added and the resulting solution is left stirring at room temperature overnight. After 1 h of stirring, the precipitate formed is filtered off and dried., Resulting in · 581 mg of product with mp. 147 _ 149 ° C.
    100 MHz NMR (SCDCii): 5.12 (1H) d,
    927122 10 '3.30 (ZN) s, 2j0 (6H) s, 1.62 (3H) s and
    1, Зb (ЗН) s.
    These NMR data show that the product is a single epimer 11,12-carbonate ester 6.9 _ hemiketal 4-deoxy-4 "-aminoeritromitsina A.
    Example 3
    A. To a suspension of 11.1 g of 11,12-carbonate of 6.9 _ half-ketal of 2-acetyl-4 '* - deoxy-4 ”- oxoerythromycin A in 300 ml of isopropanol at room temperature is added with stirring
    10.7 g of ammonium acetate. After 5 minutes, 747 mg of sodium cyanoborohydrite in 130 ml of isopropanol was added over 30 mi, and the resulting reaction mixture was allowed to stir at room temperature overnight. A pale yellow solution was poured into 1100 ml of water, to which 400 ml of diethyl ether was then added. The pH is adjusted to 4.5 and the ether layer is separated. The aqueous layer was made alkaline to pH 9.5 and extracted (2 ^ 500 ml) with chloroform. The chloroform extracts are combined, dried over sodium sulfate and concentrated, whereby 7.5 g of a yellow foam is obtained. After recrystallization of the residue from diethyl ether, 1.69 g are obtained, which are left with the mother liquors.
    The mother liquor is treated with 75 ml of water and the pH is adjusted to 5.0. The ether layer is replaced with 75 ml of fresh ether and the pH is adjusted to 5.4. The ether is replaced with ethyl acetate. and the pH is raised to 10.0. The alkaline aqueous layer was extracted. (2 * 75 ml) with ethyl acetate and the first ethyl acetate extract. Dried over sodium sulfate and concentrated to dryness. The remaining; foam (1.96 g) was added to the mixture of 75 ml of water and 50 ml of diethyl ether and the pH was adjusted to 5.05. The ether was separated and the pH of the aqueous layer was adjusted successively to 5.4. 6.0, 7.05 and 8.0, and after each pH is established, 50 ml of fresh diethyl ether are extracted. Finally, the pH is adjusted
    9.7 and vbd ethyl acetate. irradiated with 75 ml of water and Separate the ether layer, center in vacuo, resulting in 460 mg of a white foam.
    the layer was extracted with 50 ml Ethereal, extract, PoH 6.0, combined with pH, adjusted to 9.7, dried and dried.
    1
    100 MHz NMR (S, CDCEfj): 5.20 (1H) s, MOH (2H) s, 3.40 (1H) s, 2.38 (6H) s, 2.16 (3H) s, Ί, 70 (ZN) s and 1.54 (3 ").
    'The obtained NMR product is a mixture of the epimers of 11, 12-carbonate of 6.9 half-ketal of' 2 1 -acetyl-4-deoxy-4 * -aminoerythromycin A.
    69 g of the substance obtained above are dissolved in a mixture of 75 ml of water and 75 ml of diethyl ether and the pH is adjusted to 4.7. The ether is separated, and then the aqueous layer is extracted with fresh ether (75 ml) at pH 5.05, and ethyl acetate (2x75 ml) at pH 9.7 * 0 - 15%. The ethyl acetate extracts are dried over sodium sulfate and concentrated under reduced pressure. resulting in 1.26 g of a white foam. After crystallization of the residue, 411 mg of product are obtained, mp. 19319b 0 C (with decomposition) · The mother liquor is concentrated to dryness, and the residue is dissolved in hot ethyl acetate. The solution is left to stand overnight at room temperature. The crystalline solid that precipitates is filtered off and dried, and 182 mg of additional product is obtained, mp; 19 & “202 ° C (with decomposition). 100 MHz NMR (S, COCO ^): 5, 10 (1H) s, 3.34 (2H) s, 3.30 (1H) s, 2.30 (6H) s, 2.08 (3H) s, 1, b2 (ZN) s and 1.48 (ZN) s.
    These NMR data indicate that the product is a mixture of the epimers of 11, 12-carbonate 2 * -acetyl-4-deoxy-4-aminoerythromycin A.
    B. A solution of 400 ml of 11,12-carbonate of 6,9-half-ketal of 2 1- acetyl-4-deoxy-4-aminoerythromycin A in 20 ml of methanol was stirred at room temperature overnight. The reaction solution was poured into 100 ml of water, after which 50 ml of ethyl acetate was added. The pH is adjusted to 9.5 and the organic phase is separated. The extraction is repeated using 50 ml of fresh ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to 50 to give 392 mg of a white foam. Rubbing with diethyl ether and scraping with a glass rod causes crystallization. After standing at room temperature for 30 minutes, the resulting crystalline substance is filtered off and dried, to obtain 123 mg of substance
    927122 12stv ·, and the mother liquor is retained.
    The product turned out to be identical in NMR spectrum to the material obtained in example 2C.
    100 MHz NMR (S, CDCe g ): 3.2b (3H) s, 2.32 (6H) s, 1, b1 (3H) s, and 1.44 (3H) s.
    NMR data indicate that the crystalline product is one epimer of 11,12-carbonate of 4-deoxy-4-aminoerythromycin A.
    The mother liquor is concentrated in vacuo to give 244 mg of a white foam.
    The resulting product is identical to the product obtained in example 2 A.
    NMR data indicate that the product is a mixture of the epimers of 11,12-carbonate of 6,9-half-ketal of 4-deoxy-4-aminoerythromycin A and that it is identical to the product obtained in example 2a.
    PRI me R 4. 4- th- deoxy-4-aminoerythromycin A.
    g of 4-deoxy-4-oxoerythromycin A, 31.6 g of ammonium acetate and 10 g of 10% palladium on charcoal in 200 ml of methanol are shaken at ambient temperature in a hydrogen atmosphere at an initial pressure of 3.5 kg / cm (50 lb / sq.inch) during the night. The spent catalyst is filtered off and the filtrate is concentrated to dryness in vacuo. The residue was partitioned between a water-chloroform mixture at pH 5.5. The aqueous layer was separated, pH. establish 9.6 and add chloroform. The organic layer was separated, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residual white foam (19 g) p was triturated with 150 ml of diethyl ether at room temperature for 30 minutes. The resulting solid was filtered off and dried, resulting in 9.45 g of one epimer of 4 th β-deoxy-4 ”aminoerythromycin A, m.p. 140-147 ° C.
    The diethyl filtrate was concentrated to dryness, whereby 6.89 g of product was obtained, which consists of a second epimer of 4-deoxy-4-aminoerythromycin A and a certain amount of impurities.
    PRI me R 5 · 4-deoxy-4-aminoerythromycin A.
    g of 4 ”-deoxy-4-oxoerythromycin A, 3.1 g of ammonium acetate and 2.0 g of Raney nickel in 50 ml of methanol are shaken at room temperature in a hydrogen atmosphere at an initial pressure of 3.5 kg / cm ^ (5 psi) . inch) during the night. Then, an additional 3.16 g of ammonium acetate and 2.0 g of Raney nickel are added, and hydrated, if R (£ is hydrogen, then R $ is hydrogen, or their salts, it differs in that the compound of the general formula g1e continues for another 5 hours, the solid is filtered off and the filtrate is concentrated in vacuo to dryness, the residue is added with stirring to water-chloroform and the pH is adjusted to 9.6, then fresh chloroform is added. under reduced pressure, resulting in 15 to obtain 1.02 g of 4-de hydroxy-4-aminoerythromycin A in the form of a yellow foam. The preferred isomer has a 4 ”configuration opposite to that observed for the 20 compounds of Example 4.
    权利要求:
    Claims (1)
    [1]
    TOM of ammonium in methanol or isopropanol, provided that when R ,, acetyl, isopropanol is used, at room temperature followed by reduction with alkali metal cyanoborohydride or catalytic reduction using palladium on carbon or Rane nickel in hydrogen, and, if necessary, RQ and Rg together O II - C -, hydrolysis in water and diethyl ether.  The desired product is isolated in the free state or as a salt.  Although it is necessary to use one mole of ammonium acetate per mole of ketone, it is preferable to use a tenfold excess of it to ensure complete and rapid formation of imine. Such large excess amounts have almost no effect on the quality of the target product.  With regard to the amount of reducing agent used per mole of ketone, it is preferable to use about two moles of sodium cyanide hydride per mole of ketone.  The reaction time varies depending on the concentration, the temperature at which the reaction is carried out, and the intrinsic viscosity of the reagents. At room temperature (the most preferred temperature, the reaction is almost completely completed in 1 to 3 h.  It is preferable to use isopropanol as a solvent for the reaction.  When separating the target derivatives of if -deoxy-V -aminoerythromycin A from minor, by-products or starting compounds, the main character of the final product is used as an advantage.  Accordingly, the aqueous solution of the product is extruded in the range of gradually increasing pH values, so that neutral or minor materials are extracted at lower pH values, and the product itself is extracted at pH values higher than 5.  The extraction solvent, either ethyl acetate or diethyl ether, is washed with saline and water, dried over sodium sulfate, and after removal of the solvent, the desired product is obtained.  If necessary, additional purification can be carried out using silica gel column chromatography in accordance with known procedures.  The reduction of the imines can also be carried out by using hydrogen and an appropriate hydrogenation catalyst.  The latter can be used in various quantities, depending on how you should carry out the reaction.  Such amounts of catalyst as 10–200 wt. Can be used quite effectively. % by weight of compound 11.  The pressure of hydrogen gas in the hydrogenation reactor also affects the reaction rate.  To ensure a typical reaction time, it is preferable to use an initial pressure of 3.5 kg / cm.  It is also preferable for convenience to carry out the recovery at ambient temperature.  The reaction time depends on numerous factors, including temperature, pressure, concentration and characteristic viscosities of the reactants.  If the reaction is carried out under these conditions, it is completed in 12-2 hours.  Examples of acids that provide pharmaceutically acceptable salts are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, sulfurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic, and aspartic acid.  When compounds II are converted to amines using the process described herein, the formation of two epimeric amines is possible.  In practice, it has been observed that both epimeric amines are present in the final product in different ratios, depending on the chosen synthesis method.  If the isolated product contains predominantly one of the epimers, then this epimer can be purified by re-recrystallization from a suitable solvent to obtain a product with a constant melting point.  Although this mixture of epimers can be separated using known methods, for practical reasons it is advantageous to use this mixture as it is isolated from the reaction.  However, it is often advantageous to purify the mixture of epimers with at least one recrystallization from an appropriate solvent, and then purify using high pressure column chromatography, distribution between solvents or trituration in an appropriate solvent.  This purification, if it is not necessary to separate the epimers, leads to the removal of the initial compounds and undesirable by-products. Both epimers of the indicated compounds have the same type of activity, e.  are antibacterial agents.  According to the invention, the new C-deoxy-α-amino-erythromycin A derivatives demonstrate in vitro activity against various gram-positive microorganisms, such as Staphylococcus aureus and Streptococcu aureus, and against some gram-negative microorganisms, for example, spherical or ellipsoid form. .  Their activity is readily monitored by in vitro testing against various microorganisms in cardiovascular stretching as a medium using the conventional two-time serial dilution technique.  Their in vitro activity makes them useful when applied externally in the form of ointments, creams, etc. P. , for the purpose of sterilization, for example, objects in the patient's room, and as industrial antimicrobial preparations, for example, when treating water, mucous surfaces to protect paints and wood.  In addition, many of the compounds and their acid addition salts are active against gram-positive and some gram-negative microorganisms, such as PasfeureBba muEfocida and Neisseria sicca in vivo, in oral and / or parenteral administration or administration to animals and humans.  Their in vivo activity is more limited in terms of the sensitivity of organisms, and it is determined using the usual method, which involves infecting mice of almost the same weight with a test organism and processing them accordingly with oral or subcutaneous administration of test compounds.  In practice, ten mice were given intraperitoneal vaccinations of suitable 226 diluted cultures containing from about one to ten (the lowest concentration of organisms.  Drive to YuO to the lethal outcome).  At the same time, control tests are performed in which mice are inoculated with more heavily diluted cultures, as a check for possible variations in. virulence of test organisms.  The test compound is administered half an hour after inoculation and repeated after jjZ and kB h.  The surviving mice are kept for k days after the last treatment and the number of surviving individuals is counted.  When used in vivo, these novel compounds can be administered orally or parenterally, for example, with subcutaneous and intraperitoneal injections in doses ranging from about 1 mg / kg to about 200 mg / kg of live weight per day.  The desired dosage is from about 5 mg / kg to about 100 mg / kg of live weight per day, and the preferred interval is a dose range of from about 5 mg / kg to about 50 mg / kg of live weight per day.  Solvents suitable for parenteral injections can be aqueous media such as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueous media such as vegetable oils of fatty origin (cottonseed oil, peanut oil, corn oil, sesame oil). oil), dimethyl sulfoxide, and other non-aqueous solvents that do not affect the therapeutic efficacy of the drugs and are not toxic in the volumes or proportions used (glycerin, propylene glycol, sorbitol) They may be formulated for rapid preparation of solutions immediately before use.  Such compositions may include liquid wrap.  for example, propylene glycol, diethyl carbonate, glycerin, sorbitol, etc. d. buffers, hyaluronidase, local anesthetics and inorganic salts in order to impart desirable pharmaceutical properties.  These compounds can also be combined with various pharmaceutically acceptable inert carriers, including solid diluents, aqueous media, non-toxic pj pharmaceutical solvents in the form of capsules, tablets, dry mixes, suspensions, solutions, elixirs and parenteral solutions or suspensions.  These compounds are used in various dosages, with the concentration level varying from 0.5 to about 90 by weight of the total composition.  Example.  6.9 semiketal 11-acetyl-V -deoxy- | -aminoerythromycin A.  To a stirred solution of 4.4 g of 6.9 half-ketal 11-acetyl 4 -deoxy-4-oxoerythromycin A and 4.38 g of ammonium acetate in 75 ml of methanol, 305 mg of 85% cyanoborohydride and sodium are added.  After stirring overnight at room temperature, the reaction mixture was poured into 300 ml of water, to which 250 ml of chloroform was then added, the pH of the aqueous layer was adjusted to 9. 8 and the chloroform layer is made up.  Then the aqueous layer was extracted again with chloroform, and the chloroform 1e extracts were combined, dried over sodium sulfate, and concentrated to a white foam.  The remaining foam is dissolved in a stirred mixture of 125 ml of water and 125 ml of fresh chloroform, the pH of the mixture is adjusted to 4, the e-chloroform is separated and drained, the pH of the aqueous layer is adjusted to 5, -6, 7 and 8, and after each pH was extracted with fresh chloroform.  The extracts from the aqueous phases of pH 6 and 7 are combined, washed with brine and dried over sodium sulfate.  After removal of the solvent, 1.72 g of the desired product is obtained in the form of a white foam.  The product is dissolved in a minimum amount of diethyl ether and then treated with hexane until cloudy.  The resulting crystalline 6,9-hemiacetal 11-acetyl-4-deoxy-V-amino-erythromycin A is filtered off and dried; yield 1.33 g, t. square  204-206.5 ° C.  NMRMP (S, SECEUS): 3:31 (2H) s, 3.28 (1H) s, 2.31 (6H) s, 2.11 (3H) s and 1.5 (3H) s. , PRI me R 2.  one.  Complex 11-12-carbonate ester of 6,9-polyketal 4 -deoxy-4 -aminoerythromycin A.  BUT.  To 189 g of 6,9-hemi-4-deoxy-4-oxoerythromycin A complex 11,12-carbonate ester in 1200 ml of 2 methanol at room temperature are added with stirring 193 g of ammonium acetate.  After 5 minutes, the resulting solution was cooled to about -5 ° C and treated with 13.4 g of 85% sodium cyanoborohydride in 200 ml of methanol over an addition period of 45 minutes.  The cooling bath was removed and the reaction mixture was stirred at room temperature overnight.  The reaction mixture is then evaporated in vacuo to a volume of 800 ml and 1800 ml of water and 900 ml of chloroform are added to the stirred mixture.  The pH is adjusted from 6.2 to 4. 3 with 6N hydrochloric acid and the chloroform layer is separated.  The chloroform is combined with 1 l of water and the pH is adjusted to 9.5. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure to obtain 17.4 g of a white foam.  The residue is dissolved in a mixture of 1 l of water and 500 ml of ethyl acetate and the pH is adjusted. The ethyl acetate layer is separated and the aqueous layer is adjusted in pH to 5.7 and 9.5, and 500 ml of fresh ethyl acetate is extracted after each adjustment.  The ethyl acetate extract at pH 9.5 is dried over sodium sulfate and concentrated in vacuo to dryness, resulting in a yield of 130 g.  120 g of the remaining foam is dissolved in a mixture of 1 liter of water and 1 liter of methylene chloride and the pH of the aqueous layer is adjusted 4J4, 4.9 and 9.4 sequentially, and after each adjustment of the pH, extraction is carried out with a fresh portion of 1 l of methylene chloride.  The methylene chloride extract at pH 9.4 is dried over sodium sulfate and concentrated under reduced pressure, whereby 32 g of product is obtained as a white foam.  After crystallization. From a 250 ml acetone-water mixture (1: 1 volume ratio), 28.5 g of crystalline epimers of the 11,9-carbonate 6,9-hemiketal 4 -deoxy-4-amino-erythromycin A complex are obtained.  100 MHz NMR (S, CDCE9): 5.20 (1H) m, 3.37 (1. 5H) s. , 3.34 (1.5H) s, 2.3b {6n) s, 1, 66 (ZN) s, and 41 (ZN) s.  AT.  Separation of epimers of 11,12-carbonate 6,9-hemiketal 4 -deoxy-4 -aminoerythromycin A.  For a high pressure liquid chromatography column filled with GF 254 silica gel impregnated with formamide and eluted with chloroform, 200 mg of 11.12 carbonate 6.9 poluketal C-deoxy-aminooerythromycin L are placed.  Under pressure of 16.9 kg / cm (2 0-lb / ka. inch) at a rate of 4.7 bcm / min, fractions of 10 ml each are collected.  Collect fractions from H to 21 and from 2 to 36.  The Itt fractions of 21 are combined and concentrated to about 50 ml.  Water (50 ml) is then added and the pH is adjusted.  The chloroform layer was separated, dried over sulphate by three and concentrated to give 106 mg of a white foam.  Rubbing with diethyl ether causes the foam to crystallize.  After stirring at room temperature for 1 h, the crystalline 11,12-carbonate ester 6, ukethale 4-dioxy-4-amino-erythromycin A is filtered and dried, yield 31.7 mg, t. square  19t-196 ° C.  NMR 100 MHz (S, SOS): B, 2 (1H) d 5.00 (lH) t, 3, (3N) s, 2,) s,. 1.66 {ЗН) с and 1, (ЗН) с.  WITH.  8, g of the epimeric mixture of the 6,1-semi-ketal V-deoxy-C-amino-erythromycin A 11,1-carbonate ester from step A of Example 2 is dissolved in 50 ml of diethyl ether.  The products are made to crystallize, scraped with a glass rod.  After 20 minutes of stirring, the crystalline product is filtered off and dried, yielding 1.91 substances, t. square  198.5-200 ° C.  NMR 100 MHz (S,): 3.2b (3N) s, 2.30 (6H) s, 1, B1 (3N) si 1, M5 (3N) s.  The NMR data indicates that the crystalline product is a single epimer of the 11,12-carbonate ester of β-deoxy-D-amino-erythromycin A and is identical to the ketone obtained in Example 3 B.  AND.  1 g of the epimer of 11,12-carbonate 6,9 semi-ketal V-deoxy-C -aminoerythromycin A from example 2 C is dissolved in 20 ml of acetone and heated on a steam bath until a point is reached.  boil.  25 ml of water are added and the resulting solution is left under stirring at room temperature overnight. After 1 hour of stirring, the precipitate formed is filtered off and dried, whereby 581 mg of product are obtained with t. square  1 7-1t9 C.  NMR 100 MHz {5 ° C): 5. 12 (1H) d, 2 3.30 (ZN) s, 2.0 (6H) s, 1, b2 (ZN) s and 1, Zb (ZN) s.  This NMR data indicates that the product is a single epimer of 11,12-carbonate ester of 6,9-polyketal -deoxy-amino-erythromycin A.  PRI me R 3.  BUT.  To a suspension of 11.1 g of 11,12-carbonate 6,9-polyketal 2-acetyl-4-deoxy-α-oxoerythromycin A in 300 ml of isopropanol at room temperature, 10.7 g of ammonium acetate are added with stirring.  After 5 minutes, mg of cyanoborohydrite of sodium in 130 ml of isopropanol was added over 30 minutes. The resulting reaction mixture was allowed to stir at room temperature overnight.  The pale yellow solution was poured into 1100 ml of water, to which 00 ml of diethyl ether was then added.  The pH is adjusted to C, 5 and the ether layer is separated.  The aqueous layer was basified to pH 9.5 and extracted (ml) with chloroform.  The chloroform extracts are combined, dried over sodium sulfate, and concentrated to give 7.5 g of a yellow foam.  After recrystallization of the residue from diethyl ether, 1.69 is obtained. g which are left together with the stock solutions. .  The mother liquor is treated with 75 ml of water and the pH is adjusted to pH.  The ether layer was replaced with 75 ml of fresh ether and the pH was adjusted to 5 ,.  The ether is replaced with ethyl acetate and the pH is raised to 10.0.  The alkalinized aqueous layer is extracted.  (ZJs75 ml) with ethyl acetate and the first ethyl acetate extract. dried over sodium sulfate and concentrated to dryness.  The rest; foam (1.96 g) was added to a mixture of 75 ml of water and 50 ml of diethyl ether and the pH was adjusted to 5.05.  The ether is separated and the pH of the aqueous layer is adjusted in series to 5,.  6.0, 7.05 and 8.0, and after each adjustment of the pH, extraction is carried out with 50 ml of fresh diethyl ether. .  Finally, the pH is adjusted to 9.7 and the on-board layer is extracted with 50 ml of ethyl acetate.  The ethereal extract obtained at aH 6.0 is combined with 75 ml of water and the pH is adjusted to 9.7 °. The ether layer is made, dried and concentrated in vacuo to give 6Q mg of white foam.  11 100 MHz NMR (S, eOC (i): 5.20 (lH) f, 3. f3 (2H) s, 3.0 {1H) s, 2.38 (6H) s, 2.16 (ZN) s, L70 (ZN) e, and 1.5 (ZN).   According to the NMR data obtained, the product is a mixture of epimers 11, 12-cargonate 6.9 hemiketal 2 -acetyl-4 -deoxy-amino-erythromycin A.  1.9 g of the substance obtained is dissolved in a mixture of 75 ml of water and 75 ml of diethyl ether and the pH is adjusted to 4.7.  Ether Separate The aqueous layer is extracted with a press of ether (75 ml) at pH and ethyl acetate (2x75 ml) at pH 9 (7.  The combined ethyl acetate extracts are dried over sodium sulfate and concentrated under reduced pressure to give 1.26 g of a white foam.  After crystallization of the residue, til mg of product is obtained, t. ll  193-19bs (with decomposition).  The mother liquor is concentrated to dryness, and the residue is dissolved in hot ethyl acetate.  The solution is left to stand overnight at room temperature.  The crystalline solid, which precipitates, is filtered off and dried, and 182 mg of additional product are obtained, t: pl.  19S-202 ° C (with decomposition).  NMR 100 MHz (S, CDCE5): 5.10 (1H) t, 3.3 (2H) s, 3.30 (1H) s,. 2.30 (6H) s, 2.08 (GH) s, 1, b2 (GH) s and l, «} 8 (3H) c.  These NMR data indicate that the product is a mixture of epimers of 11,12 carbonate 2-acetyl-β-deoxy-i-amino-erythromycin A.  AT.  Solution lOO ml 11, 12-carbona b. EPO-luketal 2-acetyl-V-deo C-4 -aminoerithromycin A in 20 ml of methanol is stirred at room temperature overnight.  The reaction solution is poured into 100 m of water, after which 50 ml of ethyl acetate are added.  The pH is adjusted and the organic phase is separated.  The extraction is repeated using 50 ml of fresh ethyl acetate.  The combined ethyl acetate extracts were dried with sodium sulfate and concentrated to give 392 mg of bepena.  Rubbing with diethyl ether and scraping with a glass rod causes crystallization.  After drying at room temperature for 30 minutes, the formed crystalline substance is filtered and dried, to obtain 123 mg of be 2.  12, and the mother liquor is retained.  The product appeared to be identical in its NMR spectrum to the material obtained in Example 2C.  NMR 100 MHz (3, SOSEgz): 3.2b (3N) s, 2.32 (6H) s, 1, b1 (3N) si 1, (3H) c.  The NMR data indicates that the crystalline product is a single epimer of 1 1, 12-carbonate k -deoxy-amino aminothromycin A.  The mother liquor is concentrated in vacuo, whereby mg of white foam is obtained.  The product obtained is identical to the product obtained in Example 2A. The NMR data indicates that the Product is a mixture of epimers 11 ,, 12-carbonate 6,9-hemiketal 4 -deoxy-} amino-erythromycin A and that it is identical to the product obtained in example 2a.  P rime p k.  k -deoxy-aminoerythromycin A.  20 g (α-deoxy-β-oxoerythromycin A, g of ammonium acetate and 10 g of 10% palladium on carbon in 200 ml of methanol are shaken at ambient temperature under a hydrogen atmosphere at an initial pressure of 3.5 kg / cm (50 psi . inch) overnight.  The spent catalyst is filtered off and the filtrate is concentrated to dryness in vacuo.  The residue is distributed between a water-chloroform mixture at pH 5.5.  The aqueous layer was separated, the pH was adjusted to 9. 6 and chloroform was added.  The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to dryness.  The residual white foam (19 g) is triturated with 150 ml of diethyl ether at room temperature for 30 minutes.  The obtained solid is filtered off and dried, resulting in a gain of 9.5 g  one epimer 4 -deoxy-α-amino erythromycin A, t. square  YoY7 S.  The diethyl filtrate is concentrated.  dry, resulting in a yield of 6.89 g of the product, which consists of the second epimer C-deoxy-it-amino-erythromycin A and a certain amount of impurities.  PRI me R 5- -deoxy - + - amino erythromycin A.  2 g of V-deoxy-α-oxoerythromycin A, 3.1 g of ammonium acetate and 2.0 g of Rene nickel in 50 ml of methanol are shaken at room temperature under a hydrogen atmosphere at an initial pressure of 3.5 kg / cm (5 psi).  inches over night.  Then, an additional 3.16 g of ammonium acetate and 2.0 g of Rene nickel are added, and the hydrogenation continues for another 5 hours.  The solid is filtered off and 5) the filtrate is concentrated in vacuo to dryness.  The residue is added to the water-chloroform mixture with stirring and the pH is adjusted, after which fresh chloroform is added.  The chlorophene extract is separated, dried over sodium sulfate, and concentrated under reduced pressure, yielding 1.02 g of 4-deoxy - + - amnoyrythromycin A as a yellow foam. The predominant isomer is in a position opposite to the false one. / is introduced for the compound of Example 4.  The invention The method for producing 4-deoxy-α-amino erythromycin A derivatives of the general formula 1J (CH5) 2 "v g RsO O BjO-t" M.  where R and RI are each hydrogen or acetyl; R ij g hydrogen or Rq together - O; R is OH, and Rj means a bond to a carbon atom to which R is attached, or R4 is oxygen, and Rg is hydrogen, provided 221 that if hydrogen, then R5 is 8 ° hydrogen, or their salts, which differ by the fact that the compound of the general formula IftCHjb) -LOL B O 4 0 "// xOX" X where R5 has the indicated values, is reacted with ammonium acetate in the environment of tetanol or isopropanol, provided that when R- (- acetyl) isopropanol is used , at room temperature and reduced with an alkali metal cyanoborohydride or catalytically using palladium on carbon or Rene's nickel as a catalyst, followed, if necessary, when R (and R, together - O, a guide (in water and diethyl ether) and isolating the desired product in a free state or as a salt.  Priority signs: 0.02. 77 reduction is carried out with alkaline etalla cyanoborohydride.  01 12. 77, catalytic reduction is performed.  Sources of information taken into account during the examination 1.  Borch Bernstein.  Durst.  Cyanohydridoborate Anion as a selective reducing agent.  -Jt, m.  Chem.  Soc.  2897, 1971.
    类似技术:
    公开号 | 公开日 | 专利标题
    RU2192427C2|2002-11-10|Erythromycin derivatives showing antibacterial activity, method of their synthesis |, pharmaceutical composition and method of regulation of bacterial infection in mammal
    DK172636B1|1999-03-22|6-o-methylerythromycin a derivative
    DK158357B|1990-05-07|9-DEOXO-9A- | -9A-AZA-9A-HOMOERYTHROMYCIN A AND PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS
    SU886749A3|1981-11-30|Method of preparing 4&#34;-desoxy-4-amino-erythromycin a
    SU927122A3|1982-05-07|Process for producing derivatives of 4&#39;&#39;-deoxy-4&#39;&#39;-aminoerythromycin or their salts
    CS235036B2|1985-04-16|Method of 4&#34;-epierythromycine a production
    DE2804508C2|1982-06-24|Epimeric 4 &#34;-substituted amino derivatives of oleandomycin and their use as antibacterial agents
    DE2953969C2|1987-09-03|
    DK159853B|1990-12-17|METHOD OF ANALOGUE FOR PREPARING 9-DIHYDRO-11,12-O-ISOPROPYLIDENE ERYTHROMYCIN A OR -4AE-EPI-ERYTHROMYCIN A OR 2&#39;-O-ACYLATES THEREOF OR PHARMACEUTICAL ACCEPTABLE ACCEPTABLE ACCEPTABLE
    DK153795B|1988-09-05|METHOD OF ANALOGUE FOR THE PREPARATION OF 20-DEOXO-TYLOSIN MACROLIDE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS
    SU1020004A3|1983-05-23|Process for preparing derivatives of oleandomycin
    WO1989004167A1|1989-05-18|Antibacterial 9-deoxo-9a-allyl and propargyl-9a-aza-9a-homoerythromycin a derivatives
    DK172766B1|1999-07-05|Derivatives of the neutral macrolide designated CP-63693 and pharmaceutical compositions containing these
    EP0114486B1|1989-10-18|Alkylation of oleandomycin
    KR0132671B1|1998-04-14|9-r-azacyclic erythromycin antibiotics
    DE60115851T2|2006-08-10|ANTI-INFECTANTS WHICH ARE USEFUL AGAINST MULTIPLE DRUGS RESISTANT BACTERIAL STRAINS
    DE69626040T2|2004-01-22|3-DEOXY-3-DESCLADINOSE DERIVATIVES OF ERYTHROMYCIN A AND B
    DE3628486A1|1988-02-25|Piperidine derivatives
    KR820001218B1|1982-07-02|Process for preparing semi-synthetic 4-amino-oleandomycin derivatives
    AT371481B|1983-06-27|METHOD FOR PRODUCING NEW 4 &#39;&#39; DEOXY-4 &#39;&#39; ACYLAMIDO DERIVATIVES OF ERYTHROMYCIN
    AT361629B|1981-03-25|METHOD FOR PRODUCING NEW 4 &#39;&#39; --ERYTHROMYCIN-A DERIVATIVES
    KR820000742B1|1982-05-03|Process for preparing 4&#34;-deoxy-4&#34;-arylglyoxamido-and aroylhioformamido derivatives of oleando mycin
    DE2900119A1|1979-07-05|4 &#39;&#39; - DESOXY-4 &#39;&#39; - CARBAMATE AND DITHIOCARBAMATE DERIVATIVES OF OLEANDOMYCIN AND ITS ESTERS, METHODS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING SUCH DERIVATIVES
    DK153761B|1988-08-29|Analogy process for preparing 4&#34;-deoxo-4&#34;-acylamido derivatives of erythromycylamine, and erythromycylimine derivatives for use as starting material in this process
    同族专利:
    公开号 | 公开日
    NO146472C|1982-10-06|
    NO811913L|1978-08-07|
    PT67568B|1979-06-18|
    FR2385735A1|1978-10-27|
    GR68691B|1982-02-01|
    RO81622A|1983-04-29|
    AR222147A1|1981-04-30|
    AU501298B1|1979-06-14|
    CS221801B2|1983-04-29|
    PH16675A|1983-12-13|
    FI780354A|1978-08-05|
    YU26583A|1984-02-29|
    YU227983A|1984-04-30|
    DE2804507C2|1982-11-04|
    YU7378A|1983-04-30|
    RO77345A|1981-08-17|
    PL204428A1|1979-06-04|
    NO150484C|1984-10-24|
    HU182559B|1984-02-28|
    IE780239L|1978-08-04|
    PT67568A|1978-02-01|
    CA1106367A|1981-08-04|
    BG32718A3|1982-09-15|
    SE457086B|1988-11-28|
    YU40799B|1986-06-30|
    YU40798B|1986-06-30|
    PL116228B1|1981-05-30|
    SE8300870L|1983-02-16|
    BG33159A3|1982-12-15|
    SE7800270L|1978-08-05|
    YU40913B|1986-08-31|
    NO150484B|1984-07-16|
    IT7820005D0|1978-02-03|
    FR2385735B1|1980-10-24|
    IL61997D0|1981-02-27|
    PH14421A|1981-07-10|
    NL176174C|1985-03-01|
    DK148036B|1985-02-11|
    SE8300870D0|1983-02-16|
    NL176174B|1984-10-01|
    DK51878A|1978-08-05|
    ES466057A1|1978-10-01|
    NL7801262A|1978-08-08|
    IL53968D0|1978-04-30|
    DE2804507A1|1978-08-10|
    CH628906A5|1982-03-31|
    SE445223B|1986-06-09|
    IE46661B1|1983-08-24|
    ES472429A1|1979-04-01|
    GB1585316A|1981-02-25|
    JPS5827798B2|1983-06-11|
    IT1094209B|1985-07-26|
    NO146472B|1982-06-28|
    RO81622B|1983-04-30|
    FR2379550B1|1980-07-04|
    DD140048A5|1980-02-06|
    GB1585315A|1981-02-25|
    RO79687A7|1982-08-17|
    NZ186385A|1980-10-08|
    DK148036C|1985-07-15|
    LU79004A1|1979-09-06|
    RO79686A7|1982-08-17|
    FR2379550A1|1978-09-01|
    NO780389L|1978-08-07|
    JPS53101337A|1978-09-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3836519A|1973-05-04|1974-09-17|Abbott Lab|Sulfonyl derivatives of erythromycin|
    US3884903A|1973-06-21|1975-05-20|Abbott Lab|4{41 -Deoxy-4{41 -oxoerythromycin B derivatives|US4133950A|1978-01-03|1979-01-09|Pfizer Inc.|4"-Deoxy-4"-carbamate and dithiocarbamate derivatives of oleandomycin and its esters|
    US4124755A|1978-01-03|1978-11-07|Pfizer Inc.|11-Alkanoyl-4"-deoxy-4"-isonitrilo-oleandomycin derivatives|
    US4382085A|1982-03-01|1983-05-03|Pfizer Inc.|4"-Epi erythromycin A and derivatives thereof as useful antibacterial agents|
    US4518590A|1984-04-13|1985-05-21|Pfizer Inc.|9α-Aza-9α-homoerythromycin compounds, pharmaceutical compositions and therapeutic method|
    US6407074B1|1997-06-11|2002-06-18|Pfizer Inc|C-4″-substituted macrolide derivatives|
    HN1998000074A|1997-06-11|1999-01-08|Pfizer Prod Inc|DERIVATIVES FROM MACROLIDES C-4 SUBSTITUTED|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US76548077A| true| 1977-02-04|1977-02-04|
    US05/856,479|US4150220A|1977-02-04|1977-12-01|Semi-synthetic 4"-erythromycin A derivatives|
    [返回顶部]