• 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:
    A series of 4''-deoxy-4''-amino-erythromycin A antibacterial agents and their preparation from erythromycin A via 4''-deoxy-4''-oxo-erythromycin A intermediates.
    公开号:SU886749A3
    申请号:SU792776608
    申请日:1979-06-18
    公开日:1981-11-30
    发明作者:Кристиан Сиаволино Фрэнк
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    with dimethyl sulfoxide or trifluoroacetic anhydride, followed by contacting the reaction mixture with triethylamine, or with N-chlorosuccinimide and dimethyl sulphide, followed by contacting the reaction mixture with triethylamine. The product is isolated by filtering off the spent catalyst and removing the solvent in vacuo. The residue is successively treated with water and the main product is separated from the minor by extraction from water, changing the pH value. Catalyst (Rene nickel can be used in varying amounts depending on the speed of the reaction, e.g. 10-200 wt.% Based on the weight of the starting compound I I .. The reaction rate is also influenced by the pressure of hydrogen gas in the hydrogenation reactor. To ensure the usual reaction time preferably a pressure of 7.03 kg / s It is also more convenient to carry out the reduction at ambient temperature.The reaction time depends on many factors: temperature, pressure, late flow, and characteristic temperatures reagents under the above conditions, the reaction is completed within 12-2 hours. Hydrolysis of the 2-acetyl group from the corresponding 2-acetyl-4-deoxy-4-amino-erythromycin A derivative can be carried out by leaving a solution of Compounds in methanol are allowed to stand at room temperature overnight. When isolating the desired 4-deoxy-4-amino-erythromycin A from minor, by-products or starting compounds, the basic nature of the final product must be taken into account. The aqueous solution of the product is extracted in the range of gradually increasing pH values, so neutral or minor products are extracted at lower pH values, and the target product is at pH values greater than 5. The extraction solvent (chloroform) is washed with salt and water and dried over sodium sulfate. After removal of the solvent, the desired product is obtained. If necessary, additional purification is carried out using silica gel column chromatography in accordance with known procedures. The amines of the formula I are usually separated by selective crystallization from diethyl ether. The stereochemistry of starting materials resulting in an antibacterial agent is the same as that of natural materials. Oxidation of 4-hydroxyl groups by ketones and the subsequent conversion of the latter to 4-amines allows for a stereochemical change of the 4-substituent as compared with the natural product. When the compound of formula II is converted into amines by the method described above, the formation of two epimeric amines is possible. It turns out that both epimeric amines are present in the final product in different ratios, which depend on the chosen synthesis method. If the isolated product contains predominantly one of the epimers, then this epimer can be purified by repeated recrystallization from a suitable solvent to a constant melting point. Although this mixture of epimers can be separated using known methods, it is more advantageous to use it in the form in which it was isolated from the reaction. However, it is often preferable to purify the epimer mixture with at least one recrystallization from a suitable solvent, and then using high pressure column chromatography, distribution between solvents, or rubbing in an appropriate solvent. This purification, if it is not necessary to separate the epimers, results in the removal of the starting compounds and undesirable by-products. Both epimers of this compound have the same type of activity, i.e. into- activity as antibacterial agents, etc. "I Ki II Proposed h -deoxy-h -amino-erythromycin A exhibits in vitro activity against a variety of Gram-positive microorganisms, e.g. Storphylococcus anreus and Streptococcus anreus, and against certain Gram-negative microorganisms, such as spherical or ellipsoidal (cocci). Its activity is confirmed by in vitro tests against various microorganisms in cardio-brain stretching as a medium using the conventional two-time serial dilution technique. In vitro activity makes it useful when applied externally as ointments, creams, etc., when sterilizing, for example, objects in the patient's room, and as industrial antimicrobial agents, for example, when treating water, mucous surfaces, to protect paints and g When using in vitro, for example, for external use, it is desirable to combine the selected product with a pharmaceutically acceptable carrier such as vegetable or mineral oil or emollient creams. It can also be dissolved or dispersed in liquid carriers or solvents, such as water, alcohol, glycol or mixtures thereof, or in other pharmaceutically acceptable inert media, i.e. those that do not adversely affect the active ingredients. To do this, use the concentration of active ingredients in the range from 0.01 to about 10 weight. counting on the whole composition In addition, the proposed compound is active against gram-positive and some gram-negative microorganisms, for example, Pasteurellu multocielo and Neisseriosicca in vivo, when administered orally and / or parenterally, or when animals are administered to humans in humans. Their in vivo activity is more limited in terms of the sensitivity of organisms, and it is determined using a standard technique that involves infecting mice with the same weight with a test organism and appropriately treating them with oral or subcutaneous administration of test compounds. For example, ten mice are given intraperitoneal inoculations of suitable diluted cultures containing from about one to ten LD (the lowest concentration of organisms, resulting in 100 deaths). At the same time, control tests are performed in which mice are inoculated with more highly diluted cultures as a check for possible variations in the virulence of test organisms. The test compound is introduced half an hour after the inoculation and after k, 2k and k8 hours are rotated. The surviving mice are kept for another 9 days after the last treatment and the number of surviving individuals is counted. When used in vivo, the proposed compound can be administered orally or parenterally, for example, with subcutaneous and intramuscular injections in doses of from about 1 to about 200 mg / kg of live weight per day, preferably from about 5 to OKOJ10 100 mg / kg, but preferably from about 5 to about 50 mg / kg of live weight per day. Solvents suitable for parenteral injection are aqueous media such as water, isotonic saline, isotonic dextrose, Ringer's solution, or non-aqueous media such as vegetable fatty oils (cotton, peanut, corn sesame), dimethyl sulfoxide and other non-aqueous solvents that do not affect the therapeutic efficacy of the preparations and do not have a toxic effect in the volumes or proportions used (glycerol, propylene glycol, sorbitol. In addition, with their Compositions can be prepared for improvised preparation of solutions before use.Such solvents may include liquid diluents, for example propylene glycol, diethyl carbonate, glycerol, sorbitol, etc., buffering agents, hyaluronidase, local anesthetics and inorganic salts in order to obtain the desired pharmaceutical properties. The proposed compound can also be combined with various pharmaceutically acceptable inert carriers, including solid diluents, aqueous media, no ksichnye organic solvents in the form of capsules, tablets, dry mixes, suspensions, solutions, elixirs and parenteral solutions or suspensions. It is used in various dosages, with concentrations varying from 0.05 to about 90 by weight of the total composition, Example 1. A. 2-Acetyl-V-deoxy-4 -amino-erythromycin A. A mixture of H, 0 g 2 -acetyl-V-deoxy-, hydroxy-erythromycin A o-acetyloxy and 60 g washed with Renopen isopropanol, nickel René in COO ml isopropanol varnished in a hydrogen atmosphere and at an initial pressure of 1000 psig. doym (approximately 70, overnight at room temperature
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining ^ '' - deoxy- ^ 1 0
    R e ’and re ning formula I I by the fact that the compound
    Order 10607/89 where Ac is acetyl, is subjected to catalytic reduction in isopropanol in the presence of Raney nickel, followed by hydrolysis in the presence of methanol.
    类似技术:
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    引用文献:
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    US3884903A|1973-06-21|1975-05-20|Abbott Lab|4{41 -Deoxy-4{41 -oxoerythromycin B derivatives|
    US3842069A|1973-06-21|1974-10-15|Abbott Lab|4"-deoxy-4"-oxoerythromycin b derivatives|US4283527A|1980-04-01|1981-08-11|Pfizer Inc.|Erythromycylamine 11,12-carbonate and derivatives thereof|
    US4363803A|1982-03-01|1982-12-14|Pfizer Inc.|3",4"-Oxyallylene erythromycin and oleandomycin, composition and method of use|
    US4382085A|1982-03-01|1983-05-03|Pfizer Inc.|4"-Epi erythromycin A and derivatives thereof as useful antibacterial agents|
    US4413119A|1982-03-01|1983-11-01|Pfizer Inc.|Semi-synthetic macrolides|
    US4382086A|1982-03-01|1983-05-03|Pfizer Inc.|9-Dihydro-11,12-ketal derivatives of erythromycin A and epi-erythromycin A|
    DK149776C|1984-01-06|1987-04-21|Orion Yhtymae Oy|ANTIBIOTIC EFFECT OF ERYTHROMYCIN COMPOUND AND PREPARATION CONTAINING THE COMPOUND|
    US4518590A|1984-04-13|1985-05-21|Pfizer Inc.|9α-Aza-9α-homoerythromycin compounds, pharmaceutical compositions and therapeutic method|
    US4512982A|1984-04-13|1985-04-23|Pfizer Inc.|9α-Aza-9α-homoerythromycin compounds, pharmaceutical composition and therapeutic method|
    US4847242A|1985-03-12|1989-07-11|Beecham Group P.L.C.|11-ether derivatives of erythromycins|
    US5175150A|1985-08-31|1992-12-29|Kitasato, Kenkyusho|Erythromycin derivative|
    US4672056A|1985-11-12|1987-06-09|Abbott Laboratories|Erythromycin A derivatives and method of use|
    FR2639945B1|1988-12-07|1994-03-25|Oreal|LIPOPHILIC D-DESOSAMINE ETHERS AND / OR ESTERS, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ANTIBACTERIAL AND ANTIFUNGAL AGENTS|
    US5808017A|1996-04-10|1998-09-15|Abbott Laboratories|Process for preparing erythromycin A oxime|
    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|
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