• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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    • 专利摘要:

    公开号:SU876060A3
    申请号:SU792853125
    申请日:1979-12-11
    公开日:1981-10-23
    发明作者:Шеттле Эрнст；Вебер Альфред；Кеннеке Марио；Даль Хельмут；Капп Йоахим-Фридрих；Вендт Ханс；Аннен Клаус；Лаурент Хенри；Вихерт Рудольф
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING CORTICOIDS
    1, the invention relates to a new method for producing corticoids of the formula
    OCHgOKf
    where Y and Z together are a carbon-carbon bond; R is interrupted by atoms of a Ciel group; C -). A 0-alkyl group; R- - agom. hydrogen, fluorine atom, chlorine atom or C-acyloxy group.
    It is known that corticosteroid regional anti-inflammatory effect Sh
    The known reaction is deg (C1H halogenation using lithium chloride 2J,
    The purpose of the invention is to expand the means of influencing a living organism.
    This goal is achieved by the method of obtaining new corticoids of general form / w. 1, where Y, Z, R n R / j. The above values are based on a known dehydrohalogenation reaction using lithium chloride and the fact that the 9-halogen-steroid of the general formula G, where R and RjL have the above value, is a chlorine atom or a bromine atom and Y is a hydrogen atom, cleaves ng in the presence of lithium chloride and allocate the desired product.
    15
    Etc. and meper 1. a) 1.8 g of 21-acetone, szhsi-17s1 .- (1,3,6-trioxaheptyl) -1,4, 9 pregnatriene-3,20-dione is dissolved in 18 ml of dnoxane and mixed with 1.6 g of N-bromosuccinimide. After adding
    20 in several portions of 8.5 ml of 10% aqueous perchloric acid, the reaction mixture is stirred for a further 30 min at a triple temperature and poured into a saturated solution.
    25% salt and sodium bisulfite in ice water. 2.3 g of crude 21 acyl Jsi-9 "1-bromo-110-hydroxy-17e1- (1.3, b-trisixaheptyl) -1,4-pregnadien-3, 20 dioa are obtained.
    权利要求:
    Claims (2)
    [1]
    30 c) 2.0 g of the above crude product is dissolved in 20 ml of hexamethyltriamidephosphoric acid and stirred with 2.4 g of lithium chloride for a half-hour — at. The target product is planted in a saturated solution of sodium chloride in ice water and purified 350 mg column chromatography; silica gel eluting with methylene chloride-acetose (85-15). yield 570 mg of 21-acetoxy-11 (g1-hydroxy-17c (, - (1,3, 6-trioxageptyl 1,4,8-pregnatrien-3, 20-dione with melting point. Example 2. a) Analogously to example 1a 1, O21-ftor-177-L-metocimetoxy-1, 4,9-pregnathriene-3, 20-dione is treated with 900 mg of N-bromo-succinimine and 5 ml of 10% aqueous perchloric acid. 1.1 g of 9 oU are isolated. -6pOM-21fluoro-11r -oxy-17s1-methoxymethoxy-1, 4 pregnadien-3,2b-dione. C) 1.1 g of crude 9s-bromo-21-fluoro 11 L-oxy-17s1-methoxymethoxy-1, 4- preg nadien-3,20-dione is treated with 1.4 g of lithium chloride as in Example 1c. 21-fluoro-11 (L-hydroxy-17 1 / methoxy-1, 4.8-pregnatrien-3, 20-dione is obtained with 490 mg. T melting point Example 3. a) 3.3 g of 21-chloro 17-oxy-1, 4.9 pregnatriene-3,20-dio is reacted with formaldehyadmethylacetone. 2.4 g of 21-chloro are isolated. 17 zi-methoxymethoxy-1,4,9pregnatrien-3, 20-dione. C) 1.4 g of 21-chloro-17o1-methoxymetho sy-1,4,9-pregnatrien-3/20-dione are treated with N-bromosuccinimide in the conditions of example 1a and 1.7 g of 9a / bromo-21-chloro-11- |% -oxy-17o1-labels of simethoxy-1,4-pregnatriene-3, 20-dione as a crude product. c) CONDITIONS of example 1 to 1.7 g of 9-bromo-21-chloro-11 | L-hydroxy-1751-methox-methoxy-1,4-pregnadien-3,20-dione treatment of 2.1 g of lithium chloride. The crude product is purified 300 g silica gel column chromatography eluting with methylene chloride-acetone (Acetone concentration 0-8%). Yield 530 mg 21-chloro-11 (L-hydroxy-1711.-methoxy methoxy-1,4, 8-pregnatriene-3,20-dione Melting point 166 C. Corticoid oidea of formula I, when used locally, have a pronounced anti-inflammatory effect as well as good The difference was between the desired local effect and the undesired systemic side effect. The local effect was determined using Tecta on vasoconstriction in the following way. The test was performed with healthy subjects 8 each of both sexes, which in the last two weeks did not receive local corticosteroid treatment. . Vascular dilution was evaluated visually after 4 and 8 hours by checking for the following degrees of action: 1 absolute blanching, 2 slight residual erythema, 3 moderate erythema, erythema intensity in the middle area of the naked, untreated and intact skin, 4 erythema with small clarifications , 5 no blanching or enhancement of erythema. In each series of experiments, diflucortolone-21-valerate (-6ot, 9 1-difluoro-11p-oxy-16o1.-Methyl-21-valeryloxy-1, 4 -pregnadien-3, 20-dione-DFV). Find the difference & in the moderate degrees of action, the DFVs determined in separate series of studies and test substances. Positive deviations indicate a favorable evaluation of the test substance in comparison with the DFV, negative deviations indicate an unfavorable evaluation. The table shows the results of tests that were obtained during the processing of the test 1 F 1x with preparations containing OD of the active substance. The systemic effect of the compounds was determined using the test for additional edema as follows. Rats weighing from 130 to 150 g were injected with 0.1 ml of a 0.5% suspension of Husobacterlum bytyricum in the right hind paw to obtain an inflammatory focus. Before injection, rat paw volume was measured. 24 hours after the injection, the volume of the paw was measured again to determine the size of the edema. Then, various amounts of the test substance, dissolved in a mixture of 29% benzyl benzoate and 71% of castor oil, were injected orally or subcutaneously into rats. After the next 24 hours, the paw volume was again determined. Controls were treated in the same way, but they injected a mixture of benzyl benzoate with castor oil free of the test substance. From the paw volume obtained, the amount of BeinecTva being tested was found necessary to achieve a 50% nbgO decrease in the volume of the experimentally obtained paw edema. The table shows the results of the tests, and the substances were compared with similar in structure, previously known corticoids contained in x-dimensional preparations, in particular, with II (i, ,, 21 trioxy-1,4-pregngen-3, 20-dione (predisolone Formula of the invention The method of obtaining corticoids of the general formula, OCHiOIif Z together - carbon-carbon bond} R is interrupted by oxygen atoms of the C.d-alkyl group; R is a hydrogen atom, a fluorine atom, a chlorine atom or a C-acyloxy group, which differs from 9-halo-halide ..,., .. of general formula t, where .R and Rj have 20 5 Q The above value, g is a chlorine atom or a bromine atom and Y is a hydrogen atom, H2 is cleaved in the presence of lithium chlorite and the target product is added. Priority is given by: 25.01.78R - interrupted by an oxygen atom C.-Alkyl group 12.19.79R - interrupted by an oxygen atom St-C-alkyl group Sources of information taken into account during the examination 1. Mashkovsky MD Drugs. Medicine, M., 1972, T. 2, 94-108. V .. ".1рЧ"
    [2]
    2. Fizur L. and Fizler M. Reagents for organic synthesis. World, 1970, t. 2, p. 204.
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    同族专利:
    公开号 | 公开日
    AU4365779A|1979-08-02|
    IE47729B1|1984-05-30|
    CS207753B2|1981-08-31|
    RO81116B|1983-05-30|
    BG33736A3|1983-04-15|
    DD150749A5|1981-09-16|
    GB2014150A|1979-08-22|
    SU890979A3|1981-12-15|
    GB2014150B|1982-11-24|
    RO81116A|1983-06-01|
    US4207316A|1980-06-10|
    EP0003341B1|1984-06-27|
    SU876059A3|1981-10-23|
    DD141523A5|1980-05-07|
    IE790134L|1979-07-25|
    DE2967070D1|1984-08-02|
    BG33737A3|1983-04-15|
    SU1103797A3|1984-07-15|
    DK28779A|1979-07-26|
    FI66023B|1984-04-30|
    PH18164A|1985-04-09|
    SU927123A3|1982-05-07|
    FR2422689A1|1979-11-09|
    NZ189460A|1981-11-19|
    FI790240A|1979-07-26|
    IL56494D0|1979-03-12|
    ES477162A1|1979-07-01|
    IL56494A|1983-02-23|
    RO76163A|1981-08-17|
    EG14273A|1984-06-30|
    PT69126A|1979-02-01|
    EP0003341A2|1979-08-08|
    NO154583C|1986-11-05|
    EP0003341A3|1979-08-22|
    NO790229L|1979-07-26|
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    SU880253A3|1981-11-07|
    NO154583B|1986-07-28|
    FI66023C|1984-08-10|
    引用文献:
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    BR6682287D0|1965-08-30|1973-12-04|Merck & Co Inc|PROCESS TO PREPARE 17-ALCOXY-PROGESTERONE|
    NL6605514A|1966-04-25|1967-10-26|
    US3453297A|1968-07-24|1969-07-01|Merck & Co Inc|17alpha-lower alkoxy-pregna-4,6-diene-3,20-dione steroids|DE2952003A1|1979-12-21|1981-07-02|Schering Ag Berlin Und Bergkamen, 1000 Berlin|NEW KORTIKOID-17-THIOACETALE, THEIR PRODUCTION AND USE|
    DE3038855A1|1980-10-10|1982-05-27|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW D-HOMO CORTICOIDS, THEIR PRODUCTION AND USE|
    PL178307B1|1993-01-08|2000-04-28|Astra Ab|Novel ileum and colon specific steroid derivatives|
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    US8729108B2|2008-06-17|2014-05-20|Christopher J Dannaker|Waterborne topical compositions for the delivery of active ingredients such as azelaic acid|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19782803661|DE2803661A1|1978-01-25|1978-01-25|Pregnane derivs. microbiological 11-beta-hydroxylation - using starting materials 17 alpha-substd. by an acetal group|
    DE19782855465|DE2855465A1|1978-12-19|1978-12-19|17-Alpha-hydroxy-corticoid derivs. substd. by acetal or thio:acetal - antiinflammatories with greater topical activity than unsubstituted cpds.|
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