• 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:
    Compounds of the formula I <IMAGE> (I), wherein R2 is hydrogen or an organic acid residue; R3 is methyl or ethyl; R4 is hydrogen or methyl; <IMAGE>+TR <IMAGE> wherein R1 is lower alkyl; and <IMAGE> and when R2 is a dibasic acid residue, the physiologically acceptable salts thereof with the free acid moiety of the R2 group, are physiologically active, e.g., are diuretics having aldosterone antagonist effects.
    公开号:SU786905A3
    申请号:SU782613350
    申请日:1978-05-15
    公开日:1980-12-07
    发明作者:Вишерт Рудольф；Биттлер Дитер；Керб Ульрих；Казаль-Штенцель Йорг；Лозерт Вольфганг
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of 17 b-hydroxy-4-androsten-3-ones of the general formula ON not described in the literature. .ieHjU - “% rf PGG n. where hydrogen or an aliphatic acid residue, ime11BP1 to 4 carbon atoms; -D-C- are a group or 5 "with pharmacological activity. The use of the known methylation method of unsaturated ketones with dimethylsulfoxonium methyl in dimethyl sulfoxide 1 allows the preparation of new pharmacologically active steroids. The purpose of the invention is to obtain new pharmacologically active P-oxy-4-androsten-3-ones. A method is proposed for the preparation of 17 | b-hydroxy-4-androsten-3-ones of Formula I, which consists in the fact that 3-keto-4, 6-androst spirolactone of the general formula P / I f where -0-C- has the above values, is treated with lithium aluminum hydride in an aprotic solvent, the 3-keto group is previously protected, methylated with dimethylsulfoxoniummethyl in dimethylsulfoxide and, if necessary, the resulting product is sterilized in the presence of an esterification catalyst, after which the desired products are added. The carbonyl group is preferably protected by ketalization with ethylaglycol in methylene chloride in the presence of three tetro-formate. The reduction with lithium aluminum hydride is preferably carried out in tetrahydrofuran or dioxane at a temperature not higher than room temperature.
    The methylenating agent is obtained from the trimethyl phosphonic acid and hydride sodium or sodium hydroxide. An acid anhydride or acid halide is used to esterify a hydroxyl group in the presence of a tertiary amine, such as pyridine, collidine, triethylamine, or a strong acid, such as p-toluenesulfonic acid.
    Compounds of the formula G have an aldosterone antagonist-type action mechanism.
    Example 1. 12.0 g of J-OKCO-4, 6,15-androstrieno-17 P -1-spiro-5-perhydrofuran-2-one from 60 ml. , methylene chloride is mixed with 36 ml of ethylene glycol, 24 ml of tr.ethyl ether tartaric acid and 120 mg of p-toluenesulfonic acid and stirred for 75 minutes at 0 ° C, diluted with agyr, washed with water, dried and evaporated to dryness in vacuo. 13.5 g of crude 3, 3-ethylenedioxy-4, 6.15-androstrieno-17p1-1 spiro-5-perhydro-Luran-2-one are obtained. 13.5 g of the obtained compound is dissolved in 650 ml of absolute tetrahydrofuran, cooled with an ice bath, mixed with 2.9 g of lithium aluminum hydride and further stirred for 30 minutes while cooling. Excess reagent is decomposed with water, the reaction solution is diluted with methylene chloride, washed with 2N sulfuric acid and water, dried and evaporated in vacuo. The residue is chromatographed on silica gel. 5.1 g of 17 hydroxy-17O1- (3-hydroxypropyl) -4,6,15-androstatrien-3-one are obtained. UV spectrum: 286 25200.
    Example 2. 2.1 g of trimethylsulloxonium iodide in 40 ml of dimethylsulfoxide are mixed with 390 t-ll of 55% oil suspension of sodium hydride for 1.5 hours at room temperature. 1.5 g of 17ft-OKCH-17o - (3-hydroxypropyl) -4,6,15-androstatrien-3-one is added to this solution under a nitrogen atmosphere and stirred for 24 hours at room temperature. After precipitating with ice, -, the precipitate is filtered, washed with water, dissolved in methylene chloride, dried and evaporated. The residue is purified by repeated preparative layer chromatography. 350 mg of 171 -oxy-17O1 .- (3-hydroxypropyl) -6 | b, 7p -methylene-4, 15-androstadien-3-one are obtained. UV spectrum: € 266 18,000.
    PRI me R. 3. 600 mg of 17b-hydroxy-17c1 .- (3-hydroxypropyl), 16o, methylene-4, 6-androstadiene-3-one in 6 ml of pyridine is boiled with 600 mg of succinic anhydride for 30 minutes. It is then diluted with ether, washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel. 580 mg of 17-oxy-17Og are obtained.
    - - (3-oxysuccinyloxypropyl) -15o (,, 16nL -methylene-4,6-androstadiene-З-she in the form of oil. UV spectrum: g vb 23500.
    250 mg of 17f-oxy-17o6- (3-oxysuccinyloxypropyl) -1 Sod., 1 bob-methylene-4, 6-α-androstadien-3-one is dissolved in 25 ml of absolute methanol and reacted with 0.1 n . a solution of potassium methylate in methanol to the equivalence point. The reaction solution is concentrated in vacuo to about 5 ml and precipitated in absolute ether. The precipitate is filtered off with suction, washed with absolute ether and dried. Get 210 mg 17 | -oxy-17O1- (3-oxycycinyl-oxyc-propyl) -15od, -methylene-4,6-androstadien-3-one as a calcium salt. UV spectrum: 285 25100.
    Example 4. 250 mg of 17 / -oxy-17c - (3-oxysuccinyloxypropyl) -I5d,
    0 16c, -methylene-4, 6-androstadiene-3-she is reacted, as described in Example 7, with O, 1N sodium methoxide solution in methanol. And treated. 185 mg of 17G -oxy5 -17oL- (3-hydroxysuccinyloxypropyl) -15of, 16o -methylene-4, 6-androstadiene-3-one are obtained in the form of sodium salt. UV spectrum: 6284 24800.
    Example 5. 1.4 g of trimethylsulfoxonium iodide in 28 ml of dimethyl sulfoxide is stirred with 171 ml of an 80% oil suspension of sodium hydride for 2 hours at room temperature. 1.0 g of 17r-ox-17o - (3-hydroxypropyl) -15o, 1 bob-methylene-4, 6-androstadiene-3-one is added to the almost clear solution under nitrogen and mixed for another 24 hours at room temperature. It is then poured into ice water, the precipitate is filtered off, washed with water and dissolved in methylene chloride. After drying and evaporation, the residue is purified by repeated preparative layer chromatography. Get 130 mg
    , 17D-hydroxy-17c 1- (3-hydroxypropyl) -6/3, 7 Р15ci, 16о6-dimethylene-4-androsten-3-one. UV spectrum: 266 17500.
    Example 6. 10.0 g of 15p., 16-methylene-3-oxo-4, 6-androstadieneQ-17 (il-spiro-5) -perhydrofuran-2 -one in 50 ml of methylene chloride is mixed with 30 ml of ethylene glycol, 20 ml o-formic acid triethyl ester to 300 mg of p-toluenesulfonic acid
    - and stirred for 75 min at. Then 3 ml of pyridine are added, the reaction solution is diluted with ether, washed with water, dried and evaporated to dryness in vacuo. 12 g of crude 3,3-ethylenedioxy-15p, 16p are obtained
    0-methylene-4, 6-androstadiene-l7f-l-spiro-5-perhydro-Luran-2-one.
    12 g of 3,3-ethylenedioxy-15p (, 16f-methylene-4, 6-androstadiene-17 p-l-spiro-53-perhydropyran-2-ona) is dissolved in 600 ml of absolute tetra
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining 170-hydroxy-4-androsten-3-ones of the general formula (CH 2 ) 3-0R t where R ^ is hydrogen or the residue of an aliphatic acid having up to 4 carbon atoms B
    I represents a group of O. characterized in that Z-keto-4,6-andrs stenespirolactone of the general formula where p has the above values, is treated with lithium aluminum hydride in an aprotic solvent, the 3-keto group being previously protected, methyleneated with dimethyl sulfoxonium methyl methyl in dimethyl and if necessary, the resulting product is esterified in the presence of an esterification catalyst, after which the desired products are isolated.
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    同族专利:
    公开号 | 公开日
    FR2391224B1|1980-06-13|
    FR2391224A1|1978-12-15|
    GR71590B|1983-06-17|
    DK213878A|1978-11-17|
    IL54718D0|1978-07-31|
    IL54718A|1982-08-31|
    US4180570A|1979-12-25|
    SE8100829L|1981-02-05|
    IE780977L|1978-11-16|
    SE7805413L|1978-11-17|
    IE46896B1|1983-10-19|
    DK147406B|1984-07-23|
    JPS53141258A|1978-12-08|
    AU515595B2|1981-04-09|
    ATA348378A|1980-06-15|
    CH639105A5|1983-10-31|
    DK147406C|1985-02-11|
    LU79652A1|1978-11-06|
    AU3615578A|1979-11-22|
    IT1094627B|1985-08-02|
    NL7805114A|1978-11-20|
    AT360676B|1981-01-26|
    ES469510A1|1978-12-01|
    HU179345B|1982-10-28|
    CS200235B2|1980-08-29|
    CA1105004A|1981-07-14|
    SE433356B|1984-05-21|
    DD135497A5|1979-05-09|
    IT7823392D0|1978-05-15|
    GB1602986A|1981-11-18|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CH609357A5|1973-05-25|1979-02-28|Schering Ag|
    DE2439082A1|1974-08-12|1976-02-26|Schering Ag|17 ALPHA-HYDROXY-1,3,5 , 15-OESTRATETRAENE AND THE METHOD OF MANUFACTURING IT|
    CH631462A5|1976-03-05|1982-08-13|Schering Ag|METHOD FOR PRODUCING NEW STEROIDS OF THE ANDROSTANE OR OESTRANE SERIES.|DE2922500A1|1979-05-31|1980-12-04|Schering Ag|6 BETA. 7 BETA|
    DE3130644A1|1981-07-29|1983-02-17|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW ANDROSTAN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS THAT CONTAIN THESE COMPOUNDS|
    JPH0373560B2|1982-07-22|1991-11-22|Schering Ag|
    DE3410880A1|1984-03-21|1985-10-03|Schering AG, Berlin und Bergkamen, 1000 Berlin|17-SUBSTITUTED ESTRADIENE AND ESTRATRIENE|
    JPS6248694A|1985-08-28|1987-03-03|Shionogi & Co Ltd|Antialdosterone active steroid derivative|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19772722705|DE2722705A1|1977-05-16|1977-05-16|Diuretic testosterone derivs. - are 17-beta-hydroxy-17-alpha 3-hydroxypropyl-androsta-4,6,15-tri:ene-3-one derivs.|
    DE19772722706|DE2722706A1|1977-05-16|1977-05-16|Diuretic testosterone derivs. - are 17-beta-hydroxy-17-alpha 3-hydroxypropyl-androsta-4,6,15-tri:ene-3-one derivs.|
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