• 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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  • 优先权
    • 专利摘要:
    1511559 Daunomycin and adriamycin derivatives SOC FARMACEUTICI ITALIA SpA 21 Sept 1976 [26 Sept 1975] 39471/75 Heading C2C Novel 4<SP>1</SP>-deoxy-daunomycins of the general formula wherein R 1 =R 3 =H and R 2 is H, methyl, methoxy, Cl or Br; R 1 = R 2 = H and R 3 is C 1-4 alkoxy; or R 2 =H and R 1 and R 3 are methyl, methoxy, Cl or Br, are prepared by condensing an aglycone of the general formula with 2,3,4,6 - tetradeoxy - 3 - trifluoroacetamido - L - threo - hexopyranosyl chloride, followed by removal of the protecting group. They may be brominated and the resulting 14 - bromo derivative hydrolysed to give the corresponding novel adriamy cin derivative. 2,3,4,6 - Tetradeoxy - 3 - trifluoroacetamido - L- threo-hexopyranosyl chloride is prepared by reacting methyl N - trifluoroacetyl - daunosaminide with methanesulphonyl chloride, treating the resulting 4-O-mesyl derivative with sodium iodide, hydrogenating catalytically the resulting 4 - desoxy - 4 - iodo derivative, hydrolysing the resulting 4-desoxy derivative with an acid, treating the resulting 2,3,4,6-tetradeoxy-3- trifluoroacetamido - L - threo - hexopyranose with p-nitrobenzoyl chloride and reacting the resulting 1-p-nitrobenzoate with HCl.
    公开号:SU730310A3
    申请号:SU772523451
    申请日:1977-09-22
    公开日:1980-04-25
    发明作者:Пенко Серджо；Аркамоне Федерико；Ди Марко Аурелио
    申请人:Сочиета Фармасьютичи Италиа С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    Hydrolysis comes with better yields and no by-products.
    It should be noted that the yield using the new method of converting 4-deoxidounomycin hydrochloride to 4-deoxyadriamycin hydrochloride is 50% of theoretical, while the yield by the known method is only 30%.
    Example 4 -deoxyadriamycin.
    0.35 g of 4-deoxidaunomycin hydrochloride is dissolved in 20 ml of a mixture of anhydrous methanol and dioxane (v / v and 0.35 ml of ethyl orthoformate. 1.4 ml of a solution of 0.93 g of bromine in 10 MP of chloroform is added to this solution. 30 min at room temperature, the reaction mixture was poured into 100 ml of ethyl ether / petroleum ether (2: 1 v / v). The resulting red precipitate after filtering and washing with ethyl ether 11 1 was dissolved in a mixture of 6 ml of acetone and b ml of 0.25 n aqueous hydrobromic acid.
    After 12-15 hours at room temperature, the mixture is diluted with water and extracted with chloroform. The aqueous phase is extracted several times with n-bu-tanol and the combined extracts are evaporated under vacuum to a small volume to yield a 14-bromo-glucoside derivative, which is then dissolved in 6.7 ml of 0.25 n. hydrobromic acid and treated with 0.5 g of sodium phosphate in 5 ml of water. The reaction mixture is kept under stirring for 90-110 hours at room temperature and then evaporated to dryness in vacuo.
    The resulting residue is dissolved in 120 MP chloroform-methanol mixture
    (2: 1 v / v) and washed twice with 2.5% aqueous solution of NaHCOj and then re-extracted with Chloroform. The combined chloroform extract is dried over and evaporated under
    vacuum to low volume. With help
    anhydrous methanolic hydrogen chloride, the pH of the resulting red solution was adjusted to 3.5, and then an excess of ethyl ether was added to precipitate 0.17 g of 4-deoxyadriamycin as hydrochloride. T.sht. 163 ° C
    (with decomposition.), l +320 (with 0.05 MeOH).
    Chromatography in a thin layer on Kieselgur NG Merck when buffered to pH 7 with phosphate M / 15, used methylene chloride methanol - water (10: 2: 0.2 v / v) as an eluent, W 0.13.
    The antitumor effect of 4 -deoxyadriamycin a, established on many transplanted tumors in ml, compared with the known anti-tumor agent-adriamycin, is given in Table 1.
    Leukemi - L 1210.
    BDF mice were intraperitoneally infected with 10 leukemia cells per person and then (intraperitoneally) one day after infection with the tumor, treatment was carried out with different doses of the test compounds. .Table
    Adriamidine
    4-Deoxyadriamycin
    2/20 2/20
    3/18
    2/10 1/10
    6/10 10/10
    Female mice
    intravenous were
    infected with a suspension of lymphenods leukemia and spleen cells (2 x 10 cells of leukemia per mea) and vnu triAmitsin
    4-Deoxyadriamycin
    The male MOP mice were intraperitoneally infected with 10 leukemia cells per mouse and a day after infection the lecteric sarcoma was injected intraperitoneally 180
    Fifteen CDs, Swiss (Suiss), fragments of neoplastic tissue (solid sarcoma 180) were grown subcutaneously. And animals 1, 2, 3, 4 and 5 days later intravenously, 1.2 and 3 days after the infection, treatment was carried out for the test and connection km . The research results are summarized in table 1.
    table 2
    183,200
    3/10 216
    200
    1/10 233
    1/9
    2.75 233
    different doses of the test compound.
    The research results are summarized in table 3. Table 3
    were treated with the test compound. Tumor growth was measured 11 days after tumor implantation. The research results are summarized in table 4.
    T / C - the average tumor weight of the treated mouse / / average tumor weight of the control mouse X 100.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 4-deoxyadriamycin hydrochloride of the general formula
    OO
    Nzso about he I
    NSSGG - /,
    HC1 (1)
    / --- Mr.
    Shg
    including the interaction of the 4-deck of sidounomycin hydrochloride of the formula
    Table
    "C1 (and
    with bromine to produce a 14-bromo-derivative and transferring the base of 4-deoxyadriamycin to the hydrochloride, characterized in that, in order to increase the yield of the target product, the 14-bromo-derivative obtained is treated with an aqueous mixture of hydrogen bromide and sodium formate for 90-110 hours at room temperature with obtaining base 4 kdeoksiadriamitsin, Sources of information,
    taken into account in the examination of se 1, UK Patent No. 1217133 Cl. C 2 A, pub. 1970 (prototype).
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    同族专利:
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    引用文献:
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    US3803124A|1968-04-12|1974-04-09|Farmaceutici It Soc|Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives|
    DE1792346C3|1968-08-22|1980-10-23|Rotta Research Laboratorium S.P.A., San Fruttuoso Di Monza, Mailand |Pharmaceutical preparation for the treatment of degenerative joint diseases|
    FR2183710B1|1972-05-06|1976-05-28|Farmaceutici Italia|
    US4020270A|1974-05-02|1977-04-26|Societa' Farmaceutici Italia S.P.A.|L-lyxohex-1-enopyranose derivative|GB1567456A|1976-11-16|1980-05-14|Farmaceutici Italia|Daunomycin derivatives|
    GB1550879A|1976-12-22|1979-08-22|Farmaceutici Italia|Antitumour glycosides|
    US4362720A|1977-04-14|1982-12-07|Chembiomed Ltd.|Synthesis of 2-amino-2-deoxyglycoses and 2-amino-2-deoxyglycosides from glycals|
    GB1573036A|1977-05-05|1980-08-13|Farmaceutici Italia|Anthracyclines|
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    US4201773A|1978-07-26|1980-05-06|The United States Of America As Represented By The Department Of Health, Education And Welfare|7-O--daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone|
    US4259476A|1979-04-02|1981-03-31|Kende Andrew S|Novel heterocyclic anthracycline compounds|
    AT1101T|1979-09-01|1982-06-15|Farmitalia Carlo Erba S.P.A.|ANTHRACYCLIN GLYCOSIDES, METHOD FOR THE PRODUCTION THEREOF AND THE PHARMACEUTICAL COMPOSITION CONTAINING THE SAME.|
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    ZA814722B|1980-07-18|1982-07-28|Hoffmann La Roche|Novel anthracycline glycosides|
    US4345070A|1980-09-29|1982-08-17|Farmitalia Carlo Erba S.P.A.|Process for the preparation of 4'-deoxy-daunorubicin and 4'-deoxy-doxorubicin|
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    法律状态:
    优先权:
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