• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    <IMAGE> Compounds of the above formula (X=H or OH, R1=H, OH or OCH3, R2=Br, Cl or F) and their acid addition salts are useful as antitumour agents. Those in which X=H may be prepared by an exchange reaction between a 4'-epi-4'-O-trifluoromethanesulphonyl-N-protected-daunorubicin (or a corresponding 4-demethyl or 4-demethoxy derivative) and (C4H9)4NCl, (C4H9)4NBr or CsF. Those in which X=OH are prepared from those in which X=H by bromination and reaction with aqueous sodium formate.
    公开号:SU1579465A3
    申请号:SU843781800
    申请日:1984-08-07
    公开日:1990-07-15
    发明作者:Суарато Антонино；Пенко Серджио；Джиулиани Фернандо；Аркамоне Федерико
    申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    cd i
    ;with
    This invention relates to a process for the preparation of new derivatives of 4 -halo-id-anthracycline glycosides of the general formula
    0 he pine2x
    Н3СО О ОН
    ns b-0-7
    Ri NH2
    where X is hydrogen or hydroxyl
    Group;
    R (is bromine or chlorine,
    having antitumor activity.
    The purpose of the invention is to obtain new 4-halogen-anthracycline glycosides, which are more active than the ancestors of this range of compounds - doxorubicin and da-norubicin and the closest structural analogue of the corresponding 4-iodine derivative.
    SL
     ABOUT
    This goal is achieved by reacting 4 -epi-4-0-trifluoromethanesulfonyl-N-substituted daanorubicin in aqueous methylene chloride with tetra (n-butyl) ammonium bromide or tetra (n-butyl) ammonium chloride to produce the corresponding 4 - bromo- or 4-chloro derivatives, which undergo soft alkaline hydrolysis in order to remove zardite groups, and the resulting 4 -halogen daunorubicin, if necessary, is transferred to the corresponding 4 -halogen derivative of doxorubicin (f
    Example 1. 4-Deoxy-4-bromo-daunorubicin (XH, R4-OCH3,), 2 g of tetra (n-butyl) ammonium bromide are introduced into a solution of 4.0 g of 4-epi-4-O-trifluoromethanesulfonyl -I-trifluoroacetyl daunorubicin (2: R-OCHj, R-COCFj) in 80 ml of aqueous methylene chloride. After 1. h at room temperature, the reaction mixture is washed with water and the organic phase is evaporated in vacuo. The evaporation residue is purified on silica gel using methylene chloride: acetone as eluent, to give 3.5 g of 4-deoxy-4-bromo-N-β-trifluoroacetyldaunorubicin with m.p. 130 ° C; FD, MS 685 (M). Thin layer chromatography on Kiesel-gel plates (Merck F 254) using the solvent system methylene chloride: acetone (in a volume ratio of 10: 1), Rf 0.5.,
    To a solution of 3 g of 4-deoxy-4-bromo-N-trifluoroacetyldaunorubicin in 20 ml of acetone is added 160 ml of a 0.1 N aqueous solution of sodium hydroxide. After 4 hours at room temperature, the pH of the solution was adjusted to 8.6 with 0.1 N acid and the solution was extracted with methylene chloride. The solvent is evaporated and the residual product is evaporated and treated with a methanol solution of hydrogen chloride, resulting in the formation of the chlorine hydrate of the target product (2.2 g, mp. 180 ° C with simultaneous decomposition); thin-layer chromatography on Kieselgel plates (Merck F 254) using the solvent system methylene chloride: methanol: water: acetic acid in a volume ratio of 80:: 20: 7: 3, Rf - 0.32.
    Example 2. 4-Deoxy-4-bromo-doxorubicin (X-OH, Rf-Br).
    Jq to
    94654
    2 g of 4-deoxy-4-bromo daunorubicin, prepared as described in example 1, is dissolved in a mixture of methanol and dioxane. The solution is processed in the usual manner, first with bromine, resulting in 14-bromine
    Q 5
    five
    0
    five
    0
    five
    0
    processing a 4-epi-4 derivative and then an aqueous solution of sodium formate, resulting in 4-deoxy-4-bromdoxorubicin. This compound is converted to its hydrochloride by treatment with a methanol solution of hydrogen chloride. M.p. of this product is 170 ° C (with decomposition), FD, MS 605 (M), thin-layer chromatography on Kieselgel plates (Merck F 254) using the methylene chloride: methanol: water: acetic acid solvent system in a 80: 20: 7 ratio by volume : 3, Rf 0.20.
    Example 4-Deoxy-4-chloro-daunorubicin (XH,).
    AT
    -0-trifluoromethanesulfonyl-M-trifluoroacetyl daunorubicin (2, R —OCHj, R —COCF) tetra (n-butyl) ammonium chloride, as described in Example 1, gives 4-deoxy-4-chloro daunorubicin, mp. 175 C with decomposition, FD, MS 545 (M), thin layer chromatography on Kieselgel plates (Merck F 254) using the solvent system methylene chloride: methanol: water: acetic acid in a volume ratio of 8: 20: 7: 3, Rf 0.32 .
    EXAMPLE 4. 4J-Deoxy-4-chloro-doxorubicin (X — OH, Rj — C1).
    According to the procedure of Example 2, 4-deoxy-4-chloro-daunorubicin is converted to 4-deoxy-4-chloro-oxorubicin and isolated as a hydrochloride: mp. 180 ° C with decomposition; FQ mass spectrum 551 (M +). Thin layer chromatography on Kieselgel plates (Merr-k F 254) using the solvent system methylene chloride: methanol: water: acetic acid in a volume ratio of 80: 20: 7: 3 Rf 0.2.
    Tests on biological activity.
    The compounds of Examples 1, 2 and 3 were tested in vitro versus downsrubicin (DNR) and doxorubicin (DX) against HeLa cells, P388 sensitive and resistant cells and Pu (P388 (HR)).
    The results of the cytotoxic activity of the compounds of examples 4, 3 and 2 are presented in table. one.
    All new derivatives showed more cytotoxic than their parental compounds against HeLa cells and P388 sensitive to DH. However, this increased cytotoxicity is more pronounced when considering the activity of these compounds against P 388 10. In this case, these new derivatives show a 100-250-fold increase in cytotoxicity compared with the parent drug. These compounds were tested in vivo against three different types of experimental leukemia.
    The antitumor effect on ascithic leukemia P388 is given in Table. 2
    As can be seen from the table. 2, the activity of the activity shown by the compounds of Example 3 is equal to the activity of the DNR, while the other derivative of DNR (the compound of Example 1) shows an anti-tumor activity that is clearly higher than the DNR.
    The compound of Example 2, with a maximum tolerated dose (4.15 mg / kg), has approximately the same activity potency as DX. All of these new compounds are active against P388 / DX leukemia (see Table 3), while DNR and DX are ineffective.
    These three new compounds were tested after their intravenous injection for their effect against disseminated total leukemia (Gross heukemia), the test results are given in Table. four.
    In this system, compound 3 is as active as DNR, while the compound of example 1 is more active than the parent compound. The compound of Example 2 shows about the same efficacy as the DX compound. Both of these compounds were tested after ingestion through the mouth and showed significant activity, while DNR and 1) X were not active when administered in the same way.
    , The cytotoxic effect on HeLa cells is comparable (3 ng / ml) for 4-bromdoxorubicin and structural ana
    log is 4-iodoxorubicin, while in-vitro acts against P 388 tumor cells, 4-bromdoxorubicin is much more active (0.2 ng / ml) compared to the structural analogue (5 + 2 ng / ml).
    Similarly (in relation to the action of .in vivo against Gross - leukemia), an indicator T / C of 258% was found for 4-bromdoxorubicin at a dose of 5.27 mg / kg; 4-iodoxorubicin has a T / C ratio of 150-183% at a dose of 6.0 mg / kg.
    In addition, poisoning deaths are 2/17 for 4-iodoxidoxin and 0/20 for a similar bromine derivative.
    five
    权利要求:
    Claims (1)
    [1]
    20 Formula of Invention
    The method of obtaining 4-halide-anthracycline glycosides of the general formula
    25
    COCH2X
    HE
    /
    Н3СО О ОН X нзс --- О- /
    h mh
    where X is hydrogen NH2 or hydroxyl
    Group;
    R (is bromine or chlorine, characterized in that 41-epi-4 -O-trifluoromethanesulfonyl-N- -substituted daunorubicin of the general formula
    about
    so CFjSop where R is trifluoroacetyl dissolved in aqueous methylene chloride, at room temperature, is reacted with tetra (.n-butyl) ammonium bromide or tetra (n-butyl) ammonium chloride to give an N-protected glycoside of the general formula
    About him
    Н3СО О ОН I Н3С- °
    one
    -0- NHR2
    where R, and R have the indicated meanings,
    which is subjected to deprotection by soft alkaline hydrolysis with an aqueous solution of 0, III sodium hydroxide followed by isolation of the desired product, where X is hydrogen, as hydrochloride and, if necessary, the compound obtained is reacted with chlorine bromine solution, obtained according to Table 2
    Activity against ascitic leukemia P388
    ep 1
    ep 3
    ep 2
    2.9
    4.4
    6,6
    2.9
    4.4
    6.6 10
    2.9
    4.4
    6.6 10
    4.4
    6.6 10
    2.4
    2.88
    3.46
    4.15
     Experiments were performed on mice CDF, inoculated with leukemia cells (10), by intraperitoneal injection.
    Treatment by intraperitoneal injection a day after injection of the tumor inoculum.
    The average survival time of treated mice (average survival time of control mice x 100).
    Long-term survivors (60 days)
    "
    Determined by auto-optical measurements.
    The 14-bromo derivative is hydrolyzed with an aqueous solution of sodium formate, followed by isolation of the desired product, where X is OH, in the form of hydrochloride.
    Table 1
    #
    An inhibition test after a drug effect for 24 hours. Cytotoxicity determined after a drug effect for 48 hours (data from several experiments).
    155 135 115
    0/20
    0/18
    0/20
    0/10
    0/10
    0/10
    3/10
    0/10
    0/10
    0/10
    0/8
    0/10
    0/10
    4/10
    0/10
    0/10
    0/10
    4/10
    0/20 0/18 12/20 0/10 0/10 0/10 0/10 0/10 0/10 0/10 6/8 0/10 0/10 0/10 0/10 0/10 / 10 1/10
    157946510
    Table 3
    Activity against ascitic leukemia P388 / X

    Experiments were performed on BDF mice inoculated with cells (10), administered by intraperitoneal injection. Treatment by intraperitoneal injection one day after entering the tumor inoculum. The average survival time of treated mice (average survival time of control mice x 100). Determined by utopic measurements.
    Table 4 Efficacy against total leukemia
    DNR
    Intravenously
    Example 1 As Example 3 - Through the mouth
    Dx
    Intravenously
    Example 2 Similarly
    eleven
    157946512
    Continuation of table 4
    By mouth
     Experiments were performed on SEN mice inoculated with leukemia cells (2x10) by
    intravenous injection.
    Treatment by injection of the drug by intravenous injection or through the mouth through the day after entering the tumor inoculum.
    The average survival time of the treated mice (cf. the mean survival time of the control mice x 100).
    Determined by authentic measurements.
    Editor M. Kelemesh
    Compiled by G. Konnova
    Tehred L. Oliynyk Proofreader V. Girn to
    Order 1925
    Circulation 302
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
    Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
    242,114,157
    3/10 0/10 0/10
    Subscription
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    同族专利:
    公开号 | 公开日
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    引用文献:
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    FR892943A|1942-03-06|1944-05-24|Ig Farbenindustrie Ag|Process for purifying gamma-keto-pimelic dilactone|
    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|
    US4438105A|1982-04-19|1984-03-20|Farmaitalia Carlo Erba S.P.A|4'-Iododerivatives of anthracycline glycosides|GB8414619D0|1984-06-08|1984-07-11|Erba Farmitalia|Anthracyclines|
    GB2159518A|1984-06-08|1985-12-04|Erba Farmitalia|New anthracyclines and process for manufacture|
    DE3500017A1|1985-01-02|1986-07-10|Farmitalia Carlo Erba S.p.A., Mailand/Milano|4'-Haloanthracycline esters|
    GB2218087B|1988-04-22|1991-01-30|Erba Carlo Spa|4-demethoxy-4'-deoxy-4'iodo anthracycline glycosides|
    AU601857B2|1988-06-30|1990-09-20|Pharmacia & Upjohn S.P.A.|A new antitumor agent obtained by microbial stereoselective reduction of 4'-deoxy-4'-iododoxorubicin|
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    GB9418260D0|1994-09-09|1994-10-26|Erba Carlo Spa|Anthracycline derivatives|
    法律状态:
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