• 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:
    Anthracycline glycosides represented by the general formulae (I) and (II): <IMAGE> in which R1 represents a hydrogen atom or a hydroxyl group, and their pharmaceutically acceptable addition salts with an acid. Use of these compounds as antitumour agents.
    公开号:SU1590045A3
    申请号:SU874202740
    申请日:1987-06-11
    公开日:1990-08-30
    发明作者:Суарато Антонино；Карузо Микеле；Пенко Серджио；Джулиани Фернандо
    申请人:Фармиталиа Карло Эрба С.П.А.(Фирма)；
    IPC主号:
    专利说明:

    SP
    F
    This invention relates to a process for the preparation of new anthracycline glycosides of the general formula
    °
    n co
    HC1 ,. (I)
    where R is hydrogen or hydroxyl
    Group,
    having antitumor activity.
    The pell of the invention — obtaining new derivatives of anthracycline glycosides with better properties than the ancestors of this range of glycosides daunorubicin and doxorubicin is achieved by synthesis starting from Z-amino-3-Epidaunorubicin and through the corresponding 3-epi-E-salicylicidene and N- salicylidene-3-epi-4-O-trifluoro-methanesulfonate derivatives, the last

    SP

    om
    then subjected to acid hydrolysis, obtained: 3 -deamino-4 -deoxy-3 4 -epi-3, 4-epiminodagnarubischis through the corresponding N-trifluoroacetyl, the derivative is converted into 4-deoxy-4 -epi-H-trifluoroacetyl -3-diamino-3-hydroxydinomycin, which after a mild alkaline hydrolysis is transferred to the target product 1a, which in Q, if necessary, through 14-bromine: the derivative of dauymycin, is converted into doxorubicin derivative 16,
    ; | Example 1. 3-Epi-N-salicy- 15
    Gleidendaurubicin (III).
    A solution of 2 g of 3-α-amino-3-epidaino-rubicin (II) in a mixture of 80 ml of water and 20 ml of acetone is treated with the crude product obtained, dissolved in 50 ml of methanol and 0.2 g of p-toluenesulfonic acid monohydrate is added. Solution B was kept at room temperature for 1 hour, then 100 ml of water was added to it and extracted with a small amount of dichloromethane. The aqueous phase is adjusted to pH 8.0. 1 With sodium hydroxide and dichloromethane is added. The organic phase is separated, washed with water, dried over anhydrous sodium sulphate and the solvent is evaporated to a small volume.
    The mixture is purified on a chromatographic column with silica gel, maintained at pH 7, using a mixture of dichloromethane / ethanol as the eluting solvent. The eluate containing rljl sids- i Vrtd .a. i kJlJJ-i ivy 1. i. V - - an ambient temperature of 0.5 ml salicilapa- 2o left product (IV), washed with water,
    ... j-k. l. - "-1G-gto, -gch". . TL VT4tJrr Til P.TTICH VTOT.
    After 10 minutes, ethyl acetate is added and the organic phase is separated, washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under 25 g.
    The residue is first triturated with hexane to remove traces of salide schaldehyde, then collected, dried under vacuum at 30 ° C, and the target product is obtained in almost quantitative yield, Rft 0.21 with thin layer chromatography on Kieselgel F 254 (Keri) , is- use as an eluting solvent a mixture of methylene chloride - acetone 8: 2 v / v.
    Example 2. 3-Deamico-4-de-hydroxy-3-epi-4-epi-3, 4-epi tindo-norubicin (IV) (aziridine),
    To a solution of 2 g of 3 -epi-N-salicyl-. dendunorubicin (III) in 20 h of anhydrous dichloromethane and 2 ml of dry pyridine were added with the following: a thief of 0.8 ml of trifluoromethanesulfonic acid in 10 ml of dichloromethane. After making the mixture for 1 h, it is diluted with dichloromethane and washed with water, cold 0.1 M hydrochloric acid, cold aqueous 5% sodium bicarbonate and water, the organic phase is dried over anhydrous sodium sulfate, the solvent is distilled off in vacuo to give K-salicyl: adeno-3 - -epi-4-O-trifluoromethanesulfonate.
    50
    dichloromethane and crystallize,
    Mass spectrum 509 (m); m.p. 135 -.
    , 38 at thin-layer chromatography on Kieselgel F 254 (Merck). using as an eluting solvent a mixture of dichloromethane - methanol - acetic acid - water. (30: 4:: 1} 0.5 v / v.).
    H NMR spectrum (200 MHz, in CDCl,): 8.02 (double doublet, J 1.1, 7.7 Hz, W, H-1); 7.76 (double doublet, J, 7 7, 7 Hz, 1H, H-2); 7.37 (double, J 1.1, 7.7 Hz, 1I, H-3); 5.31 (double doublet, J 3.0, 4.8 Hz, 1H, H-1); 5.17 (double doublet, J 2.0, 3.6 Hz, 1H, H-7); 4.32 (double doublet, J 1, 6.7 Hz, 1H, H-5); 4.07 (singlet, GZ, OCHs-4); 3.17 (double doublet, J 19.2 Hz, 1H, H-10e); 2.95 (doublet, J 19.2 Hz, 1H, H, Yooh); 2.46 (triple doublet, J 2.0, 2.0, 15.0 Hz, 1H, H-8e); 2.43 (singlet, KN SOCNs); 2.30 (triple doublet, J 1.5 4.37 6.4 Hz, 1H, H-3); 1.9-2.0 (multishtet, 2H, H-8ax, H-2ax); 1.87 (triple doublet, J 1.57 3.0, 14.6 Hz, 1H H2 e); 1.44 (doublet, J 6.7 Hz, ЗН, CHj-5) .I
    Example 3. 3-Deamino-4-deoxy-3, -oxy-4-epi-4-aminodounorubicin hydrochloride (la).
    1 g of aziridine is converted into N-trifluoride-detailed derivative (V) of Rop 0.50 by thin-layer chromatography of 1.2 ml of trifluoroacetic anhydride, At, „UO c-1 opto-t-opto 7Si CMpTTK i. isoic acid In anhydrous dichloromethane.
    After processing the raw product (R
    graphs on Kieselgel F 254 (Merck), using as elution solvent a mixture of dichloromethane n acetone in a ratio of 95: 5 vol / v.
    f
    0.7 using thin-layer chromatography on Kieselgel F 254
    The resulting crude product is dissolved in 50 ml of methanol and 0.2 g of p-toluenesulfonic acid monohydrate is added. Solution B was kept at room temperature for 1 hour, then 100 ml of water was added to it and extracted with a small amount of dichloromethane. The aqueous phase is adjusted to pH 8.0. 1 With sodium hydroxide and dichloromethane is added. The organic phase is separated, washed with water, dried over anhydrous sodium sulphate and the solvent is evaporated to a small volume.
    The mixture is purified on a chromatographic column with silica gel, maintained at pH 7, using a mixture of dichloromethane / ethanol as the eluting solvent. The eluate containing the whole product (IV) is washed with water,
    "-1G-gto, -gch". . TL VT4tJrr Til P.TTICH VTOT.
    j
    0
    dichloromethane and crystallize,
    Mass spectrum 509 (m); m.p. 135 -.
    , 38 at thin-layer chromatography on Kieselgel F 254 (Merck). using as an eluting solvent a mixture of dichloromethane - methanol - acetic acid - water. (30: 4:: 1} 0.5 v / v.).
    H NMR spectrum (200 MHz, in CDCl,): 8.02 (double doublet, J 1.1, 7.7 Hz, W, H-1); 7.76 (double doublet, J, 7 7, 7 Hz, 1H, H-2); 7.37 (double, J 1.1, 7.7 Hz, 1I, H-3); 5.31 (double doublet, J 3.0, 4.8 Hz, 1H, H-1); 5.17 (double doublet, J 2.0, 3.6 Hz, 1H, H-7); 4.32 (double doublet, J 1, 6.7 Hz, 1H, H-5); 4.07 (singlet, GZ, OCHs-4); 3.17 (double doublet, J 19.2 Hz, 1H, H-10e); 2.95 (doublet, J 19.2 Hz, 1H, H, Yooh); 2.46 (triple doublet, J 2.0, 2.0, 15.0 Hz, 1H, H-8e); 2.43 (singlet, KN SOCNs); 2.30 (triple doublet, J 1.5, 4.37 6.4 Hz, 1H, H-3); 1.9-2.0 (multishtet, 2H, H-8ax, H-2ax); 1.87 (triple doublet, J 1.57 3.0, 14.6 Hz, 1H H2 e); 1.44 (doublet, J 6.7 Hz, ЗН, CHj-5) .I
    Example 3. 3-Deamino-4-deoxy-3, -oxy-4-epi-4-aminodounorubicin hydrochloride (la).
    1 g of aziridine is converted to N-trifluorodehyde derivative (V) after processing the crude product (R
    f
    0.7 using thin-layer chromatography on Kieselgel F 254
     51590045
    (Kirk), used as an eluerukg-H-2e); 1, 70 (triple doublet, J 4.0 Solvent mixture mixture of dichloromethane - 4.6, 13.2 Hz, 1H; Нт2ах); 1.31 (doublet acetone in the ratio 4: 1 v / v) ra- J 6.3 Hz, 3N, CHj-S). 20 ml of acetone and treated with a catalytic amount of sulfuric acid at. The mixture is diluted with 200 ml of dichloromethane, washed with water, aqueous 5% sodium bicarbonate. Example 4.3 Deamino-3-oxide-4-deoxy-4-epi-4-aminodoxorubicin hydrochloride (16).
    0.5 g of the obtained compound 1a, dissolved in a mixture of 7.5 ml of dry water 10
    methanol, 21 ml of dioxane and 0.5 ml of ethyl fluoroformate, treated with 2.1 ml of a solution of 0.93 g of bromine in 10 ml of chloroform. After 3 hours, the mixture was poured into a mixture of 105 ml of ethyl and water. The solvent is distilled off in vacuo, the residue is purified on a silica gel column using dichloromethane as the eluting solvent. 0.7 g of 4-deoxy-4-epi-N-trifopropacetyl-3-deamino-3-ester and 50 ml of petroleum ether-hydroxidunomycin (VI) .p are obtained. The resulting red precipitate after
    RI 0.21, using thin layer filtration and washing with ethyl ether chromatography on Kieselheler, is dissolved in a mixture of 15 ml of acetone.
    F 254 (Kirk), using as a 15 ml 0.25 N aqueous bromide volumizing solvent a mixture of dichloro-20-natorod. After 15 h at room
    - methane and acetone (4: 1 v / v). 9 ml of water are added and the product (VI) is slowly dissolved; the solvent is extracted with chloroform, boiling with a 0.1N aqueous solution of sodium hydroxide aglycones.
    at OS, carried out the hydrolysis of the N-three-Then the aqueous phase is extracted
    fluoroacetyl protecting group. After 25 N-butanol, until the extra-1-hour distillation at O®C solution discolor TC.
    adjusted to pH 8.6 decine-normal co-organic extracts (-butanol)
    acid and extracted with dichloro-evaporated under vacuum to slightly methane. The solvent is evaporated, according to volume (about 9 ml), and the
    Beam, 0.5 g of residue, which was treated with ethyl ether, received 0.45 g of methanol and hydrogen chloride, which was converted into the hydrochloride of the desired product (1a).
    Mass Spectrum DG 527 (M), so pl. (with decomposition).
    Rf 0.18 on a thin-layer chromatogram on Kieselgel F 254 (Kirk), using diphromomethane - methanol - acetic acid - water as a solvent in a ratio of 30: 4: 1:: 0.5 v / v.
    H-NMR (200 MHz, CDCl1): 8.02 (double doublet, J 0.9, 8.5 Hz, 1H, H-1); 7.77 (double doublet, J 8.5,
    35
    40
    a corresponding 14-bromo derivative. The resulting derivative is dissolved in 9 ml of a 0.25 N. aqueous solution of hydrogen bromide and treated with 0.75 g of sodium formate in 8 ml of water.
    The reaction mixture is held at room temperature with stirring for 48 hours and then 1N hydrochloric acid is added to adjust the pH to 4.
    The resulting mixture is extracted with 1: 1 ethyl ether - ethyl acetate to remove some linofilic contaminants. The aqueous phase, after the back-extraction, is extracted with chloroform until the extracts are discolored with TC.
    8.5 Hz, 1H, H-2); 7.38 (double duplicate pH to 7.6 years old NaHCOj, J 0.9, 8.5 Hz, 1H, H-3); 5.52. (double doublet, J 1.40 Hz, 1H, H-1); 5.28 (double doublet, J 1.8, 4.0 Hz, 1H, H-7); 4.07 (singlet, 3N, OCHj-4); 3.69 (double quartet, J 6.3, 9.5 Hz, 1H, H-5); 3.51 (triple doublet, J 4.8, 9.5, 11.6 Hz, 1H, H-3); 3.22 (double doublet, J 1.9, 18.9 Hz, 1H,
    50
    All the collected chloroform extracts are dried over Na2S (evaporated to a small volume (about 45 ml) under vacuum. The red solution obtained is brought to pH 3.5 with aqueous methanolic H-1Oe); 2.94 (doublet, J 18.9 Hz, IH ,. solution of hydrogen chloride and do-H-10x); 2.40 (singlet OG, COCHj); Bavle. an excess of ethyl ester-2.2-2.4 (multiplet, 1H, and-8x); 2.30 Pa, obtaining 0.30 g of the title compound- (double doublet, J 9.5, 9.5 Hz, 1H H-4); 2.0-2.2 (multiplet, 2H, H-8e,
    nor (ib). M.p. (different). DRS-MS 543 (M).
    H-2e); 1, 70 (triple doublet, J 4.0 4.6, 13.2 Hz, 1H; Ht2x); 1.31 (doublet J 6.3 Hz, 3N, CHj-S).
    Example 4.3 Deamino-3-Oxy-4-deoxy-4-epi-4-aminodoxorubicin hydrochloride (16).
    0.5 g of the obtained compound 1a, dissolved in a mixture of 7.5 ml of anhydrous
    methanol, 21 ml of dioxane and 0.5 ml of ethyl fluoroformate, treated with 2.1 ml of a solution of 0.93 g of bromine in 10 ml of chloroform. After 3 hours, the mixture is poured into a mixture of 105 ml of ethyl ether and 50 ml of petroleum ether5
    0
    a corresponding 14-bromo derivative. The resulting derivative is dissolved in 9 ml of a 0.25 N. aqueous solution of hydrogen bromide and treated with 0.75 g of sodium formate in 8 ml of water.
    The reaction mixture is held at room temperature with stirring for 48 hours and then 1N hydrochloric acid is added to adjust the pH to 4.
    The resulting mixture is extracted with 1: 1 ethyl ether - ethyl acetate to remove some linofilic contaminants. The aqueous phase, after the back-extraction, is extracted with chloroform until the extracts are discolored with TC.
    pH value up to 7.6 aqueous NaHCO
    All collected chloroform extracts are dried over Na2S (, evaporated to a small volume (about 45 ml) under vacuum. The red solution obtained is taken to pH 3.5 with an aqueous methanolic solution of hydrogen chloride and the excess ethyl ether is added - ra, yielding 0.30 g of the target compound
    nor (ib). M.p. (different). DRS-MS 543 (M).
    those on Kieselgel F 254 (Merck) using the eluent system dichloroethane: methanol: acetic acid; water (30: 4: 1: 0.5 v / v) shows R 0.1.
    Biological activity.
    The cytotoxic activity of new anthracycline glycosides was determined in vitro on Hela cells of the human cervical epithelial carcinoma, P-388 cells of leukemia, sensitive to doxorubicin; cages
     Dose determining 50% suppression
    control.
    Compounds tested in vivo against P-388 ascitic leukemia and Gross-leukemia have shown good antitumor activity compared with daunorubicin, especially when peroralism has occurred. Jq
    Experiments were performed on CDF groups infected intraperitoneally with 10 P-388 cells of ascitic leukemia. The results are shown in Table. 2
    Table 2
     Treatment intraperitoneally one day after infection with tumor cells ... The average lifetime of those treated with the ttbmeVi preparation, related to the average lifetime in the control group X 100, 0 estimate held on the scale;
    intravital biopsy.
     Actions against Troseu-leukemia were performed on the ESR of mice inoculated with intravenous 20 x 10 leukemia babies.
    P-388 / Dx leukemia resistant to dockbrood inu; Human lovo cells of colon adenocarcinoma sensitive to doxorubicin; Lovo / Dx - human colon adenocardioma cells resistant to doc sorubicin.
    t.
    The duration of action of the compound is 24 hours (compared with daunorubicin).
    The results are presented in table. 1. Table
    cell numbers compared to
    The results are shown in Table. 3. Table 3
    Intravenous treatment one day after inoculation, tumor. The average life expectancy of treated mice to the average duration of mice in the control group.
     Estimation based on data from intravital biopsy.
    F
    formula of invention
    The method of producing glycoside of the general formula
    Nzso about
    HC1
    where R is hydrogen (la) or hydroxyl
    (sixteen),
    characterized in that the 3- -amino-3 -epidaunorubicin of the formula
    NCSO O ON ZHG O
    dissolved in a mixture of water - acetone 4: 1 vol / v, is reacted at room temperature with salivd-aldehyde to obtain the corresponding 3-epi-N-salicylidene derivative (III), which is reacted with trifluoromethanesulfonic anhydride in anhydrous chloromethane and in the presence of dry pyridine and the resulting N-salicylidene-E - -epi-4-O-trifluoromethanesulfonate is grown
    o
    s
    0
    five
    stolen in methanol and acidic hydrolyzed at room temperature for 1 hour with p-toluenesulfonic acid to give 3-deca-4 -deoxy-3-epi-4-epi-3, 4 -epimine Dauronubicin (IV), which is converted. to the corresponding N-trifluoroacetyl-Derivative (V) by treating with trifluoroacetic anhydride in dichloromethane solution, which in turn is reacted with a catalytic amount of sulfuric acid in acetone and 4-deoxy-4 -epi-N-trifluoroacetyl obtained -3-Deamino 3 -Hydroxidounomine (VI) is subjected to mild alkaline hydrolysis with 0.1N aqueous sodium hydroxide solution for 1 h, obtaining the desired product 1a as hydrochloride by treating with methanol hydrogen chloride in methanol, which, if necessary, , P evraschayut in Correspondingly) Vul worked yuschee 14-bromo derivative by treatment with aqueous bromine solution from which, after hydrolysis with aqueous sodium formate at room temperature provided the desired product 16 as a hydrochloride,
    权利要求:
    Claims (1)
    [1]
    Form
    The method of the invention for the preparation of a common glycoside * Treatment intraperitoneally day ’after infection by tumor cells.
    ** The average life time of the treated 50 formulas with the preparation of mice, referred to the average life time in the control group x 100.
    *** 0 score based on intravital biopsy data.
    Actions against Gross-leukemia were carried out on SZN mice inoculated intravenously with 20 x 10 6 leukemia cells.
    9 1590045 where R is hydrogen (1a) or hydroxyl (16), characterized in that 3’— -amino-3 ′ -epidaunorubicin of the formula
    OH dissolved in a water - acetone 20 4: 1 v / v mixture is reacted at room temperature with salicylaldehyde to give the corresponding 3'-epi-N-salicylidene derivative (III), which is reacted with trifluoromethanesulfonic anhydride at -10 ° C in anhydrous dichloromethane and in the presence of dry pyridine and the obtained N-salicylidene-3'-epi-4-0-trifluoromethanesulfonate is dissolved in methanol and subjected to acid hydrolysis at room temperature for 1 h η- toluenesulfonic acid to give 3 x -deami -deoksi o-4-epi-3-epi-g 'G 4' -epimino-daunorubicin (IV), which was converted. to the corresponding N-trifluoroacetyl derivative (V) by treatment with trifluoroacetic anhydride in a solution of dichloromethane, which in turn is reacted with a catalytic amount of sulfuric acid in acetone at 10 ° C and the resulting 4 * -deoxy · -4 Ζ -epi-U-trifluoroacetyl-3 * -deamino-3 ^ -hydroxidownomine (VI) is subjected to mild alkaline hydrolysis at 0 ° C for 1 h with a 0.1 N aqueous solution of sodium hydroxide to obtain the desired product 1a as a hydrochloride by treatment with methanolic hydrogen chloride in methanol, which, in if necessary, n evraschayut to the corresponding 14-bromo derivative by treatment with aqueous bromine solution from which, after hydrolysis with aqueous sodium formate at room temperature provided the desired product 16 as hydrochloride.
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