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    • 专利摘要:
    3-Spiro-5''-oxazolidine-2'',4''-dione derivatives of Vinca alkaloids, useful as anti-tumor agents and as intermediates.
    公开号:SU843753A3
    申请号:SU772549952
    申请日:1977-12-05
    公开日:1981-06-30
    发明作者:Корин Миллер Джин；Эдвард Гутовски Джеральд
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD OF OBTAINING DIMERNK
    indoldigidioindoldionovyh
    CONNECTIONS
    where R, R f R, R5 are as defined above and is a hydroxy group or OCOCHj, is reacted with isocyanag CMSO. where R is as defined above, in an inert organic solvent, followed by depreciation of the target products.
    For the preparation of compounds of general formula .1, where R is hydrogen, R is a CABD process, it is preferably carried out at room temperature, and in the case of compounds of general formula 1, where R® and R together form a bond between C and N, the process is preferably at 30-110 ° C
    Compounds of general formula 1 have antitumor activity.
    Example 1. Obtaining vinblastin-3-methyl-3-spiro-5-oxazolidin-2, 4-dione.
    A solution containing 2.84 g of vinblastine free base in 40 ml of anhydrous benzene is mixed with 15 ml of methyl isocyanate, the reaction mixture is boiled for 6 hours, then cooled and the volatile components are removed by evaporation. The residue containing vinblastin-3-methyl-3-spiro-3-oxazolidin-2, 4-dion is subjected to chromatography on 200 g of silica (activity 1). The chromatogram is treated with 1 l of methanol in benzene, followed by treatment with 2.5 l of 6% methanol in benzene, with which vinblastin-3-methyl-3-spiro-5-oxazolidin-2, 4-dione is eluted; yield 0.9764 g, M 835.
    According to this method, 270 g of the free base of vinblastine is reacted with butyl isocyanate, to obtain vinblastine 3 -n-butyl-3-spiro-5-oxazolidin-2, 4-dione, yield 41 mg, mass spectrum: 891, 877, 859, 837 , 836, 819, 818, 792, 747,, 543, 536 (512), 381, 380, 355, 341, 325, 295 (188), 154, 149, 135, 136, 122, 121. 107.
    98.9 mg of vinblastine free base are reacted with allyl isocyanate to give vinblastin-3-allyl 3-spiro-5-oxazolidin-2, 4-dione, yield 31.3 mg. The peaks of the mass spectra are at 875, 861, 844, 830, 831, 802, 803 (784), 650, 543, 520, 380, 381, 355, 295,273,242,154, 149/143, g35, 122, 121,107.
    Example 2. Obtaining vincristin-3 -methyl-Z-spiro-5-oxazoline-2, 4-dione.
    Vincristine (free base), prepared from 158.3 mg of vinristine sulfate using standard methods, is dissolved in 15 ml of anhydrous benzene, mixed with 2.5 ml of methyl isocyanate, boiled for 6 hours, left at room temperature, the mixture is boiled 4 hours. After evaporation, a residue weighing 159, 6 mg is obtained, which dissolves in methanol, but:
    does not dissolve in methylene dichloride. After preparative thin layer chromatography using a solvent consisting of ethyl acetate and ethanol, 3: 1, four bands are obtained, of which one third, tio polarity, is vincristine-3-methyl-3-spiro-5 - oxazolidin-2, 4 -dione, yield 26.8 mg. The peaks of the mass spectrum ions at 863, 8.49, 831, 818, 806, 790, 751, 708, 647, 650, 635, 480, 393, 369, 355, 283, 270, 268, 183, 171, 168, 154, 141, 126, 122, 121.
    Example 3 Preparation of 1-desmethyl-4-deacetyl-4- (N-methylcarbamoyloxy) -vinblast-3-methyl-3-spiro-5-ox Azolidin-2, 4-dione.
    Using the procedure described in Example 1, 21.7 g of 1-desmethyl-4-deacetyl-vinblastine is reacted with 3 ml of methyl isocyanate in 12 ml of anhydrous methylene dichloride at boiling point. 1-Desmethyl-4-desacetyl-4- (N-methylcarbamoyloxy) -vinblastin-s-methyl-3-spiro-5-oxazolidine 2, 4-d-ion is isolated using the procedure described in Example 1 and purified by preparative thin-layer chromatography using methanol, 5.5 mg of purified product are obtained. The resulting compound has the following physical characteristics. The peaks of the mass spectrum ions at 836, 834, 779, 777, 368, 256, 241, 213, 155 and 149.
    Example 4. Obtaining vinblastin-3 - ((L-chloroethyl-) - 3-spiro-5-oxazolidin-2, 4 -dione.
    Using the procedure described in Example 1, 1.624 g of vinblastine is exposed to 15 ml / 2-chloroethyl isocyanate in 100 ml of anhydrous benzene. The reaction mixture is stirred for 16 hours at room temperature, then boiled for 2 hours. The resulting residue, containing the water-soluble complex of vinblastine and β-chloroethyl isocyanate, is separated. The precipitate in the amount of 1.692 g is dissolved in 30 ml of water, and the resulting aqueous solution is stirred at room temperature for 16 hours. This solution is alkalinized with a dilute sodium hydroxide solution, and vinblastin-3 - ((-chloroethyl) -3-spiro-5 - oxazolidin-2, 4-dion is separated and extracted with methylene dichloride. The methylene dichloride extracts are combined, the solvent is removed by evaporation. The residue containing vinblastine-3-. - () L-chloroethyl) -3-spiro-5-oxazolidine 2, 4-dione, purified by chromatography using 150 g of silica (activity 1) and obtain 1,127 g of purified material. Chromatogram. This is treated with 6% methanol in benzene.
    Ions of the mass spectrum of the obtained compound: 883, 847, 816, 789, 650, 592, 591, 543, 506, 485, 451, 355, 295, 154, 136, 135, 122, 121, 107.
    Example 5. Obtaining vinblastin-3- () L-chloroethyl) -3-spiro-oxa-oolidin-2, 4-dione and vinblastin-3-N- (P) -CHLORETHYL) -carbamate.
    7 ml of L-chloroethyl isocyanate was added to a solution containing 481.2 mg of free vinblastine base in 14 ml of anhydrous β-benzene, boiled for 16 hours. The benzene was removed in vacuo, and the residue was subjected to preparative chromatography on a thin layer of silica using solvent consisting of ethyl acetate and methanol, in the ratio of 3; 1. Two unseparated mobile bands are combined (total yield 379.4 m and po) re-chromatographic. From 47 mg of this mixture on the preparative plate, vinblastin-3 - (p | -chloroethyl) -3-spiro-5 -oxazolidin-2, 4-dione (147 mg) and vinblastin-3-N- {(g) -chloroethyl ) Carbamate (69 mg). This last substance has mass spectra with peaks at - (881) ,. 835, 821, 780, 763, 692, 59O 543, 480, 409, 353, 295, 293, 283, 281, 278, 243, 188, 154, 149 and 135.
    Example 6. Obtaining 4-deacetyl-vinblastin-3-methyl-3-spiro-5-oxazolid 6n-2,4-dione.
    In 99.7 mg of vinblastin-3 -methyl-3-spiro-5-oxazolidin-2, 4-dione, 0.5-n is boiled. aqueous solution of hydrochloric acid for 1.5 h, alkalinized and the precipitate was separated and extracted with methylene dichloride. Methylenedichloride. extracts are evaporated in vacuo. The resulting precipitate was subjected to preparative thin-layer chromatography using silica gel and a solvent consisting of ethyl acetate and methanol in a ratio of 3: 1. The main band contains 4-deacetyl-vinblastin-3 -methyl-3-spiro-5-oxazolidone-2, 4-dione (32.3 mg of purified material). Mass spectra: 807, 793, 763, 762, 749, 734, 690, 493, 453, 408, 355, 295, 268, 167, 171, 154.149, 143, 135, 122, 121, 107.
    Example 7. Preparation of 5-deacetyl-vinblastin-3-methyl-3-spiro-5-oxazolidin-2,4-dione-4- (L-methyl-) -carbamate.
    A solution containing 304 mg of 4-deacetylvinblastin in 10 ml of anhydrous benzene is mixed with 5 ml of methyl etiocyanate,. boil for 6 hours. The solvent is removed in vacuo, the residue (444.4 mg) is chromatographed in a thin layer with a solvent consisting of ethyl acetate and methanol, in a ratio of 3: 1, to obtain purified 4-deacetyl VLB-3 methyl-3-spiro-5-oxazlidin-2, 4-dione-4- (M-methyl) -carbamate,
    having the following physical characteristics: the peaks of .ions of the mass spectrum at 850, 807, 793, 775, 762, 734, 452, 355, 154 and 135.
    Example 8. Preparation of 4-deacetyl-vinblast-3 - (-chloroethyl) -3-spiro-5-oxazolidin-2, 4-dione.
    25 ml of anhydrous methanol saturated with hydrogen chloride at is added to 96.9 mg of vinblastine-3 - (-chloroethyl) -3-spiro-5-oxazolidin0 -2,4-dione, stirred for 18 h, the solvent is evaporated in vacuum Ice water is added. This solution is alkalinized by adding ammonium hydroxide and extracted, four times with methylene dichloride. Further, the methylene dichloride extracts are evaporated in vacuo. The residue in the amount of 88.6 mg is subjected to preparative chromatography in a thin
    0 on silica gel using chromatograms for processing of the solvent, which is a mixture consisting of ethyl acetate and methanol, in a ratio of 3: 1. A band corresponding to Vn 4 was eluted, yield 14.3 mg.
    5 Mass spectra: 841,816,782 ,.
    Example 9. Preparation of 4-deacetyl-vinblastin-3 - (fb-chloroethyl) - -3-spiro-5 -oxazolidin-2, 4 -dione.
    25 ml of L-chloroethyl isocyanate is added to 9.86 g of vinblastine free base. To 200 ml of anhydrous benzene, the reaction mixture is further stirred overnight at room temperature and then boiled for 2.5 hours. A precipitate formed are dissolved in 300 ml of 0.1N. hydrochloric acid solution and boiled overnight. The reaction solution is cooled and alkalinized by the addition of hydroxide.
    0 ammonium, and then extracted with methylene dichloride. Then these extracts are mixed and the solvent is evaporated in vacuo, the residue in the amount of 2.8 g is purified by chromatography on silica gel. The chromatogram is treated with benzene with an increasing methanol gradient. Yield: 192 mg.
    权利要求:
    Claims (3)
    [1]
    1. A method for preparing dimeric indol-dihydroindoldione compounds of general formula 1
    five
    Q)
    0
    -CiHs
     OCNRB
    where R is alkyl with 1-4 carbon atoms, allyl or p is chloroethyl, hydrogen / methyl or formyl, one of R and R is hydrogen or hydroxy, and the other ethyl, R is hydrogen, or R and R are taken together epoxy ring, and ethyl, R - OC-NH-R or -O-C-CH-, R9 ve IIII. E
    o ° 9
    separately hydrogen and R is taken
    separately - OCHijj, or R taken одну together form one bond between C and N, characterized in that the dimeric indol-diindoindole is of general formula II
    "QW
    where R, R, R and R are as defined above, and bxyprop or O-C-CHj is reacted with
    ABOUT
    an isocyanate of the formula RNCO, where R is as defined above, in an inert organic solvent followed by isolation of the desired products,
    [2]
    2. Method POP.1, characterized in that to obtain
    compounds of formula 1, where R is hydrogen, R is OCHij, the process is carried out at
    room temperature.
    [3]
    3. Method POP.1, characterized in that in order to obtain a compound of the formula 1, where R and R together, they form a bond between c and, the process is carried out at an SO-IO C temperature.
    Sources of information taken into account in the examination
    1. Fizer L., Fizer M., Organic Chem. M., Himi, 1970, Vol.2, p.249.
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    引用文献:
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    IT649883A|1960-05-24|
    HU165986B|1973-02-16|1974-12-28|
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    US4012390A|1974-10-16|1977-03-15|Eli Lilly And Company|Vinblastinoic acid|HU181874B|1977-08-08|1983-11-28|Lilly Co Eli|Process for preparing amides of deacetyl-leurosine and deacetyl-leuroformine|
    US4357334A|1980-03-20|1982-11-02|Eli Lilly And Company|Use of VLB 3- carboxamide in treating neoplasms|
    US4362664A|1980-12-29|1982-12-07|Eli Lilly And Company|Vinblastine oxazolidinedione disulfides and related compounds|
    GR81790B|1983-04-29|1984-12-12|Omnichem Sa|
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    优先权:
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    US05/747,575|US4096148A|1976-12-06|1976-12-06|Oxazolidinedione derivatives of Vinca alkaloids|
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