• 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:
    4-Desacetyl vincaleucoblastine C-3 carboxhydrazides of the formula …<CHEM>… wherein Q is …<CHEM>… R is, when taken singly, C1-C3 alkyl, beta -hydroxyethyl, beta -acetoxyethyl, C2-C4 alkanoyl, dichloroacetyl, benzoyl or C1-C3 alkyl carbazyl;… R<1> is, when taken singly, methyl or H only when R is C1-C3 alkyl and is H otherwise; and… R and R<1>, when taken together, form a C1-C3 alkylidene group. …<??>The compounds are prepared by reacting the C-3 carboxazides with …<CHEM>… or by reacting the unsubstituted C-3 carboxhydrazide with acetone or with the appropriate aldehyde, acid anhydride or acid chloride. …<??>The compounds are useful in inhibiting the growth of tumors.
    公开号:SU1225490A3
    申请号:SU792925606
    申请日:1979-04-20
    公开日:1986-04-15
    发明作者:Джозеф Куллинан Джордж；Джерзон Коерт
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    I
    This invention relates to a process for the preparation of new derivatives of 0-disodium-acetylvinkleicoblastin-c3 carboxyhydrazide of the general formula
    he
    1j, -CzHs
    12254902
    This goal is achieved by the method of obtaining new derivatives of O-de-acetylvinkleicoblast-C-carboxyhydrazide, which means that O-. Desacetylvinklecoblastin C-carboxyxazide is reacted with a compound of the formula
    and
    ten
     -N
    Where
    - C, -Cj, -alkyl, 2-hydroxyethyl, 2-acetoxyethyl or ethoxycarbonyl;
    R is a hydrogen atom or methyl if R is C-C-alkyl, or a hydrogen atom at the other specified R values,
    or their salts with anticarcinogenic effects.
    Natural vinca alkaloids, such as vindesine O -dezacetyl-vincalecoblastin-c-carboxamide, have a pronounced anticarcinogenic effect. However, they do not have sufficiently high activity against a number of malignant tumors, for example, osteogenic Rajue sarcoma and Gardner lymphosarcoma.
    The reaction of acyl azides with various organic compounds with a sufficiently reactive amino group is known. The reaction usually proceeds under mild conditions at room temperature in an inert organic solvent and gives a high yield of the corresponding acyl ester 3 in one.
    The aim of the invention is to expand the means of action on a living organism.
    ar, s v
    and
     -N
    Where
    R - C; | -C-alkyl, 2-hydroxyethyl, 2-acetoxyethyl or ethoxycarbonyl;
    a hydrogen atom or methyl, if R C,
    te
    1 K, or a hydrogen atom at other specified R values,
    in an inert organic solvent, such as methylene chloride, optionally with pos. acetylation, if R is 2-hydroxyethyl, and isolate the product in free form or as a salt.

    Pr i.-m e p 1. Preparation of O-dezadetilvinc lecoblastin-C-carboxy- (L-methyl) -g, Drazid,
    To a solution containing 1 g of O-dezacetyl-vinca-lecoblast C-carboxy-acid in 150 ml of methylene dichloride 5 is added 20 ml of methyl hydrazine. The reaction vessel is hermetically sealed. The solution is sealed) and left for 6 hours at room temperature. The dichloromethane solution is extracted several times with water to remove excess
    methyl hydrazine. The dichloromethane solution is dried and the solvent is evaporated in vacuo. O-Distacene-vincale-lecoblastin-C-carboxy- (N-methyl) -hydrazide is obtained in the form of a tan brown amorphous powder. The target product has the following physical characteristics: ts t / s 782 (M), 441,355,154. IR spectrum 3450 cm FMN), 1715
    (-SORSN,); 1655 hl (-SOOSh).
    Example 2. Obtaining O-dezatsetilvinkaykoblastin-C-carboxy- (bF, No.-dimethyl) -hydrazide
    20 mm of N, N-dimethylhydrazine is added to a solution of 1.5 g of 0-dezacetyl-vinylcalobate-C-carboxazid in dichloromethane. The reaction vessel is sealed and left for 60 hours at room temperature. The resulting solution is evaporated to dryness and dissolved in dichloromethane. The dichloromethane solution is extracted once with dilute aqueous ammonia
    and then water to remove excess N, N-dimethylhydrazine., The dichloromethane solution is dried and evaporated to dryness. The resulting chromatographic powder on silica gel. Target product eluirugate with ethyl acetate: methanol 1: 1. The fractions containing the desired product according to thin layer chromatography (silica gel eluted with ethyl acetate: methanol 1: 1 are combined and evaporated to dryness. This is obtained
    0-desacetyl-vinca-leukoblast-C -carboxy- (No., No.-dimethyl) -hydrazide as a tan powder of amorphous. The entrance is 250 mg. The target product has the following physical characteristics: ts t / e 796 (), 737, 455, 355, 154. IR spectrum: 1715 cm- (COO); 1670 cm (CON).
    EXAMPLE 3. Preparation of O-dis-acetyl-vincale-6-platinum-C-carboxylic acid No.- (2-oxyethyl) -hydrazide.
    3 g of O-deacetyl-vinca-leukoblast-C -carboxazide is dissolved in dichloromethane and 15 ml of 2-hydroxyethylhydrazine are added. The reaction vessel was sealed and the reaction mixture was stirred overnight at room temperature, after which it was evaporated and the residue was distributed between methylene chloride and water. The solution with methylene chloride was washed twice with water, dried and evaporated to dryness. The amorphous powder is chromatographed on silica gel, the target product is eluted with ethyl acetate: methol 1: 1. The fractions containing the target product according to thin layer chromatography (silica gel, eluted with ethyl acetate: methanol 1: 1, are combined and evaporated to dryness. This is obtained
    1g of the desired product in the form of a tan brown amorphous powder. The target product has the following physical characteristics: IR spectrum 1720 cm (COO); 1655 (CON).
    Example 4. Preparation of O-dis-acetyl-vinca-lecoblastin-C-carboxy- (2-acetoxyethyl) hydrazide.
    162-4 mg of o-desacetyl-vinalecoblasin-C-carboxy-N 2 - (2-hydroxyethyl) - hydraeid is dissolved in 50 ml of dichloromethane. 220 mg of acetic anhydride was added to the resulting solution. The reaction vessel is sealed and left overnight at room temperature. . temperature Then the reaction mixture is washed with a dilute solution of ammonium hydroxide and water. Received
    -.



    The dichloromethane solution is dried and evaporated to dryness. Amorphous powder chromatography on silica gel in the system ethyl acetate: methanol 1: 1.
    5 The fractions containing the desired product according to thin layer chromatography are combined and evaporated to dryness. 215 mg of a tan amorphous powder are obtained. The product has the following physical characteristics: MS t / e 854 (m), 795, 651, 513, 355, 154.
    PRI me R 5. Preparation of O-disintegrating, gteykoblastin-C-carboxy15 (N-ethoxycarbonyl) -hydrazide and its sulfate salt.
    900 mg of O-desacetyl-vinky lecoblast-C -carboxazide is dissolved in dichloromethane. 1 g of ethyl hydrazide
    The 20 carbonic ester was dissolved in dichloromethane and added to the resulting solution. The reaction vessel was sealed and left overnight at room temperature. Then the reaction mixture is evaporated to dryness and the residue is partitioned between dichloromethane and water. The dichloromethane layer is washed twice with a large amount of water, dried. And evaporated to dryness.
    30 O-de-acetyl-vincal-leco-clastine-C carboxy- (N-ethoxycarbonyl) - hydrase hell is obtained in 1 Hz of a tan-colored amorphous powder. The desired product is converted to the corresponding sulfuric acid salt by dissolving the amorphous powder in anhydrous ethanol, followed by adjusting the pH to approximately 4 with a 2% solution of sulfuric acid in absolute ethanol. You .Q. The precipitated sulfate is filtered and dried. 104mg of the expected product is obtained in the form of a tan powder.
    45 The proposed compounds were found to be active by inhibition of growth of resuscitated tumors in mice and / or with an increase in life expectancy in mice inoculated with a tumor. In order to show the activity of the compounds obtained, this drug is administered, usually parenterally, at a given dosage level for 7-10 days. Tumor size is measured at 3rd
    55 or 7th day in case of tumor growth inhibition. In the study of the prolongation of life, the treated animals are compared with the controls.
    35
    The table shows the results. The new compounds differ in their
    Experimental studies, in the ho-antitumor spectrum from a vincade, which are treated with transplanted oiu-leucoblastin, vincristine, and vindechule, are treated with prod- um co-zine. €; dynamic
    GLS 0,25-0,5x10 Tok-Toxic
    sichna
    Order 1971/62 Circulation 379Subscription
    VNIRSHI State Committee of the USSR
    for inventions and discoveries 113035, Moscow Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod; st. Project, 4
    权利要求:
    Claims (2)
    [1]
    A method of obtaining derivatives! ABOUT-. deacetylvincaleukoblastin-C 3 -carboc- where Q is NH-NRR.,,
    R is C 4 -C g- alkyl, 2-hydroxyethyl, 2acetoxyethyl or ethoxycarbonyl;
    R 4 - hydrogen or methyl, if R - C f -C 2 -alkyl, or hydrogen with other specified values of R, or their salts, characterized I that the g ^ O-C 3 -dezatsetilvinkaleykoblastin -karboksazid reacted with the compound of General ^ formula 'H 2 N-NRR 4 , where R is Cf-Cj, -alkyl, 2-hydroxyethyl,
    [2]
    2-acetoxyethip or ethoxycarbonyl;
    R. is a hydrogen atom or methyl, if R is C ^ -C ^ -alkyl, or a hydrogen atom at other indicated R values in an inert organic solvent such as methylene chloride, if necessary followed by acetylation, if R is 2- hydroxyethyl, and the desired product is isolated in free form or in the form of a salt.
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    同族专利:
    公开号 | 公开日
    SU1061698A3|1983-12-15|
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    CS218584B2|1983-02-25|
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    PL215911A1|1980-03-24|
    DK160679A|1979-10-21|
    IL57168D0|1979-07-25|
    US4166810A|1979-09-04|
    PL119416B1|1981-12-31|
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    EP0005051B1|1982-12-01|
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    GB2019396B|1982-09-15|
    AR228940A1|1983-05-13|
    BG33296A3|1983-01-14|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    US3370057A|1964-04-27|1968-02-20|Lilly Co Eli|Leurosine|
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    US4801688A|1986-05-27|1989-01-31|Eli Lilly And Company|Hydrazone immunoglobulin conjugates|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/899,032|US4166810A|1978-04-20|1978-04-20|Derivatives of 4-desacetyl VLB C-3 carboxyhydrazide|
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