• 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:
    Compounds of the formula I : wherein R₁ =H, CH₃; m = 0,1;R₂ = R₃ = H or R₂, R₃ = bond, R₄ = C₁-C₄ hydrocarbon, n = 1 or 2 and their pharmaceutically acceptable salts are antihypertensive agents. Their preparation and pharmaceutical compositions containing them are also described.
    公开号:SU1517763A3
    申请号:SU874202920
    申请日:1987-07-20
    公开日:1989-10-23
    发明作者:Темперилли Альдемио；Эччел Розанна；Брамбилла Энцо；Сальвати Патриция
    申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
    IPC主号:
    专利说明:

     cm
    This invention relates to a process for the preparation of tetracyclic indolce derivatives, namely, to new derivatives of 5 () abeergoline of the general formula
    sn,
    n
    HN
    20
    where n 1 OR 2, m O or 1, possessing properties to reduce blood pressure.
    The purpose of the invention is to obtain new ergoline derivatives, which have pharmacological advantages over a known drug - catalum,
    Example 1.1- ((5- () Lbeo-25 9,10-didehydro-6-methylergolin-8r-yl) methyl) -2,4- (1H, 3N) -pyrimidinedione-Pgoxide.
    l 5- 0.) Abeo-9,10 DV Dehydro-6-ethylergoline-3B-methaneamine.30
    10.3 g of triphenylphosphine, 5.4 g of phta-imide and 6.9 g of ethylazodicarboxylate are added with stirring and 25 ° C to a solution of 5 g of 5- (1) abeo-9.1 0-didehydro-6-methylergoline-CI -methanol 35 in 1OO ml of tetrahydrofuran. After h
    the solvent is evaporated in vacuo, the residue is dissolved in 10% tartaric acid. This solution is re-extracted with ethyl acetate, then basified with ammonium hydroxide and extracted with dichloromethane. After evaporation of dichloromethane, a crude residue of 6.3 g of 2 - ((5 - () abeo-9, 10-didehydro-6-methylergoline-8 | 3-d3 -yl) methyl) -1H-ISOINDOL-1,3- (2H) -dione,
    m.p. 174-176 C.
    This substance is dissolved in 80 ml.
    ethanol and 80 ml of tetrahydrofuran, 3.15 ml of hydrazine hydrate are added, and the Q solution is refluxed for 5 hours. After evaporation of the solvent, the residue is dissolved in water and dichloromethane. After evaporation of the organic layer, 4 g of the title compound remained (amorphous).
    B. 1 - ((5-10- 9) Abeo-9,10-didehyde-po-6-methyl-ergolin-8A-yl) methyl) -2.4- - (1H, 3N) -pyrimidinedione.
    55
    0
    five
    0
    five
    0
    five
    Q З

    A mixture of 3.25 g of 5- (1 0-9) abeo-9,10-α-dehydro-6-methylergolIN-8Y-methane-amine and 1.45 ml of ethyl acrylate in 50 ml of ethanol is refluxed for 6 h. The solvent is evaporated, the residue is purified chromytographically on a column of silica gel, using ethyl acetate as an eluent with increasing amounts of ethanol (from 0 to 10%), 3.3 g of ethyl ester are obtained (((5 - () abeo-9,10- -hydro-6-methylpergolin-8p-yl) -methyl) - | -alanine, melted at 1 28-130 ° С.
    To a solution of 1.53 g of potassium cyanate in 15 ml of water is added a solution of 3.3 g of ethyl ester N - ((5-O) abeo-9,10-didehydro-6-methylergoline -8 | 3-yl) metsh1) - alanine in 60 ml of water and 18.6 ml of 1N. hydrochloric acid. The mixture is heated for 9 hours at 90 ° C., then the separated solid is filtered off and purified by chromatography on a C silica gel using dichloromethane with increasing amounts of methanol (from 0 to 8%) as eluent, 2.1 g of the above substance is obtained, Shake at 234-236 ° C.
    V. 1 - ((5 - () Abeo-9,0-didehydro-6) methyleneglin-8I-yl) methyl) -2.4- (1H, 3N) -pyrimidinedione-K-oxide. A solution of 1.37 g of 1 - ((5 - () abeo-9, 10-didehydro-6-methyl ergoline--. -8A-yl) methyl) -2,4-OH, 3N) -pyrimidine-, dione 80 ml of tetrahydrofuran and 1 O ml of dimethylformamide are treated with 0.84 g of metachlorobenzoic acid in 10 ml of tetraprofrofuran. This solution was left at room temperature for 1 hour and then the solvent was evaporated. Adding 6 ml of water containing 0.42 g of sodium bicarbonate gives 1.1 g of this substance, which is isolated by filtration. T. pl. 198-200 ° C.
    Example 2. 1 - ((5- (la-) Abeo-9, 1 0-didehydro-6-methylergolin-8/9-yl) methyl) -2,4-imidazolidandion-H - oxide.
    L. 1 - ((5ЧЛО- 9) / 6ed-9,10-didegid-po-6-methyl-ergolin-8A-yl) metip) -2,4-imidazolidinedione.
    A solution of 1.93 ml of bromoacetic acid ethyl ester in 10 ml of dimethylformamide is added to a cooled suspension of 4.3 g of 5- (1) abeo-9, 10-β-dihydro ro-6-methyl er gol-8/3-methylamine and 2.4 potassium carbonate in 50 ml of dimethylformamide. At the end of the reaction, the solution is evaporated in-vacuum, poured into ice water and extracted with dichloromethane.
    The residue of the organic layer is purified chromatographically on a column of silica gel, using ethyl acetate as a component with increasing amounts of ethanol (from 0 to 10%). 3.5 g of N- (3- (10-; 9) abeo, 10-didehydro-6-methyl-argolin-8ft-yl) methyl ethyl) glycine ethyl ester are obtained, which melt at 141-142 ° C.
    This ethyl ester of N - (((5- (I) abeo-9,10-didehydro-6-methyl-ergolin-8-yl) methyl) paper (3.5 g) is treated with 1.67 g of potassium cyanate, as described in Example 1 B. The substance is obtained with a yield of 75%, i.e. 170-172 ° C.
    B. 1 - ((5 - () abo-9,10-dide- | Hydro-6-methylergolin-8/3-yl) methyl) - -2,4-imidazolidinedione-T1-oxy.
    Acting as in Example 1B, but using 1- ((5 - () abeo-9,10-di-degdeprod-b-me tylergolin- -yl) methyl) -2.4-imidazolidine 11 dione, the title substance is - house 75%. M.p. 218-220 ° C.
    Example 3. 1 - ((Trans-5- () abo-1, 6-dimethylergol-8p-yl) -methyl) 2,4- (1P, 3N) -pyrimidine dione.
    I act as in example 1, but using trans-5-) abeo-1,6-dimethylergoli-8A-methamine instead of 5- () a6eo-9, J O-didehydro-6-methyl
    ergolin-8p-methanamino get
    yield 55% of the specified substance, So pl. 185-187 ° C.
    Example 4. 1 - ((Trans-5- (abeo-1,6-dimethylergoline-Bp-yl) IU -2.4- (1H, 3N) -pyrimidinedione-K -s
    I act as in example 1, but I 1- (((trans-5- (1) abeo-1, 6, tylergolin-8 | -yl) methyl) -2.4- (1H

    pyrimidinedione, the substance is obtained with a yield of 83%. Mp 204-206 ° C. zo Example 5. 1- ((Trans-5- ()
    As a standardized comparison drug, it was also tested kato; adj The table shows the ED25 values that were obtained for the studied compounds.
    abeo-6-methyl ergoline) methyl) -2,4-imidazolidinedione.
    When assessing the toxicity of three CJ mice, males in each group were given oral medications with different dosage levels for an approximate determination of toxicity. Behind the mice
    Acting as in example 2, but using trans-5- (1) abeo-6-methyl-ergolin-8p-methanamine, prepared as in example 1, starting from trans-5- - (1) abeo-6 methylergoline-8I- Managed for seven days after

    0 5
    0
    five
    0
    five
    Q
    j dose response.
    tanol get the specified substance with a yield of 55%. M.p. 168-170 0.
    Example 6. 1 - ((Trans-5- - (1 0 ---. 9) abeo-6-methylergol (tn-8/3-yl) methyl-2,4-imidaelindione-N, -oxide.
    ABOUT
    Acting as in Example 2, but using I- ((trans-5- (1) abeo-6-methylergolin-8-yl) methyl-2,4-imidazolidinedione), the title compound is obtained in 80% yield, mp 187-189 ° C.
    The proposed substance and its pharmaceutically acceptable salts are useful antihypertensive agents with a slow onset of action and a prolonged action of the activity.
    I
    When evaluating antihypertensive activity. Intra-arterial measurements of mean blood pressure (KDF) were performed using catheters inserted into the right rat carotid artery under allothen anesthesia. Twenty-four hours after the surgery, the F {7 cells were {still in the Ballman cells, the arterial hollow tubes connected via a pressure transducer to a Beckman blood pressure recorder to continuously monitor the mean blood pressure.
    Mean blood pressure was recorded before oral administration of the drug (baseline values 15, 30, 60, 120, 240 minutes to 24 hours after treatment. Groups of 7-8 rats were orally administered a single dose of the test compound or vehicle, method 0, 5 weight / volume (0.2 ml / 100 g weight). The ED dose values lowering the mean blood pressure by 25 mmHg were calculated for each compound from the regression line.
    As a standardized comparison drug, catholicity was also tested. The table shows the ED25 values that were obtained for the studied compounds.
    watching for seven days after
    7
    drug administration. The resulting lethal dose for 5 is summarized in the table.
    about lethal dose for 50%
    Thus, the compounds obtained are more active in comparison with the cata-ple.
    权利要求:
    Claims (1)
    [1]
    Formula invented and
    The method of obtaining the derivative 5 (10-9) abeergoline formula
    ABOUT
    L
    sn;
    .fJH (ss „-to
    HN
    th)
    Over 800 Over 800
    Over 800 Over 800
    More than 800
    Compiled by And, Fedoseeva Editor N. Bobkova Tehred A. Kravchuk Proofreader V. Kabatsy
    Order 6404/58
    Circulation 352
    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
    eight
    where n 1 or 2i ha O or 1,
    characterized in that the compound of formula
    SNGLN (CH2) -СООСгН5
    N-CH:
    nk
    where p has the indicated values, obtained by reacting the corresponding 5 () aboergoline with an ethyl acrylate or ethyl bromoacetate, is dissolved in water and condensed with a compound of the formula
    (I1D
    at 90 ° g for 6 hours to obtain the desired compound of formula (I), m O, followed, if necessary, by oxidation with an organic peracid at room temperature for 1-2 hours in a mixture of tetrahydrofuran and dimethylformamide to obtain the desired compounds of formula (I), where m 1,
    1,229 (0,661-1,845)
    0.402 (0.297-0.511)
    2.051 (1.180-2.971)
    4,272 (3,256-5,514)
    13.73 (7.86-23.04)
    Subscription
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    优先权:
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