• 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:
    1. Claims (for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE) S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy) phenyl]-1,1-diethylurea (S(-)-celiprolol) and its pharmaceutically acceptable acid addition salts. 1. Claims (for the Contracting State AT) Process for the preparation of S(-)-3-[3-acetyl-4-(3-tert.butylamino-2-hydroxypropoxy) phenyl]-1,1-diethylurea (S(-)-celiprolol) and its pharmaceutically acceptable acid addition salts, characterised in that a) the racemate of the formula see diagramm : EP0155518,P10,F1 in the form of the base is reacted with an enantiomer of a chiral resolving acid in a suitable organic solvent, the mixture of the two diastereomeric salts formed in this manner is separated by fractional crystallisation, and, after separating each diastereomeric salt which contains the laevorotatory enantiomer of the compound of the formula I in the S configuration, is reconverted into the free base or a pharmaceutically acceptable addition salt and the resolving acid is recovered, or b) S(+)-3-[3-acetyl-4-(2,3-epoxypropoxy)-phenyl]- 1,1-diethylurea of the formula see diagramm : EP0155518,P10,F2 is reacted with tertiary butylamine in the presence of water at room temperature or with gentle heating to a maximum of 40 degrees C, and then the laevorotatory enantiomer of the compound of the formula I thus obtained is converted as required into a pharmaceutically acceptable addition salt.
    公开号:SU1309908A3
    申请号:SU853865408
    申请日:1985-03-14
    公开日:1987-05-07
    发明作者:Целс Герхар；Гратц Рихард；Шлегл Карл；Хофер Отмар；Джей Гордон Роберт
    申请人:Хеми Линц Аг (Фирма)；
    IPC主号:
    专利说明:

    one
    1309908
    This invention relates to a process for the preparation of a new compound, S (-) - 3-C3-acetyl-4- (3-tert-butylamino-2-; hydroxypropoxy) phenyl -1,1-diethyl urea (S (-) - tseliprolol) forgum

    I 6 GSH
    About II
    S-Shz.
    0-CH CH-CH -N;
    Ontret.
    or its hydrochloride, with a beta-receptor blocking effect, which can be used in the pharmaceutical industry.
    The purpose of the invention is to develop a method for obtaining new compounds that have a higher activity than lime compounds.
    Example 1. In a mixture of 0.86 ml of tert-butylamine and 0.86 ml of water, 250 mg of 5 (+) - 3-acetyl 4- (2,3-epoxypropoxy) phenyl -1,1- diethyl urea are added at room temperature and then stirred for 6 hours. Excess tert-butylamine is then distilled off without heating to vacuum. The residue is diluted with water and the isolated base is extracted to exhaustion with chloroform. The solution of chloroform after drying with Na2SO4 in vacuo is completely ci-strained.
    The residue obtained is mixed with 1.5 MP of acetone, the solution is contaminated with a crystal, and, to improve crystallization, it is cooled for 5 hours to Ot, the precipitated crystalline is sucked off and dried
    The yield of the base S (-) - zeliprolol 225 mg.
    Ujyjg -6.3 (from 0% c). CD (ethanol) spectra: (320 0.25..
    Example 2. Getting hydrochloride.
    12.0 g of base S (-) - celiprolol is dissolved in 54 ml of acetone and mixed with a calculated amount of 4 and. HC and the resulting crystallized acid is removed after 2 hours at 4 seconds, washed with acetone and dried.
    Output 5 (-) - goalprapol-hydrochloride and 11.2, g,
    2
    (with
    10% in methane188
    five
    0
    0
    Found,%: C 57.5; H 8.5; N 9.9; About 15.5; CE 8.5.
    Calculated,%: C 57.7; H 8.24; N 10.1; O 15.4; CP 8.5
    Example 3. The process is carried out analogously to example 1 with the difference that stirring is performed for 6 hours at 10, 20, 30 and 40 ° C. At the same time receive 5 (-) - tseliprolol, mg:
    Temperature, C
    10218
    20225
    30211
    40184
    Example 4. A. Effect on positive chronotropic isoprenalin activity.
    Female and male rats whose body weight is 200-300 g are anesthetized with pentobarbitol (30 mg / kg i.p.). The investigated substances are administered intraperitoneally (i.p.) at a dose of 40 mg / kg. Fifteen minutes after the intraperitoneal administration of the test substance, 1-00 µg / kg of isoprenaline is injected intraperitoneally. Isoprenaline-induced increase in heart rate is determined using an electrocardiogram. When isoprenaline is administered without prior administration of the test substance, the increase in heart rate, which was caused by isoprenaline (too µg / kg), is 146 beats per minute.
    This value is taken as 100%, 0 and the increase in heart rate under the action of the same dose of isoprenaline, however, after applying the test substance, is determined as a percentage of the ratio to the action of isoprenaline, taken as 100%.
    The effect of the test substance on isoprenaline-induced tachycardia is a good method for determining the activity of a substance that has an I1-adrenergic blocking effect. The substance under investigation is more active, the less pronounced is caused by isoprenaline tachycars 5 days after the injection of the test substance.
    B. Inhibition of 1-HBP-, respectively ICYP-binding on rat cardiac membrane.
    0
    The rat heart membranes are incubated with constant amounts of 125 iodine-hydroxybenzylpinolol (1-HBP) or 125 iodine-cyanopindolol (1-CYP) and increasing concentrations of 5 (-) - celiprolol or (E, 5) -seliprolol (comparative ) The solutions are filtered and washed, after which the Gammacounter quantitatively determines the bound quantities of iodine-oxy-: benzylpinolol, respectively, iodine-cyanopindolol. Evaluation of numerical data gives the inhibition constant K of the test substances.
    The following results were obtained;
    A. Effect on the positive) chronotropic activity of isoprenaline. The U, p (such dose of celiprolol, which weakens the effect of 100 µg / kg of isoprenaline on 50% of the control experiment), mcg / kg:
    S (-) - Tseliprolol 0.1-0.3
    (K, 5) -Tseliprolol 0.76
    In this test, 5 (-) - targets are in
    at least three mice. The doses studied were: intravenously 25-100 mg / kg, per OS 700-2500 mg / kg.
    The results of LD (mg substance / kg body weight) are presented in the table.
    fO
    15
    20
    S (-) - Purpose intravenously
    (K, 8) —It is targeted by intravenous
    5 (-) - Purpose LOL per OS (R, 5) -Targerolol per OS
    75-100 50-75
    75
    1500
    2000
    50-60
    1500
    2000
    As can be seen. From the table, the acute toxicity of S (-) - tseliprolol and (R, S) -seliprolol administered intravenously is
    two times more active than (R, S) -ce-25 is approximately the same, with the introduction of prolol.
    B. Inhibition of 1-HBP, respectively, 1-SUR-binding to the rat cardiac membrane.
    Braking 1-NVR
    Inhibition constant K, mol / l: 8 (-) - Celiprolol 1,4-10 (K, 8) -Celiprolol 3,7 Srbdstvo S (-) - tseliprolol to the beta-receptors of the rat cardiac membrane is 2.6 times stronger, than affinity (R, S) - goal of prolol.
    Brake; 1-SUR;
    Inhibition constant K, mol / l: 5 (-) - Celiprolol 1,3-10 (R, S) -Cyliprolol 3,3-10
    at least three mice. The doses studied were: intravenously 25-100 mg / kg, per OS 700-2500 mg / kg.
    The results of LD (mg substance / kg body weight) are presented in the table.
    fO
    five
    0
    S (-) - Purpose intravenously
    (K, 8) —It is targeted by intravenous
    5 (-) - Purpose LOL per OS (R, 5) -Targerolol per OS
    75-100 50-75
    75
    1500
    2000
    50-60
    1500
    2000
    As can be seen. From the table, the acute toxicity of S (-) - tseliprolol and (R, S) -seliprolol administered intravenously is
    approximately the same, when administered orally with 5 (-) - targets, prolapol compared to (K, 5) -seliprolol exhibits a slightly higher acute toxicity. This difference can
    to be explained by a stronger pharmacological activity of 8 (-) - target prolol. Since, due to a stronger pharmacological activity, the substance is administered in a smaller amount:
    this fully compensates for the disadvantage of increased acute toxicity when administered by mouth.
    formula of invention
    The affinity of S (-) - tseliprolol to the beta receptors of the rat cardiac membrane is 2.5 times stronger than the affinity of (R, S) -seliprolol.
    Thus, as shown by the results obtained during the experiments, the results of 5 (-) - goals of cycrolol are at least two times more active than (R, S) - goals of goalsrol.
    B. Acute toxicity of 5 (-) - targets - prolol compared to (I, 8) - target - prolol.
    The acute toxicity of 8 (-) - target cells or (R, 8) -eliprolol is determined after intravenous administration or oral administration to mice. For each sex and each dose, apply
    The method of obtaining 8 (-) - 3- 3-acetic st-4- (3-tert-butsh1amino-2-hydroxy-propoxy) phenyl -1,1-diethylurea or its hydrochloride, characterized in that 8 :( +) - 3- 3-acetyl-4- (2,3-epoxypropoxy) F-, 1-diethyl urea formula
    C2H5 C
    ABOUT . CH-t. 0
    513099086
    is reacted with tert-butafi, if necessary, is converted with tylamine in the presence of water to hydrochloride by treatment with hydrochloric temperature from room temperature to 45 ° C, with acid. the resulting product highlighted
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining S (-) - 3- [3-acetyl-4- (3-tert-butylamino-2-hydroxypropoxy) phenyl] -1,1-diethylurea or its hydrochloride, characterized in that S: (+) - 3 {3-Acetyl-4- (2,3-epoxypropoxy) phenyl] -1,1-diethylurea of the formula with 2 n 5
    II S-SSH o-sn 2 -sn-sn 2
    () they are reacted with tert-butylamine in the presence of water at a temperature from room temperature to 45 ° C, the product obtained is isolated · * removed or, if necessary, transferred to the hydrochloride by treatment with hydrochloric acid.
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    同族专利:
    公开号 | 公开日
    EP0155518B1|1989-08-30|
    CS250683B2|1987-05-14|
    DD232489A1|1986-01-29|
    PT80135A|1985-04-01|
    HUT37392A|1985-12-28|
    SU1333235A3|1987-08-23|
    FI850860L|1985-09-22|
    DK124585D0|1985-03-20|
    GR850496B|1985-03-15|
    AU567797B2|1987-12-03|
    DK124585A|1985-09-22|
    FI83636B|1991-04-30|
    NO161254C|1989-07-26|
    RO91352A|1987-04-30|
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    YU44385A|1987-06-30|
    NO850834L|1985-09-23|
    PT80135B|1987-10-20|
    ES8603390A1|1985-12-16|
    HU193596B|1987-11-30|
    RO91352B|1987-05-02|
    RO91353B|1987-05-01|
    JPS60209557A|1985-10-22|
    PL252463A1|1985-11-19|
    EP0155518A3|1986-06-25|
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    IL74383D0|1985-05-31|
    CA1236116A|1988-05-03|
    IL74383A|1988-09-30|
    DE3572656D1|1989-10-05|
    YU45707B|1992-07-20|
    RO91353A|1987-04-30|
    AU3972285A|1985-09-26|
    CS250682B2|1987-05-14|
    DD234860A1|1986-04-16|
    EP0155518A2|1985-09-25|
    FI850860A0|1985-03-04|
    AT45945T|1989-09-15|
    NO161254B|1989-04-17|
    YU44485A|1987-06-30|
    DE3410380A1|1985-10-10|
    PL252462A1|1985-11-19|
    ZA852086B|1985-11-27|
    FI83636C|1991-08-12|
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    AT388099B|1986-11-26|1989-04-25|Chemie Holding Ag|Process for the production of solid pharmaceutical forms of 3-phenyl)-1,1-diethylurea hydrochloride|
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    US5227526A|1992-06-16|1993-07-13|Mallinckrodt Specialty Chemicals Company|Resolution of 3-dimethylamino-2-methylpropiophenone |
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19843410380|DE3410380A1|1984-03-21|1984-03-21|S- CELIPROLOL, THEIR PHARMACEUTICALLY COMPATIBLE SALT, METHOD FOR THE PRODUCTION THEREOF, USE IN THERAPY AND PHARMACEUTICAL PREPARATIONS|
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