• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Compounds of the formula <CHEM> and therapeutically acceptable salts thereof, in which formula n is 1, 2 or 3; R<1> is selected from the group consisting of H, aliphatic acyl groups containing 2 to 5 carbon atoms, and unsubstituted or substituted benzoyl of the formula <CHEM> wherein R<3> is selected from the group consisting of hydrogen and methyl; and wherein R<2> is selected from the group consisting of H, aliphatic alkyl groups containing 1-4 carbon atoms, benzyl, aliphatic acyl groups containing 2-5 carbon atoms, and unsubstituted or substituted benzoyl of the formula <CHEM> wherein R<4> is selected from the group consisting of hydrogen and methyl; pharmaceutical preparations containing an effective amount of such compounds, and the medicinal use of the compounds.
    公开号:SU961557A3
    申请号:SU792746153
    申请日:1979-04-09
    公开日:1982-09-23
    发明作者:Агне Торстен Олссон Отто；Генри Альфонс Перссон Нильс；Оке Свенссон Лейф；Бертиль Вальдек Карл；Ингвар Леопольд Веттерлин Кьель
    申请人:Актиеболагет Драко (Фирма)；
    IPC主号:
    专利说明:

    pressure in the presence of 0.5 g of Pd / C. After the calculated amount of hydrogen was taken up, the catalyst was filtered and the filtrate was evaporated. After recrystallization of the residue from the ethanol, 1.5 g of the title compound are obtained. 100.5 NMR: (flMCO-dg) (ppm): 0.65 (6H, s), 1.92 (DMSO) 2, (H, m), W.Y. (ZN, s) ,, 25 (1H, m 6.50 (8H, m). Mass spectrum: TMS derivative: M m / e L60; (M-15) m / e kkS. Analogously to examples 1 and 2, the following compounds were obtained: I. 1-4-pivaloyloxyphenylZ-2-tl, -dimethyl-3 (2-methoxyphenyl) propylamino-ethanol in the form of sulfate, NMR: (CDCB) (G (ppm): 1.0 (9H, s), 1.52 (6H, s), (2H, m), 2.90 (2H, m), 3.25 (2H, m), 3.90 (ZN, s), 5.25 (1H, m) , 7.18 (8H, mb, II.1-14-Y-methylbenzoyloxy) -fe D, 1 -dimethyl-3- (2-methoxyphene-propylamino-ethanol in the form of sulfate NMR: (neighbor +) (5 (h ./million): 1.52 (6H, s), 2.02 (2H, m), 2.50 (ZI, s), 2.75 (2H, m), 3.15 (2H, m), 3.85 (3N, s), 5.25 (1H, m), 7.20 (12H, m), III.1- (-oxif enyl) -2-11,1-dimethyl-3- (2-ethoxyphenyl) -propyl-H0-ethanol in the form of hydrochloride. calc. 9.0 GR, Q namd, NMR: (DMSO-dg) (G (ppm) ): 1.1 (ZN, t), where t is a triplet, 1.15 (6H, s), 1.7 (2H, m), 2.2 (DMSO), 2.9 (2H, m), 3.9 ( 2H, KB), i, 8 (1H, m), 7.0 (8H, m IV.1- (A-hydroxyphenyl), 1-dimethyl-A- (2-methoxyphenyl) butyl but-ethanol as sulfate . Mass spectrum: (Ø) PL 3. Purity: 98.6% (determined by chromatography). V. 1- (4-hydroxyphenyl), 1-dimethyl-3 (2-hydroxyphenyl) propylamino-ethanol as sulfate. Mass spectrum: (NH) MH 316. NMR: (CDcjOD 4-CF3COOH) rf (ppm): 1.0 (6H, s), 1.5 (2H, m), 2.8 (2H, m), 2.95 (CD, OD) k, S (1H, m 6.8 (8H, m). The synthesized compounds were tested for pharmacological activity A. Simultaneous determination of bronchospasmolytic, tremogenic, and cardiac stimulating activity. Bronchospasmolytic and tremogenic actions were simultaneously determined on anesthetized cats. Cats weighing 2, 5 kg were anesthetized with pentobarbital by prior intra (1 peritoneal injection ((mg mg / kg) and subsequent intravenous infusion, with In order to ensure a constant degree of anesthesia during the experiment, the arterial blood pressure was measured with an instrument connected to a cannula inserted into the carotid artery. Also, the heart rate was measured with an ECG. made of plastic with a rubber coating. The whole leg was wrapped in metal foil equipped with a plastic coating in order to ensure a constant temperature C. The cat’s back was placed on the operating table and and the rear leg fixed. The tendon was connected to a device for measuring voltage. The isometric voltage was set at 50 g (voltage at rest) and 500 g (maximum voltage). A bipolar platinum electrode was placed on the tibial nerve near the soleus muscle. Incomplete tetanic contractions were measured using a Grass S 8 type stimulator. The pulse wave duration (L | was 0.05 ms at a frequency of 8–12 Hz and a voltage of 5–8 V. Each 20 s was stimulated for 1 8. The cannulae were inserted into the trachea and the lungs were blown through with room air using a Brown apparatus. The frequency was in minutes and the tidal volume was 8-10 ml / kg. The changes in the tidal volume caused by the contraction agent were measured as the amount of air difference between the supplied air and the air, the spirit is necessary breathing pressure. The pressure was constantly measured and excess air was determined using a PT 5 A. The bronchial tone was increased by inhalation of histamine aerosol prepared using 0.1-0.3 mg / ml histamine as a 5 solution in glycerol. Aerosol 79 was obtained using a nebulizer, which was connected to the entrance of the respirator if bronchospasm was caused. If the excess breathing air reached an equal level, the test compound was injected into the bronchial vein. At the same time, bronchospasmolytic, tremogenic, and stimulating cardiac activity of anesthetized cats are determined. The results are summarized in table. 1. Bronchodynamic effect was defined as the dose in moles per kg of body weight of an animal, at which histamine-induced bronchospasm is reduced by 30%. The tremogenic effect was defined as the dose in moles per kg of animal body weight, in which the electrically-induced contractions of the soleus muscle are reduced by 30%. The stimulating cardiac activity was defined as a dose of 7 mol x per kg of body weight of the animal, at which the heart rate increased by 25%. The activity of the synthesized compounds was determined in relation to the activity of terbutaline, which is widely used, in clinical practice. Compared with terbutaline, the proposed compounds exhibit somewhat better bronchospasmolytic effects than tremorogenic effects. For example, compound I exhibits a bronchospasmolytic effect, which is almost three times the bronchospasmolytic effect of terbutaline, whereas its tremorogenic effect is only 0.5 times the tremorogenic effect of terbutaline, and its stimulating heart activity is at the same level , as the stimulating cardiac activity of terbutaline. Table 1
    I2.9 ± 0.6
    sn,
    2
    II0,12tO, 03
    1 2 2 sn
    III1, iftO, 2
    SaN,
    IV0.28 ± 0.07
    sn. sn
    H C-Sons.
    0.9 iO, 1 0.02 1 0,, 05
    V 0,2510,05
    Terbutaline
    0.26io, OA
    0.18 ± 0.03 1B. Bronchospasmolytic activity in oral and subcutaneous applications.
    Bronchospasmolytic activity in guinea pigs of the compound of Example 1 was studied in oral
    and subcutaneous cottage. 8 as a comparison served terbutaline.
    The bronchospasmolytic effect was defined as an effect inhibiting the narrowing of the bronchi caused by histamine on unanesthetized guinea pigs.
    权利要求:
    Claims (1)
    [1]
    The animals were given a solution of 0.3 mg / ml histamine, which was nebulized. In the experiment, guinea pigs of both sexes weighing 190–250 g were used. The control animals, which were given a saline solution, showed increased and irregular breathing after k min after giving histamine aerosol. The breathing of animals that were given the proposed and known compounds did not change after k min after giving histamine aerosol. Before oral application of the proposed and known compounds, the animals were given only water for 15 hours. 30 minutes after the oral application, the animals were given a histamine aerosol .. the activity of the proposed compound is 2.7 times the activity of terbutaline, and in oral dacha 2, 1-fold of terbutaline activity. Formula of the invention. Method of obtaining alkylaminoethanol derivatives of general formula I OH CKj CH-U.S.-Tyan-CC (CHj where R is hydrogen, aliphatic acyl per group with 5-5 hydrogen atoms, unsubstituted or substituted benzoyl of formula
    Subcutaneous application was carried out 15 minutes before giving histamine aerosol. In both experiments, the test compounds were given to animals and the dose of ED was determined, i.e. a dose that protects 50 animals from the action of histamine for more than a minute.
    The dose of the unit was determined in micmop x / kg body weight of the animal.
    0
    i The bronchospasmolytic effect of the proposed compound, 1 - (- hydroxyphenyl), 1-dimethyl-3- (2-methoxyphenyl) -propylamino-3-ethanol, and the known compound, terbutaline, with oral and subcutaneous application are listed in Table 2. with the number of carbon atoms and p 1,2, 3. or their salts in the form of a racemate or an optically active antipode, aphid -j due to the fact that styrene oxide of the general formula 11 g - where R has the indicated values go means protecting hydroxyl a group such as alkyl or benzyl is reacted with a compound of the general formula 1) 1 CHS,. I / l w - c - (sddu- /) (. -J7 l where R and n have the indicated meanings, R- means hydrogen or an amino group protecting the group, for example benzyl, followed by, if necessary, removing the protective groups
    11, 961557. 2
    and highlighting the target product in the sources of information
    free form, in the form of salt, racemate taken into account during the examination of that or optically active is 1. USSR Patent No. 638252, measure.kl. C 07 C 91/32, 1976.
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    同族专利:
    公开号 | 公开日
    NO791199L|1979-10-11|
    EP0004835A1|1979-10-17|
    CY1228A|1984-06-29|
    MY8500403A|1985-12-31|
    BR7902193A|1979-12-04|
    HU178207B|1982-03-28|
    DE2960968D1|1981-12-24|
    FI791118A|1979-10-11|
    IE48569B1|1985-03-06|
    SG6984G|1984-08-03|
    GR66484B|1981-03-24|
    DK146779A|1979-10-11|
    CS228114B2|1984-05-14|
    FI70405C|1986-09-19|
    IE790754L|1979-10-10|
    CA1150296A|1983-07-19|
    NO147103C|1983-02-02|
    AT367022B|1982-05-25|
    ES479440A1|1980-06-16|
    FI70405B|1986-03-27|
    DD142875A5|1980-07-16|
    AU520787B2|1982-02-25|
    SU1011046A3|1983-04-07|
    PT69459A|1979-05-01|
    PH17202A|1984-06-19|
    ATA265579A|1981-10-15|
    ZA791403B|1980-05-28|
    HK35184A|1984-05-04|
    JPS54145624A|1979-11-14|
    AU4568879A|1980-10-09|
    EP0004835B1|1981-10-14|
    ES486580A1|1980-10-01|
    NZ190078A|1984-07-06|
    JPS638936B2|1988-02-25|
    NO147103B|1982-10-25|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NL6610530A|1966-07-27|1968-01-29|
    DE1768167A1|1968-04-06|1971-08-05|Troponwerke Dinklage & Co|1- -2- [3-phenyl-2-methylpropyl- -amino] -aethynol- |
    DE2008654A1|1970-02-25|1971-09-09|C H Boehnnger Sohn, 6507 Ingel heim|Ammoathanoldenvate|
    JPS5721182B2|1976-03-19|1982-05-06|JPS6010021B2|1979-01-31|1985-03-14|Tanabe Seiyaku Co|
    JPS6241829Y2|1980-03-28|1987-10-26|
    EP0052963B1|1980-11-20|1985-02-20|Beecham Group Plc|Secondary amines|
    US4454337A|1981-06-29|1984-06-12|Smithkline Beckman Corporation|Semicarbazide intermediates for preparing 4-substituted indoles|
    CH653322A5|1982-12-01|1985-12-31|Siegfried Ag|METHOD FOR PRODUCING PHENYLETHANOLAMINES.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB1403378|1978-04-10|
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