• 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:
    The present invention relates to new compounds of the formula as well as their preparation, pharmaceutical preparations containing same, and method of treating acute myocardial infarction. The compounds which possess beta-adrenoceptor blocking activity are very shortacting and are preferably intended for treatment of acute myocardial infarction by administration by means of injection.
    公开号:SU1082317A3
    申请号:SU813289352
    申请日:1981-06-01
    公开日:1984-03-23
    发明作者:Ингемар Карлсон Энар；Беньямин Рудольф Густафсон Билл；Торстен Лундгрен Бо
    申请人:Аб Хессле (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of novel aminopropanol derivatives having blocking / 3-receptor activity, in particular, to a process for the preparation of aminopropanol derivatives of the general formula
    1082317
    interaction with the compound of the formula OCHCHOHCHglfflCHg (CH2) ftCOORj - lower alkyl R2 and Ra - hydrogen, lower alkyl, lower alkenyl, lower alcoxy forces, cyano group, (0) (CH2) CONHR4-group, where R4 is hydrogen or lower alkyl; n means O or I t means 0-3, or a group (CH2) NHCONHR4, where R4 and have the indicated meanings, or their salts. Aminopropanol derivatives are known to have (J-adrenoblocking activity), such as anapril practicalolol CO. The most similar in structure to the target products are aminopropanol derivatives of the formula OC CHOHCHgHH-), J. -l where R. is alkoxyalkyl. alkyl alkyl C-. 2 halo, hydrogen; R ,, is hydrogen, alkyl C ,, R. And Rr is hydrogen, alkoxy C, alkyl, alkoxyalkyl Cl, J, cyano, hydroxyl, n is an integer of 0-3. The method for producing these compounds is that the compounds. Formulas OOH CHOHCH2NH CK-CCHg) aCtg RI p. b, where R-j-R and n have the indicated values, and Z means a reactive, ethoxylated group that is complexed, where R is. and R; - have the indicated meanings. The target products are in the form of free compounds or salts, and they can be used as substances acting on the C23 sympatho-adrenal system. The aim of the invention is to expand the range of agents acting on a living organism, having improved properties. The goal is achieved by the fact that according to the method for producing aminopropanol derivatives of the formula (I), which is based on the well-known reaction of C3 J and consists in that the compound of the formula H (G J ocHgCH-cng where R and R, have the indicated meanings, is reacted with a compound of the general formula HzUCHgCCHgln COORj (III) where R and n have the indicated meanings, followed by allocation of the target product in free form or as a salt. The process is carried out under known conditions, preferably in a solvent environment at the boiling point of the reaction mixture. The preparation of K- (3- (2-cyanophenoxy) -2-hydroxypropyl-3-aminopropionic acid ester. 15.36 g of 3-aminopropionic ethyl ester hydrochloride and 6.2 g of potassium hydroxide are stirred in 50 bp absolute ethanol until neutral, observed after one hour. When heated under reflux, 8.7 g of 2- (2,3-epoxypropoxy) benzonitrile in 125 ml of absolute ethanol are added. The mixture is then heated under reflux, filtered and evaporated. The residue is taken up in ether, washed twice with water and extracted with 25 ml of 2N hydrochloric 31 P-acid. The aqueous phase is extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate, filtered and evaporated to dryness. 5.75 g of (2-cyanophenoxy) -2-hydroxypropyl-3-aminopropionic acid ethyl ester is obtained with a melting point of 120 ° C (as hydrochloride). Example 2. Preparation of N-f3- (2-N-methylcarbamoylmethoxyphenoxy) -2-hydroxypropyl 1-3-aminopropionic acid ethyl ester. This compound is prepared according to Example I using 14.1 g of ethyl ester hydrochloride 3 α-aminopropionic acid, 3.68 g of sodium hydroxy and 12 g of 2- (2, epoxypropoxy) phenoxy-M-methylacetamide in isopropanol as the pacT of the solvent. The crude oil is dissolved in methylene chloride, washed three times with water, dried over sodium sulfate, and evaporated. The residue is dissolved in 200 ml of ethyl acetate, after which 200 kp of water is added. The pH of the medium was adjusted to 5.0 with the addition of 2N hydrochloric acid. The aqueous phase is separated, adjusted to pH 9.0 by the addition of 2N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated. The oily residue is crystallized by treatment with a mixture of diisopropyl ether and diethyl ether (4: 1). The resulting crystals are washed with diethyl ether. 1.3 g of N-3-C2-N-methylcarbamoylme-toxyphenoxy) -2-hydroxypropyl-J-3-aminopropionic acid ethyl ester are obtained, with a melting point of 80 ° C (as base). Example 3. Preparation of N-Cs- (3-cyanophenoxy) -2 -oxypropyl -3-aminopropionic acid ethyl e-alcohol. This compound is prepared according to Example 1 using 15.36 g of 3-aminopropionic acid ethyl ester hydrochloride, 8.7 g of 3- (2,3-epoxypropoxy) benzonitrile, and 4.0 g of sodium hydroxide. The crude oil is dissolved in 200 ml of ethyl acetate, washed twice with water and extracted with 2N hydrochloric acid. The pH is then adjusted to 9.5 and the solution is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulphate, filtered, and packed. 2 g of ethyl H-T3- (3-cyanophenoxy) -2-hydroxypropyl-3-aminopropionic acid ethyl ester with a melting point of 93 ° C (as base) are obtained. Example 4. Preparation of N-KZ-C4- (2-M-isopropylureido) ethylphenoxn} -2-hydroxypropyl-3-aminopropionic acid ethyl ester. This compound is prepared according to Example 1 using 14.0 g of 3-aminopropionic acid hydrochloride ester, 11.2 g N- {2-4- (2,3-epoxypropoxy) phenyl} ethyl} -N-isopropylurea and 3.2 g of sodium hydroxide. The crystals are washed with water and dissolved in a mixture of 500 ml of water with 25 ml of 2N hydrochloric acid (the insoluble crystals are filtered). Ethyl ester of H- {3- 4- (2-N-isopropylureido) -ethyl pheno KS and) -2-hydroxypropyl J-3-aminopropionic acid is crystallized by treating with aqueous 25 ml of 2N sodium hydroxide. The base is converted to the hydrochloride by dissolving in acetone and adding an exsivalent amount of hydrochloric acid. 2.8 g of N-t.3-f4- (2-N-isopropylureido) ethylphenoxy} -2-hydroxypropyl-3-a} nopropionic acid ethyl ester are obtained in the form of the hydrochloride with a melting point of 185s. Example 5. Obtaining ethyl ester (3-methylphenoxy) -2-hydroxypropyl-3-aminopropionic acid. This compound is prepared according to Example 1 using 15.36 g of 3-aminopropionic acid ethyl ester hydrochloride, 8.2 g of 1,2-epoxy-3-toluene-1-propane and 4.0 g of sodium hydroxide. The crude product is treated with 200 ml of water and the pH is adjusted to 3.0 by the addition of 2N hydrochloric acid. The solution is decanted and washed with ethyl acetate. The aqueous phase is treated with sodium bicarbonate and the product is extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulphate, filtered and evaporated. The product is recrystallized from diisopropyl ether. Obtains 3.0 g of (3-methylphenoxy) -2-hydroxypropyl-3-aminopropionic acid ethyl ester with a melting point (as base).
    S10
    Example 6. The preparation of the complex:) t-yl ester N-C3- (2-allyl-4-car-6amoylmethylphenoxy; -2-hydroxypropyl-3-aminopropionic acid.
    This compound is prepared according to Example 1 using .10.8 g of 3-aminolropionic acid ethyl ester hydrochloride, g of 3-allyl-4- (2,3-epoxypropyc) phenylacetamide and 2.84 g of sodium hydroxide. The crude product is crystallized from ethyl acetate. 1.7 g of N-f3- (2-allyl-4-carbaminomethylphenoxy) -2 -oxypropyl-3-aminopropionic acid ethyl ester is obtained, with a melting point of 98 ° C (as base),
    Example 7 Preparation of complex N-C3- (2-nHaHO-4-methoxyphenoxy) -2-hydroxypropyl-3-amnopronionic acid ethyl ester.
    This compound is prepared according to Example 1 using 6.9 g of 3-aminopropionic acid ethyl ester hydrochloride, 6.0 g of 5-methoxy-2 (2,3-epoxypropoxy) -benzonitrile, and 1.8 g of sodium hydroxide. The crude oil is treated with ether and ethyl ester (2-cyano-4-methoxyphenoxy) -2 hydroxyprocyl-3-aminopropionic acid crystallizes. The yield is 0.9 g, melting point 76 ° C. (base).
    Example 8. Preparation of N-3-C3-methoxyphenoxy) -2 hydroxypropyl J-3-aminopropionic acid ethyl ester.
    This compound is prepared according to Example 1 using 7 about 6 g of 3-aminopropionic acid ethyl ester hydrochloride, 4 e5 g of H- (3 - methoxyphenoxy) 1 52-epoxypropane and 2.0 g of sodium hydroxide. The crude product is washed with 150 ml of water and dissolved in 100 ml of water and 10 ml of 2 N: hydrochloric acid. After the resulting solution is extracted with ethyl acetate, it is treated with sodium bicarbonate and extracted with methylene chloride. The organic phase is separated, the sate is over magnesium sulphate, filtered and evaporated. After crystallization, 1.2 g of (3-methoxyphenoxy) -2-hydroxypropyl-3-aminopropionic acid ethyl ester with a point of 72 ° C (base) are obtained.
    Example 9 Preparation of Ethyl Ester (2,3-dimethylphenyl17 6
    noxy) -2 hydroxypropyl-3-aminopropionic acid.
    This compound is prepared according to Example 1 using 7.6 g of 3-aminopropionic acid ethyl ester hydrochloride, 4.5 g of 3- (2,3-dimethylphenoxy) -1,2-epoxypropane and 2.0 g of sodium hydroxide. The resulting product is converted to gi, hydrochloride by adding an equivalent amount of hydrochloric gas, to obtain from 2.6 g of (2,3-dimethylphenoxy) -2-hydroxypropyl-3-aminopropanoic acid ethyl ester as a hydrochloride with a melting point of 121C.
    Example 10 Production of (2-cyanophenoxy) -2-hydroxypropyl 3-3-aminopropionic acid propyl ester.
    This compound is prepared according to Example 1 using
    6.8 g of 3-aminopropionic acid propyl ester hydrochloride, 5.5 g of 2- (2J3-enoxipropoxy) -benzonitrile, and 1.8 g of sodium hydroxide. The crude oil is treated with a simple and after crystallization, 1.5 g of N- (3- (2-cyanophenox | 1) -2-hydroxypropyl J-3-aminopropionic acid) are obtained.
    with melting point (as hydrochloride).
    Example 1 Preparation of (2-cyanophenoxy) -2-hydroxypropyl-3-aminopropionic acid pentyl ester.
    This compound is prepared according to Example I using
    6.9 g of 3-aminopropionic acid pentyl ester hydrochloride 5.5 g of 2- (2,3-zpoxypropoxy) -benzonitrile and 1.8 g of sodium hydroxide. The crude oil is treated with ether and after crystallization, 1.3 g of (2-cyanophenoxy) -2-hydroxypropyl-3-aminopropionic acid pentyl ester are obtained with a melting point of 9lc (as hydrochloride).
    An; according to the logic of Examples 1-11, the following compounds are prepared;
    4-p4- (2-hydroxy-3-isopropylaminopropoxy) ethyl-lenyl J-butyric acid ethyl ester with m.p. 85 C (as p-HO-benzoate), 35% yield;
    (2-xi-3-isopropylamino-1-propoxy) -3-labels methyl ester71 of syphenyl propionic acid, m.p. (HC1), yield 32%; (2-hydroxy-3-isopropylaminopropoxy) -phenipL-poopionic acid propyl ester with m.p. 100 C (11C1), yield 32%; The biological activity of the target compounds, the compounds listed in the table in two experiments were tested on anesthetized cats (males and females weighing 2.5-3.5 kg), which for i6 h before the start of the experiments were given intramuscularly reserpine in an amount of 5 mg / kg body weight . Reserpine was given to eliminate endogenous sympathetic control of heart rate and tone of vascular smooth muscle. Cats were anesthetized with pentobarbital (30 mg / kg body weight, intraperitoneally) and artificially ventilated with room air. The neck was made bilateral vagotomi. Blood pressure was measured with a needle inserted into the carotid artery, and the heart rate was measured with a cardiac tachometer connected to an ECG. A needle was inserted into the femoral artery of one posterior leg. Selected blood is pumped to the distal part of the artery in a constant amount. Perfusion pressure (DP) was measured, and the change indicates a change in peripheral vascular resistance in the leg. Experiment A. The maximum heart rate and vasodilation were determined by injecting a high dose of isprenaline (2.0 µmol / kg). Then, the dose of injected isoprenaline was determined, which was 0.25 µmol / kg min. The vascular response to this dose of isoprenaline was also about 80% of the maximum value. Then a dose of isoprenaline was injected for 20 minutes, with 20-minute pauses between delachis injection periods. The test compound was intravenously injected seven minutes after the injection of isoprenaline. The dose of the test compound was increased until a complete blockade of the reaction to isoprenaline was achieved. For each dose of the test compound, a decrease in the heart rate of the NII caused by isoprenaline delivery was determined as a percentage block by the formula: 178 a decrease in the heart rate caused by isoprenaline (beats / min) 100 X control of the heart rate of the scientific research institutes called isoprenaline (beats / min) the blockade (for each dose) and the log dose of the test compound were made up of the curves, which determined the dose ED; 50, i.e. dose, which provides 50% of the maximum blockade, reaction to isoprenaline during injection of the test compound, reaction to isoprenaline. By the percentage blockade and log dose of the test compound, the curves were determined, according to which the ED: 50 dose was determined. Then it was possible to compare the dose of ED: 50 for blocking the frequency of heartbeats with the dose of ED: 50 for blocking the expansion of blood vessels and thereby determine the selectivity for the test compound. Sympathomimetic activity was detected as an increase in the maximum heart rate during injection of the test compound. Experience B. Maximum heart rate and vasodilation were determined by injecting a high dose of isoprenaline {2.0 µmol / kg). Then, the dose of injected isoprenaline 5 was determined which approximated approximately 80% of the maximum heart rate. Typically, this dose was 0.4 µmol / kg. The reaction of the vessels to this dose of isoprenaline was also about 80% of the maximum value. The test compound was then injected in increasing doses. In this case, each dose was given for 12 g-ol, and 18-minute pauses were made between doses. After each giving of the test compound, a dose of isoprenaline was injected. The dose of the test compound is increased logarithmically until a complete blockade of the reaction to isoprenaline is achieved. In addition, the plasma half-life was determined. At the same time, the time from the maximum inhibitory activity of each dose was studied under study9 1082317О
    Compound up to 50% recovery is a constant value for the allocation and log dose. Then, the period of time the compound under study was plasma (t 1/2) was determined according to the curves. The slope of the resulting curve is the ratio t 1/2 0.693 / K.
    defined with linear regression. On-5 The results of experiments A and B are given
    the clone is equal to 2,303 / Kt, where Kt is in the table,
    with tJ
    As can be seen from the table, the advantage of the compounds according to the proposed method, in particular over (3., 4-dimethoxyphenyl) -ethylamino) -1- (4- (3-methyl) phenoxy 1-propanol-2, is a short half-life.
    权利要求:
    Claims (1)
    [1]
    ’METHOD FOR PRODUCING AMINOPROPANOL DERIVATIVES OR THEIR SALTS.
    (57) Method for preparing derivatives of 'aminopropanol of the general formula
    OCH 2 SNOIS 2 1 SHSN 2 (CH 2 ) and С001Ц А * · where R ^ is lower alkyl;
    R ^ h Rj is hydrogen, lower alkyl, lower alkenyl, lower alkoxyl, cyano, - (O) n (CH z ) rn C0NHR4 ~ rpynna, where 1C is hydrogen or lower alkyl, η is 0 or 1; w means 0-3, or the group - (CH ^^ NHCONHR ^, where R4 and mn have the indicated meanings, or their salts, characterized in that the compound is of the general form 2- cn-cn 2 where R 2 and R ^ have the indicated meanings, are reacted with a compound of the general formula
    NgBsn ^ sn ^ juice / where R and η have the indicated meanings, with subsequent isolation of the target product in free form or in the form of a salt.
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    优先权:
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