• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Compounds of the formula (I): <CHEM> wherein: R1 is hydrogen or fluorine; R2 is hydrogen or hydroxy; R3 is hydrogen, hydroxy, fluorine, aminocarbonyl, methylaminocarbonyl, methoxycarbonyl or acetoxy; C and C both are asymmetric carbon atoms having * and ** the R absolute stereochemical configuration; with the limitation that at least one of R1 and R2 is hydrogen; or pharmaceutically acceptable salts thereof are extremely potent inotropic agents.
    公开号:SU936804A3
    申请号:SU792784252
    申请日:1979-06-28
    公开日:1982-06-15
    发明作者:Миллз Джэк；Курт Шмайгель Клаус；Ральф Таттл Рональд
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR PRODUCING FENETHANOLAINES
    OR THEIR SALTS (ITS OPTION)
    I
    This invention relates to a method for producing new products.
    k4 x "- g ™ -sg ng-s. c ((1)
      -H
    : phenethanolamine of general formula
    sn,
    where R is hydrogen or fluorine, -,
    Rj is hydrogen or hydroxy; Rj is hydrogen, oxygen group, fluorine, aminocarbonyl, methylaminocarbonyl, methoxycarbonyl or aceacetoxy,
    C and C are asymmetric carbon atoms. Where R has absolute stereochemistry, and one of R and R- (means hydrogen. The invention also covers their salts. These compounds have pharmacological activity and can be used in medicine to treat heart failure and cause a decrease
    heart rate and inadequate ventricular function of the heart.
    Various derivatives of phenethanolamines with adrenergic activity are known.
    There is a method of obtaining proton derivatives of phenethanolamic formula
    where R represents a hydrogen atom, a hydroxyl group, alkyp, 26 alkoxy, amino group; Rj, R-, Ra and Rj may be the same or different and are hydrogen or alkyl; RP is aryl, benzodioxane cyclic group; n is an integer of 0-3, concluded from the fact that the amino ketone of the formula ad11 $ 0g ,, o} i Á D -CC is NC- (GHi) j, R5 io / ng k, where Z is a hydrogen atom or a benzyl group, R Ra, RH i - are as defined above.
    cK-CH -i H-CH-csl-dHn -h
    ji XXX.
    RI
    where Rj is as defined above; 0.1 and O, the labial groups are benzyl, or one of them is hydrogen, the protective groups Q and / or Qa are cleaved off. by catalytic hydOH O / I II .J-СНгС-БН лли / R о and R а have the above where R, meaning, M is hydrogen or a benzyl protecting group, is subjected to reduction with diborane or lithium aluminum hydride "with subsequent removal of the protecting group by catalytic hydrogenation in the case where M is not hydrogen. The reduction is carried out in an organic solvent, such as tetrahydrofuran, benzene, toluene, etc. The process is carried out at a temperature from 0 to. Benzyl protecting groups are cleaved off under standard hydrogenation conditions. The invention also encompasses salts of compounds of formula 1 with inorganic and organic acids, such as hydrochloric acid, bromine, hydrochloric acid, phosphoric acid, sulfuric acid or acetic acid, oil, citric maleic, etc. 5 10 15 2Q CH
    (L)
    Oqi
    Rene in the presence of Rene nickel or palladium, as well as its variant, consisting in that the compound of the formula is reduced by complex metal hydrides in an organic solvent, and if Z is a benzyl / group, then the benzyl group is removed by catalytic hydrogenation of l. The purpose of the invention is to expand the range of means of action on a living organism. This goal is achieved in that according to the method of producing phenethanolamine derivatives of general formula 1 and its variant, based on the known reactions of reducing the amino ketone with complex metal hydrides j, as well as removing the protective groups, for example benzyl, using catalytic hydrogenation in the presence of noble metals, 2, compound of formula. (111) Example 1. A solution of 93.9 g of R-1-metsh-3- (4-benzyloxyphenyl) -propylamine in 500 ml of NiN-dimethylformamide, containing 63.0 g of t-hydroxybenzotriazole and 104.6 g of R-2- (4-Benzyloxyphenyl) -2-hydroxyacetic acid is o-cooled to 0 ° C and stirred, adding a solution of 83.6 g of N, N-dinylcyclohexylcarbodiimide in 300 ml of dimethylformamide, dropwise over 1 hour. The reaction mixture was stirred for 12 hours at 3 ° C and then diluted with 10 ml of water, stirred once more for 1 hour, and cooled to -30 ° C in an acetone ice bath. The reaction mixture is filtered, the filtrate is concentrated by evaporation of the solvent. The concentrated solution was diluted with ethyl acetate and washed with an aqueous solution of sodium carbonate, water, 300 ml of 1N. hydrochloric acid and again with water. The organic layer is dried, the solvent is removed by evaporation and the product is obtained as a solid, which is crystallized from acetonitrile and methanol to obtain 159.7 g of R RN- 2- (4-benzyloxyphenyl) -2-hydroxide l orco-ethyl-3 methyl 3- (, 4-benzyl-oxyphenyl) -propylamine c-m.p. 145US C. Example2. To a stirred solution of 10.0 g of (6eH3Hn-r hydroxyphenyl) -2-hydroxy-1-01 with ethylethylene | -1-methyl-3- (4-benzyloxyfennet) -propylamine in 500 ml of freshly distilled tetrahydrofuran. In a nitrogen atmosphere is added dropwise over 30 mi 41 ml of a 2 M solution of the borane-dimethylsulfz complex in tetrahydrofuran. The reaction mixture is stirred at for 20 hours and then boiled under reflux and stirred again for -3 hours. After cooling the reaction mixture before and stirring for 18 hours excess, borane is decomposed by slowly adding 400 ml of methanol. The solvent is then removed from the reaction mixture by evaporation under reduced pressure to give the product as an oil. The oil is dissolved in 250 MP of hot methanol and, after concentrating to 125 m in volume, the product crystallizes from the solution, it is collected by filtration and recrystallized twice from methanol to obtain 6.65 g of RR-N-f2- (4-benzyl siloxene) I-2 gvdroksietshIJ-l-methyl-3- (4-benzyloxyphenyl) -propyl amine with so pl. 119-123 ,. The amine thus obtained is dissolved in methanol and added to a solution of hydrogen chloride in ether to give 6.49 g of RRN-2- (4-benzyloxyphenyl) -2-hydroxyethyl J-1-methyl-3- {4-benzyloxyphenyl) - propylammonium chloride with so pl. 214-21S. Froze A mixture of 51.6 g of R RN- 2- (4-benzyloxyphenyl) -2-hydroxyethyl J-1-methyl-3- (4-benz cloc sifaeyl) -prosumonium chloride and 5.0 g of Rene nickel in 2 l of ethanol and 2 l of ethyl acetate stirred at 25 ° C for. 4.5 hours in a hydrogen atmosphere at a pressure of 1.4 atm. The reaction mixture is then filtered to remove the residue of Rene Nickel and the filter is concentrated to obtain an oil by evaporation of the solvent under reduced pressure and the oil is crystallized from fresh ethanol and 044 ether to give 29.8 g of R, RN-f2- (4-hydroxyphenyl) -2- hydroxyethyl -1-metip-3- (4-hydroxyfecyl) propyl ammonium hydroxide and with so pl. 176-1 76, Example 4. R-mandelic acids in (5.58 g are mixed with 7.6 g of R-. -1 -methyl-3- (4-methoxycarbonylphenyl) -propylamine in 100 ml of dimethylformamide in the presence of 5 , 2 g of 1-hydroxybenzotriazole and 7.58 g of N, H-to cyclohexylcarbodiimide. The product obtained is dissolved in 200 ml of dry tetrahydrofuran. The reaction mixture is stirred at and in portions: a solution of 150 MP 1.02 n is added in 30 minutes diborane in tetrahydrofuran. The reaction mixture is stirred for 25 hours. Excess diborane is decomposed by adding 50 ml of methanol and then 100 ml of diethyl ether are added. hydrogen chloride. The solvent is removed and an oil is obtained, which is then dissolved in MPO of methanol. The methanol solution is heated and stirred for 20 minutes, after which the residual methanol is distilled off by evaporation. The residue is dissolved in methanol containing diluted a solution of diethyl ether and hydrogen chloride, from which the crystalline product precipitates.The product is identified as RjR-N- (2-phenyl-2-hydrosytil) -1-methyl-3 (4-methoxycarbonylphenyl) -propylammonium chloride. The amine salt thus obtained is dissolved in 800 ml of ethyl acetate and the solution is washed with a 200 mp aqueous sodium carbonate solution, with water and then dried. 2.8 g of R.R-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-methoxycarbonylphenyl) propylamine are obtained, m.p. 106-1 ° C. Example 5. A solution of 4.25 g of lithium aluminum in 500 ml of diethyl ether is added dropwise over 15 minutes to a solution of 12.92 g of Rjf RN- (2-phenyl-2-hydroxy-1-oxoethyl ) -1-methyl-3-phenylpropylamine in 60 ml of diethyl ether. Then the pockets (the ionic mixture is boiled under reflux and stirred for 6 hours. After cooling the reaction mixture, it is further stirred for 20 hours and again heated under reflux for 1 hour. Then the mixture is cooled until further 100 ml of water, 50 ml of a 5N solution of sodium hydroxide solution and again 100 ml of water are added. The organic layer is separated, the solvent is distilled off and 11.6 products are obtained in the form of a solid, which is dissolved in diethyl ether and acetonitrile, and then the solution is diluted with hydrogen chloride in ether. (2-Fensch-1-2-hydroxyethyl -1-metip-3-phenylpropane ammonium chloride with mp. 165-167. In a similar way, R I - M- (2-phenyl-2-hydroxyethyl) -1-methyl -3- (4-hydroxyphenyl) -pr opilammonium chloride with a melting point of 177.5-178.5Syu R RN- (2-phenes I-2-hydroxyethyl) - methyl g-3- (3-hydroxyphenyl) -propyl ammonium chloride with a melting point of 163.5-165, 2- (2-fluoro-2-hydroxy-1J-1methyl-3- (4-hydroxyphenyl, mp 180-propylammonium chloride with RR-N- (2-phenyl-2- hydroxyethyl) -1 - -methyl-3- (4-aminocarbonylphenyl) -propylammonium chloride with so pl. -224-246 C with Compounds obtained by the proposed method were evaluated by their HH
    sngta-schnats-sig-O,
    / about
    where R is hydrogen or ftop;
    Rj, is hydrogen or hydroxy group; RJ is hydrogen, hydroxy group, fluorine;
    aminocarbonyl, methylaminocarbonyl methoxycarbonyl or
    acetic group,
    sn,
    but)
    权利要求:
    Claims (2)
    [1]
    C and C are asymmetric carbon atoms having R is an absolute stereochemical configuration, and one of R and R / f means hydrogen, or their salts, which in combination of the formula has a tropic effect on anesthetized dogs: and on normal dogs with implanted cardiovascular sensors. The pulse rate, blood pressure, cardiac output and the pressure of the left ventricle of the heart were measured. These compounds exhibited a strong inotropic action immediately after administration and an adequate duration of action and did not show | -receptor activity, while the R.S-isomers lack inotropic activity, but are effective in inducing fat loss in obese animals. Thus, the RR and RS isomers EXPRESS-unexpected differences in pharmacological activity. Claims 1. Method for producing phenethanolamines of general formula
    (L)
    Ogi. where R is the above values of C. and Q 2. protective groups are benzyl 45 or one of them is hydrogen, protective groups C and / or O. are cleaved off by catalytic hydration of OH
     //; I
    R,
    where R is hydrogen or fluorine;
    RJ is hydrogen or hydroxy group; J Rj is hydrogen, hydroxy group, fluorine,
    aminocarbonyl, methylaminocarbonyl, methoxycarbonyl or acetoxy group,
     and asymmetric carbon atoms having R is an absolute value in the presence of Rene nickel or palladium.
    [2]
    2. The method of producing phenethanolamines of general formula I
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    法律状态:
    优先权:
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