• 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:
    Die vorliegende Erfindung betrifft (-)-2-[1-(2,6-Dichlor- phenoxy)-ethyl]-1,3-diazacyclopent-2-en und seine pharmazeutisch verträglichen Säureadditionssalze sowie Verfahren zu seiner Herstellung und diese enthaltende pharmazeutische Präparate.
    公开号:SU1241989A3
    申请号:SU823521885
    申请日:1982-12-09
    公开日:1986-06-30
    发明作者:Бидерманн Юрген；Проп Геррит；Доппельфельд Илле-Штефание
    申请人:А.Наттерманн Унд Ко,Гмбх (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to synthetic organic chemistry, and specifically to a method for producing (-) (2,6- -dichlorophenoxy) -ethyl -1, 3-diazacy lopentene-2 of the formula
    C1 SNU
    0-SK
    Sh
    or its hydrochloride, which has a clearly pronounced and long-lasting ability to lower blood pressure.
    The purpose of the invention is the preparation of a compound of formula I possessing valuable pharmacological action.
    Example 1. Synthesis of hydrochloride (-) -2- L) - 2,6-dichlorophenoxy) ethyl | -1, 3-diazacyclopentene-2.
    (+) -2-Chloropropionic acid methyl ester, 250 g (2, mol of {-) - 2-hydroxypropionic acid, 0 ° (undiluted) J is chlorinated using 264.0 g (2.218 mol) chloride thiinyl in the presence of 1.5 ml of dimethylformamide at the boiling point of the reaction mixture. The result is 93.0 g of ethyl ester (+) -2-chloropropionic acid CifHgClOi (136,6) with BP. 143 ° C d ° + 19.8 ° (undiluted).
    (-) - 2- (2,6-Dichlorophenoxy) propionic acid ethyl ester.
    65.5 g (0.402 mol) of 2,6-dichlorophenol in 300 ml of butanone are heated with stirring for 48 hours at reflux temperature of the reaction mixture with 38.0 g (0.542 mol) of potassium methylate and 76.0 g ( 0.556 mol) of (+) - 2-chloropropionic acid ethyl ester. After treatment of the reaction mixture, 62.0 g of (-) - 2- (2,6-dichlorophenoxy) propionic acid ethyl ester with /) /, Oz (263.1), .t.p. 0.3: 1 15-1 -37, 1 ° (undiluted).
    (t
    N- (2-aminoethyl amide (-) - 2- (2,6-dichlorophenoxy) propionic acid.
    46.0 g (0.1748 mol) of (-) - 2- (2,6-dichlorophenoxy) propionic acid ethyl ester are stirred at room temperature for 21 hours from 212.0 g (3.527 mol) 1, 2- -Diamino41989 .2
    ethane. After treatment of the reaction mixture, 38.0 g of H- (2-aminoethyl amide (-) - 2- (2,6-dichlorophenoxy) - propionic acid, C, g (277.2)) are obtained in the form of a viscous oil sample: hot substance, -5.8 ((ethyl alcohol)).
    (-) - 2-L - (2, 6-Dichlorophenoxy) etsh- -1,3-diazacyclopenten-2. ten
    58.6 g (0.3089 mol) of titanium tetrachloride at a temperature of
    is dissolved in a mixture consisting of 700 ml of chloroform (abs.) and 25 P1 of tetrahydrofuran, after which the solution is mixed with 35.0 g (0.1263 mol) of N- (2-aminoethyl amide (-) -2- (2 , 6-dichlorophenoxy) propionic acid. Then, at a temperature of 0 ° C and stirring, a solution of 74.0 g (0.6036 mol) of 4-dimethylaminopiridine is very slowly added to the mixture, and after completion of the addition the reaction mixture is further stirred for 36 hours at room temperature. After treatment of the reaction mixture and purification of the product using chromatography, on a column ( Lonka, filled with silica gel, eluting agent: chloroform / tetrahydrofuran 3: 1) half study-2, 0 g (-) (2, 6-dichlorophenoxy), 3-diazacyclopentene-2, S., (259.1 ), mp. 26-127 ° C, M -80.2 ° ((ethyl alcohol)).
    (-) (2,6-dichlorophenoxy) eth17-1 -1,3-diazacyclopenten-2 hydrochloride.
    10.0-g (-) (2,6-dichlorophenoxy) ztsh-. , 3-diazacyclopentene-2 is dissolved in 40 ml of propanol-2 and the prepared solution is mixed with 40 ml of a saturated solution of hydrogen chloride in propanol-2. After the appropriate. 7.8 g of (-) - 2- - l- (2,6-dichlorophenoxy) hydrochloride, 3- -diazacyclopentene-2, C are obtained by treating the reaction mixture. WITH
    HHC1 (295.6), m.p. 229-230 0,
    ; gb
    W, -. 33.2 ° (. With 1 alcohol t.
    (ethyl
    in tab. Figure 1 shows the biologic data: the main tests of compound I I (-) - lofexidine3 in comparison with the data for the previously known racemate | (4) -lofexidine 3
    3, 1241
    T a b l and c a I
    The effect of intravenous administration of (-) - lofexidine and its racemic form under the blood pressure of rats with moderate anesthesia. Calculated 5 maximal drop in low blood pressure (low ± V. EM) Table 3 Effect of intravenous administration of (-) - lofexidine and its racemic form at low arterial blood pressure of rats killed by puncturing the spinal cord. Calculated maximum boost
    9894
    blood pressure after drug injection (low ± .SEM,)
    Table 4
    Cardiovascular activity of (-) - h -lopexidine and its racemic form. Calculated values (EBgb dose, which gives a 25% reduction in pressure in rats with moderate anesthesia), ED.j-- values (- dose, which gives a 15% reduction in heart rate in rats with moderate anesthesia) and EDgo values ( EBbo - dose that gives 60 mmHg increase in blood pressure I in rats killed by puncturing the spinal cord)
    (±) -lofec-12.5
    Sidin 3.0 1.2 (/ chg / k
    (-) - lofexidine 1.5 0., 7 5.0
    PRI me R 3. Pharmaceutical
    form corresponding to the present
    the invention of the compound.
    150 mg tablets with content
    biologically active substances
    0.1 mg, kg:,, g Gdrochloride (-) - 2-U- - (2,6-dichlorophenoxy) - -ethyl} -1, 3-di4-cycliclopentene-20,006
    Avitcel7 ,, 584
    Citric acid 1,200 AerosilO, 120
    Magnesium stearate 0.090
    5, 12419896
    Thus, the proposed reducing, crown pressure itself was obtained compound X, which has an effect.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining (-) - 2- (ΐ— (2,6-dichlorophenoxy) ethyl] -1,3-diazacyclopentene-2 of the formula
    XI% to
    ^ Wo-sn-h f- 1
    or its hydrochloride, which consists in the fact that With | -C / (- alkyl ether (-)
    -2-hydroxypropionic acid is treated with thionyl chloride in the presence of catalytic amounts of dimethylformamide at boiling, obtained by reversing the configuration C /, –C /, - (+) -2-chloropropionic acid alkyl ester is reacted with 2,6-dichlorophenol in butanone in the presence of potassium methylate at boiling, formed with the C ^ -C / configuration, the alkyl ester of (-) - 2- (2,6-dichlorophenoxy) propionic acid is treated with 1,2-diaminoethane at room temperature, resulting in температуре- (2 α-aminoethyl) amide (-) - 2- (2,6-dichlorophenoxy) propionic acid is cyclized in the presence of titanium tetrachloride-tetrahydrofuran complex in absolute chloroform medium in the presence of 4-dimethylaminopyridine at 0–30 ° C and the resulting target product is isolated chromatographically in free form or in hydrochloride form.
    SC (s) 1241989 A 3
    1 1
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    引用文献:
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    US3966757A|1967-02-23|1976-06-29|A. Nattermann & Cie Gmbh|Imidazoline derivatives and processes for the production thereof|
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    DE2818367A1|1977-04-29|1978-11-02|Ciba Geigy Ag|EECTOPARASITICIDES|DE3407509A1|1984-03-01|1985-09-05|A. Nattermann & Cie GmbH, 5000 Köln|NEW COMBINATION OF MEDICINAL PRODUCTS FOR TREATING HIGH BLOOD PRESSURE AND THROMBOEMBOLIC DISEASES|
    US4801617A|1987-04-06|1989-01-31|Leclerc Gerard|Iminoimidazolidines useful in lowering intraocular pressure|
    FR2642422B1|1988-12-22|1994-07-13|Roussel Uclaf|
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    US8101779B2|2008-10-06|2012-01-24|University Of Kentucky Research Foundation|Enantioselective synthesis ofand -2-[1--ethyl]-1,3-diazacyclopent-2-ene|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813149009|DE3149009A1|1981-12-10|1981-12-10| - 2--ETHYL) -1,3-DIAZACYCLOPENT-2-EN, THE PRODUCTION AND THEIR USE IN PHARMACEUTICAL PREPARATIONS|
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