• 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 method of preparing 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of the formula "whether it is hydrochloride, from 1 to 2 and -chloro-N- (2-chloroethyl) -1-methylbeneloethaneamnn is subjected to cyclization in melted aluminum and ammonium chloride, followed by isolation of the desired product in free form or in the form of hydrochloride. O) C
    公开号:SU1238732A3
    申请号:SU823513948
    申请日:1982-11-25
    公开日:1986-06-15
    发明作者:Майкл Демаринис Роберт；Пол Хибл Джэкоб；Дэвид Мэтьюс Вильям
    申请人:Смитклайн Бекмэн Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of a novel compound, namely, 6-hlcr-3H-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of the formula
    N-CH3
    one ..
    or its hydrochloride-with antihypertensive effect.
    The invention is based on the well-known method of developing new compounds with valuable pharmacological properties.
    Example. A mixture of 125 g (0.73 mol) of o-chlorophenylacetic acid, 155 g (1.3 mol) of thionyl chloride and 2-3 drops of dimethylformamide in 1500 m of toluene is stirred at room temperature for 3 hours. Toluene is heated under reduced pressure to obtain an oil which is dissolved in 200 ml of methylene chloride. This product is added dropwise to a solution of 165 g (2.2 mol) of N-methylaminoethanol in 1 liter of methylene chloride. After the addition is complete, the solution is stirred at room temperature for 3 hours. The organic solution is washed with water, dilute hydrochloric acid and saturated sodium sulfate over magnesium sulfate, filtered and evaporated to give 2-chloro-N- (2-hydroxyethyl) -N-methylbenzole-acetamide in the form of a crystalline solid with m.p. 77 ° C.
    To 400 ml of a 1 m solution of borane in tetrahydrofuran, a solution of 43 g of the specified amide in 330 ml of tetrahydrofuran is added dropwise at a rate sufficient to maintain a slow boil under reflux. After the addition is complete, the solution is refluxed for 2 hours, cooled in an ice bath and carefully treated with dilute hydrochloric acid to decompose excess borane. The main part of the solvent was removed in vacuo and the residue was heated on the steam bath for 1 hour. The mixture was diluted with 300 ml of water and extracted with ether. The aqueous layer was made alkaline by adding 40% sodium hydroxide and extraction with ether. The combined alkaline extracts are washed with water and saturated chloride.
    sodium, dried and rotary to obtain 2- (2-chlorophenyl) ethyl (methyl-amino) ethanol.
    A suspension of 36 g (0.173 mol) of phosphorus pentachloride in 300 ml of methylene chloride is treated dropwise with a solution of 37 g (0.173 mol) of 2- (2-chlorophenyl) ethyl (methylamino) ethanol in 150 ml of methylene chloride. After the addition is complete, the mixture is boiled t under reflux overnight, rotary dry and partitioned between dilute hydrochloric acid and ether. Aqueous layer.
    5 alkalinize, add 10%
    sodium hydroxide and carefully extracted with ether. The ether extracts are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The addition of a saturated solution of ethereal hydrogen chloride gives a solid precipitate, which is isolated by filtration, washed with ether and
    5 is dried to yield 2-chloro-L- (2-chloroethyl) -I-methylbenzeneethanamine hydrochloride with m.p. 110 ° C. I
    To a mixture of 41.5 g (0.155 mol) of the above chloroethanamine hydrochloride and 6.26 g (0.117 mol) of ammonium chloride were added 41 g of anhydrous aluminum chloride. The reaction mixture becomes homogeneous, melts and produces heat. The mixture is placed in oil.
    bath heated to 175 ° C and stirred for 30 minutes. An additional amount (20 g) of aluminum chloride is added and the resulting mixture is heated for another 30 minutes. The final portion (41 g) of aluminum chloride is added and the reaction mixture is heated for 20 hours. It is cooled to 140 ° C and taken into 3 liters of ice water containing 300 ml of concentrated hydrochloric acid and stirred for 15 minutes. 60 g of sodium hydroxide is added and stirred until a solution is obtained. It is alkalinized with 40% sodium hydroxide, twice
     extracted with ether and the combined extracts are washed with water and saturated sodium chloride, dried and reduced to half. After adding a solution of saturated ether of hydrogen chloride, a solid precipitate is obtained which is collected, washed with ether and dried to obtain a white solid.
    0
    31
    After crystallization from methanol-ethyl acetate, 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 268-170 C.
    The antihypertensive activity of the obtained compound was demonstrated in vivo as follows.
    Male rats (weighing 300-450 g) were anesthetized with brevital sodium, cannulas were inserted into the femoral vein and artery. The cannulas were injected subcutaneously so that they were located in the back-sacral area on each side and secured in place with wooden clips. These rats were allowed to regain consciousness after they were placed in a small animal cage. The arterial cannula was connected to a sensor to continuously record blood pressure and heart rate. The preparations were administered either orally via gavage or intravenously via a cannula into the femoral vein at a rate of 0.06 ml / min.
    The test described is carried out on both normal and high blood pressure rats. DOSA salt of hypertensive rats is prepared from male rats. Rats of about six weeks old were slightly anesthetized with ether i and were subcutaneously implanted with 25 mg deoxycorticosterone acetate tablets in the left dorsum-sacral region. After six days on Note, n is the number of rats.
    2387324
    The ruy tablet was implanted into the right dorso-sacral region. The rats were kept on a normal laboratory diet, however, water was given to drink 5% saline solution. Rats were kept on salt drinking water for 22-24 days.
    Table I shows the results of the effect of 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine on blood pressure after intravenous administration in both normal stress and hypertensive rats.
    The data table. 1 show that although b-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine has a negligible effect on diastolic blood pressure in normotensive rats, it leads to a noticeable a decrease in diastolic blood pressure in both DOSA salt of hypertensive and spontaneously hypertensive rats. In addition, a comparison of 0.5 and 1.0 mg / kg dose indicates that the antihypertensive effect is related to the dose.
    The effect of oral administration of 6-chloro-2,3,4,5-tetrahydro-3-metip-lH-3-benanepin on the blood pressure of the DOSA salt of hypertensive rats was also determined.
    In tab. 2 shows the results of this test.
    Table 1
    Compiled by I. Bocharova Editor N. Kishtulinets Tehred I. Veres
    Order 3311/61 Circulation 379 Subscription
    VNIIPI USSR State Committee
    on inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    1238732Ь
    Table 2
    Proofreader M. Pojo
    权利要求:
    Claims (1)
    [1]
    The method of obtaining 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine of the formula
    QQn-CHj
    Cl or its hydrochloride, with the exception that 2 ~ chloro-K- (2-chloroethyl) -1-methylbeneolethanamine is subjected to melt cyclization of aluminum chloride and ammonium chloride at 175 ° C followed by the selection of the target product in free form or in the form of hydrochloride.
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    法律状态:
    优先权:
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    US32524981A| true| 1981-11-27|1981-11-27|
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