• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:

    公开号:SU891674A1
    申请号:SU792732105
    申请日:1979-02-28
    公开日:1981-12-23
    发明作者:Ручман Рудольф；Дьедьевич Небойша
    申请人:Лек Товарна Фармацевтических @Ин Кемичных Изделков(Инопредприятие)；
    IPC主号:
    专利说明:

    (54) 2-BROMERGOZIN or an addition-KISLSH salts thereof exhibit hypotensive activity The invention relates to new chemical compounds, more particularly to 2-bromergozinu formu.py CHj QHi SOTYANI4F, U4 «H (H2CH ((5ll5) 2 or its acid addition salts that have a hypotensive effect. These properties make it possible to apply these compounds in medicine as a pharmaceutical preparation. Ergosine is known, which has a reducing effect on smooth muscle and causes suppression of the sympathetic functions of the autonomic nervous system 1. Purpose Figs shadows - expansion of the range of pharmacologically active alkaloids. The goal is achieved by applying a new chemical structure - 2-bromergosin / which is expressed by the formula G, or its additive acid salts. Pyrrolidone hydrotromidine is obtained by selectively brominating ergosin at position 2. , N-bromo-substituted compounds, dioxane-dibromide, 3-bromo-4,5-dialkyl-2-oxazolidones. The process is carried out at room temperature or slightly heated in an inert solvent, prefer flax in the presence of a radical initiator, for example 2,2-azobis (2-methylpropionitrile). When using N-bromo-. The compounds and dioxanedibromide are preferably carried out at 40-50 ° C, and in the case of pyrrolidone hydrotrobromide, at room temperature. Cyclic ethers, for example dioxane and tetrahydrofuran, or chlorohydrocarbons, for example chloroform or methylene chloride, are preferably used as the solvent. Example. 9.54 g (17.4 mmol) ergosin is dissolved in 180 ml of dioxane and 3.52 g is added to the solution with stirring in an inert atmosphere.
    (19.8 Åmol) N-bromosuccinimide, dissolved in 60 ml of dioxane, is heated for 10 minutes at 40 ° C. Then the reaction mixture is evaporated in vacuo. The stack is distributed in the separating funnel between 200 ml of aqueous 2N. Sodium carbonate solution and 300 ml of ethylene chloride. The methylene chloride extracts are combined and dried in vacuo. The residue is dissolved in 40 ml of methylene chloride and chromatographed through a column filled with neutral alumina (activity P-III according to Brockmann). Elute with methylene chloride containing 0.2% ethanol. The fractions containing 2-bromergozin are dried under vacuum. Dry matter recrystallized from ethyl acetate, get 4.33 g (34.8% of theory) of pure, crystalline 2-bromergosin with the composition of Sdd H bNg-C Br CH Trd 183-185 ° C (with decomposition), specific rotation d - 9l, 6 ° (cl, chloroform).
    EXAMPLE 2: 5.47 g (10 mmol) of ergosine is dissolved in 200 ml of dioxane and a solution of 6.94 g (14 mmol) of pyrrolidone-Hydrotribromide is added to the solution under stirring in an inert atmosphere and at room temperature in 1500 ml of dioxane. The reaction is complete when a homogeneous mixture is formed. The reaction mixture is dried in vacuo. The residue is purified by partitioning between water and the organic phase and column chromatography, as described in Example 1; 5.81 g (81.3% of theory) of 2-bromergozine are obtained.
    Example 5.47 g (10 mmol) of ergosin is dissolved in 100 ml of methylene chloride and a solution of 6.94 g (14 mmol) of pyrrolidone hydrotribromide in 300 ml of methylene chloride is added to the solution under stirring and at room temperature in an inert atmosphere. The reaction mixture is evaporated to half the original volume and 3 times extracted with 200 ml of 2n. sodium carbonate. The methylene chloride solution is directly chromatographed through a silica column and eluted with methylene chloride, to which is gradually added O to 20% dioxane. The fractions containing 2-BrS 1 Ergosin are dried and recrystallized from ethyl acetate. Receive 5.06 g, or 70.7% of the theory of 2-b omergosin.
    Example 4. 2.42 g (3.86 mmol) of 2-bromergosine is dissolved in 20 ml of ethanol, which contains 0.22 ml (4.24 mmol) of methanesulfonic acid and poured into 400 ml of diethyl ether with stirring. After filtration and drying of the precipitate, 2.49 g or 89.4% of the theory of 2-bromoergozine methanesulfonate soluble in water, m.p. 191-192 ° C, 104 ° (p.1, chloroform).
    Example5. According to the method described in Example 4, a yield of 90% of 2-bromoergozine-ethanesul5 Fonat, m.p. 181-186 C. d 100 ° (p.1, chloroform).
    PRI me R 6. According to the method described in Example 4, 88% of 2-bromoergozine sulfate is obtained in a yield, m.p. 155-162 ° C (with decomposition), i (p. 0.5 water).
     PRI me R 7. According to the method described in Example 4, 86% of 2-bromoergozine tartrate is obtained in a yield of mp. 169-113 C, W 85 ° (p.1, chloroform / methanol 1: 1).
    2-Bromergozin has a hypotensive effect, affects the Q contraction of the heart chamber (positive inotropic effect) and on. heart rate (negative chronotropic effect) inhibits the increase in blood pressure caused by adrenaline and serotonin.
    Effect on arterial blood pressure.
    The effect on blood pressure is nor-; motivated anesthetized rats.
    The anesthetized Wistar 0 rats are cannulated with the artery of Carotis communis and the blood pressure is recorded using a mini-transducer on a Beckmann-type dinograph. The heart rate is recorded on a 5 dinograph using a cardiograph.
    2-Bromergozin is administered using a slow-acting intravenous injection device at doses of 10, 20, 50, 150, 450, 1 500 and 4500 mg / kg body weight in Qepa JuguEaris.
    The results in the table. 1 show that, by increasing the dose, a stronger decrease in systolic and diastolic pressure was achieved, while the pulse pressure
    increased.
    Table 1
     - Decreased systolic and diastolic pressure. t - Increased pulse pressure. These doses caused inhibition of hypertensive reflexes in the carotid sinus or led to depression of an increase in pressure, which was caused by unilateral occlusion of the artery. The effect of lowering pressure in spinal rats. Wistar rats were spinalized in urethane anesthesia (the spinal cord was divided in the area of the second cervical vertebra) and attached to artificial respiration equipment (B.Me sungen), due to which central blood pressure regulation was disabled. a decrease in blood pressure of 50 mm Hg. The results of the study showed that 2-bromergozine methanesulfonate acts to lower blood pressure only with intravenous doses of 450 mg / kg, so that it rises in the direction of the normal cr pressure. The compound has the same vasoconstrictor dihydroergotoxin and dihydroergotamine; action and contributes to the reduction of smooth muscles of blood vessels. Effect on adrenalin hypertension in anesthetized rats. In Wistar rats, which were narcotized with urethane and prepared for recording the blood pressure in the control part of the experiment by the inward use of adrenaline in doses of 10 mg / kg, short-term hypertension was caused twice, then 2-bromergosine methanesulfonate was administered at 10. 20, 50, 150, 450, 150 and 450 mg / kg and after 3 m epinephrine was applied in the same doses as in the control part. The minimum inhibitory dose for 2-bromoergozine methanesulfonate is 10 mg / kg . At higher doses, an adrenalin inverse occurs. Experiments show that 2-bromoergozine methanesulfonate inhibits the effect of adrenaline on blood pressure to about the same extent as dihydroergotoxin and dihydroergotamine. It is believed that the effect is the result of competitive antagonism of 2-bromoergozine methanesulfonate and adrenaline with respect to oi-adrenergic receptors. Effect on serotonin-induced hypertension in spinal rats. Spinalized Wistar rats were used in which the spinal cord was divided in the area of the second cervical vertebra in urethane anesthesia. The results of the experiments prove that 2-bromomergozine methanesulfonate administered intravenously at a dose of 150 mg / kg markedly reduces the effect of serotonin compared to the controllable effect of this compound. In this dose, 2-bromergozine methanesulfonate acts similarly to dihydroergotoxin and dihydroergothotiline. Effect on normotensive rats. Ten normotensive Wistar rats of both sexes with a body weight of 200-250 g were used as experimental animals. 2-Bromergozin-methanesulfonate was administered intraperitoneally at doses of 5 mg / kg / day and systolic blood pressure was measured. The blood pressure, to the beginning of the experiment, was 123-127 mm Hg, gradually decreased, at 8-10 days after the start of treatment it reached 95105 mm Hg. This value remained unchanged until the end of the experiment or up to 30 days.
    Action on spontaneously hypertensive rats.
    In this experiment, groups of 10 spontaneously hypertensive Okamato Aoki RZO rats of both sexes weighing 200-250 g were used. 2-Bromergozin-methanesulfonate was administered intraperitoneally at doses of 5 mg / kg / day and blood pressure was measured. Systolic blood pressure pressure, which by the beginning of the experiment was 174-177 mm Hg, Art., within 6-10 days decreased to 135140 mm Hg Although the treatment was continued, the blood pressure until the end of the experiment or for 30 days did not change.
    Effect on deoxycorticosteroid acetate-hypertensive rats.
    In young. Wistar both sexes. With a weight of 40 g, hypertension was caused due to the fact that the animals underwent one-sided nephrectomy1MYO /. Then the animals were supplied with a standard industrial feed and a 1% solution of sodium chloride ad gibitum.
    7 days after unilateral nephrectomy was performed, 38 mg / kg intramuscularly was administered 2 times a week, deoxycorticosteroid acetate (DOCA) as 0.1% microsuspension in 5% Tween 80 solution, to which 0.5% carboxymethylcellulose was added . After a week of DOC application, the systolic blood pressure reached a maximum value.
    Then, intraperitoneal administration of 2-bromergozine methanesulfonate was started at doses of 5 mg / kg. In the animals of the control group, the blood pressure remained elevated only for 2-3 weeks and then decreased to 135 mm Hg. In rats that were treated with 2-bromergozine methanesulfonate, in contrast, a decrease in blood pressure began already at the start of treatment. Within 10-12 days, the blood pressure dropped to the initial value of 189-187 mm Hg. in relation to the control group to its lowest value of 135-140 mm Hg.
    The difference between the two groups due to the aforementioned spontaneous decrease in blood pressure in the control group was less.
    Action, 2-bromergozina on the heart
    When experimenting with normotensive anesthetized oncate and spinal rats, 2-bromergosine-methylsulfonate in effective doses yielded bradycardia.
    The effect of 2-bromergozine methanesulfonate on the heart in glass was examined on an isolated guinea pig heart. 2-Bromergozin-. the methanesulfonate was administered using a slow injection apparatus (B.MeCsungen). The results are shown in Table. 2
    From the presented results it can be seen that 2-bromergozin has an effect on an isolated heart that is quantitatively equal to the effect of ergotsmina. Table 2
    权利要求:
    Claims (2)
    [1]
    Claim
    [2]
    2-bromergosine of formula G
    VNIIIPIZ order 11142/34
    5G or its acid addition salts exhibiting antihypertensive activity.
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    引用文献:
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