• 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:
    This invention relates to new 1-(hydroxystyryl)-5H-2,3-benzodiazepine derivatives of the general formula (I) and to a process for the preparation thereof, furthermore to pharmaceutical compositions containing the same, <IMAGE> (I) wherein R stands for a hydrogen or halogen atom, or a C1-4 alkoxy group, R1 represents a hydrogen atom or a C1-4 alkyl group, R2 and R3 are identical and denote a C1-4 alkyl group, or combined they denote a methylene group. The compounds of the general formula (I) possess valuable positive inotropic (cardiotonic) potency, are capable to increase the myocardiac contractile force (heart performance in cardiac insufficiency), thus they can be applied in the therapy of chronic heart failure and coronary ailments.
    公开号:SU1503681A3
    申请号:SU874203194
    申请日:1987-05-21
    公开日:1989-08-23
    发明作者:Ланг Тибор；Кореши Йене；Раблоцки Дьердь；Хамори Тамаш；Кухар Мария；Полгари Иштван；Элекеш Иштван；Зольоми Габор；Хелтаи Кристина；Шарошши Юдит；Ланг Жужанна；Моравчик Имре
    申请人:Эгиш Дьедьсердьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    4.5 g (10.6 mmol) of I- (4-hydroxycycryl) -3-methyl-6, 7-dimethox-2-benzopyryl-perchlorate (mp. 298-) is suspended in 90 ml 99 ,five%- . ethanol, then 1.6 ml (31.8 mmol) of 100% hydrazine hydrate is added and the solution is stirred for 2 hours at room temperature. After evaporation in vacuum, the residue is suspended in 100 ml of water, filtered, washed with 3 × 5 ml of water, the raw material is again suspended in hot water, filtered, washed with ml of water and dried at a temperature of 80-100 ° C. Output: 2.65 g, so pl. 205-207 ° C. This crude product is purified, under reflux, in 12 ml of ethanol and then dried. Output: 2.37 g (66.4%), so pl. 209-21 ° C.
    The compounds of general formula (I), which are prepared according to the method of example 1, are summarized in table. one.
    Example 8. 1- (4-Hydroxystyryl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine.
    A mixture of 5.0 g (12.3 mmol) of I- (4-hydroxystyryl) -3-methyl-6,7-methylenedioxy-2-benzopyryl-perchlorate (mp. 306-308 ° C, Rael. ), 100 ml
    99.5% ethanol and 1.05 ml (36.9 mmol) of 100% hydrazine hydrate are heated for 1 hour in the presence of phlegm. Already in the first minutes of the reaction, the end product begins to sink. The mixture is evaporated under vacuum, the more or less crystalline residue is suspended in 100 ml of water, the crystals are filtered, washed with ml of water, once again suspended in 300 ml of hot water, stirred for 30 minutes, filtered hot, washed with ml of hot water. water and dried at 80-100 C. Output: 2,18 g, so pl. 243-248 With, razl. For further purification, this product is heated in 10 ml of 99.5% ethanol in the presence of reflux, filtered after cooling, washed with ml of ethanol and dried. Yield: 2.08 g (52.8%) m.p. 246-248 With, razl.
    Example 9. 1- (3-Gl-methoxy-4-hydroxy-styryl) -4-methyl-7,8-methylene-DIOXY-5H-2,3-benzodiazepine.
    a mixture of 12.5 mp of dimethylformamide and 2.1 ml (42 mmol) of 100% padrazine hydrate is cooled with ice water until then 6.14 g is added with stirring over 15 minutes
    (14 mmol) 1- (3-methoxy-4-hydroxy-steryl) -3-methyl-6, 7-methylenedioxy-2-benzopyryl-perchlorate (mp. C00 with dec.) And stirring is continued for the next 15 min Then 12.5 ml of distilled water is added to the orange solution while cooling, which results in the isolation of the final product. The crystalline mass is kept for 12 hours at 5 ° C, then the crystals are filtered, washed three times with 20 ml of distilled water and dried at 80-100 ° C. Yield: 4.81 g, m.p. 210-213 C, decomp. For further purification, this product is heated in 24 ml of 99.5% ethanol in the presence of reflux, washed three times with 20 ml of ethanol and dried. Yield: 4.59 g (93.7%), m.p. 214-216 ° C, decomp.
    The method described in Example 9 is used to prepare the following compounds.
    Example 10. 1- (3-Methoxy-4-hydroxystyryl) -4-methyl-7,8-dimethoxy-5-5-2,3-benzodiazepine.
    Yield: 87.2%, mp. 192-193 ° C, decomp. (ethanol).
    Example 11. 1- (3-Methoxy-4-hydroxystyryl) -4-methyl-7,8-diethoxy 5H-2,3-benzodiazepine,
    Yield: 78.2%, mp. 190-191 ° C, decomp. (ethanol).
    Example 12. 1- (3-Ethoxy-4-hydroxy-steryl) -4-methyl-7,8-dimethoxy-SI-5H-2, 3-benzodiazepine: 1.5.
    The output of 69.7%, so pl. 120-122 ° C (ethanol).
    Test methods.
    A. The method of strain gauge on anesthetized cats with an open chest.
    Male and female cats were anesthetized using a 1: 5 mixture of chloralose-urethane and artificial respiration was provided through a tracheal tube using a Harvard 665 A. respirator.
    Blood pressure was measured in such a way that a catheter connected to a pressure transmitter and an electro-manometer was inserted into the femoral artery (Stitham P23 D6). The pulse was recorded continuously using a pulse meter. biologically active515
    The substances were injected through an intravenous tube. 15 minutes before the start of the experiment, 0.2 μg / kg of isoproterenol was administered intravenously as an internal standard in order to control the cat's myocardial reactivity. In these experiments, isoproterenol did not serve as the usual base substance. It was used partly to control the reaction of the test system, and partly to measure the activity of the control substances, MCF responses (heart contractile force — myocardial contraction pa force, hereinafter abbreviated; MCF) were expressed in percent changes in initial values: the effect of 5 mg / kg of the administered intravenously control substance was compared with the exposure of 0.2 µg / kg of intravenous isoproterenol administered in the same animal and expressed by a factor. The values obtained are good indicators of the positive inotropic effects of the compound, since this may exclude the individual sensitivity of the animal.
    The results are summarized in table. 2
    B. Check on narcotied dogs with open chest,
    MCF was measured according to method A, and changes in blood circulation were recorded using an electromagnetic flow meter.
    The compound of example 1 was administered intravenously at doses of 0.25; 0.5 and 1.0 mg / kg. The results are summarized in table. 3. Depending on the dose, an increase in MCP was observed in both strength and duration of action, while the coronary flow increased only slightly. A basic dose of IICF and coronary effects caused by an intravenous dose of 2 mg / kg of arminon could be achieved with a lower dose of 1 µg / kg of the proposed compound. A particular advantage of the proposed compound is that the changes induced in systolic and diastolic blood pressure never exceed 10%. The effect of the proposed compound on ischemic heart disease is another positive feature of the new compound. Niocardinal16
    on ischemia was caused by compression of the descending segment of the left coronary artery. An increase in the contractile force of the heart caused by the compound of Example 1 could be measured even during reperfusion (after the end of compression).
    C. Test on chronically catheterized, supervised cats.
    The tests on cats were carried out according to the method of Rablochka and Madera or in accordance with a modification of this method. In order to measure the blood pressure, the aorta and pulmonary artery were chronically catheterized. In accordance with the modification, the right ventricle was also catheterized to determine the dp / dt value (MCF). The compound of Example 1 was administered at an oral dose of 1 or
    2 mg / kg. These doses could not cause significant changes in either systolic or diastolic blood pressure; the pulse of cats was not affected. The effect of increasing the contractile force of the heart developed within 15-30 minutes
    and remained at this significant level for the next 60- 90 min. The maximum increase in the contractile force of the heart (peak) was 20–25%.
    The direct inotropic effect was confirmed in the following experiments under laboratory conditions.
    D. The compound of Example 1 caused a dose-dependent positive inotropic effect in the electrically stimulated, isolated right ventricular papillary muscle of the hare. Already insignificant dose in
    10 M led to a significant response; a dose of 5-10 M led to an increase of 200%.
    E. The compound of Example 1 caused a dose-dependent increase in MCF in an electrically stimulated, isolated rabbit left atrium preparation. In the unstimulated preparation (right atrium) there was a slight 15% increase in frequency.
    Tab. 2 and 3 proved that the proposed compounds of examples 1 and 7 are the most effective, they are the same or more effective than the known compound a finon. Based on biochemical studies, they have a positive inotropic effect due to the fact that they inhibit phosphodiesterase enzymes.
    The proposed compounds were identified using elemental analysis, insoluble residue, and mass spectrometry. The protons of the double bond were either exclusively or mostly in the trans position.
    权利要求:
    Claims (1)
    [1]
    The proposed compounds are of minor toxicity. LDgg is orally administered 200 mg / kg and subcutaneously 100 mg / kg (mouse). Invention Formula
    The method of obtaining derivatives of 1- (hydroxystyryl) -5H-2,3-benzodiazepi on the general formula,
    / CH3. CH2-s
    E, 0
    X
    N
    Where
    R is hydrogen, halogen, C-C-alkoxy;
    R and R are the same and mean C alkyl or together they mean a methylene group, characterized in that 2-benzopyryl-perchlorate of the general formula,,
    Cn de R, R, and Rfl have the indicated meanings, reacting with the threefold
    Decomposition.
    5 5 5
    2.04 1.56 0.25
    T abli1 and 2
    +40 -35
    +35 -33
    +5 +23
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    同族专利:
    公开号 | 公开日
    GB2190677B|1990-01-10|
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    SE8702120D0|1987-05-21|
    DE3717080C2|1996-02-08|
    CS369087A2|1988-08-16|
    IL82613D0|1987-11-30|
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    引用文献:
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    DK118660B|1966-12-09|1970-09-21|Egyt Gyogyszervegyeszeti Gyar|Analogous process for the preparation of 1- -3-methyl-4-ethyl-6,7-dimethoxy-isoquinoline-N-imide.|
    HU179018B|1978-10-19|1982-08-28|Gyogyszerkutato Intezet|Process for producing new 5h-2,3-benzodiazepine derivatives|
    HU191698B|1984-07-27|1987-03-30|Gyogyszerkutato Intezet|Process for producing new 1-aryl-5h-2beta-benzodiazepines|US5380721A|1990-09-10|1995-01-10|Sterling Winthrop Inc.|Aryl-fused and hetaryl-fused-2,4-diazepine and 2,4-diazocine antiarrhythmic agents|
    EP0726256A1|1995-02-09|1996-08-14|Egis Gyogyszergyar Rt.|1-Arylvinyl-3,4-dihydro-5H-2,3-benzodiazepine derivatives useful for the treatment of central nervous system disorders|
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    HU224435B1|1995-02-09|2005-10-28|EGIS Gyógyszergyár Rt.|Benzodiazepine derivatives, process for producing them, their use and pharmaceutical compositions containing them|
    ES2111493B1|1996-02-08|1999-08-01|Egyt Gyogyszervegyeszeti Gyar|DERIVATIVES OF 1- ) -5H-2,3-BENZO-DIAZEPINE, PROCEDURE FOR ITS PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND CORRESPONDING UTILIZATIONS.|
    HU227128B1|1999-07-07|2010-07-28|Egyt Gyogyszervegyeszeti Gyar|New 2,3-benzodiazepine derivatives|
    JP2006510634A|2002-12-03|2006-03-30|ヴェラファーマスーティカルズインコーポレイテッド|Pharmaceutical composition of 1--4-methyl-5-ethyl-7-methoxy-8-hydroxy-5H-2,3-benzodiazepine and use thereof|
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    法律状态:
    优先权:
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    HU862140A|HU195788B|1986-05-21|1986-05-21|Process for producing 1-/hydroxy-stiryl/-5h-2,3-benzobiazepines and pharmaceutical compositions containing them|
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