• 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 present invention relates to novel 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives, processes for producing said derivatives, intermediate compounds to produce said derivatives, processes to produce said intermediate compounds, and compositions containing said derivatives with potent diuretic activity that can be used for treating and/or preventing hypertension, oedema and/or for removing ascites. The present invention is based on the selection of 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives, namely 0-sulfate, 0-mesylate, 0-methylphosphate and 0-carboxymethyl ether, especially 0-sulfate of 4-oxime. The compounds of the present invention containing these substituents have potent hypotensive, antioedematous and diuretic effect as well as an activity to remove ascites and are extremely useful for the treatment of diseases and disorders mentioned above.
    公开号:SU1722227A3
    申请号:SU874203894
    申请日:1987-12-30
    公开日:1992-03-23
    发明作者:Мотида Эй；Уемура Акио；Като Казуо；Токунага Хироки；Хага Акинори
    申请人:Мотида Фармасьютикал Ко, Лтд (Фирма)；Ходогая Кемикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new 1-acyl-2,3-di-hydro-4 (1H) -quinolinone-4-oxime derivatives or their salts, which can be used for the treatment and / or prevention of hypertension, and / or swelling, and / or elimination of ascites.
    The purpose of the invention is the synthesis of new compounds with a higher diuretic activity than a structural analogue, which has the same type of activity, and furosemide, a drug currently used.
    Example 1. Obtaining the potassium salt of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinon-4-oxime-0-sulfonic acid (compound I).
    Stage 1.
    In a mixture of 14.9 g of 7-chloro-2,3-dihydro-1- (2-methylbenzoyl) -4 (1H) -quinolinone, 7 g of hydroxylamine hydrochloride and 8.5 g of pyridine and 250 ml of ethanol are added. this mixture is maintained at reflux for 1.5 h. After cooling, the reaction mixture is poured into 1000 ml of water and the precipitated crystals are filtered, washed, dried and recrystallized with ethanol, resulting in white 7-chloro-2,3-di-hydro-1- (2-methylbenzoyl) -4 (1H) -quinolin-4-oxime (7.6 g) is obtained as crystals.
    Melting point 166.0 - 168.4 ° C.
    XJ You Yu E fO VI
    IR spectrogram (potassium bromide), 3330,1635,1400.
    NMR spectrogram (DMCO-de), ppm: 2.20 (ZN, s), 2.81 (2H, t), 3.77 (2H, t), 7.05-7.98 (7H , m., aromatic).
    Stage 2.
    13.6 g of the product of stage 1 are dissolved in 250 ml of dichloromethane and 7 g of sulfur trioxide-pyridine complex are added to the solution. The reaction mixture is stirred at room temperature for 24 hours and approximately 150 ml of solvent are removed in vacuo. 200 ml of methanol are added to the residue, and then in one portion of a solution of 6 g of potassium carbonate in 10 ml of water and the mixture is processed according to the procedure described in Example 6, resulting in 13 g of potassium salt 7-chloro as white crystals -2,3-dihydro-1- (2-methyl-benzoyl) -4 (1H) -quinolin-4-oxime-0-sul-phonic acids.
    Example 2. Preparation of the potassium salt of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinon-4-oxime-0-sulfonic acid (compound II).
    Stage 1.
    To a mixture of 17.5 g of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinone prepared in Example 5 with 250 ml of ethanol was added 7 g of hydroxylamine hydrochloride and 8.5 g of pyridine and the mixture is maintained at reflux for 1.5 h. After cooling, the reaction mixture is poured into 1000 ml of water and the crystals which have precipitated are separated by filtration, washed, dried and recrystallized from ethanol, as a result 16 g of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinon-4-oxime are obtained as white crystals.
    Melting point 230.7-232.3 ° C,
    IR spectrogram (potassium bromide), 3250, 1635, 1420,945.
    NMR spectrogram (DMCO-de), ppm: 2.72 (2H, t.), 3.57 (2H, t.), 7.05-7.94 (6H, m, aromatic).
    Stage 2.
    16 g of the product of stage 1 is dissolved in 250 ml of dichloromethane and 7 g of sulfur trioxide-pyridine complex are added. The reaction mixture is stirred at room temperature for 24 hours and the solvent is removed in vacuo, 200 ml of methanol are added to the residue, and then a solution is added in one portion: 6 g of potassium carbonate in 10 ml of water, resulting in the form of white crystals 13 g of the potassium salt of 7-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinon-4-oxime-0-sulfonic acid,
    Example 3. Obtaining 6-chloro-2,3-di-hydro-1- (1-oxopropyl) -4 (1H) -quinolin-4
    oxime-0-acetic acid.
    In a mixture of 7.7 g of bromoacetic acid with
    6.5 g of potassium hydroxide with 60 ml of water with cooling in an ice bath are carefully added 12.7 g of 6-chloro-2,3-dihydro-1- (1-oxopropyl) -4 (1H) -quinolinone -4-oxime. This mixture is stirred for 24 hours at
    at room temperature, then acidified by adding 2N hydrochloric acid to a pH of 3.0 in an ice bath. The acidified mixture is poured into 150 ml of water and then shaken with
    500 ml of ethyl acetate. The organic layer is washed once with 500 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is subjected to chromatography on a silica gel column, eluted with a mixture of dichloromethane and methanol in a ratio of 9: 1, resulting in 10.5 g of 6-chloro 2, 3-dihydro-1- in the form of white crystals. (1-oxopropyl) -4 (1 H) -quinolin-4-oxime-O-acetic acid,
    Melting point 142.8-144.0 ° C, IR spectrogram (potassium bromide), cm 1: 3300-2800, 1740, 1650, 1480, 1390.
    NMR spectrogram (DMCO-de), h / m; 1.03 (ZN, t.), 2.52 (2H, q.), 2.84 (2H, t.), 3.79 (2H, t,), 4.69 (2H, s.), 7.26-7.75 (ЗН, m., Aromatic).
    EXAMPLE 4 Preparation of 6-chloro-2,3-dihydro-1- (1-oxo-propyl) -4 (1H) -quinolinone-4-oxime-0-phosphoric acid monomethyl ester.
    In a cold (-75 ° C) solution of 7.5 g of 6-chloro-2,3-dihydro-1- (1-hydroxypropyl) -4 (1H) -quinolinone-4-oxime in 150 ml of aqueous tetrahydrofuran is added dropwise 21 mg of a 1.6N solution of butyl lithium in n-hexane are added in a stream of nitrogen over a 30-minute period and stirring is continued for a further
    30 min at -75 ° C. 4.9 g of methyl dichlorophosphate is added dropwise to this mixture at a temperature of -75 ° C over a 30-minute period and stirring is continued for 30 minutes, and then at (-70)
    - (-60) ° C - for 2 h. Next, the reaction mixture is carefully heated to 0 ° C and acidified with normal hydrochloric acid to a pH of 2.0. The acidified mixture is stirred for
    5 hours at room temperature, after which it was poured into 200 ml of water and shaken with 500 ml of ethyl acetate. The organic layer was washed once with 200 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate is removed in vacuo and the residue is chromatographed on a silica gel column, eluting with a mixture of dichloromethane and methanol in a ratio of 19: 1, resulting in 6-chloro-2,3-di-hydro-C1-1 monomethyl ester oxopropyl) -4 (1H) -quinolinon-4-oxime-0-phosphoric acid (yield 7.2 g).
    Melting point 71.0-75.0 ° C.
    IR spectrogram (potassium bromide), 3420.2950, 1680, 1395, 1195.
    NMR spectrogram (DMCO-de). ppm: 1.01 (ZN, t.), 2.50 (2H, k.), 2.88 (2H, t.), 3.62 (ZN, d.), 3.78 (2H, t ), 7.22-7.85 (ЗН, m „aromatic).
    Example 5. Preparation of 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinoline-4-hydroxymesylate.
    To a mixture of 10.0 g of 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 (1H) -quinolinon-4-oxyma with 4.1 g of triethylamine and 150 ml of dichloromethane at -20 ° C, 3.5 g of methanesulfonyl chloride was added dropwise with stirring. This mixture was stirred at -20 ° C for 30 minutes and 300 ml of dichloromethane was added to it. Next, the reaction mixture was successively washed with normal hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the residue is recrystallized using diethyl ether and n-hexane, whereby 6-chloro-1- (2,4-dichlorobenzoyl) -2,3-dihydro-4 is obtained as white crystals. (1H) -quinolin-4-oxymemesyate (yield 11 g).
    Melting point 197.4-198.1 ° C.
    IR spectrogram (potassium bromide), 1660, 1365, 1180.
    NMR spectrogram (DMCO-de), ppm: 3.03 (2H, t.), 3.38 (3N, s.), 3.72 (2H, t.), 7.12-7, 92 (6H, m, aromatic).
    The compounds shown in Table 2 were prepared analogously. one.
    Diuretic effect on dogs.
    Dogs with weights ranging from 7 to 15 kg were kept on the leash overnight. Under anesthesia by means of pentobarbital (30 mg / kg body weight intravenously), animals were immobilized by placing them on their backs, and a physiological saline solution was continuously infused into the femoral vein using a catheter at a rate of 0.15 ml / kg / min. The dogs were then opened the abdominal cavity and the urethra was connected to the cannula so that urine could be collected in 10-minute periods. Test compounds were administered via
    0
    five
    0
    vein and recorded changes in the amount of urine collected. The percentage increase in the amount of collected urine was calculated by the formula below.
    The increase in the amount of collected urine is equal to the amount of urine collected in a 90-minute period after the compound is injected, minus the amount of urine collected in the 30-minute period before the compound is introduced into the body and multiplied by 3.
    The percentage increase in the amount of collected urine is equal to the ratio of the increase in the amount of collected urine as a result of the effect of the compound and the amount of collected urine due to the effect of furosemide multiplied by 100,
    Biological tests "osojKk-oa
    Yrt
    CHAN
    CHS
    1n
    hh
    Compound I Compound II (known)
    Diuretic activity in rats.
    Rats (males) that did not receive feed the night before were tested compounds in a volume of 1 to 2 ml / kg. Immediately after this, physiological saline was orally administered to the rats in a volume of 25 ml / kg. Urine discharges were observed after a 5-hour period after taking the formulation
    The diuretic activity was demonstrated in percent, and the urine excretion in rats that were injected with only physiological saline was taken as 100%. The result is shown in table 2.
    Compound I showed a diuretic activity in relation to the control group of animals in the amount of 15%. Furosemide demonstrated 190% diuretic activity at dosage 3
    mg / kg intravenous administration in relation to the control group of animals. Compound II showed 296% significant diuretic activity at a dosage of 0.3 mg / kg, which is one-tenth of the dosage in which the two mentioned compounds were used. Diuretic activity in dogs. Muddy-blooded dogs (males and females) that have not taken food since evening have been anesthetized at a dosage of 30 mg / kg body weight intravenous
    using pentobarbital sodium, and a tracheal catheter was inserted through their mouth, maintaining artificial respiration with a device for prolonged artificial respiration under conditions of 20 ml / kg of beats and 18 beats / min. The femoral vein of the dog is dissected and a polyethylene tube is inserted into it to infuse physiological saline. Then the left-sided abdomen of the dog is incised, the left urethra (urethra) is dissected and a polyethylene tube is inserted into it to collect urine. The dog's left artery is dissected, and a catheter, the L-shaped injection needle of which is connected to a polyethylene tube, is pierced through (a needle, cannula) to enter the medication. After the operation, physiological saline solution was poured at a dosage of 3 ml / kg through the femoral vein and thereafter with the aid of an intravenous infusion pump, a continuous infusion of physiological saline was started at a dosage of 0.1 ml / kg-min and at the same time 10 mg / kg of furosemide was injected into the renal artery, and the animals were left for approximately 1 hour. First of all, urine excretion was determined 20 minutes after administration. Then, 10 µg / mg of furosemide was injected into the renal artery, and thereafter, changes in urine excretion were determined after a 20-minute period of time. In addition, at the time when the amount of urine was stabilized after the passage of 20 minutes, 10 µg / kg of test compounds were injected into the renal artery, and changes in the amount of urine after the passage of 20 minutes were determined.
    Evaluation of the effectiveness of diuretic activity is carried out according to the following formula: AUV is equal to the difference of urine excreted in a 20-minute period after administration and before administration.
    Score h
    DC V test compound
    D U V furosemide (comparison with the same dog
    The result is given in table. 3
    Furosemide is a control compound. When comparing the diuretic activity of compounds I and I with respect to dogs, no diuretic activity was found for compound II. Compound I showed a significant diuretic activity of 423% compared with furosemide when the same dose was given with furosemide in the renal artery.
    As regards the comparison of diuretic activity with the introduction of furosemide and compounds I and II into the femoral vein, it is given in table. four.
    The diuretic activity on dogs in the case of furosemide is 100.
    权利要求:
    Claims (1)
    [1]
    The invention The method of obtaining 1-acyl-2,3-dihydro-4 (1H) -quinolinone-4-oxime derivatives of the general formula -
    th "
    R,
    R,
    } R
    Before
    R,
    where RI is phenyl, which may be substituted by 1-2 substituents selected from C1-C4 alkyl, halogen or hydroxyl group;
    R2 and Pz - hydrogen;
    R4 is a sulfo group;
    RS and RS are identical or different - hydrogen, halogen, hydroxyl group, and the bond indicated by the wavy line is an antiform or syn form,
    or salts thereof, characterized in that the 1-acyl-2,3-dihydro-4 (1H) -quinolinone derivatives of the general formula
    R5
    s
    Hj
    r4R
    CO R,
    where RI is RG, RS and Re have the indicated values,
    is reacted with hydroxylamine and the resulting oxime is reacted with sulfur trioxide complex to release the desired product in free form or as a salt,
    Priority featured:
    05/02/86 when RI is phenyl, which may be substituted with 1-2 substituents selected from the group of methyl or halogen; R2 and RS are hydrogen, RA is a sulfo group; RS and Re are the same or different hydrogen or halogen.
    04.15.87 when Rt is phenyl, which may be substituted with 1-2 substituents selected from the group C 1 -C 4 alkyl, halo, or hydroxyl; Ra and Ra are hydrogen; RA - sulfo group; RS and Re are the same or different - hydrogen, halogen or hydroxyl.
    ten
    Table 1
    table 2
    Table 3
    Table 4
    Continuation of table 4
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    同族专利:
    公开号 | 公开日
    NO875495D0|1987-12-30|
    FI875771A0|1987-12-30|
    NO174465B|1994-01-31|
    CA1314888C|1993-03-23|
    DK694487A|1988-03-02|
    DK171379B1|1996-10-07|
    IL82399D0|1987-11-30|
    HUT47912A|1989-04-28|
    EP0243982B1|1991-04-17|
    GR3001800T3|1992-11-23|
    US4839368A|1989-06-13|
    DK694487D0|1987-12-30|
    US5077410A|1991-12-31|
    WO1987006580A1|1987-11-05|
    RU1779246C|1992-11-30|
    AU596657B2|1990-05-10|
    ZW7887A1|1987-09-09|
    HU199803B|1990-03-28|
    FI90071C|1993-12-27|
    DE3769358D1|1991-05-23|
    NZ220168A|1990-02-26|
    AU7244187A|1987-11-05|
    AU630716B2|1992-11-05|
    IE871154L|1987-11-02|
    AU5861890A|1990-11-15|
    NO875495L|1988-03-01|
    FI875771A|1987-12-30|
    FI90071B|1993-09-15|
    NO174465C|1994-05-11|
    EP0243982A1|1987-11-04|
    IE60105B1|1994-06-01|
    ES2036542T3|1993-06-01|
    引用文献:
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    US3976650A|1975-11-04|1976-08-24|Pfizer Inc.|Process for preparing optically active 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid ester analgesics|
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    US4421919A|1980-07-28|1983-12-20|Hodogaya Chemical Co., Ltd.|4-Oximino-1,2,3,4-tetrahydroquinoline derivatives|
    GB2092130B|1980-07-28|1984-05-10|Hodogaya Chemical Co Ltd|4-oximino-1,2,3,4-tetrahydroquinoline derivatives|
    GB2081091B|1980-07-28|1984-03-07|Mochida Pharm Co Ltd|Hypotensive diuretic pharmaceutical compositions containing tetrahydroquinoline derivatives|
    US4521607A|1981-02-27|1985-06-04|Takeda Chemical Industries, Ltd.|Chromanyl glycines|
    CA1189078A|1982-07-30|1985-06-18|Hodogaya Chemical Co., Ltd.|Process for producing 4-oximino-1,2,3,4-tetrahydroquinoline derivatives and said derivativesproduced thereby|
    DE3416695A1|1984-05-05|1985-11-07|Bayer Ag, 5090 Leverkusen|AMIDINOHYDRAZONE OF TETRALINE, CHROMONE, THIOCHROMONE AND TRETRAHYDROQUINOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS|
    PH21213A|1984-10-26|1987-08-21|Fujisawa Pharmaceutical Co|Benzene- and pyrazole- fused heterocyclic compound and pharmaceutical composition comprising the same|
    EP0199672B1|1985-04-12|1988-06-01|Ciba-Geigy Ag|Oxime sulphonates containing reactive groups|
    US4839368A|1986-05-02|1989-06-13|Mochida Pharmaceutical Co., Ltd.|1-acyl-2,3-dihydro-4-quinolinone-4-oxime derivatives|US4839368A|1986-05-02|1989-06-13|Mochida Pharmaceutical Co., Ltd.|1-acyl-2,3-dihydro-4-quinolinone-4-oxime derivatives|
    JP2602037B2|1987-10-31|1997-04-23|持田製薬株式会社|1-acyl-2,3-dihydro-4-quinolinone-4-oxime derivatives, process for preparing the same, and pharmaceutical compositions containing diuretic, antihypertensive, anti-edema and ascites removal based on them|
    AU661159B2|1992-07-15|1995-07-13|Sumitomo Chemical Company, Limited|N-acyldihydroquinoline derivatives, a method for producing the same and their use as herbicides|
    DK1221440T3|1994-06-15|2007-09-17|Otsuka Pharma Co Ltd|Benzoheterocyclic derivatives useful as vasopressin or oxytocin modulators|
    HN2000000203A|1999-11-30|2001-06-13|Pfizer Prod Inc|PROCEDURE FOR OBTAINING 1,2,3,4-TETRAHYDROQUINOLINS 4-CARBOXYAMIN-2-SUBSTITUTED.|
    GB2532990A|2014-12-05|2016-06-08|Schlumberger Holdings|Corrosion inhibition|
    GB2543498A|2015-10-19|2017-04-26|Schlumberger Holdings|Corrosion inhibition|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP10284786|1986-05-02|
    JP62092788A|JPH0446951B2|1986-05-02|1987-04-15|
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