• 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 obtaining 5- (2-chlorobenzsh1) -3-hydroxy-5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridinone-2 of the formula HO0 or its salts, differing that the compound of formula a is subjected to nitrosation with sodium nitrite in glacial acetic acid in an inert atmosphere, the resulting compound of the formula is hydrogenated in the presence of palladium on carbon and perchloric acid in alcohol, the resulting compound of the formula HON is heated to boiling with hydrochloric acid in isopropyl alcohol in - atmosphere and isolate the desired product in free form or in salt form. 1chE Jbd x 4
    公开号:SU1207394A3
    申请号:SU833604954
    申请日:1983-06-15
    公开日:1986-01-23
    发明作者:Фреель Даниель；Маффран Жан-Пьер；Валлее Эрик
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to a process for the preparation of new chemical compounds, namely 5- (2-chlorobenzyl) -3- -ox-556, 7 9 7a-tetrahydro-4H-thieno (3,2-c) gshridinone-2 of formula
    ,
    oSS
     S.С1Ш
    lly its salts, which can be used as biologically active substances.
    The aim of the invention is to develop, on the basis of a known method, a method for producing new compounds; possessing valuable pharmacological properties.
    Example. 5- (2-Chlorobenzyl) 3- hydroxy-5,6,7s 7a-tetrahydro 4H-thieno- (3,2-c) pyridinone 2 (J).
    a) 5- (2-Chlorobensyl) 3-oxyim: no-4, 5,6, 7-tetrahydro-3H-thieno (3,2-e) pyridinone-2 (III).
    . 25 g (O ,, 0068 mol) oxalate 5- (2-chlorobenzyl) -55b, 1 7a-tetrahydro-4H-thieno-{3 J 2-c) -pyridinone-2 (I) sous pendiruyut in 125 ml of ice acetic acid in an inert atmosphere and after cooling the reaction mixture g 0-5 C, 5 g (mol) of sodium nitrite dissolved in 30 m of water are added dropwise. Leave at room temperature for 7 hours. The crystals of the filter are washed with ether and dried. The product is recrystallized from water. Yellow crystals are obtained. MPLC 22Q ° C, yield 70%, weight. 19 Go
    b) 5- (2 Chlorobenzyl) -3-oxyimino-3a, 4, 5,6, 7, 7a - hexahydro-3H-thieno- (3,2-e) -pyridinone-2 (IV).
    15 g (mol) of the compound of the formula (ill) 5 obtained above; Dissolve in a mixture of 900 ml of methanol and 8 ml of 70% perchloric acid. 4 i 10% palladium-on-carbon as a suspension in 100 ml of ethanol is added to the reaction medium. The reaction mixture is hydrogenated in a reactor at ordinary pressure (1 atm) and left for 6 hours at room temperature. After filtering off the catalyst, the reaction medium is scorched to dryness.
    The residue dissolved in water is neutralized with an aqueous saturated sodium bicarbonate solution. Water phase
    1207394
    extracted with dichloromethane, the organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The oily residue was purified by chromatography on a silica column (eluent: toluene-ethyl acetate 1: 1). The resulting compound was converted to oxalate.
    a) 5- (2-7-chlorobenzyl) -3-hydroxy-55b, 7, 7a-tetrahydro-4H-thieno- (3,2-e) -pyridine-2 (i).
    10.4 g (0.0334 mol) of the compound of formula (IV) obtained in the previous step are dissolved in a mixture of 250 kp of isopropyl alcohol and 45 ml of 2 n hydrochloric acid. The mixture is refluxed under an inert gas atmosphere for 4 hours, evaporated to dryness and the residue is treated with aqueous saturated sodium bicarbonate solution. The aqueous phase is extracted with dichloromethane. The organic phase is dried over anhydrous sulfur, sodium fate and evaporated to dryness. The resulting oil residue is purified by filtration through a layer of silica (eluant: toluene-ethyl acetate 1: 1). A base is obtained in the form of beige crystals. Yield 81%, m.p. 12 s ° C ,, weight. 9.25
    Elemental anscia for hemi-oxalate of compound (I).
    C, H, C1N02S, 0.5.
    M 341,801.
    Found,%: С 52 „85 | H 4.47; and 4.28.
    Calculated,%: C, 52.86; H 4.43; Ы 4 J i.
    Mass: m 295.
    KK (KVg) (base) 1685 () 5 3400 (OH); 1650 ().
    NMR NShVS) (base) ppm : 1.20-3.25 (multiplet, 5H, SCHCH,.,); 3.80 ppm (singlet, 2H ,,); 3-90-4.40 (r-guliplet, 2H, YN-cyanyl); and 65 (multiplet 4, aromatic).
    51MP C (CDC1.,) (Base):
    (95.24 (CO; 145.17 (C2); 133.10 (03) 52J4 (C4); 51.11 (C5); 33.57 (C6); 44J4 (C7) | 58.09 (C8) 135.16 (C9);
    134.62 (CJ); 129.76 (C11); 128.79 (C12); 127.09 (C13); 131.22 (C14).
    Various salts are obtained in bulk.
    Hemi-oxalate: cream-colored crystals with m.p. 170 s (from a mixture of isopropyl and acetonitrile).
    Nitrate: pink crystals with m.p. 181 ° C (from a mixture of isopropanol and methanol).
    Hydrochloride: beige crystals with m.p. 139 with (from isopropanol).
    The toxicological study of compound (I) for acute toxicity, chronic toxicity, subchronic and prolonged toxicity, show its good tolerability and weak toxicity.
    A pharmacological study of compound (I) shows its inhibitory activity against platelet aggregation and antithrombocytic activity. Compound (1) is tested as hemi-oxalate
    Inhibitory platelet aggregation activity.
    The experiment was carried out on a rat that received 100 mg of oral compound for three days; (1) at time points of 48, 24, and 2 hours. At time O, 4 ml of blood is taken from a belt vein of anesthetized animal for analysis. This citrated blood is used to measure aggregation.
    a) Measurement of platelet aggregation with adenosine diphosphate.
    2 ml of citrated blood is quickly poured into a small cup placed on a magnetic stirrer and equipped with a magnetized rod. After stirring for a few seconds, 0.4 ml of a solution containing-O, 66 µg of adenosine diphosphate (ADP) per 1 ml is introduced into a glass. After stirring for 90 s, two samples of 0.5 ml of blood are taken: the first one is mixed with 0.5 ml of a solution of EDTA-formol, the second is mixed with a 0.5 MP solution of one of EDTA
    The addition of EDTA-formol is carried out in order to stabilize the blood and, consequently, fix aggregation, while EDTA, on the contrary, causes disaggregation of all platelet aggregations.
    After holding for 10 minutes and centrifuging both mixtures
    five
    C
    five
    0 5
    about
    ,
    five
    five
    at a slow rate for 5 4In, in order to separate the red blood cells (erythrocytes), a supernatant plasma enriched with PRP platelets is removed, diluted. And the platelets are dissected.
    The intensity of aggregation is determined by the relation:
    platelet count in EDTA formol
    platelet count in EDTA
    X 100% non-aggregated platelets.
    The test product inhibits platelet aggregation more, the closer the ratio to 100.
    Thus, it is determined that in the lot (5 rats) treated with compound (I), the percentage obtained is 44 ± 13, whereas for the control lot (5 rats) the percentage is 6 + 2.
    b) Measurement of platelet aggregation with collagen.
    To 1.5 ml of citrated blood, 0.10 mp of a solution containing 10 µg of collagen per mp is added. The medium is maintained while stirring, platelet counting is carried out without interruption.
    The decrease in the number of free platelets depending on the time proceeds continuously and allows you to draw a curve, the slope of which gives the initial velocity of aggregation.
    For the batch (5 rats) treated with compound (1), the initial aggregation rate is 2.33 + 1.18, while for the untreated control batch (5 rats) it is 12.44 + 2.65.
    The study of inhibitory activity against platelet aggregation is also directed to the effects of the compound (3L) depending on the bleeding time.
    The experiment was carried out on a rat that received for 65, 41 and 17 hours before the Negro oral 200 mg of compound (J) in the form of a suspension in 10 ml / kg of an aqueous solution of gum arabic. After anesthesia with pentobarbital, the rat's tail is cut off 5 mm from the end. Blood is thoroughly wiped off for 15 seconds, taking care not to touch the wound. Hemostasis is reached when bleeding stops within one
    five
    minutes The bleeding time is expressed in seconds, and the release time of 1200 s (20 # 1i) is no longer counted.
    It is thus determined that for control animals that receive only gum arabic, the average bleeding time is 390 s, whereas for treated animals it is above 1200 s.
    Anti-platelet activity is studied according to two methods:
    a) The method of experimental thrombosis on a silk thread.
    In rats anesthetized by intraperitoneal injection of pentobarbital, the left stratum vein and the right external carotid artery are exposed.
    The bypass arterio-anastomo is formed by a central catheter and two lateral catheters, a natural white silk thread is inserted into the central part, and circulation is restored within 20 minutes. After the circulation is stopped, the thread is carefully pulled out and immediately weighed by applying a clamp. The average weight of the wet silk thread is determined by the precursor ;; Gelno.
    The treatment is carried out 48 hours 24 and 2 hours before the start of blood circulation in the bypass anastomosis due to the oral administration of 200 mg / kg of compound (1) as a suspension in 10 ml / kg of 5% gum arabic, and only 5 % gummyarbik.
    Thus, the average thrombus weight in two batches of 10 rats is determined to be 38562 + 1518 mg for control animals and 26.00 + + 6.42 for treated, animals (-35%)
    b) Vein thrombosis method with a coil (with a corkscrew),




    Editor 0. Bugir
    Compiled by Terenin Tehred A. Kabkney
    Order 8745/61 Circulation 379Subscription
    VNISHI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., d. 4/5
    Filial PPP Patent, g, Uzhgorod, st. P: roktna, 4
    6
    The cut {uk1 metal helix is placed in the rat inferior vena cava, which, for 48, 24 and 2 hours, was orally administered 200 mg / kg of the test compound suspended in 10 ml / kg of aqueous 5% gum arabic.
    After 5 hours, this spiral is taken out with a blood clot that it holds,
    gently dried by successive swabbing on filter paper and weighed. The helix is then free from the clot, dried again and weighed again. In this way, the difference is the average weight of the thrombus, which is 3.4 + + 0.4 mg for the control rats (10 rats 5 that receive only gum arabic) and 251 + 0.3 mg for those treated with compound (I) (-36%) rats (10 rats),
    The table presents the comparative data of anti-platelet activity and inhibitory activity against thrombogenic aggregation, and compound (s) and the known compound in the range of thienopyridine 5- (2-chlorobenzyl) -4,5,65 7-tetrahydrothieno- (3,2-s ) - pyrkdina (ticlopidine).
    Connection;
    Ticlopidine

    44 + 13
     one
    ) test with collagen2, 33 + 1
    18 2.29 + 2.04
    Antithrombotic effect,%:
    a) silk thread
    b) corkscrew

    Proofreader L. Patay
    权利要求:
    Claims (1)
    [1]
    The method of obtaining 5- (2-chlorobenzyl) -Z-hydroxy-5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridinone-2 of the formula or its salts, characterized in that the compound of the formula • with 2 n 2 about 4, they are nitrosated with sodium nitrite in glacial acetic acid in an inert atmosphere, the obtained compound of the formula is hydrogenated in the presence of palladium on carbon and perchloric acid in alcohol, the resulting compound of the formula • С2Н2Р4 is heated to boiling with hydrochloric acid in isopropyl alcohol in inert atmosphere and emit the target product in free form or in the form of salt.
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    同族专利:
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