• 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 derivatives of 5, 6, 7, 7a-tetrahydro-4H-thieno
    公开号:SU1176843A3
    申请号:SU813358458
    申请日:1981-11-27
    公开日:1985-08-30
    发明作者:Маффран Жан-Пьер；Суцуки Норио；Матсубайаши Киуичи；Ашида Шиничиро
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing 5,6,7,7a-tetrahydro-4H-thieno (3,2-c) -pyridinone-2 derivatives of the general formula of the formula A, where R is phenyl, unsubstituted or substituted by a halogen atom, lower alkyl radical by nitro or cyano group, Rj is hydrogen or lower alkyl radical, or their salts with mineral or organic acids with pharmacological activity. The purpose of the invention is to develop a method for producing new 5,6,7,7a-tetrahydrothieno (3,2-c) pyridinone-2 derivatives of the general formula} or their salts, which have high antiaggregate activity against platelets. Example 1. 5- (2-Chlorobenzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) 2-pyridium. A.. Preparation of 1- (2-chloro-benzyl) -4-oxo-3-piperidine methyl acetate. A solution of 100 g (0.355 mol) of C1- (2-chloro-benzyl) -4-oxo-3-piperidine-ethylcarboxylate in 400 cm 1 of.-Dimethoxyethane is added to the mixture in a mixture of 17.04 g (0.355 mol) sodium hydride (suspension 50%) in 250 cm 1 of 2-dimethoxyethane, stirred at room temperature for 30 minutes, then a solution of 59.28 g (0.355 mol) of ethyl bromoacetate in 250 cm of 1,2-dimexyethane is added dropwise . Stir at room temperature for 2 hours, filter the resulting precipitate, wash it with ether, and concentrate the filtrate in vacuo. The precipitate is dissolved in water and extracted with methylene chloride. The organic extracts are washed with water, dried with sodium sulfate, filtered on a layer of silica and concentrated in vacuo. The resulting yellow resin (123.2 g is dissolved in 850 cm of 6N hydrochloric acid and the solution is heated under nitrogen for 4 hours. After cooling, the reaction mixture is concentrated in vacuo, water is added and the mixture is extracted with ether. Aqueous phases alkalinized with caustic soda, then adjusted to pH 4 with acetic acid and extracted with methylene chloride .. The organic phases are washed with water, dried with sodium sulfate and evaporated to dryness. The resulting gummy product (93.8 g) is dissolved in acetone and treated with ether chloride solution in The obtained C1- (2-chloro-benzyl) -4-oxo-3-piperidine-acetic acid hydrochloride is filtered, washed with acetone, then ether, and dried in vacuo: white crystals, t.p. (180) C, yield 64%. A solution of 30 g of the obtained hydrochloride in 300 cm of methanol saturated with hydrogen chloride is stirred at room temperature for 3 hours. The solution is evaporated at a lower temperature, added, made alkaline by the addition of sodium bicarbonate and extracted with chloride methylene. The organic extracts are washed with water, dried with sodium sulfate and evaporated to dryness. The keto ester obtained in the form of a yellow resin is used without purification in the next step. IR spectrum (film: CP: 1720 cm). NMR (CDCl1): 7.05-7.76 (m4H); t 3.72 (S 2H); 3,62 (S ЗН). B. 5- (2-Chloro-benzyl) -5,6,7,7a-tetrahydro-4H-thieno (3,2-c) -pyridinone-2. At the same time, bubbling of hydrogen chloride and hydrogen sulfide flows into the solution heated to 85 ° C and containing 4.5 g (0.0152 mol) of the ketoester obtained in 45 cm of acetic acid is carried out. It is concentrated under vacuum, the precipitate is taken up in water, brought to alkaline with sodium bicarbonate and extracted with methylene chloride. The extracts are washed with water, dried with sodium sulfate and evaporated to dryness. Get the target product in the form of a yellow oil (3.6 g, yield 86%), is converted to the oxalate with m. PP. (ethanol) by adding an acetone solution of oxalic acid. Hydrochloride hemihydrate: m. P. with different at 180 C (precipitation in acetone), Base: so pl. 73-74 C, 5 C (ethanol). Examples 2-9. The following compounds are similarly synthesized. Derivative 2: 5-benzyl-5,6,7,7a-tetragvdro-4H-thieno (3,2-c) -pyridinone-2. Maleate: beige crystals, so pl. 132-134 ° C (isopropanol). Derivative 3: 5- (4-chlorobenzsh1) -5., 6, 7, 7a-tetrahydro-4H-thieno (3,2-c) pyridinone-2. Maleate: beige crystals, so pl. 158-160 0 (ethanol). Derivative 4: 5- (2-methylbenzyl) 5, 6, 7,7a-tetrahydro-4H-thieno (3,2-c) pyridinone-2. Oxapat: beige crystals, so pl. 195-197 ° C (methanol). Derivative 5: 5-C (2-chlorophenyl) -1-ethI -5.6, 7, 7a-tetrahydro-4H-thieno (3,2-e) pyridinone-2. Hydrochloride: yellow crystals, so pl. 140-142 C. Base: NMR (CDCI,): 7.30 (m4H 6.05 and 5.95 (2S, 1H), (2 diasterioisomers), Derivative 6: (2-chlorophenyl) -propyl-5.6 , 7, 7a-tetrahydro-4H-thieno (3,2-e) -pyridinol-2. Hydrochloride: beige crystals, mp 124-126 0. Base: NMR (CDOIj): 7.30 (m4H 6, 05 and 5.90 (2S, 1H) i (2 diasterioisomers; Derivative 7: 5- (2-cyanobenzyl) -5, 6,7,7a-tetrahydro-4H-thieno (3,2-s) pyridinone-2 Oxapat: beige crystals, mp 176-178 ° (acetonitrile) Base: NMR (ODOl): 7.50 (m4H); 6.00 (S, 1H); 3.80 (S, 2H). Derivative 8: 5- (2-nitrobenzyl) -5, 6,7,7A-tetrahydro-4H-thieno (3,2-c) pyridinone-2. Oxapat: beige crystals, t. Pl 186-188 ° 0 (isopropanol -ethanap5. concept: NMR (OB013): 7.50 (t, 4H) 5.95 (S, 1H); 3.90 (S, 2H), Derivative 9: 5- (2-bromobenzyl) -5, 6.7, 7a-tetrahydro-4H-thieno (3,2-s) -pyridinone-2. Okeapat: beige crystals, m, pl 151-153 0 (isopropanol). Base: (ODOIj): 7.30 (m, AN), 5.96 (S, 1H), - 3.75 (S, 2H). Toxicological and pharmacological studies were carried out in comparison with analogues with the structure of 2-chloro-5-benzyl-4, 5,6,7-tetrahydrothien (3 , 2-e) pyridinone, (comparative compound A) and 2-cyano-5-benzyl-4, 5,6, 7-tetrahydro-thien (3, 2-e) pyridinone (compound B). Toxicological study. Acute, chronic, subchronic and delayed toxicity has been studied. Experiments conducted on various species of animals (mice, rats and rabbits), indicate a weak toxicity of compounds of General formula T, as well as their good tolerance. Below are (25 h / kg body weight) calculated according to method 1 1 of the killer and Tenter, intravenously administered to mice, and the results obtained for derivatives of formula f and comparative compounds A and B. These results show that the toxicity of derivatives of the general formula 1 at least half the toxicity of compounds A and B. In addition, experiments have shown that the derivatives of the general formula do not cause in animals of various species in the course of the conducted local or general reactions, violations of the regularly conducted bio ogicheskogo control, micro- or macroscopic character disorders. The progeny study did not detect the teratogenic effects of the tested compounds.
    Pharmacological study.
    The ability to inhibit platelet aggregation and anti-thrombotic activity was studied compared with compounds A and B.
    Platelet Compound Suppression
    In Wistar rats pretreated with the test compound, blood is taken from the strap veins. Plasma containing 800 + 20 thousand platelets of 1 mm is obtained from this blood after treatment with citrate and centrifugation, which is then used for all definitions of platelet aggregation ..
    Determination of platelet aggregation with ADP (adenodine diphosphate).
    Place 0.4 ml of plasma in a silicone tube fitted with a magnetized silicone rod. The tube is placed in an aggregometer connected to a device that allows recording changes in optical density. When the passage of light reaches a constant value, 0.5 ml of a solution containing 10 µmol ADP is introduced into the tube.
    Platelet aggregation causes an increase in the transmittance of light, which is accompanied by a subsequent decrease in transmittance during the separation phase.
    The maximum change in optical density, thus determined in relation to a plasma that does not contain thrombogs, characterizes the intensity of the compound.
    Determinations are carried out within 2 hours after treatment with the test compound.
    Determination of platelet compound using collagen.
    The ADP solution is replaced with a collagen solution taken from bovine tendons.
    Results.
    Drink out applied batches of 20 rats each. Each batch received a single dose of the test derivative orally, and the same derivative was given in separate doses from 5 to 100 mg / kg.
    A significant activity of the derivatives of general formula J occurs at a dose of 12.5 mg / kg, whereas for compounds A and B, doses of 100 mg / kg are required to obtain the same activity. The results are summarized in table. one
    (experiments with ADP) and 2 (experiments with collagen), which shows the percentage inhibition of platelet aggregation, achieved compared with the control experiment, 3 hours after treatment with the test compound.
    Investigation of platelet aggregation kinetics.
    An experiment related to the study of the kinetics of compounds of general formula 1 was carried out. Derivative 1 and compound A are dissolved in propylene glycol and given to rats intraperitoneally at a dose of 100 mg / kg body weight, while control mice receive intraperitoneally only 1 ml / kg of propnpenglycol.
    Blood is collected 10 and 60 minutes after administration, then it is centrifuged to obtain thrombodate-rich plasma.
    Plasma platelet aggregation induced by ADP is determined using the Braiston aggregometer using the Born nephelometric method.
    The dependence of the event on the time obtained as a result of this experiment is presented in Table. 3
    Tab. 3 shows that, with respect to compound A, the derivative. T of the general formula T suppresses platelet aggregation by activity much more strongly and this action occurs much faster.
    Anti-thrombotic activity.
    Studied by experimental thrombosis by extracorporeal circulation.
    In the rat anesthetized by intraperitoneal administration of pentobarbital, the left ventricle and right artery are exposed. The shun is composed of one central and two lateral catheters: a thread of natural silk is whitened and injected into the central part and the blood circulation is restored within 20 minutes.
    After circulatory arrest by clamping, the thread is gently pulled and slowly weighed.
    The average weight of one wet silk thread is according to a preliminary determination of 5.10 mg.
    The treatment is carried out 48, 24 and 2 hours before the start of blood circulation through the shunt.
    Products are administered orally to different batches of 20 animals each as a suspension in 10 ml / kg of 5% gum arabic in doses of 12.5i 25 50i 100 and 200 mg / kg.
    In tab. 4 summarizes the results of experiments with derivatives 1 and 3 of general formula 1 and compound A, presented as mean values calculated for each batch.
    These data show the activity of compounds of general formula 1, which cause a significant decrease in the average weight of blood clots, starting with a dose of 25 mg / kg, while comparative compound A does not show an anti-thrombotic effect even at elevated doses.
    5 In addition, experiments show that, in contrast to compounds A and B, the derivatives of general formula 1 do not possess anti-inflammatory properties and do not have a vasodilating effect. Consequently, they exhibit more selective properties (additional actinosity, if not required, can
    hurt the patient). five
    Toxicological and pharmacological studies indicate a weak toxicity of compounds of the general formula T and their good tolerance, as well as their ability to suppress platelet aggregation and antithrombotic properties, which
    I
    They determine the feasibility of their use in the treatment of humans and animals,
    Table 1
    table 2
    T a b l and c a A
    Comparative
    compound A
    Control experience with 5% gum arabic
    28.8623.04
    23.13
    30.09
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives
    5. 6, 7, 7a-tetrahydro-4H-thieno (3,2-c) pyridiyone-2 of the general formula i where is phenyl unsubstituted or substituted by a halogen atom, a lower alkyl radical, a nitro or cyano group;
    - hydrogen or a lower alkyl radical, or their salts with mineral or organic acids, characterized in that the compound of the general formula ΙΪ
    R 3 OOCCH 2 ^ x NCH / R1 where R 1 and R 2 - have the indicated meanings;
    R 3 - hydrogen or alkyl with 1 to 4 carbon atoms, treated with hydrogen chloride and hydrogen sulfide in acetic acid at 85 ° C, followed by isolation of the target product in free form or in the form of a salt with mineral or organic acid.
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