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    • 专利摘要:
    The method of obtaining derivatives 5,6,7,7a-tetrahydro-4H-thieno-
    公开号:SU1110385A3
    申请号:SU813357149
    申请日:1981-11-27
    公开日:1984-08-23
    发明作者:Буажегрэн Робер；Маффран Жан-Пьер；Суцуки Норио；Матсубайаши Киуичи；Ашида Шиничиро
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing non-grammed 5,6,7,7о1-tetrahydro-4H-thieno (3,2-c) pyridinone-2 derivatives of the general formula-b, j :: u -n. where R is phenyl, unsubstituted or substituted by a halogen atom by an alkyl radical with 1-4 carbon atoms, nitro and cyano; R is hydrogen or alkyl for cal with 1-4 carbon atoms or their salts, possessing pharmacological activity. The reactions of oxidation of boric acid or their esters with hydrogen peroxide C11 and hydrolysis of the corresponding esters thus obtained with water C21 are known. However, there is no information in the literature about the method of obtaining pharmacologically active derivatives of 5,6,7,7-tetrahydro-4H-thieno (3,2-e) pyridinone-2 of general formula (I) or their salts. The purpose of the invention is a method for preparing pharmacologically active derivatives of 5,6,7, 7a-tetrahydro-4H-thieno (3,2-c) pyridinone-2 of general formula (I) or their salts. This goal is achieved by the fact that according to the method for producing derivatives 5,6,7,7a-tetrahydro-4H-thieno, 2-c) -pyridinone-2 of the general formula (I) or their salts, the böther derivative of the general formula RI, (II) (R20) zB § and R - have the indicated values H — hydrogen or lower alkyl radical, are oxidized with hydrogen peroxide in an inert solvent at 0–30 ° C, and the resulting boronic acid derivative of general formula (III) has the indicated value 1 5 2 is subjected to hydrolysis with water followed by by isolating the target product in free form or as a salt after processing inorganic and whether organic pharmaceutically acceptable acid. Example 1. 5-o-Chlorobenzyl-5, 6,7,7a-tetrahydro-4H-thien (3,) pyridinone. To a solution of 32.6 g (0.128 mol) of 5-o-chlorobenzsh1-4, 5,6,7-tetrahydro- (3,2-e) thien-pyridine in 320 cm of tetrahydrofuran (THF) cooled to -20 ° C 79 cm of a 12% solution of lithium butyl in hexane (0.147 mol) is dropwise. After the addition is complete, the organolithium compound precipitates and the temperature is allowed to rise to. Then 15 cm of hexamethylphospho triamide (HMPT), previously dried on a 4A molecular sieve, is added. The color of the precipitate turns dark red. The temperature is reduced to and a solution of tributylborate (39.8 cm; 0.147 mol) in 40 cm of anhydrous THF is added dropwise over 30 minutes. The precipitate disappears, and the color of the reaction medium turns light yellow. The temperature is maintained for 30 minutes, then it is raised to (2 hours). 33 cm (0.291 mol) of 30% hydrogen peroxide is added dropwise, keeping the temperature of the reaction medium below. As the hydrogen peroxide is added, a precipitate is formed intensively (it is stirred for 1 hour at room temperature). The reaction mixture is then extracted into water, extracted with 3x200 cm of ether, the organic phases are dried with sodium sulfate and evaporated in vacuo at a temperature below. The liquid residue is chromatographed on a silica gel column (cyclohexane / ethyl acetate 6/4) to remove residual SchPT. After evaporation, it is treated with molar oxalic acid in acetone and the resulting light yellow crystals are filtered. After recrystallization from ethanol, beal oxalate crystals are obtained, yield 52%, t, pl. . m.p. 73-74, (this Foundation: Nile).
    31
    The hydrochloride, hemihydrate: m.p., decomposes around (precipitation from acetone).
    EXAMPLE 2. 5-Benzyl-5,6,7,7 sC -tetrahydro-4H-thien- (3, 2-s.) - 2-pyridinone.
    It is prepared according to Example 1, the outcome of the 5-benzyl-4,5,6,7-tetrahydro-thia- (3,2-c) -pyridine short-term compound
    Maleate: beige crystals, so pl. 132-134 ° C (isopropanol); The code is 33%.
    Example 3. 5-l-Chlorobenzyl-5, 6,7, 7a tetrahydro-4H-thien- (3,2-s) -2-pyridinone.
    It is prepared according to example 1 of 5-p-chlorobenzyl-4,5,6,7-tetrahydro-thien- (3,2-C.) -pyridine.
    Maleate: beige crystals, so pl. 158-160 ° C (ethanol); yield 42%.
    Example 4. 5 - & - Methylbenzyl-5, 6,7,7a-tetrahydro-4H-thien- (3,2-s.) - 2-pyridinone.
    It is prepared according to example 1 of 5-0-methylbenzyl-4,5,6,7-tetrahydro-thien- (3,2-s.) - pyridine.
    Oxalate: beige crystals, so pl. 195-197 ° C (methanol); yield 33%.
    P i mi p 5. 5-G1 (2-chloro-phenyl) -ethyl-5,6,7,7-tetrahydro-4H-thien- (3,2-с) -2-pyridinone.
    It is prepared as in example 1 of 5-t1- (2-chloro-phenyl) -ethyl 1-4,5,6,7 tetrahydro-thien- (3,2-c) -pyridine.
    Hydrochloride: yellow crystals, so pl. 140-142 ° C; yield 24%.
    Pr and m p 6. 5- 1 (2-Chloro-phenyl) -propyl-5,6,7, 7a-tetrahydro-4H-thien- (3,2-d) -2-pyridinone.
    It is prepared according to example 1 of 5-C1 - (2-chloro-phenyl) -propyl -4,5,6,7-those trahydro-thien- (3.2-s), -pyridine.
    Hydrochloride: beige crystals, so pl. 124-126 ° C; yield 27%.
    Example 7. 5-Trimethylsilyl-4, 5,6,7-tetrahydro-thien- (3,2-s;) - pyridine. .one . .
    To a solution of 80 g (0.571 mol) of tetragvdro-4, 5,6,7-thien- (3,2-e) -pyridine and 63, 4 g (0.28 mol) of triethylamine in 1100 cm of toluene are added under a nitrogen atmosphere 65 g (0.628 mol) of chlorotrimethylsilane in 50 cm of toluene. The reaction medium is agar-revanzt for 3 hours. After cooling, the white precipitate of triethanolamine hydrochloride is filtered and the filtrate is evaporated in vacuo. The residue is distilled at
    0385
    60-70 ° C and a pressure of 0.1 mm RT. Art., get a colorless liquid, yield 55%.
    Example 8. 4,5,6,7-Tetragid5 ro-thien- (3, 2-c) -2-pyridineboronic acid.
    To a solution of 15 g (0.07 mol) of 5-trimethylsilyl-4, 5,6,7-tetrahydro-thieno- (3,2-s) -pyridine, prepared in Example 7, cooled to a solution, is obtained in 150 cm THF. dropwise, under a nitrogen atmosphere, 45.4 cm of a 12% butyl lithium solution in hexane (0.084 mol), allow the temperature to rise to 5 ° C and add 3. After cooling to -50 ° C, a solution of 19.3 g (0.084 mol) of tributylborate in 30 cm THF is added dropwise. Stir for 2 hours, allowing the mixture to
    0 to warm to room temperature, then 28 cm of H is added. hydrochloric acid (0.084 mol) and the precipitate formed is filtered. The crystals are washed with acetone and diisopropyl ether, then dried in a vacuum. White crystals: mp. more yield is quantitative.
    Example 9. 5-0-Cyanobenzyl-4, 5,6,7-tetrahydro-thieno- (3,2-c) 0 -2-pyridineboronic acid.
    A mixture of 3.68 g (0.02 mol) of 4,5,6,7-tetrahydro-thieno- (3,2-s) -2-pyridineboronic acid (prepared in Example 8), 9 , 09 g (0.06 mol) o-cyanbenzyl chloride and 5.52 g (0.04 mol) of potassium carbonate in 40 cm of dimethylformamide. After evaporation of the solvent, water is added to the reaction mixture.
    0 then extract three times with 100 cm of methylene chloride. The organic solution is dried with sodium sulfate, then evaporated in vacuo. The resulting crystals are washed with diisopropyl
    5 ether.
    White crystals: so pl. 140-142 0; yield 45%.
    Take p10. 5-o-Cyanobenzyl-5, 6,7, 7schg-tetrahydro-4H-thien- (3,2-C) -2-pyridinone.
    To the solution cooled to 5 ° C: 1.8 g (0.006 mol) of 5-o-cyanobenzyl-4, 5,6,7-tetrahydro-thiene- (3,2-C) -2-pyridineboronic acid obtained in the example 9, in 30 cm THF, 0.23 g (0.006 mol) of a 30% hydrogen peroxide solution is added dropwise. The temperature is brought to ambient temperature and stirred for 2 hours. Water is added to the reaction medium, then extracted with methylene chloride. The organic solution is cyiaaT sodium sulfate and evaporated in vacuo. The residue is chromatographed on a silica gel column (cyclohexane-ethyl acetate 1/1). After evaporation, it is treated with an equivalent of oxalic acid in acetone and the formed crystals are filtered. Oxalate: beige crystals, so pl. Pb-Pv C (acetonitrile); yield 28%. Example 11. 5-about-Nitrobenzyl-5, 6,7, 7q -tetrahydro-4H-thien- (3,2-c) -2-pyridinone. a) Preparation of 5-o-nitrobenzyl-4,5, 6,7-tetrahydro-thia- (3,2-с) -2-pyridineboronic acid. It is prepared according to example 9 of 4,5,6,7-tetrahydro-thien- (3,2-e) -2-pyridineboronic acid and o-nitrobenyl 3-chloride. Brown crystals: so pl. 132134 0; yield 40%. NMR (DM50Db): 8.0 (t, 4H); 7.50 (s, 1H); 4.00 (5, 2H) 3.60 (5, 2H); , 2.70 (t, 4H). b) The desired product is obtained according to Example 10 from 5-o-nitrobenzyl-4,5, 6,7-tetrahydro-thien- (3,2-s.) - 2-pyridineboronic acid. Oxalate: beige crystals, so pl. 186-188 C (isopropanol ethanol); yield 17%. Example 12. 5-0-Bromobenzyl-5,6,7,7a-tetrahydro-4H-tyen- (3) -2-pyridine. a) Preparation of 5-0-bromobenzyl-4,5, 6,7-tetrahydro-thien- (3,2-e) -2-pyridineboronic acid. Prepared according to example 9 of 4,5,6,7 tetrahydro-thiene- (3,2-c) -2-pyridineboronic acid and o-bromobenzyl bromide. Yellow crystals: so pl. 129-131 With an exit of 53%. b) Obtaining the desired product is carried out under the conditions of example 10 from 5- (o-bromobenzyl) -4,5,6,7-tetrahydrothieno (3,2-c) -pyridineboronic acid. Oxalate: beige crystals with t. 151-153C (isopropanol); output The results of toxicological and pharmacological studies given below show the properties of the derivatives of the general formula. These studies were carried out in comparison with the well-known 2-chlorobenzyl-5-tetrahydro-4, 5,6,7-thien- (3,2-c) -pyridine, hereinafter referred to as compound A, and 2-cyano-5-benzyl -4, 5,6,7-tetrahydro-thien- (3,2-c) -pyridine, hereinafter referred to as compound B. Toxicology, a large study. Sharp, 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 (I), as well as their good tolerance. In tab. 1 shows the LD 50/24 p / kg body weight when administered intravenously to the mice, and presents the results obtained for the derivatives of formula (I) and for comparative compounds A and B. These results show that the toxicity of the derivatives of general formula (I) is at least less than half The toxicity of comparative compounds A and B. Table 1 Compounds in LD50, Mr Examples Comparative Compound 711 In addition, experiments showed that the derivatives of general formula (I) did not cause various types of local or general reactions in animals, biological control disorders, or microscopic or macroscopic disorders. The progeny study did not detect the teratogenic effect of the compounds of general formula (I). Pharmacological study. The ability to inhibit platelet aggregation and anti-thrombotic activity was compared with compounds A and B. 1. Inhibition of platelet aggregation was studied. In Wistar rats pretreated with the test compound, blood is taken from the strap veins. From this blood, after treatment with citrate and centrifugation, plasma is obtained containing 600,000 + 20,000 platelets per millimeter, which is subsequently used for all definitions of platelet aggregation. Determination of platelet aggregation using ADP. Place 0.4 ml of plasma in a silicone tube fitted with a magnetized silicone rod. The tube is installed 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 is introduced into the tube.
    Table 2 85 of a solution containing 10 µmol ADP (adenosine diphosphate). Platelet aggregation results in an increase in light transmittance, which is accompanied by a subsequent decrease in transmittance at the phase boundary. The maximum change in optical density, thus determined in relation to a plasma that does not contain platelets, characterizes the intensity of aggregation. Determination is performed within 2 hours after treatment with the test compound. Determination of thrombocyte aggregation with collagen. The ADP solution is replaced with a collagen solution taken from bovine tendons. Various batches of 20 rats each were investigated. Each batch received a single dose of the test derivative orally, and the derivative was also given in different doses from 5 to 100 mg / kg. Significant activity of the derivatives of general formula (I) occurs at a dose of 12.5 mg / kg, whereas for comparative compounds A and B, doses of 100 mg / kg are required to obtain the same activity. The results of experiments with ADP and collagen are summarized respectively in Table. 2 and 3, where the percentage suppression of platelet aggregation, achieved compared with the control experiment, 3 h after treatment with the test compound is shown.
    51.0
    83.6
    83.7
    84.0
    84.1
    ten
    1110385
    Continued tabl, 2
    Investigation of platelet aggregation kinetics.
    An experiment was conducted relating to the study of the kinetics of compounds of general formula (I). The derivative of Example 1 and Comparative Compound A is dissolved in propylene glycol and given to rats intraperitoneally at a dose of 100 mg / kg body weight, whereas control mice receive intraperitoneally only 1 ml / kg propylene glycol. Blood is taken through From the table. But it can be seen that, in relation to Comparative Compound A, the compound from Example No. 1 suppresses platelet aggregation significantly, and this action occurs much faster. 2. Anti-thrombus activity. This activity has been studied according to the experimental thrombosis method by extracorporeal circulation. In the rat anesthetized by intraperitoneal administration of pentobarbital, the left strap and the right external artery are exposed. The shu t is composed of one central: and two lateral catheters; white thread and natural silk are introduced into the central part and blood circulation is restored within 20 minutes.
    10 and 60 minutes after administration, then et; centrifugal flow to obtain platelet-rich plasma.
    Platelet aggregation in plasma, induced by ADP, is determined using the Brayston aggregometer using the Born neplometric method.
    The dependence of the percent inhibition on the time obtained as a result of this experiment is presented in Table. four.
    Table 4 After the circulation has been stopped by clamping the thread, gently pull the thread and immediately weigh it. The average weight of one wet silk thread according to the proposed definition is 5.10 mg. c: Treatment is carried out 47, 24 and 2 hours before the start of blood circulation through the shunt. . ,,; .- - Products are orally administered to different batches consisting of 20 animals each, in the form of a suspension of 10 ml / kg of 5% gum arabic in doses of 12.5; 25; 50; 100 and 200 mg / kg. In tab. 5 summarizes the results of experiments with derivatives of examples 1 and 3 of the general formula (1) and comparative compound A, presented in the form of averages, calculated for each batch. - T a b l and c a 5
    30.09
    30.45
    30.41
    This experiment demonstrates the activity of compounds of the general formula (1), which cause a significant decrease in the average weight of blood clots, starting with a dose of 25 mg / kg, whereas comparative compound A does not show any anti-thrombotic effect at all even at higher doses.
    In addition, experiments show that, in contrast to compounds A and B, the derivatives of general formula (I) do not possess anti-inflammatory properties at all and do not have a vasodilating effect. Consequently, they exhibit much more selective properties, which gives them great interest from the point of view of therapy, when additional activity, if not required, can harm the patient.
    The described toxicological and pharmacological studies indicate a weak toxicity of compounds of the general formula (I) and their good tolerance, as well as about
    23.13
    23.04
    28.86
    their ability to inhibit platelet aggregation and anti-thrombotic properties, which determine the feasibility of their use in the treatment of humans and animals.
    The compounds of formula (I) can be used for oral administration in the form of tablets, dragees, capsules, drops, for parenteral administration in the form of solutions for injection and for rectal administration in the form of suppositories.
    . Compounds of general formula (I) can be used in medicine because of their ability to suppress aggregation
    platelet and their anti-thrombosis jj
    activity. Because of their ability to inhibit certain platelet functions by affecting the mechanism of arterial and venous thrombosis, these compounds are indicated in the treatment and prevention of thrombotic disorders caused by extracorporeal currents or resulting from atheroma.
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives of 5,6,7,7c-tetrahydro-4H-thieno- (3,2-e) · pyridinone-2 of the General formula
    C ^ -C ^ alkyl to a nitro or cyano group;
    1½ is hydrogen or C ^ -C / alkyl, or their salts, characterized in that, the ester derivative of the general formula (R Z O) 2 B
    R
    R1 where R and have the indicated meanings; R ^ - hydrogen or a lower alkyl radical, is oxidized with hydrogen peroxide in an inert solvent at 0-30 ° C and the resulting boroxide derivative of the general formula where R is phenyl unsubstituted or substituted by a halogen atom, where R, Rή and · Rj - have the indicated meanings, hydrolysed with water, followed by isolation of the target product in free form or in the form of salt.
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8025274A|FR2495156B1|1980-11-28|1980-11-28|
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