• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    This invention relates to thieno derivatives.
    公开号:SU1272994A3
    申请号:SU833618709
    申请日:1983-07-12
    公开日:1986-11-23
    发明作者:Обер Даниель；Ферран Клод；Маффран Жан-Пьер
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new chemical compounds, namely derivatives of thieno (3,2-c) pyridine of the general formula
    where X is hydrogen, fluorine, chlorine, methyl;
    Y - hydroxyl, C, - C4 - alkoxyl, amino, C, - C 4 -alkylamino pyrrolidinyl-1, piperidinyl-1, morpholinyl-1, 4-benzylpiperazinyl-1, or their salts, which show the ability to inhibit platelet aggregation and antiplatelet activity.
    The purpose of the invention is the development, on the basis of the known method, of a method for producing new chemical compounds of the thieno (3,2-c) pyridine series having valuable pharmacological properties.
    Example 1. Os - [4,5,6,7-tetrahydro-5thieno (3.2-s.) Pyridyl] chlorophenylacetic acid methyl ester hydrochloride.
    To a solution of 20 g (0.144 mol), 4,5 ,, 6,7-tetrahydrothieno (3,2-c) pyridine in 200 ml of dimethylformamide, 31.37 g (0.144 mol) of 2-chloro-o-chlorophenylmethyl acetate and 19, 82 g (0.144 mol) of potassium carbonate, after which the reaction mixture is heated at 90 ° C for 4 hours. Then the reaction mixture is cooled to room temperature, inorganic salts are filtered off and the solvent is distilled off. The residue was taken up in water and extracted with ethyl ether. The ether extracts were washed with water, dried over sodium sulfate and, after distillation of the solvent, a yellow oil was collected, which was purified through the intermediate formation of hydrochloride to give white crystals, mp. 130-140 C (ethyl acetate, isopropanol).
    Are they getting 16 5 g. Yield 45%.
    Found,%: C 53.92; H 4.80;
    N, 4.11.
    C 16 H | 6 C1NO 2 'HC1 (M = 358.30)
    Calculated,%: C 53.64; H 4.78; ' N, 3.91.
    • Example 2. OC - [4,5,6,7-tetrahydro-5thieno (3,2-c) pyridyl] phenylacetic acid methyl ester hydrochloride.
    This compound was prepared according to the procedure described in Example 1 by reacting 4,5,6,7tetrahydrothieno (3,2-c) pyridine with 25 chlorphenylmethyl acetate.
    Hydrochloride - white crystals having a melting point of 200 C (ethanol).
    Get 13 g. Yield of 50%.
    Found,%: C 59.23; H 5.59; . W N 4.25.
    С | е Н, t N0 2 S · НС1 (М = 323.82) Calculated,%: С 59.34; H 5.60;
    N, 4.32.
    Example 3. Methyl [• 5-ester o / - [4,5,6,7-tetrahydro-5thieno (3,2-c) pyridyl] -o-fluorophenylacetic acid hydrochloride.
    This compound is prepared according to. the procedure described in example 1, by alkylation of 4,5,6,7tetrahydro g hyeno (3,2-c) -pyridine with 2 chloro-0-fluorophenylmethyl acetate.
    Hydrochloride - white crystals, mp 100 ° C.
    2 · * Get 31.5 g, yield 76.5%.
    Found,%: C 56.09 * H 4.87 ', * N 4.09.
    C L F NO. 2 S HC1 (M = 341.85)
    Calculated,%: C 56.22; H 5.01: 30 N4.10.
    II p and m ζ p 4. Ethyl ether hemisulfate U. - [4., 5,6, 7-tetrahydro-5thieno (3,2-c) pyridyl] -o-methylphenylacetic acid.
    This compound was prepared according to the procedure described in Example 1 by alkylation of 4,5,6,7tetrahydrothieno (3,2-c) pyridine with 2xlo-o-methylphenylethyl acetate. ' ‘
    Hemisulfate - white crystals, so pl. 188-190 C (isopropanol).
    Obtain 32.1 g, yield 54%. Found,%: C 52.30; H 5.74; ' N, 3.24. .
    45 C, g H 2 , NO 2 S. H, SO, (M = 413.52)
    Calculated,%: C 52.58; Η 5.6θ / N 3.39.
    Example 5. o <- [4,5,6,7-Tetrahydro-5-thieno (3,2-c) pyridyl] -0 573 chlorophenylacetic acid, hydrate.
    C. For 2.5 hours, a mixture of 157.9 g of c / - [4,5,6,7-tetrahydro-5thieno (3,2-c) pyridyl] -0-chlorophenyl 5® ethyl acetate is heated under reflux. 100 ml of an alkaline solution of 30% sodium hydroxide in 800 ml of ethanol. After distillation of ethanol, the reaction mixture was acidified with glacial acetic acid and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and the solvent is distilled off. After recrystallization from water, the product is isolated in the form of a monohydrate, which is a white crystal having a melting point of 125 C (yes).
    Obtain 4.4 g, yield 46%.,
    Found,%: C 55.23; H 4.82; N, 4.49.
    С (5 Н н С1 N0 2 S -Н 2 о (M = 325.83)
    Calculated,%: C 55.29; H 4.95; N, 4.30.
    Example 6. Sodium salt! [4,5,6,7-tetrahydro-5-thienyl (3,2-c) pyridyl] phenylacetic acid.
    This compound is prepared according to the procedure described in Example 9 by saponification of οί - [4,5,6,7tetrahydro-5-thieno (3,2-c) pyridyl] phenylethyl acetate. The resulting product is purified through an intermediate preparation of sodium salt. White crystals, mp 210-215 ° C (ethanol, methanol).
    7.4 g are obtained, yield 74%. Found,%: C 61.17; ' H 4.62 / N 4.72,
    C, 5 H, 4 NO 2 SNa (M = 295.29)
    Calculated,%: C 61.01; H 4.78; ' N 4.74.
    Example 7. Hemisulfate H-propyl ester N. - [4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -o-chlorophenyl acetic acid.
    Within 12 hours, 10 g (0.0306 mol) of οι - [4.5,
    6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -0-chlorophenipacetic acid as a monohydrate (see Example 5) in 100 ml of n-propanol a stream of hydrogen chloride gas, while maintaining the solution at reflux. Then from the reactionary. media, the solvent is distilled off, and the residue is taken up in water, made basic with sodium bicarbonate and extracted with ethyl ether. The ether extracts are washed with water, dried over sodium sulfate and, after distillation of the solvent, a yellow oil is collected, which is purified through the intermediate preparation of hemisulfate. White crystals, mp 146 ° C (crude product).
    Get 7, 1 g, yield 78%.
    Found,%: C 48.30; ’H 4.88; ' N, 3.15.
    C, g H 2o C1NO 2 SH 2 SO 4
    Calculated,%: C 48.37, ’H 4.13 '
    N, 3.13. *
    Example 8. Hemisulfate and β-butyl ether of o - [4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -o-chlorophenylacetic acid.
    This compound is prepared according to the procedure described in Example 5 by esterification of fi - [4,5,6,7tetrahydro-5-thieno (3,2-c) pyridyl] -0chlorophenylacetic acid as a monohydrate (prepared according to Example 5) with N-butanol. Purification is carried out through an intermediate preparation of hemisulfate, the product is white crystals, so pl. 155 ° C.
    7.5 g of yield 79.5% are obtained.
    With „H 22 C1NO 2 S 'H 2 SO 4 (M = 462, OO)
    Example 9. Isopropyl ether hemisulfate οί - [4,5,6,7-tetra ( Hydro-5-thieno (3,2-c) pyridyl] -0-chlorophenylacetic acid.
    To a suspension of 1 g (0.0031 mol) of (A- [4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -o-chlorophenylacetic acid as a monohydrate (see, example 5) in 20 ml of propanol, cooled to -10 ° C., 2 ml of thionyl chloride are added dropwise, after which the reaction mixture is heated for 6 hours at the boil under reflux, after distillation of the solvent, the residue is taken up in water, made basic with sodium bicarbonate and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and the solvent is distilled off. A colorless resin is collected to purity 1 is purified through an intermediate preparation of hemisulfate.The product is white crystals, mp 140150 ° C.
    . Yield 44% (0.6 g).
    Found,%: C 48.17; H 4.87 / N, 3.02.
    c ie H M C1N ° 2 S 'H 2 SO 4 (M = 447.97) Calculated,%: C 4B, 26; H 4.95; ' N, 3.13.
    Example 10. Ethyl ester bromide - [4,5,6,7-tetrahydro-
    5-thieno (3,2-c) pyridyl] -o-chlorophenenoacetic acid.
    yield 94%.
    48.99; H 4.65;
    S
    To a solution of 15 g (0.046 mol) оС [4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -O-chlorophenylacetic acid as a monohydrate (see example 5) and 7.12 ml (0.051 mol) of triethylamine in 150 mp chloroform, cooled to a temperature of from -5 to 0 ° C, 4.88 ml (0.051 mol) of ethyl chloroformate are added dropwise. At the end of administration, the solution is warmed to room temperature and stirred for half an hour. Then the reaction mixture is cooled to a temperature of about 10 ° C and 30 ml of ethanol are added dropwise to it. The reaction mixture was stirred at 1 room temperature overnight, then washed with water, the organic phase was dried over sodium sulfate and the solvent was distilled off to obtain a colorless oil, which was purified through: intermediate production of bromide hydrate. The product is white crystals having a melting point of 180 ° C (with decomposition).
    10.1 g are obtained.
    Found,%: C N 3.34.
    , C „H ,, C1NO 2 S
    Calculated, X: N 3.36.
    Example 11. L, M-Dimethype - £ e0 ^ 4,5,6,7-tetrahydro-5-thieno (3,2 ^ -s) pyridyl] ^ -0-chlorophenylacetamide.
    To a solution of 30 g (0.092 mol) v £ 4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -o-chlorophenylacetic acid as a monohydrate and 14.24 ml (0.102 mol) of triethylamine in 300 ml of chloroform, cooled to a temperature of from -5 to 0 ° C, 9.72 ml (0.102 mol) of ethylchloroformate are added dropwise. After the introduction, the solution is warmed to room temperature and the reaction mixture is stirred for half an hour. Then the reaction mixture was cooled to a temperature of about 10 ° C and 4.57 ml (0.102 mol) of dimethylamine in 60 ml of chloroform was added dropwise to it, and then stirred at room temperature overnight.
    N • HBr (M = 416.77) C 48.99; H 4.59;
    ι 45
    Water was added to the mixture, the organic phase was decanted and the organic phase was dried over sodium sulfate, after which the solvent was distilled off. The result is a colorless resin which crystallize. The product is
    95-100 ° C (from
    49%
    H 5.68; ' exit bo, 9o;
    (M = 334.87) C, 60.97; H 5.72;
    12. 1 - [(2-Chlorophenyl) g, yield 61.3%.
    63.30; H 5.86;
    (M = 360.92)
    C 63.23; H 5.86;
    13. Hemihydrate chlorine 1272994 "white crystals, mp propyl ether), 5 g are obtained. Found,%: C
    8.44. s 17 n 19 C1N 2 O Calculated,%: 8.36.
    Example (4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl) acetyl] pyrrolidine.
    This compound is prepared according to the procedure described in Example 11 by condensation of & L - [4,5,6,7tetrahydro-5-hyeno (3,2-c) pyridyl] chlorophenylacetic acid in the form of monohydrate and pyrrolidine. The product is a white crystals, so pl. 130 ° C (isopropyl ether).
    Get 1.9 Found,%: C 7.74.
    s n g , C1N 2 OS
    Calculated,%:
    7.76.
    Example of 1- [(2-chlorophenyl) (4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl) acetyl] morpholine hydrate.
    To a solution of 10 g (0.031 mol) about [4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl] -o-chlorophenylacetic acid as a monohydrate and 13.3 g (0.064 mol) of dicyclohexylcarbodiimide 2.67 g (0.031 mol) of morpholine are added to 100 ml of 1,2-dichloroethane and the resulting mixture is stirred at room temperature overnight. The solvent is distilled off, the residue is extracted with hydrochloric acid (2N) and ethyl ether. After filtering off the resulting dicyclohexylurea, the filtrate is decanted and the aqueous phase 2n is made basic. sodium hydroxide, and then extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and the solvent is distilled off to obtain a yellow gum, which is purified through the intermediate preparation of hydrochloride hemihydrate. The product is a white crystals, so pl. 215-225 ° C (isopropanol).
    . 6.2 g are obtained, yield 71%. Found,%: C 54.30; H, 5.24] 6.59.
    C | q H 2) ClN ^ OjS.HCl · 0.5 H 2 0
    Calculated,%: C 54.03, H5.49, 6.63.
    Ί
    Example 14. 1 - [(2-Chlorophenyl) (4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl) acetyl] piperidine,
    This compound was prepared according to the procedure described in Example 13, in 5, by condensation of o - [4,5,6,7tetrahydro-5-thieno (3,2-c) pyridyl] -0chlorophenylacetic acid as a monohydrate and piperidine. The product is white crystals. 1 °
    so pl. 139 ° C (isopropanol).
    Obtain 3.5 g, yield 51.5%.
    Found,%: C 64.16; H, 6.32;
    N, 7.61.
    C 2o H ii C1N 2 0s (M = 374.93) ' 5
    Calculated,%: C 64.07; H 6.18 ’
    N 7-, 47.
    According to the method described in example 11, receive the following compounds. 20
    Example 15. (X - [4, 5,6,7-Tetrahydro-5-thieno (3,2-s) pyridyl) -Q chlorophenylacetamide. White crystals, mp 126-128 ° C (isopropanol-isopropyl ether). Yield 46%. 25
    Example 16. 4-Benzyl-1 - [(2chlorophenyl) (4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl) acetyl] piperazine. Oxalate, white crystals, mp 178 C (ethanol). Yield 82.5%, 30
    Example 17. Ν, Ν-Dimethyl-sb [4,5,6,7-tetrahydro-5-thieno (3,2-s) pyridyl] -o-ft orphenylacetate amide, with et al o ~ yellow powder, t. pl. 125 C (isopropanol-isopropyl ether). You are 35 move 41%.
    Example 18. P-Methyl-o0- (4,5, -
    6.7-tetrahydro-5-thieno (3,2-s) pyridyl] -o-chlorophenylacetamide. White crystals, mp 137 C (isopropanol). 40 Yield 85.5%,
    Example 19. K-Butyl-o <- (4,5, -
    6.7-tetrahydro-5-thieno (3,2-s) pyridyl-O-chlorophenylacetamide. White crystals, mp 101 0 С (isopropyl ether) .45 Yield 65%.
    Example 20. N, N-Dimethyl-ob, [4,5,6, 7-τβτρ3ΓΗΛρο · -5-ΤΗεΗο · (3,2-с) pyridyl phenylacetamide. White Chris - 50 talls, mp 138 C (isopropyl ether). Yield 39%.
    Example 21. N, N-Dimethyl-ob-
    14.5.6.7-tetrahydro-5-thieno (3,2-s) 55 pyridyl] -o-methylphenylacetamide. White crystals, mp 119 ° C (hexane). Yield 15%.
    Toxicity study.
    The compounds of general formula (I) have very good tolerance and very low toxicity. In addition, studies of acute toxicity, chronic, subchronic and delayed toxicity in relation to various animal species did not show any local or general reaction, disorder or anomaly during biochemical, macroscopic or microscopic experiments carried out during these research.
    The toxicity data are presented in table 1.
    Pharmacological studies.
    1. Inhibitory effect on platelet aggregation. This series of experiments was carried out on rats, which were administered orally tested compounds 1 for 3 days at the following time points: 48 hours, 24 hours and 2 hours (suspension in gum arabic). 4 ml of blood is taken according to the Renault method from the jugular vein of an animal under anesthesia. This citrated blood is used to measure the degree of aggregation.
    A. Measurement of platelet aggregation by adenosine diphosphate. 2 ml of citrated blood is quickly poured into a small beaker located above the magnetic stirrer and containing a magnetic rod. After stirring for several seconds, 0.4 ml of a solution containing 0.66 μg of adenosine diphosphate (ADP) per 1 ml is introduced into the beaker. After stirring for 90 s, two samples of 0.5 ml of blood are taken: the first is mixed with 0.5 ml of a solution of EDTA-formalin, the second with 0.5 ml of a solution containing only EDTA (ethylenediaminetetraacetic acid).
    Mixtures of EDTA with formalin are added in order to stabilize the blood and thereby stop aggregation, while EDTA causes the disaggregation of all platelet aggregations.
    After holding for 10 minutes: and centrifuging both mixtures at low speed for 5 minutes, followed by separation of red blood cells, the plasma enriched with platelets is separated as sludge, diluted and counted platelets.
    ABOUT
    The intensity of aggregation is defined as the ratio:
    Platelet count in EDTA _______ Formaldehyde ------ χ 100 = pro _ 5 Platelet count in EDTA cent of non-aggregated platelets
    Therefore, the test product 10 is the greater the inhibitor of platelet aggregation, the more this ratio approaches 100%.
    The results, which are the average percentage of non-aggregated platelets for groups of 5 rats (treated and comparative), are shown in Table 2.
    B. Measurement of platelet aggregation using collagen.
    To 1.5 ml of citrated blood add 0.10 ml of a solution containing 25 10 μg of collagen per 1 ml. The mixture is kept under stirring and the platelet count is calculated without interrupting mixing.
    The decrease in the number of free thrombotic-30 cytomas depending on time is a continuous process and makes it possible to construct a dependence curve, the slope of which gives the initial aggregation rate.
    The results, which are the average values for each of the groups of 5 rats (comparative and past treatment) are given in table 3.
    B. Measurement of bleeding time.
    Study of the inhibitory activity against platelet aggregation was carried out also in the study of the compounds on exposure time kro- 1 votecheniya.
    The experiments were carried out on rats, which were injected 65 hours, 41 hours and 17 hours before the experiment, an intraosseous suspension of the compounds tested, at a concentration of 10 ml / kg, in an aqueous solution of gum arabic (5%). After anesthetization with pentabarbital, the rat tail was cut off 5 mm from the base. Blood was carefully collected with a sponge for 15 s, being careful not to affect the wound.
    Hemostasis is considered achieved if it is possible to stop bleeding within 1 min.
    The results, which are the average bleeding time in seconds, determined for a group of 5 rats (comparative and past treatment), are shown in Table 4 (a time exceeding 1200 s (20 min) was not determined further).
    Antiplatelet activity.
    This type of activity was investigated according to the experimental method of thrombosis on a silk thread. In rats, anesthetized as a result of an intraperitoneal injection of pentobarbital, the left jugular vein and the right carotid artery are exposed.
    Arterio-venous shunt consists of a central and two lateral catheters, a white thread from natural silk is inserted. It flows into the central part and blood circulation is restored within 20 minutes. After stopping the blood circulation as a result of applying the clamp, the thread is carefully removed and immediately weighed. Subtracting from the obtained weight the predetermined weight of the wet silk thread, the thrombus weight is obtained by the difference.
    Processing of animals is carried out 48 hours, 24 hours and 2 hours before the start of blood circulation through a shunt, by oral administration of the test compound in the form of a suspension in 5% gum arabic at a dose of 10 ml / kg, only a solution of 5% gum arabic is administered to comparative animals.
    The results obtained are presented in table.5.
    权利要求:
    Claims (3)
    [1]
    The invention relates to a method for producing new chemical compounds, namely, P |) derivatives of thieno (3,2-c) pyridine of the general formula where X is hydrogen, fluorine, chlorine, methyl; Y is hydroxyl, C (- C4 alkoxy amino group, C, - C-alkylamino pyrrolidinyl-1, piperidinyl-1, morpho, linyl-1, 4-benzylpiperazinyl 1, "pg, UV gpry, which exhibit their salts or salts which demonstrate the ability to inhibit thrombocyte aggregation and anti-thrombocytic activity.The aim of the invention is to develop, based on a known method, a method of obtaining new chemical compounds of thieno (3,2-e) pyridine, possessing valuable pharmacological properties. Example 1. Hydrochloride methyl ester about, 5,6, 7-tetrahydro-5tieno (3,2-e) pyridyl-chlorine phenylacetic acid. To a solution of 20 g (0.144 mol), 4.5 6.7-tetrahydrothieno (3,2-c) pyridine in 200 ml of dimethylformamide, 31.37 g (0.144 mol) of 2-chloro-o-chlorophenyl methyl acetate and 19.82 g (0.144 mol) of potassium carbonate, after which the reaction mixture is heated at 90 ° C for 4 hours. Then the reaction is completed, the mixture is cooled to room temperature, the inorganic salts are filtered off and the solvent is distilled off. The residue is taken up in water and extracted with ethyl acetate by ether. The ether extracts are washed with water, dried over sodium sulfate and, after distilling off the solvent, the yellow oil is collected, which is purified through an intermediate formation of chlorine hydrate, to obtain white crystals, mp. 130-140 C (ethyl acetate, isopropanol). . Receive 16.5 g. Yield 45%. Found,%: C 53.92; H 4.80; N4.11. C, bN, b C1NO, .HC1 (, 30) Calculated,%: C 53.64; H 4.78; N 3.91. Example 2. Methyl chlorohydrate oC, 5,6,7-tetrahydro-5thieno (3,2-c) pyridyl-phenylacetic acid. This compound is prepared according to the procedure described in Example 1, by reacting 4,5,6,7 tetrahydrothieno, 2-c) pyridine with 2 chlorophenylmethyl acetate. Hydrochloride - bad crystals, i.e. 200 ° C (ethanol). Get 13, the yield of 50%. Found,%: C 59.23; H 5.59; . N 4.25. C, bN, t N0.5 HC1 (, 82) Calculated,%: C 59.34; H 5.60; N 4.32. . , Example 3, methylhydrochloride. , G / s / i tc ester od -14,5,6,7-tetrahydro-5 / h% thieno (3,2-e) pyridyl-o-fluorophenylacetic acid. This compound is obtained according to. to the procedure described in Example 1, as a result of the alkylation of 4,5,6,7 tetrahydrothieno (3,2-c) -pyridine with 2 chloro-0-fluorophenyl methyl acetate. Hydrochloride - white crystals, so pl. . Receive 31.5 g, yield 76.5%. Found,%: C 56.09J H 4.87, N 4.09. C, bN, e NOiS HCl (, 85) Calculated,%: C 56.2.2; H 5.01; N 4,10, Pr and m 4 4, Hem sulfate ethyl ester ot., 5,6, 7-tetrahydro-5-thieno (3,2-e) pyridyl-o-methylphenylacetic acid. This is obtained by the procedure described in Example 1, by alkylation of 4,5,6,7 tetrahydrothieno (3,2-e) pyridine with 2-glot-o-methyl phenylethyl acetate. Hemisulphate - white crystals, so pl. 188-190 ° C (isopropanol). 32.1 g yield 54% is obtained. Found,%: C 52.30; And 5.74; N 3.2A. , C, aH ,, NO ,, S Н SO (, 52) 18 21 g 7. Calcined,%: C 52.58; H 5.60; N 3.39. Example 5. (K, 5,6,7-Tetrahydro-5-thieno (3,2-c) pyridyl-0-chlorophenylacetic acid, hydrate. C. For 2.5 hours, the mixture is heated at reflux with a mixture of 157.9 - 4 , 5,6, 7-tetrahydro-5-thieno (3,2-c) pyridyl-0-chlorophenyl ethyl acetate and 100 ml of an alkaline solution of 30% sodium hydroxide in 800 ml of ethanol. After the ethanol is distilled off, the reaction mixture is poured with icy acid and :: is built with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and the solvent is distilled off. After recrystallization from water, the product is extracted as monogram. It is white crystals, having a melting point of 125 ° C (water), 4.4 g, yield 46%, Found: C, 55.23; H, 4.82; N, 4.49. C, 5 H, C1 NOjS -HjO (, 83) Calculated,%: C 55.29-, H 4.95; N 4.30. Example 6. Sodium salt 4,5,6,7-tetrahydro-5-thienyl (3 , 2-e) pyridyl-phenylacetic acid This compound is prepared according to the procedure described in Example 9, as a result of saponification of ° C, 5,6,7 tetrahydro-5-thieno (3, 2-e) pyridyl phenylethyl acetate. The resulting product is purified through an intermediate preparation of the sodium salt. White crystals so pl. 210-215 C (ethanol, methanol). 7.4 g are obtained, yield 74%. Found,%: C 61.17; H 4.62 / N 4.72, C, 5H, (, 29) Calculated,%: C 61.01; H 4.78; N 4.74. Example 7. Hemisulphate -pr sawn ether of (,, 5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl 1 -o-chloro-nickel acetic acid. For 12 hours, pass through a solution of 10 g ( 0.0306 mol) оС, 5, 6,7-tetrahydro-5-thieno (3,2-s) pyridyl-0-chlorophenylacetic acid in the form of monohydrate (see example 5) in 100 MP H-propanol stream of gaseous chloride hydrogen, while boiling the solution under reflux. Then the solvent is distilled off from the reaction medium, and the residue is taken up in water, alkalinized with sodium bicarbonate and extracted with ethyl ether. The ether extracts rinse with water, dry over sodium sulfate, and after distilling off the solvent, the yellow oil is collected, which is purified through an intermediate preparation of hemisulphate. White crystals, mp (crude product). 94 Obtain 7.1 g, yield 78%. Found,% : C 48.30; H 4.88; N3.15. C, gH.j ClNOjS-HjS04 Calculated,%: C 48.37: H 4.13 N 3.13. Example 8. C-butyl ether hemisulfate od , 5,6,7-tetrahydro-5-thieno (3,2-e) pyridyl-o-chlorophenylacetic acid. This compound is prepared according to the procedure described in Example 5, by esterifying d, 5,6,7 tetrahydro-5-thieno (3,2-c) pyridyl-chlorophenylacetic acid as a monohydrate (prepared according to example 5) with K-butanol. Purification is carried out through the intermediate Preparation of Hemisulphate, the product is white crystals, m.p. 155 ° C. Obtain 7.5 g yield of 79.5%. C „H2.jClN02S (, 00) Example 9. Hemisulfate of isopropyl ester on -f4, 5, 6, 7-tetrahydro-5-thieno (3,2-e) pyridyl-0-chlorophenylacetic acid. To a suspension of 1 g (0.0031 mol) (, 5,6, 7-tetrahydro-5-thieno (3,2-e) pyridyl-o-chlorophenylacetic acid in the form of a monohydrate (see example 5) in 20 ml of propanol, 2 ml of thionyl chloride is added dropwise to the mixture cooled to -10 ° C, then the reaction mixture is heated under reflux for 6 h. After the solvent has been distilled off, the residue is taken up in water, basified with sodium bicarbonate and extracted with methylene chloride. water, dried over sodium sulfate and the solvent is distilled off. The colorless emol is collected; Ory is purified through the intermediate preparation of hemisulphate. The product is white crystals, mp 140150 ° C., Yield 44% (0.6 g). Found: C 48.17; H 4.87 / N 3.02 .le wClNO S —H.SO (, 97) Calculated,%: C 4B, 26; H 4,95: 3,13. Example 10. Ethiol bromohydrate oi - 4,5,6, 7-tetrahydro5-thieno (3,2-e) pyridyl-o-chlorophenylacetic acid. To a solution of 15 g (0.046 mol) oi, 5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl-0-chlorophenylacetic acid in monohydrate (see Example 5) and 7.12 ml (0.051 mol) of triethylamine in 150 n chloroform, cooled to a temperature of from -5 to 0 ° C, 4.88 ml (0.051 mol) are added dropwise lhlorformnata. After the introduction is complete, the solution is heated to room temperature and stirred for half an hour. The reaction mixture is then cooled to a temperature of about 10 ° C and 30 ml of ethanol is added dropwise to it. The reaction mixture is stirred at room temperature overnight, then washed with water, dried the organic phase over sodium sulfate and the solvent is distilled off. oil, which is purified through the intermediate preparation of the hydrobromide. The product is white crystals having a mp. 180 ° С (with dilution). 10.1 g are obtained, yield 94%. Found,%: C 48.99; H 4.65; N 3.34,, С „Н ,, С1ЫО, 5 НВг (, 77) Calculated,%: С 48.99; H 4 59N 3.36. Example 11. K, K-Dimeti. , 5,6,7-tetrahydro-5-thieno (3,) pyridyl | -0-chlorophenylacetamide. To a solution of 30 g (0.092 mol) of cxS, 5,6,7-tetrahydro-5-thieno (35 2-е) pyridyl-o-chlorophenylacetic acid in the form of monohydrate and 14,24 ml (0,102 mol) of triethylamine in 300 ml of chloroform 9.72 ml (0.102 mol) of ethyl chloroformate is added dropwise, cooled to -5 to 0 ° C. After the introduction is complete, the solution is warmed to room temperature and the reaction mixture is stirred for half an hour. The reaction mixture is then cooled to a temperature of about 10 ° C and 4.57 ml (0.102 mol) of dimethylamine in 60 ml of chloroform is added dropwise to it, then the mixture is stirred at room temperature overnight. Water is added to the mixture, the organic phase is decanted and dried over sodium sulfate, after which the solvent is distilled off. As a result, a colorless grinding is obtained which is crystallized. The product is white crystals, m.p. 95-10US C (isopropyl ether). 5 g are obtained, yield 49%. Found,%: C 60.90 H 5.68; N 8.44. C, jH ,, ClNjO (M-334.87) Calculated,%: C 60.97; H 5.72; 8.36. Example 12. 1- (2-Chlorophenyl) (4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl) -acetyl-G1irrolidine. This compound is prepared according to the procedure described in Example 11, as a result of the condensation of oi, 5,6,7 tetrahydro-5-thieno (3,2-c) pyridyl-chlorophenylacetic acid in the form of monohydrate and pyrrolidine. The product is white crystals, m.p. 130 ° C (isopropyl ether). 1.9 g are obtained, yield 61.3%. Found,%: C 63.30; H 5.86; N 7.74, C1K ,, OS (, 92), Calculated,%: C 63.23; H 5.86; N 7.76. Example 13. Hemihydrate 1- (2-chlorophenyl) hydrochloride (4,5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl) -acetyl-morpholine, To a solution of 10 g (0.03t mol) o, 5,6,7-tetrahydro-5-thieno (3,2-e) pyridyl-j-o-chlorophenylacetic acid in the form of monohydrate and 13.3 g (0.064 mol) of dicyclohexylcarbodiimide SOO ml of 1,2-dichloroethane are added 2, 67 g (0.031 mol) of morpholine and stir the resulting mixture at room temperature overnight. The solvent is distilled off, the residue is taken up with hydrochloric acid (2N) and ethyl acetate. After filtering off the formed dicyclohexylurea, the filtrate is decanted and the aqueous phase is alkalinized 2n. caustic soda, then extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, and the solvent is distilled off to obtain a yellow resin, which is purified through an intermediate hydrochloride hemihydrate. The product is white crystals, m.p. 215-225 ° C (isopropanol). . Get 6.2 g, yield 71%. Found,%: C 54.30; H 5.24 N 6.59. C | Hj, .HC10.5 HjO Calculated,%: C 54.03, H5.49 6 63 Example 14. 1- (2-Chlorophenyl (4,5,6,7-tetrahydro-5-thieno (3,2-s ) pyridyl) -acetyl-piperidine. This compound is prepared according to the procedure described in example 13, by condensation of oi, 5,6,7 tetrahydro-5-thieno (3,2-c) pyridyl-0 chlorophenylacetic acid as monohydrate and piperidine. The product is white crystals, mp (isopropanol). 3.5 g are obtained, yield 51.5%. Found: C 64, l6; H 6.32; N 7.61, ..OS (, 93) Calculated,%: C 64.07; H 6.18 N 7-, 47. Co1; according to the method described in example 11, the following compound is obtained. Example 15. ct, 5,6,7-Tet ragidro-5- ieno (3,2-c) pyridyl) -ohlorfenilatsetamid. White crystals, so pl. 126-128 ° C (isopropanol-isopropyl ether). Yield 46%. Example 16. 4-Benzyl-1- (2-chlorophenyl) (4,5,6,7-tetrahydro-5-but 3,2-c) pyridyl) acetyl piperazine. Oxalate, white crystals, mp.178 (ethanol). Yield 82.5%, Example 17. H, L-Dimethyl-C 4, 5,6,7-tetrahydro-5-thieno (3,2-e) pyridyl} -0-fluorophenylacetamide, light yellow powder, mp . 125 C (isopropanol-isopropyl ether). Yield 41%. Example 18. N-Methyl-o6- (4,5, 6,7-tetrahydro-5-thieno (3,2-c) pyridyl-o-chlorophenylacetamide. White crystals, mp 137 C (isopropanol). Yield 85.5%, Example 19. S-Butyl-o6- (4,5, 6,7-tetrahydro-5-thieno (3,2-s) pyrid-0-chlorophenylacetamide. White crystals, m.p. (isopropyl ether Yield 65%. Example 20. N, N-Dimethyl-oC 4, 5,6, 7-tetrahydro 5-thieno- (3,2-e) pyridyl phenylacetamide. White crystals, mp. 138 C ( isopropyl ether). Yield 39%. Example 21. H, N-Dimethyl - "; 14, 5,6,7-tetrahydro-5-thieno (3,2-c) pyridyl-o-methylphenylacetamide. White crystals, t. mp 119 C (hexane) Yield 15%. Toxicity study. Connected and general formula (I) have very good tolerance and very low toxicity. In addition, acute toxicity studies, chronic, subchronic and delayed toxicity with respect to various species of animals did not show any local or general reaction, disorder or anomalies in biochemical, macroscopic or microscopic experiments carried out during these studies. These toxicity are presented in table.1. Pharmacological studies. 1. Inhibitory effects on platelet aggregation. This series of experiments was carried out on rats, which were orally administered for 3 days at the following times: 48 hours, 24 hours and 2 hours (suspension in gum arabic). 4 ml of blood is taken according to the method of Renault from the celiac vein of an animal under anesthesia. This citrated blood is used to measure the degree of aggregation. A. Measurement of the degree of platelet aggregation by adenosine diphosphate. 2 ml of citrated blood is quickly poured into a small beaker located above the magnetic stirrer and containing a magnetic rod. After stirring for a few seconds, 0.4 ml of a solution containing 0.66 µg of adenosine diphosphate (ADP) per 1 ml is introduced into the beaker. After stirring for 90 s, two samples of 0.5 ml of blood are taken: the first is mixed with 0.5 ml of EDTA-formalin solution, the second with 0.5 ml of solution containing only EDTA (ethylenediaminetetraacetic acid). Mixtures of EDTA with formalin are added in order to stabilize blood and thereby stop aggregation, while EDTA causes disaggregation of all platelet aggregations. After 10 minutes: centrifuging both mixtures at low speed for 5 minutes with the next separation of the red blood cells, the plasma enriched with thrombocytes is separated as sediment, deconstructed and the platelets are counted. The intensity of aggregation is defined as the ratio: Platelet count in EDTA Formaldehyde Platelet count in EDTA cent of unaggregated platelet Therefore, the test product is the greater the inhibitor of platelet aggregation, the greater this ratio approaches 100%. The results, which represent the average percentage of non-aggregated platelets for groups of 5 rats (treated and comparative), are shown in Table 2.
    [2]
    2. B. Measurement of the degree of platelet aggregation using collage on. To 1.5 ml of citrated blood is added 0.10 ml of the solution, containing 10 µg of collagen per 1 ml. The mixture was kept under agitation and the platelet count was calculated without interrupting the agitation. A decrease in the number of free platelets as a function of time is a continuous process and makes it possible to construct a dependency curve, the slope of which gives the initial rate of aggregation. The results, which are average values for each of the groups of 5 rats (comparative and treated) are given in Table.
    [3]
    3. B. Measurement of bleeding time A study of inhibitory activity on platelet aggregation was also carried out in the study of the effect of compounds on bleeding time. Experiments were carried out on a rat that was injected 65 h and 17 h before the intraosseous suspension test of the compounds tested at a concentration of 10 ml / kg in an aqueous solution of gum arabic (5%). After anesthetization with pentabarbital, the rat tail was cut off 5 mm from the base. Blood was carefully collected with a sponge for 15 seconds, trying to be careful not to touch the wound. Hemostasis is considered achieved if it is possible to stop the bleeding for 1 minute. The results, which are the average bleeding time in seconds, determined for a group of 5 rats (comparative and last treatment), are shown in Table 4 (the time exceeding 1200 s (20 min) was not further determined). Antiplatelet activity. This type of activity was investigated according to the experimental silk thread thrombosis method. In rats anesthetized by intraperitoneal injection of pentobarbital, the left stratum vein and the right carotid artery are exposed. The artery-venous shunt consists of a central and two lateral catheters, a white silk thread is inserted. It goes to the central part and within 20 minutes the blood circulation is restored. After stopping the circulation of blood as a result of clamping, the thread is carefully removed and immediately weighed. Subtracting the previously determined weight of the wet silk thread from the obtained weight, the weight of the thrombus is obtained from the difference. Animals are treated 48 hours, 24 hours and 2 hours before the circulation through the shunt is started, by oral administration of the test compound as a suspension in 5% gum arabic at a dose of 10 ml / kg, only 5% solution is administered to comparative animals. gum arabic. The results are presented in table.5. Claims of Invention The method of producing thieno derivatives (3,2-c) pyrvine one of general formula S X where X is hydrogen, fluorine, chlorine, methyl U is gpfoksil., C, is alkoxy, amino group; C, alkylamino group, PIRROLIDINSH1-1, piperidinyl-1, MORFOLINSH1-1, 4-benzylpiperazinyl-1, or their salts, characterized in that 4,5,6,7-tetrahydrothieno (3,2-e) pyridine of the formula
    V "
    subjected to interaction with o (chlorophenylacetate of General formula
    L-sn-sooy
    where X - has the specified zyacheni;
    R is lower alkyl,
    in the presence of potassium carbonate in dimethylformamide, the target product is added as ether or the ester is washed to an acid, which is either isolated in a free form, or esterified, or converted into an amide.
    Table 1
    LD,., (Intravenously.
    Example
    40
    msh)
    Behavior (200 mg / kg, 3 days, oral)
    note 3 X 25 3 X 100
    table 2
    16 ± 4
    94 ± 3 60 ± 7
    1272994
    13
    Note. The route of administration is oral.
    lA Continuation of table 2
    sixteen
    1272994
    15 Table 3
    Connection example 17 Comparative
    Connection example 21
    3 X 100
    The mode of administration is oral,
    Note. The route of administration is orally.
     2.22 + 0.10 5.01 ± 0.79
    3.04 ± 0.22 11.35 ± 1.01
    10.82 t 0.81
    Table 4
    Table 5
    : ii: i
    Comparative
    Connection example 3
    Comparative
    Connection example 1
    Also . Comparative
    Connection example 1
    Comparative
    Connection example 2
    Compound by
    II p and m e. 4 a n and e. Method of administration is oral.
    -94
    -82 -56
    -32
    -79
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    申请号 | 申请日 | 专利标题
    FR8212599A|FR2530247B1|1982-07-13|1982-07-13|NOVEL THIENOPYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATION|
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