Optically active 2-hydroxythiophenopyridine derivatives, processes for their preparation and uses thereof

Abstract

The application provides an optically active 2-hydroxy tetrahydrothienopyridine derivative, a new type of 2-hydroxy tetrahydrothienopyridine derivative is introduced by modifying the structure of clopidogrel, mainly including derivatives of esterification with indobufen. The compound can be rapidly metabolized into effective metabolites and indobufen to exert the drug efficacy after entering the body, and is applied to the preparation of a drug for preventing and / or treating embolic diseases caused by thrombus. The compound can effectively improve the pharmacokinetic property, improve the bioavailability of the active metabolite of clopidogrel, and is expected to realize the significant reduction of the drug dosage, the fast onset and the high efficacy, and the reduction of the side effects such as bleeding of the anti-platelet aggregation drug. Meanwhile, the compound has good water solution stability, and can meet the requirements of developing into a liquid preparation (such as an injection).

Description

[0001] This application claims priority to the Chinese Patent Application No. 202210026839.7 filed on January 11, 2022, and entitled “Optically active 2-hydroxytetrahydrothienopyridine derivative and preparation method and use thereof”, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to an optically active 2-hydroxytetrahydrothienopyridine derivative and a preparation method and use thereof. BACKGROUND

[0003] Clopidogrel is one of the most widely used anti-platelet aggregation drugs in the world, with domestic sales of over 10 billion yuan in 2019. It is clinically used for the treatment of atherosclerotic diseases, acute coronary syndrome, and thrombotic complications. Years of clinical trials have confirmed the efficacy and safety of clopidogrel for thrombotic cardiovascular and cerebrovascular diseases (Lancet, 1996, 348: 1329). Clopidogrel is a prodrug that is metabolized in the liver by the P450 enzyme system in two steps to produce an active metabolite. The active metabolite forms a covalent bond with the P2Y12 receptor on the surface of platelets, thereby inhibiting platelet aggregation by antagonizing the P2Y12 receptor (Thromb Haemost, 2000, 84, 891). However, in the study of its metabolic process, two defects were found: 1) 85% of the clopidogrel prodrug is esterified by the human liver carboxylesterase 1 (hCE1) in the liver to form an inactive clopidogrel carboxylic acid derivative (J Pharmacol Exp Ther, 2006, 319: 1467), which greatly reduces the oral bioavailability of clopidogrel, and further leads to the use of a large dose of clopidogrel in clinical use (a loading dose of 300 mg of clopidogrel), slow onset, delayed inhibition of platelets, and bleeding risk (Cardiovascular drug reviews, 1993, 11: 180); 2) due to the difference in the expression of P450 enzyme system in different individuals, the clinical treatment effect of clopidogrel, which depends on the P450 enzyme system for metabolism, has a large individual difference, such as the phenomenon of “clopidogrel resistance”, and cardiovascular events such as stent thrombosis still occur (Circulation, 2004, 109: 166).

[0004] In view of the limitations and shortcomings of clopidogrel, there is a need to develop new clopidogrel derivatives with better pharmacokinetic and pharmacodynamic properties and fewer side effects.

[0005] One of the hotspots of the research of new anti-platelet aggregation drugs is to develop water-soluble injectable drug formulations. The existing technology has attempted to develop the marketed clopidogrel into an injection formulation to improve the efficacy and shorten the onset time, but all have failed. For example, ASD-002 nanoemulsion of Ascendia Company, MDCO-157 (cyclodextrin inclusion) injection of CyDex Company, and JIN-2013 nano-liposome injection of Jina Pharmaceuticals Company. The main reason is that although MDCO-157 can improve the stability of clopidogrel to hydrolytic degradation, thermal degradation and photodegradation, the active metabolite production threshold is insufficient after injection, and even at a dose of 300 mg, it cannot sufficiently inhibit the effect of platelets, and the adverse reactions are significantly greater than oral formulations. In addition, clopidogrel free base is an oil, which is unstable itself and needs to be salted with strong acids such as hydrochloric acid and sulfuric acid. The product is unstable and prone to degradation, and its low solubility in water at neutral pH makes it very difficult to develop an injection product with high bioavailability and good physical stability.

[0006] Patents CN103554132B and CN107304215A also report a series of clopidogrel derivative compounds, but these compounds have certain problems. Although these compounds have improved bioavailability or efficacy to some extent compared with clopidogrel or prasugrel, the degree of improvement is not significant.

[0007] The purpose of the present application is to modify the structure of clopidogrel and introduce a new type of 2-hydroxy tetrahydrothienopyridine derivatives, mainly including ester derivatives with indobufen and ester derivatives with ozagrel. The inventors have surprisingly found that the obtained derivative compounds can be rapidly metabolized into effective metabolites and indobufen or ozagrel to exert efficacy after entering the body, wherein indobufen and ozagrel have anti-platelet effects and can form a synergistic effect to solve the defects of clopidogrel. They have better pharmacokinetics and efficacy characteristics, faster onset time, larger therapeutic index, and effectively reduce side effects such as bleeding compared with clopidogrel or existing clopidogrel derivatives. In addition, the obtained derivatives are in solid form and have better aqueous solution stability and other excellent physicochemical properties, which can meet the requirements of developing oral formulations and liquid formulations (such as injections). Compared with the existing clopidogrel which can only be developed into oral formulations, the compounds provided by the present application have greater clinical potential advantages, meet the needs of more clinical patients for medication, and are expected to become a new generation of anti-platelet aggregation drugs with good efficacy and low side effects, which can be used for injection and oral administration. SUMMARY

[0008] In order to achieve the above object, the present application provides an optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof having the formula (I):

[0009]

[0010] G is selected from a bond,

[0011] n is an integer from 0 to 12;

[0012] The dotted line represents the connecting site with the thienyl ring, and the wavy line represents the connecting site with R;

[0013] R is selected from:

[0014]

[0015]

[0016] The wavy line represents the connecting site;

[0017] R1 is selected from halogen;

[0018] R2 is selected from CH3, CD3.

[0019] In some preferred embodiments, the optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds:

[0020]

[0021]

[0022] In some preferred embodiments, the optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof is selected from any one of the following compounds:

[0023]

[0024] Another aspect of the present application provides a pharmaceutical composition comprising any one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Further, the compound of the present application or the pharmaceutical composition thereof is applied in the preparation of a drug for preventing and / or treating thrombus-induced embolic diseases.

[0025] ​The compound of the present application can effectively improve the pharmacokinetic property, improve the bioavailability of the active metabolite of clopidogrel, the generation amount of the active metabolite is significantly higher than that of clopidogrel or the existing clopidogrel derivative, can significantly reduce the drug dosage, reduce the side effects such as bleeding of anti-platelet aggregation drugs and cardiovascular events of stent thrombosis while achieving fast onset and high efficacy. At the same time, the compound of the present application has good aqueous solution stability, which can meet the requirements of developing oral preparations and developing liquid preparations (such as injection), compared with clopidogrel which can only be developed as oral preparations, the present application has greater clinical potential advantage, and can meet the drug demand of more clinical patients. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical scheme and advantages of the present application more clear, the following examples are used to further illustrate the present application. Obviously, the described examples are only part of the examples of the present application, not all examples. Based on the examples in the present application, all other examples obtained by those skilled in the art belong to the scope of protection of the present application.

[0027] The content of the present application is specifically illustrated by the following examples. In the present application, the following examples are used to better illustrate the present application, and are not used to limit the scope of the present application.

[0028] As used herein, room temperature refers to about 20-30℃; "overnight" refers to about 10h-16h; 1N is 1mol / L;

[0029] Yield = actual synthesis product mass / theoretical synthesis product mass x 100%;

[0030] Purity test: the purity of the product is detected by high performance liquid chromatography (HPLC).

[0031] Example 1

[0032] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothiophene[3,2-c]pyridin-2-yl((3,5,6-trimethylpyrazin-2-yl)methyl) maleate (compound 1)

[0033]

[0034] Step one: in a 100 mL flask, add compound f (5 g, 32.90 mmol), dichloromethane (50 mL), triethylamine (6.65 g, 65.80 mmol) and compound b (3.22 g, 32.90 mmol), react at room temperature overnight, after TLC spot plate detection reaction is complete, add appropriate amount of water, separate, the organic phase is washed with water (30 mL x 2), saturated sodium chloride solution (30 mL) in turn, dry over anhydrous sodium sulfate, spin dry, and then silica gel column chromatography (V 石油醚 :V 乙酸乙酯 = 1:1), to obtain compound 1-1 (3.67 g, purity 95%, yield 44.6%).

[0035] Characterization data: [M+H] + : 251.2; 1 H NMR (400 MHz, Chloroform-d) δ 6.49 (d, J = 11.9 Hz, 1H), 5.93 (d, J = 11.9 Hz, 1H), 5.22 (s, 2H), 2.52 (s, 3H), 2.48 (d, J = 4.8 Hz, 6H).

[0036] Step two: in a 100 mL flask, add compound 1-1 (2 g, 8 mmol), dichloromethane 40 mL, compound c (2.72 g, 8 mmol), 4-dimethylaminopyridine (DMAP) (0.51 g, 4 mmol) and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) (3.07 g, 16 mmol), react at room temperature overnight, after TLC spot plate detection reaction is complete, add appropriate amount of water, separate, the organic phase is washed with water (20 mL x 2), saturated sodium chloride solution (20 mL) in turn, dry over anhydrous sodium sulfate, spin dry, and then silica gel column chromatography (V 石油醚 :V 乙酸乙酯 = 3:1), to obtain oily compound 1 (1.5 g, purity 95%, yield 39.27%).

[0037] Characterization data: [M+H] + : 573.1; 1 H NMR (400 MHz, Chloroform-d) δ 7.72-7.67 (m, 1H), 7.45-7.40 (m, 1H), 7.33-7.22 (m, 2H), 6.65 (s, 2H), 6.15 (s, 1H), 5.45 (s, 2H), 4.84 (s, 1H), 3.70-3.61 (m, 1H), 3.54 (dt, J = 14.3, 1.8 Hz, 1H), 2.95-2.83 (m, 2H), 2.80 (ddd, J = 7.5, 6.1, 1.3 Hz, 2H), 2.53-2.49 (m, 9H).

[0038] Example 2

[0039] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl((3,5,6-trimethylpyrazin-2-yl)methyl)fumarate (Compound 2)

[0040]

[0041] Step one: In a 250 mL three-necked flask, compound f (5 g, 32.90 mmol), dichloromethane (100 mL), compound d (5.66 g, 32.9 mmol), DMAP (2.09 g, 16.45 mmol), EDCI (12.61 g, 65.80 mmol) were added, and the reaction was carried out at room temperature overnight. After TLC detection, the reaction was complete, and an appropriate amount of water was added, and the liquid was separated. The organic phase was washed with water (50 mL x 2), saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and rotary evaporated. After silica gel column chromatography (V 石油醚 :V 乙酸乙酯 = 5:1), compound 2-1 (4.2 g, purity 96%, yield 41.75%) was obtained. Characterization data: [M+H] + : 307.3.

[0042] Step two: In a 100 mL three-necked flask, compound 2-1 (4 g, 13.1 mmol), dichloromethane (20 mL), trifluoroacetic acid (20 mL) were added, and the reaction was carried out at room temperature for 4 h. After TLC detection, the reaction was complete, and rotary evaporation was directly carried out to obtain compound 2-2 (3.2 g, purity 95%, yield 98%).

[0043] Characterization data: [M+H] + : 251.2; 1 H NMR (400 MHz, Chloroform-d) δ 6.81 (d, J = 1.9 Hz, 2H), 5.26 (d, J = 1.8 Hz, 2H), 2.53 - 2.40 (m, 9H).

[0044] Step three: In a 100 mL three-necked flask, compound 2-2 (2 g, 8 mmol), dichloromethane 40 mL, compound c (2.72 g, 8 mmol), DMAP (0.51 g, 4 mmol), EDCI (3.07 g, 16 mmol) were added, and the reaction was carried out at room temperature overnight. After TLC detection, the reaction was complete, and an appropriate amount of water was added, and the liquid was separated. The organic phase was washed with water (20 mL x 2), saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and rotary evaporated. After silica gel column chromatography (V 石油醚 :V乙酸乙酯 = 3: 1), to obtain compound 2 (2.1 g, purity 95%, yield 54.98%) in oil.

[0045] Characterization data: [M+H] + : 573.1; 1 H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.67 (m, 1H), 7.45 - 7.40 (m, 1H), 7.33 - 7.22 (m, 2H), 6.40 (s, 2H), 6.15 (s, 1H), 5.44 (s, 2H), 4.85 (s, 1H), 3.70 - 3.60 (m, 1H), 3.55 (dt, J = 14.3, 1.8 Hz, 1H), 2.94 - 2.83 (m, 2H), 2.81 (ddd, J = 7.5, 6.1, 1.3 Hz, 2H), 2.54 - 2.49 (m, 9H).

[0046] Example 3

[0047] Synthesis of 5-((S)-1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl-2-(4-(1-oxoisoquinolin-2-yl)phenyl)butanoate (Compound 3)

[0048]

[0049] Into a 250 mL three-necked flask was added compound c (3 g, 8.8 mmol), dichloromethane 100 mL, compound e (2.61 g, 8.8 mmol), DMAP (0.56 g, 4.4 mmol), EDCI (3.39 g, 17.6 mmol), and the reaction was carried out at room temperature for 2 h. After TLC detection, the reaction was complete, and an appropriate amount of water was added, and the mixture was separated. The organic phase was washed with water (50 mL x 2), saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (V 石油醚 : V 乙酸乙酯 = 2: 1) to obtain compound 3 (1.7 g, purity 98%, yield 31.25%) in white solid.

[0050] Characterization data: [M+H] + : 618.2; 1H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.71 - 7.66 (m, 1H), 7.66 - 7.60 (m, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.46 - 7.38 (m, 3H), 7.34 - 7.29 (m, 2H), 6.25 (s, 1H), 4.90 (s, 1H), 4.88 (s, 2H), 3.69 (t, J = 7.8 Hz, 1H), 3.62 (s, 1H), 3.52 (d, J = 14.4 Hz, 1H), 2.88 (t, J = 5.3 Hz, 2H), 2.78 (d, J = 5.9 Hz, 2H), 2.21 (dp, J = 14.6, 7.2 Hz, 1H), 1.93 (dq, J = 14.1, 7.3 Hz, 1H), 0.98 (t, J = 7.3 Hz, 3H).

[0051] Example 4

[0052] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl((3,5,6-trimethylpyrazin-2-yl)methyl)pentanedioate (Compound 4)

[0053]

[0054] Synthesis method same as Example 1 to get Compound 4 as an oil (HPLC purity 97.32%, yield 52.29%).

[0055] Characterization data: [M+H] + : 589.2; 1 H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.65 (m, 1H), 7.45 - 7.39 (m, 1H), 7.34 - 7.29 (m, 2H), 6.26 (s, 1H), 5.23 (s, 2H), 4.92 (s, 1H), 3.66 (dt, J = 14.3, 1.8 Hz, 1H), 3.57 - 3.49 (m, 1H), 2.89 (t, J = 5.3 Hz, 2H), 2.79 (d, J = 5.8 Hz, 2H), 2.65 (t, J = 7.3 Hz, 2H), 2.58 - 2.46 (m, 11H), 2.09 (d, J = 7.3 Hz, 2H).

[0056] Example 5

[0057] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl((3,5,6-trimethylpyrazin-2-yl)methyl) hexanedioate (Compound 5)

[0058]

[0059] The synthesis was carried out as per Example 1 to obtain Compound 5 as an oil (HPLC purity 98.15%, yield 58.08%).

[0060] Characterization data: [M+H] + : 603.3; 1 HNMR (400 MHz, Chloroform-d) δ 7.69 (dd, J = 7.1, 2.4 Hz, 1H), 7.42 (dd, J = 7.3, 2.0 Hz, 1H), 7.35 - 7.28 (m, 2H), 6.26 (s, 1H), 5.21 (s, 2H), 4.91 (s, 1H), 3.66 (d, J = 14.3 Hz, 1H), 3.53 (d, J = 14.3 Hz, 1H), 2.89 (t, J = 5.6 Hz, 2H), 2.79 (d, J = 5.7 Hz, 2H), 2.59 - 2.49 (m, 11H), 2.44 (t, J = 6.6 Hz, 2H), 1.77 (dd, J = 7.1, 3.6 Hz, 4H).

[0061] Example 6

[0062] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl(10-(4,5-dimethoxy-2-methyl-3,6- dioxabicyclo[4.4.0]undec-1-yl)decyl)succinate (Compound 6)

[0063]

[0064]

[0065] The synthesis was carried out as per Example 1 to obtain Compound 6 as an oil (HPLC purity 97.21%, yield 42.70%).

[0066] Characterization data: [M+H] + : 761.3; 1HNMR (400 MHz, Chloroform-d) δ 7.72 - 7.63 (m, 1H), 7.44 - 7.35 (m, 1H), 7.34 - 7.29 (m, 1H), 7.26 (dd, J = 7.3, 2.1 Hz, 1H), 6.28 (s, 1H), 4.90 (s, 1H), 4.10 - 4.05 (m, 2H), 4.00 (d, J = 1.2 Hz, 6H), 3.69 - 3.60 (m, 1H), 3.56 - 3.48 (m, 1H), 2.91 - 2.80 (m, 4H), 2.78 (d, J = 5.6 Hz, 2H), 2.74 - 2.66 (m, 2H), 2.45 (t, J = 7.4 Hz, 2H), 2.05 (s, 3H), 1.62 (t, J = 7.1 Hz, 2H), 1.39 - 1.27 (m, 14H).

[0067] Example 7

[0068] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl ((3,5,6-trimethylpyrazin-2-yl)methyl)propanedioate (Compound 7)

[0069] Synthesis method same as Example 2 to get Compound 7 as an oil (HPLC purity 96.13%, yield 8.14%).

[0070] Characterization data: [M+H] + : 561.2; 1 H NMR (400 MHz, Chloroform-d) δ 7.73 - 7.66 (m, 1H), 7.43 - 7.39 (m, 1H), 7.33 - 7.27 (m, 2H), 6.15 (s, 1H), 5.45 (s, 2H), 4.84 (s, 1H), 3.71 - 3.63 (m, 1H), 3.56 (dt, J = 14.3, 1.8 Hz, 1H), 3.22 (s, 2H), 2.93 - 2.85 (m, 2H), 2.55 - 2.50 (m, 9H), 2.40 (m, 2H).

[0071] Example 8

[0072] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl ((3,5,6-trimethylpyrazin-2-yl)methyl)propanedioate (Compound 7)

[0073]

[0074] The synthetic procedure was same as example 3 to get solid powdered compound 8 (HPLC purity 98.13%, yield 70.10%).

[0075] Characterization data: [M+H] + : 551.2; 1 H NMR (400 MHz, Chloroform-d) δ 7.69 - 7.57 (m, 4H), 7.47 - 7.45 (m, 1H), 7.30 - 7.24 (m, 3H), 7.20 - 7.11 (m, 3H), 6.88 (d, J = 5.7 Hz, 1H), 6.35 (d, J = 10.8 Hz, 1H), 6.15 (s, 1H), 5.39 (s, 2H), 4.83 (s, 1H), 3.66 (d, J = 14.2 Hz, 1H), 3.60 - 3.48 (m, 1H), 2.95 - 2.90 (m, 2H), 2.69 - 2.63 (m, 2H).

[0076] Example 9

[0077] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl((3,5,6-trimethylpyrazin-2-yl)methyl)succinate (Compound 9)

[0078]

[0079] Step one: In a 100 mL three-necked flask was added compound f (1 g, 6.6 mmol), acetonitrile (30 mL), stirred to dissolve, added anhydrous potassium carbonate (1.36 g, 9.9 mmol), compound g (0.79 g, 7.9 mmol), reacted overnight, after TLC detection of complete reaction, added ethyl acetate (10 mL), filtered, collected solid, the solid was dissolved with 20 mL water, adjusted pH less than 3 with 2N HCl (20 mL), extracted with ethyl acetate (20 mL) three times, combined organic phase, washed with saturated sodium chloride solution (20 mL), dried with anhydrous sodium sulfate, rotary evaporated to near dryness, added ethyl acetate (20 mL) to dissolve, added petroleum ether (60 mL) dropwise, precipitated solid, stirred for 1 h, filtered, the solid was washed with petroleum ether, dried to get white solid compound 9-1 (1.1 g, yield 66%). 二氯甲烷(DCM) :V 甲醇(MeOH) = 4:1 (25 mL) three times, combined organic phase, washed with saturated sodium chloride solution (20 mL), dried with anhydrous sodium sulfate, rotary evaporated to near dryness, added ethyl acetate (20 mL) to dissolve, added petroleum ether (60 mL) dropwise, precipitated solid, stirred for 1 h, filtered, the solid was washed with petroleum ether, dried to get white solid compound 9-1 (1.1 g, yield 66%).

[0080] Characterization data: [M+H] + : 253.1; 1H NMR (400 MHz, Chloroform-d) δ 5.25 (s, 2H), 2.72 (s, 4H), 2.63 - 2.40 (m, 9H).

[0081] Step two: In a 10 mL vial, add intermediate 9-1 (100 mg, 0.40 mmol), anhydrous dichloromethane (1 mL), sulfur chloride (47.2 mg, 0.40 mmol), and stir at room temperature for 20 min to obtain a reaction solution of intermediate 9-2, which is directly used in the next step.

[0082] Step three: In a 10 mL vial, add compound m (50 mg, 0.15 mmol), anhydrous dichloromethane (0.5 mL), and stir to dissolve. Add triethylamine (90 mg, 0.90 mmol), and slowly drop the reaction solution of intermediate 9-2 above. Stir at room temperature for 2 h. After TLC detection shows that the reaction is complete, spin dry and subject to silica gel column chromatography (V 石油醚 :V 乙酸乙酯 = 5:1) to obtain compound 9 (15 mg, 18% yield) as an oil.

[0083] Characterization data: [M+H] + : 572.2; 1 H NMR (400 MHz, Chloroform-d) δ 7.70 (dd, J = 7.3, 2.2 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.35 - 7.29 (m, 2H), 6.26 (s, 1H), 5.24 (s, 2H), 4.93 (s, 1H), 3.74 (s, 3H), 3.66 (d, J = 14.2 Hz, 1H), 3.60 - 3.48 (m, 1H), 2.95 - 2.85 (m, 4H), 2.85 - 2.73 (m, 4H), 2.56 - 2.47 (m, 9H).

[0084] Example 10

[0085] Synthesis of (S)-5-(1-(2-chlorophenyl)-2-(trideuteromethoxy)-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl((3,5,6-trimethylpyrazin-2-yl)methyl)succinate (Compound 10)

[0086]

[0087] Synthesis method: Refer to step three of Example 9 to obtain compound 10 (purity 97.12%, yield 44%) as an oil.

[0088] Characterization data: [M+H] + : 575.2;1 H NMR (400 MHz, Chloroform-d) δ 7.73 - 7.67 (m, 1H), 7.46 - 7.40 (m, 1H), 7.35 - 7.29 (m, 2H), 6.26 (s, 1H), 5.25 (s, 2H), 4.94 (s, 1H), 3.71 - 3.63 (m, 1H), 3.56 (dt, J = 14.3, 1.8 Hz, 1H), 2.95 - 2.85 (m, 4H), 2.80 (ddd, J = 7.5, 6.1, 1.3 Hz, 4H), 2.55 - 2.50 (m, 9H).

[0089] 2.50 (m, 9H).

[0090] Example 11

[0091] Synthesis of 5-((S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-2-yl-2-(4-(1-oxoisoquinolin-2-yl)phenyl)butanoate (Compound 11)

[0092]

[0093] Synthesis method same as Example 3 to get solid compound 11 (HPLC purity 98.13%, yield 70.10%).

[0094] Characterization data: [M+H] + : 615.2; 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.71 - 7.66 (m, 1H), 7.66 - 7.60 (m, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.46 - 7.38 (m, 3H), 7.34 - 7.29 (m, 2H), 6.25 (s, 1H), 4.90 (s, 1H), 4.88 (s, 2H), 3.77 (s, 3H), 3.69 (t, J = 7.8 Hz, 1H), 3.62 (s, 1H), 3.52 (d, J = 14.4 Hz, 1H), 2.88 (t, J = 5.3 Hz, 2H), 2.78 (d, J = 5.9 Hz, 2H), 2.21 (dp, J = 14.6, 7.2 Hz, 1H), 1.93 (dq, J = 14.1, 7.3 Hz, 1H), 0.98 (t, J = 7.3 Hz, 3H).

[0095] Example 12

[0096] Pharmacokinetic study of the compound of the present application

[0097] Background: Clopidogrel as a prodrug, itself has no activity, in vivo most of the liver by carboxylesterase 1 (carboxylesterase 1, CES1) rapidly metabolized to inactive carboxylic acid metabolites, accounting for 85% of the total. Less than 15% of the original drug by cytochrome oxidase P450 (CYP enzyme), mainly CYP3A4, CYP2C19, two-step oxidation to generate the final active metabolite. Active metabolites through the platelet surface P2Y12 receptor irreversible binding to play anti-platelet activity, clopidogrel active metabolite concentration on the anti-platelet efficacy of play is extremely important. Clopidogrel active metabolite structure contains a thiol group, very unstable in vivo, so the thiol group must be derivatized to protect the determination of clopidogrel active metabolite derivative, to represent the content of clopidogrel active metabolite.

[0098] Rat pharmacokinetic study

[0099] The following compound of structural formula as a control group 1 sample set, prepared according to the method of the invention patent CN103554132A.

[0100]

[0101] Experimental method: 60 female SD rats (200-300g) were randomly divided into six groups (n=10): clopidogrel group, compound 3, compound 4, compound 8, compound 10 and control group 1. Intravenous injection of clopidogrel sulfate (0.73mg / kg), compound 3 (1.07mg / kg), compound 4 (1.02mg / kg), compound 8 (0.95mg / kg), compound 10 (1.00mg / kg), control group 1 (0.66mg / kg), wherein the above groups are equimolar dose, each group of drug volume is 5mL·kg -1 . Before and after administration of 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 8.0h, 12h, the blood was taken, and the derivative protection treatment was taken. The plasma was taken by centrifugation, and the concentration of clopidogrel active metabolite derivative was detected. The experimental results are shown in Table 1.

[0102] Table 1 Pharmacokinetic parameters of intravenous administration in rats (Mean ± SD)

[0103]

[0104] Experimental conclusion:

[0105] The experimental results show that the compound provided by the application has excellent pharmacokinetic properties, wherein the AUC of the derivative product of the active metabolite of clopidogrel in the plasma of rats in the compound 3, compound 4, compound 8, compound 10 and clopidogrel group, and the control group 1 (intravenous injection administration of equal molar) is 220, 225, 164, 204 and 40.8, and 69 respectively, which indicates that the degree of conversion of the compound provided by the application into the active metabolite of clopidogrel is obviously superior to the conversion degree of clopidogrel or the control group 1 compound of the same kind of deuterium analog. 0-t (h*ng / mL) respectively, which indicates that the degree of conversion of the compound 3 (oral administration or intravenous injection administration) into the active metabolite of clopidogrel is improved by more than 4.5 times relative to the conversion degree of oral administration of clopidogrel.

[0106] Dog pharmacokinetic study

[0107] Experimental method: male beagle dogs (8-12 kg) are randomly divided into groups (n=3), and are respectively administered with clopidogrel sulfate (2.2 mg / kg) orally, administered with compound 3 (3.25 mg / kg) orally, administered with compound 3 (3.25 mg / kg) intravenously, and administered with compound 10 (3.0 mg / kg) intravenously, wherein the above groups are administered with equal molar doses. Blood is taken before administration and at 0.083 h, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 4.0 h, 6.0 h, 8.0 h, 12 h and 24 h after administration, and is subjected to derivative protection treatment, centrifuged to obtain plasma, and subjected to detection of the concentration of the derivative product of the active metabolite of clopidogrel in the plasma. The experimental results are shown in Table 2.

[0108] Table 2 Pharmacokinetic parameters of beagle dogs after administration (Mean±SD)

[0109]

[0110] Experimental conclusion:

[0111] The experimental results show that the AUC of the derivative product of the active metabolite of clopidogrel in the plasma of beagle dogs in the oral clopidogrel group, the oral compound 3 group and the intravenous injection compound 3 group (administration of equal molar) is 42, 548 and 199 respectively, which indicates that the degree of conversion of the compound 3 (oral administration or intravenous injection administration) into the active metabolite of clopidogrel is improved by more than 4.5 times relative to the conversion degree of oral administration of clopidogrel. 0-t

[0112] The above research results show that the compound of the application has an unpredictable effect on improvement of pharmacokinetic properties, improves the exposure of the active metabolite of clopidogrel, and the generation amount of the active metabolite is significantly higher than that of clopidogrel or existing clopidogrel derivatives, which is expected to significantly reduce the drug dosage, achieve fast onset and high efficacy, reduce the side effects such as bleeding of anti-platelet aggregation drugs, and has the potential to be developed into an injection and an oral preparation to meet the medication needs of clinical patients.​

[0113] Example 13

[0114] Pharmacodynamic study of the compound of the present application

[0115] ADP-induced platelet aggregation experiment

[0116] Female SD rats (200-300 g) were randomly divided into 7 groups (n=8), and the vehicle was 4 vol% dimethyl sulfoxide (DMSO) + 16 vol% polyethylene glycol 400 (PEG400) + 80 vol% saline, respectively intravenous injection of clopidogrel sulfate (0.73 mg / kg), control group 1 (0.66 mg / kg), ozagrel (0.40 mg / kg), indobufen (0.51 mg / kg), compound 3 (1.07 mg / kg), compound 8 (0.95 mg / kg), and the vehicle group was given the same volume of 4 vol% DMSO + 16 vol% PEG400 + 80 vol% saline, wherein each of the above groups was administered at an equimolar dose. Four hours after administration, isoflurane anesthesia, abdominal aortic blood, 1:9 anticoagulation with sodium citrate, centrifugation to obtain platelet-rich plasma and platelet-poor plasma, and the mixture ratio of the two was platelet-poor plasma:platelet-rich plasma=3:1. After preparing the mixed platelet plasma, the optical turbidity method was used to detect the platelet aggregation rate after adding adenosine diphosphate (ADP) using a platelet aggregometer. The experimental results are shown in Table 3.

[0117] Table 3 Platelet aggregation rate after administration in rats

[0118] Group Platelet aggregation rate (%) Solvent group 81.2±3.5### Clopidogrel group 70.3±4.1**## Control group 1 61.2±3.1** Ozagrel group 75.9±2.8*## Indobufen group 74.8±2.4*## Compound 3 38.5±4.5***### Compound 8 51.5±5.9***##

[0119] Note: Compared with the vehicle group, *P≤0.05, **P≤0.01, ***P≤0.001; compared with the control group 1, #P≤0.05, ##P≤0.01, ###P≤0.001

[0120] Experimental conclusion:

[0121] The experimental results show that in the ADP-induced platelet aggregation experiment, each administration group has a significant inhibitory effect on the platelet aggregation of rats, and can reverse the platelet aggregation and cause disaggregation. The platelet aggregation degree of the compound 3 group and the compound 8 group is significantly lower than that of the clopidogrel group / control group 1 / ozagrel group / indobufen group, and the anti-platelet aggregation activity is significantly stronger than that of clopidogrel / control group 1 / ozagrel / indobufen. It is shown that the compound has strong anti-platelet aggregation activity, and is expected to achieve fast onset and high efficacy while reducing the side effects such as bleeding of anti-platelet aggregation drugs by significantly reducing the drug dosage. In addition, the experiment shows that the compound 3 group and the compound 8 group can be rapidly metabolized into effective metabolites and indobufen or ozagrel to exert the drug efficacy after entering the body, wherein indobufen and ozagrel have anti-platelet effects, and form a synergistic effect with the clopidogrel metabolite, thereby producing better anti-platelet aggregation activity.

[0122] Example 14

[0123] Safety research of the compound of the present application

[0124] Acute toxicity experiment of rats

[0125] Compound single intravenous administration (solvent 5vol% DMSO+10vol% polyethylene glycol-15 hydroxystearate (HS-15)+85vol% saline) is carried out on SD rats (4-6 dose groups are set for each compound, 10 rats in each dose group, half male and half female), and clinical observation is carried out after administration. The clinical observation is carried out twice on the first day, once a day from the second day, and continuously for 14 days. Behavior observation, spontaneous activity, nervous system behavior and death are included, and the maximum tolerance dose (MTD value) and the median lethal dose (LD 50 value) of the compound are obtained. The experimental results are shown in Table 4.

[0126] Table 4: Acute toxicity experiment data of intravenous administration of rats

[0127] No. MTD (mg / kg) LD50 value (mg / kg) Clopidogrel 72 104 Compound 3 86 121

[0128] Experimental conclusion:

[0129] The experimental results show that the MTD value and the LD 50 value of the compound of the present application in the single intravenous administration of rats are improved compared with clopidogrel, indicating that the compound has good safety.

[0130] Example 15

[0131] Stability investigation of the compound of the present application: the stability of the compound in different solutions (a small amount of ethanol is used for solubilization), and the experimental results are shown in Table 5.

[0132] Table 5: Compound stability test table

[0133]

[0134]

[0135] Further, the stability of the compounds in 20% sulfobutyl ether-beta-cyclodextrin (SBECD) aqueous solution at room temperature was investigated, and the experimental results are shown in Table 6.

[0136] Table 6: Stability of the compounds in 20% SBECD aqueous solution at room temperature

[0137] Compound No. 0h(％) 2h(％) 4h(％) 6h(％) Compound 10 97.06 96.55 / / Compound 3 99.10 99.12 99.06 99.02 Compound 4 97.98 97.64 97.30 96.62

[0138] Note: The stability results in Table 5 and Table 6 are all based on the purity of the compounds, which is determined by high performance liquid chromatography (HPLC), and the purity is the relative purity in liquid phase;

[0139] Liquid phase conditions:

[0140] Phase A: 0.1% phosphoric acid aqueous solution;

[0141] Phase B: acetonitrile;

[0142] Gradient elution, and the elution program is shown in Table 7;

[0143] Table 7 Elution program

[0144]

[0145]

[0146] Column temperature: 30°C;

[0147] Flow rate: 1 mL / min;

[0148] Sample concentration: 0.5 mg / mL;

[0149] Detection wavelength: 210 nm;

[0150] Chromatographic column: Titank C18.

[0151] Experimental conclusion: The compounds provided by the present invention have excellent stability in different solutions, especially compounds 3 and 4 show unexpected aqueous solution stability, which meets the physical and chemical property requirements for development into liquid preparations (such as injections). It solves the technical difficulties in the prior art that clopidogrel salts are unstable in aqueous solutions and severely degrade, making it very difficult to prepare clopidogrel or its salts for injection. It overcomes the long-standing technical difficulties in the prior art of developing marketed antiplatelet aggregation drugs such as clopidogrel or prasugrel into injectable preparations to improve efficacy and shorten the onset time, but has not been successful. It is expected to become a new generation of antiplatelet and antiaggregant drugs with good efficacy and low side effects that are feasible for both injection and oral administration.

[0152] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. An optically active 2-hydroxytetrahydrothienopyridine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof: wherein G is selected from a bond; The R is selected from: in, Wavy lines indicate junction sites; R1 is selected from halogen; R2 is selected from CH3, CD3.

2. The optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The derivatives are optionally selected from the following compounds:

3. An optically active 2-hydroxytetrahydrothienopyridine derivative or a pharmaceutically acceptable salt thereof, characterized in that: Any one of the following compounds: 4 . A pharmaceutical composition comprising the derivative according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

5. Use of the derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4, in the preparation of a medicament for preventing and / or treating embolic diseases caused by thrombus.

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