WO2022028347A1 - 一种光学活性2-羟基四氢噻吩并吡啶类衍生物及其制备方法和用途 - Google Patents

一种光学活性2-羟基四氢噻吩并吡啶类衍生物及其制备方法和用途 Download PDF

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WO2022028347A1
WO2022028347A1 PCT/CN2021/109965 CN2021109965W WO2022028347A1 WO 2022028347 A1 WO2022028347 A1 WO 2022028347A1 CN 2021109965 W CN2021109965 W CN 2021109965W WO 2022028347 A1 WO2022028347 A1 WO 2022028347A1
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compound
clopidogrel
derivative
formula
group
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French (fr)
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刘军华
任滔
王衡新
邓俐丽
宋志林
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天地恒一制药股份有限公司
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Priority to CN202180002186.2A priority Critical patent/CN114286823B/zh
Publication of WO2022028347A1 publication Critical patent/WO2022028347A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and particularly relates to an optically active 2-hydroxytetrahydrothienopyridine derivative and a preparation method and application thereof.
  • Clopidogrel is currently one of the most widely used antiplatelet agglutination drugs in the world, with a domestic sales of more than 10 billion in 2019. It is clinically used for the treatment of atherosclerotic disease, acute coronary syndrome and thrombotic complications. disease, etc. Years of clinical trials have confirmed the efficacy and safety of clopidogrel on thrombotic cardiovascular and cerebrovascular diseases (Lancet, 1996, 348: 1329). Clopidogrel is a prodrug that undergoes two-step oxidation by the liver P450 enzyme system in vivo, and metabolizes to produce active metabolites. Agglutination (Thromb Haemost, 2000, 84, 891). However, in the study of its metabolic process, it was found that there are two defects:
  • clopidogrel Due to the differences in the expression of P450 enzymes in the liver of different individuals, clopidogrel, which depends on the metabolism of P450 enzymes, has large individual differences in clinical therapeutic effects. For example, the phenomenon of "clopidogrel resistance” will still occur. Cardiovascular events including stent thrombosis occur (Circulation, 2004, 109:166).
  • Patents CN103554132B, CN107304215A, etc. also reported a series of derivative compounds of clopidogrel, but these compounds all have certain problems, although these compounds have improved bioavailability or efficacy compared to clopidogrel or prasugrel to a certain extent , but the increase was not significant.
  • Deuterium is a stable, non-radioactive isotope of hydrogen with a weight of 2.0144. Since the deuterium content in the produced deuterated compound is much higher than the content of 0.015% in nature, it can be regarded as a new type of compound.
  • the improvement of deuterated drugs has been recognized as patentability in many countries around the world, such as Alogliptin (WO2009045476A1), Pomalidomide (WO2012015986A2) and Dabrafenib (US2013053562A1), Deutetrabenazine (WO2010044981A3) and other deuterated drug patents entered into corresponding countries have been approved. approve.
  • the purpose of the present invention is to introduce various derivatives of a new type of 2-hydroxytetrahydrothienopyridine to solve the defects of clopidogrel, and they have better pharmacokinetics and pharmacodynamics than clopidogrel It is expected to become a new generation of antiplatelet and anticoagulant drugs with good curative effect and low side effects due to its characteristics, faster onset time, larger therapeutic index, and effectively reduced side effects such as bleeding.
  • the present invention has conducted in-depth research on thienopyridine derivatives, and found that the compound of general formula (I) has excellent anti-platelet aggregation effect.
  • the present invention provides an optically active 2-hydroxytetrahydrothienopyridine derivative, comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof:
  • G represents a hydrolyzable or metabolizable linking group, selected from
  • the dotted lines all represent the connection site with the thiophene ring, and the wavy lines all represent the connection site with R;
  • R is selected from
  • the wavy line indicates the connection site
  • R 3 is selected from H, CH 3 , CH 2 ONO 2 , CN; preferably, R 3 is selected from H, CH 2 ONO 2 , CN;
  • R 1 is selected from halogen
  • R 2 is selected from CH 3 , CD 3 .
  • G is selected from
  • the dotted lines all indicate the connection site with the thiophene ring, and the wavy lines indicate the connection site with R.
  • R is selected from
  • R 1 is selected from Cl.
  • optically active 2-hydroxytetrahydrothienopyridine derivatives of the general formula (I) of the present invention are as follows:
  • compound 1 or compound 2 is prepared by reacting the compound of formula (III) with the compound of formula (IV) in a suitable solvent to obtain the corresponding ester;
  • R 1 is selected from halogen;
  • R 2 is selected from CH 3 , CD 3 ;
  • the solvent is dichloromethane and triethylamine
  • the preparation method of compound 3 or 4 is obtained by reacting the compound of formula (V) with the compound of formula (VI) in a suitable solvent to obtain the corresponding ester;
  • R 1 is selected from halogen;
  • R 2 is selected from CH 3 , CD 3 ; preferably , the solvent is dichloromethane and triethylamine;
  • Another aspect of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I) or a salt thereof and a pharmaceutically acceptable carrier. And further use the compound of the general formula I of the present invention or the composition thereof in the preparation of medicines for preventing or treating embolic diseases caused by thrombus.
  • Another aspect of the present invention provides the above derivatives or pharmaceutical compositions for preventing or treating embolic diseases caused by thrombus.
  • Another aspect of the present invention provides a method of treating or preventing an embolic disease comprising administering to an individual in need thereof an effective amount of the above-described derivative or pharmaceutical composition.
  • Another aspect of the present invention provides the use of the above derivatives or pharmaceutical compositions in the manufacture of a medicament for preventing or treating a disease associated with thrombosis or thromboembolism.
  • Another aspect of the present invention provides the above derivatives or pharmaceutical compositions for use in the prevention or treatment of diseases associated with thrombosis or thromboembolism.
  • Another aspect of the present invention provides a method of preventing or treating a disease associated with thrombosis or thromboembolism, comprising administering to an individual in need thereof an effective amount of the above-described derivative or pharmaceutical composition.
  • “Hydrolyzable or metabolizable linking group” as used in the present invention means that the structure of the linking group is such that the compound of formula (I) or a salt thereof can be decomposed in vivo by hydrolysis or metabolism to yield two groups of active ingredients.
  • specific hydrolyzable or metabolizable linking groups are selected and hydrolyzed by esterase in vivo to control the ratio of active and inactive carboxylic acid derivatives, thereby improving bioavailability and reducing drug efficacy caused by individual differences.
  • esterase a hydrolyzed by esterase in vivo to control the ratio of active and inactive carboxylic acid derivatives, thereby improving bioavailability and reducing drug efficacy caused by individual differences.
  • the present invention adopts the method that methyl is carried out deuteration, utilizes deuteration to reduce methyl ester hydrolysis, increases active metabolites, reduces inactive metabolites, thereby reducing the occurrence of adverse events.
  • the compound of the present invention can effectively improve the pharmacokinetic properties, increase the bioavailability of the active metabolite of clopidogrel, the generation amount of the active metabolite is significantly higher than that of clopidogrel, and can significantly reduce the drug dose and achieve the desired At the same time, it can reduce the bleeding of antiplatelet aggregation drugs and reduce the side effects of stent thrombosis such as cardiovascular events.
  • the first step in a 500mL there-necked flask, add compound a (11.02g, 61mmol), DMF (216mL), stir to dissolve the clear, add anhydrous potassium carbonate (7.7g, 56mmol), compound b (10.8g, 56mmol), The reaction was carried out overnight. After TLC detected the reaction, ethyl acetate (110 mL) was added, filtered, and the filtrate was collected. The filtrate was poured into 440 mL of water, stirred for separation, and the aqueous phase was extracted once with 110 mL of ethyl acetate, and the organic phases were combined.
  • the second step in a 250mL single-neck bottle, add 72mL trifluoroacetic acid, crude intermediate 1-1 (18g), react at room temperature for 3h, after TLC detects the reaction is complete, directly spin dry, add 50mL ethyl acetate while hot, dissolve the clear Stir, slowly add 150 mL of petroleum ether dropwise, a solid is precipitated, continue to stir for 30 min, filter, rinse the filter cake with petroleum ether (100 mL), and drain to obtain 10 g of intermediate compound 1-2 as a white solid, with a two-step yield of 75.5 %.
  • the third step in a 100mL single-neck flask, add compound intermediate 1-2 (3g, 12.6mmol), dichloromethane (60mL), add 1 drop of DMF, and slowly add thionyl chloride (3.86g, 31.5mmol) dropwise After completion, the temperature was raised to 40°C, and the reaction was carried out for 3 hours. After TLC detected that the reaction was complete, it was directly spin-dried to obtain 3.1 g of intermediate compound 1-3 as a white solid with a yield of 96%.
  • the fourth step in a 100mL there-necked flask, add compound intermediate 1-6 (3g, 8.9mmol), dichloromethane 60mL, triethylamine (1.8g, 17.8mmol), compound intermediate 1-3 (3.42g, 13.4 mmol), completed, reacted at room temperature overnight, processed directly, poured into a separatory funnel, washed with water (30 mL*2), washed once with 30 mL of saturated sodium chloride, dried over sodium sulfate, spin-dried, petroleum ether: ethyl acetate (5 : 1) Column chromatography to obtain 1.7 g of the target compound with a purity of 99% and a yield of 34.3%.
  • the first step in a 25mL single-necked bottle, add compound c (5g), deuterated methanol (7.5mL), concentrated sulfuric acid (0.25g), heat up to 70 ° C and react for 4h, TLC detection, after the reaction is complete, spin to remove the solvent with Adjust the pH to 8 with 10% sodium bicarbonate, extract with ethyl acetate (10 mL*2), combine the organic phases, wash with 10 mL of saturated sodium chloride, dry over sodium sulfate, and spin dry to obtain 5 g of crude intermediate 2-1.
  • Structural characterization LC-MS m/z: 204.0 [M+H] + .
  • the second step in a 250mL three-necked flask, add crude intermediate 2-1 (5g, 24.9mmol), dichloromethane (20mL), cool to 0°C, add triethylamine (3.27g, 32.4mmol), DMAP (0.31 g, 2.5 mmol), control the temperature at 0-5 °C, slowly add the solution of compound d (5.5 g, 24.9 mmol) in dichloromethane (26 mL) dropwise, keep the reaction for 1 h, add 20 mL of dichloromethane after completion, and slowly dropwise add 1N Hydrochloric acid (50 mL), separated, the organic phase was washed once with 1N hydrochloric acid (50 mL), the aqueous phases were combined, the aqueous phase was extracted once with 30 mL of dichloromethane, all the organic phases were combined, and saturated sodium chloride (30 mL*2) Washed, dried over sodium sulfate, and spin-dried to obtain
  • the third step in a 500mL there-necked flask, add the crude compound Intermediate 2-2 (10g, 26.0mmol), acetonitrile (200mL), anhydrous potassium carbonate (8.96g, 64.9mmol), compound e (4.97g, 26.0mmol) ), reacted at room temperature overnight, TLC showed that the reaction was complete, added ethyl acetate (200 mL), filtered, collected the filtrate, rinsed with 20 mL of ethyl acetate, washed the organic phase with water (200 mL*2), washed once with 200 mL of saturated sodium chloride, and washed with sulfuric acid Dry over sodium and spin to dryness, and perform column chromatography on petroleum ether:ethyl acetate (8:1) to obtain 4.1 g of compound intermediate 2-3 in the form of yellow oil with a purity of 97.99% and a yield of 44.8% in the first three steps.
  • Structural characterization LC-MS m
  • the fourth step in a 100mL there-necked flask, add compound intermediate 2-3 (2g, 5.9mmol), dichloromethane 40mL, triethylamine (1.2g, 12mmol), intermediate 1-3 (2.28g, 8.9mmol) ), completed, reacted at room temperature overnight, processed directly, poured into a separatory funnel, washed with water (20 mL*2), washed with 20 mL of saturated sodium chloride, dried over sodium sulfate, spin-dried, petroleum ether:ethyl acetate (5:1 ) through the column to obtain 1.2 g of the target compound 2 with a purity of 97% and a yield of 36.5% in the first four steps.
  • the second step in a 10mL single-neck bottle, add Intermediate 3-1 (100mg, 0.40mmol), anhydrous dichloromethane (1mL), thionyl chloride (47.2mg, 0.40mmol), and react at room temperature for 20min to obtain an intermediate
  • the reaction system of body 3-2 was directly used in the next step.
  • the third step in a 10mL single-neck bottle, add compound 1-6 (50mg, 0.15mmol), anhydrous dichloromethane (0.5mL), stir to dissolve, add triethylamine (90mg, 0.90mmol), complete, slowly
  • the reaction solution of the above intermediate 3-2 was added dropwise, and the reaction was carried out at room temperature for 2 h. After TLC detection showed that the basic reaction was complete, column chromatography petroleum ether: ethyl acetate (5:1) was used to obtain 15 mg of oily substance 3 with a yield of 18%. .
  • the synthesis method was referred to the third step of Example 3, and only the intermediate 1-6 was replaced by the intermediate 2-3 (500 mg, 1.45 mmol) to obtain 370 mg of compound 4 with a yield of 44%.
  • the synthesis method was the same as that of Example 5, except that starting material h was replaced with starting material i (500 mg, 2.62 mmol) to obtain 135 mg of compound 6 with a yield of 30%.
  • the synthesis method was the same as that in Example 5, except that the starting material h was replaced with the starting material j (500 mg, 3.47 mmol) to obtain 56 mg of compound 7 with a yield of 35%.
  • the first step in a 250mL there-necked flask, add Intermediate 2-3 (3g, 8.9mmol), triethylamine (2.25g, 22.3mmol), slowly dropwise add chloromethyl chloroformate (2.30g, 17.8mmol), The reaction was carried out overnight at room temperature, TLC detected the reaction was complete, the organic phase was washed once with 30 mL of water, washed once with 30 mL of saturated sodium chloride, dried over sodium sulfate, spin-dried, and subjected to column chromatography on petroleum ether:ethyl acetate (8:1) to obtain 1.2 g of intermediate Body 8-1, yield 31.5%. Structural characterization: LC-MS m/z: 433.1 [M+H] + .
  • the second step in a three-necked flask, add compound f (100mg, 0.66mmol), cool down to 0°C in an ice-salt bath, add sodium hydride (26mg, 0.63mmol) in batches, keep stirring for 1h, add the intermediate at this temperature 8-1 (22.2 mg, 0.66 mmol), completed the reaction at 70 °C for 2 hours, the TLC reaction was complete, cooled in an ice-water bath, quenched with 1N dilute hydrochloric acid (1 mL), column chromatography petroleum ether:ethyl acetate (5:1), 67 mg of compound 8 were obtained in 19% yield.
  • the synthetic method was referred to the second step of Example 8, and only the intermediate 8-1 was replaced by the intermediate 9-1 (524 mg, 1.21 mmol) to obtain 153 mg of the target compound 9 with a yield of 23%.
  • clopidogrel itself has no activity. After oral absorption, most of it is rapidly metabolized by carboxylesterase 1 (CES1) in the liver to generate inactive carboxylic acid metabolites, accounting for 85% of the total. %. Only less than 15% of the original drug is oxidized by CYP enzymes, mainly CYP3A4, CYP2C19 and other two steps to generate the final active metabolites. Active metabolites exert antiplatelet activity by irreversibly binding to P2Y12 receptors on the surface of platelets, and the concentration of clopidogrel active metabolites is extremely important for antiplatelet efficacy.
  • CES1 carboxylesterase 1
  • the active metabolite of clopidogrel contains an active sulfhydryl group, which is very unstable in vivo, so the sulfhydryl group must be derivatized and protected, and the derivatized product of the active metabolite of clopidogrel is determined to indicate the content of active metabolite of clopidogrel.
  • Clopidogrel (7.5mg/kg) was administered by gavage, control group 1 (7.5mg/kg clopidogrel and 10mg/kg aspirin were physically mixed), compound 1 (13mg/kg), compound 2 (13.1mg/kg) ), compound 3 (13.4mg/kg), compound 4 high dose (13.4mg/kg), wherein the above groups were equimolar clopidogrel administration, compound 4 medium dose (5mg/kg), compound 4 low dose ( 1 mg/kg), and the administration volume of each group was 10 mL ⁇ kg -1 .
  • the compound of the present invention has unexpected effects on the improvement of pharmacokinetic properties, improves the bioavailability of clopidogrel active metabolites, and the generation amount of active metabolites is significantly higher than that of clopidogrel, which is expected to By significantly reducing the dose of the drug, it can achieve rapid onset of action and high curative effect, and at the same time reduce side effects such as bleeding of antiplatelet aggregation drugs.
  • mice were randomly divided into 8 groups, 12 rats in each group, respectively: vehicle control group (4% DMSO + 16% polyethylene glycol 400 + 80% 0.9% sodium chloride injection) , Clopidogrel group (15mg/kg), Compound 2 low-dose group (1mg/kg), Compound 2 medium-dose group (5mg/kg), Compound 2 high-dose group (15mg/kg), Compound 4 low-dose group ( 1mg/kg), compound 4 middle-dose group (5mg/kg), compound 4 high-dose group (15mg/kg), the administration volume was 10mL/kg, after the rats were given intragastric administration for 4h, they were placed in a fixed cage and used The surgical blade was quickly transectioned at 5mm from the tip of the tail of the rat, and the stopwatch was started when blood flowed out, and the blood was gently wiped from the tail with filter paper once every 30s until there was no bleeding after wiping, and the time from the start of bleeding to the stop of bleeding is the bleeding time of the
  • the compound of the present invention reduces the risk of bleeding, wherein, the middle-dose group (5 mg/kg) and the low-dose group (1 mg/kg) have a significant effect on reducing the risk of bleeding, especially the low-dose group. (1 mg/kg). Therefore, the compounds of the present invention have achieved unexpected effects, and can achieve the same or better efficacy results by significantly reducing the dosage, thereby significantly reducing the risk of bleeding and reducing the side effects of bleeding.
  • Healthy SD rats weighing 200-250 g, female, clean grade, were divided into three groups: model group, clopidogrel group (0.65 mg/kg), and compound 4 group (1 mg/kg), with 18 animals in each group (each group). 6 animals at each time point), in which the clopidogrel group and the compound 4 group were given equimolar administration.
  • the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate 0.35mL/100g, and the rats were fixed in a supine position.
  • PE7 tubes are connected to each end of a 10cm PE4 polyethylene tube, the whole tube is filled with normal saline, and the cannula is connected to the carotid artery and jugular vein of the rat, resulting in an arteriovenous short circuit.
  • the arteriovenous short circuit time is 30 minutes, cut off the blood flow, take out the silk thread with thrombus inside the catheter, and use lens tissue to absorb the blood attached to the thrombus.
  • Drying box (100 degrees, 12h), weigh the total dry weight of thrombus and silk thread, subtract the silk thread weight, it is the dry weight of thrombus, calculate the inhibition rate of dry weight of thrombus in the administration group relative to the model group.
  • the experimental results are shown in Table 3.

Abstract

一种光学活性2-羟基四氢噻吩并吡啶类衍生物，其具有如下式(I)的化合物或其药学上可接受的盐，或包含式(I)的化合物或其盐和药学上可接受的载体的药物组合物。将式(I)的化合物或其盐或其药物组合物，用于制备预防或治疗由血栓引起的栓塞性疾病药物中的应用。所述化合物能有效的改善药代动力学性质，提高了氯吡格雷活性代谢产物的生物利用度，活性代谢产物的生成量显著的高于氯吡格雷，有望实现通过显著降低药物剂量，在达到起效快和疗效高的同时，降低抗血小板聚集药物的出血等副作用。

Description

一种光学活性2-羟基四氢噻吩并吡啶类衍生物及其制备方法和用途 技术领域
本发明属于药物化学技术领域，具体涉及光学活性2-羟基四氢噻吩并吡啶类衍生物及其制备方法和用途。
背景技术
氯吡格雷(Clopidogrel)是目前世界范围内应用最为广泛的抗血小板凝集药物之一，2019年国内销售100多亿，临床上用于治疗动脉粥样硬化疾病、急性冠脉综合征及血栓性并发症等。多年临床试验已经证实了氯吡格雷对血栓性心脑血管疾病的疗效及安全性(Lancet,1996,348:1329)。氯吡格雷是一个前药，在体内经过肝脏P450酶系的两步氧化，代谢产生活性代谢物，活性代谢物与血小板表面P2Y12受体形成共价结合，通过拮抗P2Y12受体，从而抑制血小板的凝集(Thromb Haemost,2000,84,891)。然而，在对其代谢过程的研究中人们发现，存在两个方面的缺陷：
1)有85％的氯吡格雷原型药物经由肝脏内人体肝羧酯酶1(hCE1)酯解为非活性的氯吡格雷羧酸衍生物(J Phmamacol Exp Ther,2006,319:1467)，大大降低了氯吡格雷口服生物利用度，进而导致氯吡格雷临床使用剂量大(负荷剂量为300mg氯吡格雷)，起效慢，对血小板的抑制有延迟以及出血风险等缺点(Cardiovascular Drug Reviews,1993,11:180)；
2)由于不同个体肝脏内P450酶系表达的差异，使得依赖P450酶系代谢起效的氯吡格雷在临床治疗效果上产生较大的个体差异，例如出现“氯吡格雷抵抗”现象，仍会发生包括支架内血栓形成在内的心血管事件(Circulation,2004,109:166)。
鉴于氯吡格雷的局限性和缺点，需要开发新的具有更好药代动力学和药效学特性，且具有较少副作用的氯吡格雷衍生物。
专利CN103554132B、CN107304215A等，也报道了一系列氯吡格雷的衍生物化合物，但这些化合物均存在一定问题，虽然这些化合物一定程度上相比氯吡格雷或者普拉格雷生物利用度或药效有提高，但提高程度均不显著。
氘是氢的一种稳定非放射性同位素，重量为2.0144。由于生产的氘代化合物中的氘含量远远高于自然界中0.015％的含量，所以可以将其看做是一种新型的化合物。氘代对于药物的改善已经得到了全球许多国家可专利性的认可，比如Alogliptin(WO2009045476A1)、Pomalidomide(WO2012015986A2)和Dabrafenib(US2013053562A1)、Deutetrabenazine (WO2010044981A3)等进入相应国家的氘代药物专利都已经被批准。
本发明的目的在于介绍一类新型2-羟基四氢噻吩并吡啶的各种衍生物，以解决氯吡格雷存在的缺陷，它们相对于氯吡格雷，具有更好的药代动力学和药效特性、起效时间更快，治疗指数更大，并有效地降低了出血等副作用，有望成为新一代具有疗效好、副作用低的抗血小板抗凝集药物。
发明内容
为了实现上述目的，本发明对噻吩并吡啶衍生物进行了深入的研究，结果发现所示通式(I)化合物具有优异的抗血小板凝集作用。
本发明提供了一种光学活性2-羟基四氢噻吩并吡啶类衍生物，包括通式(I)的化合物或其药学上可接受的盐：
Figure PCTCN2021109965-appb-000001
其中：G代表可水解或可代谢之连接基团，选自
Figure PCTCN2021109965-appb-000002
其中，虚线均表示与噻吩环的连接位点，波浪线均表示与R的连接位点；
R选自
Figure PCTCN2021109965-appb-000003
其中，波浪线表示连接位点；
R 3选自H、CH 3、CH 2ONO 2、CN；优选地，R 3选自H、CH 2ONO 2、CN；
R 1选自卤素；
R 2选自CH 3、CD 3。
优选的，G选自
Figure PCTCN2021109965-appb-000004
其中虚线均表示与噻吩环的连接位点，波浪线均表示与R的连接位点。
优选的，R选自
Figure PCTCN2021109965-appb-000005
波浪线表示连接位点。
进一步，R 1选自Cl。
本发明通式(Ⅰ)光学活性2-羟基四氢噻吩并吡啶类衍生物，其具有代表性的化合物如下：
Figure PCTCN2021109965-appb-000006
其中，化合物1或化合物2其制备方法为使式(Ⅲ)化合物与式(Ⅳ)化合物在合适溶剂中反应成相应的酯得到；R 1选自卤素；R 2选自CH 3、CD 3；
优选的，溶剂为二氯甲烷和三乙胺；
Figure PCTCN2021109965-appb-000007
其中，化合物3或4的制备方法为使式(Ⅴ)化合物与式(Ⅵ)化合物在合适溶剂中反应成相应的酯得到；R 1选自卤素；R 2选自CH 3、CD 3；优选的，所述溶剂为二氯甲烷和三乙胺；
Figure PCTCN2021109965-appb-000008
本发明的另一方面是提供一种药物组合物，该药物组合物包含通式(I)的化合物或其盐和药学上可接受的载体。并进一步的将本发明通式I的化合物或其组合物应用于预防或治疗血栓引起的栓塞性疾病药物的制备中的应用。
本发明的另一方面提供上述衍生物或药物组合物，其用于预防或治疗由血栓引起的栓塞性疾病。
本发明的另一方面提供治疗或预防栓塞性疾病的方法，其包括向需要其的个体给药有效量的上述衍生物或药物组合物。
本发明的另一方面提供上述衍生物或药物组合物在制备用于预防或治疗与血栓形成或血栓栓塞相关的疾病的药物中的应用。
本发明的另一方面提供上述衍生物或药物组合物，其用于预防或治疗与血栓形成或血栓栓塞相关的疾病。
本发明的另一方面提供预防或治疗与血栓形成或血栓栓塞相关的疾病的方法，其包括向需要其的个体给药有效量的上述衍生物或药物组合物。
本发明所用的“可水解或可代谢之连接基团”意指连接基团之结构应使得式(Ⅰ)之化合物或其盐可由水解或代谢在活体内分解以产生两组活性成分。
本发明采用选取特定的可水解或可代谢之连接基团，通过体内酯酶水解，控制活性与非活性羧酸衍生物产生的比例，从而提高生物利用度，同时减少因个体差异引起的药效和毒性的差异，克服“氯吡格雷抵抗”现象。进一步，本发明采用将甲基进行氘代的方法，利用氘代 作用减少甲酯水解，增加活性代谢产物，减少非活性代谢物，从而降低不良反应事件的发生。
本发明化合物能有效的改善药代动力学性质，提高了氯吡格雷活性代谢产物的生物利用度，活性代谢产物的生成量显著的高于氯吡格雷，能够通过显著降低药物剂量，在达到起效快和疗效高的同时，降低抗血小板聚集药物的出血以及减少支架内血栓形成的心血管事件等副作用。
具体实施例
下面通过实施例具体说明本发明的内容。本发明中，以下所述的实施例是为了更好的阐述本发明，并不是用来限制本发明的范围。
实施例1
化合物1：(S)-2-((5-(1-(2-氯苯基)-2-甲氧基-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)氧基)-2-氧代乙基2-乙酰氧基苯甲酸酯，其合成路线如下：
Figure PCTCN2021109965-appb-000009
第一步骤：于500mL三口瓶中，加入化合物a(11.02g，61mmol)，DMF(216mL)，搅拌溶清，加入无水碳酸钾(7.7g，56mmol)，化合物b(10.8g，56mmol)，反应过夜，TLC检测反应完全后加入乙酸乙酯(110mL)，过滤，收集滤液，滤液倒入440mL水中，搅拌分液，水相再用110mL乙酸乙酯萃取一次，合并有机相。有机相用饱和氯化钠(200mL)洗涤一次，硫酸钠干燥，旋干，得到18g粗品中间体1-1。结构表征：LC-MS m/z：295.1[M+H] +。
第二步骤：于250mL单口瓶中，加入72mL三氟乙酸，中间体1-1粗品(18g)，室温反应3h，TLC检测反应完全后，直接旋干，趁热加入50mL乙酸乙酯，溶清搅拌，缓慢滴加150mL石油醚，析出固体，继续搅拌30min，过滤，滤饼用石油醚(100mL)淋洗，抽干，得到10g中间体化合物1-2，呈白色固体，两步收率75.5％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ8.11(dd,J＝7.9,1.9Hz,1H),7.62(tt,J＝7.7,2.0Hz,1H),7.36(tt,J＝7.6,1.7Hz,1H),7.15(dt,J＝8.2,1.6Hz,1H),4.87(d,J＝2.0Hz,2H),2.37(d,J＝2.0Hz,3H)；LC-MS m/z：239.1[M+H] +。
第三步骤：于100mL单口瓶中，加入化合物中间体1-2(3g，12.6mmol)，二氯甲烷(60mL)，加入1滴DMF，缓慢滴加氯化亚砜(3.86g，31.5mmol)完毕升温到40℃，反应3小时，TLC检测反应完全后，直接旋干，得到3.1g中间体化合物1-3，呈白色固体，收率96％。
第四步骤：于100mL三口瓶中，加入化合物中间体1-6(3g，8.9mmol)，二氯甲烷60mL，三乙胺(1.8g，17.8mmol)，化合物中间体1-3(3.42g，13.4mmol)，完毕，室温反应过夜，直接处理，倒入分液漏斗，水(30mL*2)洗，30mL饱和氯化钠洗一次，硫酸钠干燥，旋干，石油醚：乙酸乙酯(5:1)柱层析，得到1.7g目标化合物，纯度99％，收率34.3％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ8.10(dd,J＝7.8,1.7Hz,1H),7.66(dd,J＝7.3,2.2Hz,1H),7.60(td,J＝7.8,1.7Hz,1H),7.44–7.37(m,1H),7.37–7.30(m,1H),7.31–7.23(m,2H),7.13(dd,J＝8.1,1.2Hz,1H),6.34(s,1H),5.00(s,2H),4.91(s,1H),3.72(s,3H),3.64(dt,J＝14.4,1.9Hz,1H),3.53(dt,J＝14.3,1.9Hz,1H),2.88(t,J＝5.3Hz,2H),2.80–2.70(m,2H),2.34(s,3H)；LC-MS m/z：558.1[M+H] +。
实施例2
化合物2：(S)-2-((5-(1-(2-氯苯基)-2-(甲氧基-d 3)-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)氧基)-2-氧代乙基2-乙酰氧基苯甲酸酯，其合成路线如下：
Figure PCTCN2021109965-appb-000010
第一步骤：于25mL单口瓶中，加入化合物c(5g)，氘代甲醇(7.5mL)，浓硫酸(0.25g)，升温到70℃反应4h，TLC检测，反应完全后，旋去溶剂用10％碳酸氢钠调节pH值到8，乙酸乙酯萃取(10mL*2)，合并有机相，饱和氯化钠10mL洗一遍，硫酸钠干燥，旋干，得到5g粗品中间体2-1。结构表征：LC-MS m/z：204.0[M+H] +。
第二步骤：250mL三口瓶中，加入粗品中间体2-1(5g，24.9mmol)，二氯甲烷(20mL)，降温到0℃，加入三乙胺(3.27g，32.4mmol)，DMAP(0.31g，2.5mmol)，控制温度在0-5℃，缓慢滴加化合物d(5.5g，24.9mmol)的二氯甲烷(26mL)溶液，保温反应1h，完毕加入20mL二氯甲烷，缓慢滴加1N盐酸(50mL)，分液，有机相再用1N盐酸(50mL)洗一次，合并水相，水相用30mL二氯甲烷萃取一次，合并所有的有机相，用饱和氯化钠(30mL*2)洗，硫酸钠干燥，旋干，得到化合物中间体2-2粗品(10g)。结构表征LC-MS m/z：389.0[M+H] +。
第三步骤：于500mL三口瓶中，加入粗品化合物中间体2-2(10g，26.0mmol)，乙腈(200mL)，无水碳酸钾(8.96g，64.9mmol)，化合物e(4.97g，26.0mmol)，室温反应过夜，TLC表明反应完全，加入乙酸乙酯(200mL)，过滤，收集滤液，20mL乙酸乙酯淋洗，有机相用水(200mL*2)洗，200mL饱和氯化钠洗一次，硫酸钠干燥旋干，柱层析石油醚：乙酸乙酯(8:1)，得到4.1g化合物中间体2-3，呈黄色油状，纯度为97.99％，前三步收率为44.8％。 结构表征：LC-MS m/z：341.1[M+H] +。
第四步骤：于100mL三口瓶中，加入化合物中间体2-3(2g，5.9mmol)，二氯甲烷40mL，三乙胺(1.2g，12mmol)，中间体1-3(2.28g，8.9mmol)，完毕，室温反应过夜，直接处理，倒入分液漏斗，水(20mL*2)洗，20mL饱和氯化钠洗一遍，硫酸钠干燥，旋干，石油醚：乙酸乙酯(5:1)过柱，得到1.2g目标化合物2，纯度为97％，前四步收率为36.5％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ8.10(dd,J＝7.9,1.7Hz,1H),7.71–7.64(m,1H),7.60(td,J＝7.8,1.7Hz,1H),7.45–7.39(m,1H),7.38–7.30(m,1H),7.30–7.23(m,2H),7.13(dd,J＝8.1,1.2Hz,1H),6.34(s,1H),5.00(s,2H),4.90(s,1H),3.64(dt,J＝14.4,1.9Hz,1H),3.53(dt,J＝14.3,1.9Hz,1H),2.88(t,J＝5.3Hz,2H),2.80–2.72(m,2H),2.34(s,3H)；LC-MS m/z：561.1[M+H] +。
实施例3
化合物3：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基((3,5,6-三甲基吡嗪-2-基)甲基)琥珀酸酯，其合成路线如下：
Figure PCTCN2021109965-appb-000011
第一步骤：于100mL三口瓶中，加入化合物f(1g，6.6mmol)，乙腈(30mL)，搅拌溶清，加入无水碳酸钾(1.36g，9.9mmol)，化合物g(0.79g，7.9mmol)，完毕反应过夜，TLC检测，反应完全，加入乙酸乙酯(10mL)，过滤，收集固体，固体用20mL水溶解，用2N HCl(20mL)调节pH小于3，用DCM:MeOH＝4:1(25mL)萃取三次，合并有机相，用20mL饱和氯化钠洗一遍，硫酸钠干燥，旋至近干，加入20mL乙酸乙酯溶清，滴加60mL石油醚，析出固体，搅拌1h，过滤，固体用石油醚淋洗，干燥，得到1.1g白色固体中间体3-1，产率为66％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ5.25(s,2H),2.72(s,4H),2.63–2.40(m,9H)；LC-MS m/z：253.1[M+H] +。
第二步骤：于10mL单口瓶中，加入中间体3-1(100mg，0.40mmoL),无水二氯甲烷(1mL),氯化亚砜(47.2mg，0.40mmoL),室温反应20min，得到中间体3-2的反应体系，直接用于下一步。
第三步骤：于10mL单口瓶中，加入化合物1-6(50mg，0.15mmoL)，无水二氯甲烷(0.5mL)，搅拌溶清，加入三乙胺(90mg，0.90mmoL)，完毕，缓慢滴加上述中间体3-2的反应溶液，室温反应2h，TLC检测表明基本反应完全后，柱层析石油醚：乙酸乙酯(5:1)，得到15mg 油状物3,产率为18％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.70(dd,J＝7.3,2.2Hz,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＝14.2Hz,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)；LC-MS m/z：572.2[M+H] +。
实施例4
化合物4：(S)-5-(1-(2-氯苯基)-2-(甲氧基-d 3)-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基((3,5,6-三甲基吡嗪-2-基)甲基)琥珀酸酯，其合成路线如下：
Figure PCTCN2021109965-appb-000012
合成方法参照实施例3的第三步骤，仅将中间体1-6替换成中间体2-3(500mg，1.45mmol)，得到370mg化合物4，收率为44％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.73–7.67(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＝14.3,1.8Hz,1H),2.95–2.85(m,4H),2.80(ddd,J＝7.5,6.1,1.3Hz,4H),2.55–2.50(m,9H)；LC-MS m/z：575.2[M+H] +。
实施例5
化合物5：(S)-4-(((4-((5-(1-(2-氯苯基)-2-(甲氧基-d 3)-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)氧基)-4-氧代丁酰基)氧基)甲基)-3-甲基-1,2,5-恶二唑2-氧化物，其合成路线如下：
Figure PCTCN2021109965-appb-000013
合成方法参照实施例3，仅将起始原料f替换成起始物料h(500mg，3.85mmol)，中间体1-6替换成中间体2-3(264mg，0.78mmol)，得到150mg化合物5，收率为35％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.71-7.68(m,1H),7.26–7.20(m,3H),6.25(s,1H),5.35(s,2H),4.84(s,1H),3.67(s,2H),2.90–2.87(m,5H),2.73-2.58(m,6H)；LC-MS  m/z：553.1[M+H] +。
实施例6
化合物6：(S)-4-(((4-((5-(1-(2-氯苯基)-2-(甲氧基-d 3)-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)氧基)-4-氧代丁酰基)氧基)甲基)-3-((硝基氧基)甲基)-1,2,5-恶二唑2-氧化物，其合成路线如下：
Figure PCTCN2021109965-appb-000014
合成方法同实施例5，仅将起始原料h替换成起始物料i(500mg，2.62mmol)，得到135mg化合物6，收率为30％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.73–7.67(m,1H),7.45–7.39(m,1H),7.34–7.28(m,2H),6.31(s,1H),5.67(s,2H),5.42(s,2H),4.77(s,1H),3.62(s,2H),2.95–2.85(m,2H),2.73-2.58(m,6H)。LC-MS m/z：614.1[M+H] +。
实施例7
化合物7：(S)-4-(((4-((5-(1-(2-氯苯基)-2-(甲氧基-d 3)-2-氧代乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)氧基)-4-氧代丁酰基)氧基)甲基)-3-氰基-1,2,5-恶二唑2-氧化物，其合成路线如下：
Figure PCTCN2021109965-appb-000015
合成方法同实施例5，只是将起始原料h替换成起始物料j(500mg，3.47mmol)，得到56mg化合物7，收率为35％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.73-7.69(m,1H),7.45-7.40(m,1H),7.32-7.24(m,2H),6.13(s,1H),5.35(s,2H),4.74(s,1H),3.67(s,2H),2.92(s,2H),2.78(m,6H)。LC-MS m/z：564.1[M+H] +。
实施例8
化合物8：甲基-d 3(S)-2-(2-氯苯基)-2-(2-(((((3,5,6-三甲基吡嗪-2-基)甲氧基)甲氧基)羰基)氧基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸酯，其合成路线如下：
Figure PCTCN2021109965-appb-000016
第一步骤：于250mL三口瓶中，加入中间体2-3(3g，8.9mmol)，三乙胺(2.25g，22.3mmol)，缓慢滴加氯甲酸氯甲酯(2.30g，17.8mmol)，室温反应过夜，TLC检测反应完全，有机相加入30mL水洗一次，30mL饱和氯化钠洗一次，硫酸钠干燥，旋干，柱层析石油醚：乙酸乙酯(8:1)，得到1.2g中间体8-1，产率31.5％。结构表征：LC-MS m/z：433.1[M+H] +。
第二步骤：于三口瓶中，加入化合物f(100mg，0.66mmol)，冰盐浴降温到0℃，分批加入氢化钠(26mg，0.63mmol)，保温搅拌1h，于此温度下加入中间体8-1(22.2mg，0.66mmol)，完毕70℃反应2小时，TLC反应完全，冰水浴降温，1N稀盐酸(1mL)淬灭，柱层析石油醚：乙酸乙酯(5:1)，得到67mg化合物8，产率19％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.73-7.67(m,1H),7.46-7.40(m,1H),7.35-7.29(m,2H),6.35(s,2H),6.17(s,1H),4.74(s,1H),4.15(s,2H),3.71-3.63(m,2H),2.95-2.85(m,4H),2.56-2.51(m,9H)。LC-MS m/z：549.2[M+H] +。
实施例9
化合物9：甲基-d 3(2S)-2-(2-氯苯基)-2-(2-(((1-((3,5,6-三甲基吡嗪-2-基)甲氧基)乙氧基)羰基)氧基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸酯，其合成路线如下：
Figure PCTCN2021109965-appb-000017
合成方法参照实施例8的第二步骤，仅将中间体8-1替换成中间体9-1(524mg，1.21mmol)，得到153mg目标化合物9，产率为23％。
结构表征： 1H NMR(400MHz,Chloroform-d)δ7.74–7.68(m,1H),7.43–7.39(m,1H),7.35–7.29(m,2H),6.61(s,1H),6.17(s,1H),4.74(s,1H),4.60(s,2H),3.71–3.63(m,2H),2.93–2.84(m,4H),2.58–2.52(m,9H),1.62–1.57(m,3H)；LC-MS m/z：563.2[M+H] +。
实施例10
本发明化合物在大鼠体内的药代动力学及生物利用度研究
研究背景：氯吡格雷作为前药，本身没有活性，其口服吸收后大部分在肝脏中经过羧酸酯酶1(carboxylesterase1，CES1)迅速代谢生成无活性的羧酸代谢物，占总量的85％。只有不 到15％的原药经CYP酶，主要是CYP3A4、CYP2C19等2步氧化生成最终的活性代谢产物。活性代谢产物通过跟血小板表面的P2Y12受体不可逆结合从而发挥抗血小板活性，氯吡格雷活性代谢物浓度对抗血小板药效的发挥极其重要。氯吡格雷活性代谢物结构中含有活泼巯基，生物体内十分不稳定，所以必须对巯基进行衍生化保护，测定氯吡格雷活性代谢物的衍生化产物，来表示氯吡格雷活性代谢物含量。
实验方法：雄性SD大鼠(200-300g)80只，随机分成八组(n＝10)：氯吡格雷组、对比组1(氯吡格雷与阿司匹林的物理混合)、化合物1、化合物2、化合物3、化合物4高、中、低三个剂量组。分别灌胃给予氯吡格雷(7.5mg/kg)，对比组1(7.5mg/kg氯吡格雷与10mg/kg阿司匹林进行物理混合)，化合物1(13mg/kg)，化合物2(13.1mg/kg)，化合物3(13.4mg/kg)，化合物4高剂量(13.4mg/kg)，其中以上各组为等摩尔氯吡格雷给药，化合物4中剂量(5mg/kg)，化合物4低剂量(1mg/kg)，各组给药体积为10mL·kg -1。分别于给药前和给药后0.083h、0.25h、0.5h、1.0h、2.0h、3.0h、4.0h、8.0h、12h取血，衍生化保护处理，离心取血浆，检测血浆中氯吡格雷活性代谢物的衍生化产物浓度。实验结果见表1。
表1大鼠口服给药的药代动力学参数(Mean±SD)
Figure PCTCN2021109965-appb-000018
实验结论：根据实验结果得出以下主要结论：
①实验结果表明化合物2、氯吡格雷、对比组1血浆中氯吡格雷活性代谢物的衍生化产 物的AUC 0-t(h*ng/mL)分别为1136.859、18.428和9.709，说明化合物2转化为氯吡格雷活性代谢产物的程度相对于氯吡格雷的转化程度提高了60.69倍，相对于对比组1的转化程度提高了116.09倍；
②实验结果表明化合物4高剂量(13.4mg/kg)、氯吡格雷组、对比组1血浆中氯吡格雷活性代谢物的衍生化产物的AUC0-t(h*ng/mL)分别为1288.297、18.428和9.709，说明化合物4转化为氯吡格雷活性代谢产物的程度相对于氯吡格雷提高了68.91倍，相对于对比组1的转化程度提高了131.68倍；
③实验结果表明化合物4高剂量(13.4mg/kg)、化合物4中剂量(5mg/kg)、化合物4低剂量(1mg/kg)、氯吡格雷组血浆中氯吡格雷活性代谢物的衍生化产物的AUC 0-t(h*ng/mL)分别为1288.297、236.847、23.369、18.428，说明化合物4转化为氯吡格雷活性代谢产物的程度随着剂量增加而增加，呈剂量依赖性，并且化合物4低剂量(1mg/kg)转化为氯吡格雷活性代谢产物的程度高于氯吡格雷组。
上述研究结果表明：本发明化合物对药代动力学性质改善有出乎预料的效果，提高了氯吡格雷活性代谢产物的生物利用度，活性代谢产物的生成量显著的高于氯吡格雷，有望通过显著降低药物剂量，实现达到起效快和疗效高的同时，降低抗血小板聚集药物的出血等副作用。
实施例11
本发明化合物对大鼠出血时间的影响实验研究
实验方法：SD雄性大鼠96只，随机分为8组，每组12只，分别为：溶媒对照组(4％DMSO+16％聚乙二醇400+80％0.9％氯化钠注射液)、氯吡格雷组(15mg/kg)、化合物2低剂量组(1mg/kg)、化合物2中剂量组(5mg/kg)、化合物2高剂量组(15mg/kg)、化合物4低剂量组(1mg/kg)、化合物4中剂量组(5mg/kg)、化合物4高剂量组(15mg/kg)，给药体积10mL/kg，大鼠灌胃给药4h后，置于固定笼中，用手术刀片距鼠尾尖5mm处迅速横断，在有血液流出时开始秒表计时，每隔30s用滤纸轻轻于尾部拭血1次，直至拭后不再出血为止，从开始出血至停止出血的时间为大鼠出血时间。若出血时间超过60min，按60min记录，实验结果见表2。
表2本发明系列化合物对大鼠出血时间影响(Mean±SD)
组别 出血时间(min)
溶媒对照组 20±4
氯吡格雷组(15mg/kg) 37±7***
化合物2低剂量组(1mg/kg) 24±5 ###
化合物2中剂量组(5mg/kg) 31±8***
化合物2高剂量组(15mg/kg) 35±8***
化合物4低剂量组(1mg/kg) 26±6 ###
化合物4中剂量组(5mg/kg) 32±4***
化合物4高剂量组(15mg/kg) 34±7***
注：*P＜0.05，**P＜0.01，***P＜0.001与溶媒对照组比较； #P＜0.05， ##P＜0.01， ###P＜0.001与氯吡格雷组比较。
实验结论：根据实验结果可以看出：
①各组与溶媒对照组比，出血时间都有所延长了，其中低剂量组(1mg/kg)与溶媒组相比，两者出血时间相差最小。与氯吡格雷组(15mg/kg)相比，各组的出血时间都有所降低，其中低剂量组(1mg/kg)呈显著降低。
②各剂量组之间随着剂量的增加出血时间延长，呈现剂量依赖性。说明降低化合物的给药剂量，出血时间一定程度缩短，可以减少出血风险。
上述研究结果表明：本发明化合物与氯吡格雷相比，降低了出血风险，其中，中剂量组(5mg/kg)、低剂量组(1mg/kg)减少出血风险效果显著，特别是低剂量组(1mg/kg)。因此，本发明化合物取得了出乎预料的效果，可以实现通过显著减少给药剂量而达到同等或更优药效结果，从而显著降低了出血风险，减少了出血副作用。
实施例12
本发明化合物在对大鼠动静脉吻合(AV-Shunt)模型的药效研究
健康SD大鼠，体重200～250g，雌性，清洁级，分为模型组、氯吡格雷组(0.65mg/kg)、化合物4组(1mg/kg)共3组，每组18只动物(每个时间点6只)，其中氯吡格雷组与化合物4组为等摩尔给药。10％水合氯醛0.35mL/100g腹腔注射麻醉实验大鼠，将大鼠仰卧位固定，分离左颈静脉和右颈动脉，用AV-SHUNT导管(长8cm的聚乙烯PE7管内封闭一段长6cm型号3-0的外科缝合线，PE7管两端各连接一段10cm的PE4聚乙烯管，整个管道充满生理盐水，插管连接大鼠的颈动脉和颈静脉，造成动静脉短路，分别于给药后0.5、1、2小时进行动静脉短路，动静脉短路时间为30分钟，切断血流，取出导管里面的附带血栓的丝线，用擦镜纸吸取血栓附着血液后，将附带血栓的丝线放入恒温干燥箱(100度，12h)，称取血栓 和丝线总干重，减去丝线重量，即为血栓干重，计算给药组相对于模型组的血栓干重抑制率。实验结果见表3。
表3本发明系列化合物对大鼠动静脉吻合(AV-Shunt)模型的血栓干重抑制率(Mean±SD)
组别 给药0.5h血栓抑制率 给药1h血栓抑制率 给药2h血栓抑制率
氯吡格雷组(0.65mg/kg) 26.22％ 24.11％ 34.00％
化合物4组(1mg/kg) 31.30％ 58.27％ 49.22％
实验结论：根据实验结果可以看出在给药0.5h、1h、2h，化合物4均比氯吡格雷的血栓干重抑制率高，说明化合物4具有更强的抗凝血作用。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (10)

  1. 一种光学活性2-羟基四氢噻吩并吡啶类衍生物，其特征在于，包括式(Ⅰ)
    所示的化合物、其药学上可接受的盐：
    Figure PCTCN2021109965-appb-100001
    其中，G代表可水解或可代谢之连接基团，选自
    Figure PCTCN2021109965-appb-100002
    虚线均表示与噻吩环的连接位点，波浪线均表示与R的连接位点；
    所述R选自
    Figure PCTCN2021109965-appb-100003
    其中，波浪线表示连接位点；
    R 3选自H、CH 3、CH 2ONO 2、CN；优选地，R 3选自H、CH 2ONO 2、CN；
    R 1选自卤素；
    R 2选自CH 3、CD 3。
  2. 根据权利要求1所述的衍生物，其特征在于，所述G选自
    Figure PCTCN2021109965-appb-100004
    其中虚线均表示与噻吩环的连接位点，波浪线均表示 与所述R的连接位点。
  3. 根据权利要求2所述的衍生物，其特征在于，R选自
    Figure PCTCN2021109965-appb-100005
    其中波浪线表示连接位点。
  4. 根据权利要求1-3任一项所述的衍生物，其特征在于，R 1选自Cl。
  5. 根据权利要求1所述的衍生物，其特征在于，其具有代表性的化合物如下：
    Figure PCTCN2021109965-appb-100006
  6. 根据权利要求5所述的衍生物，其特征在于，所述化合物1或化合物2由式(Ⅲ)化合物与式(Ⅳ)化合物在溶剂中反应成相应的酯得到；
    Figure PCTCN2021109965-appb-100007
    其中，R 1选自卤素；R 2选自CH 3、CD 3。
  7. 根据权利要求5所述的衍生物，其特征在于，化合物3或4由式(Ⅴ)化合物与式(Ⅵ)化合物在溶剂中反应成相应的酯得到；
    Figure PCTCN2021109965-appb-100008
    其中，R 1选自卤素；R 2选自CH 3、CD 3。
  8. 根据权利要求6或7所述的衍生物，其特征在于，所述溶剂为二氯甲烷和三乙胺。
  9. 一种药物组合物，该药物组合物包含权利要求1-5任一项所述的衍生物或其盐及其药学上可接受的载体。
  10. 根据权利要求1所述的衍生物或根据权利要求9所述的药物组合物在制备用于预防或治疗与血栓形成或血栓栓塞相关的疾病的药物中的应用。
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