WO2024061097A1 - 一种新颖的氨基甲酸酯类化合物及其用途 - Google Patents

一种新颖的氨基甲酸酯类化合物及其用途 Download PDF

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WO2024061097A1
WO2024061097A1 PCT/CN2023/118773 CN2023118773W WO2024061097A1 WO 2024061097 A1 WO2024061097 A1 WO 2024061097A1 CN 2023118773 W CN2023118773 W CN 2023118773W WO 2024061097 A1 WO2024061097 A1 WO 2024061097A1
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compound
pharmaceutically acceptable
acceptable salt
solvate
unsubstituted
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English (en)
French (fr)
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曾燕群
周广林
付海霞
牟霞
周宁
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成都施贝康生物医药科技有限公司
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a carbamate compound and its use in preparing anti-platelet aggregation drugs.
  • platelet aggregation can cause a series of cardiac, cerebrovascular and other arterial circulation disorders, including (1) acute coronary syndrome (ACS), such as unstable angina (UA), acute ST-segment elevation myocardium Infarction (STEMI) and acute non-ST segment elevation myocardial infarction (NSTEMI); (2) atherosclerotic diseases, such as myocardial infarction, ischemic stroke, peripheral arterial disease; (3) and thrombotic complications, etc. .
  • ACS acute coronary syndrome
  • UA unstable angina
  • NSTEMI acute non-ST segment elevation myocardial infarction
  • atherosclerotic diseases such as myocardial infarction, ischemic stroke, peripheral arterial disease
  • clopidogrel has attracted much attention because of its low risk of bleeding.
  • the phenomenon of "clopidogrel resistance” greatly limits the drug's onset time and application scenarios, such as acute thrombosis.
  • vicagrelor a prodrug molecule based on 2-oxoclopidogrel
  • it was found that vicagrelor still has many limitations, such as unsatisfactory solubility and thermal stability, which will also greatly limit its administration form and clinical application scenarios.
  • One of the objects of the present invention is to provide a 2-oxoclopidogrel prodrug molecular compound with good stability and excellent water solubility.
  • the second object of the present invention is to provide a method for preventing and treating heart, brain and other arterial circulation disorders caused by platelet aggregation.
  • the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, solvate or deuterated product thereof:
  • X is selected from C or N;
  • R 1 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted N-containing heterocyclyl.
  • X is selected from C or N;
  • R 1 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted C 2 -C 6 N-containing heterocyclic group.
  • X is selected from N;
  • R 1 is selected from substituted or unsubstituted C 1 to C 6 alkyl, or substituted or unsubstituted C 3 to C 6 cycloalkyl; preferably, R 1 is selected from methyl, ethyl, propyl, cyclopropyl base, cyclopentyl or cyclohexyl.
  • X is selected from C
  • R 1 is selected from substituted or unsubstituted C 2 to C 6 N-containing heterocyclic groups; preferably, R 1 is selected from piperazinyl, piperidinyl or pyrrolyl.
  • the compound described in the above formula I or its pharmaceutically acceptable salt, solvate or deuterated product, the compound includes:
  • the pharmaceutically acceptable salts include but are not limited to fumarate, acetate, ascorbate, benzoate , benzenesulfonate, citrate, hydrochloride, hydrobromide, maleate, methanesulfonate, sulfate, hydrogen sulfate, nitrate, oxalate, phosphate or succinate.
  • the compounds and salts are selected from:
  • the present invention also provides a method for preparing any of the above-mentioned compounds, or a pharmaceutically acceptable salt, solvate or deuterated product thereof, which includes the following steps:
  • R1 is the same as any of the above, and X is halogen.
  • the present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts, solvates or deuterates thereof, in the preparation of medicaments for preventing and/or treating heart, brain and other arterial circulation disorders caused by platelet aggregation.
  • the above-mentioned heart, brain and other arterial circulation disorders caused by platelet aggregation include but are not limited to acute coronary syndrome, atherosclerotic disease, or thrombotic complications.
  • the above-mentioned acute coronary syndrome includes but is not limited to angina pectoris or myocardial infarction.
  • the above-mentioned acute coronary syndrome includes but is not limited to unstable angina (UA), acute ST-segment elevation myocardial infarction (STEMI) or acute non-ST-segment elevation myocardial infarction (NSTEMI).
  • UA unstable angina
  • NSTEMI acute non-ST-segment elevation myocardial infarction
  • the above-mentioned atherosclerotic diseases include but are not limited to myocardial infarction, ischemic stroke or peripheral arterial disease.
  • ischemic stroke includes but is not limited to cerebral stroke.
  • thrombotic complications include but are not limited to pulmonary infarction.
  • halogen used in the present invention refers to: fluorine, chlorine, bromine, and iodine.
  • C 1 to C 6 alkyl used in the present invention refers to a linear or branched monovalent alkyl hydrocarbon group with 1 to 6 carbon atoms.
  • the compound of the present invention has better in vitro efficacy and better pharmacokinetic characteristics. Specifically, the compound of the present invention has a strong anti-platelet aggregation effect, has a rapid onset of action, has high blood concentration and bioavailability, has a longer half-life, and has better efficacy. In addition, the compound of the present invention has good in vitro solubility, high stability, low risk of hemolysis, no cardiotoxicity, low risk of vascular stimulation, high safety, and is more conducive to being made into an injection to make up for clinical deficiencies.
  • Figure 1 shows the concentration-effect curve of compound 2 on hERG channel current
  • Figure 2 shows a schematic diagram of the hemolysis test results of compound 2 low concentration group (0.5mg/ml);
  • Figure 3 shows a schematic diagram of the hemolysis test results of compound 2 high concentration group (2.5mg/ml);
  • Figure 4 shows a schematic diagram of the vascular irritation test results of compound 2 at low concentration (0.5 mg/ml);
  • Figure 5 shows a schematic diagram of the vascular irritation test results of compound 2 at high concentration (1.5mg/ml);
  • Figure 6 shows the comparison results of properties of Comparative Example 2 at 0 days and after being left at high temperature (60)°C for two days.
  • the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts can be prepared by selecting the synthetic routes of the examples, and the conventional conditions of the reaction raw materials and reaction solvents are adjusted according to the needs of substituents or salt formation. These can be realized by those skilled in the art based on the disclosure of the present invention.
  • the column chromatography of the present invention refers to silica gel column chromatography unless otherwise specified.
  • the elution solvent can be single or mixed by combining the reaction solvent with the common knowledge or common means of those skilled in the art. Elution solvent.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or liquid mass spectrometry (LC-MS).
  • the liquid mass spectrometry instrument is Agilent G6120B (matched with liquid phase Agilent 1260); the nuclear magnetic resonance instrument ( 1 H NMR) is Bruker AVANCE-400 or Bruker AVANCE-800, and the nuclear magnetic resonance ( 1 H NMR) shift ( ⁇ ) is given in parts per million (ppm), the measurement solvent is DMSO-d 6 or CDCl 3 , the internal standard is tetramethylsilane (TMS), and the chemical shift is in 10 -6 (ppm). Units are given.
  • room temperature in the present invention means a temperature between 10 and 25°C.
  • the product was collected and concentrated to dryness to obtain 580 mg of the title product as a yellow oil, with a yield of 72.8% and a purity of 96.19%.
  • the preparation method is the same as that in Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by equimolar 4-propylpiperazine-1-formyl chloride hydrochloride to obtain the title compound. Rate: 76.3%, purity 97.10%.
  • the preparation method is the same as that in Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by an equal molar amount of 4-cyclopropylpiperazine-1-formyl chloride hydrochloride to obtain the title compound, Yield: 81.3%, purity 97.31%.
  • the preparation method is the same as that in Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by an equal molar amount of 4-cyclopentylpiperazine-1-formyl chloride hydrochloride to obtain the title compound, Yield: 84.3%, purity 98.11%.
  • the preparation method is the same as that in Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by equimolar 4-cyclohexylpiperazine-1-formyl chloride hydrochloride to obtain the title compound. Rate: 71.4%, purity 98.23%.
  • the preparation method is the same as that in Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by equimolar 4-piperidylpiperidineformyl chloride hydrochloride to obtain the title compound, yield: 88.7%, purity 98.45%.
  • the preparation method is the same as that of Example 2, except that (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxyethyl)-4,5,6,7-tetrahydrofuran Hydrothieno[3,2-c]pyridin-2-yl 4-methylpiperazine-1-carboxylate was replaced with an equimolar amount of (S)-5-(1-(2-chlorophenyl)-2 -Methoxy-2-oxyethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl[1,4'-bipiperidine]-1'- Carboxylate, replacing fumaric acid with equimolar HCl (ethyl acetate solution) gave the title compound, yield: 85.9%, purity 98.69%.
  • the preparation method is the same as that in Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by equimolar 4-(1-methylpyrrolidin-3-yl)piperidineformyl chloride hydrochloride. salt to obtain the title compound, yield: 74.7%, purity 97.79%.
  • the preparation method is the same as that of Example 1, except that 4-methylpiperazine-1-formyl chloride hydrochloride is replaced by equimolar 4-(4-methylpiperazine-1-yl)piperidineformyl chloride hydrochloride. salt to obtain the title compound, yield: 68.5%, purity 98.08%.
  • Test Example 1 Study on anti-platelet aggregation effect
  • Test purpose To evaluate and compare the anti-platelet aggregation therapeutic effects of each compound after administration at the same molar dose.
  • 70 rats were randomly and evenly divided into 7 groups: solvent control group, Comparative Example 1 (2-oxoclopidogrel) group, Comparative Example 2 (Vicagrelor) group, Compound 1 group, Compound 2 group, Compound 7 Group, compound 8 groups.
  • the anesthetized animals were transferred to the operating table, and the eyelid reflexes and pain responses of the rats were observed. The operation could not be started until the eyelid reflexes and pain responses of the limbs and tail disappeared.
  • the rat After injecting the anesthetic, the rat can be fixed on the operating table in a supine position until the whole body becomes soft. After routine disinfection, use surgical scissors to cut open the abdominal cavity along the midline of the abdomen. Use small forceps to gently peel away the fat around the blood vessels, and then remove the fat around the blood vessels with cotton. Use the ball to wipe away the excess fat covering the blood vessels until the blood vessels are clearly visible (the abdominal aorta is located above the spine; the celiac veins are thicker and darker than the abdominal aorta). First fix the blood vessel to avoid displacement of the blood vessel. Fix the fat and other organs on both sides of the blood vessel with the thumb and index finger of your left hand.
  • the needle insertion angle is about 30 degrees, and the needle is inserted toward the heart end.
  • the appropriate depth is about 5 mm.
  • the rats were anesthetized with sodium pentobarbital, and then blood was collected from the abdominal aorta, anticoagulated with 3.8% sodium citrate 1:9, mixed and centrifuged at 200 g for 10 min, and the supernatant was taken as platelet-rich plasma ( PRP); the remaining plasma was centrifuged at 1600g for 15 minutes, and the supernatant was taken as platelet-poor plasma (PPP).
  • PRP platelet-rich plasma
  • PPP platelet-poor plasma
  • ADP induces platelet aggregation
  • a platelet aggregator Helena Company, USA, model: Agg RAM
  • the platelet aggregation rate first take the PPP corresponding to the PRP to be measured from each channel for light transmittance correction, take out the PPP after correction, and then put the added Add 225 ⁇ l to the cuvette of PRP to be measured, add a stir bar, then add ADP (final concentration is 20 ⁇ M), and immediately start platelet aggregation rate detection.
  • the platelet aggregation rate (%) of the solvent control group is: 76.06 ⁇ 3.29; the platelet aggregation rates of Comparative Example 1, Comparative Example 2, Compound 1, Compound 2, Compound 7, and Compound 8 groups (%) were 31.32 ⁇ 6.07, 39.32 ⁇ 12.38, 24.08 ⁇ 6.00, 21.18 ⁇ 8.51, 27.59 ⁇ 6.99 and 27.13 ⁇ 6.50 respectively.
  • each administration group had significant inhibition of ADP-induced rat platelets. Aggregation effect (all P ⁇ 0.01).
  • Test Example 2 Effect of Compounds on Stably Overexpressed hERG Channel Current
  • the above test results show that the IC50 value of the positive drug is less than 0.1 ⁇ M, which is cardiotoxic, proving that the modeling of this test is successful.
  • the IC50 values of the compounds of the present invention are all greater than 10 ⁇ M, proving that the compounds of the present invention have a weak inhibitory effect or no inhibitory effect on hERG, that is, the compounds of the present invention have a low risk of causing ventricular repolarization toxicity and high safety.
  • Grouping and fasting SD rats were randomly divided into groups, with 6 rats in each group. Corresponding compounds were administered by gavage according to Table 3.
  • Sample collection and processing 0.2 ml of blood was collected at different time points before administration (0h) and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. After coagulation, centrifuge at 4°C for 5 min, and separate the plasma and store it at -80°C for testing.
  • LC/MS/MS method was used to detect the plasma concentration of 2-oxoclopidogrel in all PK plasma samples, and WinNonlin7.2 software was used to calculate the pharmacokinetic parameters of each compound.
  • the compound of the present invention has better absorption and high bioavailability, and is expected to be able to fully exert its medicinal effect.
  • test substance of the above negative control group a is composed of a mixture of 2% red blood cell suspension and 2.5 ml of 0.9% sodium chloride injection;
  • test substance of the positive control group b is composed of a mixture of 2% red blood cell suspension and 2.5 ml of sterile water for injection.
  • Test Example 5 Blood vessel stimulation test
  • Example Compound 2 and Comparative Example 2 (Vicagrelor), take 1 ml each of physiological saline and pH 1.2 buffer at 25-30°C, and then add 10 mg of each compound respectively.
  • the solubility data are shown in the table below: Compound 2 of the present invention has excellent solubility and can meet the clinical requirements for preparation of injections with effective concentrations, while the solubility of Comparative Example 2 is extremely low and does not meet the requirements of injections. If other co-solvents are added, it may bring potential safety risks.
  • Test method Weigh the samples of Compound 2 and Comparative Example 2 (Vicagrelor) and place them in weighing bottles respectively, and place them under high temperature (60°C), high humidity (RH80%), and light (5000Lux) conditions.
  • test results of compound 2 are shown in the table below: When compound 2 was exposed to high temperature, high humidity, and light conditions for 10 days, the content changes were small, the appearance and shape did not change significantly, and the stability was good.
  • Comparative Example 2 When Comparative Example 2 was left at high temperature (60°C) for two days, its properties changed significantly, from a white solid to a yellow-brown oil, indicating that Comparative Example 2 had poor stability under high temperature conditions.
  • the appearance characteristics of Comparative Example 2 after 0 days and two days at high temperature (60°C) are shown in Figure 6.
  • the compound of the present invention has temperature, humidity and light stability, and is better than Comparative Example 2.

Abstract

提供了一种抗血小板聚集药物及其用途。该药物为式I结构的化合物，或其药学上可接受的盐、溶剂化物或氘代物；所述化合物具有显著的抗血小板聚集效果，较适宜的水溶性和良好的稳定性，有望成为新一类的可注射用的抗血小板聚集药。

Description

一种新颖的氨基甲酸酯类化合物及其用途 技术领域
本发明属于药物化学领域，具体涉及一种氨基甲酸酯类化合物，以及所述化合物在制备抗血小板聚集药物中用途。
本申请要求于2022年9月22日提交中国专利局、申请号为202211159008.3、申请名称为“一种新颖的氨基甲酸酯类化合物及其用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
 背景技术
本领域公知，血小板聚集可以引发一系列心、脑血管及其他动脉循环障碍疾病，包括（1）急性冠状动脉综合征(ACS)，如不稳定型心绞痛(UA)、急性ST段抬高性心肌梗死(STEMI)和急性非ST段抬高性心肌梗死(NSTEMI)；（2）动脉粥样硬化疾病，如心肌梗死、缺血性卒中、外周动脉性疾病；（3）以及血栓性并发症等。针对目前的抗血小板凝集药物中，氯吡格雷因出血风险较小备受关注，但因其存在“氯吡格雷抵抗”现象大大限制了该药物的起效时间和应用场景，如急性血栓。虽然现有技术也尝试制备氯吡格雷的注射剂型，以期达到快速起效，克服急性治疗环境中起效慢等缺陷，如Ascendia公司的ASD-002纳米乳剂、CyDex公司的MDCO-157（环糊精包合）注射剂以及Jina Pharmaceuticals 公司的JIN-2013纳米脂质体注射剂；但至今因氯吡格雷的溶解度和水、光、热稳定性问题，均以失败告终。此外，以成都施贝康生物医药科技有限公司为首开发的氯吡格雷代谢中间产物2-氧代氯吡格雷，虽然克服了“氯吡格雷抵抗”不良反应，获得起效快速、生物利用度更高等优势；但在研究中发现，2-氧代氯吡格雷仍然存在水中不稳定性缺陷，对于开发成注射剂型的挑战和限制极大。因此，继而开发中间代谢物2-氧代氯吡格雷的衍生物引起了社会各界的广泛关注。
目前，以2-氧代氯吡格雷为基础的前药分子中仅维卡格雷进入临床，且是片剂形式。但在对比研究中发现，维卡格雷仍然存在诸多局限性，如溶解度和热稳定性等不理想，同样将很大程度限制其给药形式和临床应用场景。
综上，开发一种可体内持续长久释放出氯吡格雷活性代谢物成分（H4）且水溶性和稳定性较好的前药分子，同时解决氯吡格雷不可注射的特性，是目前临床亟待解决的难题。
 发明内容
本发明的目的之一在于，提供一种稳定性好、水中溶解度优良的2-氧代氯吡格雷前药分子化合物。
本发明的目的之二在于，提供一种可用于预防和治疗因血小板聚集引起的心、脑及其他动脉循环障碍疾病的用途。
本发明的技术方案如下：
本发明提供一种式I所示的化合物，或其药学上可接受的盐、溶剂化物或氘代物：
其中：
X选自C或N；
R 1选自取代或未取代的烷基、取代或未取代的环烷基、或取代或未取代的含N杂环基。
进一步地，上述式I所示的化合物，或其药学上可接受的盐、溶剂化物或氘代物中，
X选自C或N；
R 1选自取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、或取代或未取代的C 2～C 6含N杂环基。
进一步地，上述式I所述的化合物 ，或其药学上可接受的盐、溶剂化物或氘代物中，
X选自N；
R 1选自取代或未取代的C 1～C 6烷基、或取代或未取代的C 3～C 6环烷基；优选地，R 1选自甲基、乙基、丙基、环丙基、环戊基或环已基。
进一步地，上述式I所述的化合物 ，或其药学上可接受的盐、溶剂化物或氘代物中，
X选自C；
R 1选自取代或未取代的C 2～C 6含N杂环基；优选地，R 1选自哌嗪基、哌啶基或吡咯基。
进一步地，上述式I所述的化合物 ，或其药学上可接受的盐、溶剂化物或氘代物中，所述化合物包括：
。
进一步地，上述化合物，或其药学上可接受的盐、溶剂化物或氘代物中，所述药学上可接受的盐包括但不限于富马酸盐、乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、硫酸盐、硫酸氢盐、硝酸盐、草酸盐、磷酸盐或琥珀酸盐。
进一步地，上述化合物，或其药学上可接受的盐，溶剂化物或氘代物中，所述化合物及盐选自：
或
。
本发明还提供上述任一所述的化合物，或其药学上可接受的盐，溶剂化物或氘代物的制备方法，包括以下步骤：
，
其中，R1的定义同上述任一项相应定义，X为卤素。
本发明还提供上述化合物，或其药学上可接受的盐，溶剂化物或氘代物在制备预防和/或治疗因血小板聚集引起的心、脑及其他动脉循环障碍疾病中的药物中的用途。
进一步地，上述因血小板聚集引起的心、脑及其他动脉循环障碍疾病，包括但不限于急性冠脉动脉综合征、动脉粥样硬化疾病、或血栓性并发症。
进一步地，上述急性冠脉动脉综合征包括但不限于心绞痛或心肌梗死。
更进一步地，上述急性冠脉动脉综合征包括但不限于不稳定型心绞痛(UA)、急性ST段抬高性心肌梗死(STEMI)或急性非ST段抬高性心肌梗死(NSTEMI)。
进一步地，上述动脉粥样硬化疾病包括但不限于心肌梗死、缺血性卒中或外周动脉性疾病。
更进一步地，上述缺血性卒中包括但不限于脑卒中。
进一步地，上述血栓性并发症包括但不限于肺梗死。
本发明所述术语“卤素”指：氟、氯、溴、碘。
本发明所述术语“C 1～C 6烷基”指：碳原子数为1至6的直链或支链一价烷烃基。
有益效果
本发明的化合物具有更好的体外药效、更优的药代动力学特征。具体地，本发明的化合物具有较强的抗血小板聚集作用，起效快且体内药代的血药浓度和生物利用度高，半衰期较长，药效更优。此外，本发明的化合物体外溶解度好、稳定性高，溶血风险小、无心脏毒性且血管刺激风险小，安全性高，更有利于做成注射液，弥补临床不足。
 附图说明
图1 示出了化合物2 对hERG通道电流的浓度-效应曲线；
图2 示出了化合物2低浓度组（0.5mg/ml）溶血试验结果示意图；
图3 示出了化合物2高浓度组（2.5mg/ml）溶血试验结果示意图；
图4 示出了化合物2低浓度（0.5mg/ml）血管刺激性试验结果示意图；
图5 示出了化合物2高浓度（1.5mg/ml）血管刺激性试验结果示意图；
图6示出了对比例2的0天和高温（60）℃放置两天后的性状比较结果。
 本发明的实施方式
以下将结合实施例和试验例对本发明作进一步的详细描述，本发明的实施例和试验例仅用于说明本发明的技术方案，并非对本发明的限制，凡依照本发明公开的内容所作的任何本领域的等同置换，均属于本发明的保护范围。
本发明的化合物、其立体异构体或药学上可接受的盐均可选择实施例的合成路线进行制备，并根据取代基或成盐的需要，对反应原料和反应溶剂的常规条件加以调整，这些都是本领域的技术人员在本发明公开内容的基础上可以实现的。此外，本发明的柱层析在没有特别说明的情况下指硅胶柱层析，洗脱溶剂在没有特别说明的情况下可以结合反应溶剂与本领域技术人员的公知常识或者常用手段确定单一或者混合洗脱溶剂。
化合物的结构是核磁共振（ 1H NMR）或液质联用（LC-MS）来确定的。
液质联用仪（LC-MS）为安捷伦G6120B（与液相Agilent 1260配用）；核磁共振仪（ 1H NMR）为Bruker AVANCE-400或Bruker AVANCE-800，核磁共振（ 1H NMR）位移（ δ）以百万分之一（ppm）的单位给出，测定溶剂为DMSO-d 6或CDCl 3，内标为四甲基硅烷（TMS），化学位移是以10 -6（ppm）作为单位给出。
本发明的术语“室温”是指温度处于10～25℃之间。
实施例1：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-甲基哌嗪-1-羧酸酯（化合物1）的制备
50ml三口瓶中加入(2S)-2-(2-氧-7，7a-二氢噻吩并[3，2-c]吡啶-5(2H，4H，6H)-基)-2-(2-氯苯基)-乙酸甲酯(500mg,1.48mmol)和4-甲基哌嗪-1-甲酰氯盐酸盐(442mg,2.22mmol)，DMF(10ml)，搅拌降温至0℃，滴加入DBU(685g，4.5mmol)。滴加完毕，室温反应2h结束。加入EA，水洗二次，盐水洗涤一次。有机相用无水Na 2SO 4干燥且浓缩。浓缩物通过层析柱分离纯化(MeOH：DCM=2：100)，收集产物，浓缩干得到黄色油状物标题产物580mg，收率72.8%，纯度为96.19%。
ESI-MS: m/z = 464.1(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.60～7.54 (m, 1H), 7.51～7.46 (m, 1H), 7.46～ 7.35 (m, 2H), 6.39 (s, 1H), 4.86 (s, 1H), 3.67 (s, 3H), 3.57 (s, 2H), 3.40 (s, 2H), 2.80(qt, 2H), 2.63 (d, 2H), 2.48～2.39 (m, 6H), 2.34 (s, 3H)。
实施例2：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-甲基哌嗪-1-羧酸酯富马酸盐（化合物2）的制备
25ml烧瓶中加入(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-甲基哌嗪-1-羧酸酯(220mg,0.47mmol)，加入EA(2.5ml)溶解，加入富马酸(110mg，0.95mmol)搅拌，大量固体析出。搅拌3h结束，过滤，烘干得到标题化合物192mg。收率58.7%，纯度为98.39%。
ESI-MS: m/z = 464.1(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 13.82～9.71 (br, 4H), 7.64～7.56 (m, 1H), 7.56 ～7.47 (m, 1H), 7.46～7.35 (m, 2H), 6.62 (s, 4H),6.39 (s, 1H), 4.86 (s, 1H), 3.67 (s, 3H), 3.57 (s, 2H), 3.46 (s, 2H), 2.82 (qt, 2H), 2.69 (d, 2H), 2.48～2.39 (m, 6H), 2.30 (s, 3H)。
实施例3：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基-4-丙基哌嗪-1-羧酸酯（化合物3）的制备
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-丙基哌嗪-1-甲酰氯盐酸盐，得到标题化合物，收率：76.3%，纯度为97.10%。
ESI-MS: m/z = 492.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.58～7.44 (m, 1H), 7.45～7.36 (m, 1H), 7.31～ 7.22 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71 (s, 3H), 3.40 (m, 4H), 3.15～3.08 (m, 1H), 3.01 (d, 1H), 2.91 (t, 2H), 2.48～2.39 (m, 6H), 1.57 (qt, 2H), 0.88 (t, 3H)。
实施例4：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-环丙基哌嗪-1-羧酸酯（化合物4）的制备   
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-环丙基哌嗪-1-甲酰氯盐酸盐，得到标题化合物，收率：81.3%，纯度为97.31%。
ESI-MS: m/z = 490.1(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.52～7.43 (m, 1H), 7.43～7.34 (m, 1H), 7.32～ 7.21 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71 (s, 2H), 3.45 (dd, 2H), 3.35 (dd, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.74 (m, 2H), 2.61 (m, 2H), 2.53～2.45 (m, 1H), 0.77～0.50 (m, 4H)。
实施例5：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-环戊基哌嗪-1-羧酸酯（化合物5）的制备
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-环戊基哌嗪-1-甲酰氯盐酸盐，得到标题化合物，收率：84.3%，纯度为98.11%。
ESI-MS: m/z = 518.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.66～7.51 (m, 1H), 7.46～7.38(m, 1H), 7.33～7.22 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71 (s, 3H), 3.45 (dd, 2H), 3.35 (dd, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.73 (m, 2H), 2.67～2.58 (m, 2H), 2.50 (pent, 1H), 1.88～1.74 (m, 4H), 1.64～1.45 (m, 4H)。
实施例6：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-环已基哌嗪-1-羧酸酯（化合物6）的制备
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-环己基哌嗪-1-甲酰氯盐酸盐，得到标题化合物，收率：71.4%，纯度为98.23%。
ESI-MS: m/z = 532.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.62～7.50 (m, 1H), 7.46～7.35 (m, 1H), 7.30～ 7.18 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.88 (d, 2H), 3.71 (s, 3H), 3.45 (dd, 2H), 3.38 (dd, 2H), 3.18～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.73 (m, 2H), 2.67～2.58 (m, 2H), 2.34 (pent, 1H), 1.73～1.58 (m, 4H), 1.62～1.49 (m, 2H), 1.53～1.39 (m, 1H), 1.42～1.32 (m, 1H)。
实施例7：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基[1,4’-联哌啶]-1’-羧酸酯（化合物7）的制备
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-哌啶基哌啶甲酰氯盐酸盐，得到标题化合物，收率：88.7%，纯度为98.45%。
ESI-MS: m/z = 532.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.52～7.43 (m, 1H), 7.43～7.34 (m, 1H), 7.32～ 7.21 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71 (s, 3H), 3.69～ 3.59 (m, 2H), 3.39 (m, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.68 (m, 2H), 2.39 (q, 1H), 2.31 (m, 2H), 1.74～1.37 (m, 10H)。
实施例8：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基[1,4’-联哌啶]-1’-羧酸酯盐酸盐（化合物8）的制备
制备方法同实施例2的制备方法，将(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基4-甲基哌嗪-1-羧酸酯替换为等摩尔的(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基[1,4’-联哌啶]-1’-羧酸酯，将富马酸替换为等摩尔的HCl（乙酸乙酯溶液），得到标题化合物，收率：85.9%，纯度为98.69%。
ESI-MS: m/z = 532.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.58～7.46 (m, 1H), 7.46～7.34 (m, 1H), 7.39～ 7.24 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71 (s, 3H), 3.71～3.60 (m, 2H), 3.35 (m, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.68 (m, 2H), 2.39 (q, 1H), 2.31 (m, 2H), 1.74～1.37 (m, 10H)。
实施例9：5-((S)-1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基-4-(1-甲基吡咯烷-3-基)哌啶-1-羧酸酯（化合物9）的制备
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-（1-甲基吡咯烷-3-基）哌啶甲酰氯盐酸盐，得到标题化合物，收率：74.7%，纯度为97.79%。
ESI-MS: m/z = 532.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.82～7.65 (m, 1H), 7.55～7.44 (m, 1H), 7.38～ 7.25 (m, 2H), 6.29 (s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.73～3.59 (m, 5H), 3.34～3.22 (m, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.74～2.52 (m, 4H), 2.23 (s, 3H), 2.13 (m, 1H), 1.86～1.75 (m, 2H), 1.79～1.70 (m, 2H), 1.73～1.63 (m, 1H), 1.67～1.60 (m, 1H), 1.63～1.55 (m, 1H), 1.58～1.47 (m, 1H)。
实施例10：(S)-5-(1-(2-氯苯基)-2-甲氧基-2-氧乙基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基-4-(4-甲基哌嗪-1-基)哌啶-1-羧酸酯（化合物10）的制备
制备方法同实施例1的制备方法，将4-甲基哌嗪-1-甲酰氯盐酸盐替换为等摩尔的4-(4-甲基哌嗪-1-基)哌啶甲酰氯盐酸盐，得到标题化合物，收率：68.5%，纯度为98.08%。
ESI-MS: m/z = 547.2(M+H) +。
1HNMR (400 MHz, DMSO-d6) δ: 7.88～7.66 (m, 1H), 7.53～7.45 (m, 1H), 7.36～ 7.23 (m, 2H), 6.33(s, 1H), 4.75 (d, 1H), 3.90 (d, 2H), 3.71 (s, 3H), 3.65 (m, 2H), 3.39 (m, 2H), 3.15～3.08 (m, 1H), 3.02 (t, 1H), 2.91 (t, 2H), 2.68～2.58 (m, 1H), 2.62～2.54 (m, 3H), 2.57～2.50 (m, 2H), 2.54～2.45 (m, 3H), 2.40 (pent, 1H), 2.33 (s, 3H), 1.74～1.56 (m, 4H)。
对比例1：2-氧代氯吡格雷（氯吡格雷活化过程中的代谢中间体）
成都施贝康生物医药科技有限公司制备，ee=98.8%。
对比例2：维卡格雷（临床研究中）
按照CN201010624329.7制备，纯度98.22%。
试验例1：抗血小板聚集作用研究
1.试验目的：评价并比较同摩尔给药后各化合物抗血小板聚集的治疗效果。
2. 试验方法
（1）分组
将70只大鼠随机均匀分为7组：溶剂对照组、对比例1（2-氧代氯吡格雷）组、对比例2（维卡格雷）组、化合物1组、化合物2组、化合物7组、化合物8组。
（2）麻醉诱导
使用1.5%戊巴比妥钠对大鼠进行腹腔注射麻醉。
（3）固定
麻醉后的动物转移至操作台上，观察大鼠眼睑反射和痛觉反应，在眼睑反射反应及四肢和尾部痛觉反应消失后方可开始手术。
（4）大鼠腹主动脉取血
注射麻醉剂后，直到身体全身变软，方可把大鼠仰卧固定在手术台上，常规消毒后用手术剪刀沿腹正中线剪开腹腔，用小镊子轻轻扒开血管周围脂肪，再用棉球把覆盖在血管的多余脂肪擦净，直达清晰看清血管为止（腹主动脉位于脊柱上方；腹腔静脉血管比腹主动脉粗，颜色较深）。先固定血管，尽可避免血管移位，左手拇指和食指固定住血管两旁的脂肪及其它脏器，无名指按住血管进针点的上端，降低血压，可以避免喷血，右手持穿刺针，针尖斜面朝下，入针角度约 30度左右，朝向心端方向刺入，深度以5mm左右为宜，当针端回血后，将采血针另端刺入真空管中。进针后可以用止血夹夹住针头，可以避免麻醉不够挣扎导致血管被针头戳破。
（5）血小板制备
给药后3小时，戊巴比妥钠麻醉大鼠，然后腹主动脉采血，3.8%枸橼酸钠 1:9 抗凝，混匀后 200 g离心10 min，取上清为富血小板血浆（PRP）；余下血浆再以1600 g 离心15min，取上清为贫血小板血浆（PPP）。
（6）ADP诱导血小板聚集
使用血小板聚集仪（美国海伦娜公司，型号：Agg RAM）测血小板聚集率：先取各通道待测PRP所对应的PPP进行透光率校正，校正后取出PPP，再向各通道中放入已加入225 μl 待测PRP的比色皿，加入搅拌子，再加入ADP（终浓度为 20μM），立即启动血小板聚集率检测。
3. 试验结果
同摩尔给药后，各组血小板聚集率数据详见表1。
结果显示：（1）溶剂对照组血小板聚集率（%）为：76.06±3.29；对比例1组、对比例2组、化合物1组、化合物2组、化合物7组、化合物8组的血小板聚集率（%）分别为31.32±6.07、39.32±12.38、24.08±6.00、21.18±8.51、27.59±6.99和27.13±6.50，各给药组与溶剂对照组比较，均具有显著的抑制ADP诱导的大鼠血小板聚集作用（P均<0.01）。
（2）与对比例2组相比，化合物1组、化合物2组、化合物7组、化合物8组抑制ADP诱导的大鼠血小板聚集作用有显著优势（化合物1组、化合物2组：P<0.01；化合物7组、化合物8组：P<0.05），具有统计学意义。
（3）从试验结果可以看出，同等剂量下单次静脉注射给药后，本发明中化合物1、化合物2、化合物7、化合物8抑制ADP诱导的大鼠血小板聚集作用明显优于对比例2化合物，也明显优于对比例1化合物。
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试验例2：化合物对稳定过表达的hERG通道电流的影响
1. 试验样品
化合物1～10、对照化合物Cisapride。
2. 试验方法
采用手动膜片钳技术（hERG安全性评价的金标准）来研究受试化合物1～10对hERG钾通道的抑制作用，并评价其引发心室复极毒性的风险。
3. 试验结果
本研究利用手动膜片钳技术检测受试化合物1～10对hERG通道的阻断作用浓度效应关系，从而评价受试物对心脏hERG钾通道抑制作用的风险。其中化合物2的电流浓度-效应曲线如图1所示，试验结果见表2。
上述试验结果显示，阳性药的IC50值小于0.1μM，具有心脏毒性，证明本次试验造模成功。而本发明化合物的IC50值均大于10μM，证明本发明化合物对hERG为弱抑制或无抑制作用，即本发明的化合物引发心室复极毒性的风险小，安全性高。
试验例3：药代动力学研究
1. 试验目的
考察同摩尔剂量下，大鼠单次灌胃给药后，各个化合物的药代动力学特征，并对比主要药代动力学参数。
2. 材料和方法
（1）受试物
对比例1（2-氧代氯吡格雷）、化合物1、化合物2、化合物7、化合物8。
（2）给药制剂的配制
分别准确称取受试化合物于清洁给药容器中，加入适量Solutol溶解，蜗旋震荡，加入纯水，超声，蜗旋震荡，直至化合物完全溶解；给药制剂均在给药当天新鲜配制。
（3）试验分组及给药情况
健康成年SD大鼠30只，灌胃给药。具体方案见表3。
（4）试验方法
分组及禁食：SD大鼠，随机分组，每组6只，按表3灌胃给予相应化合物。
样品采集和处理：于给药前（0h）及给药后5 min、15 min、30 min、1 h、2 h、4 h、8h、24h于不同时间点采血0.2 ml，经EDTA-K2抗凝后4℃离心5 min，分离血浆于-80℃保存待测。
检测：采用LC/MS/MS法检测所有PK血浆样品中2-氧代氯吡格雷的血药浓度，并利用WinNonlin7.2软件计算各个化合物的药代动力学参数。
3. 试验结果
从上表看出，与对比例1化合物相比，化合物1、化合物2、化合物7、化合物8的T1/2、Cmax和AUC0-last均有明显的延长和提高，具有统计学意义；其中化合物1和化合物2的P<0.01，化合物7、化合物8的P<0.05。说明化合物1、化合物2、化合物7、化合物8在大鼠体内的吸收显著优于对比例1化合物，具有更优的药代动力学特征。
综上所述，本发明的化合物吸收更好，生物利用度高，预期更能充分发挥药效。
试验例4：体外溶血试验
1. 试验样品
化合物2。
2. 实验动物
成年大白耳兔，雄性，1只。  
3. 红细胞悬液制备
（1）兔经戊巴比妥钠（约30mg/kg，耳缘静脉注射）麻醉后，自心脏采血约20 ml放入适当容器中；
（2）容器放入搅拌子（或玻璃珠），慢速搅拌数分钟以除去血液中的纤维蛋白原，使其成脱纤血液；
（3）加约10倍量的生理盐水，摇匀后分装至离心管，1000～2000转/分钟，离心15分钟（由于离心管大小不同，离心机的转速和时间可根据离心后的情况调整），除去上清液；
（4）所得的沉淀红细胞再按上法以生理盐水洗涤至上清液不显红色；
（5）将所得的红细胞用生理盐水配制成2%的悬液。
4. 体外溶血试验配比量表
说明：上述阴性对照组 a的受试物由2%红细胞混悬液和0.9%氯化钠注射液各2.5ml混合组成；阳性对照组 b的受试物由2%红细胞混悬液和灭菌注射用水各2.5ml混合组成。
5. 结果判定标准
6. 试验结果
实验结果见图2和图3。根据试验结果可看出，化合物2注射液低浓度0.5mg/ml及高浓度2.5mg/ml均不会导致兔血细胞溶血。
试验例5：血管刺激试验
1.试验样品
化合物2。
2.实验动物 
日本大耳白兔4只（2kg左右），2♀/2♂。
3.试验方案
 采用同体左右侧自身对照法。设置化合物2注射液低、高剂量组，每组2只，雌雄各半。化合物2低剂量组和高剂量组的右侧耳缘静脉均注射给予化合物2注射液，给药剂量分别为2.5和7.5mg/kg，给药体积均为5 ml/kg，相应的给药浓度分别为0.5和1.5mg/ml。化合物2低剂量组和高剂量组的左侧耳缘静脉均注射给予相同给药体积的氯化钠注射液作为阴性对照。静脉输注给药，给药时长30 min。给药后观察动物的一般状态、体重、摄食量、给药局部及其周围的反应，包括水肿、充血、变性、坏死等。每天给药1次，连续给药7天。
于末次给药后72 h及继续恢复14天结束后各处死1/2动物（1♀1♂），从注射部位、耳缘静脉近心端两处分别剪取耳缘组织，肉眼观察注射部位刺激反应状况，10%中性福尔马林固定，常规组织切片进行组织病理学检查。
备注：具体给药时间根据给药后的情况酌情调整。
4.给药方案
5.试验结果
试验结果如下表、图4及图5所示， 化合物2低浓度（0.5mg/ml）时肉眼观察对兔子的耳缘静脉无血管刺激作用；化合物2高浓度（1.5mg/ml）在恢复期2d时肉眼观察雌性动物给药侧耳缘静脉有充血现象，但恢复期时间短，因此判断化合物2高浓度（1.5mg/ml）对兔子耳缘静脉无血管刺激作用。
。
试验例6：溶解性研究
准确称量实施例化合物2和对比例2（维卡格雷）样品，于25～30℃条件下，用生理盐水及pH1.2的缓冲液各取1ml，再分别加入各化合物10 mg，测得溶解度数据见下表：本发明的化合物2具有优良的溶解度，可满足临床配制成有效浓度的注射液需求，而对比例2的溶解度极低，不符合注射液要求，若加入其它助溶剂，可能会带来潜在的安全性风险。
。
试验例7：影响因素试验研究
试验方法：分别称取化合物2和对比例2（维卡格雷）样品放置于称量瓶中，分别放置于高温（60℃）、高湿（RH80%）、光照（5000Lux）条件。
化合物2的试验结果如下表所示：化合物2在高温、高湿、光照条件下10天，含量变化均较小，外观形状无明显变化，稳定性尚佳。
而对比例2高温（60℃）放置两天，性状发生重大改变，从白色固体变为黄棕色油状物，说明对比例2高温条件下稳定性差。对比例2的0天和高温（60℃）放置两天后的外观性状见图6。
综上所述，本发明的化合物具有温、湿、光稳定性，且优于对比例2。
本领域的普通技术人员在不偏离本发明的精神的情况下，可对本发明化合物、组合物以及方法进行的多种修饰和变化，这些都属于与本发明相同或等同的范围。

Claims (10)

  1. 一种式I所示的化合物，或其药学上可接受的盐、溶剂化物或氘代物：
    ，
    其中：
    X选自C或N；
    R 1选自取代或未取代的烷基、取代或未取代的环烷基、或取代或未取代的含N杂环基。
  2. 根据权利要求1所述的化合物，或其药学上可接受的盐、溶剂化物或氘代物，其特征在于，
    X选自C或N；
    R 1选自取代或未取代的C 1～C 6烷基、取代或未取代的C 3～C 6环烷基、或取代或未取代的C 2～C 6含N杂环基。
  3. 根据权利要求2所述的化合物，或其药学上可接受的盐、溶剂化物或氘代物，其特征在于，
    X选自N；
    R 1选自取代或未取代的C 1～C 6烷基、或取代或未取代的C 3～C 6环烷基；优选地，R 1选自甲基、乙基、丙基、环丙基、环戊基或环已基。
  4. 根据权利要求2所述的化合物，或其药学上可接受的盐、溶剂化物或氘代物，其特征在于，
    X选自C；
    R 1选自取代或未取代的C 2～C 6含N杂环基；优选地，R 1选自哌嗪基、哌啶基或吡咯基。
  5. 根据权利要求2所述的化合物，或其药学上可接受的盐、溶剂化物或氘代物，其特征在于，所述化合物选自：
    、 、 、 、
    、 、
    或 。
  6. 根据权利要求1～5任一所述的化合物，或其药学上可接受的盐、溶剂化物或氘代物，其特征在于，所述药学上可接受的盐包含富马酸盐、乙酸盐、抗坏血酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、硫酸盐、硫酸氢盐、硝酸盐、草酸盐、磷酸盐或琥珀酸盐。
  7. 根据权利要求6所述的化合物，或其药学上可接受的盐，溶剂化物或氘代物，其特征在于，所述化合物或其药学上可接受的盐选自：
    或
    。
  8. 权利要求1～7任一所述的化合物，或其药学上可接受的盐，溶剂化物或氘代物的制备方法，其特征在于，所述制备方法包括以下步骤：
    ，
    其中，R 1的定义同权利要求1～7任一项相应定义，X为卤素。
  9. 权利要求1～7任一所述的化合物，或其药学上可接受的盐，溶剂化物或氘代物在制备预防和/或治疗因血小板聚集引起的心、脑及其他动脉循环障碍疾病中的药物的用途。
  10. 根据权利要求9所述的用途，其特征在于，所述因血小板聚集引起的心、脑及其他动脉循环障碍疾病，包括但不限于急性冠脉动脉综合征、动脉粥样硬化疾病、或血栓性并发症。
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