(S)-methyl 2-(2-chlorophenyl)-2-(2-acetyl-salicylic acyloxy-4,5,6,7-tetrahydro-thieno[3,2-C]pyridine)-5-acetate | 1312440-98-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-methyl 2-(2-chlorophenyl)-2-(2-acetyl-salicylic acyloxy-4,5,6,7-tetrahydro-thieno[3,2-C]pyridine)-5-acetate
• 英文别名: (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl 2-acetoxybenzoate；(+)-(S)-methyl 2-(2-chlorophenyl)-2-(2-acetylsalicylate-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetate；(S)-methyl 2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate；(S)-methyl 2-(2-(2-acetoxybenzoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate；[5-[(1S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-2-yl] 2-acetyloxybenzoate
• CAS: 1312440-98-4
• 化学式: C₂₅H₂₂ClNO₆S
• 分子量: 499.972
• InChiKey: RPPPFGVXJJGCKP-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  110
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-methyl 2-(2-chlorophenyl)-2-(2-acetyl-salicylic acyloxy-4,5,6,7-tetrahydro-thieno[3,2-C]pyridine)-5-acetate 在 盐酸 作用下， 以 乙醚 为溶剂， 以85.8%的产率得到(S)-methyl 2-(2-chlorophenyl)-2-(2-acetyl-salicylic acyloxy-4,5,6,7-tetrahydro-thieno[3,2-C]pyridine)-5-acetate hydrochloride salt
  参考文献：
  名称：

  NOVEL ANTI-PLATELET COMPOUND ADDITION SALT

  摘要：

  本发明涉及使用化合物I的卤化酸盐和磺酸盐以及化合物I的盐在制备用于预防或治疗由血栓形成或栓塞引起的疾病的药物中的用途。本发明提供了化合物I的酸加成盐，特别是具有高抑制血小板聚集作用的卤化酸和磺酸加成盐，以及其制备方法，包括该化合物的药物、预防或治疗由血栓形成或栓塞引起的疾病的用途和/或方法。

  公开号：

  US20140031386A1
• 作为产物：
  描述：

  2-氯扁桃酸甲酯 在 4-二甲氨基吡啶 、 potassium hydrogencarbonate 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 50.17h， 生成 (S)-methyl 2-(2-chlorophenyl)-2-(2-acetyl-salicylic acyloxy-4,5,6,7-tetrahydro-thieno[3,2-C]pyridine)-5-acetate
  参考文献：
  名称：

  OPTICALLY ACTIVE 2-HYDROXY TETRAHYDROTHIENOPYRIDINE DERIVATIVES, PREPARATION METHOD AND USE IN MANUFACTURE OF MEDICAMENT THEREOF

  摘要：

  光学活性的2-羟基四氢噻吡啶衍生物，其化学式如下所示，并且还公开了其药用可接受的盐、制备方法以及在制备药物中的用途。药效实验结果表明，化学式I的这些化合物对抑制血小板聚集是有用的。药代动力学实验结果表明，化学式I的这些化合物在体内可以转化为药理活性代谢物，因此对于抑制血小板聚集是有用的。因此，这些化合物对于制备用于预防或治疗与血栓形成和栓塞相关的疾病的药物是有用的。

  公开号：

  US20130165476A1

文献信息

• 具有抗凝血作用的化合物
  申请人：广州赫尔氏药物开发有限公司

  公开号：CN103936756B

  公开（公告）日：2017-09-19

  本发明公开了如下所示的通式(1)化合物或其盐或其立体异构体及制备方法，以及至少包括至少一种通式(1)化合物或其盐或其立体异构体作为活性成分的药用组合物。其中，R1、R2及R3的定义如说明书所述。本发明的化合物具有抑制血小板凝集的功能，用于预防和治疗血栓或栓塞性疾病。
• W1, a Novel Oral Antiplatelet Agent With Less Resistance Than Clopidogrel
  作者：Pengxin Ge、Li Du、Chunguang Han、Hui Li、Yanguo Feng、Jie Han、Zhen Wang、Liangzhong Xiong、Meiru Yuan、Yongxue Liu

  DOI：10.1097/fjc.0000000000000449

  日期：2017.2

  Clopidogrel (CLO) is a clinical antiplatelet agent, about which there are major concerns because its antiplatelet efficiency decreases with insufficient metabolic activation, leading to “clopidogrel resistance.” We aimed to determine the antiplatelet effects of W1, a novel molecule composed of 2-O-clopidogrel and aspirin (1:1 ratio), on platelet aggregation ex vivo and thrombus formation in vivo, and its susceptibility to CLO resistance in combination with other therapies in rats. Platelets were prepared, and an arteriovenous shunt thrombosis model was established using Wistar rats to measure platelet aggregation and thrombus formation, respectively. W1 markedly inhibited adenosine 5′-diphosphate (ADP)-induced platelet aggregation and thrombus formation dose dependently (0.3, 1, and 3 mg/kg). W1 (3 mg/kg) acted rapidly at 0.5 hours and lasted for 72 hours. W1 prolonged bleeding and clotting times in mice, confirming its antithrombotic properties. Compared with CLO 10 mg/kg, the positive control, W1 3 mg/kg exerted equivalent effects on the above specifications. In addition, cyclic adenosine monophosphate levels, measured in rat platelets, increased rapidly after prostaglandin E₁ (alprostadil) stimulation of the vehicle control (0.5% methyl cellulose suspension) and W1 (3 mg/kg)-treated groups. ADP (50 μm) reduced the control levels more remarkably than W1 did (P < 0.05 in 3 minutes or P < 0.001 at 5 minutes), suggesting that W1 suppressed ADP-induced cyclic adenosine monophosphate reduction. This was associated with a significant platelet reactivity inhibition measured using the vasodilator-stimulated phosphoprotein assay. CLO or W1 coadministration with or without omeprazole and amlodipine to rats to investigate the pharmacodynamic interactions revealed that W1 exhibited more stable and potent antithrombotic effects than CLO did. In conclusion, both W1 and CLO showed antiplatelet and antithrombotic effects, while the former exhibited less CLO resistance in combination with omeprazole or amlodipine, 2 drugs that inhibit CLO metabolism. Therefore, this study implies that W1 may be a promising oral antiplatelet agent for reducing CLO resistance after percutaneous coronary intervention.

  摘要 氯吡格雷（CLO）是一种临床抗血小板药物，由于其抗血小板效率会随着代谢活化不足而降低，从而导致 "氯吡格雷耐药"，因此备受关注。我们旨在确定 W1（一种由 2-O- 氯吡格雷和阿司匹林（1:1 比例）组成的新型分子）对大鼠体内外血小板聚集和血栓形成的抗血小板作用，以及它与其他疗法联合使用时对 CLO 抗性的易感性。制备血小板，用 Wistar 大鼠建立动静脉分流血栓模型，分别测量血小板聚集和血栓形成。W1能明显抑制5′-二磷酸腺苷（ADP）诱导的血小板聚集和血栓形成，其抑制剂量与剂量有关（0.3、1和3 mg/kg）。W1（3 毫克/千克）在 0.5 小时内迅速发挥作用，并持续 72 小时。W1 延长了小鼠的出血和凝血时间，证实了其抗血栓形成的特性。与阳性对照组 CLO 10 毫克/千克相比，W1 3 毫克/千克对上述指标具有同等效果。此外，在前列腺素 E1（阿普芪地尔）刺激大鼠血小板后，载体对照组（0.5% 甲基纤维素悬浮液）和 W1（3 毫克/千克）处理组的环磷酸腺苷水平迅速升高。与 W1 相比，ADP（50 μm）更显著地降低了对照组的水平（3 分钟内 P < 0.05 或 5 分钟内 P < 0.001），这表明 W1 抑制了 ADP 诱导的环磷酸腺苷减少。这与使用血管扩张剂刺激磷蛋白测定法测量的血小板反应性明显抑制有关。为研究药效学相互作用，大鼠在服用或不服用奥美拉唑和氨氯地平的情况下同时服用 CLO 或 W1，结果表明 W1 比 CLO 表现出更稳定、更有效的抗血栓作用。总之，W1 和 CLO 都具有抗血小板和抗血栓作用，而前者与奥美拉唑或氨氯地平这两种抑制 CLO 代谢的药物合用时，CLO 的抗药性较低。因此，这项研究表明，W1 可能是一种很有前途的口服抗血小板药物，可减少经皮冠状动脉介入治疗后的 CLO 耐药性。
• Optically active 2-hydroxy tetrahydrothienopyridine derivatives, preparation method and use in manufacture of medicament thereof
  申请人：Sun Hongbin

  公开号：US08772489B2

  公开（公告）日：2014-07-08

  Optically active 2-hydroxytetrahydrothienopyridine derivatives represented by Formula I and pharmaceutically acceptable salts, preparation method and use in the manufacture of a medicament thereof are disclosed. The pharmacodynamic experiment results show that the present compounds of Formula I are useful for inhibiting platelet aggregation. The pharmacokinetic experiment results show that the present compound of Formula I can be converted in vivo into pharmacologically active metabolites and are therefore useful for inhibiting platelet aggregation. Therefore, the present compounds are useful for the manufacture of a medicament for preventing or treating thrombosis and embolism related diseases.

  本发明公开了由式I所表示的光学活性2-羟基四氢噻吩吡啶衍生物及其药学上可接受的盐、制备方法和用于制备药物的用途。药效学实验结果表明，式I的化合物对于抑制血小板聚集是有用的。药代动力学实验结果表明，式I的化合物能在体内转化为药理活性代谢物，因此对于抑制血小板聚集是有用的。因此，本发明的化合物对于制备预防或治疗与血栓形成和栓塞有关的疾病的药物是有用的。
• Overcoming Clopidogrel Resistance: Discovery of Vicagrel as a Highly Potent and Orally Bioavailable Antiplatelet Agent
  作者：Jiaqi Shan、Boyu Zhang、Yaoqiu Zhu、Bo Jiao、Weiyi Zheng、Xiaowei Qi、Yanchun Gong、Fang Yuan、Fusheng Lv、Hongbin Sun

  DOI：10.1021/jm300038c

  日期：2012.4.12

  A series of optically active 2-hydroxytetrahydrothienopyridine derivatives were designed and synthesized as prodrugs of clopidogrel thiolactone in order to overcome clopidogrel resistance. The final compounds were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. Compound 9a was selected for further in vitro and in vivo metabolism studies, since its potency was comparable to that of prasugrel and was much higher than that of clopidogrel. Preliminary pharmacokinetic study results showed that the bioavailability of clopidogrel thiolactone generated from 9a was 6-fold higher than that generated from clopidogrel, implying a much lower clinically effective dose for 9a in comparison with clopidogrel. In summary, 9a (vicagrel) holds great promise as a more potent and a safer antiplatelet agent that might have the following advantages over clopidogrel: (1) no drug resistance for CYP2C19 poor metabolizers; (2) lower dose-related toxicity due to a much lower effective dose; (3) faster onset of action.
• US8772489B2
  申请人：——

  公开号：US8772489B2

  公开（公告）日：2014-07-08