4-(3-bromopropionyl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine | 865432-93-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: 4-(3-bromopropionyl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine
• 英文别名: 3-bromo-1-(7-methoxy-3,5-dihydro-2H-1,4-benzothiazepin-4-yl)propan-1-one
• CAS: 865432-93-5
• 化学式: C₁₃H₁₆BrNO₂S
• 分子量: 330.246
• InChiKey: YBGSGBBJOSQWRO-UHFFFAOYSA-N

物化性质

• 沸点：
  489.8±45.0 °C(Predicted)
• 密度：
  1.439±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  54.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-苄基哌啶 、 4-(3-bromopropionyl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine 生成 4-[3-(4-苯甲基哌啶-1-基)丙酰]-7-甲氧基-2,3,4,5-四氢-1,4-苯并硫氮杂卓
  参考文献：
  名称：

  Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof

  摘要：

  本发明提供了限制或预防受试者中RyR2结合FKBP12.6水平下降的方法。本发明进一步提供了治疗和预防受试者中心房和心室心律失常、心力衰竭以及运动诱发的突发性心脏死亡的方法。此外，本发明提供了在限制或预防受试者中RyR2结合FKBP12.6水平下降的方法中使用JTV-519的用途，该受试者患有或有可能患上心房颤动。还提供了1,4-苯并噻唑啉衍生物在治疗和预防受试者中心房和心室心律失常以及心力衰竭，以及预防运动诱发的突发性心脏死亡的方法中的用途。本发明还提供了用于识别用于治疗和预防心房颤动和心力衰竭的药剂的方法，以及通过这些方法识别的药剂。

  公开号：

  US20050215540A1
• 作为产物：
  描述：

  2,3,4,5-四氢-7-甲氧基-1,4-苯并硫氮杂卓 、 3-溴丙酰氯 生成 4-(3-bromopropionyl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine
  参考文献：
  名称：

  Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof

  摘要：

  本发明提供了限制或预防受试者中RyR2结合FKBP12.6水平下降的方法。本发明进一步提供了治疗和预防受试者中心房和心室心律失常、心力衰竭以及运动诱发的突发性心脏死亡的方法。此外，本发明提供了在限制或预防受试者中RyR2结合FKBP12.6水平下降的方法中使用JTV-519的用途，该受试者患有或有可能患上心房颤动。还提供了1,4-苯并噻唑啉衍生物在治疗和预防受试者中心房和心室心律失常以及心力衰竭，以及预防运动诱发的突发性心脏死亡的方法中的用途。本发明还提供了用于识别用于治疗和预防心房颤动和心力衰竭的药剂的方法，以及通过这些方法识别的药剂。

  公开号：

  US20050215540A1

文献信息

• [EN] COMPOUNDS AND METHODS FOR MODULATING ACTIVITY OF CALCIUM RELEASE CHANNELS<br/>[FR] COMPOSÉS ET PROCÉDÉS DE MODULATION DE L'ACTIVITÉ DES CANAUX DE LIBÉRATION DE CALCIUM
  申请人：OREGON STATE

  公开号：WO2010120382A1

  公开（公告）日：2010-10-21

  The present teachings provide compounds of Formulae I and II: and and pharmaceutically acceptable salts, hydrates, complexes, esters, and prodrugs thereof, wherein R1, R1', R2, R2', R3, R3', and X are as defined herein. The present teachings also provide methods of making the compounds of formulae I and II, and methods of treating RyR-associated conditions, disorders, and diseases that include administering a therapeutically effective amount of a compound of formula I or II to a subject in need thereof. In addition, the present teachings relate to methods of reducing the open probability of a ryanodine receptor, and methods of reducing Ca2+ release across a ryanodine receptor (e.g., into the cytoplasm of a cell), by contacting a compound of formula I or II with a ryanodine receptor.

  本教学提供了Formulae I和II的化合物：以及其在药用上可接受的盐、水合物、络合物、酯和前药，其中R1、R1'、R2、R2'、R3、R3'和X的定义如本文所述。本教学还提供了制备Formulae I和II的化合物的方法，以及治疗与RyR相关的病症、紊乱和疾病的方法，包括向需要的受试者施用Formula I或II的化合物的治疗有效量。此外，本教学还涉及减少Ryanodine受体的开放概率的方法，以及通过与Ryanodine受体接触Formula I或II的化合物来减少Ca2+释放跨越Ryanodine受体（例如，进入细胞的细胞质）的方法。
• Compounds and methods for treating and preventing exercise-induced cardiac arrhythmias
  申请人：——

  公开号：US20040229781A1

  公开（公告）日：2004-11-18

  The present invention provides a method for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject, a method for treating or preventing exercise-induced cardiac arrhythmia in a subject, and a method for preventing exercise-induced sudden cardiac death in a subject. Also provided are uses of JTV-519 in these methods. The present invention further provides methods for identifying agents for use in preventing exercise-induced sudden cardiac death, as well as agents identified by such methods. Also provided are methods for preventing exercise-induced sudden cardiac death by administering these agents. Additionally, the present invention provides methods for synthesizing JTV-519, radio-labeled JTV-519, and 1,4-benzothiazepine intermediates and derivatives.

  本发明提供了一种限制或预防受试者中RyR2-结合FKBP12.6水平下降的方法，一种治疗或预防受试者运动引起的心律失常的方法，以及一种预防受试者运动引起的猝死的方法。此外，本发明还提供了JTV-519在这些方法中的用途。本发明还提供了一种用于识别用于预防运动引起的猝死的药剂的方法，以及由这些方法识别出的药剂。此外，本发明还提供了通过给予这些药剂预防运动引起的猝死的方法。此外，本发明还提供了合成JTV-519，放射性标记的JTV-519以及1,4-苯并噻唑中间体和衍生物的方法。
• Designing Calcium Release Channel Inhibitors with Enhanced Electron Donor Properties: Stabilizing the Closed State of Ryanodine Receptor Type 1
  作者：Yanping Ye、Daniel Yaeger、Laura J. Owen、Jorge O. Escobedo、Jialu Wang、Jeffrey D. Singer、Robert M. Strongin、Jonathan J. Abramson

  DOI：10.1124/mol.111.074740

  日期：2012.1

  sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase type 1. Moreover, the FKBP12 protein, which stabilizes RyR1 in a closed configuration, is shown to be a strong electron donor. It seems as if FKBP12, K201, its dioxole derivative, and 4-MmC inhibit RyR1 channel activity by virtue of their electron donor characteristics. These results embody strong evidence that designing new drugs to target RyR1 with enhanced electron

  具有增强的电子供体特性的新药物靶向骨骼肌肌浆网 (RyR1) 的兰尼碱受体，被证明是单通道活性的有效抑制剂。在本文中，我们合成了通道激活剂 4-chloro-3-methyl phenol (4-CmC) 和 1,4-benzothiazepine 通道抑制剂 4-[-31-(4-benzyl) piperidinyl}propionyl] 的衍生物-7-甲氧基-2,3,4,5-四氢-1,4-苯并噻嗪 (K201, JTV519) 具有增强的电子供体特性。4-CmC [4-甲氧基-3-甲基苯酚 (4-MmC)] 的 4-甲氧基类似物不是激活通道活性 (~100 μM)，而是在亚微摩尔浓度下抑制通道活性 (IC(50) = 0.34 ± 0.08微米）。通过合成其二氧杂环戊烯同源物来增加 K201 的电子供体特性，可产生约 16 倍的强效 RyR1 抑制剂（IC(50) = 0。24 ± 0
• NOVEL ANTI-ARRHYTHMIC AND HEART FAILURE DRUGS THAT TARGET THE LEAK IN THE RYANODINE RECEPTOR (RyR2)
  申请人：Marks Andrew Robert

  公开号：US20100152440A1

  公开（公告）日：2010-06-17

  The present invention provides novel 1,4-benzothiazepine intermediates and derivatives, methods for synthesizing same, and methods for assaying same. The present invention also provides methods for using these novel compounds to limit or prevent a decrease in the level of RyR2-bound FKBP12.6 in a subject; to prevent exercise-induced sudden cardiac death in a subject; and to treat or prevent heart failure, atrial fibrillation, or exercise-induced cardiac arrhythmia in a subject. The present invention further provides methods for identifying an agent that enhances binding of RyR2 and FKBP12.6, and agents identified by these methods. Additionally, the present invention provides methods for identifying agents for use in treating or preventing heart failure, atrial fibrillation, or exercise-induced cardiac arrhythmia, and in preventing exercise-induced sudden cardiac death. Also provided are agents identified by such methods.

  本发明提供了新颖的1,4-苯并噻唑啉中间体和衍生物，以及合成这些化合物的方法和检测这些化合物的方法。本发明还提供了使用这些新化合物限制或预防受试者中RyR2-结合FKBP12.6水平下降的方法；预防受试者运动引起的突发性心脏死亡的方法；以及治疗或预防受试者心力衰竭、心房颤动或运动引起的心脏心律失常的方法。本发明还提供了用于识别增强RyR2和FKBP12.6结合的试剂的方法和由这些方法识别的试剂。此外，本发明还提供了用于识别用于治疗或预防心力衰竭、心房颤动或运动引起的心脏心律失常以及预防运动引起的突发性心脏死亡的试剂的方法，以及由这些方法识别的试剂。
• Compounds And Methods For Modulating Activity Of Calcium Release Channels
  申请人：Abramson Jonathan J.

  公开号：US20120101085A1

  公开（公告）日：2012-04-26

  The present teachings provide compounds of Formulae I and II: and pharmaceutically acceptable salts, hydrates, complexes, esters, and prodrugs thereof, wherein R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , and X are as defined herein. The present teachings also provide methods of making the compounds of formulae I and II, and methods of treating RyR-associated conditions, disorders, and diseases that include administering a therapeutically effective amount of a compound of formula I or II to a subject in need thereof. In addition, the present teachings relate to methods of reducing the open probability of a ryanodine receptor, and methods of reducing Ca 2+ release across a ryanodine receptor (e.g., into the cytoplasm of a cell), by contacting a compound of formula I or II with a ryanodine receptor.

  本发明提供了公式I和II的化合物：以及其药学上可接受的盐，水合物，配合物，酯和前药，其中R1，R1'，R2，R2'，R3，R3'和X如本文所定义。本发明还提供了制备公式I和II化合物的方法，以及治疗与RyR相关的疾病和疾病的方法，包括向需要的受体中投与公式I或II的化合物的治疗有效量。此外，本发明涉及通过将公式I或II的化合物与Ryanodine受体接触，以降低Ryanodine受体的开放概率和减少Ca2+释放（例如进入细胞质）的方法。