7-chloro-5-(4-pyridinyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one

• 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: 7-chloro-5-(4-pyridinyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one
• 英文别名: 7-chloro-5-(pyridin-4-yl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one；7-Chloro-5-pyridin-4-yl-1,5-dihydro-4,1-benzothiazepin-2-one
• 化学式: C₁₄H₁₁ClN₂OS
• 分子量: 290.773
• InChiKey: NQUJITWCODYJRL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  67.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4'-氯代新戊酰苯胺 在 正丁基锂 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 27.0h， 生成 7-chloro-5-(4-pyridinyl)-1,2,3,5-tetrahydro-4,1-benzothiazepin-2-one
  参考文献：
  名称：

  Efficient Syntheses of Benzothiazepines as Antagonists for the Mitochondrial Sodium−Calcium Exchanger:  Potential Therapeutics for Type II Diabetes

  摘要：

  Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.

  DOI：

  10.1021/jo020446t

文献信息

• Synthesis and Biological Assessment of 4,1-Benzothiazepines with Neuroprotective Activity on the Ca2+ Overload for the Treatment of Neurodegenerative Diseases and Stroke
  作者：Lucía Viejo、Marcos Rubio-Alarcón、Raquel L. Arribas、Manuel Moreno-Castro、Raquel Pérez-Marín、María Braun-Cornejo、Martín Estrada-Valencia、Cristóbal de los Ríos

  DOI：10.3390/molecules26154473

  日期：——

  have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result

  在可兴奋细胞中，线粒体在调节细胞溶质 Ca 2+水平中起关键作用。线粒体 Ca 2+缓冲机制的失调源于严重的病理学，其中神经退行性疾病突出。由于线粒体 Na + /Ca 2+交换器 (NCLX) 是 Ca 2+到胞质溶胶的主要外排途径，因此已经提出能够阻断 NCLX 的药物在因 Ca 2+加剧的神经元损伤情况下充当神经保护剂超载。在我们寻找具有增强药物相似性的优化 NCLX 阻断剂的过程中，我们在此描述了由我们的研究小组合成的一流 NCLX 阻断剂 CGP37157 及其进一步衍生物 ITH12575 的新型苯并噻嗪类类似物的合成和药理学表征。结果，我们发现了两种新化合物，它们具有增强的神经保护活性、神经元 Ca 2+调节活性和改善的药物相似性和药代动力学特性，如PAMPA 实验测量的堵塞p或脑渗透性。
• Efficient Syntheses of Benzothiazepines as Antagonists for the Mitochondrial Sodium−Calcium Exchanger:  Potential Therapeutics for Type II Diabetes
  作者：Yazhong Pei、Michael J. Lilly、David J. Owen、Lawrence J. D'Souza、Xiao-Qing Tang、Jinghua Yu、Ramina Nazarbaghi、Andrew Hunter、Christen M. Anderson、Susan Glasco、Nicholas J. Ede、Ian W. James、Uday Maitra、S. Chandrasekaran、Walter H. Moos、Soumitra S. Ghosh

  DOI：10.1021/jo020446t

  日期：2003.1.1

  Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.