5-(2-(piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one hydrochloride | 1255207-10-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: 5-(2-(piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one hydrochloride
• 英文别名: 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride；5-(2-piperazin-1-ylethyl)-3H-2-benzofuran-1-one;hydrochloride
• CAS: 1255207-10-3
• 化学式: C₁₄H₁₈N₂O₂*ClH
• 分子量: 282.77
• InChiKey: IZUUEFUOYINQJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.23
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  41.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(2-(piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one hydrochloride 、 2-fluoro-4-(2-oxoethyl)benzonitrile 在 三乙胺 、 三乙酰氧基硼氢化钠 、 盐酸 作用下， 以 二氯甲烷 、 乙醚 、 水 为溶剂， 反应 25.5h， 以20%的产率得到2-fluoro-4-(2-(4-(2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)ethyl)benzonitrile
  参考文献：
  名称：

  Discovery of Selective Small Molecule ROMK Inhibitors as Potential New Mechanism Diuretics

  摘要：

  The renal outer medullary potassium channel (ROMK or K(ir)1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a potent ROMK inhibitor. It is worth noting that this compound was identified as a minor impurity in a screening hit that was responsible for all of the initially observed ROMK activity. Structure-activity studies resulted in analogues with improved rat pharmacokinetic properties and selectivity over the hERG channel, providing tool compounds that can be used for in vivo pharmacological assessment. The featured ROMK inhibitors were also selective against other members of the inward rectifier family of potassium channels.

  DOI：

  10.1021/ml3000066
• 作为产物：
  描述：

  5-溴苯酞 在 盐酸 、 palladium diacetate 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.08h， 生成 5-(2-(piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one hydrochloride
  参考文献：
  名称：

  INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL

  摘要：

  公开号：

  EP2632465B1

文献信息

• [EN] INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL<br/>[FR] INHIBITEURS DU CANAL POTASSIQUE MÉDULLAIRE EXTERNE RÉNAL
  申请人：MERCK SHARP & DOHME

  公开号：WO2010129379A1

  公开（公告）日：2010-11-11

  This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

  这项发明涉及具有结构式I的化合物及其药学上可接受的盐，这些化合物是肾外髓钾（ROMK）通道（Kir1.1）的抑制剂。式I的化合物可用作利尿剂和钠利尿剂，因此可用于治疗和预防由过多盐分和水分潴留引起的疾病，包括高血压和慢性和急性心力衰竭等心血管疾病。
• Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure
  作者：Haifeng Tang、Yuping Zhu、Nardos Teumelsan、Shawn P. Walsh、Aurash Shahripour、Birgit T. Priest、Andrew M. Swensen、John P. Felix、Richard M. Brochu、Timothy Bailey、Brande Thomas-Fowlkes、Lee-Yuh Pai、Caryn Hampton、Aaron Corona、Melba Hernandez、Joseph Metzger、Michael Forrest、Xiaoyan Zhou、Karen Owens、Vincent Tong、Emma Parmee、Sophie Roy、Gregory J. Kaczorowski、Lihu Yang、Magdalena Alonso-Galicia、Maria L. Garcia、Alexander Pasternak

  DOI：10.1021/acsmedchemlett.6b00122

  日期：2016.7.14

  represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted

  ROMK是肾脏的外部髓质钾通道，参与了在Henle的厚上升环处的钾循环以及在肾脏的肾单位皮质收集管中的钾分泌。由于这种双重作用，与护理标准环和噻嗪类利尿剂相比，ROMK的选择性抑制剂有望代表一类新型的利尿剂/利尿剂，具有优越的功效并减少钾的尿流失。在我们的早期工作之后，本交流将详细介绍随后的药物化学工作，以进一步提高针对hERG通道的铅选择性和临床前药代动力学特性。将描述突出显示的抑制剂的药理学评估，包括在自发性高血压大鼠的急性大鼠利尿/利尿模型和亚慢性血压模型中的药效学研究。这些生物学证据研究首次确定了人类和啮齿动物遗传学能够准确预测ROMK抑制剂的体内药理学，并支持鉴定第一个小分子ROMK抑制剂临床候选药物MK-7145。
• Inhibitors of the renal outer medullary potassium channel
  申请人：Pasternak Alexander

  公开号：US08673920B2

  公开（公告）日：2014-03-18

  This invention relates to compounds having structural Formula I: and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

  本发明涉及结构式I的化合物及其药学上可接受的盐，它们是肾外髓质钾（ROMK）通道（Kir1.1）的抑制剂。公式I的化合物可用作利尿剂和钠利尿剂，因此可用于治疗和预防由过度盐和水潴留引起的疾病，包括心血管疾病，如高血压和慢性和急性心力衰竭。
• Inhibitors of the Renal Outer Medullary Potassium Channel
  申请人：Pasternak Alexander

  公开号：US20130217680A1

  公开（公告）日：2013-08-22

  This invention relates to compounds having structural Formula (I); and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir 1.1). The compounds of Formula I are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

  本发明涉及具有结构式（I）的化合物及其药学上可接受的盐，它们是肾外髓质钾（ROMK）通道（Kir 1.1）的抑制剂。公式I的化合物可用作利尿剂和钠利尿剂，因此可用于治疗和预防由过度盐和水潴留引起的疾病，包括高血压和慢性和急性心力衰竭等心血管疾病。
• INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2632465B1

  公开（公告）日：2015-12-30