(3S,4R,5R)-tert-butyl-3-(cyclopropyl-(5-isopropylpyri-din-2-yl)carbamoyl)-5-((R)-1-ethoxy-4-methylpentan-2-ylcarbamoyl)-4-hydroxypiperidine-1-carboxylate | 1093955-56-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (3S,4R,5R)-tert-butyl-3-(cyclopropyl-(5-isopropylpyri-din-2-yl)carbamoyl)-5-((R)-1-ethoxy-4-methylpentan-2-ylcarbamoyl)-4-hydroxypiperidine-1-carboxylate
• 英文别名: tert-butyl (3S,4R,5R)-3-[cyclopropyl-(5-propan-2-ylpyridin-2-yl)carbamoyl]-5-[[(2R)-1-ethoxy-4-methylpentan-2-yl]carbamoyl]-4-hydroxypiperidine-1-carboxylate
• CAS: 1093955-56-6
• 化学式: C₃₁H₅₀N₄O₆
• 分子量: 574.761
• InChiKey: DBBJSYFYNPOUFI-NRLAXTHWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3S,4R,5R)-tert-butyl-3-(cyclopropyl-(5-isopropylpyri-din-2-yl)carbamoyl)-5-((R)-1-ethoxy-4-methylpentan-2-ylcarbamoyl)-4-hydroxypiperidine-1-carboxylate 在 盐酸 作用下， 以 醋酸异丙酯 、 水 为溶剂， 反应 5.0h， 以94 g的产率得到(3S,4R,5R)-3-N-cyclopropyl-5-N-((2R)-1-ethoxy-4-methylpentan-2-yl)-4-hydroxy-3-N-(5-isopropylpyridin-2-yl)piperidine-3,5-dicarboxamide
  参考文献：
  名称：

  总伸缩合成含3,4,5-取代哌啶并带有酰胺键的肾素抑制剂的开发。

  摘要：

  描述了用于通过五步合成路线制造包含3,4,5-取代的哌啶的具有空间位阻酰胺键的肾素抑制剂的望远镜式合成。这种可扩展的合成方法的重点包括：（1）在温和的除酸剂存在下，使用Ghosez试剂进行副产物控制的酰胺化方案，以形成第一个空间位阻酰胺键。（2）位阻酯的化学选择性水解；（3）利用可溶的碳二亚胺导致第二个空间位阻酰胺键的有效酰胺化反应；（4）过滤最终药物的富马酸盐，这是整个合成过程中唯一必要的分离步骤。无需隔离任何中间体，这种伸缩式过程可以节省设备的使用，消耗更少的溶剂，并最大程度地减少了工艺废物的产生，能耗，人员暴露和环境影响。它提供了千克数量的高质量活性药物成分。

  DOI：

  10.1021/op500116w
• 作为产物：
  描述：

  (R)-tert-butyl-(1-ethoxy-4-methylpentan-2-yl)carbamate 在 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 0.5h， 生成 (3S,4R,5R)-tert-butyl-3-(cyclopropyl-(5-isopropylpyri-din-2-yl)carbamoyl)-5-((R)-1-ethoxy-4-methylpentan-2-ylcarbamoyl)-4-hydroxypiperidine-1-carboxylate
  参考文献：
  名称：

  Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors

  摘要：

  A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.

  DOI：

  10.1021/ml500137b

文献信息

• ORGANIC COMPOUNDS
  申请人：Yokokawa Fumiaki

  公开号：US20080319018A1

  公开（公告）日：2008-12-25

  The present invention relates to a compound of the formula I wherein R1, R2, R3, R4 and R5 are as defined in the specification, for use in the diagnostic and therapeutic treatment of a warm-blooded animal, especially for the treatment of a disease (=disorder) that depends on activity of renin; the use of a compound of that class for the preparation of a pharmaceutical formulation for the treatment of a disease that depends on activity of renin; the use of a compound of that class in the treatment of a disease that depends on activity of renin; pharmaceutical formulations a compound of that class; a method of treatment comprising administering a compound of that class and a method for its manufacture.

  本发明涉及一种具有以下公式I的化合物，其中R1、R2、R3、R4和R5如规范中所定义，用于诊断和治疗温血动物，特别是用于治疗依赖肾素活性的疾病；该类化合物用于制备用于治疗依赖肾素活性疾病的药物配方；该类化合物用于治疗依赖肾素活性的疾病；该类化合物的药物配方；包括给予该类化合物的治疗方法以及其制造方法。
• Development of a Total Telescoped Synthesis of a Renin Inhibitor Containing 3,4,5-Substituted Piperidine with Sterically Hindered Amide Bonds
  作者：Wen-Chung Shieh、Zhengming Du、Hongyong Kim、Yugang Liu、Mahavir Prashad

  DOI：10.1021/op500116w

  日期：2014.11.21

  telescoped synthesis for the manufacturing of a renin inhibitor containing 3,4,5-substituted piperidine with sterically hindered amide bonds via a five-step synthetic route is described. Highlights of this scalable synthesis include: (1) the byproduct-controlled amidation protocol using Ghosez’s reagent in the presence of a mild acid scavenger for the formation of the first sterically hindered amide bond;

  描述了用于通过五步合成路线制造包含3,4,5-取代的哌啶的具有空间位阻酰胺键的肾素抑制剂的望远镜式合成。这种可扩展的合成方法的重点包括：（1）在温和的除酸剂存在下，使用Ghosez试剂进行副产物控制的酰胺化方案，以形成第一个空间位阻酰胺键。（2）位阻酯的化学选择性水解；（3）利用可溶的碳二亚胺导致第二个空间位阻酰胺键的有效酰胺化反应；（4）过滤最终药物的富马酸盐，这是整个合成过程中唯一必要的分离步骤。无需隔离任何中间体，这种伸缩式过程可以节省设备的使用，消耗更少的溶剂，并最大程度地减少了工艺废物的产生，能耗，人员暴露和环境影响。它提供了千克数量的高质量活性药物成分。
• US8383650B2
  申请人：——

  公开号：US8383650B2

  公开（公告）日：2013-02-26
• US8497286B2
  申请人：——

  公开号：US8497286B2

  公开（公告）日：2013-07-30
• Structure-Based Design of Substituted Piperidines as a New Class of Highly Efficacious Oral Direct Renin Inhibitors
  作者：Takeru Ehara、Osamu Irie、Takatoshi Kosaka、Takanori Kanazawa、Werner Breitenstein、Philipp Grosche、Nils Ostermann、Masaki Suzuki、Shimpei Kawakami、Kazuhide Konishi、Yuko Hitomi、Atsushi Toyao、Hiroki Gunji、Frederic Cumin、Nikolaus Schiering、Trixie Wagner、Dean F. Rigel、Randy L. Webb、Jürgen Maibaum、Fumiaki Yokokawa

  DOI：10.1021/ml500137b

  日期：2014.7.10

  A cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model.