(3S,8AR)-2-(Tert-butoxycarbonyl)octahydropyrrolo[1,2-A]pyrazine-3-carboxylic acid | 1266229-03-1

• 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: (3S,8AR)-2-(Tert-butoxycarbonyl)octahydropyrrolo[1,2-A]pyrazine-3-carboxylic acid
• 英文别名: (3S,8aR)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-3-carboxylic acid
• CAS: 1266229-03-1
• 化学式: C₁₃H₂₂N₂O₄
• 分子量: 270.329
• InChiKey: XUCMGTQNJKIUTJ-ZJUUUORDSA-N

物化性质

• 沸点：
  404.2±45.0 °C(predicted)
• 密度：
  1.23±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.15
• 重原子数：
  19.0
• 可旋转键数：
  1.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  70.08
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (3S,8AR)-2-(Tert-butoxycarbonyl)octahydropyrrolo[1,2-A]pyrazine-3-carboxylic acid 在 盐酸 、 4-二甲氨基吡啶 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、303.99 kPa 条件下， 反应 55.0h， 生成 tert-butyl ((S)-1-(((S)-2-((3S,8aR)-3-(((R)-chroman-4-yl)carbamoyl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1-(4,4-difluorocyclohexyl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate
  参考文献：
  名称：

  Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic

  摘要：

  To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo-[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to X1AP and to cIAPI was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over X1AP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).

  DOI：

  10.1021/jm301674z
• 作为产物：
  描述：

  D-焦谷氨酸 在 盐酸 、 lithium aluminium tetrahydride 、 lithium hydroxide monohydrate 、 palladium 10% on activated carbon 、 氢气 、 碳酸氢钠 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 、 乙腈 为溶剂， 反应 36.0h， 生成 (3S,8AR)-2-(Tert-butoxycarbonyl)octahydropyrrolo[1,2-A]pyrazine-3-carboxylic acid
  参考文献：
  名称：

  Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic

  摘要：

  To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo-[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC50: 1.3 nM) and XIAP (IC50: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to X1AP and to cIAPI was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over X1AP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg).

  DOI：

  10.1021/jm301674z

文献信息

• Heterocyclic Compound
  申请人：HASHIMOTO Kentaro

  公开号：US20110034469A1

  公开（公告）日：2011-02-10

  The present invention provides a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof. The compound of the present invention shows a strong IAP antagonistic activity.

  本发明提供了一种由下式表示的化合物 其中，每个符号如说明书中所定义，或其盐。本发明的化合物表现出强烈的IAP拮抗活性。
• Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy
  作者：Abhisek Banerjee、Ranganadh Velagaleti、Sandip Patil、Mahesh Pawar、Pravin Yadav、Pradip Kadam、Mohammad Mohsin Qadri、Samitabh Chakraborti、Jagmohan S. Saini、Dayanidhi B. Behera、Keya Karanjai、Pravin S. Iyer、Laxmikant A. Gharat、Sanjib Das

  DOI：10.1016/j.bmcl.2021.128202

  日期：2021.9

  series of Cathepsin C inhibitors, we started working around AZD5248 (1), an α-amino acid based scaffold having potential liability of aortic binding. A novel series of amidoacetonitrile based Cathepsin C inhibitors were developed by the application of a conformational restriction strategy on 1. In particular, this work led to the development of a potent and selective Cathepsin C inhibitor 3p, free of

  组织蛋白酶 C 在激活与慢性炎症和自身免疫疾病中的组织破坏相关的几种降解酶中起关键作用。因此，组织蛋白酶 C 抑制剂可能成为治疗慢性阻塞性肺病 (COPD) 或急性呼吸窘迫综合征 (ARDS) 等疾病的有效疗法。在我们致力于开发一系列新型组织蛋白酶 C 抑制剂的过程中，我们开始围绕 AZD5248 ( 1 ) 工作，这是一种基于 α-氨基酸的支架，具有潜在的主动脉结合倾向。通过将构象限制策略应用于1. 特别是，这项工作导致开发了一种有效的、选择性的组织蛋白酶 C 抑制剂3p，没有主动脉约束力。