(+/-)-2-(9H-fluoren-9-yl)methyl-5-tert-butyl-2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate | 1228675-23-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (+/-)-2-(9H-fluoren-9-yl)methyl-5-tert-butyl-2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate
• 英文别名: 2-(tert-Butoxycarbonyl)-5-(9H-fluorene-9-ylmethoxycarbonyl)-2,5-diazabicyclo[4.1.0]heptane；5-O-tert-butyl 2-O-(9H-fluoren-9-ylmethyl) 2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate
• CAS: 1228675-23-7
• 化学式: C₂₅H₂₈N₂O₄
• 分子量: 420.508
• InChiKey: JPRGEENLSVYMEI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (+/-)-2-(9H-fluoren-9-yl)methyl-5-tert-butyl-2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate 在 1-辛硫醇 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙醚 为溶剂， 反应 4.0h， 以80%的产率得到(+/-)-tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate
  参考文献：
  名称：

  Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

  摘要：

  Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N'-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons-Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald-Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK(a) of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74 +/- 0.05, which is 1.3 pK(a) units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2010.02.046
• 作为产物：
  描述：

  二碘甲烷 、 1-(9H-fluoren-9-yl)methyl 4-tert-butyl 2,3-dihydropyrazine-1,4-dicarboxylate 在 diethylzinc 、 氯化铵 作用下， 以 乙醚 、 正己烷 、 水 为溶剂， 反应 18.0h， 以70%的产率得到(+/-)-2-(9H-fluoren-9-yl)methyl-5-tert-butyl-2,5-diazabicyclo[4.1.0]heptane-2,5-dicarboxylate
  参考文献：
  名称：

  Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue

  摘要：

  Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N'-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons-Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald-Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK(a) of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74 +/- 0.05, which is 1.3 pK(a) units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2010.02.046

文献信息

• Inhibitors of the renal outer medullary potassium channel
  申请人：Pasternak Alexander

  公开号：US09056859B2

  公开（公告）日：2015-06-16

  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，这些化合物是肾外髓质钾（ROMK）通道（Kir 1.1）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。
• Substituted 2,5-diazabicyclo[4.1.0]heptanes and their application as general piperazine surrogates: synthesis and biological activity of a Ciprofloxacin analogue
  作者：Rivka R.R. Taylor、Heather C. Twin、Wendy W. Wen、Rebecca J. Mallot、Alan J. Lough、Scott D. Gray-Owen、Robert A. Batey

  DOI：10.1016/j.tet.2010.02.046

  日期：2010.5

  Piperazines and modified piperazines, such as homopiperazines and 2-methylpiperazines, are found in a wide range of pharmaceutical substances and biologically active molecules. In this study 2,5-diazabicyclo[4.1.0]heptanes, in which a cyclopropane ring is fused onto a piperazine ring, are described as modified piperazine analogues. Differentially N,N'-disubstituted and N-monosubstituted compounds can be readily prepared from 2-ketopiperazine in a few steps, using a Simmons-Smith reaction of 1,2,3,4-tetrahydropyrazines with diethylzinc and diiodomethane for the key cyclopropane ring formation. An analogue of the fluoroquinolone antibacterial Ciprofloxacin was synthesized using a palladium-catalyzed Buchwald-Hartwig cross-coupling to attach the diazabicyclo[4.1.0]heptane core to the 7-position of the fluoroquinolone core. The resultant analogue was demonstrated to have similar antibacterial activity to the parent drug Ciprofloxacin. X-ray crystallographic analysis of this analogue reveals a distorted piperazine ring in the diazabicyclo[4.1.0]heptane core. The pK(a) of the conjugate acid of N-Cbz-monoprotected 2,5-diazabicyclo[4.1.0]heptane was determined to be 6.74 +/- 0.05, which is 1.3 pK(a) units lower than the corresponding N-Cbz-monoprotected piperazine compound. The lower basicity of diazabicyclo[4.1.0]heptanes is due to the electron-withdrawing character of the adjacent cyclopropane rings. The modified physicochemical and structural properties of diazabicyclo[4.1.0]heptanes relative to piperazines are expected to lead to interesting changes in the pharmacokinetic and biological activity profile of these molecules. (C) 2010 Elsevier Ltd. All rights reserved.