3-chloro-4,5-dihydro-3H-pyrazole-3-carbonitrile | 681128-28-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-chloro-4,5-dihydro-3H-pyrazole-3-carbonitrile
• 英文别名: 5-Chloro-3,4-dihydropyrazole-5-carbonitrile
• CAS: 681128-28-9
• 化学式: C₄H₄ClN₃
• 分子量: 129.549
• InChiKey: RWKDYPSPFQHOKO-UHFFFAOYSA-N

物化性质

• 沸点：
  224.5±40.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  8
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  48.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-chloro-4,5-dihydro-3H-pyrazole-3-carbonitrile 以 苯 为溶剂， 反应 16.0h， 生成 2-chlorobut-2-enenitrile 、 1-chlorocyclopropanecarbonitrile
  参考文献：
  名称：

  Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability

  摘要：

  Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the PI position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (K-i = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg). (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.06.040
• 作为产物：
  描述：

  1-甲基-3-硝基-1-亚硝基胍 、 2-氯丙烯腈 在 氢氧化钾 作用下， 以 乙醚 、 水 为溶剂， 反应 0.5h， 生成 3-chloro-4,5-dihydro-3H-pyrazole-3-carbonitrile
  参考文献：
  名称：

  Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability

  摘要：

  Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the PI position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (K-i = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg). (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.06.040