7-bis{[(isopropoxycarbonyl)oxy]methyl}-{2-[8,9dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 7-bis{[(isopropoxycarbonyl)oxy]methyl}-{2-[8,9dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate
• 英文别名: {2-[8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonic acid di[(isopropoxycarbonyl)methyl] ester；[2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate
• 化学式: C₁₉H₂₉N₂O₁₁P
• 分子量: 492.42
• InChiKey: RUSWEGNWNKRMNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  33
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  156
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  7-bis{[(isopropoxycarbonyl)oxy]methyl}-{2-[8,9dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate 以 乙腈 为溶剂， 反应 24.0h， 生成
  参考文献：
  名称：

  Prodrugs of Perzinfotel with Improved Oral Bioavailability

  摘要：

  Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic Studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by. a 30 mg/kg oral dose of L Consistent with these results, 3a was significantly more potent and had a longer duration of activity than I following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

  DOI：

  10.1021/jm8011799
• 作为产物：
  描述：

  环己基甲酸氯甲酯 、 [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]-phosphonic Acid 在 N,N-二异丙基乙胺 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 24.5h， 生成 7-bis{[(isopropoxycarbonyl)oxy]methyl}-{2-[8,9dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl}phosphonate
  参考文献：
  名称：

  [EN] DERIVATIVES OF 2-(8,9-DIOXO-2,6-DIAZABICYCLO(5.2.0)NON-1(7)-EN-2-YL)ALKYL PHOSPHONIC ACID AND THEIR USE AS N-METHYL-D-ASPARTATE (NMDA) RECETOR ANTAGONISTS
  [FR] DERIVES D'ACIDE 2-(8,9-DIOXO-2,6-DIAZABICYCLO(5.2.0)NON-1(7)-EN-2-YL)ALKYL PHOSPHONIQUE ET LEUR UTILISATION COMME ANTAGONISTES DU RECEPTEUR N-METHYL-D-ASPARTATE (NMDA)

  摘要：

  提供了式（I）的化合物或其药用可接受的盐，其中R2或R3中至少有一个不是氢。本发明的化合物是N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，对治疗受益于抑制NMDA受体的哺乳动物中存在的各种疾病是有用的。

  公开号：

  WO2004092189A1

文献信息

• Prodrugs of Perzinfotel with Improved Oral Bioavailability
  作者：Reinhardt B. Baudy、John A. Butera、Magid A. Abou-Gharbia、Hong Chen、Boyd Harrison、Uday Jain、Ronald Magolda、Jean Y. Sze、Michael R. Brandt、Terri A. Cummons、Diane Kowal、Menelas N. Pangalos、Bojana Zupan、Matthew Hoffmann、Michael May、Cheryl Mugford、Jeffrey Kennedy、Wayne E. Childers

  DOI：10.1021/jm8011799

  日期：2009.2.12

  Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3-5%), prodrug derivatives (3a-h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic Studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by. a 30 mg/kg oral dose of L Consistent with these results, 3a was significantly more potent and had a longer duration of activity than I following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.
• [EN] DERIVATIVES OF 2-(8,9-DIOXO-2,6-DIAZABICYCLO(5.2.0)NON-1(7)-EN-2-YL)ALKYL PHOSPHONIC ACID AND THEIR USE AS N-METHYL-D-ASPARTATE (NMDA) RECETOR ANTAGONISTS<br/>[FR] DERIVES D'ACIDE 2-(8,9-DIOXO-2,6-DIAZABICYCLO(5.2.0)NON-1(7)-EN-2-YL)ALKYL PHOSPHONIQUE ET LEUR UTILISATION COMME ANTAGONISTES DU RECEPTEUR N-METHYL-D-ASPARTATE (NMDA)
  申请人：WYETH CORP

  公开号：WO2004092189A1

  公开（公告）日：2004-10-28

  Compounds of formula (I) or pharmaceutically acceptable salts thereof are provided where at least one of R2 or R3 is not hydrogen. The compounds of the present invention are N-methyl-D-aspartate (NMDA) receptor antagonists and are useful in treating a variety of conditions present in a mammal that benefit from inhibiting the NMDA receptor.

  提供了式（I）的化合物或其药用可接受的盐，其中R2或R3中至少有一个不是氢。本发明的化合物是N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，对治疗受益于抑制NMDA受体的哺乳动物中存在的各种疾病是有用的。