(4-(2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid) | 1365735-38-1

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: (4-(2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid)
• CAS: 1365735-38-1
• 化学式: C₁₂H₁₅NO₁₀P₂
• 分子量: 395.199
• InChiKey: FLVKJGWRDOXOFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.26
• 重原子数：
  25.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  187.5
• 氢给体数：
  5.0
• 氢受体数：
  7.0

反应信息

• 作为产物：
  描述：

  邻乙酰水杨酰氯 在 盐酸 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.67h， 生成 (4-(2,4-dioxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid)
  参考文献：
  名称：

  Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis

  摘要：

  There is an important medical need for effective therapies to redress the general bone loss associated with advanced osteoporosis. Prostaglandin E-2 and related EP4 receptor agonists have been shown to stimulate bone regrowth but their use has been limited by systemic side effects. Herein is described the design and synthesis of novel dual-action bone-targeting conjugate pro-drugs where two classes of active agents, a bone growth stimulating prostaglandin E-2 EP4 receptor subtype agonist (5 or 6) and a bone resorption inhibitor bisphosphonate, alendronic acid (1), are coupled using metabolically labile carbamate or 4-hydroxyphenylacetic acid based linkers. Radiolabelled conjugates 9, 11a/b and 25 were synthesized and evaluated in vivo in rats for uptake of the conjugate into bone and subsequent release of the EP4 agonists over time. While conjugate 11a/b was taken up (9.0% of initial dose) but not released over two weeks, conjugates 9 and 25 were absorbed at 9.4% and 5.9% uptake of the initial dose and slowly released with half-lives of approximately 2 weeks and 5 days respectively. These conjugates were well tolerated and offer potential for sustained release and dual synergistic activity through their selective bone targeting and local release of the complimentary active components. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.01.024