RA 14 | 16908-39-7

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: RA 14
• 英文别名: RA14；2,2',2'',2'''-(2,6-di-piperidin-1-yl-pyrimido[5,4-d]pyrimidine-4,8-diylbisazanediyl)-tetrakis-ethanol；N⁴,N⁴,N⁸,N⁸-tetrakis-(2-hydroxy-ethyl)-2,6-dipiperidino-pyrimido[5,4-d]pyrimidine-4,8-diyldiamine；N⁴,N⁴,N⁸,N⁸-Tetrakis-(2-hydroxy-aethyl)-2,6-dipiperidino-pyrimido[5,4-d]pyrimidin-4,8-diyldiamin；2-[[8-[Bis(2-hydroxyethyl)amino]-2,6-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4-yl]-(2-hydroxyethyl)amino]ethanol
• CAS: 16908-39-7
• 化学式: C₂₄H₄₀N₈O₄
• 分子量: 504.633
• InChiKey: YCWBGLOEGNFGDM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  145
• 氢给体数：
  4
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  2,4,6,8-四氯嘧啶并[5,4-d]嘧啶 以 四氢呋喃 为溶剂， 生成 RA 14
  参考文献：
  名称：

  Resistance-Modifying Agents. 11. Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein

  摘要：

  The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of H-3-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.

  DOI：

  10.1021/jm040772w

文献信息

• 一种2,6-双(二乙醇胺)-4,8-二哌啶-嘧啶-[5,4-d]并嘧啶的合成方法
  申请人：锁浩

  公开号：CN108752350A

  公开（公告）日：2018-11-06

  本发明公开了一种制备2，6‑双(二乙醇胺)‑4，8‑二哌啶‑嘧啶‑[5，4‑d]并嘧啶的方法，采用乳清酸作为起始原料，与现有技术的起始物质完全不同，省去了二乙醇胺的使用，从而获得的终产物为均一的目的产物，目的产物为化学式I，同时，终产物得率的提高使本发明在工业生产上变得经济实用。
• Resistance-Modifying Agents. 11. Pyrimido[5,4-<i>d</i>]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein
  作者：Nicola J. Curtin、Hannah C. Barlow、Karen J. Bowman、A. Hilary Calvert、Richard Davison、Bernard T. Golding、Bing Huang、Peter J. Loughlin、David R. Newell、Peter G. Smith、Roger J. Griffin

  DOI：10.1021/jm040772w

  日期：2004.9.1

  The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of H-3-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.