2,6-dichloro-4,8-di-morpholin-4-yl-pyrimido[5,4-d]pyrimidine | 54093-81-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2,6-dichloro-4,8-di-morpholin-4-yl-pyrimido[5,4-d]pyrimidine
• 英文别名: 2,6-Dichlor-4,8-dimorpholino-pyrimido[5,4-d]pyrimidin；4-(2,6-Dichloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl)morpholine
• CAS: 54093-81-1
• 化学式: C₁₄H₁₆Cl₂N₆O₂
• 分子量: 371.226
• InChiKey: CKEDESQLMAKPDI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  76.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2,6-dichloro-4,8-di-morpholin-4-yl-pyrimido[5,4-d]pyrimidine 、 C.I.酸性橙108 以 二甲基亚砜 为溶剂， 反应 6.0h， 以211 mg的产率得到2-({6-[(2-Hydroxyethyl)amino]-4,8-bis(morpholin-4-yl)pyrimido[5,4-d][1,3]diazin-2-yl}amino)ethan-1-ol
  参考文献：
  名称：

  Synthesis, Flow Cytometric Evaluation, and Identification of Highly Potent Dipyridamole Analogues as Equilibrative Nucleoside Transporter 1 Inhibitors

  摘要：

  Dipyridamole (Persantine) is a clinically used vasodilator with equilibrative nucleoside transporters I and 2 (ENT1 and ENT2) inhibitory activity albeit less potent than the prototype ENT1 inhibitor nitrobenzylmercaptopurine riboside (NBMPR). Dipyridamole is a good candidate for further exploration because it is a non-nucleoside and has a proven record of safe use in humans. A series of dipyridamole analogues were synthesized with systematic modification and evaluated as ENT1 inhibitors by flow cytometry. Compounds with much higher potency were identified, the best being 2,6-bis(diethanolamino)-4,8-diheptamethylene-iminopyrimido[5,4-d]pyrimidine (13) with a K-i of 0.49 nM compared to a Ki of 308 nM for dipyridamole. Compound 13 is similar in potency to the prototype potent ENT1 inhibitor NBMPR (0.43 nM). For the first time, a dipyridamole analogue has been identified that is equipotent with NBMPR. The SAR indicated that diethanolamine substituted analogues were more active than monoethanolamine compounds. Also, free hydroxyl groups are not essential for activity.

  DOI：

  10.1021/jm070311l
• 作为产物：
  描述：

  2,4,6,8-四羟基嘧啶并[5,4-D]嘧啶 在 五氯化磷 、 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 2,6-dichloro-4,8-di-morpholin-4-yl-pyrimido[5,4-d]pyrimidine
  参考文献：
  名称：

  发现具有增强代谢稳定性的双嘧达莫类似物治疗特发性肺纤维化

  摘要：

  双嘧达莫除了具有众所周知的抗血小板和磷酸二酯酶抑制活性外，还是一种很有前途的治疗肺纤维化的老药。然而，双嘧达莫在大鼠肝微粒体 (RLM) 中显示出较差的药代动力学特性，半衰期 (T 1/2 ) 为 7 分钟。为了提高双嘧达莫的代谢稳定性，在分子对接的帮助下设计了一系列嘧啶并嘧啶衍生物。在所有 24 种合成化合物中，化合物( S )-4h在 RLM 中表现出出色的代谢稳定性（T 1/2 = 67 min），IC 50对 PDE5 的 332 nM。此外，在分子对接的帮助下解释了一些有趣的构效关系（SAR）。

  DOI：

  10.3390/molecules27113452

文献信息

• GB807826
  申请人：——

  公开号：——

  公开（公告）日：——
• US6232312B1
  申请人：——

  公开号：US6232312B1

  公开（公告）日：2001-05-15
• Synthesis, Flow Cytometric Evaluation, and Identification of Highly Potent Dipyridamole Analogues as Equilibrative Nucleoside Transporter 1 Inhibitors
  作者：Wenwei Lin、John K. Buolamwini

  DOI：10.1021/jm070311l

  日期：2007.8.1

  Dipyridamole (Persantine) is a clinically used vasodilator with equilibrative nucleoside transporters I and 2 (ENT1 and ENT2) inhibitory activity albeit less potent than the prototype ENT1 inhibitor nitrobenzylmercaptopurine riboside (NBMPR). Dipyridamole is a good candidate for further exploration because it is a non-nucleoside and has a proven record of safe use in humans. A series of dipyridamole analogues were synthesized with systematic modification and evaluated as ENT1 inhibitors by flow cytometry. Compounds with much higher potency were identified, the best being 2,6-bis(diethanolamino)-4,8-diheptamethylene-iminopyrimido[5,4-d]pyrimidine (13) with a K-i of 0.49 nM compared to a Ki of 308 nM for dipyridamole. Compound 13 is similar in potency to the prototype potent ENT1 inhibitor NBMPR (0.43 nM). For the first time, a dipyridamole analogue has been identified that is equipotent with NBMPR. The SAR indicated that diethanolamine substituted analogues were more active than monoethanolamine compounds. Also, free hydroxyl groups are not essential for activity.
• Discovery of Dipyridamole Analogues with Enhanced Metabolic Stability for the Treatment of Idiopathic Pulmonary Fibrosis
  作者：Meng-Xing Huang、Yan-Quan Chen、Run-Duo Liu、Yue Huang、Chen Zhang

  DOI：10.3390/molecules27113452

  日期：——

  Dipyridamole, apart from its well-known antiplatelet and phosphodiesterase inhibitory activities, is a promising old drug for the treatment of pulmonary fibrosis. However, dipyridamole shows poor pharmacokinetic properties with a half-life (T1/2) of 7 min in rat liver microsomes (RLM). To improve the metabolic stability of dipyridamole, a series of pyrimidopyrimidine derivatives have been designed with

  双嘧达莫除了具有众所周知的抗血小板和磷酸二酯酶抑制活性外，还是一种很有前途的治疗肺纤维化的老药。然而，双嘧达莫在大鼠肝微粒体 (RLM) 中显示出较差的药代动力学特性，半衰期 (T 1/2 ) 为 7 分钟。为了提高双嘧达莫的代谢稳定性，在分子对接的帮助下设计了一系列嘧啶并嘧啶衍生物。在所有 24 种合成化合物中，化合物( S )-4h在 RLM 中表现出出色的代谢稳定性（T 1/2 = 67 min），IC 50对 PDE5 的 332 nM。此外，在分子对接的帮助下解释了一些有趣的构效关系（SAR）。