2-((2-(bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-yl)thio)pyrimidine-4,6-diamine | 1268273-27-3

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 2-((2-(bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-yl)thio)pyrimidine-4,6-diamine
• 英文别名: 2-(2-(bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-ylthio)pyrimidine-4,6-diamine；2-(2-(Bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-ylthio) pyrimidine-4,6-diamine；2-[2-[bis[(4-methoxyphenyl)methyl]amino]-4,6-diethoxypyrimidin-5-yl]sulfanylpyrimidine-4,6-diamine
• CAS: 1268273-27-3
• 化学式: C₂₈H₃₃N₇O₄S
• 分子量: 563.681
• InChiKey: DLOKUYYLDQGBIB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  169
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  2-((2-(bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-yl)thio)pyrimidine-4,6-diamine 在 4-二甲氨基吡啶 正己烷 、 乙酸乙酯 作用下， 以 乙酸酐 为溶剂， 反应 2.0h， 以to afford 1.2 g (89%) of 32的产率得到N,N′-(2-((2-(bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-yl)thio)pyrimidine-4,6-diyl)diacetamide
  参考文献：
  名称：

  HEAT SHOCK PROTEIN BINDING COMPOUNDS, COMPOSITIONS, AND METHODS FOR MAKING AND USING SAME

  摘要：

  本主题涉及一种由通式(I)或(I′)表示的化合物或其药学上可接受的盐；包含至少一种这些化合物的制药组合物；制备至少一种这些化合物的方法；使用至少一种这些化合物治疗和/或预防各种癌症和/或增殖障碍的方法；使用至少一种这些化合物监测抗癌治疗对各种癌症的有效性的方法。在一种实施方式中，本主题涉及与热休克蛋白70（Hsp70）具有特异性结合的化合物。在另一种实施方式中，本主题涉及与具有特异性抑制热休克蛋白70（Hsp70）和热休克同源蛋白70（Hsc70）的化合物的结合。

  公开号：

  US20120252818A1
• 作为产物：
  描述：

  4,6-diethoxy-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine 在 N-碘代丁二酰亚胺 、 copper(l) iodide 、 新铜试剂 、 potassium carbonate 作用下， 以 二甲基亚砜 、 乙腈 为溶剂， 反应 17.0h， 生成 2-((2-(bis(4-methoxybenzyl)amino)-4,6-diethoxypyrimidin-5-yl)thio)pyrimidine-4,6-diamine
  参考文献：
  名称：

  Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5-(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70

  摘要：

  Heat shock protein 70 (Hsp70) is an important emerging. cancer. target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5'-thiodipyrimidine and 5-(phenylthio)-pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives 17a and 20a, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics.

  DOI：

  10.1021/jm401551n

文献信息

• Heat shock protein binding compounds, compositions, and methods for making and using same
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：US10052325B2

  公开（公告）日：2018-08-21

  The present subject matter relates to a compound represented by the general formula (I) or (I′) or a pharmacologically acceptable salt thereof; pharmaceutical compositions containing at least one of these compounds; methods of making at least one of these compounds; methods of using at least one of these compounds for treating and/or preventing various cancers and/or proliferation disorders; methods of using at least one of these compounds for monitoring the effectiveness of an anticancer therapy against various cancers. In one embodiment, the subject matter relates to compounds that bind with a level of specificity to heat shock protein 70 (Hsp70). In another embodiment, the subject matter relates to compounds that bind with a level of specificity to inhibit both heat shock protein 70 (Hsp70) and heat shock cognate protein 70 (Hsc70).

  本主题涉及通式(I)或(I′)代表的化合物或其药理学上可接受的盐；含有至少一种这些化合物的药物组合物；制造至少一种这些化合物的方法；使用至少一种这些化合物治疗和/或预防各种癌症和/或增殖障碍的方法；使用至少一种这些化合物监测抗癌疗法对各种癌症的疗效的方法。在一个实施方案中，该主题涉及与热休克蛋白 70（Hsp70）具有一定特异性结合的化合物。在另一个实施方案中，本发明涉及的化合物具有一定程度的特异性，可同时抑制热休克蛋白70（Hsp70）和热休克同源蛋白70（Hsc70）。
• [EN] HEAT SHOCK PROTEIN BINDING COMPOUNDS, COMPOSITIONS, AND METHODS FOR MAKING AND USING SAME<br/>[FR] COMPOSÉS DE LIAISON À UNE PROTÉINE DE CHOC THERMIQUE, COMPOSITIONS ET PROCÉDÉS POUR LES FABRIQUER ET LES UTILISER
  申请人：MEMORIAL SLOAN KETTERING CANCER CENTER

  公开号：WO2011022440A9

  公开（公告）日：2016-11-10
• 2-(Pyrimidin-5-yl)-thiopyrimidine derivatives as Hsp70 and Hsc70 modulators for the treatment of proliferative disorders
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：EP2467142B1

  公开（公告）日：2016-09-21
• EP3205647A2
  申请人：——

  公开号：EP3205647A2

  公开（公告）日：2017-08-16
• 2-(PYRIMIDIN-5-YL)-THIOPYRIMIDINE DERIVATIVES AS HSP70 AND HSC70 MODULATORS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS
  申请人：Memorial Sloan-Kettering Cancer Center

  公开号：EP3205647B1

  公开（公告）日：2020-05-13