4-chloro-3-((7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)benzene-1,2-diol | 1241906-33-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 4-chloro-3-((7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)benzene-1,2-diol
• CAS: 1241906-33-1
• 化学式: C₂₆H₃₂ClN₅O₅
• 分子量: 530.024
• InChiKey: OMZDJNOCGGOSRJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.62
• 重原子数：
  37.0
• 可旋转键数：
  8.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  112.44
• 氢给体数：
  3.0
• 氢受体数：
  10.0

反应信息

• 作为产物：
  描述：

  四氢吡喃-4-醇 在 偶氮二甲酸二叔丁酯 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 12.12h， 生成 4-chloro-3-((7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-yl)amino)benzene-1,2-diol
  参考文献：
  名称：

  Process Research and Development for the Kilogram Manufacture of the SRC Kinase Inhibitor AZD0530

  摘要：

  Process research and development of a synthetic route towards a novel SRC kinase inhibitor is described. The Medicinal Chemistry route was very long and suffered from extensive use of chlorinated solvents and chromatography. A number of steps in the Medicinal Chemistry route were also unattractive for large-scale use for a variety of reasons. The route was modified to produce a shorter synthetic scheme that started from more readily available materials. By using the modified route, the title compound was manufactured on kilogram scale without recourse to chromatography and in significantly fewer steps. The scaled synthesis required two Mitsunobu couplings, which were developed and scaled successfully. An interesting hydrazine impurity was identified in the second Mitsunobu coupling; a mechanism for its formation is proposed, and a method for its control is described. The formation and control of some other interesting impurities are also described.

  DOI：

  10.1021/op100161y

文献信息

• Cytochrome P450 Mediated Bioactivation of Saracatinib
  作者：Jiaming Chen、Ying Peng、Jiang Zheng

  DOI：10.1021/acs.chemrestox.6b00242

  日期：2016.11.21

  Saracatinib is a highly selective Src kinase inhibitor against all Src kinase family members and has demonstrated anticancer effects in preclinical models. Unfortunately, it has shown multiple adverse effects during its clinical trials, along with time-dependent inhibition of P450 enzymes. The major objective of this study was to identify reactive metabolites of saracatinib in vitro and in vivo. Four oxidative metabolites (M1–M4) were detected in rat and human liver microsomal incubation systems after exposure to saracatinib. An ortho-quinone-derived reactive metabolite existing as a GSH conjugate (M5) was found in microsomes fortified with GSH as a trapping agent. The formation of the metabolites detected was NADPH dependent. Metabolites M2–M4 were also observed in bile and urine of rats given saracatinib, and M5 was only detected in bile. Inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the primary enzyme responsible for the metabolic activation of saracatinib. The metabolism study facilitates the understanding of correlation between saracatinib-induced hepatotoxicity and bioactivation.

  萨拉卡替尼是一种高度选择性的Src激酶抑制剂，作用于所有Src激酶家族成员，并在临床前模型中表现出抗癌效果。不幸的是，它在临床试验中显示出多种不良反应，并伴随对P450酶的时间依赖性抑制。本研究的主要目标是识别萨拉卡替尼在体外和体内的反应性代谢物。在大鼠和人类肝脏微粒体培养体系中，暴露于萨拉卡替尼后检测到四种氧化代谢物（M1-M4）。在添加了谷胱甘肽（GSH）作为捕获剂的微粒体中，发现一种来源于邻醌的反应性代谢物以GSH结合物的形式存在（M5）。检测到的代谢物的形成依赖于NADPH。给予萨拉卡替尼的大鼠胆汁和尿液中也观察到代谢物M2-M4，而M5仅在胆汁中被检测到。抑制实验和重组P450酶的孵育研究表明，P450 3A4是负责萨拉卡替尼代谢激活的主要酶。该代谢研究有助于理解萨拉卡替尼引起的肝毒性与生物活化之间的关系。