索拉非尼布杂质 | 757251-59-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 索拉非尼布杂质
• 英文名称: methyl 4-(4-aminophenoxy)pyridine-2-carboxylate
• 英文别名: methyl 4-(4 minophenoxy)picolinate；methyl 4-(p-aminophenoxy)pyridine-2-carboxylate；methyl 4-(4-aminophenoxy)picolinate
• CAS: 757251-59-5
• 化学式: C₁₃H₁₂N₂O₃
• 分子量: 244.25
• InChiKey: LKNOOBDGFHXDIE-UHFFFAOYSA-N

物化性质

• 沸点：
  433.7±40.0 °C(Predicted)
• 密度：
  1.262±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  74.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  索拉非尼布杂质 在 一水合肼 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 氘代甲醇-d 、 N,N-二甲基甲酰胺 为溶剂， 反应 22.0h， 生成 1-(4-(2-(2-(4-phenylphenylacetyl)hydrazinocarbonyl)pyridine-4-yloxy)phenyl)-3-(4-chloro-3-trifluoromethylphenyl)urea
  参考文献：
  名称：

  Synthesis and in vitro cytotoxic activities of sorafenib derivatives

  摘要：

  A series of novel sorafenib derivatives have been designed and synthesized. The cytotoxic activities of these compounds were tested in three tumor cell lines. Most of the compounds showed potent antiproliferative activity against the tested cell lines with IC50 = 0-20 mu mol/L. Some compounds demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines. Among them, compound 5g demonstrated significant inhibitory activity against A549, ACHN and MDA-MB-231 cell lines with IC50 values of 1.29, 1.99, 3.11 mu mol/L, respectively. (C) 2014 Zhi-Qiang Feng. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

  DOI：

  10.1016/j.cclet.2014.03.020
• 作为产物：
  描述：

  4-(p-aminophenoxy)pyridine-2-hydrazide 在 一水合肼 作用下， 以 甲醇 为溶剂， 反应 18.0h， 以1.4 g的产率得到索拉非尼布杂质
  参考文献：
  名称：

  N′-芳乙酰基邻吡啶酰肼衍生物及其制法和 药物组合物与用途

  摘要：

  本发明公开了式I所示的N′‑芳乙酰基邻吡啶酰肼衍生物，其可药用盐，及其制备方法，含有一个或多个这化合物的组合物，和该类化合物在治疗与蛋白激酶有关的疾病如免疫失调和肿瘤疾病方面的用途。

  公开号：

  CN104109121B

文献信息

• Introduction of Mercaptoethyl at Sorafenib Pyridine-2-Amide Motif as a Potentially Effective Chain to Further get Sorafenib-PEG-DGL
  作者：Ke Wang、Kudelaidi Kuerbana、Qi Wan、Zhihui Yu、Li Ye、Ying Chen

  DOI：10.3390/molecules25030573

  日期：——

  The crystal structure of the sorafenib and B-RAF complex indicates that the binding cavity occupied by the pyridine-2-carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti-cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine-2-amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC50 58.79 and 63.67 μM, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib-PEG-DGL, which could be developed as a delivery vehicle to improve the concentration of anti-tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.

  索拉非尼和B-RAF复合物的晶体结构表明，索拉非尼中吡啶-2-羧酰胺所占据的结合腔具有较大的可变空间，使其成为一个合理的修饰位点。为了寻找具有抗癌活性、更好的安全性和极性基团以供进一步应用的新化合物，设计并合成了五个具有新吡啶-2-酰胺侧链的索拉非尼类似物。初步药理研究显示，这些化合物的毒性明显低于索拉非尼。其中，携带巯基乙基基团的10b化合物在Huh7和Hela细胞系中与索拉非尼相比保持了相关的抗增殖活性，IC50值分别为58.79和63.67μM。作为靶向蛋白酪氨酸激酶的小分子抑制剂，10b化合物中的巯基可在温和条件下与马来酰亚胺发生反应，形成纳米粒子索拉非尼-PEG-DGL，可作为传递载体，提高抗肿瘤治疗药物在靶癌组织中的浓度，并在下一阶段研究中减少副作用。
• Synthesis of Mono- and Binuclear Cu(II) Complexes Bearing Unsymmetrical Bipyridine–Pyrazole–Amine Ligand and Their Applications in Azide–Alkyne Cycloaddition
  作者：Wenjing Ye、Xiao Xiao、Lan Wang、Shicheng Hou、Chun Hu

  DOI：10.1021/acs.organomet.7b00154

  日期：2017.6.12

  Mono- and binuclear Cu(II) complexes bearing an unsymmetrical bipyridine–pyrazole–amine ligand were synthesized and characterized using X-ray diffraction. The mononuclear complex could be converted to the corresponding binuclear complexes under basic conditions due to the lability of the pyrazolyl N–H. Both complexes proved to be effective catalysts for azide–alkyne cycloaddition to form triazoles

  合成了带有不对称联吡啶-吡唑-胺配体的单核和双核Cu（II）配合物，并使用X射线衍射对其进行了表征。由于吡唑基N– H的不稳定性，在基本条件下单核复合物可以转化为相应的双核复合物。。两种络合物均被证明是叠氮化物-炔烃环加成反应生成三唑的有效催化剂，双核络合物显示出比相应的单核更高的催化活性。双核络合物在低至0.0125 mol％的催化剂负载量下有效，使其成为迄今为止该反应最具活性的催化剂之一。因此，该催化剂被用于合成潜在的生物活性分子。在催化剂负载量为0.1–0.3 mol％时，以优异的产率合成了索拉非尼类似物的三种前体。一锅法反应，原位生成叠氮化物也可以使用双核络合物作为催化剂进行。带有不对称配体的过渡金属络合物可以表现出优异的催化活性，这代表了开发新型高活性催化剂的方向。
• Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs
  作者：Wenjing Ye、Qi Yao、Simiao Yu、Ping Gong、Mingze Qin

  DOI：10.3390/molecules22101759

  日期：——

  1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenoxy)-N-methylpicolinamide (8f) potently suppressed the proliferation of HT-29 cancer cells by inducing

  使用高效的双核铜配合物作为催化剂，16 个炔烃和两个叠氮化物之间的 1,3-偶极环加成反应成功进行，并产生了 25 种新的含三唑的索拉非尼类似物。几种化合物被评估为有效的抗肿瘤剂。其中，4-(4-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)phenoxy)-N-methylpicolinamide (8f) 有效抑制 HT-29 癌细胞的增殖通过诱导细胞凋亡并在低微摩尔浓度下几乎完全抑制集落形成。
• RAF KINASE INHIBITORS CONTAINING A ZINC BINDING MOIETY
  申请人：Cai Xiong

  公开号：US20080234332A1

  公开（公告）日：2008-09-25

  The present invention relates to Raf kinase inhibitors containing zinc-binding and their use in the treatment of Raf related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.

  本发明涉及含有结合锌的Raf激酶抑制剂及其在治疗Raf相关疾病和紊乱（如癌症）中的应用。所述衍生物还可能作为HDAC抑制剂。
• [EN] METHOD AND PROCESS FOR PREPARATION AND PRODUCTION OF DEUTERATED O-DIPHENYLUREA<br/>[FR] MÉTHODE ET PROCÉDÉS DE PRÉPARATION ET DE PRODUCTION DE O-DIPHÉNYLURÉE DEUTÉRÉE
  申请人：SUZHOU ZELGEN BIOPHARMACEUTICAL CO LTD

  公开号：WO2011113367A1

  公开（公告）日：2011-09-22

  Methods and processes for preparation and production of deuterated ω-diphenylure are disclosed. Especially, a kind of deuterated ω-diphenylurea compounds which can inhibit phosphokinase and the preparation method of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-1',1',1'-d3-methylcarbamoyl)-4-pyridinyloxy)phenyl)urea are disclosed. The said deuterated diphenylurea compounds can be used for treating or preventing tumors and relative diseases.

  本发明公开了制备和生产氘代ω-二苯基脲的方法和过程。特别是，公开了一种可以抑制磷酸激酶的氘代ω-二苯基脲化合物以及N-(4-氯-3-(三氟甲基)苯基)-N'-(4-(2-(N-1'，1'，1'-d3-甲基氨基甲酰)-4-吡啶氧基)苯基)脲的制备方法。所述的氘代二苯基脲化合物可用于治疗或预防肿瘤及相关疾病。