Az08931 2-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-n-甲基乙酰胺 | 848942-61-0

• 物质功能分类: 生物化工 - 抑制剂 - 蛋白酪氨酸激酶
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: Az08931 2-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-n-甲基乙酰胺
• 中文别名: Az089312-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-n-甲基乙酰胺；2-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-N-甲基乙酰胺；沙普替尼；EGFR抑制剂(SAPITINIB)；AZ089312-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-N-甲基乙酰胺；4-(3-氯-2-氟苯胺基)-7-甲氧基-6-[[1-(N-甲基氨基甲酰甲基)哌啶-4-基]氧基]喹唑啉；AZD8931(Sapitinib)抑制剂；AZD8931；AZD-8931
• 英文名称: Sapitinib
• 英文别名: 2-(4-[4-(3-chloro-2-fluoro[U-14C]-phenylamino)-7-methoxy-quinazolin-6-yloxy]-piperidin-1-yl)-N-methyl-acetamide difumarate；2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide；4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline；2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-N-methylacetamide；sapatinib；2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-N-methylacetamide
• CAS: 848942-61-0
• 化学式: C₂₃H₂₅ClFN₅O₃
• 分子量: 473.935
• InChiKey: DFJSJLGUIXFDJP-UHFFFAOYSA-N

物化性质

• 沸点：
  632.8±55.0 °C(Predicted)
• 密度：
  1.339
• 溶解度：
  DMSO 中≥23.7 mg/mL；不溶于水；温和加热时，EtOH 中≥57.8 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  88.6
• 氢给体数：
  2
• 氢受体数：
  8

安全信息

• 危险性防范说明：
  P280,P305+P351+P338
• 危险性描述：
  H302

制备方法与用途

生物活性

Sapitinib (AZD8931) 是一种可逆的、ATP 竞争性 EGFR、ErbB2 和 ErbB3 抑制剂，在无细胞试验中 IC50 值分别为 4 nM、3 nM 和 4 nM。与 Gefitinib 或 Lapatinib 相比，AZD8931 在作用于 NSCLC 细胞方面更为有效，并且对 ErbB 家族的选择性是 MNK1 和 Flt 的 100 倍。该药物处于二期临床试验阶段。

靶点

• ErbB2 (无细胞试验): 3 nM
• EGFR (无细胞试验): 4 nM
• ErbB3 (无细胞试验): 4 nM

体外研究

AZD8931 在 NSCLC 和 SCCHN 细胞系中的作用效果有所不同。在 PC-9 细胞（EGFR 激活突变型）中，AZD8931 的 GI50 值为 0.1 nM；而在 NCI-1437 细胞中活性较低，GI50 大于 10 μM。与 Lapatinib 或 Gefitinib 相比，AZD8931 对 PE/CA-PJ41、PE/CA-PJ49、DOK 和 FaDu 细胞的作用更有效，能更显著地抑制 p-EGFR、p-ErbB2 和 p-ErbB3。

体内研究

在 BT474c、Calu-3、LoVo、FaDu 和 PC-9 移植瘤中，AZD8931 表现出抗肿瘤活性。急性处理 BT474c 移植瘤后，观察到 p-AKT 和 Ki67 的表达降低及 p-ERK 的减少。此外，与 Gefitinib 和 Lapatinib 相比，AZD8931 在治疗 LoVo 移植瘤时表现出更有效的促凋亡作用，并诱导产生 M30 凋亡标记。

反应信息

• 作为反应物：
  描述：

  Az08931 2-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-n-甲基乙酰胺 在 lithium chloride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  The first radiosynthesis of [ 11 C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling

  摘要：

  The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl)oxy) piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [C-11] AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl)-N-[C-11] methylacetamide} ([C-11]11a) was prepared from N-desmethyl-AZD8931 (11b) with [C-11]CH3OTf under basic condition (NaH) through N-[11C] methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [C-11]CO2 and decay corrected to end of bombardment (EOB) with 370-1110 GBq/mu mol specific activity at EOB. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.07.092
• 作为产物：
  描述：

  2-氨基-4,5-二甲氧基苯甲酸乙酯 在 吡啶 、 4-二甲氨基吡啶 、 甲烷磺酸 、 L-蛋氨酸 、 氨 、 potassium carbonate 、 cesium fluoride 、 N,N-二乙基苯胺 、 potassium iodide 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 N,N-二甲基乙酰胺 、 水 、 异丙醇 、 乙腈 为溶剂， 反应 62.0h， 生成 Az08931 2-(4-(4-(3-氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)-n-甲基乙酰胺
  参考文献：
  名称：

  The first radiosynthesis of [ 11 C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling

  摘要：

  The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl)oxy) piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2-5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl) acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2-4% overall chemical yield. The target tracer [C-11] AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl) amino)-7-methoxyquinazolin-6-yl) oxy) piperidin-1-yl)-N-[C-11] methylacetamide} ([C-11]11a) was prepared from N-desmethyl-AZD8931 (11b) with [C-11]CH3OTf under basic condition (NaH) through N-[11C] methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [C-11]CO2 and decay corrected to end of bombardment (EOB) with 370-1110 GBq/mu mol specific activity at EOB. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.07.092

文献信息

• [EN] QUINAZOLINE DERIVATIVES<br/>[FR] DERIVES DE QUINAZOLINE
  申请人：ASTRAZENECA AB

  公开号：WO2005028469A1

  公开（公告）日：2005-03-31

  The invention concerns quinazoline derivatives of Formula (I): wherein each of R1, X1, R2, R3, R5, n and m have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of EGF and erbB receptor tyrosine kinases.

  这项发明涉及式(I)的喹唑啉衍生物：其中R1、X1、R2、R3、R5、n和m中的每一个具有描述中定义的任意含义；它们的制备方法，含有它们的药物组合物以及它们在制造用作抗增殖剂的药物时的用途，用于预防或治疗对EGF和erbB受体酪氨酸激酶抑制敏感的肿瘤。
• The Development of a Dimroth Rearrangement Route to AZD8931
  作者：William R. F. Goundry、Kay Boardman、Oliver Cunningham、Matthew Evans、Martin F. Jones、Kirsty Millard、Raquel Rozada-Sanchez、Yvonne Sawyer、Paul Siedlecki、Brian Whitlock

  DOI：10.1021/acs.oprd.6b00412

  日期：2017.3.17

  Synthetic methods are required to make this structure on a multikilo scale and in high purity. The initial route to aminoquinazoline AZD8931 suffered from the formation of late-stage impurities. To avoid these impurities, a new high-yielding Dimroth rearrangement approach to the aminoquinazoline core of AZD8931 was developed. Assessment of route options on a gram scale demonstrated that the Dimroth rearrangement

  最近，氨基喹唑啉基序已在抗癌药物化合物中高度流行。需要合成方法以多公斤级的规模和高纯度制造该结构。制备氨基喹唑啉AZD8931的最初途径是后期杂质的形成。为避免这些杂质，开发了一种新的高产Dimroth重排方法，用于AZD8931的氨基喹唑啉核心。以克为单位的路线选项评估表明，Dimroth重排是一种可行的方法。然后从一公斤的战役和两家工厂规模的制造商那里学习，逐步发展了该工艺以进行大规模生产。关键工艺杂质的鉴定为Dimroth重排以及关键中间体加氢的机理提供了见解。
• NOVEL SALT-554
  申请人：Dobson Andrew Hornby

  公开号：US20090286982A1

  公开（公告）日：2009-11-19

  4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate, pharmaceutical compositions containing the difumarate, the use of the difumarate in the treatment of hyperproliferative disorders such as cancer and processes for the manufacture of the difumarate are described.

  描述了含有二富马酸的4-(3-氯-2-氟苯胺基)-7-甲氧基-6-[1-(N-甲基氨甲酰基甲基)哌啶-4-基]氧基}喹唑啉的制药组合物，以及二富马酸在治疗癌症等高增殖性疾病中的用途，以及制备二富马酸的方法。
• [EN] 3 -CYANO- 5 -ARYLAMINO-7 -CYCLOALKYLAMINOPYRROLO [1, 5 -A] PYRIMIDINE DERIVATIVES AND THEIR USE AS ANTITUMOR AGENTS<br/>[FR] DÉRIVÉS DE PYRIMIDINE 3-CYANO-5-ARYLAMINO -7-CYCLOALKYLAMINOPYRROLO [1, 5-A] ET LEURS UTILISATIONS COMME AGENTS ANTITUMORAUX
  申请人：ASTRAZENECA AB

  公开号：WO2013144532A1

  公开（公告）日：2013-10-03

  The invention relates to chemical compounds of Formula (I): or a salt thereof. In some embodiments, the invention relates to inhibitors of CK2. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein and their use in the prevention and treatment of CK2-related conditions and diseases, e.g., cancer.

  该发明涉及化合物的化学结构式(I)：或其盐。在某些实施例中，该发明涉及CK2的抑制剂。在更进一步的实施例中，该发明涉及包括本文披露的化合物的药物组合物及其在预防和治疗与CK2相关的疾病和疾病，例如癌症中的应用。
• Quinazoline Inhibitors of activating mutant forms of Epidermal Growth Factor Receptor
  申请人：AstraZeneca AB

  公开号：US20150320751A1

  公开（公告）日：2015-11-12

  The invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof: which possess inhibitory activity against activating mutant forms of EGFR, and are accordingly useful for their anti-cancer activity and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of the compounds, or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.

  该发明涉及公式（I）的化合物或其药学上可接受的盐：该化合物具有抑制EGFR活化突变形式的活性，因此在抗癌活性及人体或动物体的治疗方法中有用。该发明还涉及制造该化合物或其药学上可接受的盐的过程，包含它们的制药组成物以及它们在制造用于在温血动物（如人）中产生抗癌效果的药物中的应用。