2-[2-(2-2-[4-(3-bromo-phenylamino)-6-nitro-quinazolin-7-yloxy]-ethoxyethoxy)-ethoxy]-ethanol | 936942-17-5

• 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: 2-[2-(2-2-[4-(3-bromo-phenylamino)-6-nitro-quinazolin-7-yloxy]-ethoxyethoxy)-ethoxy]-ethanol
• 英文别名: 2-(2-(2-(2-(4-(3-Bromophenylamino)-6-nitroquinazolin-7-yloxy)ethoxy)ethoxy)ethoxy)ethanol；2-[2-[2-[2-[4-(3-bromoanilino)-6-nitroquinazolin-7-yl]oxyethoxy]ethoxy]ethoxy]ethanol
• CAS: 936942-17-5
• 化学式: C₂₂H₂₅BrN₄O₇
• 分子量: 537.367
• InChiKey: ZLOZOYNXLGCZPK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  34
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  141
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-[2-(2-2-[4-(3-bromo-phenylamino)-6-nitro-quinazolin-7-yloxy]-ethoxyethoxy)-ethoxy]-ethanol 在 吡啶 、 potassium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.5h， 生成 7-[2-[2-[2-[2-[3,5-bis(trifluoromethyl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]-N-(3-bromophenyl)-6-nitroquinazolin-4-amine
  参考文献：
  名称：

  JP5676853

  摘要：

  公开号：
• 作为产物：
  描述：

  13,13,14,14-四甲基-3,6,9,12-四氧杂-13-硅-1-十五醇 、 4-[(3-bromophenyl)amino]-7-fluoro-6-nitro-quinazoline 在 potassium trimethylsilonate 、 水 作用下， 以 二甲基亚砜 、 乙酸乙酯 为溶剂， 反应 2.0h， 以48%的产率得到2-[2-(2-2-[4-(3-bromo-phenylamino)-6-nitro-quinazolin-7-yloxy]-ethoxyethoxy)-ethoxy]-ethanol
  参考文献：
  名称：

  Modified PEG-anilinoquinazoline derivatives as potential EGFR PET agents

  摘要：

  表皮生长因子受体酪氨酸激酶(EGFR-TK)的抑制已成为癌症靶向治疗的主要方法。因此,对于使用标记的EGFR-TK抑制剂作为正电子发射断层扫描(PET)成像剂产生了极大的兴趣。目前,开发的代理并未产生充分的动物模型的PET成像,可能由于其较差的溶解性、从血液中快速洗脱和在体内低稳定性。为了克服这些障碍,设计并合成了先前报道的抑制剂(ML04, 2)的新衍生物,这些衍生物具有减小的log P和增加的溶解性。这些化合物(3–5)显示出高的自磷酸化抑制效力,IC50值为5–35 nM,相对先前报道的母体化合物2(log P=3.7,溶解性=3.5 µg/mL),具有减小的log P(分别为3.1,3.34和3.45)和显著增加的溶解性(分别为630,300和120 µg/mL)。化合物5与[18F]、化合物3和4分别与[11C]和[124I]的标记涉及一步放射合成。化合物3–5获得的总衰变校正放射化学产率分别为13%,31%和5%,发现它们在血液中稳定。化合物3–5获得的正面结果值得进一步作为PET生物探针进行体内评估。版权所有 © 2008 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.1569

文献信息

• Polyalkylene glycol derivatives of inhibitors of epidermal growth factor receptor tyrosine kinase
  申请人：Mishani Eyal

  公开号：US20080056990A1

  公开（公告）日：2008-03-06

  Novel epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors, pharmaceutical compositions including same and their use in the treatment of EGFR-TK related diseases or disorders are disclosed. Novel radiolabeled EGFR-TK inhibitors as their use as biomarkers for medicinal radioimaging such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) and as radiopharmaceuticals for radiotherapy are further disclosed. The disclosed EGFR-TK inhibitors comprise a polyalkylene glycol moiety and/or a hydroxy-containing moiety and are characterized by improved solubility, biostability and bioavailability. Processes of preparing the disclosed EGFR-TK inhibitors and of radiolabeling same, via, for example, one-step radiosyntheses, are also disclosed.

  本发明揭示了新型表皮生长因子受体酪氨酸激酶（EGFR-TK）抑制剂，包括同样的药物组合物及其在治疗EGFR-TK相关疾病或疾病中的应用。进一步揭示了新型放射性标记的EGFR-TK抑制剂，以及它们作为医学放射成像（如正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT））的生物标记物的应用，以及作为放射性药物用于放射治疗。所揭示的EGFR-TK抑制剂包括聚烷基醚基团和/或含羟基的基团，并具有改善的溶解性、生物稳定性和生物利用度。还揭示了制备所述EGFR-TK抑制剂和放射性标记同样的过程，例如一步放射合成。
• POLYALKYLENE GLYCOL DERIVATIVES OF 4 - (PHENYLAMINO)QUINAZOLINES USEFUL AS IRREVERSIBLE INHIBITORS OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE
  申请人：T.K. Signal Ltd.

  公开号：EP1957468A2

  公开（公告）日：2008-08-20
• US8461166B2
  申请人：——

  公开号：US8461166B2

  公开（公告）日：2013-06-11
• [EN] POLYALKYLENE GLYCOL DERIVATIVES OF IRREVERSIBLE INHIBITORS OF EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE<br/>[FR] DERIVES POLYALKYLENE-GLYCOL D'INHIBITEURS IRREVERSIBLES DE LA TYROSINE KINASE DU RECEPTEUR DU FACTEUR DE CROISSANCE EPIDERMIQUE
  申请人：T K SIGNAL LTD

  公开号：WO2007029251A2

  公开（公告）日：2007-03-15

  [EN] Novel epidermal growth factor receptor tyrosine kinase (EGFR-TK) irreversible inhibitors, pharmaceutical compositions including same and their use in the treatment of EGFR-TK related diseases or disorders are disclosed. Novel radiolabeled EGFR-TK irreversible inhibitors as their use as biomarkers for medicinal radioimaging such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) and as radiopharmaceuticals for radiotherapy are further disclosed. The disclosed EGFR-TK irreversible inhibitors comprise a polyalkylene glycol moiety and are characterized by improved solubility, biostability and bioavailability.
  [FR] L'invention concerne de nouveaux inhibiteurs irréversibles de la tyrosine kinase du récepteur du facteur de croissance épidermique (EGFR-TK); des compositions pharmaceutiques comprenant ces inhibiteurs et l'utilisation des inhibiteurs dans le traitement de maladies ou troubles associés à EGFR-TK. L'invention concerne en outre de nouveaux inhibiteurs irréversibles, radiomarqués, d'EGFR-TK, et leur utilisation comme marqueurs biologiques destinés à la radiologie médicale, telle que la tomographie par émission de positrons (TEP) et la tomographie monophotonique d'émission (SPECT), et comme produits radiopharmaceutiques destinés à la radiothérapie. Les inhibiteurs irréversibles d'EGFR-TK de l'invention comprennent un fragment de polyalkylène-glycol et se caractérisent par une solubilité, une biostabilité et une biodisponibilité améliorées.
• Modified PEG-anilinoquinazoline derivatives as potential EGFR PET agents
  作者：Samar Dissoki、Renana Eshet、Hana Billauer、Eyal Mishani

  DOI：10.1002/jlcr.1569

  日期：2009.2

  Inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) has emerged as a major approach for cancer-targeted therapy. Consequently, there has been a great interest in the use of labeled EGFR-TK inhibitors as positron emission tomography (PET) imaging agents. Currently, the developed agents did not yield adequate PET imaging of animal models probably due to poor solubility, rapid washout from blood, and low stability in vivo. In order to overcome these hurdles, new derivatives of previously reported inhibitors (ML04, 2) with decreased log P and increased solubility were designed and synthesized. These compounds (3–5) exhibited high autophosphorylation inhibitory potency with an IC50 of 5–35 nM, decreased log P's (3.1, 3.34, and 3.45, respectively), and significantly increased solubility (630, 300, and 120 µg/mL, respectively) relative to the previously reported parent compound 2 (log P=3.7, solubility=3.5 µg/mL). The labeling of compound 5 with [18F] and compounds 3 and 4 with [11C] and [124I], respectively, involved a one-step radiosynthesis. Compounds 3–5 were obtained with a total decay-corrected radiochemical yields of 13, 31, and 5%, respectively, and were found to be stable in blood. The positive outcome achieved with compounds 3–5 merits further in vivo evaluation as PET bioprobes. Copyright © 2008 John Wiley & Sons, Ltd.

  表皮生长因子受体酪氨酸激酶(EGFR-TK)的抑制已成为癌症靶向治疗的主要方法。因此,对于使用标记的EGFR-TK抑制剂作为正电子发射断层扫描(PET)成像剂产生了极大的兴趣。目前,开发的代理并未产生充分的动物模型的PET成像,可能由于其较差的溶解性、从血液中快速洗脱和在体内低稳定性。为了克服这些障碍,设计并合成了先前报道的抑制剂(ML04, 2)的新衍生物,这些衍生物具有减小的log P和增加的溶解性。这些化合物(3–5)显示出高的自磷酸化抑制效力,IC50值为5–35 nM,相对先前报道的母体化合物2(log P=3.7,溶解性=3.5 µg/mL),具有减小的log P(分别为3.1,3.34和3.45)和显著增加的溶解性(分别为630,300和120 µg/mL)。化合物5与[18F]、化合物3和4分别与[11C]和[124I]的标记涉及一步放射合成。化合物3–5获得的总衰变校正放射化学产率分别为13%,31%和5%,发现它们在血液中稳定。化合物3–5获得的正面结果值得进一步作为PET生物探针进行体内评估。版权所有 © 2008 John Wiley & Sons, Ltd.