拉帕替尼杂质10 | 1152131-73-1

• 物质功能分类: 分析化学 - 标准品 - 药典标准品和杂质标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 拉帕替尼杂质10
• 中文别名: 拉帕替尼碱杂质10
• 英文名称: N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-carboxy-2-furyl)-4-quinazolinamine
• 英文别名: Unii-2T859uzj2V；5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]furan-2-carboxylic acid
• CAS: 1152131-73-1
• 化学式: C₂₆H₁₇ClFN₃O₄
• 分子量: 489.89
• InChiKey: ALLDUFLYKPDTCS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  97.5
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  拉帕替尼杂质10 在 氯化亚砜 、 硫酸 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.0h， 生成 N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((4-methoxybutyl)amino)methyl)-2-furyl)-4-quinazolinamine
  参考文献：
  名称：

  QUINAZOLINE DERIVATIVE, COMPOSITION HAVING THE DERIVATIVE, AND USE OF THE DERIVATIVE IN PREPARING MEDICAMENT

  摘要：

  公开号：

  EP2740729B1
• 作为产物：
  描述：

  4-氯-6-碘喹唑啉 在 bis(triphenylphosphine)palladium(II) dichloride 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 为溶剂， 反应 1.0h， 生成 拉帕替尼杂质10
  参考文献：
  名称：

  Novel Chimeric Histone Deacetylase Inhibitors: A Series of Lapatinib Hybrides as Potent Inhibitors of Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and Histone Deacetylase Activity

  摘要：

  Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.

  DOI：

  10.1021/jm100665z

文献信息

• [EN] NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES<br/>[FR] NOUVEAUX COMPOSÉS BIFONCTIONNELS QUI INHIBENT LES PROTÉINES KINASES ET LES HISTONES DÉSACÉTYLASES
  申请人：4SC AG

  公开号：WO2009063054A1

  公开（公告）日：2009-05-22

  The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth.

  本发明涉及公式I的双功能化合物或其药用可接受的盐或溶剂A-L-B（I），其中A是组蛋白去乙酰化酶（HDAC）抑制基团，L是单键或连接基团，B是蛋白激酶抑制基团。根据公式（I）的双功能化合物可用于治疗恶性和非恶性肿瘤以及与异常细胞生长相关的疾病。
• N-[3-氯-4-(3-氟苄氧基)苯基]-6-[5-[[2-(甲亚 磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉 胺多晶型物及其制备方法
  申请人：齐鲁制药有限公司

  公开号：CN103819461B

  公开（公告）日：2016-06-15

  本发明涉及N-[3-氯-4-(3-氟苄氧基)苯基]-6-[5-[[2-(甲亚磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺的多晶型物及其制备方法，具体涉及作为酪氨酸激酶抑制剂N-[3-氯-4-(3-氟苄氧基)苯基]-6-[5-[[2-(甲亚磺酰基)乙基]氨基]甲基]-2-呋喃基]-4-喹唑啉胺晶型A或B。本发明还涉及该多晶型物的制备方法，它的药物组合物以及它们的制药用途。
• NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
  申请人：Bar Thomas

  公开号：US20110065734A1

  公开（公告）日：2011-03-17

  The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth.

  本发明涉及一种式I的双功能化合物或其药学上可接受的盐或溶剂A-L-B(I)，其中A是组蛋白去乙酰化酶（HDAC）抑制基团，L是单键或连接基团，B是蛋白激酶抑制基团。根据式（I）的双功能化合物对于治疗恶性和非恶性肿瘤以及与异常细胞生长相关的疾病非常有用。
• Novel bifunctional compounds which inhibit protein kinases and histone deacetylases
  申请人：4SC AG

  公开号：EP2060565A1

  公开（公告）日：2009-05-20

  The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates         A-L-B     (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth.

  本发明涉及式 I 的双官能团化合物或其药学上可接受的盐或溶解物 A-L-B (I) 其中 A 是组蛋白去乙酰化酶（HDAC）抑制分子，L 是单键或连接基团，B 是蛋白激酶抑制分子。根据式（I）的双功能化合物可用于治疗恶性和非恶性肿瘤以及与细胞异常生长有关的疾病。
• Discovery of a potent dual EGFR/HER-2 inhibitor L-2 (selatinib) for the treatment of cancer
  作者：Long Zhang、Chuanwen Fan、Zongru Guo、Ying Li、Shuyong Zhao、Shaobo Yang、Yingying Yang、Jianrong Zhu、Dong Lin

  DOI：10.1016/j.ejmech.2013.09.032

  日期：2013.11

  To develop potent dual EGFR/HER-2 inhibitors with improved druggability, a series of new lapatinib analogs were designed and synthesized. Compared with lapatinib, L-2, L-4 and M-6 were more active against BT-474 or NCI-N87 cells. In vivo efficacy studies indicated that L-2 significantly suppressed tumor growth in NCI-N87 (94.8% inhibition) or SK-OV-3 xenograft (85.7% inhibition) without causing significant loss of body weight. And the inhibition rates of lapatinib in the two xenograft models were 89.7% and 78.8%, respectively. Moreover, further studies revealed that the potent in vivo activities of L-2 may be mainly attributed to its superior aqueous solubility and oral bioavailability. In addition, a high-yielding one-pot procedure was developed for the synthesis of lapatinib and its analogs. (C) 2013 Elsevier Masson SAS. All tights reserved.