4-(4-氯-2-氟苯胺基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉 | 338992-08-8

• 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: 4-(4-氯-2-氟苯胺基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉
• 英文名称: 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline
• 英文别名: N-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-amine
• CAS: 338992-08-8
• 化学式: C₂₁H₂₂ClFN₄O₂
• 分子量: 416.883
• InChiKey: AVQNSHZBOYOSQZ-UHFFFAOYSA-N

物化性质

• 熔点：
  220-222 °C
• 沸点：
  533.1±50.0 °C(Predicted)
• 密度：
  1.308±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  68.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(4-氯-2-氟苯胺基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉 在 sodium triacetoxyborohydride 、 吡啶盐酸盐 、 溶剂黄146 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 3.33h， 生成 4-((4-chloro-2-fluorophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-ol
  参考文献：
  名称：

  Radiosynthesis of [11C]Vandetanib and [11C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer

  摘要：

  Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC50 values. [C-11]Vandetanib and [C-11]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555 GBq/mu mol specific activity at end of bombardment (EOB). (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.049
• 作为产物：
  描述：

  4-氯-2-氟苯胺 在 盐酸 、 potassium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 5.0h， 生成 4-(4-氯-2-氟苯胺基)-6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉
  参考文献：
  名称：

  Radiosynthesis of [11C]Vandetanib and [11C]chloro-Vandetanib as new potential PET agents for imaging of VEGFR in cancer

  摘要：

  Vandetanib (ZD6474) and its chlorine analogue chloro-Vandetanib are potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with low nanomolar IC50 values. [C-11]Vandetanib and [C-11]chloro-Vandetanib, new potential PET agents for imaging of VEGFR in cancer, were first designed, synthesized and labeled at nitrogen and oxygen positions from their corresponding N- and O-des-methylated precursors, in 40-50% decay corrected radiochemical yield and 370-555 GBq/mu mol specific activity at end of bombardment (EOB). (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.049

文献信息

• [EN] QUINAZOLINE DERIVATIVES AS INHIBITORS OF VEGF RECEPTOR TYROSINE KINASES<br/>[FR] DERIVES DE QUINAZOLINE UTILISES EN TANT QU'INHIBITEURS DES RECEPTEURS A ACTIVITE TYROSINE KINASE DU FACTEUR VEGF
  申请人：ASTRAZENECA AB

  公开号：WO2005013998A1

  公开（公告）日：2005-02-17

  The present invention relates to compounds of the Formula (I): wherein Z is -NH-, -O- or -S-; R 1 represents bromo or chloro; R 3 represents C 1-3 alkoxy or hydrogen; R 2 is selected from one of the following three groups: (i) Q 1 X 1 - wherein X 1 and Q 1 are as defined herein; (ii) Q 15 W 3 - wherein Q 15 and W 3 are as defined herein; and (iii) Q 21 W 4 C 1-5 alkylX 1 wherein X 1 , W 4 and Q 21 are as defined herein; and salts thereof; their use in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm blooded animals; processes for the preparation of such compounds; pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and methods of treating disease states involving angiogenesis by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

  本发明涉及以下式(I)的化合物：其中Z为-NH-，-O-或-S-；R1代表溴或氯；R3代表C1-3烷氧基或氢；R2从以下三个组中选择一个：(i) Q1X1-其中X1和Q1如本文所定义；(ii) Q15W3-其中Q15和W3如本文所定义；以及(iii) Q21W4C1-5烷基X1其中X1，W4和Q21如本文所定义；及其盐；它们在制造用于在温血动物中产生抗血管生成和/或血管通透性降低作用的药物中的用途；制备这种化合物的方法；含有式(I)的化合物或其药学上可接受的盐的药物组合物以及通过给予式(I)的化合物或其药学上可接受的盐来治疗涉及血管生成的疾病状态的方法。式(I)的化合物抑制VEGF的作用，在治疗包括癌症和类风湿性关节炎在内的多种疾病状态中具有价值的特性。
• [EN] QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS<br/>[FR] DERIVES DE QUINAZOLINE UTILISES EN TANT QU'INHIBITEURS DU FACTEUR DE CROISSANCE ENDOTHELIALE VASCULAIRE (VEGF)
  申请人：ASTRAZENECA AB

  公开号：WO2001032651A1

  公开（公告）日：2001-05-10

  The invention relates to quinazoline derivatives of formula (I), wherein m is an integer from 1 to 3; R1 represents halogeno or C¿1-3?alkyl; X?1¿ represents -O-; R2 is selected from one of the following three groups: 1) C¿1-5?alkylR?3¿ (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C¿1-4?alkyl, C1-4hydroxyalkyl and C1-4alkoxy; 2) C2-5alkenylR?3¿ (wherein R3 is as defined hereinbefore); 3) C¿2-5?alkynylR?3¿ (wherein R3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

  本发明涉及式（I）的喹噁啉衍生物，其中m为1至3的整数；R1代表卤素或C1-3烷基；X1代表-O-；R2从以下三组中选择一组：1）C1-5烷基R3（其中R3是哌啶-4-基，可以带有一个或两个取自羟基、卤素、C1-4烷基、C1-4羟基烷基和C1-4烷氧基的取代基）；2）C2-5烯基R3（其中R3如前所定义）；3）C2-5炔基R3（其中R3如前所定义）；其中任何烷基、烯基或炔基可以带有一个或多个取自羟基、卤素和氨基的取代基；以及它们的盐；制备它们的过程，含有式（I）化合物或其药学上可接受的盐作为活性成分的制药组合物。式（I）化合物及其药学上可接受的盐抑制VEGF的作用，这是治疗包括癌症和类风湿性关节炎在内的多种疾病状态的有价值的特性。
• Quinazoline derivatives as VEGF inhibitors
  申请人：Thomas Peter Andrew

  公开号：US20070265286A1

  公开（公告）日：2007-11-15

  The invention relates to quinazoline derivatives of formula (I), wherein m is an integer from 1 to 3; R 1 represents halogeno or C 1-3 alkyl; X 1 represents —O—; R 2 is selected from one of the following three groups: 1) C 1-5 alkylR 3 (wherein R 3 is piperidinyl-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy; 2) C 2-5 alkenylR 3 (wherein R 3 is as defined hereinbefore); 3) C 2-5 alkynylR 3 (wherein R 3 is as defined hereinbefore); and wherein any alkyl, alkenyl or alkynyl group may bear one or more substituents selected from hydroxy, halogeno and amino; and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

  本发明涉及式（I）的喹唑啉衍生物，其中m是1到3的整数; R1代表卤素或C1-3烷基; X1代表—O—; R2从以下三个组中选择一个：1）C1-5烷基R3（其中R3是哌啶基-4-基，可以带有一个或两个从羟基，卤素，C1-4烷基，C1-4羟基烷基和C1-4烷氧基中选择的取代基; 2）C2-5烯基R3（其中R3如上所定义）; 3）C2-5炔基R3（其中R3如上所定义）; 其中任何烷基，烯基或炔基可以带有一个或多个从羟基，卤素和氨中选择的取代基;以及它们的盐;制备它们的过程，包含式（I）的化合物或其药学上可接受的盐作为活性成分的制药组合物。式（I）的化合物和其药学上可接受的盐抑制VEGF的作用，在治疗包括癌症和类风湿性关节炎在内的多种疾病状态中具有价值的性质。
• Therapeutic agents comprising an anti-angiogenic agent in combination with an src-inhibitor and their therapeutic use
  申请人：Curwen Owen Jon

  公开号：US20060223815A1

  公开（公告）日：2006-10-05

  The invention relates to the use of an anti-angiogenic agent in combination with an inhibitor of the Src family of non-receptor tyrosine kinases in the manufacture of a medicament for use in the substantially normotensive treatment in a warm-blooded mammal such as a human being of a disease state associated with angiogenesis, the Src kinase inhibitor being administered in an amount effective to counteract substantially the hypertension induced by the anti-angiogenic agent.

  本发明涉及在制造一种药物时使用抗血管生成剂与Src家族非受体酪氨酸激酶抑制剂相结合，用于治疗与血管生成有关的疾病状态，如在温血哺乳动物（如人类）中进行实质性正常血压治疗。 Src激酶抑制剂的用量有效地对抗抗血管生成剂引起的高血压。
• THERAPEUTIC AGENTS COMPRISING AN ANTI-ANGIOGENIC AGENT IN COMBINATION WITH AN SRC-INHIBITOR AND THEIR THERAPEUTIC USE
  申请人：CURWEN Jon Owen

  公开号：US20100029673A1

  公开（公告）日：2010-02-04

  The invention relates to a method for the production of an anti-cancer effect or a method for the treatment of a sold tumour disease by administration of an anti-angiogenic agent selected from 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline and 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline and pharmaceutically-acceptable acid-addition salts thereof, in combination with a Src kinase inhibitor selected from 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline and pharmaceutically-acceptable acid-addition salts thereof.

  本发明涉及一种通过给予选择自4-(4-氟-2-甲基吲哚-5-氧基)-6-甲氧基-7-(3-(吡咯烷-1-基)丙氧基)喹唑啉和4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉及其药学上可接受的酸盐，结合选择自4-(6-氯-2,3-亚甲二氧基苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-氧基喹唑啉及其药学上可接受的酸盐的Src激酶抑制剂，以产生抗癌效应或治疗固体肿瘤疾病的方法。