N-(4-bromo-2,6-difluorophenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine | 257938-40-2

• 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: N-(4-bromo-2,6-difluorophenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine
• 英文别名: 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline；4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazolin-7-ol
• CAS: 257938-40-2
• 化学式: C₁₅H₁₀BrF₂N₃O₂
• 分子量: 382.164
• InChiKey: MIUNPJOHLJTRHN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  67.3
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(4-bromo-2,6-difluorophenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine 在 三苯基膦 、 三氟乙酸 、 偶氮二甲酸二乙酯 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline
  参考文献：
  名称：

  Novel 4-Anilinoquinazolines with C-7 Basic Side Chains:  Design and Structure Activity Relationship of a Series of Potent, Orally Active, VEGF Receptor Tyrosine Kinase Inhibitors

  摘要：

  We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC50 0.02 muM, range 0.001-0.04 muM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC50 0.55 muM, range 0.02-1.6 muM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC50 0.2 muM, range 0.075-0.8 muM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC50 2.5 muM, range 0.9-19 muM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC50 0.06 muM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC50 0.04 muM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC50 range: 1.1 to >100 muM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 muM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 muM at pH 7.4) and good oral bioavailability in rat and dog (>80 and >50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.

  DOI：

  10.1021/jm011022e
• 作为产物：
  描述：

  2-氨基-4-苄氧基-5-甲氧基苯甲酰胺 在 氯化亚砜 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 异丙醇 为溶剂， 反应 29.33h， 生成 N-(4-bromo-2,6-difluorophenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine
  参考文献：
  名称：

  一类新型有效的VEGF受体酪氨酸激酶抑制剂的设计与构效关系。

  摘要：

  合成了一系列取代的4-苯胺基喹唑啉和相关化合物，作为血管内皮生长因子（VEGF）受体（Flt和KDR）酪氨酸激酶活性的潜在抑制剂。酶筛查表明，对于双环系统而言，存在窄的构效关系（SAR），喹唑啉，喹啉和cinnolines具有活性，通常优选喹唑啉和喹啉。对苯胺的取代进行了研究，并清楚地表明，在C-4'位置优选使用较小的亲脂性取代基，例如卤素或甲基。在C-2'位置优选小的取代基，例如氢和氟。在苯胺的间位引入羟基会产生最有效的Flt和KDR酪氨酸激酶活性抑制剂，其IC（50）值在纳摩尔范围内（例如10、12、13、16和18）。对喹唑啉C-6和C-7位置的研究表明，在C-7可以容忍大范围的取代基，而C-6的变化受到更大的限制。在C-7处，中性，碱性和杂芳族侧链产生非常有效的化合物，如甲氧基乙氧基衍生物13（IC（50）<2 nM）所示。与与FGF受体相关的抑制剂（50至3800倍）相比，我们的

  DOI：

  10.1021/jm990345w

文献信息

• [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。
• Quinazoline Derivatives as VEGF Inhibitors
  申请人：AstraZeneca AB

  公开号：US20140121228A1

  公开（公告）日：2014-05-01

  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 herein; 3) C 2-5 alkynylR 3 , wherein R 3 is as defined herein; 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 an active ingredient.

  本发明涉及公式（I）的喹唑啉衍生物，其中m是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如上定义；3）C2-5炔基R3，其中R3如上定义；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；制备它们的方法；含有公式（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。
• QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
  申请人：AstraZeneca AB

  公开号：EP1244647B1

  公开（公告）日：2006-06-21
• New quinazoline derivatives
  申请人：AstraZeneca AB

  公开号：EP1676845B1

  公开（公告）日：2008-06-11