N-(2-fluoro-4-methylphenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine | 338992-33-9

• 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-(2-fluoro-4-methylphenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine
• 英文别名: 4-(2-fluoro-4-methylanilino)-7-hydroxy-6-methoxyquinazoline；4-(2-fluoro-4-methylanilino)-6-methoxyquinazolin-7-ol
• CAS: 338992-33-9
• 化学式: C₁₆H₁₄FN₃O₂
• 分子量: 299.304
• InChiKey: ZJTCVOGUUPEOGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  67.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-(2-fluoro-4-methylphenyl)-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 4.0h， 生成 4-(2-fluoro-4-methylanilino)-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-氟-4-甲基苯胺 在 盐酸 、 三氟乙酸 作用下， 以 异丙醇 为溶剂， 反应 6.5h， 生成 N-(2-fluoro-4-methylphenyl)-7-hydroxy-6-methoxy-4-quinazolinylamine
  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

文献信息

• [EN] SUBSTITUTED QUINAZOLINE INHIBITORS OF GROWTH FACTOR RECEPTOR TYROSINE KINASES<br/>[FR] INHIBITEURS DE TYROSINE KINASES DE RÉCEPTEUR DE FACTEUR DE CROISSANCE DE TYPE QUINAZOLINE SUBSTITUÉE
  申请人：AUSPEK PHARMACEUTICALS INC

  公开号：WO2010028254A2

  公开（公告）日：2010-03-11

  The present invention relates to new substituted quinazoline inhibitors of vascular endothelial growth factor receptor tyrosine kinase, epidermal growth factor receptor tyrosine kinase, and/or rearranged during transfection tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.

  本发明涉及新的取代喹唑啉血管内皮生长因子受体酪氨酸激酶、表皮生长因子受体酪氨酸激酶和/或转录重排期间酪氨酸激酶抑制剂、其制药组合物以及使用方法。
• [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：AstraZeneca AB

  公开号：US07173038B1

  公开（公告）日：2007-02-06

  The invention relates to quinazoline derivatives of formula (I), wherein m is an integer from 1 to 3; R1 represents halogeno or C1-3alkyl; X1 represents —O—; R2 is selected from one of the following three groups: 1) C1-5alkylR3 (wherein R3 is piperidin-4-yl which may bear one or two substituents selected from hydroxy, halogeno, C1-4hydroxyalkyl and C1-4alkoxy; 2) C2-5alkenylR3 (wherein R3 is as defined hereinbefore); 3) C2-5alkynylR3 (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 a 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 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为1至3的整数；R1代表卤素或C1-3烷基；X1代表-O-；R2选自以下三个基团之一：1）C1-5烷基R3（其中R3为哌啶-4-基，可以带有一个或两个取自羟基、卤素、C1-4羟基烷基和C1-4烷氧基的取代基）；2）C2-5烯基烷基R3（其中R3如前所定义）；3）C2-5炔基烷基R3（其中R3如前所定义）；其中任何烷基、烯基或炔基可能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）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）的化合物及其药学上可接受的盐抑制VEGF的效果，在治疗包括癌症和类风湿性关节炎在内的许多疾病状态中具有价值的特性。
• CHEMICAL PROCESS
  申请人：BLIXT Jorgen

  公开号：US20120095229A1

  公开（公告）日：2012-04-19

  The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

  本发明涉及用于制造某些喹噁啉衍生物或其药学上可接受的盐的化学过程。本发明还涉及用于制造制造喹噁啉衍生物的某些中间体的过程，以及利用该中间体制造喹噁啉衍生物的过程。特别地，本发明涉及用于制造化合物4-(4-溴-2-氟苯氨基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹噁啉的化学过程和中间体。
• 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。