N-(4-bromo-2-fluorophenyl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine | 205194-14-5

• 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: N-(4-bromo-2-fluorophenyl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine
• 英文别名: 4-(4-bromo-2-fluoroanilino)-7-(3-chloropropoxy)-6-methoxyquinazoline
• CAS: 205194-14-5
• 化学式: C₁₈H₁₆BrClFN₃O₂
• 分子量: 440.699
• InChiKey: RLWDIJYLBFQFRC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  56.3
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-甲基哌嗪 、 N-(4-bromo-2-fluorophenyl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine 反应 2.0h， 以45%的产率得到(4-Bromo-2-fluoro-phenyl)-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-amine
  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：

  1-溴-3-氯丙烷 、 4-(4-溴-2-氟苯胺基)-7-羟基-6-甲氧基喹唑啉 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以70%的产率得到N-(4-bromo-2-fluorophenyl)-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine
  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

• Quinazoline derivatives and pharmaceutical compositions containing them
  申请人：Thomas Peter Andrew

  公开号：US20050239777A1

  公开（公告）日：2005-10-27

  The invention relates to quinazoline derivatives of formula (1) wherein m is an integer from 1 to 2; R 1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6 (wherein R 5 and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl); R 2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R 3 represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X 1 represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 8 —, —SO 2 NR 9 —, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 8 , R 9 , R 10 and R 11 each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); R 4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, 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 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.

  本发明涉及公式（1）的喹唑啉衍生物，其中m为1到2的整数；R1代表氢、羟基、卤素、硝基、三氟甲基、氰基、C1-3烷基、C1-3烷氧基、C1-3烷硫基或-NR5R6（其中R5和R6可以相同或不同，每个代表氢或C1-3烷基）；R2代表氢、羟基、卤素、甲氧基、氨基或硝基；R3代表羟基、卤素、C1-3烷基、C1-3烷氧基、C1-3酰氧基、三氟甲基、氰基、氨基或硝基；X1代表-O-、-CH2-、-S-、-SO-、-SO2-、-NR7CO-、-CONR8-、-SO2NR9-、-NR10SO2-或-NR11-（其中R7、R8、R9、R10和R11各自独立地代表氢、C1-3烷基或C1-3烷氧基C2-3烷基）；R4代表可选取代的5或6成员饱和碳环或杂环基或烯基、炔基或可选取代的烷基，其中烷基基团可以包含一个杂原子连接基团，烯基、炔基或烷基基团可以携带一个末端可选取代的基团，所选的基团为烷基或5或6成员饱和碳环或杂环基，以及其盐；制备它们的方法，含有公式（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。公式（I）化合物及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特性。
• QUINAZOLINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
  申请人：ZENECA LIMITED

  公开号：US20040242574A1

  公开（公告）日：2004-12-02

  The invention relates to quinazoline derivatives of formula (I) wherein m is an integer from 1 to 2; R 1 represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, or —NR 5 R 6 (wherein R 5 and R 6 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), R 2 represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R 3 represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro, X 1 represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 7 CO—, —CONR 8 —, —SO 2 NR 9 —, —NR 10 SO 2 — or —NR 11 — (wherein R 7 , R 8 , R 9 , R 10 and R 11 each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl); R 4 represents an optionally substituted 5 or 6 membered saturated carbocyclic or hetrocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, 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. 1

  本发明涉及式（I）的喹唑啉衍生物，其中m是1到2的整数；R1代表氢、羟基、卤素、硝基、三氟甲基、氰基、C1-3烷基、C1-3烷氧基、C1-3烷硫基或-NR5R6（其中R5和R6，可以相同也可以不同，分别代表氢或C1-3烷基）；R2代表氢、羟基、卤素、甲氧基、氨基或硝基；R3代表羟基、卤素、C1-3烷基、C1-3烷氧基、C1-3酰氧基、三氟甲基、氰基、氨基或硝基；X1代表-O-、-CH2-、-S-、-SO-、-SO2-、-NR7CO-、-CONR8-、-SO2NR9-、-NR10SO2-或-NR11-（其中R7、R8、R9、R10和R11各自独立地代表氢、C1-3烷基或C1-3烷氧基C2-3烷基）；R4代表可选择取代的5或6成员饱和碳环或杂环基团或烯基、炔基或可选择取代的烷基，该烷基可能含有一个异原子连接基，该烯基、炔基或烷基可能携带一个端基可选择取代的基团，所述基团选择自烷基和一个5或6成员饱和碳环或杂环基团，并且其盐；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，这是治疗许多疾病状态包括癌症和类风湿性关节炎的有价值的特性。
• USRE042353E1
  申请人：——

  公开号：——

  公开（公告）日：——
• US6414148B1
  申请人：——

  公开号：US6414148B1

  公开（公告）日：2002-07-02
• US6673803B2
  申请人：——

  公开号：US6673803B2

  公开（公告）日：2004-01-06