N-(3-bromophenyl)-7,8-dihydro[1,4]dioxino[2,3-g]quinazolin-4-amine

• 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-(3-bromophenyl)-7,8-dihydro[1,4]dioxino[2,3-g]quinazolin-4-amine
• 英文别名: (7,8-dihydro[1,4]dioxino[2,3-g]quinazolin-4-yl)-(3'-bromophenyl)amine；N-(3-bromophenyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amine
• 化学式: C₁₆H₁₂BrN₃O₂
• 分子量: 358.194
• InChiKey: NFRPHQQIEMLXRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  56.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  7-氨基-2,3-二氢-1,4-苯并二氧杂环己-6-羧酸 在 哌啶 、 盐酸 、 N,N-二甲基苯胺 、 三氯氧磷 作用下， 以 乙醇 、 异丙醇 为溶剂， 反应 50.0h， 生成 N-(3-bromophenyl)-7,8-dihydro[1,4]dioxino[2,3-g]quinazolin-4-amine
  参考文献：
  名称：

  1,4-二恶烷融合的 4-苯胺基喹唑啉作为表皮生长因子受体激酶抑制剂

  摘要：

  4-苯胺基喹唑啉 PD 153035 (1) 是一种潜在的抗肿瘤剂，通过与酶的 ATP 位点的竞争性结合来抑制表皮生长因子受体 (EFGR) 的酪氨酸激酶活性。通过 6-氯衍生物 5 与几种苯胺亲核试剂的反应，制备了一系列带有 1,4-二恶烷环的 PD 153035 环状类似物。评估了它们抑制 EGFR 激酶和原代人类肿瘤细胞培养物生长的能力。所有新的 4-苯胺基喹唑啉对 EGFR 激酶的效力均低于 PD 153035。然而，化合物 2b、2c、2e、2g 和 2h 对 A431 肿瘤细胞系的生长显示出比 PD 153035 更高的抑制活性。含有 3-氯苯胺环的化合物 2b 与 PD 153035 一样有效对抗 EGFR 激酶，显示约 5。

  DOI：

  10.1002/1521-4184(200112)334:11<357::aid-ardp357>3.0.co;2-q

文献信息

• Compositions and methods for treating cancer
  申请人：The Regents of the University of California

  公开号：US11377451B2

  公开（公告）日：2022-07-05

  The present disclosure relates to compounds, compositions and methods for treating cancer, including compounds that are capable of penetrating the blood brain barrier to modulate the activity of EGFR tyrosine kinase. The disclosure further relates to methods of treating cancer in the brain, including glioblastoma and other EGFR mediated cancers. The disclosure further relates to methods of treating cancers such as glioblastoma and other EGFR mediated cancers that have been determined to have altered glucose metabolism in the presence of inhibitors. The present disclosure also provides methods of administering to a subject a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.

  本公开涉及治疗癌症的化合物、组合物和方法，包括能够穿透血脑屏障调节表皮生长因子受体酪氨酸激酶活性的化合物。本公开进一步涉及治疗脑癌的方法，包括胶质母细胞瘤和其他表皮生长因子受体介导的癌症。本公开进一步涉及治疗已确定在抑制剂存在的情况下葡萄糖代谢改变的癌症如胶质母细胞瘤和其他表皮生长因子受体介导的癌症的方法。本公开还提供了向受试者施用葡萄糖代谢抑制剂和细胞质 p53 稳定剂的方法。
• Development of a Potent Brain-Penetrant EGFR Tyrosine Kinase Inhibitor against Malignant Brain Tumors
  作者：Jonathan E. Tsang、Lorenz M. Urner、Gyudong Kim、Kingsley Chow、Lynn Baufeld、Kym Faull、Timothy F. Cloughesy、Peter M. Clark、Michael E. Jung、David A. Nathanson

  DOI：10.1021/acsmedchemlett.9b00599

  日期：2020.10.8

  The epidermal growth factor receptor (EGFR) is genetically altered in nearly 60% of glioblastoma tumors; however, tyrosine kinase inhibitors (TKIs) against EGFR have failed to show efficacy for patients with these lethal brain tumors. This failure is attributed to the inability of clinically tested EGFR TKIs to cross the blood-brain barrier (BBB) and achieve adequate pharmacological levels to inhibit various oncogenic forms of EGFR that drive glioblastoma. Through SAR analysis, we developed compound 5 (JCN037) from an anilinoquinazoline scaffold by ring fusion of the 6,7-dialkoxy groups to reduce the number of rotatable bonds and polar surface area and by introduction of an orthofluorine and meta-bromine on the aniline ring for improved potency and BBB penetration. Relative to the conventional EGFR TKIs erlotinib and lapatinib, JCN037 displayed potent activity against EGFR amplified/mutant patient-derived cell cultures, significant BBB penetration (2:1 brain-to-plasma ratio), and superior efficacy in an EGFR-driven orthotopic glioblastoma xenograft model.
• COMPOSITIONS AND METHODS FOR TREATING CANCER
  申请人：The Regents of the University of California

  公开号：US20220064177A1

  公开（公告）日：2022-03-03

  The present disclosure relates to compounds that are capable of penetrating the blood brain barrier to modulate the activity of EGFR tyrosine kinase. The disclosure further relates to methods of treating glioblastoma and other EGFR-mediated cancers, such as those that have been determined to have altered glucose metabolism in the presence of inhibitors. The present disclosure also provides methods of administering to a subject a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.
• 1,4-Dioxane-fused 4-anilinoquinazoline as inhibitors of epidermal growth factor receptor kinase
  作者：Jae Yeol Lee、Yong Kyu Park、Seon Hee Seo、In-Seop So、Hee-Kyung Chung、Beom-Seok Yang、Sook Ja Lee、Hokoon Park、Yong Sup Lee

  DOI：10.1002/1521-4184(200112)334:11<357::aid-ardp357>3.0.co;2-q

  日期：2001.12

  potential antitumor agent which acts by inhibiting tyrosine kinase activity of epidermal growth factor receptor (EFGR) via competitive binding at the ATP site of enzyme. A series of cyclic analogues of PD 153035 bearing the 1,4‐dioxane ring was prepared by reaction of 6‐chloro derivative 5 with several aniline nucleophiles. These were evaluated for their ability to inhibit the EGFR kinase and the growth of

  4-苯胺基喹唑啉 PD 153035 (1) 是一种潜在的抗肿瘤剂，通过与酶的 ATP 位点的竞争性结合来抑制表皮生长因子受体 (EFGR) 的酪氨酸激酶活性。通过 6-氯衍生物 5 与几种苯胺亲核试剂的反应，制备了一系列带有 1,4-二恶烷环的 PD 153035 环状类似物。评估了它们抑制 EGFR 激酶和原代人类肿瘤细胞培养物生长的能力。所有新的 4-苯胺基喹唑啉对 EGFR 激酶的效力均低于 PD 153035。然而，化合物 2b、2c、2e、2g 和 2h 对 A431 肿瘤细胞系的生长显示出比 PD 153035 更高的抑制活性。含有 3-氯苯胺环的化合物 2b 与 PD 153035 一样有效对抗 EGFR 激酶，显示约 5。