4-(1,2-benzisothiazol-4-yloxy)-3-chloroaniline | 1124250-10-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(1,2-benzisothiazol-4-yloxy)-3-chloroaniline
• 英文别名: 4-(1,2-benzoisothiazol-4-yloxy)-3-chloroaniline；4-(Benzo[d]isothiazol-4-yloxy)-3-chloroaniline；4-(1,2-benzothiazol-4-yloxy)-3-chloroaniline
• CAS: 1124250-10-7
• 化学式: C₁₃H₉ClN₂OS
• 分子量: 276.746
• InChiKey: XSEANNDNXRGZCS-UHFFFAOYSA-N

物化性质

• 沸点：
  376.4±42.0 °C(Predicted)
• 密度：
  1.448±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  76.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(1,2-benzisothiazol-4-yloxy)-3-chloroaniline 在 盐酸 、 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 乙醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 28.0h， 生成 N-[2-(4-{[4-(1,2-benzisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide
  参考文献：
  名称：

  Design and Synthesis of Pyrrolo[3,2-d]pyrimidine Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors: Exploration of Novel Back-Pocket Binders

  摘要：

  To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI(50), 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.

  DOI：

  10.1021/jm300185p
• 作为产物：
  描述：

  2-氯-6-氟-苯甲醛 在 potassium tert-butylate 、 sodium acetate 、 氯化铵 、 sulfur 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 为溶剂， 反应 6.0h， 生成 4-(1,2-benzisothiazol-4-yloxy)-3-chloroaniline
  参考文献：
  名称：

  A Convergent Scale-up Synthesis of A HER2/EGRF Dual Kinase Inhibitor

  摘要：

  A practical and scalable synthesis of the human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual kinase inhibitor 1 has been developed. The key features of the process development include convenient construction of the benzisothiazole skeleton directly from commercially available materials in high yield, a practical O-demethylation utilizing an ethanethiol or octanethiol/aluminium chloride system without harsh conditions, and development of a more convergent alternative route that coupled two key intermediates in the final step. The novel synthesis allowed the manufacturing process to produce high quality API 1 (>99% purity (LCAP)) over 7 steps, compared to 9 steps in the original, route, without chromatographic purification.

  DOI：

  10.3987/com-17-13663

文献信息

• FUSED HETEROCYCLIC COMPOUND
  申请人：ISHIKAWA Tomoyasu

  公开号：US20090233937A1

  公开（公告）日：2009-09-17

  The present invention provides a fused heterocyclic compound having a tyrosine kinase inhibitory action, which is represented by the formula: wherein ring A is an optionally substituted benzene ring; ring B is an optionally substituted benzoisothiazole ring; R 1 is a hydrogen atom, a halogen atom, or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom; R 2 is a hydrogen atom, or an optionally substituted group bonded via a carbon atom or a sulfur atom; R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; or R 1 and R 2 , or R 2 and R 3 are optionally bonded to each other to form an optionally substituted ring structure; or R 3 is optionally bonded to the carbon atom on ring A to form an optionally substituted ring structure; or a salt thereof.

  本发明提供了一种具有酪氨酸激酶抑制作用的融合杂环化合物，其由以下式表示： 其中 环A是一个可选择取代的苯环； 环B是一个可选择取代的苯并异噻唑环； R1是氢原子、卤素原子或通过碳原子、氮原子或氧原子键合的可选择取代基团； R2是氢原子，或通过碳原子或硫原子键合的可选择取代基团； R3是氢原子或可选择取代的脂肪烃基团； 或 R1和R2，或R2和R3可选择键合在一起形成一个可选择取代的环结构； 或 R3可选择键合到环A上的碳原子上形成一个可选择取代的环结构； 或其盐。
• A Convergent Scale-up Synthesis of A HER2/EGRF Dual Kinase Inhibitor
  作者：Osamu Yabe、Akihiro Suzuki、Tomomi Ikemoto

  DOI：10.3987/com-17-13663

  日期：——

  A practical and scalable synthesis of the human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual kinase inhibitor 1 has been developed. The key features of the process development include convenient construction of the benzisothiazole skeleton directly from commercially available materials in high yield, a practical O-demethylation utilizing an ethanethiol or octanethiol/aluminium chloride system without harsh conditions, and development of a more convergent alternative route that coupled two key intermediates in the final step. The novel synthesis allowed the manufacturing process to produce high quality API 1 (>99% purity (LCAP)) over 7 steps, compared to 9 steps in the original, route, without chromatographic purification.
• Design and Synthesis of Pyrrolo[3,2-<i>d</i>]pyrimidine Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors: Exploration of Novel Back-Pocket Binders
  作者：Youichi Kawakita、Hiroshi Banno、Tomohiro Ohashi、Toshiya Tamura、Tadashi Yusa、Akiko Nakayama、Hiroshi Miki、Hidehisa Iwata、Hidenori Kamiguchi、Toshimasa Tanaka、Noriyuki Habuka、Satoshi Sogabe、Yoshikazu Ohta、Tomoyasu Ishikawa

  DOI：10.1021/jm300185p

  日期：2012.4.26

  To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI(50), 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.