N-[2-(4-{[4-(1,2-benzisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methylalaninamide | 1187732-17-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[2-(4-{[4-(1,2-benzisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methylalaninamide
• 英文别名: N-[2-(4-{[4-(1,2-Benzoisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methylalaninamide；2-amino-N-[2-[4-[4-(1,2-benzothiazol-4-yloxy)-3-chloroanilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-2-methylpropanamide
• CAS: 1187732-17-7
• 化学式: C₂₅H₂₄ClN₇O₂S
• 分子量: 522.03
• InChiKey: AVHNHPHSQMBYAJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-[2-(4-{[4-(1,2-benzisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methylalaninamide 、 对甲苯磺酸一水合物 、 乙酸乙酯 以 乙醇 为溶剂， 以to give the title compound (61 mg) as a white powder的产率得到N-[2-(4-{[4-(1,2-benzoisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methylalaninamide di-p-toluenesulfonate
  参考文献：
  名称：

  FUSED HETEROCYCLIC COMPOUND

  摘要：

  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，其表示为以下式子：其中，环A是可选择取代的苯环；环B是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；或者R1和R2，或R2和R3可选择相互键合以形成可选择取代的环结构；或者R3可选择与环A上的碳原子键合以形成可选择取代的环结构；或其盐。

  公开号：

  US20090233937A1
• 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 乙醇 、 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 14.5h， 生成 N-[2-(4-{[4-(1,2-benzisothiazol-4-yloxy)-3-chlorophenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]-2-methylalaninamide
  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

• 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.
• [EN] FUSED HETEROCYCLIC COMPOUND<br/>[FR] COMPOSÉ HÉTÉROCYCLIQUE FUSIONNÉ
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2009113560A1

  公开（公告）日：2009-09-17

  　チロシンキナーゼ阻害作用を有する縮合複素環化合物を提供する。　本発明化合物は、式 〔式中、環Ａは、置換されていてもよいベンゼン環；環Ｂは、置換されていてもよいベンゾイソチアゾール環；Ｒ１は、水素原子、ハロゲン原子、または炭素原子、窒素原子もしくは酸素原子を介して結合し、置換されていてもよい基；Ｒ２は、水素原子、または炭素原子もしくは硫黄原子を介して結合し、置換されていてもよい基；Ｒ３は、水素原子または置換されていてもよい脂肪族炭化水素基；を表すか、あるいは、Ｒ１とＲ２、またはＲ２とＲ３はそれぞれ結合して、置換されていてもよい環構造を構築してもよく；あるいは、Ｒ３は環Ａの炭素原子と結合して、置換されていてもよい環構造を構築してもよい；を表す。〕で表される化合物またはその塩である。
• [EN] THERAPEUTIC AGENT FOR BRAIN TUMOR<br/>[FR] AGENT THÉRAPEUTIQUE POUR UNE TUMEUR CÉRÉBRALE
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2011040212A1

  公开（公告）日：2011-04-07

  The present invention relates to an agent for the prophylaxis or treatment of metastatic tumor that has spread to the brain from other tissue, comprising N-2-[4-(3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide or a salt thereof.
• 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.