(R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one | 1130137-76-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one
• 英文别名: 2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-5-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one
• CAS: 1130137-76-6
• 化学式: C₂₄H₂₇FN₄O₄
• 分子量: 454.501
• InChiKey: WUWVRXPSSGTMJL-CJMVGXJBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  97.9
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  L-苹果酸 、 (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 以 甲醇 、 乙腈 为溶剂， 反应 1.08h， 生成 (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one L-malate
  参考文献：
  名称：

  Novel Potent Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitors: Synthesis, Structure−Activity Relationships, and Antitumor Activities of 2-Indolinone Derivatives

  摘要：

  The inhibition of receptor tyrosine kinases (RTKs) has become a successful approach in the development of anticancer agents. Many potent small-molecule kinase inhibitors have been discovered. We report herein a series of pyrrolo-fused-heterocycle-2-indolinone analogues as inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR). and c-Kit. Among them, some pyrrolo-fused six- and seven-membered-heterocycle derivatives such as 9, 15, 23, and 25 are potent inhibitors of VEGFR, PDGFR, and c-Kit both enzymatically ( < 50 nM) and cellularly, ( < 50 nM). Furthermore, compounds 9 and 25 possess favorable pharmacokinetic profiles and demonstrate good efficacies against human HT-29 cell colon tumor xenografts in nude mice. Further evaluations are in progress.

  DOI：

  10.1021/jm101036c
• 作为产物：
  描述：

  5-carboxymethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 在 哌啶 、 硼烷四氢呋喃络合物 、 1-羟基苯并三唑 、 乙二醇 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 lithium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.75h， 生成 (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one
  参考文献：
  名称：

  Novel Potent Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitors: Synthesis, Structure−Activity Relationships, and Antitumor Activities of 2-Indolinone Derivatives

  摘要：

  The inhibition of receptor tyrosine kinases (RTKs) has become a successful approach in the development of anticancer agents. Many potent small-molecule kinase inhibitors have been discovered. We report herein a series of pyrrolo-fused-heterocycle-2-indolinone analogues as inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR). and c-Kit. Among them, some pyrrolo-fused six- and seven-membered-heterocycle derivatives such as 9, 15, 23, and 25 are potent inhibitors of VEGFR, PDGFR, and c-Kit both enzymatically ( < 50 nM) and cellularly, ( < 50 nM). Furthermore, compounds 9 and 25 possess favorable pharmacokinetic profiles and demonstrate good efficacies against human HT-29 cell colon tumor xenografts in nude mice. Further evaluations are in progress.

  DOI：

  10.1021/jm101036c
• 作为试剂：
  描述：

  (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 、 5-氟吲哚-2-酮 、 哌啶 在 (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以to give the title compound (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1 (256 mg, 90%) as a yellow solid的产率得到(R,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-ylpropyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one
  参考文献：
  名称：

  2-(2-oxoindoline-3-ylidene)methyl-5-(2-hydroxy-3-morpholin-4-yl-propyl)-6,7-dihydro-1H-pyrrol[3,2-C]pyridine-4(5H)-one compounds and use as protein kinase inhibitors

  摘要：

  Pyrrolo[3,2-c]pyridine-4-one-2-indolinone化合物，特别是2-(2-氧代吲哚-3-基亚甲基)-5-(2-羟基-3-吗啡啶-4-基-丙基)-6,7-二氢-1H-吡咯[3,2-c]吡啶-4(5H)-酮化合物。它们的制备方法和制药组合物，以及作为蛋白激酶抑制剂的制药用途。

  公开号：

  US08299069B2

文献信息

• 2-(2-OXOINDOLINE-3-YLIDENE)METHYL-5-(2-HYDROXY-3-MORPHOLIN-4-YL-PROPYL)-6,7-DIHYDRO-1H-PYRROL[3,2-C]PYRIDINE-4(5H)-ONE COMPOUNDS AND USE AS PROTEIN KINASE INHIBITORS
  申请人：Tang Peng Cho

  公开号：US20100160317A1

  公开（公告）日：2010-06-24

  Pyrrolo[3,2-c]pyridine-4-one-2-indolinone compounds, especially 2-(2-oxoindoline-3-ylidene)methyl-5-(2-hydroxy-3-morpholin-4-yl-propyl)-6,7-dihydro-1H-pyrrol[3,2-c]pyridine-4(5H)-one compounds. Their preparation and pharmaceutical composition, and pharmaceutical use as protein kinase inhibitors.

  吡咯并[3,2-c]吡啶-4-酮-2-吲哚酮化合物，特别是2-(2-氧基吲哚-3-基亚甲基)-5-(2-羟基-3-吗啉-4-基丙基)-6,7-二氢-1H-吡咯并[3,2-c]吡啶-4(5H)-酮化合物。它们的制备和制药组合物，以及作为蛋白激酶抑制剂的制药用途。
• 2-(2-OXOINDOLINE-3-YLIDENE)METHYL-5-(2-HYDROXY-3-MORPHOLIN-4-YL -PROPYL)-6,7-DIHYDRO -1H- PYRROL[3,2-C]PYRIDINE-4(5H)-ONE COMPOUNDS AND USE AS PROTEIN KINASE INHIBITORS
  申请人：Jiangsu Hengrui Medicine Co., Ltd.

  公开号：EP2179998B1

  公开（公告）日：2012-08-29
• US8299069B2
  申请人：——

  公开号：US8299069B2

  公开（公告）日：2012-10-30
• Novel Potent Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitors: Synthesis, Structure−Activity Relationships, and Antitumor Activities of 2-Indolinone Derivatives
  作者：Peng Cho Tang、Yi Dong Su、Jun Feng、Jian Hong Fu、Jiang Liang Yang、Lu Xiao、Jiang Hua Peng、Ya Li Li、Lei Zhang、Bing Hu、Ying Zhou、Fang Qiong Li、Bei Bei Fu、Li Guang Lou、Ai Shen Gong、Gao Hong She、Wei Hong Sun、Xian Tai Mong

  DOI：10.1021/jm101036c

  日期：2010.11.25

  The inhibition of receptor tyrosine kinases (RTKs) has become a successful approach in the development of anticancer agents. Many potent small-molecule kinase inhibitors have been discovered. We report herein a series of pyrrolo-fused-heterocycle-2-indolinone analogues as inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR). and c-Kit. Among them, some pyrrolo-fused six- and seven-membered-heterocycle derivatives such as 9, 15, 23, and 25 are potent inhibitors of VEGFR, PDGFR, and c-Kit both enzymatically ( < 50 nM) and cellularly, ( < 50 nM). Furthermore, compounds 9 and 25 possess favorable pharmacokinetic profiles and demonstrate good efficacies against human HT-29 cell colon tumor xenografts in nude mice. Further evaluations are in progress.
• 2-(2-oxoindoline-3-ylidene)methyl-5-(2-hydroxy-3-morpholin-4-yl-propyl)-6,7-dihydro-1H-pyrrol[3,2-C]pyridine-4(5H)-one compounds and use as protein kinase inhibitors
  申请人：Jiangsu Hengrui Medicine Co., Ltd.

  公开号：US08299069B2

  公开（公告）日：2012-10-30

  Pyrrolo[3,2-c]pyridine-4-one-2-indolinone compounds, especially 2-(2-oxoindoline-3-ylidene)methyl-5-(2-hydroxy-3-morpholin-4-yl-propyl)-6,7-dihydro-1H-pyrrol[3,2-c]pyridine-4(5H)-one compounds. Their preparation and pharmaceutical composition, and pharmaceutical use as protein kinase inhibitors.

  Pyrrolo[3,2-c]pyridine-4-one-2-indolinone化合物，特别是2-(2-氧代吲哚-3-基亚甲基)-5-(2-羟基-3-吗啡啶-4-基-丙基)-6,7-二氢-1H-吡咯[3,2-c]吡啶-4(5H)-酮化合物。它们的制备方法和制药组合物，以及作为蛋白激酶抑制剂的制药用途。