苹果酸法米替尼 | 1256377-67-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 中文名称: 苹果酸法米替尼
• 英文名称: (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylaminoethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one L-malate
• 英文别名: Famitinib malate；5-[2-(diethylamino)ethyl]-2-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-3-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4-one;(2S)-2-hydroxybutanedioic acid
• CAS: 1256377-67-9
• 化学式: C₄H₆O₅*C₂₃H₂₇FN₄O₂
• 分子量: 544.58
• InChiKey: JNDRBKCNKMZANY-QLTVYZEUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  163
• 氢给体数：
  5
• 氢受体数：
  9

制备方法与用途

苹果酸法米替尼(SHR1020苹果酸)是一种口服活性多靶向激酶抑制剂，能够抑制c-kit、VEGFR-2和PDGFRβ的活性，其IC50值分别为2.3nM、4.7nM和6.6nM。这种药物能诱导细胞凋亡，并且在人胃癌细胞和异种移植物中表现出强大的抗肿瘤活性，可用于癌症研究[1][2]。

反应信息

• 作为产物：
  描述：

  2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid 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 、 lithium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.33h， 生成 苹果酸法米替尼
  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

文献信息

• WO2007/85188
  申请人：——

  公开号：——

  公开（公告）日：——
• 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.