5-chloro-N⁴-(2-(isopropylsulfonyl)phenyl)-N²-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 5-chloro-N⁴-(2-(isopropylsulfonyl)phenyl)-N²-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine
• 英文别名: 5-chloro-2-N-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine
• 化学式: C₂₃H₂₆ClN₅O₃S
• 分子量: 488.01
• InChiKey: NEBHHPFFBCTEBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-chloro-N⁴-(2-(isopropylsulfonyl)phenyl)-N²-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine 在 N-溴代丁二酰亚胺(NBS) 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 2.0h， 以51%的产率得到5-chloro-N⁴-(2-(isopropylsulfonyl)phenyl)-N²-(7-methoxy-3,4-dihydroisoquinolin-6-yl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors

  摘要：

  Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.12.004
• 作为产物：
  描述：

  N-<2-(4-methoxy-3-nitrophenyl)ethyl>-2,2,2-trifluoroacetamide 在 盐酸 、 硫酸 、 palladium on activated charcoal 、 氢气 、 palladium diacetate 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 乙酸乙酯 为溶剂， 反应 45.0h， 生成 5-chloro-N⁴-(2-(isopropylsulfonyl)phenyl)-N²-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrimidine-2,4-diamine
  参考文献：
  名称：

  PYRIMIDINE-2,4-DIAMINE DERIVATIVE AND ANTICANCER PHARMACEUTICAL COMPOSITION COMPRISING SAME AS EFFECTIVE INGREDIENT

  摘要：

  本发明涉及一种嘧啶-2,4-二胺衍生物或其药学上可接受的盐，以及包含该衍生物作为有效成分的用于预防或治疗癌症的药物组合物。根据本发明的化合物具有良好的抑制间变性淋巴瘤激酶（ALK）活性的效果，从而能够增强对含有间变性淋巴瘤激酶（ALK）融合蛋白（如EML4-ALK、NPM-ALK等）的癌细胞的治疗效果，并有望有效抑制癌症的复发。因此，该化合物可有效地用于预防或治疗癌症的药物组合物中。

  公开号：

  US20170145007A1

文献信息

• PYRIMIDINE-2,4-DIAMINE DERIVATIVE AND ANTICANCER PHARMACEUTICAL COMPOSITION COMPRISING SAME AS EFFECTIVE INGREDIENT
  申请人：KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY

  公开号：US20170145007A1

  公开（公告）日：2017-05-25

  The present invention relates to a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for prevention or treatment of cancer comprising the same as an effective ingredient. A compound according to the present invention has the good effect of inhibiting anaplastic lymphoma kinase (ALK) activity, whereby a therapeutic effect on cancer cells having an anaplastic lymphoma kinase (ALK) fusion protein such as EML4-ALK, NPM-ALK, etc. can be enhanced and it is expected that a recurrence of cancer will be effectively inhibited. As such, the compound can be effectively used in a pharmaceutical composition for prevention or treatment of cancer.

  本发明涉及一种嘧啶-2,4-二胺衍生物或其药学上可接受的盐，以及包含该衍生物作为有效成分的用于预防或治疗癌症的药物组合物。根据本发明的化合物具有良好的抑制间变性淋巴瘤激酶（ALK）活性的效果，从而能够增强对含有间变性淋巴瘤激酶（ALK）融合蛋白（如EML4-ALK、NPM-ALK等）的癌细胞的治疗效果，并有望有效抑制癌症的复发。因此，该化合物可有效地用于预防或治疗癌症的药物组合物中。
• Pyrimidine-2,4-diamine derivative and anticancer pharmaceutical composition comprising same as effective ingredient
  申请人：KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY

  公开号：US10053458B2

  公开（公告）日：2018-08-21

  The present invention relates to a pyrimidine-2,4-diamine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for prevention or treatment of cancer comprising the same as an effective ingredient. A compound according to the present invention has the good effect of inhibiting anaplastic lymphoma kinase (ALK) activity, whereby a therapeutic effect on cancer cells having an anaplastic lymphoma kinase (ALK) fusion protein such as EML4-ALK, NPM-ALK, etc. can be enhanced and it is expected that a recurrence of cancer will be effectively inhibited. As such, the compound can be effectively used in a pharmaceutical composition for prevention or treatment of cancer.

  本发明涉及一种嘧啶-2,4-二胺衍生物或其药学上可接受的盐，以及一种预防或治疗癌症的药物组合物，该组合物作为有效成分包含嘧啶-2,4-二胺衍生物或其药学上可接受的盐。根据本发明的化合物具有抑制无性淋巴瘤激酶（ALK）活性的良好效果，从而可以增强对具有无性淋巴瘤激酶（ALK）融合蛋白（如 EML4-ALK、NPM-ALK 等）的癌细胞的治疗效果，并有望有效抑制癌症复发。因此，该化合物可有效地用于预防或治疗癌症的药物组合物中。
• Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors
  作者：Raghavendra Achary、Jeong In Yun、Chi Min Park、Gangadhar Rao Mathi、Joo Yun Lee、Jae Du Ha、Chong Hak Chae、Sunjoo Ahn、Chi Hoon Park、Chong Ock Lee、Jong Yeon Hwang、Chang-Soo Yun、Hee Jung Jung、Sung Yun Cho、Hyoung Rae Kim、Pilho Kim

  DOI：10.1016/j.bmc.2015.12.004

  日期：2016.1

  Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378. (C) 2015 Elsevier Ltd. All rights reserved.