5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine | 1126602-48-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine
• 英文别名: 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine propanamide
• CAS: 1126602-48-9
• 化学式: C₁₀H₈ClN₅
• 分子量: 233.66
• InChiKey: WSLPSVJNLGXWQJ-UHFFFAOYSA-N

物化性质

• 熔点：
  245.2-246.3 °C
• 沸点：
  629.0±65.0 °C(Predicted)
• 密度：
  1.681±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  93.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-奈硫酚 、 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine 在 potassium carbonate 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 0.5h， 以70%的产率得到5-(1-naphthylsulfanyl)-9H-pyrimido[4,5-b]indole-2,4-diamine
  参考文献：
  名称：

  Synthesis and evaluation of 5-(arylthio)-9 H -pyrimido[4,5- b ]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents

  摘要：

  In an effort to optimize the structural requirements for combined cytostatic and cytotoxic effects in single agents, a series of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines 3-7 were synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs) as well as thymidylate synthase (TS). The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-bromo/5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate aryl thiols. A novel four step synthetic scheme to the common intermediate was developed which is more efficient relative to the previously reported six-step sequence. Biological evaluation of these compounds indicated dual activity in RTKs and human TS (hTS). In the VEGFR-2 assay, compound 5 was equipotent to the standard compound semaxanib and was better than standard TS inhibitor pemetrexed, in the hTS assay. Compounds 3, 6 and 7 were nanomolar inhibitors of hTS and were several fold better than pemetrexed. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.02.018
• 作为产物：
  描述：

  N-(4,5-dichloro-9H-pyrimido[4,5-b]indol-2-yl)-2,2-dimethylpropanamide 在 甲醇 、 氨 作用下， 反应 48.0h， 以39%的产率得到5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine
  参考文献：
  名称：

  具有设计联合化疗潜力的单一药物：取代嘧啶并 [4,5-b] 吲哚作为受体酪氨酸激酶和胸苷酸合成酶抑制剂以及作为抗肿瘤剂的合成和评价

  摘要：

  抗血管生成剂 (AA) 与细胞毒剂的组合在癌症治疗中显示出巨大的前景，目前正在进行多项此类临床试验。我们设计、合成并评估了两种化合物，它们分别抑制血管内皮生长因子受体 2 (VEGFR-2) 和血小板衍生生长因子受体 β (PDGFR-β) 以产生抗血管生成作用，并且还抑制人胸苷酸合酶 (hTS ) 用于单一药物的细胞毒性作用。这些化合物的合成涉及常见中间体 5-chloro-9 H - pyrimido[4,5- b]indole-2,4-diamine 与适当的苯硫醇。这两种单一药物对 VEGFR-2、PDGFR-β 和 hTS 的抑制效力优于或接近标准。在 COLO-205 异种移植小鼠模型中，与标准药物以及对照和因此在体内证明了有效的肿瘤生长抑制、转移抑制和抗血管生成作用。这些化合物在单一药剂中提供联合化疗的潜力。

  DOI：

  10.1021/jm9011142

文献信息

• TRICYCLIC COMPOUNDS HAVING CYTOSTATIC AND/OR CYTOTOXIC ACTIVITY AND METHODS OF USE THEREOF
  申请人：Gangjee Aleem

  公开号：US20090062318A1

  公开（公告）日：2009-03-05

  The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.

  本发明提供了一种三环化合物，其在单个分子中具有受体酪氨酸激酶、二氢叶酸还原酶、胸苷酸合成酶和/或二氢甲氧呋喃脱氢酶的抑制活性，这些化合物具有细胞静止和细胞毒活性，可用作抗血管生成和抗肿瘤药物。还提供了利用这些抑制剂治疗肿瘤细胞和其他增殖性疾病和紊乱的方法。
• Tricyclic Compounds Having Cytostatic and/or Cytoxic Activity and Methods of Use Thereof
  申请人：Gangjee Aleem

  公开号：US20110207757A1

  公开（公告）日：2011-08-25

  The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.

  本发明提供了三环化合物，其在单一分子中具有受体酪氨酸激酶、二氢叶酸还原酶、胸腺嘧啶合成酶和/或二氢乳酸脱氢酶抑制活性，具有细胞增殖抑制和细胞毒性活性，可用作抗血管生成和抗肿瘤剂。还提供了利用这些抑制剂治疗肿瘤细胞和其他增殖性疾病和疾病的方法。
• Tricyclic Compounds Having Cytostatic and/or Cytotoxic Activity and Methods of Use Thereof
  申请人：Duquesne University of the Holy Ghost

  公开号：US20150141445A1

  公开（公告）日：2015-05-21

  The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.

  本发明提供了三环化合物，其在单个分子中具有受体酪氨酸激酶、二氢叶酸还原酶、胸腺嘧啶合成酶和/或二氢乳酸脱氢酶抑制活性，具有细胞增殖抑制和细胞毒性活性，可用作抗血管生成和抗肿瘤剂。还提供了利用这些抑制剂治疗肿瘤细胞和其他增殖性疾病和疾病的方法。
• Tricyclic compounds having cytostatic and/or cytotoxic activity and methods of use thereof
  申请人：Duquesne University of the Holy Ghost

  公开号：US10208051B2

  公开（公告）日：2019-02-19

  The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.

  本发明提供了在单分子中具有细胞抑制和细胞毒性活性的三环化合物，它们具有受体酪氨酸激酶、二氢叶酸还原酶、胸腺嘧啶酸合成酶和/或二氢烟酸脱氢酶抑制活性，可用作抗血管生成和抗肿瘤药物。此外，还提供了利用这些抑制剂治疗肿瘤细胞和其他增殖性疾病和失调的方法。
• US7960400B2
  申请人：——

  公开号：US7960400B2

  公开（公告）日：2011-06-14