9-cyclopentyl-3-methoxy-9H-pyrimido[5′,4′:4,5]pyrrolo[2,3-c]pyridazin-7-amine | 1169699-42-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 9-cyclopentyl-3-methoxy-9H-pyrimido[5′,4′:4,5]pyrrolo[2,3-c]pyridazin-7-amine
• 英文别名: 9-Cyclopentyl-3-methoxy-9H-pyrimido[5',4':4,5]pyrrolo[2,3-c]pyridazin-7-amine；8-cyclopentyl-12-methoxy-4,6,8,10,11-pentazatricyclo[7.4.0.02,7]trideca-1(13),2,4,6,9,11-hexaen-5-amine
• CAS: 1169699-42-6
• 化学式: C₁₄H₁₆N₆O
• 分子量: 284.321
• InChiKey: PVUSXGJEQXPUIX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  91.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  9-cyclopentyl-3-methoxy-9H-pyrimido[5′,4′:4,5]pyrrolo[2,3-c]pyridazin-7-amine 在 1,1'-双(二苯基膦)二茂铁 、 甲酸 、 palladium diacetate 、 吡啶盐酸盐 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.66h， 生成 9-cyclopentyl-9H-pyrimido[5′,4′:4,5]pyrrolo[2,3-c]pyridazin-7-amine
  参考文献：
  名称：

  Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

  摘要：

  We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

  DOI：

  10.1021/jm500118j
• 作为产物：
  描述：

  N⁴-cyclopentyl-5-(3,6-dimethoxy-4-pyridazinyl)-2,4-pyrimidinediamine 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 以95%的产率得到9-cyclopentyl-3-methoxy-9H-pyrimido[5′,4′:4,5]pyrrolo[2,3-c]pyridazin-7-amine
  参考文献：
  名称：

  Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

  摘要：

  We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb+) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

  DOI：

  10.1021/jm500118j

文献信息

• Fused Pyridine, Pyrimidine and Triazine Compounds as Cell Cycle Inhibitors
  申请人：Connors Richard V.

  公开号：US20110142796A1

  公开（公告）日：2011-06-16

  Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of CDK4-mediated disorders, such as cancer. The subject compounds are fused pyridine, pyrimide and triazine derivatives.

  本发明提供了一种在治疗CDK4介导的疾病（如癌症）中有用的化合物、药物组合物和方法。所述化合物是融合的吡啶、嘧啶和三嗪衍生物。
• Fused pyridine, pyrimidine and triazine compounds as cell cycle inhibitors
  申请人：Amgen Inc.

  公开号：US08980903B2

  公开（公告）日：2015-03-17

  Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of CDK4-mediated disorders, such as cancer. The subject compounds are fused pyridine, pyrimide and triazine derivatives.

  本文提供了一种在治疗CDK4介导的疾病，如癌症中有用的化合物、制药组合物和方法。所述化合物为融合的吡啶、嘧啶和三嗪衍生物。
• FUSED PYRIDINE, PYRIMIDINE AND TRIAZINE COMPOUNDS AS CELL CYCLE INHIBITORS
  申请人：AMGEN INC.

  公开号：US20140350244A1

  公开（公告）日：2014-11-27

  Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of CDK4-mediated disorders, such as cancer. The subject compounds are fused pyridine, pyrimide and triazine derivatives.

  本发明提供了在治疗CDK4介导的疾病，如癌症中有用的化合物、制药组合物和方法。所述化合物为融合的吡啶、嘧啶和三嗪衍生物。
• US8841312B2
  申请人：——

  公开号：US8841312B2

  公开（公告）日：2014-09-23
• US8980903B2
  申请人：——

  公开号：US8980903B2

  公开（公告）日：2015-03-17