6-Cyclohexylmethoxy-N⁴-(4-methoxy-phenyl)-5-nitroso-pyrimidine-2,4-diamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 6-Cyclohexylmethoxy-N⁴-(4-methoxy-phenyl)-5-nitroso-pyrimidine-2,4-diamine
• 英文别名: 6-(cyclohexylmethoxy)-4-N-(4-methoxyphenyl)-5-nitrosopyrimidine-2,4-diamine
• 化学式: C₁₈H₂₃N₅O₃
• 分子量: 357.412
• InChiKey: VAWNEAWGVRMLFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,4-dichloro-6-(4-methoxyphenylamino)pyrimidine 在 sodium 、 溶剂黄146 、 三乙胺 、 三氟乙酸 、 sodium nitrite 作用下， 以 正丁醇 为溶剂， 生成 6-Cyclohexylmethoxy-N⁴-(4-methoxy-phenyl)-5-nitroso-pyrimidine-2,4-diamine
  参考文献：
  名称：

  4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2

  摘要：

  The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1 = 2.9 +/- 0.1 muM and IC50 vs cdk2/cyclinA3 = 2.2 +/- 0.6 muM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O-4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1 = 12 +/- 2 muM and cdk2/cyclinA3 = 13 +/- 4 muM) retaining significant activity. Substitutions at the N-6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1 = 35 +/- 3 muM and cdk2/cyclinA3=43 +/- 3 muM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Angstrom resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00884-3