N⁴-cyclohexyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine | 842129-17-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N⁴-cyclohexyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine
• 英文别名: 4-cyclohexylamino-2-(4-(4-methylpiperazin-1-yl)phenylamino)-5-nitropyrimidine；intermediate 15；4-N-cyclohexyl-2-N-[4-(4-methylpiperazin-1-yl)phenyl]-5-nitropyrimidine-2,4-diamine
• CAS: 842129-17-3
• 化学式: C₂₁H₂₉N₇O₂
• 分子量: 411.507
• InChiKey: SWNWPOIQFPSFMQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  102
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N⁴-cyclohexyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine 在 palladium 10% on activated carbon 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 50.0 ℃ 、101.33 kPa 条件下， 反应 18.0h， 生成 8-phenylamino-9-cyclohexyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)-9H-purine
  参考文献：
  名称：

  Structural Optimization and Structure–Activity Relationships of N²-(4-(4-Methylpiperazin-1-yl)phenyl)-N⁸-phenyl-9H-purine-2,8-diamine Derivatives, a New Class of Reversible Kinase Inhibitors Targeting both EGFR-Activating and Resistance Mutations

  摘要：

  This paper describe the structural optimization of a hit compound, N-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-8-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.

  DOI：

  10.1021/jm301365e
• 作为产物：
  描述：

  1-甲基-4-(4-硝基苯基)哌嗪 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 、 正丁醇 为溶剂， 反应 14.0h， 生成 N⁴-cyclohexyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine
  参考文献：
  名称：

  Structural Optimization and Structure–Activity Relationships of N²-(4-(4-Methylpiperazin-1-yl)phenyl)-N⁸-phenyl-9H-purine-2,8-diamine Derivatives, a New Class of Reversible Kinase Inhibitors Targeting both EGFR-Activating and Resistance Mutations

  摘要：

  This paper describe the structural optimization of a hit compound, N-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-8-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N-2-(4-(4-methylpiperazin-1-yl)phenyl)-N-8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.

  DOI：

  10.1021/jm301365e

文献信息

• Arylamino Purine Derivatives, Preparation Method and Pharmaceutical Use Thereof
  申请人：Yang Shengyong

  公开号：US20130203986A1

  公开（公告）日：2013-08-08

  Arylamino purine derivatives represented by formula I and their preparation method are disclosed, wherein each substituent is defined as in the description. The derivatives have an inhibitory effect on non-small cell lung cancer with deletion mutation of exon 19 or L858R point mutation of exon 21 in epidermal growth factor receptor (EGFR).

  公开了由公式I所代表的芳基氨基嘌呤衍生物及其制备方法，其中每个取代基在说明书中有定义。这些衍生物对于表皮生长因子受体（EGFR）的外显子19缺失突变或外显子21的L858R点突变所致的非小细胞肺癌具有抑制作用。
• ARYLAMINO PURINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF
  申请人：Si Chuan University

  公开号：EP2578584B1

  公开（公告）日：2020-08-12
• [EN] TRIAZOLOPYRIMIDINE DERIVATIVES AS GLYCOGEN SYNTHASE KINASE 3 INHIBITORS<br/>[FR] DERIVES DE TRIAZOLOPYRIMIDINE EN TANT QU'INHIBITEURS DE GLYCOGENE SYNTHASE KINASE 3
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005012304A3

  公开（公告）日：2007-04-26
• WO2006/74985
  申请人：——

  公开号：——

  公开（公告）日：——
• TRIAZOLOPYRIMIDINE DERIVATIVES AS GLYCOGEN SYNTHASE KINASE 3 INHIBITORS
  申请人：Janssen Pharmaceutica NV

  公开号：EP1781659B1

  公开（公告）日：2008-11-05