8-(3-ethynylphenylamino)-9-cyclopentyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)-9H-purine | 1350545-11-7

• 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: 8-(3-ethynylphenylamino)-9-cyclopentyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)-9H-purine
• 英文别名: 9-cyclopentyl-8-N-(3-ethynylphenyl)-2-N-[4-(4-methylpiperazin-1-yl)phenyl]purine-2,8-diamine
• CAS: 1350545-11-7
• 化学式: C₂₉H₃₂N₈
• 分子量: 492.627
• InChiKey: OYORTPGVBRNZTB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  74.1
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1,4-Diazabicyclo[2.2.2]octane;(3-ethynylphenyl)carbamodithioic acid 在 三光气 、 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 二氯甲烷 为溶剂， 反应 17.0h， 生成 8-(3-ethynylphenylamino)-9-cyclopentyl-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

文献信息

• [EN] ARYLAMINO PURINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL USE THEREOF<br/>[FR] DÉRIVÉS ARYLAMINÉS DE PURINE, LEUR PROCÉDÉ DE PRÉPARATION ET LEUR UTILISATION PHARMACEUTIQUE
  申请人：SI CHUAN UNIVERSITY

  公开号：WO2011147066A1

  公开（公告）日：2011-12-01

  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).

  本发明揭示了由公式I表示的芳基氨基嘌呤衍生物及其制备方法，其中每个取代基在描述中有定义。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：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
• US9096601B2
  申请人：——

  公开号：US9096601B2

  公开（公告）日：2015-08-04
• Structural Optimization and Structure–Activity Relationships of <i>N</i>²-(4-(4-Methylpiperazin-1-yl)phenyl)-<i>N</i>⁸-phenyl-9<i>H</i>-purine-2,8-diamine Derivatives, a New Class of Reversible Kinase Inhibitors Targeting both EGFR-Activating and Resistance Mutations
  作者：Jiao Yang、Li-Jiao Wang、Jing-Jing Liu、Lei Zhong、Ren-Lin Zheng、Yong Xu、Pan Ji、Chun-Hui Zhang、Wen-Jing Wang、Xing-Dong Lin、Lin-Li Li、Yu-Quan Wei、Sheng-Yong Yang

  DOI：10.1021/jm301365e

  日期：2012.12.13

  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.