6-chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine | 848696-09-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 6-chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine
• 英文别名: 2-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-4-methoxy-3,5-dimethyl-1-oxidopyridin-1-ium；6-chloro-9-[(4-methoxy-3,5-dimethyl-1-oxidopyridin-1-ium-2-yl)methyl]purin-2-amine
• CAS: 848696-09-3
• 化学式: C₁₄H₁₅ClN₆O₂
• 分子量: 334.765
• InChiKey: FLKOQKIGYYKSHM-UHFFFAOYSA-N

物化性质

• 熔点：
  190-200 °C
• 沸点：
  697.5±65.0 °C(Predicted)
• 密度：
  1.55±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  104
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine 在 三氯氧磷 作用下， 反应 2.0h， 以24%的产率得到6-chloro-9-(6-chloro-4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine
  参考文献：
  名称：

  Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity

  摘要：

  Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 mu M in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 mu M in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (> 80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.

  DOI：

  10.1021/jm050752+
• 作为产物：
  描述：

  BIIB 021; 6-氯-9-[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]-9H-嘌呤-2-胺 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 以69%的产率得到6-chloro-9-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-ylmethyl)-9H-purin-2-ylamine
  参考文献：
  名称：

  Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity

  摘要：

  Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 mu M in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 mu M in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (> 80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.

  DOI：

  10.1021/jm050752+

文献信息

• 2-Aminopurine Analogs Having HSP90-Inhibiting Activity
  申请人：Kasibhatla Rao Srinivas

  公开号：US20070185064A1

  公开（公告）日：2007-08-09

  2-Aminopurine analogs are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

  本文描述了2-氨基嘌呤类似物，并证明或预测其在治疗和预防各种HSP90介导的疾病（如增生性疾病）中作为HSP90抑制剂具有实用价值。还描述和声称了这种化合物的合成方法和使用方法。
• Anti-Tumor Methods Using Multi Drug Resistance Independent Synthetic HSP90 Inhibitors
  申请人：Zhang Hong

  公开号：US20070105874A1

  公开（公告）日：2007-05-10

  The present invention provides a method of treating an individual having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a synthetic heterocyclic HSP90 inhibitor, wherein the activity of the HSP90 inhibitor is substantially independent of multi drug resistance. In one embodiment, the activity of the HSP90 inhibitor is substantially independent of P-gp and MRP expression.
• Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity
  作者：Srinivas R. Kasibhatla、Kevin Hong、Marco A. Biamonte、David J. Busch、Patricia L. Karjian、John L. Sensintaffar、Adeela Kamal、Rachel E. Lough、John Brekken、Karen Lundgren、Roy Grecko、Gregg A. Timony、Yingqing Ran、Robert Mansfield、Lawrence C. Fritz、Edgar Ulm、Francis J. Burrows、Marcus F. Boehm

  DOI：10.1021/jm050752+

  日期：2007.6.1

  Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 mu M in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 mu M in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (> 80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.