tert-butyl 4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)-sulfanyl]purin-9-yl]ethyl]piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: tert-butyl 4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)-sulfanyl]purin-9-yl]ethyl]piperidine-1-carboxylate
• 英文别名: tert-butyl 4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-carboxylate；tert-butyl 4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]purin-9-yl]ethyl]piperidine-1-carboxylate
• 化学式: C₂₄H₂₉BrN₆O₄S
• 分子量: 577.502
• InChiKey: DBXSCNVRLCZDMG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  143
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)-sulfanyl]purin-9-yl]ethyl]piperidine-1-carboxylate 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 2-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}ethyl)piperidine-1-yl]-2-oxoethanol
  参考文献：
  名称：

  Discovery of (2S)-1-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a Purine-Based Hsp90 Inhibitor

  摘要：

  Modulation of Hsp90 (heat shock protein 90) function has been recognized as an attractive approach for cancer treatment, since many cancer cells depend on Hsp90 to maintain cellular homeostasis. This has spurred the search for small-molecule Hsp90 inhibitors. Here we describe our lead optimization studies centered on the purine-based Hsp90 inhibitor 28a containing a piperidine moiety at the purine N9 position. In this study, key SAR was established for the piperidine N-substituent and for the congeners of the 1,3-benzodioxole at C8. These efforts led to the identification of orally bioavailable 28g that exhibits good in vitro profiles and a characteristic molecular biomarker signature of Hsp90 inhibition both in vitro and in vivo. Favorable pharmacokinetic properties along with significant antitumor effects in multiple human cancer xenograft models led to the selection of 28g (MPC-3100) as a clinical candidate.

  DOI：

  10.1021/jm3004619
• 作为产物：
  描述：

  4-哌啶乙醇 在 N-溴代丁二酰亚胺(NBS) 、 potassium carbonate 、 caesium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.0h， 生成 tert-butyl 4-[2-[6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)-sulfanyl]purin-9-yl]ethyl]piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of (2S)-1-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a Purine-Based Hsp90 Inhibitor

  摘要：

  Modulation of Hsp90 (heat shock protein 90) function has been recognized as an attractive approach for cancer treatment, since many cancer cells depend on Hsp90 to maintain cellular homeostasis. This has spurred the search for small-molecule Hsp90 inhibitors. Here we describe our lead optimization studies centered on the purine-based Hsp90 inhibitor 28a containing a piperidine moiety at the purine N9 position. In this study, key SAR was established for the piperidine N-substituent and for the congeners of the 1,3-benzodioxole at C8. These efforts led to the identification of orally bioavailable 28g that exhibits good in vitro profiles and a characteristic molecular biomarker signature of Hsp90 inhibition both in vitro and in vivo. Favorable pharmacokinetic properties along with significant antitumor effects in multiple human cancer xenograft models led to the selection of 28g (MPC-3100) as a clinical candidate.

  DOI：

  10.1021/jm3004619

文献信息

• THERAPEUTIC COMPOUNDS AND THEIR USE IN CANCER
  申请人：Bajji C. Ashok

  公开号：US20070299258A1

  公开（公告）日：2007-12-27

  The invention relates to compounds of Formulae I-III and their therapeutic uses.

  这项发明涉及到I-III式化合物及其治疗用途。
• Therapeutic compounds and their use in cancer
  申请人：Myriad Pharmaceuticals, Inc.

  公开号：US07595401B2

  公开（公告）日：2009-09-29

  The invention relates to compounds of Formula I and their therapeutic uses, wherein substituent A is chosen from a substituted or unsubstituted aryl, heteroaryl, heterocyclic, or carboxylic group, B is chosen from a substituted or unsubstituted piperidine, homopiperidine, piperazine, pyrrolidine or azetidine group, R1 is chosen from hydro, alkyl, aryl, heteroaryl amino and halo, and L1 and L2 are as defined in the specification.

  本发明涉及I式化合物及其治疗用途，其中取代基A选择自取代或未取代的芳基、杂芳基、杂环基或羧基，取代基B选择自取代或未取代的哌啶基、同哌啶基、吡咯烷基或氮杂环基，R1选择自氢、烷基、芳基、杂芳基氨基和卤素，L1和L2如说明书所定义。
• Purine-core inhibitors of HSP90 and their use in treating cancer
  申请人：Bajji Ashok C.

  公开号：US08476285B2

  公开（公告）日：2013-07-02

  The invention relates to compounds of Formulae I-III: and therapeutic uses thereof, wherein A is chosen from a substituted or unsubstituted aryl, heteroaryl, heterocyclic, or carbocyclic group; B is chosen from a substituted or unsubstituted piperidine, homopiperidine, piperazine, pyrrolidine or azetidine group; R1 is chosen from hydro, alkyl, aryl, heteroaryl, amino, or halo; and L1, L2, are as defined herein.

  本发明涉及I-III式化合物及其治疗用途，其中A选择取代或未取代的芳基，杂芳基，杂环或碳环基；B选择取代或未取代的哌啶，同哌啶，吡咯烷或氮杂环基；R1选择氢、烷基、芳基、杂芳基、氨基或卤素；L1，L2定义如本文所述。
• Therapeutic Compounds and Their Use in Treating Diseases and Disorders
  申请人：Bajji Ashok C.

  公开号：US20100292255A1

  公开（公告）日：2010-11-18

  The invention provides novel therapeutic compounds, pharmaceutical compositions comprising these compounds, and methods for using these compounds and compositions to treat diseases and disorders, such as cancer.

  该发明提供了新型治疗化合物、包含这些化合物的药物组合物以及使用这些化合物和组合物治疗疾病和疾病的方法，例如癌症。
• Discovery of an l-alanine ester prodrug of the Hsp90 inhibitor, MPC-3100
  作者：Se-Ho Kim、Rajendra Tangallapally、In Chul Kim、Richard Trovato、Daniel Parker、J. Scott Patton、Leslie Reeves、Chad Bradford、Daniel Wettstein、Vijay Baichwal、Damon Papac、Ashok Bajji、Robert Carlson、Kraig M. Yager

  DOI：10.1016/j.bmcl.2015.09.053

  日期：2015.11

  Various types of Hsp90 inhibitors have been and continue to undergo clinical investigation. One development candidate is the purine-based, synthetic Hsp90 inhibitor 1 (MPC-3100), which successfully completed a phase I clinical study. However, further clinical development of 1 was hindered by poor solubility and consequent formulation issues and promoted development of a more water soluble prodrug. Towards this end, numerous pro-moieties were explored in vitro and in vivo. These studies resulted in identification of L-alanine ester mesylate, 2i (MPC-0767), which exhibited improved aqueous solubility, adequate chemical stability, and rapid bioconversion without the need for solubilizing excipients. Based on improved physical characteristics and favorable PK and PD profiles, 2i mesylate was selected for further development. A convergent, scalable, chromatography-free synthesis for 2i mesylate was developed to support further clinical evaluation. (C) 2015 Elsevier Ltd. All rights reserved.