benzyl (2S,5R)-2-{[(3R)-3,4-dimethylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidine-1-carboxylate | 1033714-69-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: benzyl (2S,5R)-2-{[(3R)-3,4-dimethylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidine-1-carboxylate
• 英文别名: benzyl (2S,5R)-2-[(3R)-3,4-dimethylpiperazine-1-carbonyl]-5-ethylpyrrolidine-1-carboxylate
• CAS: 1033714-69-0
• 化学式: C₂₁H₃₁N₃O₃
• 分子量: 373.495
• InChiKey: YNYDQFQJWUTPMN-QRQLOZEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  53.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  benzyl (2S,5R)-2-{[(3R)-3,4-dimethylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidine-1-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 24.0h， 以100%的产率得到(2R)-1,2-dimethyl-4-[(5R)-5-ethyl-L-prolyl]piperazine
  参考文献：
  名称：

  Synthesis and evaluation of novel orally active p53–MDM2 interaction inhibitors

  摘要：

  We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.04.056
• 作为产物：
  描述：

  1-benzyl 2-tert-butyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate 在 copper(I) bromide dimethylsulfide complex 、 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 乙醚 、 二氯甲烷 、 氯仿 为溶剂， 反应 48.5h， 生成 benzyl (2S,5R)-2-{[(3R)-3,4-dimethylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidine-1-carboxylate
  参考文献：
  名称：

  Synthesis and evaluation of novel orally active p53–MDM2 interaction inhibitors

  摘要：

  We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.04.056

文献信息

• Synthesis and evaluation of novel orally active p53–MDM2 interaction inhibitors
  作者：Masaki Miyazaki、Hiroyuki Naito、Yuuichi Sugimoto、Keisuke Yoshida、Haruko Kawato、Tooru Okayama、Hironari Shimizu、Masaya Miyazaki、Mayumi Kitagawa、Takahiko Seki、Setsuko Fukutake、Yoshinobu Shiose、Masashi Aonuma、Tsunehiko Soga

  DOI：10.1016/j.bmc.2013.04.056

  日期：2013.7

  We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. (C) 2013 Elsevier Ltd. All rights reserved.