tert-butyl (5R)-1-{[(5R,6S)-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazol-2-yl]carbonyl}-5-ethyl-L-prolinate | 1443977-81-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: tert-butyl (5R)-1-{[(5R,6S)-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazol-2-yl]carbonyl}-5-ethyl-L-prolinate
• CAS: 1443977-81-8
• 化学式: C₃₃H₃₉Cl₂N₃O₃S
• 分子量: 628.663
• InChiKey: FSHUSZLXFGFAAQ-RAGLCNHVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.35
• 重原子数：
  42.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  62.21
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  tert-butyl (5R)-1-{[(5R,6S)-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazol-2-yl]carbonyl}-5-ethyl-L-prolinate 在 1-羟基苯并三唑 、 苯甲醚 、 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 、 三氟乙酸 作用下， 以 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (5R,6S)-5,6-bis(4-chlorophenyl)-2-[((2S,5R)-2-{[(3S)-3,4-dimethylpiperazin-1-yl]carbonyl}-5-ethylpyrrolidin-1-yl)carbonyl]-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole
  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：

  CBZ-L-焦谷氨酸 在 高氯酸 、 copper(I) bromide dimethylsulfide complex 、 palladium 10% on activated carbon 、 氢气 、 三乙基硼氢化锂 、 对甲苯磺酸 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 水 为溶剂， -78.0~20.0 ℃ 、101.33 kPa 条件下， 反应 98.0h， 生成 tert-butyl (5R)-1-{[(5R,6S)-5,6-bis(4-chlorophenyl)-3-isopropyl-6-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazol-2-yl]carbonyl}-5-ethyl-L-prolinate
  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