(2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid | 112513-48-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid
• 英文别名: (2S,3S)-3-[(2-methylpropan-2-yl)oxy]-2-(phenylmethoxycarbonylamino)butanoic acid
• CAS: 112513-48-1
• 化学式: C₁₆H₂₃NO₅
• 分子量: 309.362
• InChiKey: QJYMOTAFFJDTAG-AAEUAGOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3S)-2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)butanoic acid 在 N-甲基吗啉 、 tris-(dibenzylideneacetone)dipalladium(0) 、 全氟丁基磺酰氟 、 sodium hydride 、 caesium carbonate 、 triethylamine tris(hydrogen fluoride) 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 、 mineral oil 为溶剂， 反应 49.92h， 生成 tert-butyl 4-(4-((S)-1-((4-((R)-4-((R)-1-fluoroethyl)-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)ethyl)benzyl)piperazine-1-carboxylate
  参考文献：
  名称：

  [EN] MUTANT IDH1 INHIBITORS
  [FR] INHIBITEURS DE LA IDH1 MUTANTE

  摘要：

  本申请提供了化合物的化学式I: 化学式(I)，这些化合物可用作突变IDH1的抑制剂，制药组合物，并用于治疗癌症。

  公开号：

  WO2017213910A1

文献信息

• [EN] 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH<br/>[FR] 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES COMME INHIBITEURS D'IDH MUTANTE
  申请人：NOVARTIS AG

  公开号：WO2014141104A1

  公开（公告）日：2014-09-18

  The invention is directed to a formula (I), or a pharmamceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

  这项发明涉及一种式(I)的配方，或其药用可接受的盐，其中R1、R2a、R2b和R3-R7在此处。该发明还涉及含有式(I)化合物的组合物，以及在抑制具有新型活性的突变IDH蛋白中使用这种化合物的用途。该发明还涉及在治疗与这种突变IDH蛋白相关的疾病或紊乱中使用式(I)化合物，包括但不限于细胞增殖紊乱，如癌症。
• Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Orally Bioavailable and Brain Penetrant Mutant IDH1 Inhibitors
  作者：Qian Zhao、James R. Manning、James Sutton、Abran Costales、Martin Sendzik、Cynthia M. Shafer、Julian R. Levell、Gang Liu、Thomas Caferro、Young Shin Cho、Mark Palermo、Gregg Chenail、Julia Dooley、Brian Villalba、Ali Farsidjani、Jinyun Chen、Stephanie Dodd、Ty Gould、Guiqing Liang、Kelly Slocum、Minying Pu、Brant Firestone、Joseph Growney、Tycho Heimbach、Raymond Pagliarini

  DOI：10.1021/acsmedchemlett.8b00182

  日期：2018.7.12

  Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of

  突变异柠檬酸脱氢酶1（IDH1）是治疗各种癌症（例如AML，神经胶质瘤和胶质母细胞瘤）的有吸引力的治疗靶标。我们已经评估了3-pyrimidin-4-yl-oxazolidin-2-ones作为与IDH1 R132H的变构，诱导口袋结合的突变IDH1抑制剂。这封信描述了针对改善化合物的体外和体内代谢稳定性的SAR探索，从而将19鉴定为有效的和选择性的突变IDH1抑制剂，该IDH1抑制剂已证明在啮齿动物中具有大脑渗透性和出色的口服生物利用度。在临床前患者衍生的IDH1突变异种移植肿瘤模型研究中，19 有效地抑制了生物标记物2-HG的产生。
• Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
  作者：Young Shin Cho、Julian R. Levell、Gang Liu、Thomas Caferro、James Sutton、Cynthia M. Shafer、Abran Costales、James R. Manning、Qian Zhao、Martin Sendzik、Michael Shultz、Gregg Chenail、Julia Dooley、Brian Villalba、Ali Farsidjani、Jinyun Chen、Raviraj Kulathila、Xiaoling Xie、Stephanie Dodd、Ty Gould、Guiqing Liang、Tycho Heimbach、Kelly Slocum、Brant Firestone、Minying Pu、Raymond Pagliarini、Joseph D. Growney

  DOI：10.1021/acsmedchemlett.7b00342

  日期：2017.10.12

  Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the

  突变IDH1的抑制作用正在临床上评估为Arg 132处具有热点突变的各种癌症的有前途的治疗选择。确定了IDH1 R132H的变构，诱导口袋后，我们探索了3-嘧啶-4-基-恶唑烷-2-酮作为IDH1突变体抑制剂，用于体内调节2-HG的产生和潜在的脑渗透。我们在这里报告优化工作，以鉴定临床候选者IDH305（13），这是一种有效且选择性的突变体IDH1抑制剂，已在啮齿动物中证明了其对大脑的暴露。该化合物在临床上的临床前表征患者体内IDH1突变异种移植肿瘤模型中2-HG降低与疗效的相关性。IDH305（13）已进入用于治疗具有IDH1突变的癌症的人类临床试验。
• 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
  申请人：NOVARTIS AG

  公开号：US20150152093A1

  公开（公告）日：2015-06-04

  The invention is directed to a formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b and R 3 -R 7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

  该发明涉及一种公式(I)或其药学上可接受的盐，其中R1、R2a、R2b和R3-R7如下。该发明还涉及含有公式(I)化合物的组合物，并且涉及使用这些化合物来抑制具有新型活性的突变IDH蛋白质。该发明进一步涉及使用公式(I)化合物来治疗与这种突变IDH蛋白质相关的疾病或障碍，包括但不限于细胞增殖障碍，如癌症。
• 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
  申请人：NOVARTIS AG

  公开号：US10112931B2

  公开（公告）日：2018-10-30

  The invention is directed to a formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.

  本发明涉及式 (I)： 或其药学上可接受的盐，其中 R1、R2a、R2b 和 R3-R7 在此处。本发明还涉及含有式（I）化合物的组合物，以及此类化合物在抑制具有新变态活性的突变 IDH 蛋白中的用途。本发明进一步涉及式（I）化合物在治疗与此类突变IDH蛋白相关的疾病或紊乱中的用途，包括但不限于细胞增殖紊乱，如癌症。