tert-butyl (3S,4S)-3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl (3S,4S)-3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate
• 英文别名: (3S,4S)-tert-butyl 3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate
• 化学式: C₁₆H₂₃FN₂O₂
• 分子量: 294.369
• InChiKey: FYDLKIMTIIGWBV-UONOGXRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  55.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (3S,4S)-3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四氧化锇 、 potassium carbonate 、 1-羟基苯并三唑 、 N-甲基吗啉氧化物 、 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 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 tert-butyl (3S,4S)-4-(3-fluorophenyl)-3-(5-(4-formyl-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamido)piperidine-1-carboxylate
  参考文献：
  名称：

  发现吡唑-噻吩衍生物为高度有效的口服活性Akt抑制剂

  摘要：

  在构象限制策略的基础上，获得了一系列表现出良好的Akt抑制活性的吡唑-噻吩衍生物，从而发现了化合物1d和1o对多种血液癌细胞具有优异的体外抗肿瘤作用及其诱导潜力。凋亡，阻断S期的细胞周期，并显着抑制癌细胞Akt激酶下游生物标记的磷酸化。其中，化合物1o在MM1S异种移植模型中也表现出良好的PK特性，并抑制了约40％的肿瘤生长。化合物1o可能是进一步开发的潜在候选者。

  DOI：

  10.1016/j.ejmech.2019.07.017
• 作为产物：
  描述：

  3-fluorocinnamaldehyde 在 (2S)-2-[二苯基[(三甲基硅酯)氧基]甲基]-吡咯烷 、 三乙基硅烷 、 铁粉 、 氯化铵 、 苯甲酸 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 10.0h， 生成 tert-butyl (3S,4S)-3-amino-4-(3-fluorophenyl)piperidine-1-carboxylate
  参考文献：
  名称：

  发现吡唑-噻吩衍生物为高度有效的口服活性Akt抑制剂

  摘要：

  在构象限制策略的基础上，获得了一系列表现出良好的Akt抑制活性的吡唑-噻吩衍生物，从而发现了化合物1d和1o对多种血液癌细胞具有优异的体外抗肿瘤作用及其诱导潜力。凋亡，阻断S期的细胞周期，并显着抑制癌细胞Akt激酶下游生物标记的磷酸化。其中，化合物1o在MM1S异种移植模型中也表现出良好的PK特性，并抑制了约40％的肿瘤生长。化合物1o可能是进一步开发的潜在候选者。

  DOI：

  10.1016/j.ejmech.2019.07.017

文献信息

• Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design
  作者：Xiaowu Dong、Wenhu Zhan、Mengting Zhao、Jinxin Che、Xiaoyang Dai、Yizhe Wu、Lei Xu、Yubo Zhou、Yanmei Zhao、Tian Tian、Gang Cheng、Zegao Jin、Jia Li、Yanfei Shao、Qiaojun He、Bo Yang、Qinjie Weng、Yongzhou Hu

  DOI：10.1021/acs.jmedchem.9b00891

  日期：2019.8.8

  A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, Al2, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure activity relationship of compound Al2, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Aktl and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
• Phenotypic Screening-Based Identification of 3,4-Disubstituted Piperidine Derivatives as Macrophage M2 Polarization Modulators: An Opportunity for Treating Multiple Sclerosis
  作者：Qinjie Weng、Jinxin Che、Zhikang Zhang、Jiahuan Zheng、Wenhu Zhan、Sendong Lin、Tian Tian、Jincheng Wang、Renhua Gai、Yongzhou Hu、Bo Yang、Qiaojun He、Xiaowu Dong

  DOI：10.1021/acs.jmedchem.8b01635

  日期：2019.4.11

  Multiple sclerosis (MS) is a disease of the autoimmune-mediated disorder in the central nervous system, for which no effective therapeutic agent is currently available. The regulation of macrophage polarization toward M2 is a general benefit for treating MS. The gene biomarker-based phenotypic screening approach was developed, and 3,4-disubstituted piperidine derivative S-28 was identified as a lead compound modulating macrophage M2 polarization. Further SAR studies resulted in the discovery of the most potent modulator D11 that showed good oral bioavailability and significant in vivo therapeutic effects. Mechanistic studies demonstrated that the M2 polarization macrophages modulated by D11 mainly functioned through inhibiting the proliferation of T-cells and activating the phosphorylation of Stat3 and Akt. Therefore, the gene biomarker-based phenotypic screening was demonstrated as a promising tool for the discovery of novel macrophage M2 polarization modulators. Compound D11 may serve as a promising starting point for the development of therapeutics to treat MS.
• Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment
  作者：Jinxin Che、Shaowei Bing、Jialiang Lu、Zegao Jin、Jian Gao、Haichao Sheng、Dan Li、Bo Yang、Qiaojun He、Meidan Ying、Xiaowu Dong

  DOI：10.1021/acs.jmedchem.3c00829

  日期：2023.10.12