2-(7-cyano-4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride | 389628-22-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-(7-cyano-4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride
• CAS: 389628-22-2
• 化学式: C₁₁H₄ClFN₂O₂
• 分子量: 250.616
• InChiKey: XTHDSLLREWKXDP-UHFFFAOYSA-N

物化性质

• 沸点：
  500.7±60.0 °C(Predicted)
• 密度：
  1.59±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  73.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(7-cyano-4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride 在 盐酸羟胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 52.0h， 生成 C₂₂H₂₀FN₅O₄
  参考文献：
  名称：

  Inhibitors of HIV-1 attachment. Part 8: The effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indole-based inhibitors

  摘要：

  As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M-and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.117
• 作为产物：
  描述：

  7-溴-4-氟吲哚 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 89.0h， 生成 2-(7-cyano-4-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride
  参考文献：
  名称：

  HIV-1附着抑制剂。第9部分：评估口服前药方法以改善含四唑衍生物的血浆暴露的方法

  摘要：

  发现7-（2 H-替他唑-5-基）-1 H-吲哚3是HIV-1附着的有效抑制剂，但该化合物在大鼠中缺乏口服生物利用度。该低曝光的原因被认为是吸收差归因于四唑部分的酸性性质，并且在为了解决这个责任，三个亲脂性的四唑类似物，Ñ -acetoxymethyl 4，Ñ -pivaloyloxymethyl 5，和Ñ -甲基6被评估为大鼠中潜在的口服前药。前药5在提高体内3的血浆浓度方面无效，但化合物4提供了3的血浆浓度的15倍增强。最有趣的是，与母体给药相比，类似物6的口服给药使大鼠中母体的血浆浓度显着增加。这代表了甲基四唑的新实例，该甲基四唑用作游离的含NH四唑的化合物的前药。

  DOI：

  10.1016/j.bmcl.2012.10.125

文献信息

• Inhibitors of HIV-1 attachment. Part 9: An assessment of oral prodrug approaches to improve the plasma exposure of a tetrazole-containing derivative
  作者：Kap-Sun Yeung、Zhilei Qiu、Zheng Yang、Lisa Zadjura、Celia J. D’Arienzo、Marc R. Browning、Steven Hansel、Xiaohua Stella Huang、Betsy J. Eggers、Keith Riccardi、Ping-Fang Lin、Nicholas A. Meanwell、John F. Kadow

  DOI：10.1016/j.bmcl.2012.10.125

  日期：2013.1

  7-(2H-Tetrazol-5-yl)-1H-indole 3 was found to be a potent inhibitor of HIV-1 attachment but the compound lacked oral bioavailability in rats. The cause of the low exposure was believed to be poor absorption attributed to the acidic nature of the tetrazole moiety and, in an effort to address this liability, three more lipohilic tetrazole analogs, N-acetoxymethyl 4, N-pivaloyloxymethyl 5, and N-methyl

  发现7-（2 H-替他唑-5-基）-1 H-吲哚3是HIV-1附着的有效抑制剂，但该化合物在大鼠中缺乏口服生物利用度。该低曝光的原因被认为是吸收差归因于四唑部分的酸性性质，并且在为了解决这个责任，三个亲脂性的四唑类似物，Ñ -acetoxymethyl 4，Ñ -pivaloyloxymethyl 5，和Ñ -甲基6被评估为大鼠中潜在的口服前药。前药5在提高体内3的血浆浓度方面无效，但化合物4提供了3的血浆浓度的15倍增强。最有趣的是，与母体给药相比，类似物6的口服给药使大鼠中母体的血浆浓度显着增加。这代表了甲基四唑的新实例，该甲基四唑用作游离的含NH四唑的化合物的前药。
• Inhibitors of HIV-1 attachment. Part 8: The effect of C7-heteroaryl substitution on the potency, and in vitro and in vivo profiles of indole-based inhibitors
  作者：Kap-Sun Yeung、Zhilei Qiu、Zhiwei Yin、Ashok Trehan、Haiquan Fang、Bradley Pearce、Zheng Yang、Lisa Zadjura、Celia J. D’Arienzo、Keith Riccardi、Pei-Yong Shi、Timothy P. Spicer、Yi-Fei Gong、Marc R. Browning、Steven Hansel、Kenneth Santone、Jonathan Barker、Thomas Coulter、Ping-Fang Lin、Nicholas A. Meanwell、John F. Kadow

  DOI：10.1016/j.bmcl.2012.10.117

  日期：2013.1

  As part of the SAR profiling of the indole-oxoacetic piperazinyl benzamide class of HIV-1 attachment inhibitors, substitution at the C7 position of the lead 4-fluoroindole 2 with various 5- and 6-membered heteroaryl moieties was explored. Highly potent (picomolar) inhibitors of pseudotyped HIV-1 in a primary, cell-based assay were identified and select examples were shown to possess nanomolar inhibitory activity against M-and T-tropic viruses in cell culture. These C7-heteroaryl-indole analogs maintained the ligand efficiency (LE) of 2 and were also lipophilic efficient as measured by LLE and LELP. Pharmacokinetic studies of this class of inhibitor in rats showed that several possessed substantially improved IV clearance and half-lives compared to 2. Oral exposure in the rat correlated with membrane permeability as measured in a Caco-2 assay where the highly permeable 1,2,4-oxadiazole analog 13 exhibited the highest exposure. (C) 2012 Elsevier Ltd. All rights reserved.