(+)-(S)-6-Fluoro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-2,3,4,5-tetrahydro-1H-<1,4>benzodiazepine | 137332-64-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: (+)-(S)-6-Fluoro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-2,3,4,5-tetrahydro-1H-<1,4>benzodiazepine
• 英文别名: (S)-6-fluoro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine；(+)-(S)-6-Fluoro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine；(3S)-6-fluoro-3-methyl-4-(3-methylbut-2-enyl)-9-nitro-1,2,3,5-tetrahydro-1,4-benzodiazepine
• CAS: 137332-64-0
• 化学式: C₁₅H₂₀FN₃O₂
• 分子量: 293.341
• InChiKey: PGCZOIVTABSSTL-NSHDSACASA-N

物化性质

• 沸点：
  392.7±42.0 °C(Predicted)
• 密度：
  1.138±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  61.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (+)-(S)-6-Fluoro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-2,3,4,5-tetrahydro-1H-<1,4>benzodiazepine 在 镍 一水合肼 作用下， 以 四氢呋喃 为溶剂， 生成 (+)-(S)-4,5,6,7-Tetrahydro-8-fluoro-5-methyl-6-(3-methyl-2-butenyl)imidazo<4,5,1-jk><1,4>benzodiazepine-2(1H)-thione
  参考文献：
  名称：

  Synthesis and Anti-HIV-1 Activity of 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TlBO) Derivatives. 4

  摘要：

  In previous papers, we have described the discovery of a new series of compounds, 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-ones, TlBO (1 and 1a), with potent anti-HIV-1 activity and the synthesis of analogues to better define the structure-activity relationships (SAR) in terms of changes in substituents at the N-6 position and variations of the five-membered urea ring as well as the seven-membered diazepine ring. This paper describes the synthesis of TlBO analogues with various substituents on the aromatic ring and their SAR in terms of anti-HIV-1 properties. Substituents on the 8-position furnished the most rewarding results and gave a large improvement in potency versus the parent compound. These included halogen, thiomethyl, and methyl. Analogues like 8-cyano, -methoxy, and -acetylene were equipotent, while 8-amino, -acetylamino, -dimethylamino, and -nitro were inactive (Table 1). Substituents at the 9-position tended to have little effect on activity, and 10-substituents decreaseed activity. The 8-chloro compound 6a with IC50 = 0.0043 mu M is currently under clinical development.

  DOI：

  10.1021/jm00005a006
• 作为产物：
  描述：

  (2S)-2-[(2,6-difluoro-3-nitrophenyl)methylamino]propanamide 在 硼烷四氢呋喃络合物 、 sodium carbonate 、 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 22.5h， 生成 (+)-(S)-6-Fluoro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-2,3,4,5-tetrahydro-1H-<1,4>benzodiazepine
  参考文献：
  名称：

  Synthesis and Anti-HIV-1 Activity of 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one (TlBO) Derivatives. 4

  摘要：

  In previous papers, we have described the discovery of a new series of compounds, 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-ones, TlBO (1 and 1a), with potent anti-HIV-1 activity and the synthesis of analogues to better define the structure-activity relationships (SAR) in terms of changes in substituents at the N-6 position and variations of the five-membered urea ring as well as the seven-membered diazepine ring. This paper describes the synthesis of TlBO analogues with various substituents on the aromatic ring and their SAR in terms of anti-HIV-1 properties. Substituents on the 8-position furnished the most rewarding results and gave a large improvement in potency versus the parent compound. These included halogen, thiomethyl, and methyl. Analogues like 8-cyano, -methoxy, and -acetylene were equipotent, while 8-amino, -acetylamino, -dimethylamino, and -nitro were inactive (Table 1). Substituents at the 9-position tended to have little effect on activity, and 10-substituents decreaseed activity. The 8-chloro compound 6a with IC50 = 0.0043 mu M is currently under clinical development.

  DOI：

  10.1021/jm00005a006

文献信息

• Process for preparing enantiomerically pure imidazo[4,5,1-jk]-[1,4]-benzodiazepin-2(1H)-thiones
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP0534539A1

  公开（公告）日：1993-03-31

  Process for preparing enantiomerically pure imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thiones of formula starting from 2,6-dihalo-3-nitrobenzyl derivatives (II) and suitably N-protected 1,2-diaminopropanes (III) Novel enantiomerically pure intermediates of formula (III) and (IV) prepared in the course of the present process.

  式中对映体纯咪唑并[4,5,1-jk][1,4]苯并二氮杂卓-2(1H)-硫酮的制备工艺 从 2,6-二卤-3-硝基苄基衍生物（II）和适当的 N 保护的 1,2-二氨基丙烷（III）开始 在本工艺过程中制备的式 (III) 和 (IV) 的新型对映体纯中间体。
• Regioselectivity in intramolecular nucleophilic aromatic substitution. Synthesis of the potent anti HIV-I 8-halo TIBO analogs
  作者：Kathlyn A. Parker、Craig A. Coburn

  DOI：10.1021/jo00027a019

  日期：1992.1

  Regioselective intramolecular nucleophilic substitution of 2,6-dihalo-3-nitrobenzyl diamines 2b and 2c gave benzodiazepines 3. These intermediates are useful in the preparation of the 8-halo TIBO derivatives 1, inhibitors of HIV-I replication in cell culture.
• Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctional triphosphate
  作者：Dongyuan Piao、Aravind Basavapathruni、Pinar Iyidogan、Guangxiu Dai、Wolfgang Hinz、Adrian S. Ray、Eisuke Murakami、Joy Y. Feng、Fei You、Ginger E. Dutschman、David J. Austin、Kathlyn A. Parker、Karen S. Anderson

  DOI：10.1016/j.bmcl.2012.12.015

  日期：2013.3

  The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA. (c) 2013 Elsevier Ltd. All rights reserved.
• PROCESS FOR PREPARING ENANTIOMERICALLY PURE IMIDAZO 4,5,1-jk] 1,4]-BENZODIAZEPIN-2(1H -)-THIONES
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：EP0605499B1

  公开（公告）日：1997-11-12
• US5463049A
  申请人：——

  公开号：US5463049A

  公开（公告）日：1995-10-31