5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one | 899374-45-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one
• 英文别名: 5-chloro-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzimidazol-2-one；5-chloro-1,3-dimethyl-6-nitrobenzimidazol-2-one
• CAS: 899374-45-9
• 化学式: C₉H₈ClN₃O₃
• mdl: MFCD07022074
• 分子量: 241.634
• InChiKey: LWWKJTPDNAEDJA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  69.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-甲基哌嗪 、 1,8-萘二甲酸酐 、 5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one 在 sodium carbonate 、 palladium on activated charcoal 、 氢气 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 、 乙醇 为溶剂， 120.0 ℃ 、100.0 kPa 条件下， 反应 4.0h， 以6%的产率得到2-[1,3-dimethyl-6-(4-methylpiperazin-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-1H-benzo[de]isoquinoline-1,3(2H)-dione
  参考文献：
  名称：

  Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

  摘要：

  Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.

  DOI：

  10.1021/acs.jmedchem.7b00306
• 作为产物：
  描述：

  5-氯-6-硝基-1H-苯并[D]咪唑-2(3H)-酮 、 碘甲烷 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 5-chloro-1,3-dimethyl-6-nitro-1H-benzo[d]imidazol-2(3H)-one
  参考文献：
  名称：

  [EN] AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS
  [FR] DÉRIVÉS AMINOPYRIMIDINIQUES UTILISÉS COMME MODULATEURS DE LRRK2

  摘要：

  式(I)的化合物或其药用可接受的盐，其中A、X、R1、R2、R3和R4如本文所定义。还公开了制备这些化合物的方法，并将这些化合物用于治疗与LRRK2受体相关的疾病，如帕金森病。

  公开号：

  WO2013079505A1

文献信息

• AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS
  申请人：Genentech, Inc.

  公开号：US20130158006A1

  公开（公告）日：2013-06-20

  Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein A, X, R 1 , R 2 , R 3 and R 4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.

  化合物I的公式或其药学上可接受的盐，其中A、X、R1、R2、R3和R4的定义如本文所述。还揭示了制备该化合物的方法，并将其用于治疗与LRRK2受体相关的疾病，如帕金森病。
• Aminopyrimidine derivatives as LRRK2 modulators
  申请人：Genentech, Inc.

  公开号：US08796296B2

  公开（公告）日：2014-08-05

  Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein A, X, R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.

  化合物I的公式或其药学上可接受的盐，其中A、X、R1、R2、R3和R4的定义如本文所述。还公开了制备该化合物的方法，并使用该化合物治疗与LRRK2受体相关的疾病，如帕金森病。
• US8796296B2
  申请人：——

  公开号：US8796296B2

  公开（公告）日：2014-08-05
• [EN] AMINOPYRIMIDINE DERIVATIVES AS LRRK2 MODULATORS<br/>[FR] DÉRIVÉS AMINOPYRIMIDINIQUES UTILISÉS COMME MODULATEURS DE LRRK2
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013079505A1

  公开（公告）日：2013-06-06

  Compounds of the formula (I): or pharmaceutically acceptable salts thereof, wherein A, X, R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with LRRK2 receptor, such as Parkinson's disease.

  式(I)的化合物或其药用可接受的盐，其中A、X、R1、R2、R3和R4如本文所定义。还公开了制备这些化合物的方法，并将这些化合物用于治疗与LRRK2受体相关的疾病，如帕金森病。
• Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains
  作者：Léa Bouché、Clara D. Christ、Stephan Siegel、Amaury E. Fernández-Montalván、Simon J. Holton、Oleg Fedorov、Antonius ter Laak、Tatsuo Sugawara、Detlef Stöckigt、Cynthia Tallant、James Bennett、Octovia Monteiro、Laura Díaz-Sáez、Paulina Siejka、Julia Meier、Vera Pütter、Jörg Weiske、Susanne Müller、Kilian V. M. Huber、Ingo V. Hartung、Bernard Haendler

  DOI：10.1021/acs.jmedchem.7b00306

  日期：2017.5.11

  Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.