methyl 2-((4-methoxy-2-nitrophenyl)amino)benzoate | 1359967-63-7

• 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: methyl 2-((4-methoxy-2-nitrophenyl)amino)benzoate
• 英文别名: Methyl 2-(4-methoxy-2-nitroanilino)benzoate
• CAS: 1359967-63-7
• 化学式: C₁₅H₁₄N₂O₅
• 分子量: 302.287
• InChiKey: GMVRUVZMXLTOQA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.13
• 重原子数：
  22.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  90.7
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  methyl 2-((4-methoxy-2-nitrophenyl)amino)benzoate 在 铁粉 、 sodium hydride 、 对甲苯磺酸 、 溶剂黄146 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 55.0h， 生成 8-methoxy-10-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one
  参考文献：
  名称：

  BU-4664L 衍生物作为潜在抗癌剂的合成和生物学评价

  摘要：

  BU-4664L 是一种天然存在的N-法尼基化二苯并二氮杂卓，具有重要的生物活性。在此，我们报告了在二苯并二氮杂酮核心上具有不同取代基模式并具有不同侧链的两个系列 BU-4664L 衍生物的合成和抗肿瘤评估。所有的衍生物都对人前列腺癌 PC-3 细胞表现出微摩尔活性，而对人肺 H460 细胞的活性较低或没有活性。最具活性的衍生物是10a和16c，它们对 PC-3 细胞具有抗增殖活性，GI 50值分别为 5.66 和 5.94 μM，因此代表了有希望进一步开发的先导化合物。

  DOI：

  10.1016/j.bmcl.2021.128474
• 作为产物：
  描述：

  2-(三氟甲基磺酰氧基)苯甲酸甲酯 、 2-硝基-4-甲氧基苯胺 在 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 甲苯 为溶剂， 以77%的产率得到methyl 2-((4-methoxy-2-nitrophenyl)amino)benzoate
  参考文献：
  名称：

  Development of Potent and Selective Inhibitors of Aldo–Keto Reductase 1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase) Based on N-Phenyl-Aminobenzoates and Their Structure–Activity Relationships

  摘要：

  Aldo-keto reductase 1C3 (AKR1C3; type 5 17 beta-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5 alpha-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of Sa-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.

  DOI：

  10.1021/jm201547v

文献信息

• Significant Broadening of the Substrate Scope for the Hydrated Imidazoline Ring Expansion (HIRE) via the Use of Lithium Hexamethyldisilazide
  作者：Mikhail Krasavin、Sergey Grintsevich、Alexander Sapegin

  DOI：10.1055/s-0040-1719882

  日期：2022.5

  Substrates that are insufficiently activated towards the hydrated imidazoline ring expansion (HIRE) process have been previously found to deliver exclusively the products of aminoalkyl side-chain ring expansion. Attempted reversal of the process by thermal activation towards HIRE failed. We have found that for such problematic substrates the HIRE-type ring expansion can be effectively achieved by applying lithium hexamethyldisilazide (LHMDS) in toluene. LHMDS is thought to promote intramolecular transamidation, which leads to ring-expanded 10- and 11-membered heterocyclic products in modest to good yields. The process significantly broadens the substrate scope amenable to the HIRE strategy.

  摘要：以前发现，对水合咪唑啉环扩展（HIRE）过程不足激活的底物仅产生氨基烷基侧链环扩展产物。尝试通过热激活向HIRE反转该过程失败。我们发现，对于这类问题底物，可以通过在甲苯中应用六甲基二硅氮化锂（LHMDS）有效实现HIRE型环扩展。认为LHMDS促进分子内转酰胺化，导致产率适中至良好的环扩展的10和11元杂环产物。该过程显著扩大了适用于HIRE策略的底物范围。
• An Attempt to Achieve Hydrated Imidazoline Ring Expansion (HIRE) of Diarene-Fused [1,4]Diazepinones Delivers Selective Dopamine D2 Receptor Ligands
  作者：Mikhail Krasavin、Sergey Grintsevich、Alexander Sapegin、Beata Duszyńska、Andrzej J. Bojarski

  DOI：10.1055/a-1649-5317

  日期：2022.2

  Attempts to extend the hydrated imidazoline ring expansion (HIRE) strategy to a series of diarene-fused [1,4]diazepinones (earlier applied successfully to bis-pyrido substrate nevirapine) did not result in ring expansion but, rather, led to 2-aminoethyl side chain expulsion. This seeming setback (setting the limitations to the HIRE methodology substrate scope) led to the discovery of selective dopamine D2 ligands with elements of structure–activity relationships.

  试图将水合咪唑啉环扩展（HIRE）策略扩展到一系列二芳基融合的[1,4]二氮杂环酮（先前成功应用于双吡啶底物奈韦拉平）并未导致环扩展，而是导致2-氨基乙基侧链的排出。这一看似挫折（限制了HIRE方法的底物范围）导致了发现具有结构活性关系元素的选择性多巴胺D2配体。

• Development of Potent and Selective Inhibitors of Aldo–Keto Reductase 1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase) Based on <i>N</i>-Phenyl-Aminobenzoates and Their Structure–Activity Relationships
  作者：Adegoke O. Adeniji、Barry M. Twenter、Michael C. Byrns、Yi Jin、Mo Chen、Jeffrey D. Winkler、Trevor M. Penning

  DOI：10.1021/jm201547v

  日期：2012.3.8

  Aldo-keto reductase 1C3 (AKR1C3; type 5 17 beta-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5 alpha-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of Sa-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.
• Synthesis and biological evaluation of BU-4664L derivatives as potential anticancer agents
  作者：Chao Liu、Yuan-Yuan Xu、Zhao-Hui Wen、Yue-Hui Dong、Zhao-Peng Liu

  DOI：10.1016/j.bmcl.2021.128474

  日期：2022.1

  BU-4664L is a naturally occurring N-farnesylated dibenzodiazepinone with important biological activities. Herein, we report the synthesis and antitumor evaluation of two series of BU-4664L derivatives bearing different substituent patterns on the dibenzodiazepinone core and with diverse side chains. All of the derivatives displayed micromolar activity against the human prostate cancer PC-3 cells, while

  BU-4664L 是一种天然存在的N-法尼基化二苯并二氮杂卓，具有重要的生物活性。在此，我们报告了在二苯并二氮杂酮核心上具有不同取代基模式并具有不同侧链的两个系列 BU-4664L 衍生物的合成和抗肿瘤评估。所有的衍生物都对人前列腺癌 PC-3 细胞表现出微摩尔活性，而对人肺 H460 细胞的活性较低或没有活性。最具活性的衍生物是10a和16c，它们对 PC-3 细胞具有抗增殖活性，GI 50值分别为 5.66 和 5.94 μM，因此代表了有希望进一步开发的先导化合物。