2-chloro-3,5-dinitro-N-(2-hydroxyethyl)benzamide | 680199-29-5

• 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: 2-chloro-3,5-dinitro-N-(2-hydroxyethyl)benzamide
• 英文别名: 2-chloro-N-(2-hydroxyethyl)-3,5-dinitrobenzamide
• CAS: 680199-29-5
• 化学式: C₉H₈ClN₃O₆
• 分子量: 289.632
• InChiKey: MBOJHBJUPDBPGP-UHFFFAOYSA-N

物化性质

• 沸点：
  444.0±45.0 °C(Predicted)
• 密度：
  1.614±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  141
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-chloro-3,5-dinitro-N-(2-hydroxyethyl)benzamide 在 四氮唑 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 di(tert-butyl) 2-({2-[(2-chloroethyl)(2-hydroxyethyl)amino]-3,5-dinitrobenzoyl}amino)ethyl phosphate
  参考文献：
  名称：

  Synthesis of asymmetric halomesylate mustards with aziridineethanol/alkali metal halides: application to an improved synthesis of the hypoxia prodrug PR-104

  摘要：

  Aromatic asymmetric halomesylate mustards are efficiently prepared by reaction of activated aromatic chlorides with aziridine-ethanol/alkali metal halides, followed by mesylation of the haloalcohol. The reaction conditions are sufficiently mild to be compatible with a range of different substituents and protecting groups, including carboxylate and phosphate esters, and have been used in an improved synthesis of the anticancer bromomesylate mustard PR-104, now in clinical trials. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2007.04.044
• 作为产物：
  描述：

  2-氯-3,5-二硝基苯甲酸 以91的产率得到2-chloro-3,5-dinitro-N-(2-hydroxyethyl)benzamide
  参考文献：
  名称：

  Nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents

  摘要：

  本发明涉及一种新型的硝基苯芥和硝基苯环氧乙烷醇，它们的相应磷酸盐，它们作为靶向细胞毒性药物的使用；作为生物还原药物在低氧肿瘤中的使用，并与硝酸还原酶酶一起用于细胞消融，包括基因定向酶前药治疗（GPEPT）和抗体定向酶前药治疗（ADEPT）。

  公开号：

  US07629332B2

文献信息

• [EN] NITROANILINE-BASED ALKYLATING AGENTS AND THEIR USE AS PRODRUGS<br/>[FR] AGENTS D'ALKYLATION A BASE DE NITROANILINE ET LEUR UTILISATION EN TANT QUE PROMEDICAMENTS
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2004033415A1

  公开（公告）日：2004-04-22

  Nitroaniline-based unsymmetrical mustards of the general formula (I) are provided, together with methods of preparation and methods for their use as produgs for gene-dependent enzyme prodrug therapy (GDEPT) and cell ablation therapy in conjuction with nitroreductase enzymes as hypoxia selective cytotoxins and as anticancer agents.

  基于硝基苯胺的不对称芥末化合物，其通用公式为（I），以及它们的制备方法和使用方法，作为基因依赖性酶前药治疗（GDEPT）和与硝基还原酶酶结合的细胞消融治疗的药物，以及作为缺氧选择性细胞毒素和抗癌药物的使用方法。
• [EN] NOVEL NITROPHENYL MUSTARD AND NITROPHENYLAZIRIDINE ALCOHOLS AND THEIR CORRESPONDING PHOSPHATES AND THEIR USE AS TARGETED CYTOTOXIC AGENTS<br/>[FR] NOUVELLE MOUTARDE NITROPHENYLE ET NOUVEAUX ALCOOLS NITROPHENYLAZIRIDINE, PHOSPHATES CORRESPONDANTS ET UTILISATION DE CES DERNIERS EN TANT QU'AGENTS CYTOTOXIQUES CIBLES
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2005042471A1

  公开（公告）日：2005-05-12

  The present invention relates to novel nitrophenyl mustard and nitrophenylaziridine alcohols, to their corresponding phosphates, to their use as targeted cytotoxic agents; as bioreductive drugs in hypoxic tumours, and to their use in cell ablation, including gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme­prodrug therapy (ADEPT), in conjunction with nitroreductase enzymes.

  本发明涉及新型硝基苯基芥和硝基苯基环丙胺醇，它们的相应磷酸盐，以及它们作为靶向细胞毒性药剂的用途；作为缺氧肿瘤中的生物还原药物，并且它们在细胞消融中的应用，包括基因导向酶前药治疗（GDEPT）和抗体导向酶前药治疗（ADEPT），与硝基还原酶酶一起。
• Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans
  作者：Yongchuan Gu、Graham J. Atwell、William R. Wilson

  DOI：10.1124/dmd.109.030973

  日期：2010.3

  PR-104 is the phosphate ester of a 3,5-dinitrobenzamide nitrogen mustard (PR-104A) that is reduced to active hydroxylamine and amine metabolites by reductases in tumors. In this study, we evaluate the excretion of [3H]PR-104 in mice and determine its metabolite profile in mice, rats, dogs, and humans after a single intravenous dose. Total radioactivity was rapidly and quantitatively excreted in mice, with cumulative excretion of 46% in urine and 50% in feces. The major urinary metabolites in mice were products from oxidative N -dealkylation and/or glutathione conjugation of the nitrogen mustard moiety, including subsequent mercapturic acid pathway metabolites. A similar metabolite profile was seen in mouse bile, mouse plasma, and rat urine and plasma. Dogs and humans also showed extensive thiol conjugation but little evidence of N -dealkylation. Humans, like rodents, showed appreciable reduced metabolites in plasma, but concentrations of the cytotoxic amine metabolite (PR-104M) were higher in mice than humans. The most conspicuous difference in metabolite profile was the much more extensive O -β-glucuronidation of PR-104A in dogs and humans than in rodents. The structure of the O -β-glucuronide (PR-104G) was confirmed by independent synthesis. Its urinary excretion was responsible for 13 ± 2% of total dose in humans but only 0.8 ± 0.1% in mice. Based on these metabolite profiles, biotransformation of PR-104 in rodents is markedly different from that in humans, suggesting that rodents may not be appropriate for modeling human biotransformation and toxicology of PR-104.

  PR-104是3,5-二硝基苯氨基甲烷氮芥（PR-104A）的磷酸酯，能够通过肿瘤中的还原酶被还原为活性氢氧胺和氨基代谢物。在本研究中，我们评估了小鼠对[3H]PR-104的排泄情况，并确定了在小鼠、大鼠、狗和人类在单次静脉给药后其代谢物的特征。小鼠中总放射活性迅速且定量地排泄，其中46%通过尿液排出，50%通过粪便排出。小鼠尿液中的主要代谢物是氮芥部分经过氧化N-去烷基化和/或谷胱甘肽结合产生的产物，包括后续的巯酸代谢通路代谢物。在小鼠胆汁、小鼠血浆以及大鼠尿液和血浆中也观察到了类似的代谢物特征。狗和人类也显示出广泛的硫醇结合，但N-去烷基化的证据较少。与啮齿动物类似，人类在血浆中显示出显著的减少代谢物，但细胞毒性胺代谢物（PR-104M）的浓度在小鼠中高于人类。代谢物特征中最明显的差异是狗和人类的O-β-葡萄糖苷酸化（PR-104A）程度远高于啮齿动物。O-β-葡萄糖苷酸（PR-104G）的结构通过独立合成得到了证实。其尿液排泄占人类总剂量的13 ± 2%，而在小鼠中仅为0.8 ± 0.1%。基于这些代谢物特征，PR-104在啮齿动物中的生物转化显著不同于在人类中的情况，这表明啮齿动物可能不适合用于模拟人类的PR-104生物转化和毒理学。
• Nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents
  申请人：Auckland Uniservices Limited

  公开号：US07629332B2

  公开（公告）日：2009-12-08

  The present invention relates to a novel nitrophenyl mustard and nitrophenylaziridine alcohols, to their corresponding phosphates, to their use as targeted cytotoxic agents; as bioreductive drugs in hypoxic tumors, and to their use in cell ablation, including gene-directed enzyme-prodrug therapy (GPEPT) and antibody-directed enzymeprodrug therapy (ADEPT), in conjunction with nitroreductase enzymes.

  本发明涉及一种新型的硝基苯芥和硝基苯环氧乙烷醇，它们的相应磷酸盐，它们作为靶向细胞毒性药物的使用；作为生物还原药物在低氧肿瘤中的使用，并与硝酸还原酶酶一起用于细胞消融，包括基因定向酶前药治疗（GPEPT）和抗体定向酶前药治疗（ADEPT）。
• Nitroaniline-based alkylating agents and their use as prodrugs
  申请人：Denny Alexander William

  公开号：US20050256191A1

  公开（公告）日：2005-11-17

  Nitroaniline-based unsymmetrical mustards of the general formula (I) are provided, together with methods of preparation and methods for their use as prodrugs for gene-dependent enzyme prodrug therapy (GDEPT) and cell ablation therapy in conjunction with nitroreductase enzymes as hypoxia selective cytotoxins and as anticancer agents.

  提供了基于硝基苯胺的不对称芥子气的一般式（I），以及其制备方法和用作基因依赖性酶前药治疗（GDEPT）和细胞消融治疗的前药的方法，与硝酸还原酶酶一起使用作为缺氧选择性细胞毒素和抗癌剂。