N,N-bis(2-{[tert-butyldimethylsilyl]oxy}ethyl)-4-nitroaniline | 304015-61-0

• 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: N,N-bis(2-{[tert-butyldimethylsilyl]oxy}ethyl)-4-nitroaniline
• 英文别名: 4-nitro-N,N-bis[2'-(tert-butyldimethylsilyloxy)ethyl]aniline；N,N-bis(2-(tert-butyldimethylsilyloxy)ethyl)-4-nitroaniline；4-nitro-bis[2'-(tert-butyldimethylsilyloxy)ethyl]-aniline；N,N-bis[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-nitroaniline
• CAS: 304015-61-0
• 化学式: C₂₂H₄₂N₂O₄Si₂
• 分子量: 454.757
• InChiKey: AGEBWEJNRUAYDB-UHFFFAOYSA-N

物化性质

• 沸点：
  475.3±40.0 °C(Predicted)
• 密度：
  1.000±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.44
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  67.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N,N-bis(2-{[tert-butyldimethylsilyl]oxy}ethyl)-4-nitroaniline 在 palladium on activated charcoal 4-二甲氨基吡啶 、 triethylamine trihydrofluoride 、 氢气 、 三乙胺 、 lithium bromide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 22.0h， 生成 4-bis(2'-bromoethyl)amino-N-tert-butyloxycarbonylaniline
  参考文献：
  名称：

  Self-Immolative Nitrogen Mustards Prodrugs Cleavable by Carboxypeptidase G2 (CPG2) Showing Large Cytotoxicity Differentials in GDEPT

  摘要：

  Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-{N-[4'-Bis(2"-iodoethyl)aminophenyll-N'-methylcarbamoyloxymethyl}phenylcarbamoyl-L-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-{4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl}-L-glutamic acid (CMDA) prodrug.

  DOI：

  10.1021/jm020462i
• 作为产物：
  描述：

  N-(4-硝基苯基)二乙醇胺 、 叔丁基二甲基氯硅烷 在 咪唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 以95%的产率得到N,N-bis(2-{[tert-butyldimethylsilyl]oxy}ethyl)-4-nitroaniline
  参考文献：
  名称：

  用于硝基还原酶介导的基因指导的酶前药治疗的硝基杂环氨基甲酸酯前药的合成和评估。

  摘要：

  苯二胺芥末的1-甲基-2-硝基咪唑-5-氨基甲酸氨基甲酸酯被EMT6-NTR（neo）快速代谢，但未被EMT6细胞代谢，表明它是NTR的有效底物。尽管如此，苯二胺芥末的氨基甲酸酯在IC（50）分析中对NTR + ve细胞显示出相对较低的细胞毒性差异，显然是因为它们保留了足够的烷基化反应性，因此大多数前药在药物暴露期间会与亲核试剂反应。相反，相应的氨基-seco-CBI-TMI前药的NTR底物效率较低，但化学稳定性更高，效力更高，并且在细胞系面板中显示出相当大的NTR-ve / NTR + ve比，比例为15氨基-seco-CBI-TMI的1-甲基-2-硝基-1H-咪唑-5-基甲基和1-甲基-5-硝基-1H-咪唑-2-基甲基氨基甲酸酯的100倍。评估了这两种前药对表达NTR的EMT6肿瘤的活性，其中EMT6肿瘤约占10％。10％NTR + ve细胞。观察到对NTR + ve细胞的杀伤作用很小

  DOI：

  10.1021/jm030308b

文献信息

• [EN] TREATMENT OR PROPHYLAXIS OF PROLIFERATIVE CONDITIONS<br/>[FR] TRAITEMENT OU PROPHYLAXIE D'ÉTATS PROLIFÉRATIFS
  申请人：UNIV DUNDEE

  公开号：WO2010125350A1

  公开（公告）日：2010-11-04

  The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.

  该发明涉及用于治疗或预防癌症和其他增殖性疾病的新化合物，例如这些疾病的特征是细胞表达细胞色素P450 1B1（CYP1B1）及其等位基因变体。该发明还提供包含一种或多种此类化合物的药物组合物，用于医学治疗，例如用于治疗或预防癌症或其他增殖性疾病，以及用于治疗人类或非人类动物患者的癌症或其他疾病的方法。该发明还提供用于识别用于治疗或预防癌症和其他增殖性疾病的新化合物的方法，例如这些疾病的特征是细胞表达CYP1B1及其等位基因变体。该发明还提供一种用于确定该发明中化合物治疗癌症的疗效的方法。
• [EN] ENZYME ACTIVATED SELF-IMMOLATIVE N-SUBSTITUTED NITROGEN MUSTARD PRODRUGS<br/>[FR] PROMEDICAMENTS ACTIVES PAR UNE ENZYME ET AUTO-IMMOLATEURS A BASE DE MOUTARDE D'AZOTE N-SUBSTITUTE
  申请人：CANCER REC TECH LTD

  公开号：WO2004020400A1

  公开（公告）日：2004-03-11

  This invention pertains to certain enzyme (CPG2) activated self-immolative nitrogen mustard prodrugs, which are useful in enzyme prodrug therapy (EPT), such as ADEPT and GDEPT, for the treatment of proliferative conditions, such as cancer, and which have the following formula: wherein RN is independently C1-7alkyl; X1 is independently -I, -Br, or Cl; X2 is independently -I, -Br, or -Cl; the group -N(CH2CH2X1)(CH2CH2X2) is independently attached at the 2-position or at the 4-position; each RG is independently -H or an ester substituent; n is independently an integer from 0 to 4; each RP, if present, is independently a phenyl substituent; m is independently an integer from 0 to 4; each RM, if present, is independently a mustard substituent; and pharmaceutically acceptable salts, solvates, amides, and esters thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds; such compounds and compositions for use in methods of treatment of the human or animal body by therapy; the use of such compounds and compositions for the manufacture of medicaments for the treatment of proliferative conditions; and the like.

  本发明涉及一种特定的酶（CPG2）活化的自灭性亚硝基芥子前药，用于酶前药疗法（EPT），如ADEPT和GDEPT，用于治疗增殖性疾病，如癌症，并具有以下结构式：其中RN独立地是C1-7烷基；X1独立地是-I，-Br或Cl；X2独立地是-I，-Br或-Cl；该基团-N(CH2CH2X1)(CH2CH2X2)独立地连接在2位或4位；每个RG独立地是-H或酯基取代物；n独立地是0到4的整数；每个RP（如果存在）独立地是苯基取代物；m独立地是0到4的整数；每个RM（如果存在）独立地是芥子取代物；以及其药学上可接受的盐、溶剂化合物、酰胺和酯。本发明还涉及包含这种化合物的药物组合物；这种化合物和组合物用于通过治疗治疗人体或动物体的方法；这种化合物和组合物用于制造用于治疗增殖性疾病的药物；等等。
• Enzyme activated self-immolative n-substituted nitrogen mustard prodrugs
  申请人：Springer J Caroline

  公开号：US20060069154A1

  公开（公告）日：2006-03-30

  This invention pertains to certain enzyme (CPG2) activated self-immolative nitrogen mustard prodrugs, which are useful in enzyme prodrug therapy (EPT), such as ADEPT and GDEPT, for the treatment of proliferative conditions, such as cancer, and which have the following formula: wherein: R N is independently C 1-7 alkyl; X 1 is independently —I, —Br, or —Cl; X 2 is independently —I, —Br, or —Cl; the group —N(CH 2 CH 2 X 1 )(CH 2 CH 2 X 2 ) is independently attached at the 2-position or at the 4-position; each R G is independently —H or an ester substituent; n is independently an integer from 0 to 4; each R P , if present, is independently a phenyl substituent; m is independently an integer from 0 to 4; each R M , if present, is independently a mustard substituent; and pharmaceutically acceptable salts, solvates, amides, and esters thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds; such compounds and compositions for use in methods of treatment of the human or animal body by therapy; the use of such compounds and compositions for the manufacture of medicaments for the treatment of proliferative conditions; and the like.

  本发明涉及某些酶（CPG2）活化的自我毁灭性亚硝基芥前药，其在酶前药疗法（EPT）如ADEPT和GDEPT中有用，用于治疗增殖性疾病，如癌症，其化学式如下：其中：RN独立地是C1-7烷基；X1独立地是—I，—Br或—Cl；X2独立地是—I，—Br或—Cl；—N(CH2CH2X1)(CH2CH2X2)基团独立地连接在2位或4位；每个RG独立地是—H或酯基取代基；n独立地是0到4的整数；每个RP（如存在）独立地是苯基取代基；m独立地是0到4的整数；每个RM（如存在）独立地是芥子气取代基；以及其药学上可接受的盐，溶剂化合物，酰胺和酯。 本发明还涉及包含这种化合物的制药组合物；这种化合物和组合物用于治疗人体或动物体的治疗方法；使用这种化合物和组合物制造治疗增殖性疾病药物等。
• Synthesis and Evaluation of Nitroheterocyclic Carbamate Prodrugs for Use with Nitroreductase-Mediated Gene-Directed Enzyme Prodrug Therapy
  作者：Michael P. Hay、Robert F. Anderson、Dianne M. Ferry、William R. Wilson、William A. Denny

  DOI：10.1021/jm030308b

  日期：2003.12.1

  carbamate prodrugs of phenylenediamine mustard and 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H- benz[e]indoline (amino-seco-CBI-TMI), covering a wide range of reduction potential, were prepared and evaluated for use in gene-directed enzyme prodrug therapy (GDEPT) using a two-electron nitroreductase (NTR) from Escherichia coli B. The carbamate prodrugs and corresponding

  苯二胺芥末的1-甲基-2-硝基咪唑-5-氨基甲酸氨基甲酸酯被EMT6-NTR（neo）快速代谢，但未被EMT6细胞代谢，表明它是NTR的有效底物。尽管如此，苯二胺芥末的氨基甲酸酯在IC（50）分析中对NTR + ve细胞显示出相对较低的细胞毒性差异，显然是因为它们保留了足够的烷基化反应性，因此大多数前药在药物暴露期间会与亲核试剂反应。相反，相应的氨基-seco-CBI-TMI前药的NTR底物效率较低，但化学稳定性更高，效力更高，并且在细胞系面板中显示出相当大的NTR-ve / NTR + ve比，比例为15氨基-seco-CBI-TMI的1-甲基-2-硝基-1H-咪唑-5-基甲基和1-甲基-5-硝基-1H-咪唑-2-基甲基氨基甲酸酯的100倍。评估了这两种前药对表达NTR的EMT6肿瘤的活性，其中EMT6肿瘤约占10％。10％NTR + ve细胞。观察到对NTR + ve细胞的杀伤作用很小
• Self-Immolative Nitrogen Mustards Prodrugs Cleavable by Carboxypeptidase G2 (CPG2) Showing Large Cytotoxicity Differentials in GDEPT
  作者：Dan Niculescu-Duvaz、Ion Niculescu-Duvaz、Frank Friedlos、Jan Martin、Panos Lehouritis、Richard Marais、Caroline J. Springer

  DOI：10.1021/jm020462i

  日期：2003.4.1

  Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-N-[4'-Bis(2"-iodoethyl)aminophenyll-N'-methylcarbamoyloxymethyl}phenylcarbamoyl-L-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl}-L-glutamic acid (CMDA) prodrug.