bis(2-bromoethyl)phosphoramidic dichloride | 150756-67-5

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: bis(2-bromoethyl)phosphoramidic dichloride
• 英文别名: 2-bromo-N-(2-bromoethyl)-N-dichlorophosphorylethanamine
• CAS: 150756-67-5
• 化学式: C₄H₈Br₂Cl₂NOP
• 分子量: 347.801
• InChiKey: SNALSUZCFAYGNZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  11
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  5-nitro-4-cyano-2-thiophenecarboxaldehyde diacetate 、 bis(2-bromoethyl)phosphoramidic dichloride 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 0.86h， 生成
  参考文献：
  名称：

  Synthesis and Evaluation of Nitroheterocyclic Phosphoramidates as Hypoxia-Selective Alkylating Agents

  摘要：

  A series of novel nitroheterocyclic phosphoramidates has been prepared, and the cytotoxicity of these compounds has been evaluated in clonogenic assays against B16, wild-type and cyclophosphamide-resistant MCF-7, and HT-29 cells under aerobic conditions and HT-29 cells under hypoxic conditions. All compounds were comparable in toxicity to wild-type and resistant MCF-7 cells and were also selectively toxic to HT-29 cells under hypoxic conditions (selectivity ratios 1.7 to >20). Analogues lacking the nitro group were not cytotoxic. Electron-withdrawing substituents increased cytotoxicity under aerobic conditions and thereby decreased hypoxic selectivity. In contrast, an electron-donating substituent markedly decreased both aerobic and hypoxic cytotoxicity but enhanced hypoxic selectivity. Chemical reduction of the nitro group resulted in rapid expulsion of the cytotoxic phosphoramide mustard. The most potent of these compounds show significant cytotoxicity under both aerobic and hypoxic conditions.

  DOI：

  10.1021/jm0001020
• 作为产物：
  描述：

  双(2-溴乙基)胺氢溴酸盐 在 三乙胺 、 三氯氧磷 作用下， 以 二氯甲烷 为溶剂， 反应 24.08h， 生成 bis(2-bromoethyl)phosphoramidic dichloride
  参考文献：
  名称：

  青蒿素-哌嗪-磷酰胺芥菜杂化物作为潜在抗癌剂的设计、合成和生物学评价

  摘要：

  通过高效、无催化剂的两步顺序置换合成了12 种新型青蒿素-哌嗪-磷酰胺芥 (PPM) 杂化物7a - l 。Artemisinin-PPM 杂交体7表现出比 DHA 和 VCR 更好的细胞毒性。通过引入噻唑部分显着增强了细胞毒性。Hybrid 7 h显示出比 VCR 强 7.4 倍的效力，并且是合成的最有效的化合物，也是最具选择性的（选择性指数 = 16）。

  DOI：

  10.1002/cmdc.202200239

文献信息

• Phosphoramidate analogs of 2'-deoxyuridine
  申请人：University of Rochester

  公开号：US05233031A1

  公开（公告）日：1993-08-03

  The present invention provides a series of cytotoxic phosphoramidate analogs of 5-fluoro-2'-deoxyuridine of the general formula (I): ##STR1## wherein R.sup.1 is H, F or (C.sub.1 -C.sub.4)alkyl; R.sup.2 is CH.sub.2 CH.sub.2 X wherein X is Cl, Br, I or p-toluenesulfonyl; R.sup.3 is (C.sub.1 -C.sub.4)alkyl or CH.sub.2 CH.sub.2 X wherein X is Cl, Br, I or p-toluenesulfonyl; or wherein R.sup.2 and R.sup.3, taken together with the N atom, can be a 5- or 6-membered heterocyclic ring which is aliphatic or aliphatic interrupted by a ring oxygen or a second ring nitrogen; R.sup.4 is H, one equivalent of a pharmaceutically-acceptable cation or (4,4,6-trimethyltetrahydro-1,3-oxazin-2-yl)ethyl, and the pharmaceutically-acceptable salts thereof.

  本发明提供了一系列细胞毒性的5-氟-2'-脱氧尿嘧啶的磷酰胺类似物，其一般式为(I)：##STR1##其中R.sup.1为H，F或(C.sub.1 -C.sub.4)烷基；R.sup.2为CH.sub.2 CH.sub.2 X，其中X为Cl，Br，I或对甲苯磺酰基；R.sup.3为(C.sub.1 -C.sub.4)烷基或CH.sub.2 CH.sub.2 X，其中X为Cl，Br，I或对甲苯磺酰基；或其中R.sup.2和R.sup.3，与N原子一起，可以是一个5-或6-成员杂环，其为脂肪族的或被一个环氧原子或第二个环氮原子中断的脂肪族；R.sup.4为H，一个等效的药用阳离子或(4,4,6-三甲基四氢-1,3-噁唑啉-2-基)乙基，以及其药用盐。
• Synthesis and Biological Evaluation of 5-Fluoro-2'-deoxyuridine Phosphoramidate Analogs
  作者：Kristin M. Fries、Carolyn Joswig、Richard F. Borch

  DOI：10.1021/jm00014a019

  日期：1995.7

  compound, the piperidine analog 1g was only 2-fold less potent, confirming that nitrogen basicity may be as important as the presence of an alkylating group. Addition of thymidine reversed the growth inhibition of the morpholine and piperidine analogs, suggesting that these compounds may also undergo intracellular conversion to 5-fluoro-2'-deoxyuridine 5'monophosphate. The thymidine and deoxyuridine derivatives

  已经制备了一系列5-氟-2'-脱氧尿苷的烷基化氨基磷酸酯类似物，并在体外评估了它们对鼠L1210白血病和B16黑素瘤细胞的生长抑制活性。这些化合物被设计为可在胞内释放氨基磷酸酯阴离子，希望它们可作为胸苷酸合酶的不可逆抑制剂起作用。期望的是核苷部分的结合将随后经由氨基磷酸酯使酶烷基化。氯化物，溴化物，碘化物和甲苯磺酸酯类似物是L1210细胞增殖的高效抑制剂，在较高的药物浓度和较长的暴露时间下均观察到抑制作用增强。胸苷的添加完全逆转了所有化合物的抑制作用，提示这些化合物通过抑制胸苷酸合酶起作用。尽管非烷基化吗啉类似物1f为约。哌啶类似物1g的效力比甲基（氯乙基）氨基化合物低50倍，效力仅低2倍，这证明氮的碱性与烷基化基团的存在同样重要。胸苷的添加逆转了吗啉和哌啶类似物的生长抑制，表明这些化合物也可能经历细胞内转化为5-氟-2'-脱氧尿苷5'单磷酸酯。胸苷和脱氧尿苷衍生物2和3在L1210分析中
• Phosphoramidates useful as antitumor agents
  申请人：Research Corporation Technologies, Inc.

  公开号：US05306727A1

  公开（公告）日：1994-04-26

  Cyclophosphamide analogs are provided of the general formula: ##STR1## wherein R.sup.1 and R.sup.2 are each (C.sub.2 -C.sub.6)alkyl, substituted with a leaving group such as halo or alkylsulfonyl, R.sup.3 and R.sup.4 are the same as R.sup.1 and R.sup.2 or are H and Ar is a heteroaromatic ring and the pharmaceutically acceptable salts thereof.

  环磷酰胺类似物提供了一般式为：其中R.sup.1和R.sup.2分别是(C.sub.2-C.sub.6)烷基，经过取代的含有卤素或烷基磺基的离去基团，R.sup.3和R.sup.4与R.sup.1和R.sup.2相同或为H，Ar为杂芳环及其药用盐。
• Phosphoramide compounds
  申请人：——

  公开号：US20030008850A1

  公开（公告）日：2003-01-09

  The invention provides a compound of formula I: 1 wherein R 1 , R a , R b , R c , and R d have any of the values defined in the specification, as well as pharmaceutical compositions comprising such compounds or salts. The compounds are useful for treating cancer in animals.

  本发明提供了一种I式化合物：1，其中R1、Ra、Rb、Rc和Rd的任何值均定义在规范中，以及包含这种化合物或盐的药物组合物。这些化合物对于治疗动物的癌症具有用处。
• Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs
  作者：Jian-Xin Duan、Hailong Jiao、Jacob Kaizerman、Timothy Stanton、James W. Evans、Leslie Lan、Gustavo Lorente、Monica Banica、Don Jung、Jinwei Wang、Huaiyu Ma、Xiaoming Li、Zhijian Yang、Robert M. Hoffman、W. Steve Ammons、Charles P. Hart、Mark Matteucci

  DOI：10.1021/jm701028q

  日期：2008.4.1

  A series of achiral hypoxia-activated prodrugs were synthesized on the basis of the DNA cross-linking toxin of the prodrug, ifosfamide. The hypoxia-selective cytotoxicity of several of the compounds was improved over previously reported racemic mixtures of chiral bioreductive phosphorami date prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced cytotoxicity toward H460 cells in culture under hypoxia versus their potency under aerobic conditions. Compounds were further assessed for their stability to cytochrome P450 metabolism using a liver microsome assay. The 2-nitroimidazole containing lead compound 3b (TH-302) was selectively potent under hypoxia and stable to liver microsomes. It was active in an in vivo MIA PaCa-2 pancreatic cancer orthotopic xenograft model as a monotherapy and demonstrated dramatic efficacy when used in combination with gemcitabine, extending survival with one of eight animals tumor free at day-44. Compound 3b has emerged as a promising antitumor agent that shows excellent in vivo efficacy and is currently being evaluated in the clinic.