N,N-bis-(2-chloro-ethyl)-N'-methyl-phosphorodiamidic acid but-3-enyl ester | 39800-37-8

• 英文名称: N,N-bis-(2-chloro-ethyl)-N'-methyl-phosphorodiamidic acid but-3-enyl ester
• 英文别名: N-[but-3-enoxy(methylamino)phosphoryl]-2-chloro-N-(2-chloroethyl)ethanamine
• CAS: 39800-37-8
• 化学式: C₉H₁₉Cl₂N₂O₂P
• 分子量: 289.142
• InChiKey: OGLNZNMASFHUFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  16
• 可旋转键数：
  10
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N,N-bis-(2-chloro-ethyl)-N'-methyl-phosphorodiamidic acid but-3-enyl ester 在 二甲基硫 、 双氧水 、 臭氧 作用下， 以 甲醇 、 水 为溶剂， 反应 0.33h， 生成 2-{(2S,4S)-2-[Bis-(2-chloro-ethyl)-amino]-3-methyl-2-oxo-2λ5-[1,3,2]oxazaphosphinan-4-ylsulfanyl}-ethanesulfonic acid anion
  参考文献：
  名称：

  N-取代对4-羟基环磷酰胺类似物激活机制的影响。

  摘要：

  比较了N-取代的4-羟基环磷酰胺类似物4-羟基异磷酰胺（2b），4-羟基三磷酰胺（2c）和3-甲基-4-羟基环磷酰胺（2d）的活化机理与未取代的母体化合物2a的活化机理。顺式2b，-2c和-2d的反应动力学与2a的反应动力学在质量上相似，因为它们分别对相应的醛磷酸酰胺中间体3进行开环反应，该中间体可以与顺式或反式-4-羟基异构体重合或经历碱催化的β-消除反应生成相应的磷酰胺芥末产物4。与2a和2d开环观察到的一般酸催化相反，N-（氯乙基）取代的类似物2b和2c经历了特定的碱催化开环。通过在酸性条件下2a和2d与2-巯基乙磺酸钠（Mesna）的快速反应，得到了4-（烷硫基）取代的环磷酰胺衍生物5a和5d，也说明了这种机理上的差异。在这些条件下，化合物2b和2c不会与Mesna反应生成5b和5c。处于平衡状态的醛/水合物分数和体外对L1210细胞的细胞毒性均以大于2c大于2b大于2a大于2d的

  DOI：

  10.1021/jm00127a016
• 作为产物：
  描述：

  O-(3-Butenyl)-N,N-bis(2-chlorethyl)-phosphoramidoylchlorid 、 盐酸甲胺 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成 N,N-bis-(2-chloro-ethyl)-N'-methyl-phosphorodiamidic acid but-3-enyl ester
  参考文献：
  名称：

  N-取代对4-羟基环磷酰胺类似物激活机制的影响。

  摘要：

  比较了N-取代的4-羟基环磷酰胺类似物4-羟基异磷酰胺（2b），4-羟基三磷酰胺（2c）和3-甲基-4-羟基环磷酰胺（2d）的活化机理与未取代的母体化合物2a的活化机理。顺式2b，-2c和-2d的反应动力学与2a的反应动力学在质量上相似，因为它们分别对相应的醛磷酸酰胺中间体3进行开环反应，该中间体可以与顺式或反式-4-羟基异构体重合或经历碱催化的β-消除反应生成相应的磷酰胺芥末产物4。与2a和2d开环观察到的一般酸催化相反，N-（氯乙基）取代的类似物2b和2c经历了特定的碱催化开环。通过在酸性条件下2a和2d与2-巯基乙磺酸钠（Mesna）的快速反应，得到了4-（烷硫基）取代的环磷酰胺衍生物5a和5d，也说明了这种机理上的差异。在这些条件下，化合物2b和2c不会与Mesna反应生成5b和5c。处于平衡状态的醛/水合物分数和体外对L1210细胞的细胞毒性均以大于2c大于2b大于2a大于2d的

  DOI：

  10.1021/jm00127a016

文献信息

• Chemically Stable N-Methyl-4-(alkylthio)cyclophosphamide Derivatives as Prodrugs of 4-Hydroxycyclophosphamide
  作者：Ki-Young Moon、Frances N. Shirota、Nesrine Baturay、Chul-Hoon Kwon

  DOI：10.1021/jm00005a012

  日期：1995.3

  Two prototype N-methyl-4-thio-substituted cyclophosphamide (CP) derivatives (5 and 6), prodrugs of 4-hydroxycyclophosphamide (4-HO-CP), were designed to undergo oxidative N-demethylation to release the active alkylating agent. These prodrugs were chemically stable until oxidatively N-demethylated in the presence of hepatic microsomal P-450 enzymes. While the metabolism of 5 was enhanced in the presence of phenobarbital-induced microsomes, 6 was unaffected. Compound 6 was more active than 5 against L1210 leukemia cells grown in mice and exhibited statistically significant activity against the small cell lung cancer panel in the National Cancer Institute anticancer drug screen. Compound 5, like CP (1), was inactive in this screen. Thus, placement of a dithioester at the 4-position of N-methyl-HO-CP as in 6 markedly changes its spectrum of activity and has resulted in a new type of CP-based prodrug with antitumor activity against small cell lung cancer as well as leukemia cells in vitro as shown by their ability to inhibit tumor cell growth at concentrations as low as 10(-6) M.
• Takamizawa,A. et al., Heterocycles, 1977, vol. 7, p. 1091 - 1130
  作者：Takamizawa,A. et al.

  DOI：——

  日期：——
• N3-methyl-mafosfamide as a chemically stable, alternative prodrug of mafosfamide
  作者：Ki-Young Moon、Chul-Hoon Kwon

  DOI：10.1016/s0960-894x(98)00287-x

  日期：1998.7

  The presence of an alkyl substituent at N-3 in the oxazaphosphorine ring stabilizes N-substituted 4-(alkylthio)cyclophosphamides from spontaneous decomposition. Based on this finding, N-3-methyl-mafosfamide was synthesized and examined as a chemically stable, biooxidative prodrug of mafosfamide. This prodrug was stable in aqueous buffer (pH 7.4, 37 degrees C) and underwent N-demethylation in a time dependent manner when incubated with rat hepatic microsomes. N-3-Methyl-mafosfamide was 10-fold more cytotoxic in vitro than cyclophosphamide against mouse embryo Balb/c 3T3 cells (LC50 = 3.6 mu M). Preliminary in vivo antitumor evaluation against L1210 leukemia in mice showed that this prodrug was active [Increase of life span (ILS) > 29 %]. (C) 1998 Elsevier Science Ltd. All rights reserved.