1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨羰基)肼 | 173424-77-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨羰基)肼
• 英文名称: Cloretazine
• 英文别名: Laromustine；1,2-bis(methylsulfonyl)-1-(2-chlorchloroethyl)-2-2-(methylaminocarbonyl)hydrazine；1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]-hydrazine；1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylaminocarbonyl)hydrazine；1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-methylaminocarbonylhydrazine；VNP-40101M；1-[2-chloroethyl(methylsulfonyl)amino]-3-methyl-1-methylsulfonylurea
• CAS: 173424-77-6
• 化学式: C₆H₁₄ClN₃O₅S₂
• 分子量: 307.779
• InChiKey: PVCULFYROUOVGJ-UHFFFAOYSA-N

物化性质

• 密度：
  1.527±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  121
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨羰基)肼 在 水 作用下， 以 aq. buffer 为溶剂， 反应 1.0h， 生成 2-氯乙醇
  参考文献：
  名称：

  Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells

  摘要：

  Two new agents based upon the structure of the clinically active prodrug laromustine were synthesized. These agents, 2-(2-chloroethyl)-N-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (1) and N-(2-chloroethyl)-2-methyl-1,2-bis(methylsulfonyl)-N-nitrosohydrazinecarboxamide (2), were designed to retain the potent chloroethylating and DNA cross-linking functions of laromustine, and gain the ability to methylate DNA at the O-6 position of guanine, while lacking the carbamoylating activity of laromustine. The methylating arm was introduced with the intent of depleting the DNA repair protein O-6-alkylguanine-DNA alkyltransferase (AGT). Compound 1 is markedly more cytotoxic than laromustine in both AGT minus EMT6 mouse mammary carcinoma cells and high AGT expressing DU145 human prostate carcinoma cells. DNA cross-linking studies indicated that its cross-linking efficiency is nearly identical to its predicted active decomposition product, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (90CE), which is also produced by laromustine. AGT ablation studies in DU145 cells demonstrated that 1 can efficiently deplete AGT. Studies assaying methanol and 2-chloroethanol production as a consequence of the methylation and chloroethylation of water by 1 and 2 confirmed their ability to function as methylating and chloroethylating agents and provided insights into the superior activity of 1. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.01.016
• 作为产物：
  描述：

  1,2-双(甲基磺酰基)-1-(2-氯乙基)肼 以42.4的产率得到1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨羰基)肼
  参考文献：
  名称：

  [EN] ANTITUMOR 2-AMINOCARBONYL-1,2-BIS(METHYLSULFONYL)-1-(SUBSTITUTED)HYDRAZINES
  [FR] HYDRAZINES 2-AMINOCARBONYL-1,2-BIS(METHYLSULFONYL)-1-(SUBTITUEES) ANTITUMORALES

  摘要：

  本发明涉及新型的2-氨基甲酰基-1,2-双(甲基磺酰基)-1-(2-氯乙基)肼和2-氨基甲酰基-1,2-双(甲基磺酰基)-1-甲基肼及其用于治疗恶性肿瘤的用途。这些药物在动物和人类癌症的治疗中特别有用。这个类别中两个首选的药物，特别是用于肿瘤治疗的，分别是1,2-双(甲基磺酰基)-1-(2-氯乙基)-2-(2-氯乙基)氨基甲酰基肼和1,2-双(甲基磺酰基)-1-(2-氯乙基)-2-甲基氨基甲酰基肼。这些药物的特点是：它们不能通过CNUs去亚硝化机制进行去活化，也不能通过氢氧乙基化机制产生一种特定的物种，但可以通过氯乙基化或甲基化和氨基甲酰化进行反应。

  公开号：

  WO1997002029A1
• 作为试剂：
  描述：

  1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨羰基)肼 、 、 、 、 乙腈 、 甲胺基甲酰氯 、 在 1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(甲氨羰基)肼 作用下， 以 三乙胺 为溶剂， 以In the instant invention the mesylated product BMH is isolated as a pale solid in a 55+% yield的产率得到1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(ethyloxycarbonyl)-hydrazine
  参考文献：
  名称：

  Process for the synthesis of anti-neoplasia agent VNP40101M

  摘要：

  本发明涉及一种简单、安全、高收率的合成VNP40101M的方法，即1,2-双(甲基磺酰基)-2-(2-氯乙基)-2-(甲基氨甲酰基)肼，一种抗肿瘤剂。其中一种特别优选的方法是在高温下使用氯甲酰胺一锅法反应制备高收率的VNP40101M。

  公开号：

  US08026395B1

文献信息

• WATER-SOLUBLE SHPS AS NOVEL ALKYLATING AGENTS
  申请人：——

  公开号：US20040254103A1

  公开（公告）日：2004-12-16

  The present invention relates to compounds according to the structure (I): 1 Where R is —CH 3 or —CH 2 CH 2 Cl; R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl; R 2 or R 4 is OPO 3 H 2 , NO 2 , OCO(Glu-OH), NHCO(Glu-OH), NHR 7 and unassigned groups of R 2 , R 3 , R 4 , R 5 and R 6 are, independently, H, F, Cl, Br, I, OH, OPO 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SF 5 , NH 2 , NHR 7 , N(CH 3 ) 2 , OPO 3 H 2 , or a C1-C7 alkyl group with the proviso that when any two of unassigned groups of R 2 , R 3 , R 4 , R 5 or R 6 are other than H, the other two of unassigned groups of R 2 , R 3 , R 4 , R 5 or R 6 are H. R 7 is H or polyglutamyl as described. Phosphoric acid and glutamic acid can be a free acid or pharmaceutically acceptable salt thereof.

  本发明涉及结构（I）的化合物：其中R为—CH3或—CH2CH2Cl；R′为C1-C7烷基或—CH2CH2Cl；R2或R4为OPO3H2，NO2，OCO（Glu-OH），NHCO（Glu-OH），NHR7，以及R2、R3、R4、R5和R6的未指定基团，独立地为H、F、Cl、Br、I、OH、OPO3H2、OCH3、CF3、OCF3、NO2、CN、SO2CH3、SO2CF3、COCH3、COOCH3、SCH3、SF5、NH2、NHR7、N(CH3)2、OPO3H2，或C1-C7烷基，但条件是当R2、R3、R4、R5或R6中的任意两个未指定基团不为H时，其他两个未指定基团为H。R7为H或所述的多谷氨酸。磷酸和谷氨酸可以是其自由酸或药用可接受盐。
• Antitumor 2-(Aminocarbonyl)-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)- hydrazines
  作者：Krishnamurthy Shyam、Philip G. Penketh、Regina H. Loomis、William C. Rose、Alan C. Sartorelli

  DOI：10.1021/jm9505021

  日期：1996.1.1

  antitumor activity against the murine L1210 leukemia. All of the compounds tested were capable of producing "cures" of mice bearing this tumor. One of the most active agents of this class, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)- 2(-)[[2-chloroethyl)-amino]carbonyl]hydrazine, was further evaluated against a spectrum of transplanted murine and human solid tumors. Pronounced activity was found against all

  合成了几种2-（氨基羰基）-1，2-双（甲基磺酰基）-1-（2-氯乙基）羟嗪，并初步评估了其对鼠L1210白血病的抗肿瘤活性。所有测试的化合物都能够产生带有这种肿瘤的小鼠“治愈”。对该类活性最强的试剂之一，1,2-双（甲基磺酰基）-1-（2-氯乙基）-2（-）[[[2-氯乙基）-氨基]羰基]肼，通过光谱进行了进一步评估。鼠和人实体瘤的移植。发现针对所有肿瘤，包括鼠B16F10黑色素瘤，M109肺癌，M5076网状细胞肉瘤和人LX-1肺癌，均具有明显的活性。观察到的活性与已建立的抗肿瘤药物，环磷酰胺，丝裂霉素C和亚硝基脲相比，得到了良好的评价。
• Antitumor 2-aminocarbonyl-1,
  申请人：Yale University

  公开号：US05637619A1

  公开（公告）日：1997-06-10

  The present invention relates to novel 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines and 2-aminocarbonyl-1,2-bis(methylsulfonyl)-1-methylhydrazines, and their use to treat malignant tumors. The agents are especially useful in the treatment of animal and human cancers. Two preferred agents in this class, especially for use in the treatment of tumors are 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(2-chloroethyl)aminocarbonylhy drazine and 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-methylaminocarbonylhydrazine. These agents are characterized by the following: they are incapable of undergoing inactivation by the denitrosation mechanism proposed for the inactivation of the CNUs; they are incapable of generating a hydroxyethylating species by the mechanism proposed for the CNUs; and they are capable of chloroethylation or methylation and carbamoylation.

  本发明涉及新颖的2-氨基羰基-1,2-双(甲磺酰基)-1-(2-氯乙基)肼和2-氨基羰基-1,2-双(甲磺酰基)-1-甲基肼，以及它们用于治疗恶性肿瘤。这些药物在动物和人类癌症的治疗中特别有用。在这一类别中，特别适用于肿瘤治疗的两种首选药物是1,2-双(甲磺酰基)-1-(2-氯乙基)-2-(2-氯乙基)氨基羰基肼和1,2-双(甲磺酰基)-1-(2-氯乙基)-2-甲基氨基羰基肼。这些药物具有以下特点：它们无法通过被提出用于CNUs失活的去亚硝化机制而失活；它们无法通过被提出用于CNUs的生成羟乙基化物种的机制而生成；它们能够进行氯乙基化或甲基化和羰基化。
• Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl)hydrazines and chloroethylnitrosoureas
  作者：Philip G Penketh、Krishnamurthy Shyam、Alan C Sartorelli

  DOI：10.1016/s0006-2952(99)00328-7

  日期：2000.2

  classically believed to be responsible for the alkylating (chloroethylating) and/or carbamoylating activities of the chloroethylnitrosoureas (CNUs), were compared with respect to the cross-linking and nicking of T7 DNA to that caused by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), and 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (MeCCNU)

  比较了1,2-双（磺酰基）肼衍生物，该衍生物设计用于生成几种传统上被认为负责氯乙基亚硝基脲（CNU）的烷基化（氯乙基化）和/或氨基甲酰化活性的亲电物质， T7 DNA与1,3-双（2-氯乙基）-1-亚硝基脲（BCNU），1-（2-氯乙基）-3-环己基-1-亚硝基脲（CCNU）和1-引起的T7 DNA的连接和形成切口（2-氯乙基）-3-（4-反式甲基环己基）-1-亚硝基脲（MeCCNU）。在BCNU的情况下，发现大部分T7 DNA链切口是由于2-氯乙基异氰酸酯水解产生的2-氯乙基胺的产生，而后者是在亲代亚硝基脲的分解过程中形成的。1，2-双（甲基磺酰基）-1-（2-氯乙基）肼（化合物1）比CNU具有更大的DNA交联收率。不能产生2-氯乙基异氰酸酯的化合物1及其衍生物不能产生可检测水平的链切口，这表明鸟嘌呤的N7-烷基化在这些试剂的作用下没有很大程度地发生。由于据信化合物1及其衍生物会生成氯鎓
• Water-soluble SHPs as novel alkylating agents
  申请人：Lin Xu

  公开号：US20050043244A1

  公开（公告）日：2005-02-24

  The present invention relates to compounds according to the structure (I): Where R is —CH 3 or —CH 2 CH 2 Cl; R′ is C 1 -C 7 alkyl or —CH 2 CH 2 Cl; R 2 or R 4 is OP0 3 H 2 , N0 2 , OCO(Glu-OH), NHCO(Glu-OH), NHR 7 and unassigned groups of R 2 , R 3 , R 4 , R 5 and R 6 are, independently, H, F, Cl, Br, I, OH, OP0 3 H 2 , OCH 3 , CF 3 , OCF 3 , NO 2 , CN, SO 2 CH 3 , SO 2 CF 3 , COCH 3 , COOCH 3 , SCH 3 , SFs, NH 2 , NHR 7 , N(CH 3 ) 2 , OPO 3 H 2 , or a C1-C7 alkyl group with the proviso that when any two of unassigned groups of R 2 , R 3 , R 4 , R 5 or R 6 are other than H, the other two of unassigned groups of R 2 , R 3 , R 4 , R 5 or R 6 are H. R 7 is H or polyglutamyl as described. Phosphoric acid and glutamic acid can be a free acid or pharmaceutically acceptable salt thereof.

  本发明涉及结构式(I)的化合物，其中R为—CH3或—CH2CH2Cl; R′为C1-C7烷基或—CH2CH2Cl; R2或R4为OP03H2、N02、OCO(Glu-OH)、NHCO(Glu-OH)、NHR7和未分配的R2、R3、R4、R5和R6基团，分别为H、F、Cl、Br、I、OH、OP03H2、OCH3、CF3、OCF3、NO2、CN、SO2CH3、SO2CF3、COCH3、COOCH3、SCH3、SFs、NH2、NHR7、N(CH3)2、OPO3H2或C1-C7烷基，但当R2、R3、R4、R5或R6中的任意两个未分配基团不为H时，未分配的R2、R3、R4、R5或R6中的其他两个基团为H。R7为H或如所述的多谷氨酰基。磷酸和谷氨酸可以是自由酸或药学上可接受的盐。