1,2-双(甲基磺酰基)-1-(2-氯乙基)肼 | 127792-84-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机磺酸及其衍生物
• 中文名称: 1,2-双(甲基磺酰基)-1-(2-氯乙基)肼
• 英文名称: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine
• 英文别名: 90CE；N'-(2-chloroethyl)-N'-methylsulfonylmethanesulfonohydrazide
• CAS: 127792-84-1
• 化学式: C₄H₁₁ClN₂O₄S₂
• 分子量: 250.727
• InChiKey: QVKFHBWVOPWLGX-UHFFFAOYSA-N

物化性质

• 熔点：
  138-139 °C(Solv: ethanol (64-17-5))
• 沸点：
  375.6±44.0 °C(Predicted)
• 密度：
  1.528±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  13
• 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：
  100
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1,2-双(甲基磺酰基)-1-(2-氯乙基)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：

  2-[1,2-二(甲基磺酰基)肼基]乙基甲烷磺酸酯 在 lithium chloride 作用下， 以 丙酮 为溶剂， 反应 72.0h， 生成 1,2-双(甲基磺酰基)-1-(2-氯乙基)肼
  参考文献：
  名称：

  1,2,2-三（磺酰基）肼作为抗肿瘤药和锥虫病药物的合成和评价。

  摘要：

  合成了几种1,2,2-三（磺酰基）肼，被认为是1,2-双（磺酰基）肼的前药，并评估了它们在小鼠中的抗肿瘤和锥虫活性。1-甲基-1,2,2-三（甲基磺酰基）肼是一种非常有效的抗锥虫剂，而1-（2-氯乙基）-1,2,2-三（甲基磺酰基）肼则没有活性。相比之下，1-（2-氯乙基）-1,2,2-三（甲基磺酰基）肼显示出强大的抗肿瘤活性，产生了患有白血病L1210，白血病P388或肉瘤180的小鼠数个60天的“治愈”。三（磺酰基）衍生物不会产生异氰酸酯这一事实会加剧亚硝基脲如1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）的宿主毒性，使其成为锥虫和锥虫的重要药物。癌症化疗。

  DOI：

  10.1021/jm00170a033
• 作为试剂：
  描述：

  2-[1,2-二(甲基磺酰基)肼基]乙基甲烷磺酸酯 、 1,2-双(甲基磺酰基)-1-(2-氯乙基)肼 在 1,2-双(甲基磺酰基)-1-(2-氯乙基)肼 作用下， 以53的产率得到7-氟-5-溴-1,2,3,4-四氢乙酯
  参考文献：
  名称：

  Fluoro substituted cycloalkanoindoles, compositions containing such compounds and methods of treatment

  摘要：

  氟代环烷基吲哚衍生物是前列腺素拮抗剂，因此对于治疗前列腺素介导的疾病是有用的。

  公开号：

  US07317036B2

文献信息

• Process for the synthesis of anti-neoplasia agent VNP40101M
  申请人：Nanotherapeutics, Inc.

  公开号：US08026395B1

  公开（公告）日：2011-09-27

  The present invention relates to simple, safe, high-yield methods of synthesizing VNP40101M, 1,2-bis(methylsulfonyl)-2-(2-chloroethyl)-2-(methylaminocarbonyl)hydrazine, an anti-neoplasia agent. One particularly preferred method uses methyl chloroformamide in a one-pot reaction at elevated temperatures to provide VNP40101M in high yield.

  本发明涉及一种简单、安全、高产率的合成VNP40101M、1,2-双(甲磺酰基)-2-(2-氯乙基)-2-(甲氨基甲酰)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进行一锅法反应，以高产率提供VNP40101M。
• 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。
• Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
  作者：Philip G. Penketh、Hugh S Williamson、Raymond P. Baumann、Krishnamurthy Shyam

  DOI：10.3390/molecules26020259

  日期：——

  A design strategy for macromolecular prodrugs is described, that are expected to exhibit robust activity against most solid tumor types while resulting in minimal toxicities to normal tissues. This approach exploits the enhanced permeability, and retention (EPR) effect, and utilizes carefully engineered rate constants to selectively target tumor tissue with short-lived cytotoxic moieties. EPR based tumor accumulation (half-life ~ 15 h) is dependent upon the ubiquitous abnormal solid tumor capillary morphology and is expected to be independent of individual tumor cell genetic variability that leads to resistance to molecularly targeted agents. The macromolecular sulfonylhydrazine-based prodrugs hydrolyze spontaneously with long half-life values (~10 h to >300 h dependent upon their structure) resulting in the majority of the 1,2-bis(sulfonyl)-1-alkylhydrazines (BSHs) cytotoxic warhead being released only after tumor sequestration. The very short half-life (seconds) of the finally liberated BSHs localizes the cytotoxic stress to the tumor target site by allowing insufficient time for escape. Thus, short lifespan anticancer species are liberated, and exhibit their activity largely within the tumor target. The abnormal tumor cell membrane pH gradients favor the uptake of BSHs compared to that of normal cells, further enhancing their selectivity. The reliance on physicochemical/chemical kinetic parameters and the EPR effect is expected to reduce response variability, and the acquisition of resistance.

  本文描述了一种大分子前药的设计策略，预计这些前药在对大多数实体肿瘤类型表现出强大活性的同时，对正常组织的毒性最小。该方法利用了增强渗透性和滞留（EPR）效应，并利用精心设计的速率常数，有选择性地针对肿瘤组织，使用短寿命细胞毒性物质。EPR基于肿瘤毛细血管形态的普遍异常，肿瘤积累（半衰期约为15小时）预计与导致分子靶向药物抵抗的个体肿瘤细胞遗传变异无关。基于磺酰肼基的大分子前药具有长半衰期值（约为10小时至> 300小时，取决于其结构），可自发水解，导致大部分1,2-双（磺酰基）-1-烷基肼（BSHs）细胞毒性弹头仅在肿瘤隔离后释放。最后释放的BSHs的非常短的半衰期（秒）通过允许不足的时间逃脱，将细胞毒性应激定位于肿瘤靶点。异常的肿瘤细胞膜pH梯度有利于BSHs的摄取，相比正常细胞，进一步增强了它们的选择性。预计依赖于物理化学/化学动力学参数和EPR效应将减少反应变异和获得抗性。