异氰酸正丁酯 | 111-36-4

• 物质功能分类: 化学试剂 - 有机试剂 - 氰酸酯/异氰酸酯
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 异氰酸正丁酯
• 中文别名: 1-丁基异氰酸酯；丁基异氰酸酯；正丁基异氰酸酯；异氰酸丁酯；N-异氰酸丁酯；n-异氰酸丁酯
• 英文名称: n-butyl isocyanide
• 英文别名: butyl isocyanate；n-butyl isocyanate；1-isocyanatobutane
• CAS: 111-36-4
• 化学式: C₅H₉NO
• mdl: MFCD00002046
• 分子量: 99.1326
• InChiKey: HNHVTXYLRVGMHD-UHFFFAOYSA-N

物化性质

• 熔点：
  85.5℃
• 沸点：
  115 °C(lit.)
• 密度：
  0.88 g/mL at 25 °C(lit.)
• 蒸气密度：
  3 (vs air)
• 闪点：
  64 °F
• 暴露限值：
  No exposure limit is set for this compound. On the basis of its low inhalation toxicity, a TLV-TWA value of 8 mg/m3 (2 ppm) can be safely ascribed.
• 物理描述：
  N-butyl isocyanate appears as a clear, colorless liquid with a pungent odor. Very toxic by ingestion, and may also be toxic by skin absorption and inhalation. Vapors heavier than air. Less dense than water and insoluble in water. Produces toxic oxides of nitrogen during combustion.
• 颜色/状态：
  Colorless liquid
• 溶解度：
  In water, 1.4X10+3 mg/L at 25 °C (est)
• 蒸汽密度：
  3.00 (Air= 1)
• 蒸汽压力：
  1.76X10+1 mm Hg at 25 °C (est)
• 自燃温度：
  425 °C
• 分解：
  Energy of decomposition (in range 160 to 450 °C) measured as 0.55 kJ/g.
• 表面张力：
  4.9729X10-2 N/m at 193 K
• 折光率：
  Index of refraction at 20 °C/D = 1.4060

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  7
• 可旋转键数：
  3
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  29.4
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

一般来说，活性异氰酸酯可以与含有氨基、醇基或巯基的生物分子以及水发生反应。虽然在像肺部这样的水环境中理论上可能发生水解，但测量结果显示，与芳香族异氰酸酯相比，烷基异氰酸酯对此类水解相对抵抗。

... Reactive isocyanates in general, can react with biological molecules containing amino, alcohol, or sulfhydryl groups, as well as with water. While hydrolysis in an aqueous environment, such as the lung, is theoretically possible, measurements show that alkyl isocyanates are relatively resistant (compared to arylisocyanates) to such hydrolysis.

来源:Hazardous Substances Data Bank (HSDB)

代谢

异氰酸酯...形成不稳定的谷胱甘肽结合物，它们可以从这些结合物中被释放出来。/异氰酸酯/

Isocyanates ... form labile glutathione conjugates from which they can be released. /Isocyanate/

来源:Hazardous Substances Data Bank (HSDB)

代谢

甲萘威（一种非硫代杀菌剂）通过腹腔注射给药，在小白鼠体内以7.0毫克/公斤的剂量使肝脏线粒体低Km乙醛脱氢酶（mALDH或ALDH2）活性降低50%（半抑制浓度IC50），这一抑制效力与几种已知的具有酒精增敏作用的硫代及二硫代氨基甲酸酯杀菌剂（及相关酒精滥用药物双硫仑）以及硫代氨基甲酸酯除草剂相当。因此，本研究首先通过比较甲萘威与上述单硫代和二硫代氨基甲酸酯的代谢，以及评估甲萘威代谢物的抑制效力，来探究甲萘威抑制mALDH的机制。甲萘威在腹腔注射给药的小白鼠体内转化为丁基异氰酸酯、S-(N-丁基氨基甲酰)谷胱甘肽和S-(N-丁基氨基甲酰)半胱氨酸，最终生成S-甲基-N-丁基硫代氨基甲酸酯（MBT），这是一种在肝脏中短暂存在的代谢物。MBT作为体内mALDH抑制剂，其效力比甲萘威或丁基异氰酸酯高10倍以上，也比中间体S-(N-丁基氨基甲酰)结合物更有效。甲萘威和MBT在体外抑制小鼠肝脏mALDH的IC50分别为0.77和8.7微摩尔。当线粒体被NADPH单独或加微体强化时，MBT的效力显著增强，IC50分别为0.50和0.23微摩尔。这种MBT的激活几乎被细胞色素P450抑制剂N-苄基咪唑完全阻断，而其他几种细胞色素P450失活剂则不会。MBT（可能是经过生物激活后）在体内以0.3毫克/公斤的IC50抑制mALDH。合成了两种候选激活产物以确定其效力。N-羟基MBT（通过三甲基硅基衍生物制备）未检测为MBT的代谢物；其低效力也排除了N-羟基化作为激活过程。MBT亚砜，由MBT在水溶液中与镁单过氧酞酸酯反应氧化而成，是对mALDH和酵母ALDH已知的最有效抑制剂之一（IC50 0.08-0.09微摩尔）。这些发现与甲萘威通过上述代谢物和N-丁基硫代氨基甲酸酯的生物激活六步过程一致，其中MBT是倒数第二个抑制剂，而MBT亚砜是最终的mALDH抑制剂。

Benomyl (a non-thio fungicide) inhibits hepatic mitochondrial low-Km aldehyde dehydrogenase (mALDH or ALDH2) in ip-treated mice by 50% (IC50) at 7.0 mg/kg, which is surprisingly the same potency range as that for several dithiocarbamate fungicides (and the related alcohol abuse drug disulfiram) and thiocarbamate herbicides previously known for their alcohol-sensitizing action. The mechanism by which benomyl inhibits mALDH was therefore examined, first by comparing the metabolism of benomyl with the aforementioned mono- and dithiocarbamates and second by evaluating the inhibitory potency of the benomyl metabolites. Benomyl in ip-treated mice is converted, via butyl isocyanate, S-(N-butylcarbamoyl)glutathione, and S-(N-butylcarbamoyl)cysteine, to S-methyl N-butylthiocarbamate (MBT), identified as a transient metabolite in liver. MBT is >10-fold more potent than benomyl or butyl isocyanate as an in vivo mALDH inhibitor and is also more potent than the intermediary S-(N-butylcarbamoyl) conjugates. Benomyl and MBT inhibit mouse hepatic mALDH in vitro with IC50s of 0.77 and 8.7 uM, respectively. The potency of MBT is greatly enhanced by fortification of the mitochondria with NADPH alone or plus microsomes giving IC50s of 0.50 and 0.23 uM, respectively. This activation of MBT is almost completely blocked by the cytochrome P450 inhibitor N-benzylimidazole but not by several other cytochrome P450 inactivators. MBT (probably following bioactivation) inhibits mALDH in vivo with an IC50 of 0.3 mg/kg. Two candidate activation products were synthesized for potency determinations. N-Hydroxy MBT (prepared via the trimethylsilyl derivative) was not detected as an MBT metabolite; its low potency also rules against N-hydroxylation as the activation process. MBT sulfoxide, from oxidation of MBT with magnesium monoperoxyphthalate in water, is one of the most potent inhibitors known for mALDH and yeast ALDH in vitro (IC50 0.08-0.09 uM). These findings are consistent with a six-step bioactivation of benomyl, via the metabolites above and N-butylthiocarbamic acid, with MBT as the penultimate and MBT sulfoxide as the ultimate inhibitor of mALDH.

来源:Hazardous Substances Data Bank (HSDB)

代谢

对酵母（Saccharomyces cerevesiae）代谢的抑制通过杀菌化学物质进行了研究。使用氧气电极测量了依赖于葡萄糖或乙醇的酵母呼吸，并使用气压法测定二氧化碳的释放来测量发酵。呼吸和发酵受到的本米尔的抑制大于其分解产物，卡本丹津，在相同摩尔浓度下的抑制。另一种本米尔分解产物，丁基异氰酸酯，对呼吸的抑制更强，但对发酵的抑制则不如原化合物。在测试的异氰酸酯中，己基异氰酸酯对这两种活动是最具抑制性的。克菌丹比本米尔更活跃，而异菌脲则不如本米尔活跃。因为本米尔在80%乙醇中制备时迅速分解为卡本丹津，所以在将其添加到酵母中以确定其对呼吸或发酵的影响时，只有59%的溶解本米尔是完整的。

The inhibition of yeast (Saccharomyces cerevesiae) metabolism by fungicidal chemicals was investigated. Glucose- or ethanol-dependent yeast respiration was measured with an oxygen electrode, and manometric determination of carbon dioxide release was used to measure fermentation. Both respiration and fermentation were inhibited more by benomyl than by identical molar concentrations of its breakdown product, carbendazim. Butyl isocyanate, another benomyl breakdown product, inhibited respiration more but inhibited fermentation less than the parent compound. Of the isocyanates tested, hexyl isocyanate was the most inhibitory towards both activities. Captan was more active and iprodione less active than benomyl. Because benomyl rapidly broke down to carbendazim when it was prepared in 80% ethanol, only 59% of the dissolved benomyl was intact when it was added to yeast to determine its effect on respiration or fermentation.

来源:Hazardous Substances Data Bank (HSDB)

代谢

氰化物可以通过口服、吸入和皮肤途径迅速被吸收，并分布到全身。氰化物主要通过罗丹酶或3-巯基丙酸硫转移酶代谢成硫氰酸盐。氰化物的代谢物通过尿液排出。

Cyanide is rapidly alsorbed through oral, inhalation, and dermal routes and distributed throughout the body. Cyanide is mainly metabolized into thiocyanate by either rhodanese or 3-mercaptopyruvate sulfur transferase. Cyanide metabolites are excreted in the urine. (L96)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

识别和使用：正丁基异氰酸酯是一种无色可燃液体，可溶于水。它被用作有机合成的试剂；在生产碳酸盐、尿素类杀虫剂和杀菌剂时用作中间体。它还用于生产磺酰脲类抗糖尿病药物。人类暴露和毒性：暴露于正丁基异氰酸酯的女性受试者出现了对粘膜的刺激作用和对心脏传导系统的暂时性损伤。职业暴露于正丁基异氰酸酯可能通过在工作场所吸入和皮肤接触发生，该化学物质在此处使用或制造。正丁基异氰酸酯对职业环境中的工人眼睛有刺激性。它对皮肤有强烈刺激性。有哮喘、过敏或肺功能受损史的个体暴露于正丁基异氰酸酯的副作用风险增加。动物研究：在一项重复暴露研究中，雄性大鼠通过吸入暴露于正丁基异氰酸酯。低剂量组没有观察到与治疗相关的临床体征。在高剂量组中，动物看起来不整洁，表现出呼吸困难、活动减少和鼻涕分泌增多。高剂量处理的动物肺功能显著下降。高剂量动物出现了广泛的间隔破坏，表明有肺气肿。暴露于正丁基异氰酸酯的雄性大鼠，支气管肺泡灌洗液中的中性粒细胞、乳酸脱氢酶和蛋白质升高。肺功能参数降低。这种化学物质在通过吸入暴露于豚鼠时是一种致敏剂。在兔耳暴露于正丁基异氰酸酯溶液时没有观察到刺激。当测试材料滴入兔眼的结膜囊时，正丁基异氰酸酯对兔眼具有高度腐蚀性。口服暴露于这种化学物质的猫在血液学或高铁血红蛋白形成方面没有相关临床效果。在使用鼠伤寒沙门氏菌TA 98、TA 100、TA 1535和TA 1537株进行 Ames 测试时，正丁基异氰酸酯在有和无代谢活化情况下均为阴性。

IDENTIFICATION AND USE: N-Butyl isocyanate is a colorless flammable liquid, and It is soluble in water. It is used as a reagent in organic synthesis; used as intermediates in production of carbamate, and urea insecticides, and fungicides. It is also used in the production of sulfonyl urea antidiabetic drugs. HUMAN EXPOSURE AND TOXICITY: In female subjects exposed to N-butyl isocyanate there was an irritating effect to the mucous membranes and temporary lesions to the cardiac conduction system. Occupational exposure to N-butyl isocyanate may occur through inhalation, and dermal contact in the workplace where this chemical is used or manufactured. Butyl isocyanate is an irritant to the eyes of workers in an occupational setting. It is a strong irritant to to the skin. Individuals with a history of asthma, allergies or impaired lung function are at increased risk to the adverse effects of N-butyl isocyanate exposure. ANIMAL STUDIES: In a repeated exposure study, male rats were exposed by inhalation to N-Butyl isocyanate. No treatment related clinical signs were observed in the low dose groups. At the higher dose groups animals appeared unkempt, and exhibited labored breathing, reduced motility and an increased serous discharge from the nose. Substantial decrease in pulmonary function was noted in high dose treated animals. High dose animals exhibited widespread septal destruction, indicative of emphysema. In male rats, exposed to N-butyl isocyanate, neutrophils, LDH, and protein in the bronchoalveolar lavage fluid were elevated. Lung function parameters were decreased. This chemical was a sensitizer in guinea pigs exposed by inhalation. No irritation was observed in a rabbit ear exposed to a solution of N-butyl isocyanate. Butyl isocyanate was highly corrosive to rabbit eyes when instillation of test material to the conjunctival sac. Cats exposed to this chemical orally, had no related clinical effects in hematology or methemoglobin formation. Butyl isocyanate was negative in an Ames test using Salmonella typhimurium strains TA 98, TA 100, TA 1535 and TA 1537 with and without metabolic activation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

氰化物是电子传递链第四个复合体中细胞色素c氧化酶的抑制剂（存在于真核细胞线粒体膜中）。它与这种酶中的铁原子形成复合物。氰化物与这种细胞色素的结合阻止了电子从细胞色素c氧化酶传递到氧气。因此，电子传递链被中断，细胞无法再通过有氧呼吸产生ATP能量。主要依赖有氧呼吸的组织，如中枢神经系统和心脏，受到的影响尤为严重。氰化物也通过结合过氧化氢酶、谷胱甘肽过氧化物酶、变性血红蛋白、羟钴胺素、磷酸酶、酪氨酸酶、抗坏血酸氧化酶、黄嘌呤氧化酶、琥珀酸脱氢酶和Cu/Zn超氧化物歧化酶产生一些毒性效应。氰化物与变性血红蛋白中的铁离子结合，形成无活性的氰变性血红蛋白。

Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

短时间内接触高浓度的氰化物会对大脑和心脏造成伤害，甚至可能导致昏迷、癫痫、呼吸暂停、心脏骤停和死亡。长期吸入氰化物会引起呼吸困难、胸痛、呕吐、血象改变、头痛和甲状腺肿大。皮肤接触氰化物盐可能会引起刺激并产生溃疡。

Exposure to high levels of cyanide for a short time harms the brain and heart and can even cause coma, seizures, apnea, cardiac arrest and death. Chronic inhalation of cyanide causes breathing difficulties, chest pain, vomiting, blood changes, headaches, and enlargement of the thyroid gland. Skin contact with cyanide salts can irritate and produce sores. (L96, L97)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

所有暴露途径均可能引起严重的局部影响。

Serious local effects by all routes of exposure.

来源:ILO-WHO International Chemical Safety Cards (ICSCs)

安全信息

• TSCA：
  Yes
• 危险等级：
  6.1(a)
• 危险品标志：
  F
• 安全说明：
  S23,S26,S28,S36/37/39,S45
• 危险类别码：
  R42/43,R26,R11,R21/22,R34,R37
• WGK Germany：
  1
• 海关编码：
  2929109000
• 危险品运输编号：
  UN 2485 6.1/PG 1
• 危险类别：
  6.1(a)
• RTECS号：
  NQ8250000
• 包装等级：
  I
• 储存条件：
  库房应保持通风、低温和干燥，并与氧化剂分开储存和运输。

SDS

第一部分：化学品名称

制备方法与用途

化学性质：液体。

用途：

• 正丁基异氰酸酯用作医药、农药、染料中间体。
• 它是杀菌剂苯菌灵的中间体，在光气法制备磺酰脲类除草剂时，作为催化剂使用，确保反应平稳和高收率。
• 有机合成中间体，用于生产杀菌剂苯莱特。
• 用作杀菌剂苯菌灵的生产原料。该药是一种高效广谱、内吸性杀菌剂，具有保护、铲除和治疗作用，可用于防治多种作物病害。

生产方法： 正丁基异氰酸酯可通过正丁胺与光气反应制得。具体步骤为：将正丁胺与邻二氯苯加入反应器中，在搅拌下通入干燥的氯化氢直至饱和；随后在110-160℃条件下通入过量光气，直至溶液变清后再通20-30分钟。之后蒸馏收集160℃以前馏分，并进一步蒸馏收集106-120℃馏分。加入无水碳酸钾静置后过滤可得成品。此外，通过溴丁烷与氰酸钾在有机溶剂（二甲基甲酰胺）中反应也可制备。

另一种生产方法为：将计算量的二甲苯和正丁胺投入反应釜，在常温下滴加浓盐酸1小时；随后回流分水约8小时，温度升至140℃完成成盐。稍降温后开始通光气进行回流反应，直至光气完全反应后再通氮气排出过量气体，并降至室温。将料液精馏收集114～116℃馏分即得产品。

类别：易燃液体

毒性分级：高毒

• 急性毒性：
  • 大鼠口服 LD50: 600 毫克/公斤；
  • 小鼠口服 LD50: 150 毫克/公斤

爆炸物危险特性：与空气混合可爆

可燃性危险特性：易燃；热分解排出有毒氮氧化物烟雾

储运特性：库房通风低温干燥，与氧化剂分开储存运输

灭火剂：干粉、二氧化碳、1211、泡沫

职业标准：

• 时间加权平均容许浓度 (TWA): 0.5 毫克/立方米
• 短时间接触容许浓度 (STEL): 1 毫克/立方米

反应信息

• 作为反应物：
  描述：

  异氰酸正丁酯 在 三甲基铝 、 bis(tributyltin)selenide 作用下， 以 1,4-二氧六环 、 正己烷 、 甲苯 为溶剂， 反应 3.0h， 以86%的产率得到N-butyl isoselenocyanate
  参考文献：
  名称：

  通过异氰酸酯与双（二甲基铝）硒化硒一锅法合成硒脲和硒代氨基甲酸酯

  摘要：

  通过与双（二甲基铝）硒化物反应，有效地使异氰酸酯亚硒酸酯化，得到相应的异亚硒酸酯。通过将胺和醇化物随后添加到反应混合物中，以高收率实现了不对称硒脲和硒代氨基甲酸酯的一锅法合成。

  DOI：

  10.1016/j.tetlet.2010.11.069
• 作为产物：
  描述：

  2-(butylamino)-2-oxoacetic acid 在 ammonium peroxydisulfate 、 silver nitrate 、 copper(II) sulfate 作用下， 以 正己烷 、 水 为溶剂， 反应 3.0h， 以83%的产率得到异氰酸正丁酯
  参考文献：
  名称：

  Reactivity of carbamoyl radicals: the first general and convenient free-radical synthesis of isocyanates

  摘要：

  在银盐（I）和铜盐（II）的催化下，草酸单酰胺在两相体系中被 S2O82- 氧化，首次实现了异氰酸酯的自由基合成。

  DOI：

  10.1039/c39940000679
• 作为试剂：
  描述：

  光气 、 苯磺酰胺 在 异氰酸正丁酯 作用下， 以 氯苯 为溶剂， 生成 异氰酸苯磺酰酯
  参考文献：
  名称：

  Ulrich,H.; Sayigh,A.A.R., Angewandte Chemie, 1966, vol. 78, p. 761 - 769

  摘要：

  DOI：

文献信息

• Synthesis of Thiocarbamates from Thiols and Isocyanates Under Catalyst- and Solvent-Free Conditions
  作者：Barahman Movassagh、Mohammad Soleiman-Beigi

  DOI：10.1007/s00706-007-0762-7

  日期：2008.2

  A simple and efficient procedure was developed for the synthesis of S -alkyl (aryl) thiocarbamates under solvent-free conditions without the use of a catalyst. The significant features of this protocol are (a) operational simplicity, (b) mild reaction conditions, (c) short reaction times, (d) solvent-free conditions, and (e) high product yields.

  开发了一种简单有效的方法，用于在无溶剂条件下不使用催化剂合成 S- 烷基（芳基）硫代氨基甲酸酯。该方案的显着特征是（a）操作简便，（b）反应条件温和，（c）反应时间短，（d）无溶剂条件和（e）产品收率高。
• Squaraines as Fluoro−Chromogenic Probes for Thiol-Containing Compounds and Their Application to the Detection of Biorelevant Thiols
  作者：Jose V. Ros-Lis、Beatriz García、Diego Jiménez、Ramón Martínez-Máñez、Félix Sancenón、Juan Soto、Fernando Gonzalvo、M. Carmen Valldecabres

  DOI：10.1021/ja031987i

  日期：2004.4.1

  A highly selective colorimetric chemodosimeter for thiol-containing compounds in aqueous solutions is reported. The design protocol makes use of a highly specific reaction between thiols and the electrophilic four-membered ring of highly colored, fluorescent squaraine backbones. At neutral pH selective decoloration and total emission quenching was found due to the rupture of the highly delocalized

  报道了一种用于水溶液中含硫醇化合物的高选择性比色化学剂量计。该设计方案利用硫醇与高度着色的荧光方酸骨架的亲电四元环之间的高度特异性反应。在中性 pH 值下，由于选择性亲核加成含硫醇衍生物时高度离域的方酸菁骨架破裂，发现选择性脱色和总发射猝灭。方酸衍生物已成功应用于人血浆中低分子量氨基硫醇的测定。该方法体现了化学剂量计方法在为目标客人寻找新的或改进的显色选择性或特异性探针方面的潜在适用性。
• [EN] PYRAZOLOPYRIMIDINES AS CYCLIN-DEPENDENT KINASE INHIBITORS<br/>[FR] PYRAZOLOPYRIMIDINES TENANT LIEU D'INHIBITEURS DE KINASES DEPENDANTES DE LA CYCLINE
  申请人：SCHERING CORP

  公开号：WO2004022561A1

  公开（公告）日：2004-03-18

  In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

  在其多种实施方式中，本发明提供了一类新型的吡唑并[1,5-a]嘧啶化合物，作为细胞周期依赖性激酶的抑制剂，以及制备这类化合物的方法，含有一种或多种这类化合物的药物组合物，制备包含一种或多种这类化合物的药物配方的方法，以及利用这类化合物或药物组合物治疗、预防、抑制或改善与CDKs相关的一种或多种疾病的方法。
• 4-((4-取代芳基-2-嘧啶基)氨基)苯甲酰肼衍生物及其制备方法和应用
  申请人：厦门大学

  公开号：CN107056713A

  公开（公告）日：2017-08-18

  4‑((4‑取代芳基‑2‑嘧啶基)氨基)苯甲酰肼衍生物及其制备方法和应用，涉及肿瘤药物。制备方法：制备中间体对胍基苯甲酸乙酯硝酸盐；制备中间体1‑(取代芳基)‑3‑(二甲氨基)‑2‑丙烯‑1‑酮；制备中间体4‑((4‑取代芳基‑2‑嘧啶基)氨基)苯甲酸乙酯；制备中间体4‑((4‑取代芳基‑2‑嘧啶基)氨基)苯甲酰肼；制备4‑((4‑取代芳基‑2‑嘧啶基)氨基)苯甲酰肼衍生物。一类4‑((4‑取代芳基‑2‑嘧啶基)氨基)苯甲酰肼衍生物用于制备治疗或预防肿瘤相关疾病的药物中的用途。具有显著的抑制肿瘤细胞生长和诱导肿瘤细胞凋亡的作用，可用于制备治疗或预防肿瘤相关疾病的药物。
• Synthesis and biological evaluation of (3/4-(pyrimidin-2-ylamino)benzoyl)-based hydrazine-1-carboxamide/carbothioamide derivatives as novel RXRα antagonists
  作者：Jingbo Qin、Jie Liu、Chunxiao Wu、Jianwen Xu、Bowen Tang、Kaiqiang Guo、Xiaohui Chen、Weihao Liu、Tong Wu、Hu Zhou、Meijuan Fang、Zhen Wu

  DOI：10.1080/14756366.2020.1740692

  日期：2020.1.1

  the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among

  类维生素A X受体α（RXRα）的表达和生物学功能异常改变在癌症的发展中具有关键作用。越来越多的研究探索了RXRα作为抗癌剂的潜在调节剂。合成了一系列（4 / 3-（嘧啶-2-基氨基）苯甲酰基）肼-1-羧酰胺/碳硫酰胺衍生物，并在本研究中评估了其作为RXRα拮抗剂的抗癌活​​性。在所有合成的化合物中，6A均显示出强大的拮抗剂活性（半数最大有效浓度（EC50）= 1.68±0.22 µM），对人癌细胞HepG2和A549细胞的强抗增殖活性（50％的细胞存活率（IC50）抑制） <10 µM），并且在正常细胞（如LO2和MRC-5细胞）中具有低细胞毒性（IC50值> 100 µM）。进一步的生物测定表明，6A以剂量依赖性方式抑制9-cis-RA诱导的活性，并以亚微摩尔亲和力（Kd = 1.20×10-7 M）选择性结合RXRα-=LΒD。6A诱导时间和剂量依赖性的多聚ADP-核糖聚合酶裂解，并

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