氮芥 | 51-75-2

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 氮芥
• 中文别名: N,N-二(2-氯乙基)甲胺；双(2-氯乙基)甲胺
• 英文名称: Chlormethine
• 英文别名: nitrogen mustard；mechlorethamine；2-chloro-N-(2-chloroethyl)-N-methylethan-1-amine；bis(2-chloroethyl)methylamine；2-chloro-N-(2-chloroethyl)-N-methylethanamine
• CAS: 51-75-2
• 化学式: C₅H₁₁Cl₂N
• 分子量: 156.055
• InChiKey: HAWPXGHAZFHHAD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  8
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

ADMET

代谢

经历快速的化学变化并与水或细胞的活性化合物结合，使得药物在给药后几分钟内不再以活性形式存在。

Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration.

来源:DrugBank

代谢

在其体内给药后，美克洛噻胺或其盐酸可能转化为乙烯脒离子，该离子与DNA的同一股或相邻股上的鸟嘌呤残基以及与SH基团发生反应。

Following its in vivo admin, mechlorethamine or its hydrochloride is probably converted into ethyleneimmonium ion which reacts with guanine residues in /either the same or/ adjacent strands of DNA as well as with SH groups.

来源:Hazardous Substances Data Bank (HSDB)

代谢

活体内氮芥化合物的水解裂解产生了N-甲基芥子气，这是一种在蚕豆根尖分生组织和小鼠腹水瘤中诱导染色单体畸变的强效诱导剂。在蚕豆中，硝基胍作为诱导剂的效果远低于氮芥。

In vivo hydrolytic splitting of quaternary nitrogen mustard compound gives rise to n-methyl mustard a potent inducer of chromatid aberrations in Vicia faba root meristems and ascites tumors of mouse. In Vicia faba, nitromin was much less effective inducer than nitrogen mustard.

来源:Hazardous Substances Data Bank (HSDB)

代谢

经历快速的化学转化并与水或细胞的活性化合物结合，使得药物在给药后几分钟内不再以活性形式存在。 半衰期：15分钟

Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration. Half Life: 15 minutes

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

烷基化剂通过三种不同的机制发挥作用：1）将烷基团附着到DNA碱基上，导致DNA在修复酶试图替换烷基化碱基的过程中被切碎，从而阻止受影响的DNA的合成和RNA转录；2）通过形成交联（DNA中原子之间的键）对DNA造成损伤，防止DNA分离以进行合成或转录；3）诱导核苷酸的错配，导致突变。美法仑对细胞周期阶段无特异性。

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-nonspecific.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

温和且短暂的血清转氨酶水平升高在包括甲氧基乙氧基甲烷的癌症化疗周期中并不少见，但其导致这些异常的确切作用从未完全清楚。酶水平升高通常是轻微的、短暂的，并且没有症状，因此很少需要调整甲氧基乙氧基甲烷的剂量。甲氧基乙氧基甲烷并未特别与临床上明显的肝脏损伤相关。在MOPP疗法（一种化疗方案）后报告了门脉阻塞性综合征，但这主要发生在有其他并发症风险因素的患者中，例如全身照射或之前的抗肿瘤治疗疗程。局部应用的甲氧基乙氧基甲烷并未与肝脏损伤相关，尽管系统吸收的可能性继续使肝脏不良事件被提及作为一种担忧。然而，对骨髓毒性和药物在血浆中浓度的仔细分析并未证明在使用皮肤凝胶的适当情况下有任何显著吸收的证据。

Mild and transient elevations in serum aminotransferase levels were not uncommon during cycles of cancer chemotherapy regimens that included mechlorethamine, but its role in causing these abnormalities was never entirely clear. The enzyme elevations were usually mild, transient and without symptoms, so that dose modifications of mechlorethamine were rarely needed. Mechlorethamine has not been associated specifically with clinically apparent liver injury. Sinusoidal obstruction syndrome has been reported after MOPP therapy, but largely in patients with other risk factors for this complication, such as total body irradiation or previous courses of antineoplastic therapy. Topical mechlorethamine has not been associated with liver injury, although the possibility of systemic absorption continues to make hepatic adverse events mentioned as a concern. Careful analysis for bone marrow toxicity and plasma concentrations of the drug, however, have failed to demonstrate any evidence for significant absorption with proper use of the cutaneous gel.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：氮芥

Compound:mechlorethamine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

经腔内给药部分吸收，很可能是由于体液迅速失活。当局部给药时，系统暴露无法检测到。

Partially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable.

来源:DrugBank

吸收、分配和排泄

3毫克/千克体重的氮芥剂量给狗注射后，迅速从血液中消失：在尿液中发现了0.01%，在组织中发现了低水平，骨髓中浓度最高。与全血孵化4分钟内发生了90%的分解。

Iv dose of 3 mg/kg body wt /mechlorethamine/ administered to dogs rapidly disappeared from blood: 0.01% was found in urine, and low levels were found in tissues, highest concentration being in bone marrow. 90% breakdown ... Occurred within 4 min of incubation with whole blood.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

... 给予狗0.5毫克/千克静脉注射（14）CH3-标记的盐酸氮芥，5秒或60分钟后血液中迅速消失，HN2的尿液排泄量低。在大鼠中，注射剂量的盐酸氮芥的16%存在于脾脏、肺、肾脏、肝脏和血液中，17%通过尿液排出。 ...

... Immediate disappearance of (14)CH3-labeled mechlorethamine from blood of dogs given 0.5 mg/kg iv over 5 sec or 60 min, and low urinary excretion of HN2. ... In rats, 16% of injected dose of mechlorethamine was found present in spleen, lung, kidneys, liver and blood, and 17% was excreted in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

液态或气态氮芥暴露于皮肤或眼睛后可能会被吸收，并可能导致全身毒性。氮芥类物质高度反应性，会迅速与蛋白质、DNA或其他分子结合。因此，在暴露后的几分钟内，完整的氮芥或其活性代谢物在组织或生物流体中不会再被发现。

Absorption may occur after skin or eye exposure to liquid or vapor nitrogen mustard and may cause systemic toxicity. .../Nitrogen mustards/ ...are highly reactive and combine rapidly with proteins, DNA, or other molecules. Therefore, within minutes following exposure intact mustard or its reactive metabolites are not found in tissue or biological fluids. /Nitrogen mustards/

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

制备方法：由二乙醇胺经过甲酸、甲醛甲基化及氯化亚砜氯化得到。

合成制备方法：同样地，也是通过将二乙醇胺与甲酸反应，再进行甲醛甲基化和氯化亚砜氯化获得。

反应信息

• 作为反应物：
  描述：

  氮芥 在 bis-triphenylphosphine-palladium(II) chloride 、 四(三苯基膦)钯 N-甲基吗啉 、 盐酸 、 lithium hydroxide monohydrate 、 水 、 氯甲酸乙酯 、 sodium carbonate 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 89.0h， 生成 tert-butyl (S)-1-((1R,2R)-1-carbamoyl-2-(4'(4-methylpiperazine-1-yl)biphenyl-4-yl)cyclopropylamino)-1-oxobutan-2-ylcarbamate
  参考文献：
  名称：

  [EN] PEPTIDASE INHIBITORS
  [FR] INHIBITEURS DE PEPTIDASE

  摘要：

  公式(I)中的新化合物，其中R1、R2、D、A、B和X具有本文件中定义的含义，包含它们作为有效成分的药物组合物，以及它们在医学中的应用，特别是作为肽酶抑制剂，更具体地是用于治疗/预防炎症疾病的半胱氨酸和/或丝氨酸肽酶的抑制剂。

  公开号：

  WO2012130299A1
• 作为产物：
  描述：

  N, N-bis(2-chloroethyl)-N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] methanaminium bromide 在 双氧水 作用下， 以 重水 、 二甲基亚砜 为溶剂， 反应 96.0h， 以95%的产率得到氮芥
  参考文献：
  名称：

  过氧化氢诱导型 DNA 交联剂：靶向抗癌前药

  摘要：

  抗癌化学治疗剂的主要问题是宿主毒性。开发针对癌细胞中独特生化变化的抗癌前药是实现治疗活性和选择性的有吸引力的方法。我们设计并合成了一种新型氮芥前药，可以被癌细胞中发现的高水平活性氧 (ROS) 激活以释放活性化疗药物。通过NMR分析确定活化机制。这些前药对 ROS 的活性和选择性是通过测量 DNA 链间交联和/或 DNA 烷基化来确定的。这些化合物对各种癌细胞显示出 60-90% 的抑制作用，而正常淋巴细胞不受影响。据我们所知，

  DOI：

  10.1021/ja2073824
• 作为试剂：
  描述：

  4-硝基间甲苯酚 在 镍 氢气 、 氮芥 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 79.5h， 生成 3-methyl-2,6-bis(pyrrolidin-1'-ylmethyl)-4-(7''-trifluoromethylquinolin-4''-ylamino)phenol
  参考文献：
  名称：

  Barlin, Gordon B.; Jiravinyu, Chuenjit, Australian Journal of Chemistry, 1991, vol. 44, p. 151 - 156

  摘要：

  DOI：

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• Cobalamin conjugates for anti-tumor therapy
  申请人：Weinshenker M. Ned

  公开号：US20050054607A1

  公开（公告）日：2005-03-10

  The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.

  本发明提供了一种适用于治疗肿瘤相关疾病的钴胺素-药物结合物。钴胺素通过可切割的连接剂间接共价结合到抗肿瘤药物上，还可以通过一个或多个可选的间隔物。钴胺素通过其核糖环的5'-OH与第一间隔物或可切割连接剂共价结合。药物通过其现有或添加的功能基团与可切割连接剂的第二间隔物结合。在给药后，结合物与转钴胺素（其任何同工异构体）形成复合物。然后，该复合物结合到细胞膜上的受体并被细胞摄取。一旦进入细胞，细胞内酶将切割结合物，从而释放药物。根据结合物的结构，特定类别或类型的细胞内酶影响切割。由于生长细胞对钴胺素的需求量较高，肿瘤细胞通常摄取结合物的比例高于正常非生长细胞。本发明的结合物与相应的游离药物相比，具有较低的全身毒性和增强的疗效。
• [EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
  申请人：CANCER RESEARCH TECH LTD

  公开号：WO2018215798A1

  公开（公告）日：2018-11-29

  The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.

  本发明涉及作为BCL6（B细胞淋巴瘤6）活性抑制剂的I式化合物：式中X1、X2、X3、R1、R2、R3、R4和R5分别如本文所定义。本发明还涉及制备这些化合物的方法，包括含有它们的药物组合物，以及它们在治疗增生性疾病（如癌症）以及其他BCL6活性所涉及的疾病或病况中的用途。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。

表征谱图