六甲蜜胺 | 645-05-6

• 物质功能分类: 原料药 - 抗肿瘤药 - 烷化剂类抗肿瘤药
• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 六甲蜜胺
• 中文别名: 六甲三聚氰胺；六甲聚腈胺；2,4,6-三(二甲氨基)均三嗪；六甲嘧胺
• 英文名称: Altretamine
• 英文别名: 2,4,6-tris-1,3,5-triazine；2-N,2-N,4-N,4-N,6-N,6-N-hexamethyl-1,3,5-triazine-2,4,6-triamine
• CAS: 645-05-6
• 化学式: C₉H₁₈N₆
• mdl: MFCD00549245
• 分子量: 210.282
• InChiKey: UUVWYPNAQBNQJQ-UHFFFAOYSA-N

物化性质

• 熔点：
  171-175 °C (lit.)
• 沸点：
  339.81°C (rough estimate)
• 密度：
  1.0441 (rough estimate)
• 溶解度：
  可溶于氯仿（少量）、甲醇（轻微加热）
• 物理描述：
  Hexamethylmelamine is a colorless crystalline solid. Insoluble in water. (NTP, 1992)
• 颜色/状态：
  Needles from absolute ethanol
• 蒸汽压力：
  2.95X10-4 mm Hg at 25 °C (est)
• 稳定性/保质期：
  白色针状结晶，熔点为170-173℃。它易溶于氯仿，微溶于甲醇和乙醇，并且极微溶于水。该物质对酸碱稳定且具有升华性。
• 解离常数：
  pKa1 = 4.88 (imine) (est)
• 碰撞截面：
  145.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.666
• 拓扑面积：
  48.4
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

生物转化/是/肝脏的。活性需要代谢。阿特雷坦经历快速和广泛的脱甲基作用，由细胞色素P450酶催化。

Biotransformation /is/ Hepatic. Metabolism is required for activity. Altretamine undergoes rapid and extensive demethylation, catalyzed by cytochrome P450 enzymes.

来源:Hazardous Substances Data Bank (HSDB)

代谢

研究了六甲撑蜜胺（HMM）及其代谢物在单次腹腔注射2,4,6-14C-六甲撑蜜胺（50 mg/kg）到携带20天大的M5076/73A卵巢癌的C57Bl/6J雌性小鼠后，在肝脏、肿瘤、血液、肾脏、脾脏、肺、大脑、心脏和小肠中的共价结合情况。... 还研究了HMM的代谢。在考虑的三个时间点，确定了五甲撑蜜胺（PMM）、2,2,4,6-四甲撑蜜胺（TMM）和2,4,6-三甲撑蜜胺（TriMM）的组织分布。在2小时时，药物已经广泛代谢，TriMM是确定的代谢物中的主要代谢物。

The covalent binding of hexamethylmelamine (HMM) and its metabolites was studied in liver, tumor, blood, kidney, spleen, lung, brain, heart, and small intestine after a single ip injection of 2,4,6-14C-hexamethylmelamine (50 mg/kg) to C57Bl/6J female mice bearing 20-day-old M5076/73A ovarian cancer. ... HMM metabolism was also studied. Tissue distribution of pentamethylmelamine (PMM), 2,2,4,6-tetramethylmelamine (TMM), and 2,4,6-trimethylmelamine (TriMM) was determined at the three times considered. At 2 hr the drug was already extensively metabolized, TriMM being the major metabolite among those determined.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在所有动物物种中，包括人类，亚硝脲经氧化N-脱甲基作用形成羟甲基衍生物作为中间体。羟甲基melamines被认为是药物细胞毒性和抗肿瘤活性的原因。

... In all animal species, including humans, altretamine undergoes oxidative N-demethylation with the formation of hydroxymethyl derivatives as intermediates. Hydroxymethylmelamines are believed to be responsible for the cytotoxic and antitumour activity of the drug. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

在大鼠中，给予25 mg/kg剂量的六甲基三聚氰胺或五甲基三聚氰胺后，有40%的剂量以代谢物的形式通过尿液排出，其中超过95%是N2N4-二甲基三聚氰胺和一甲基三聚氰胺。六甲基三聚氰胺或五甲基三聚氰胺及其N-去甲基化代谢物的胆汁排泄量不到给药剂量的2%。仅有3%随粪便排出，这表明有一部分进入胆汁的甲基三聚氰胺在肠道中被重吸收。在大鼠的尿液或胆汁中，只发现了极少量的甲基三聚氰胺与葡萄糖醛酸或硫酸的共轭物。然而，五甲基三聚氰胺的一种至今性质未知的共轭产物是五甲基三聚氰胺处理后的一种主要代谢物。

In the rat 40% of a dose of 25 mg/kg of hexamethylmelamine or pentamethylmelamine was excreted in the urine as metabolites, more than 95% of which were N2N4-dimethylmelamine and monomethylmelamine. Biliary excretion of hexamethylmelamine or pentamethylmelamine and their N-demethylated metabolites accounted for less than 2% of the administered dose. Only 3% was excreted with the feces, suggesting that there is intestinal reabsorption of a portion of the methylmelamines passing into the bile. Conjugates of methylmelamines with glucuronic acid or sulphate were found only in minute quantities in the urine or bile of rats treated with hexamethylmelamine or pentamethylmelamine. However a conjugation product of pentamethylmelamine, of as yet unknown nature, is a major metabolite after pentamethylmelamine treatment.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

Altretamine疗法与血清酶升高的低发生率有关，但这些通常都是轻微的和自限性的，不需要调整剂量。已经报道了罕见的情况下，归因于Altretamine的临床明显的急性肝损伤，但其临床特征尚未被描述。Altretamine并没有特别与门脉高压症相联系，但它很少在高剂量下用于恶性肿瘤疾病或在骨髓移植的调理方案中使用，这些情况下，烷化剂通常与这种并发症有关。

Altretamine therapy is associated with a low rate of serum enzyme elevations, but these are generally mild and self limited, not requiring dose adjustment. Rare instances of clinically apparent acute liver injury attributed to altretamine have been reported, but the clinical features have not been characterized. Altretamine has not been linked specifically to sinusoidal obstruction syndrome, but it is rarely used in high doses in neoplastic disease or in conditioning regimens for bone marrow transplantation, situations in which alkylating agents are commonly associated with this complication.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：白消安

Compound:altretamine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：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：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

人类尿液中代谢物为阿特雷米松的去甲基同系物，24小时内有不到1%的未代谢阿特雷米松被排出。

Human urinary metabolites were Ndemethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.

来源:DrugBank

吸收、分配和排泄

口服给药后快速且良好吸收；然而，由于肝脏快速代谢，血浆峰浓度不稳定。

Rapidly and well-absorbed following oral administration; however, because of rapid hepatic metabolism, peak plasma concentrations are variable.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服给药后，亚他米林的生物利用度的手间和患者内变异性是这种药物有效临床使用的重大缺点。这种变异性似乎主要与首次通过效应有关，因此可以通过静脉给药来克服。过去尝试静脉给药并未成功...

... The inter-hand intrapatient variability of the bioavailability of altretamine after oral administration represents an important drawback for effective clinical use of this drug. The variability appears to be mostly related to the first-pass effect and therefore may be overcome by intravenous administration of the drug. Attempts to administer the drug intravenously have not been successful in the past...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

因为阿特雷米因高度脂溶性，它会被分布到含有高比例脂质的组织中（例如，网膜和皮下组织）。

Because it is highly lipid-soluble, altretamine is distributed to tissues with a high lipid component (e.g., omentum and subcutaneous tissues).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

蛋白质结合：游离分数：亚硝基脲：6%；五甲基脲：25%；四甲基脲：50%。

Protein binding: Free fractions: Altretamine: 6%; Pentamethylmelamine: 25%; Tetramethylmelamine: 50%.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S26,S36
• 危险类别码：
  R22,R36/37/38
• WGK Germany：
  3
• 海关编码：
  2933699090
• RTECS号：
  OS1050000
• 危险标志：
  GHS07
• 危险性描述：
  H302,H315,H319,H335
• 危险性防范说明：
  P261,P305 + P351 + P338
• 储存条件：
  常温保存，或在2-8℃下冷藏，避免光照，存放在通风干燥的地方。

制备方法与用途

药物相关作用

1. 与单胺氧化酶抑制剂、抗抑郁药合用可导致严重的直立性低血压，应慎用。
2. 与甲氧氯普胺合用可能引起肌张力障碍。
3. 与维生素B6同时使用，可能减轻周围神经毒性。

生物活性

Altretamine（又称为Hexamethylmelamine、NSC13875或ENT50852）是一种抗肿瘤剂。

体外研究

Altretamine 是一种抗肿瘤剂。

体内研究

Altretamine (100, 133 mg/kg, ip.) 在与Irofulven联合使用时，能增强对携带MV522细胞的小鼠的抗肿瘤效果。

化学性质

Altretamine 是白色针状结晶，熔点为170-173℃。它易溶于氯仿，微溶于甲醇和乙醇，并极微溶于水。该物质对酸碱稳定且具有升华性。

用途

抗肿瘤药物。

生产方法

Altretamine 可由三氯三聚氰与二甲胺缩合制得。

反应信息

• 作为反应物：
  描述：

  六甲蜜胺 在 sodium acetate 、 sodium nitrite 作用下， 以 溶剂黄146 为溶剂， 反应 2.0h， 以0.05 g的产率得到N-nitrosopentamethylmelamine
  参考文献：
  名称：

  Simmonds, Richard J.; Stevens, Malcolm F. G., Journal of the Chemical Society. Perkin transactions I, 1982, # 8, p. 1821 - 1826

  摘要：

  DOI：
• 作为产物：
  描述：

  二甲基氢胺 在 2,9-二甲基-4,7二苯基-1,10-菲啰啉 、 2-Methyl-1-Propenylmagnesium Bromide 、 C₂₆H₂₀Cl₂FeN₂ 作用下， 以 四氢呋喃 、 2-甲基四氢呋喃 为溶剂， 以98 %的产率得到六甲蜜胺
  参考文献：
  名称：

  一种多功能、具有官能团耐受性且稳定的铁预催化剂，用于通过 [2+2+2] 环加成构建芳烃和三嗪环

  摘要：

  描述了一种依赖于使用空气稳定的铁预催化剂的新的[2+2+2]环加成过程，该过程允许在绿色溶剂和温和条件下构建芳香环和含氮杂芳环。据报道，1,6-或1,7-二炔与炔之间的环加成和交叉环加成具有广泛的功能耐受性，从而产生各种可功能化的支架。

  DOI：

  10.1002/chem.202400096
• 作为试剂：
  描述：

  溴乙酰氯 、 L-Cystine-N,N-di(2-chloroethyl)dihydrazide 在 六甲蜜胺 作用下， 以 乙酸乙酯 为溶剂， 以58%的产率得到N-{(R)-1-[N',N'-Bis-(2-chloro-ethyl)-hydrazinocarbonyl]-2-[(R)-2-[N',N'-bis-(2-chloro-ethyl)-hydrazinocarbonyl]-2-(2-bromo-acetylamino)-ethyldisulfanyl]-ethyl}-2-bromo-acetamide
  参考文献：
  名称：

  Zakhariev; Stoev; Maneva, Pharmazie, 1989, vol. 44, # 11, p. 763 - 765

  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] 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。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。

表征谱图