methotrexate disodium | 7413-34-5

• 物质功能分类: 生物化工 - 氨基酸及其衍生物 - 谷氨酸类衍生物
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: methotrexate disodium
• 英文别名: methotrexate；sodium;(2S)-2-[[4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioate
• CAS: 7413-34-5
• 化学式: C₂₀H₂₀N₈O₅*2Na
• 分子量: 498.409
• InChiKey: BKBBTCORRZMASO-ZOWNYOTGSA-L

物化性质

• 沸点：
  823℃
• 溶解度：
  DMSO（少许）、水（少许）
• 稳定性/保质期：
  如果遵照规格使用和储存，则不会分解。

计算性质

• 辛醇/水分配系数(LogP)：
  -5.4
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  216
• 氢给体数：
  3
• 氢受体数：
  12

安全信息

• 危险等级：
  6.1
• 海关编码：
  2933990090
• 包装等级：
  III
• 危险类别：
  6.1
• 危险性防范说明：
  P201,P202,P261,P264,P270,P271,P280,P301+P310,P302+P352,P304+P340,P305+P351+P338,P308+P313,P330,P332+P313,P362,P403+P233,P405,P501
• 危险品运输编号：
  2811
• 危险性描述：
  H301,H315,H319,H335,H340,H360
• 储存条件：
  密封于0-6°C阴凉干燥环境中。

制备方法与用途

毒理学数据

• 试验方法：腹腔摄入剂量为120毫克/千克，男性啮齿动物（鼠）在60天前交配测试。对象为啮齿动物—鼠。

  • 毒性类型：生殖毒性
  • 作用：
    • 影响父亲的睾丸、附睾和精子管的复制。
    • 影响男性生育力指数（如每只浸渍男性接触肥沃妊娠女性的数量）。

• 试验方法：腹腔摄入剂量为284毫克/千克，测试对象同样为啮齿动物—鼠。

  • 毒性类型：急性毒性
  • 作用：详细的毒副作用没有报告，但未给出其他致死剂量值。

物理性质

1. 性状：无可用
2. 密度（g/mL,25/4℃）：无可用
3. 相对蒸汽密度（g/mL,空气=1）：无可用
4. 熔点（ºC）：无可用
5. 沸点（ºC,常压）：无可用
6. 沸点（ºC,5.2kPa）：无可用
7. 折射率：无可用
8. 闪点（ºC）：无可用
9. 比旋光度（º）：无可用
10. 自燃点或引燃温度（ºC）：无可用
11. 蒸气压（kPa,25ºC）：无可用
12. 饱和蒸气压（kPa,60ºC）：无可用
13. 燃烧热（KJ/mol）：无可用
14. 临界温度（ºC）：无可用
15. 临界压力（KPa）：无可用
16. 油水（辛醇/水）分配系数的对数值：无可用
17. 爆炸上限（%,V/V）：无可用
18. 爆炸下限（%,V/V）：无可用
19. 溶解性：无可用

储存方法

密封保存于0-6ºC阴凉干燥环境。

生态学数据

该物质对环境可能有危害，特别是对水体应给予特别注意。

生物活性

甲氨蝶呤钠是四氢叶酸脱氢酶的抑制剂，是一种抗肿瘤抗代谢药物，并具有免疫抑制活性。

靶点

Target	Value
hDHFR (Activated peripheral T cells)	24 nM

反应信息

• 作为反应物：
  描述：

  溴己烷 、 methotrexate disodium 在 caesium carbonate 作用下， 以 二甲基亚砜 为溶剂， 生成 dihexyl (4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoyl)-L-glutamate
  参考文献：
  名称：

  服用中链酯前药可增强甲氨蝶呤的脑部递送：体内和体外研究

  摘要：

  在本研究中，以提高甲氨蝶呤（MTX）对大脑的通透性为目的，合成了含有酯官能团的亲脂MTX前药。通过FT-IR，NMR和质谱研究对合成前药的化学结构进行了表征和确认。根据体外细胞毒性研究的结果，所有合成的前药均导致U87癌细胞在72小时内IC50降低，与游离MTX相比，甲氨蝶呤二己基甲酸酯（MTX-DH）观察到了最佳结果。导致IC50降低多达6倍。另外，体内对卤虫（盐沼曲霉）的毒性表明，在相同浓度下，亲脂性MTX前药已能够部分掩盖游离MTX的毒性。这些发现也与溶血测定结果一致，该结果证实了缀合物没有使药物更具毒性。此外，体内在大鼠模型中进行了一项研究，确定了大脑和血浆中同时存在的药物浓度。根据获得的结果，MTX-DH和甲氨蝶呤二辛基酯（MTX-DO）组的脑血浆浓度比（Kp值）明显高于游离MTX。此外，脑实质吸收MTX的清除率显着增加（MTX-DH和MTX-DO前药分别增加3.85和9.08倍

  DOI：

  10.1016/j.ijpharm.2021.120479
• 作为产物：
  描述：

  N-[4-(methylamino)benzoyl]-L-glutamic acid disodium 在 水 、 sodium carbonate 、 potassium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.41h， 生成 methotrexate disodium
  参考文献：
  名称：

  [EN] A NEW METHOD FOR PRODUCING ANTIFOLATE AGENTS HAVING GLUTAMIC ACID PART IN THEIR STRUCTURE
  [FR] NOUVEAU PROCÉDÉ DE FABRICATION D'AGENTS ANTIFOLIQUES AYANT UNE PARTIE ACIDE GLUTAMIQUE DANS LEUR STRUCTURE

  摘要：

  一种新的制备具有谷氨酸部分结构的抗叶酸剂的方法被开发出来，通过保护谷氨酸或其N-取代衍生物的羧基为氰甲酯，得到式（II）的化合物，这些化合物在非常温和的条件下水解，以高产率和高分析和光学纯度得到抗叶酸剂。

  公开号：

  WO2012074496A1

文献信息

• Anticancer drug encapsulated in inorganic lattice can overcome drug resistance
  作者：Soo-Jin Choi、Go Eun Choi、Jae-Min Oh、Yeon-Ji Oh、Myung-Chul Park、Jin-Ho Choy

  DOI：10.1039/b925831k

  日期：——

  A methotrexate (MTX)-layered double hydroxide (LDH) hybrid have been developed as a drug delivery system, in which an anticancer drug, MTX, was intercalated into a 2-dimensional LDH nanovehicle to form a nanohybrid. According to the comparative cell viability studies between MTX only and its LDH nanohybrid on MTX sensitive and resistant cell culture lines, it was found that the MTX-LDH nanohybrid could bypass the MTX resistance and eventually inhibit cancer cell proliferation very effectively compared to free MTX, due to an enhanced permeability and retention effect of MTX-LDH nanoparticles even in dihydrofolate reductase-overexpressing MTX-resistant cells. This is definitely associated with the uptake mechanism via a clathrin-mediated endocytic pathway for the MTX-LDH nanohybrid particles, the same as for the LDH nanocarrier only, which is completely different from the cellular uptake mechanism for MTX only, the reduced folate carrier (RFC) and/or the folate receptor entries.

  甲氨蝶呤（MTX）层状双氢氧化物（LDH）杂化物已被开发为药物递送系统，其中抗癌药物MTX被插入二维LDH纳米载体中形成纳米杂化物。根据仅MTX与其LDH纳米杂化物在MTX敏感和耐药细胞培养系上的比较细胞活力研究，发现与游离MTX相比，MTX-LDH纳米杂化物可以绕过MTX耐药性并最终非常有效地抑制癌细胞增殖。这是因为即使在二氢叶酸还原酶过表达的 MTX 抗性细胞中，MTX-LDH 纳米颗粒也具有增强的渗透性和保留作用。这肯定与 MTX-LDH 纳米杂化颗粒通过网格蛋白介导的内吞途径的摄取机制有关，与仅 LDH 纳米载体相同，这与仅 MTX（还原叶酸载体）的细胞摄取机制完全不同。 RFC）和/或叶酸受体条目。
• Ionic liquids with methotrexate moieties as a potential anticancer prodrug: Synthesis, characterization and solubility evaluation
  作者：Rahman Md. Moshikur、Md. Raihan Chowdhury、Rie Wakabayashi、Yoshiro Tahara、Muhammad Moniruzzaman、Masahiro Goto

  DOI：10.1016/j.molliq.2019.01.063

  日期：2019.3

  solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility

  活性药物成分（API）转化为离子液体（ILs）后，其技术实用性得到了极大的提高。与固态盐或结晶药物相比，API-IL具有更好的水溶性和热稳定性。但是，许多此类API-IL都不具有生物相容性或生物可降解性。在当前的研究中，我们使用甲氨蝶呤（MTX）（一种潜在的抗癌前药）和生物相容性形成IL的阳离子（胆碱和氨基酸酯）合成了一系列IL-API。通过1表征了MTX-IL部分1 H NMR，FTIR，p-XRD，DSC和热重分析。在模拟体液（磷酸盐缓冲液，模拟胃液和模拟肠液）中评估了MTX-IL的溶解度。评估哺乳动物细胞系（HeLa细胞）中MTX-IL的体外抗肿瘤活性，以评估其细胞毒性。在水和模拟体液中，MTX-ILs的水溶性至少比游离MTX高5000倍，比MTX钠盐高两个数量级。重要的是，脯氨酸乙酯MTX前药显示出与MTX钠盐相似的溶解度，但提供了改进的体外抗肿瘤活性。这些结果清楚地表明，新合成的
• 一种甲氨蝶呤中间体的精制方法
  申请人：南京海润医药有限公司

  公开号：CN117800971A

  公开（公告）日：2024-04-02

  本发明属于医药技术领域，具体涉及一种甲氨蝶呤中间体(即甲氨蝶呤二钠盐)的精制方法。甲氨蝶呤成品中存在顽固杂质C(欧洲药典EP9.0中杂质C限度为≤0.5％)，普通精制方法难以去除。发明人在研究过程中惊喜的发现，通过在甲氨蝶呤二钠盐的反应液中加入氯化钠析晶，可以大幅降低顽固杂质C前体的含量，同时降低杂质峰的个数与含量、脱去甲氨蝶呤中间体中的色素，进而降低甲氨蝶呤原料药中顽固杂质C的含量，使其纯度符合欧洲药典的要求。
• Methotrexate analogs. 19. Enhancement of the antitumor effect of methotrexate and 3',5'-dichloromethotrexate by the use of lipid-soluble diesters
  作者：A. Rosowsky、C. S. Yu

  DOI：10.1021/jm00364a017

  日期：1983.10

  Lipophilic methotrexate (MTX) and 3',5'-dichloromethotrexate (DCM) diesters were prepared by HCl-catalyzed esterification or by neutral esterification using cesium carbonate and an alkyl or aralkyl halide in Me2SO. The products were tested for in vivo antitumor activity against L1210 leukemia in mice to test whether all MTX and DCM diesters are therapeutically equivalent in this species. Contrary to what has been found with simple primary dialkyl esters, ortho-substituted dibenzyl esters of MTX produce longer survival on a q3dX3 schedule than does MTX itself and show a dose-sparing effect comparable to that of MTX at shorter treatment intervals. Thus, MTX bis(6-chloropiperonyl) ester at an MTX-equivalent dose of 5.5 mg/kg gave a +88% increase in median life span (ILS), whereas for MTX a +88% ILS required 30 mg/kg. When the MTX-equivalent dose of MTX bis(6-chloropiperonyl) ester was increased to 40 mg/kg, a +167% ILS was observed, as compared with a +100% ILS with 60 mg/kg of the parent drug. High activity (greater than 100% ILS) was likewise shown by the bis(2,5-dimethylbenzyl), bis(2,6-dichlorobenzyl), and di-3-picolyl esters of MTX and by the bis(1-methylbutyl) ester of DCM. The results of this study indicate that MTX and DCM esters are not therapeutically equivalent in mice, despite the high serum esterase activity in this species, and that an up to 10-fold reduction in total administered dose on the q3dX3 schedule is feasible by this approach.
• Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats
  作者：Raul Maranhao、Maria Carolina Guido、Aline Derisio de Lima、Elaine Rufo Tavares、Alyne Franca Marques、Marcelo Dantas Tavares de Melo、Jose Carlos Nicolau、Vera Salemi、Roberto Kalil-Filho

  DOI：10.2147/ijn.s129324

  日期：——

  Purpose: Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment.Materials and methods: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy.Results: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity.Conclusion: The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials.