羟基美法仑 | 61733-01-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 羟基美法仑
• 中文别名: 美法仑杂质
• 英文名称: monohydroxymelphalan
• 英文别名: (S)-2-amino-3-(4-((2-chloroethyl)(2-hydroxyethyl)amino)phenyl)propanoic acid；mono-melphalan；(2S)-2-amino-3-[4-[2-chloroethyl(2-hydroxyethyl)amino]phenyl]propanoic acid
• CAS: 61733-01-5
• 化学式: C₁₃H₁₉ClN₂O₃
• 分子量: 286.758
• InChiKey: CPWJECQKVRUIOI-LBPRGKRZSA-N

物化性质

• 沸点：
  495.0±45.0 °C(Predicted)
• 密度：
  1.319±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.8
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  86.8
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  美法仑 在 盐酸 作用下， 以 水 、 二甲基亚砜 为溶剂， 以45 %的产率得到羟基美法仑
  参考文献：
  名称：

  A clickable melphalan for monitoring DNA interstrand crosslink accumulation and detecting ICL repair defects in Fanconi anemia patient cells

  摘要：

  摘要 范可尼贫血症（FA）是一种遗传性疾病，与发育缺陷、骨髓衰竭和癌症有关。FA途径对于DNA链间交联（ICL）的修复至关重要。在这项研究中，我们开发并鉴定了一种研究 ICL 修复的新工具：一种可点击的交联剂美法仑，我们将其命名为点击美法仑。我们的研究结果表明，click-melphalan 在生成 ICL 及相关毒性方面与未修饰的同类药物一样有效。咔嗒美法仑诱导的病变可通过荧光报告物进行标记后检测，并使用流式细胞仪进行量化。由于单击美兰同时诱导 ICL 和单加合物，为了区分这两种类型的 DNA 修复，我们生成了只诱导单加合物的单击美兰。通过使用这两种分子，我们发现敲除 FANCD2 的细胞在清除咔嗒美法仑诱导的病变方面存在缺陷。我们还发现，这些细胞在修复咔嚓-单-美兰诱导的单加合物时表现出延迟。我们的数据进一步显示，未修复的 ICL 的存在抑制了单核细胞的修复。最后，我们的研究表明，这些可点击分子可以区分原发性 FA 患者细胞和原发性色素变性患者细胞的内在 DNA 修复缺陷。因此，这些分子可能具有开发诊断测试的潜力。

  DOI：

  10.1093/nar/gkad559

文献信息

• Analysis of novel melphalan hydrolysis products formed under isolated lung perfusion conditions using liquid chromatography/tandem mass spectrometry
  作者：Jasper Boschmans、Ernst de Bruijn、Paul Van Schil、Filip Lemière

  DOI：10.1002/rcm.6515

  日期：2013.4.15

  ultra-performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS). Aqueous melphalan solutions were incubated at elevated temperatures and analyzed by UPLC/MS/MS. Two previously described hydrolysis products, mono- and dihydroxymelphalan (MOH and DOH), were formed in vitro and could be characterized during MS/MS and high-resolution experiments. RESULTS Novel compounds with m/z values >500 Da

  RATIONALE Melphalan是在癌症治疗中被广泛使用的细胞毒剂。该苯丙氨酸类似物已被证明可有效治疗乳腺癌，多发性骨髓瘤和四肢黑色素瘤。对药物降解和代谢的充分了解对于了解其在癌症治疗过程中的活性至关重要。方法使用超高效液相色谱（UPLC）串联质谱（MS / MS）研究美法仑水解产物的形成。在高温下孵育美法仑水溶液，并通过UPLC / MS / MS进行分析。在体外形成了两种先前描述的水解产物，单和二羟基马法兰（MOH和DOH），可以在MS / MS和高分辨率实验中进行表征。结果发现了m / z值> 500 Da的新型化合物。这些新分子与MOH和DOH的断裂模式的比较显示出很大的相似性。较高的质量可以通过存在两个或多个马法兰单元来解释。总共发现了15种以上的新水解产物。建立实验来研究这些分子的形成和化学结构。结论在II期临床试验（隔离肺灌注，ILuP）的范围内研究了美法仑的水解。筛选
• INJECTABLE PHARMACEUTICAL FORMULATION OF MELPHALAN
  申请人：Eriochem, S.A.

  公开号：EP2599484A1

  公开（公告）日：2013-06-05

  An injectable pharmaceutical formulation of Melphalan comprising a solid composition of melphalan hydrochloride lyophilized with a content of impurities up to 1.3 % (p/p)and a pH buffer solution; a process to prepare said solid composition. Also a reconstituted solution of melphalan comprising a solid composition of melphalan lyophilized reconstituted wherein said solution is aqueous, a perfusion free of organic solvent and a kit.

  一种美法仑注射药物制剂，包括盐酸美法仑冻干固体组合物，杂质含量不超过1.3%（p/p）和pH缓冲溶液；制备所述固体组合物的工艺。还有一种美法仑的重组溶液，包括美法仑冻干重组的固体组合物，其中所述溶液为水溶液，一种不含有机溶剂的灌流液和一种试剂盒。
• STABLE MELPHALAN LIQUID INJECTABLE FORMULATIONS
  申请人：Shilpa Medicare Limited

  公开号：EP3747428A1

  公开（公告）日：2020-12-09

  The present invention relates to a stable, non-aqueous liquid, formulation consisting essentially of melphalan, or a pharmaceutical acceptable salt thereof; and one or more solvents selected from group consisting of dimethyl acetamide, polyethylene glycol, ethanol, propylene glycol, dimethyl sulfoxide, N-methylpyrrolidone and glycerol; wherein said formulation is free of antioxidants, organic acid and added chloride ions; and the process for preparation thereof.

  本发明涉及一种稳定的非水性液体制剂，主要由美法仑或其药物可接受盐；以及一种或多种溶剂组成，这些溶剂选自二甲基乙酰胺、聚乙二醇、乙醇、丙二醇、二甲亚砜、N-甲基吡咯烷酮和甘油；其中所述制剂不含抗氧化剂、有机酸和添加的氯离子；及其制备工艺。
• Stable melphalan liquid injectable formulations
  申请人：Pradeep Shivakumar

  公开号：US10682326B1

  公开（公告）日：2020-06-16

  The present invention relates to a stable, non-aqueous liquid, formulation consisting essentially of melphalan, or a pharmaceutical acceptable salt thereof; and one or more solvents selected from group consisting of dimethyl acetamide, polyethylene glycol, ethanol, propylene glycol, dimethyl sulfoxide, N-methylpyrrolidone and glycerol; wherein said formulation is free of antioxidants, organic acid and added chloride ions; and the process for preparation thereof.

  本发明涉及一种稳定的非水性液体制剂，主要由美法仑或其药物可接受盐；以及一种或多种溶剂组成，这些溶剂选自二甲基乙酰胺、聚乙二醇、乙醇、丙二醇、二甲亚砜、N-甲基吡咯烷酮和甘油；其中所述制剂不含抗氧化剂、有机酸和添加的氯离子；及其制备工艺。
• Optimization of the N-Lost Drugs Melphalan and Bendamustine: Synthesis and Cytotoxicity of a New Set of Dendrimer−Drug Conjugates as Tumor Therapeutic Agents
  作者：Ana Maria Scutaru、Maxi Wenzel、Heike Scheffler、Gerhard Wolber、Ronald Gust

  DOI：10.1021/bc900453f

  日期：2010.10.20

  Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3-aminopropyl)-N-(3-3,5-bis[3-3,5-bis(3-aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB-231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2-hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro.