阿哌沙班杂质187 | 62522-25-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 阿哌沙班杂质187
• 英文名称: ethyl 4-morpholinobutanocarboxylate
• 英文别名: ethyl 5-morpholinovalerate；4-morpholin-4-ylbutyric acid ethyl ester；ethyl 5-morpholinepentanoate；5-morpholin-4-yl-pentanoic acid ethyl ester；Ethyl 5-morpholin-4-ylpentanoate
• CAS: 62522-25-2
• 化学式: C₁₁H₂₁NO₃
• 分子量: 215.293
• InChiKey: SPKVTBWODJYPRH-UHFFFAOYSA-N

物化性质

• 沸点：
  130-132 °C
• 密度：
  1.014±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  15
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  阿哌沙班杂质187 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 以63%的产率得到5-Morpholino-pentanol-(1)
  参考文献：
  名称：

  Talath, Sirajunisa; Gadad, Andanappa K., Arzneimittel-Forschung/Drug Research, 2006, vol. 56, # 11, p. 744 - 752

  摘要：

  DOI：
• 作为产物：
  描述：

  吗啉 、 乙基5-碘戊酸酯 在 potassium carbonate 作用下， 以 甲苯 为溶剂， 反应 7.0h， 生成 阿哌沙班杂质187
  参考文献：
  名称：

  Synthesis and pharmacological study of N-heterocyclic prostaglandin analogs

  摘要：

  DOI：

  10.1007/bf00760004

文献信息

• Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect
  作者：Jonathan P. May、Elijus Undzys、Aniruddha Roy、Shyh-Dar Li

  DOI：10.1021/acs.bioconjchem.5b00619

  日期：2016.1.20

  The chemotherapeutic gemcitabine was actively and stably loaded into lipid nanoparticles through the formation of a prodrug. Gemcitabine was chemically modified to increase the lipophilicity and introduce a weak base moiety for remote loading. Several derivatives were synthesized and screened for their potential to be good liposomal drug candidates for remote loading by studying their solubility, stability, cytotoxicity, and loading efficiency. Two morpholino derivatives of GEM (22 and 23) were chosen as the preferred prodrugs for this purpose as they possessed the best loading efficiencies (100% for drug-to-lipid ratio of 0.36 w/w). This is a considerable improvement over a passive loading strategy where typical loading efficiencies are on the order of ∼10–20% for a drug-to-lipid ratio of ∼0.01. Liposomes loaded with these two prodrugs were studied in an s.c. tumor model in vivo and showed improved therapeutic effect over free GEM (∼2-fold) and saline control (8- to 10-fold). This work demonstrates how chemical modification of a known hydrophilic drug can lead to improved loading, stability, and drug delivery in vivo.

  化疗药物吉西他滨能通过形成前药的方式，被主动且稳定地装载到脂质纳米粒中。吉西他滨经过化学修饰，增加了亲脂性并引入了一个弱碱基团以实现被动装载。合成并筛选了几种衍生物，通过研究其溶解性、稳定性、细胞毒性和装载效率，评估它们作为脂质体被动装载药物候选物的潜力。两种吗啉衍生物（22和23）被选为最优的前药，因为它们具有最高的装载效率（药物与脂质的比率为0.36 w/w时，装载效率为100%）。这相较于被动装载策略有显著提升，后者在药物与脂质比率为约0.01时，典型装载效率仅为10-20%左右。装载了这两种前药的脂质体在体内皮下肿瘤模型中进行了研究，与自由吉西他滨（约2倍）和生理盐水对照组（8至10倍）相比，显示出更强的治疗效果。这项工作展示了如何通过化学修饰已知的亲水性药物，来提高其在体内的装载效率、稳定性和药物传递效果。
• MODIFIED DRUGS FOR USE IN LIPOSOMAL NANOPARTICLES
  申请人：THE UNIVERSITY OF BRITISH COLUMBIA

  公开号：US20180221279A1

  公开（公告）日：2018-08-09

  Drag derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drag derivatized with a weak-base moiety that facilitates active loading of the drag through a LN transmembrane pH or ion gradient into the aqueous interior of the LN. The weak-base moiety can optionally comprise a lipophilic domain that facilitates active loading of the drag to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drag derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drags.

  本文提供了适用于装载到脂质体纳米粒载体中的药物衍生物。在一些首选方面，这些衍生物包括一种水溶性较差的药物衍生物，其与一种弱碱基团衍生化，有助于通过LN跨膜pH或离子梯度将药物活性地装载到LN的水相内部。弱碱基团可以选择性地包括一个亲脂性结构域，有助于将药物活性地装载到脂质体膜的内单分子层。优点是，药物衍生物的LN配方相对于相应的游离药物表现出改善的溶解度、降低的毒性、增强的疗效和/或其他优点。
• Development of a series of bis-triazoles as G-quadruplex ligands
  作者：Maysaa M. Saleh、Charles A. Laughton、Tracey D. Bradshaw、Christopher J. Moody

  DOI：10.1039/c7ra07257k

  日期：——

  across a broad spectrum of cancer types. Telomeric ends of chromosomes consist of noncoding repeat sequences of guanine-rich DNA. These G-rich ends can fold into structures called G-quadruplexes. Stabilization of G-quadruplexes by small binding molecules called G4 ligands can prevent telomerase enzyme from maintaining telomere integrity in cancer cells. G-quadruplexes can exist in other parts of the genome

  端粒酶（一种保护染色体末端的特殊复合物）的维护是由端粒酶复合物提供的，端粒酶是80％以上的癌细胞激活但在大多数正常细胞中却不存在的关键因素。靶向端粒维持机制可能会阻止多种癌症类型的肿瘤生长。染色体的端粒末端由富含鸟嘌呤的DNA的非编码重复序列组成。这些富含G的末端可以折叠成称为G-四链体的结构。通过称为G4配体的小结合分子稳定G-四链体可以阻止端粒酶维持癌细胞中端粒的完整性。G-四链体也可以存在于基因组的其他部分，尤其是在癌基因的启动子序列中，并且也是有趣的药物靶标。这里，我们描述了一系列新的新型双三唑的开发，这些双三唑旨在稳定地将G-四链体结构作为G4配体来稳定。FRET分析显示两种化合物是中等有效的G4结合剂，对由Hsp90a启动子序列形成的四链体具有特定的亲和力，并且对G-四链体DNA具有良好的选择性与双链DNA。但是，CD光谱法未能提供有关由于其与配体之一相互作用而导致的人类端粒G
• Electrochemical fluorination of several methyl and/or ethyl esters of morpholino-substituted carboxylic acids
  作者：Takashi Abe、Hajime Baba、Kunio Okuhara、Haruhiko Fukaya

  DOI：10.1016/s0022-1139(01)00443-2

  日期：2001.10

  by the α-bond cleavage of the carboxylic acid and also by the kind of alkyl group of the carboxylic acid (the latter offering the possibility of cyclization side reactions). Perfluorooxolanes were formed as a major cyclization by-product from the ECF of morpholino-substituted carboxylic acids when the chain length of the alkyl group of the carboxylic acids had a carbon number of three or more and the

  羧酸七甲基和/或乙基酯（CH 2 CH 2 C（O）OET，CH 2 CH 2 CH 2 C（O）OME，CH 2 CH 2 CH 2 C（O）OET，CH （C 2 H ^ 5）C（O）OME，CH（ñ -C 3 ħ 7）C（O）OME，CH 2 CH 2 CH 2 CH 2 C（O）中OEt和CH 2 CH 2 CH 2通道2通道2将具有吗啉代基团的C（O）OEt进行电化学氟化（ECF）。在ECF上，以中等至良好的收率获得了带有全氟吗啉代基团的相应全氟酸氟化物。含有目标全氟吗啉代全氟酸氟​​化物的产率受羧酸的α键裂解以及羧酸烷基的种类的影响（后者提供环化副反应的可能性）。当羧酸烷基的链长为3以上时，吗啉代羧酸的ECF形成全氟氧杂环戊烷作为主要的环化副产物。一种允许环化的方法。当将羧酸的乙基酯进行ECF时，全氟二氧戊环仅以很小的收率作为特定的环化产物获得。描述了所产生的具有
• 13 C CP MAS NMR, FTIR, X-ray diffraction and PM3 studies of some N -(ω-carboxyalkyl)morpholine hydrohalides
  作者：Z. Dega-Szafran、I. Gąszczyk、D. Maciejewska、M. Szafran、E. Tykarska、I. Wawer

  DOI：10.1016/s0022-2860(00)00754-7

  日期：2001.1

  centrosymmetric dimer, connected by two N + –H⋯Cl − (3.095(1) A) and two O–H⋯Cl − (3.003(1) A) hydrogen bonds. 13 C CP MAS NMR spectra, contrary to the solution, showed non-equivalence of the ring carbon atoms. The PM3 calculations predict a molecular dimer without proton transfer for an HCl complex, while for an HBr complex an ion pairs with proton transfer, and reproduces correctly the conformation of both

  摘要 N -(ω-羧基烷基)吗啉盐酸盐, OC 4 H 8 N(CH 2 ) n COOH·HCl, n = 1–5, 被 13 C 交叉极化 (CP) 魔角旋转 (MAS) NMR 分析, FTIR 和 PM3 计算。N-(3-羧丙基)吗啉盐酸盐(n = 3)的结构已通过X射线衍射法在100 K下解析并精制至R = 0.031。晶体为单斜晶系，空间群 P 2 1 / c , a =14.307(3), b =9.879(2), c=7.166(1) A , β =93.20(3)°, V=1011.3(3) A 3，Z=4。在该化合物中，氮原子被质子化，两个分子形成中心对称二聚体，由两个 N + –H⋯Cl − (3.095(1) A) 和两个 O–H⋯Cl − (3.003(1) A) 氢键连接. 与溶液相反，13 C CP MAS NMR 谱显示环碳原子不等价。PM3 计算预测 HCl