4-(4-甲基-1-哌嗪基)丁酸乙酯 | 487008-51-5

• 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: 4-(4-甲基-1-哌嗪基)丁酸乙酯
• 英文名称: ethyl 4-(4-methylpiperazin-1-yl)butanoate
• 英文别名: Ethyl 4-(4-Methyl-1-piperazinyl)butanoate
• CAS: 487008-51-5
• 化学式: C₁₁H₂₂N₂O₂
• mdl: MFCD01876880
• 分子量: 214.308
• InChiKey: OYLUXBIBVCAYHD-UHFFFAOYSA-N

物化性质

• 沸点：
  290.7±25.0 °C(Predicted)
• 密度：
  0.993±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  15
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.909
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-甲基-1-哌嗪基)丁酸乙酯 在 水 作用下， 反应 0.5h， 生成 4-(4-甲基-1-哌嗪基)丁酸
  参考文献：
  名称：

  用于局部药物递送的2-（6-甲氧基-2-萘基）丙酸（萘普生）的新型吗啉基-和甲基哌嗪基戊二酰氧基烷基前药的合成和体外评价。

  摘要：

  合成了2-（6-甲氧基-2-萘基）丙酸的各种新型吗啉基-（3a，b）和甲基哌嗪基甲酰氧基烷基（3c-f）酯，并在体外评估了其作为萘普生的潜在前药的局部药物递送。通过在二环己基碳二亚胺（DCC）和4-（二甲基氨基）吡啶（DMAP）存在下，将相应的萘普生羟烷基酯与吗啉基-或（4-甲基-1-哌嗪基）酰基偶联，制备化合物3a-f，并进行定量水解（t（1/2）= 1-26分钟）至人血清中的萘普生。与萘普生相比，化合物3c-f在pH 5.0时显示出较高的水溶性和相似的亲脂性，这取决于它们的辛醇-缓冲液分配系数（log P（app））。在pH 7.4时，它们的亲脂性明显高于萘普生。最好的前药3c导致4和1。与萘普生在pH 7.4和5.0下相比，皮肤渗透分别提高了5倍。本研究表明，使用甲基哌嗪基可产生在中性和弱酸性条件下部分未电离的前药，因此，就水溶性和亲脂性而言，可实现理想的组合。此外，所得的两相溶解性

  DOI：

  10.1021/jm991149s
• 作为产物：
  描述：

  N-甲基哌嗪 、 4-溴丁酸乙酯 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 3.0h， 生成 4-(4-甲基-1-哌嗪基)丁酸乙酯
  参考文献：
  名称：

  Synthesis of a Gemcitabine Prodrug for Remote Loading into Liposomes and Improved Therapeutic Effect

  摘要：

  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。

  DOI：

  10.1021/acs.bioconjchem.5b00619

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。
• Diaminopyrimidinecarboxamide Derivative
  申请人：Nagashima Shinya

  公开号：US20090281072A1

  公开（公告）日：2009-11-12

  A compound which may be used for the prevention or treatment of respiratory diseases in which STAT 6 is concerned, particularly asthma, chronic obstructive pulmonary disease and the like is provided. A pyrimidine derivative or a salt thereof, which has an arylamino or arylethylamino group which may be substituted with a specified substituent, at the 2-position, amino group substituted with benzyl group or the like, at the 4-position, and carbamoyl group which may be substituted, at the 5-position, is provided.

  提供了一种可用于预防或治疗呼吸系统疾病，特别是哮喘、慢性阻塞性肺疾病等与STAT 6有关的化合物。该化合物为嘧啶衍生物或其盐，其在2位具有可被取代的芳基氨基或芳基乙基氨基基团，4位具有氨基取代的苯甲基基团或类似基团，5位具有可被取代的氨基甲酰基团。
• Modified Drugs for Use in Liposomal Nanoparticles
  申请人：Cullis Peter

  公开号：US20110165225A1

  公开（公告）日：2011-07-07

  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.

  本文提供了适用于载入脂质体纳米粒子载体的拖曳导数。在某些优选方面，这些导数包括一种难溶于水的拖曳经过弱碱基团衍生化，该弱碱基团促进通过LN跨膜pH或离子梯度将拖曳活性负载到LN的水内部。弱碱基团可以选择包括一个亲脂性域，该亲脂性域促进将拖曳活性负载到脂质体膜的内单层。优点是，与相应的自由拖曳相比，拖曳导数的LN配方表现出改善的溶解度、降低的毒性、增强的功效和/或其他益处。
• Modified drugs for use in liposomal nanoparticles
  申请人：The University of British Columbia

  公开号：US08324410B2

  公开（公告）日：2012-12-04

  Drug derivatives are provided herein which are suitable for loading into liposomal nanoparticle carriers. In some preferred aspects, the derivatives comprise a poorly water-soluble drug derivatized with a weak-base moiety that facilitates active loading of the drug 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 drug to the inner monolayer of the liposomal membrane. Advantageously, LN formulations of the drug derivatives exhibit improved solubility, reduced toxicity, enhanced efficacy, and/or other benefits relative to the corresponding free drugs.

  本文提供了适用于装载到脂质体纳米粒子载体中的药物衍生物。在一些优选方面中，这些衍生物包括一种水溶性差的药物，经过衍生化处理后，衍生物中含有一个弱碱性基团，该基团有助于通过LN跨膜pH或离子梯度将药物主动装载到LN的水相内部中。弱碱性基团可以选择性地包括一个亲脂性域，该域有助于将药物主动装载到脂质体膜的内单层中。有利的是，药物衍生物的LN配方相对于相应的自由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。