naproxen-N,N'-thionyldiimidazole | 78457-23-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: naproxen-N,N'-thionyldiimidazole
• 英文别名: (R,S)-N-2-naproxenylimidazole；1-Imidazol-1-yl-2-(6-methoxynaphthalen-2-yl)propan-1-one
• CAS: 78457-23-5
• 化学式: C₁₇H₁₆N₂O₂
• 分子量: 280.326
• InChiKey: ZRCZMABYWVGAND-UHFFFAOYSA-N

物化性质

• 沸点：
  486.8±47.0 °C(Predicted)
• 密度：
  1.17±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  44.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  L-亮氨酸乙酯 、 naproxen-N,N'-thionyldiimidazole 在 TEA 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 naproxen-leucine ethyl ester
  参考文献：
  名称：

  Low-molecular-weight proteins as carriers for renal drug targeting. Preparation of drug-protein conjugates and drug-spacer derivatives and their catabolism in renal cortex homogenates and lysosomal lysates

  摘要：

  Low molecular weight proteins (LMWPs) are known to be reabsorbed and catabolized primarily by the proximal tubular cells of the kidneys. As such, LMWPs might serve as drug carriers that release drugs site-specifically in the kidney. We tested this concept in vitro by coupling different drugs to the LMWP lysozyme both directly (amide bond) and via different spacers: oligopeptides (amide bond), (poly-)alpha-hydroxy acids (ester bond), and a pH sensitive cis-aconityl spacer (amide bond). The capability of the kidney to release the parent drug from such drug-spacer derivatives and drug-LMWP conjugates by enzymatic or chemical hydrolysis of the bond was tested by incubation experiments in renal cortex homogenates and lysosomal lysates. Directly coupled conjugates of terminal carboxyl group containing drugs and lysozyme were catabolized to single amino acids, but did not result in release of the parent drug. The amide bond between the drug and the final amino acid (lysine) appeared to be stable in the incubation milieu. Different oligopeptide spacers coupled to the drugs showed similar results: the oligopeptide itself was cleaved but the amide bond between the drug and different single amino acids remained untouched. Only amide bonds of derivatives of carboxylic drugs with peptide structures themselves were cleaved. Some of the directly coupled conjugates of terminal amino drugs and oligopeptides showed clear release of the parent drug whereas others were stable. Terminal amino drugs were rapidly released from an acid-sensitive cis-aconityl spacer. Terminal carboxyl group containing drugs were enzymatically released from their glycolic and lactic ester spacers at different rates. These kinds of drugs were also released as parent drug from LMWP conjugates with ester spacers like L-lactic acid. Increasing spacer length by intercalating a tetra(L-lactic acid) molecule between the drug and the protein further increased the extent and rate of drug release, indicating increased accessability of the bond to the enzymes. Terminal amino group containing drugs were rapidly generated as parent drug from LMWP conjugates using an acid-sensitive spacer. In addition the conjugates were found to be adequately stable in plasma, considering their rapid clearance from the bloodstream. It is concluded that LMWPs may indeed be of use as carriers for specific renal delivery of drugs, since renal cortex homogenates and lysosomal lysates are able to catabolize the protein and generate the parent drug from drug-LMWP conjugates bearing suitable spacers. The option of enzymatic release is limited by the narrow specificity of the lysosomal enzymes. This has profound implications for the synthesis of suitable conjugates, since the nature of the drug itself, the type of bond, and also spacer length largely determine whether release of the parent drug will occur. Tailor-made spacers containing the correct mode of attachment and the right spacer length are required for this option. Chemical hydrolysis, using acid-sensitive linkers, is suggested as a viable alternative approach.

  DOI：

  10.1021/jm00085a012
• 作为产物：
  描述：

  2-(6-甲氧基-2-萘基)丙酸 、 N,N'-羰基二咪唑 以 苯 为溶剂， 反应 2.0h， 生成 naproxen-N,N'-thionyldiimidazole
  参考文献：
  名称：

  （R，S）-偶氮内酯作为新型底物在有机溶剂中用于脂肪酶催化的水解拆分

  摘要：

  偶氮化合物，即N-酰基唑，作为通用的酰化试剂已在文献中充分表征，其中唑结构不仅可以充当更好的离去基团，还可以使羰基碳更具亲电性，并易于发生亲核攻击。因此，期望在开发用于制备光学纯的羧酸的新的拆分方法的开发中结合这种独特的性质和脂肪酶的拆分能力。以南极假丝酵母脂肪酶B（CALB）-在有机溶剂中催化（R，S）-N-丙烯烯基唑的水解为模型系统，（R，S）-N-profenyl-1,2,4-三唑代替其相应的酯类似物被用作制备光学纯的profen（即2-芳基丙酸）的最佳底物。在45°C下水饱和的甲基叔丁基醚（MTBE）中的（R，S）-偶氮内酯的结构反应性相关性以及彻底的动力学分析进一步用于阐明四面体加合物的限速形成在酰化步骤中，没有CN键断裂或具有适度的CN键断裂与CO键形成协同作用。容易制备底物，高酶反应性和对映体选择性以及通过水萃取容易回收产物和残留底物的优势证明了使用（R，S）-偶氮内酯作为酶促拆分过程的新型底物。

  DOI：

  10.1002/adsc.200900391

文献信息

• Improvements of enzyme activity and enantioselectivity in lipase-catalyzed alcoholysis of (R,S)-azolides
  作者：An-Chi Wu、Pei-Yun Wang、Yi-Sheng Lin、Min-Fang Kao、Jin-Ru Chen、Jyun-Fen Ciou、Shau-Wei Tsai

  DOI：10.1016/j.molcatb.2009.11.001

  日期：2010.3

  With Candida antarctica lipase B (CALB)-catalyzed alcoholysis of (R,S)-naproxenyl 1,2,4-triazolide at the optimal conditions (i.e. anhydrous MTBE as the solvent, and methanol as the acyl acceptor at 45 degrees C) as the model system, the enzyme enantioselectivity in terms of V-R/V-S = 105.8 and specific activity for the fast-reacting (R)-azolide V-R/(E-t) = 0.979 mmol/(h g) were greatly improved in comparison with V-R/V-S = 8.0 and V-R/(E-t) = 0.113 mmol/(h g) of using (R,S)-naproxenyl 2,2,2-trifluoroethyl ester as the substrate. The resolution strategy was successfully extended to other (R,S)-profenyl 1,2,4-triazolides and lipases from Candida rugosa (Lipase MY) and Carica papaya (CPL) having opposite enantioselectivity to CALB. Moreover, the kinetic constants were estimated, compared with those obtained via hydrolysis, and employed for modeling time-course conversions of (R,S)-naproxenyl 1,2,4-triazolide in anhydrous MTBE. The advantages of easy substrate preparation, high enzyme reactivity and enantioselectivity, as well as easy product separation from the remaining substrate via reactive extraction demonstrate merits of using (R,S)-azolides but not the corresponding esters for the alcoholytic resolution. (C) 2009 Elsevier B.V. All rights reserved.
• [EN] ENHANCED TISSUE PENETRATION PRODRUGS<br/>[FR] PROMÉDICAMENTS DE PÉNÉTRATION RENFORCÉE DE TISSUS
  申请人：WU YONG-QIAN

  公开号：WO2006138187A1

  公开（公告）日：2006-12-28

  [EN] The present invention relates to derivatives of carboxy-containing drugs for enhancing tissue penetration and pharmaceutical compositions comprising such derivatives.
  [FR] La présente invention concerne des dérivés de médicaments contenant un élément carboxy pour renforcer la pénétration dans les tissus et des compositions pharmaceutiques comprenant de tels dérivés.