3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propionic acid benzyl ester | 596803-16-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propionic acid benzyl ester
• 英文别名: Benzyl 3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propanoate
• CAS: 596803-16-6
• 化学式: C₁₆H₁₈O₆
• 分子量: 306.315
• InChiKey: VQUDSDTVVYNVJC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  78.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propionic acid benzyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成
  参考文献：
  名称：

  Synthesis and biological evaluation of hydroxamate-Based inhibitors of glutamate carboxypeptidase II

  摘要：

  A series of hydroxamic acids has been prepared as potential inhibitors of glutamate carboxypeptidase II (GCP II). Compounds based on a Pl' residue (primed-side inhibitors) were more potent than those based on a Pl group (unprimed-side inhibitors). Inhibitory potency of the primed-side GCP II inhibitors was found to be dependent on the number of methylene units between the hydroxamate group and pentanedioic acid. Succinyl hydroxamic acid derivative, 2-(hydroxycarbamoylmethyl)pentanedioic acid, is the most potent GCP II inhibitor with an IC50 value of 220 nM The comparison of the results to those of other classes of GCP II inhibitors as well as hydroxamate-based MNIP inhibitors provides further insight into the structure-activity relationships of GCP II inhibition. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00407-4
• 作为产物：
  描述：

  丙二酸环(亚)异丙酯 、 丙烯酸苄酯 在 苄基三乙基氯化铵 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 12.0h， 以98%的产率得到3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)propionic acid benzyl ester
  参考文献：
  名称：

  轻松合成α-取代的丙烯酸酯。

  摘要：

  在甲醇中用二甲基亚甲基碘化碘（埃森莫瑟氏碘盐）处理5-单取代的麦德鲁姆酸，可得到高产率的α-取代的丙烯酸甲酯。容易获得5-单取代的Meldrum酸，使我们能够合成各种α-取代的丙烯酸甲酯。反应条件温和，可耐受有机合成中常用的许多官能团。因此，这种新方法有可能替代传统的α-取代丙烯酸酯制备方法。

  DOI：

  10.1021/jo026101s

文献信息

• [EN] PRODRUGS OF PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) INHIBITOR<br/>[FR] PROMÉDICAMENTS D'INHIBITEUR DE L'ANTIGÈNE MEMBRANAIRE SPÉCIFIQUE DE LA PROSTATE (PSMA)
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2016022827A1

  公开（公告）日：2016-02-11

  Methods and compounds are disclosed for treating a disease or condition by inhibiting PSMA (Prostate Specific Membrane Antigen) using prodrugs of 2-PMPA.

  揭示了一种通过使用2-PMPA的前药来抑制PSMA（前列腺特异性膜抗原）来治疗疾病或症状的方法和化合物。
• Facile Synthesis of α-Substituted Acrylate Esters
  作者：Bunda Hin、Pavel Majer、Takashi Tsukamoto

  DOI：10.1021/jo026101s

  日期：2002.10.1

  (Eschenmoser's iodide salt) in methanol gives alpha-substituted acrylate methyl esters in good yields. Easy access to 5-monosubstituted Meldrum's acids allowed us to synthesize a wide variety of alpha-substituted acrylate methyl esters. The reaction conditions are mild and tolerate many functional groups commonly used in organic synthesis; thus, this new method has potential as an alternative to conventional

  在甲醇中用二甲基亚甲基碘化碘（埃森莫瑟氏碘盐）处理5-单取代的麦德鲁姆酸，可得到高产率的α-取代的丙烯酸甲酯。容易获得5-单取代的Meldrum酸，使我们能够合成各种α-取代的丙烯酸甲酯。反应条件温和，可耐受有机合成中常用的许多官能团。因此，这种新方法有可能替代传统的α-取代丙烯酸酯制备方法。
• TWI588139
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery of Orally Available Prodrugs of the Glutamate Carboxypeptidase II (GCPII) Inhibitor 2-Phosphonomethylpentanedioic Acid (2-PMPA)
  作者：Pavel Majer、Andrej Jančařík、Marcela Krečmerová、Tomáš Tichý、Lukáš Tenora、Krystyna Wozniak、Ying Wu、Elie Pommier、Dana Ferraris、Rana Rais、Barbara S. Slusher

  DOI：10.1021/acs.jmedchem.6b00062

  日期：2016.3.24

  2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the alpha- and gamma-carboxylates unsubstituted. This attempt was unsuccessful due to the chemical instability of the bis-POC/POM derivatives. Addition of alpha,gamma-diesters and alpha-monoesters enhanced chemical stability and provided excellent oral exposure in mice, but these mixed esters were too stable in vivo, resulting in minimal release of 1. By introducing POC groups on both the phosphonate and a-carboxylate, we synthesized Tris-POC-2-PMPA (21b), which afforded excellent release of 1 following oral administration in both mice and dog.
• Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs
  作者：Michael Nedelcovych、Ranjeet P. Dash、Lukáš Tenora、Sarah C. Zimmermann、Alexandra J. Gadiano、Caroline Garrett、Jesse Alt、Kristen R. Hollinger、Elie Pommier、Andrej Jančařík、Camilo Rojas、Ajit G. Thomas、Ying Wu、Krystyna Wozniak、Pavel Majer、Barbara S. Slusher、Rana Rais

  DOI：10.1021/acs.molpharmaceut.7b00231

  日期：2017.10.2

  2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the gamma-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, gamma-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1 also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1 resulted in similar plasma exposure of 2-PMPA versus the IN route (AUC(IN): 76 +/- 9 h.nmol/mL versus AUC(IN): 99 +/- 24 h.nmol/mL); but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1 more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders.