(3R,4R)-1-tert-butyl 3,4-diethyl pyrrolidine-1,3,4-tricarboxylate | 595547-23-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (3R,4R)-1-tert-butyl 3,4-diethyl pyrrolidine-1,3,4-tricarboxylate
• 英文别名: (+/-)-trans-pyrrolidine-1,3,4-tricarboxylic acid 1-tert-butyl ester 3,4-diethyl ester；(3R,4R)-trans-N-Boc-pyrrolidine-3,4-dicarboxylic acid diethyl ester；(3R,4R)-5-N-Boc-pyrrolidine-3,4-dicarboxylic acid diethyl ester；1-O-tert-butyl 3-O,4-O-diethyl (3R,4R)-pyrrolidine-1,3,4-tricarboxylate
• CAS: 595547-23-2
• 化学式: C₁₅H₂₅NO₆
• 分子量: 315.367
• InChiKey: QVFYELHUZMOHPV-QWRGUYRKSA-N

物化性质

• 沸点：
  391.3±42.0 °C(Predicted)
• 密度：
  1.145±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  82.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (3R,4R)-1-tert-butyl 3,4-diethyl pyrrolidine-1,3,4-tricarboxylate 在 Amano Lipase OF N-甲基吗啉 、 sodium hydroxide 、 D-古洛糖 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 24.75h， 生成 (3R,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenylcarbamoyl]pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester
  参考文献：
  名称：

  WO2008/138754

  摘要：

  公开号：
• 作为产物：
  描述：

  富马酸二乙酯 在 palladium on activated charcoal sodium hydroxide 、 hydrolase ESP-ESL 1199 、 氢气 、 sodium chloride 作用下， 以 phosphate buffer 、 乙醇 、 甲苯 为溶剂， 反应 5.5h， 生成 (3R,4R)-1-tert-butyl 3,4-diethyl pyrrolidine-1,3,4-tricarboxylate
  参考文献：
  名称：

  Chemoenzymatic preparation of non-racemic N-Boc-pyrrolidine-3,4-dicarboxylic acid 3-ethyl esters and their 4-hydroxymethyl derivatives

  摘要：

  For the synthesis of metalloproteinase inhibitors the (R,R)- and (S,S)-monoethyl esters of N-Boe-pyrrolidine-3,4-dicarboxylic acid were prepared as key intermediates from the trans-diester racemate by two consecutive, highly selective enzymatic reactions. Reduction of the formed acids to the corresponding enantiopure hydroxymethyl derivatives ((R,R)- and (S,S)-ethyl N-Boc-4-hydroxymethyl-3-carboxylate) gives access to a new series of chiral building blocks. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0957-4166(03)00284-2

文献信息

• [EN] PHENYL-HETEROARYL DERIVATIVES AND METHODS OF USE THEREOF<br/>[FR] DÉRIVÉS DE PHÉNYL-HÉTÉROARYLE ET PROCÉDÉS D'UTILISATION DE CEUX-CI
  申请人：TRANSTECH PHARMA INC

  公开号：WO2011103091A1

  公开（公告）日：2011-08-25

  The present invention provides phenyl-heteroaryl derivatives of Formula (I) and pharmaceutically acceptable salts thereof. These compounds are useful in the treatment of RAGE-mediated diseases such as Alzheimer's Disease. The present invention further relates to methods for the preparation of compounds of Formula (I) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds, and the use of such compounds and/or pharmaceutical compositions in treating RAGE-mediated diseases.

  本发明提供了式（I）的苯基-杂环芳基衍生物及其药学上可接受的盐。这些化合物在治疗RAGE介导的疾病，如阿尔茨海默病方面是有用的。本发明还涉及制备式（I）化合物及其药学上可接受的盐的方法，包括含有这些化合物的药物组合物，以及在治疗RAGE介导的疾病中使用这些化合物和/或药物组合物的用途。
• [EN] NOVEL PYRROLIDINE-3,4-DICARBOXAMIDE DERIVATIVES<br/>[FR] NOUVEAUX DERIVES DE PYRROLIDINE-3,4-DICARBOXAMIDE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2005092881A1

  公开（公告）日：2005-10-06

  The invention is concerned with novel pyrrolidine-3,4-dicarboxamide derivatives of Formula (I) ; wherein Rl to R9 and X are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit the coagulation factor Xa and can be used as medicaments.

  这项发明涉及一种新型的 Formula (I) 中的吡咯烷-3,4-二羧酰胺衍生物；其中 R1 到 R9 和 X 如描述和索赔中定义的那样，以及其生理上可接受的盐。这些化合物抑制凝血因子 Xa，可用作药物。
• Synthesis, Characterization, and in vivo Evaluation of a Novel Potent Autotaxin-Inhibitor
  作者：Daniel Hunziker、Sabrina Reinehr、Marina Palmhof、Natalie Wagner、Thomas Biniasch、Gesa Stute、Patrizio Mattei、Petra Schmitz、Patrick DiGiorgio、Jérôme Hert、Markus G. Rudolph、Joerg Benz、Martine Stihle、Bernard Gsell、Stephan Müller、Rodolfo Gasser、Nina Schonhoven、Christoph Ullmer、Stephanie C. Joachim

  DOI：10.3389/fphar.2021.699535

  日期：——

  The autotaxin-lysophosphatidic acid (ATX-LPA) signaling pathway plays a role in a variety of autoimmune diseases, such as rheumatoid arthritis or neurodegeneration. A link to the pathogenesis of glaucoma is suggested by an overactive ATX-LPA axis in aqueous humor samples of glaucoma patients. Analysis of such samples suggests that the ATX-LPA axis contributes to the fibrogenic activity and resistance to aqueous humor outflow through the trabecular meshwork. In order to inhibit or modulate this pathway, we developed a new series of ATX-inhibitors containing novel bicyclic and spirocyclic structural motifs. A potent lead compound (IC₅₀ against ATX: 6 nM) with good in vivo PK, favorable in vitro property, and safety profile was generated. This compound leads to lowered LPA levels in vivo after oral administration. Hence, it was suitable for chronic oral treatment in two rodent models of glaucoma, the experimental autoimmune glaucoma (EAG) and the ischemia/reperfusion models. In the EAG model, rats were immunized with an optic nerve antigen homogenate, while controls received sodium chloride. Retinal ischemia/reperfusion (I/R) was induced by elevating the intraocular pressure (IOP) in one eye to 140 mmHg for 60 min, followed by reperfusion, while the other untreated eye served as control. Retinae and optic nerves were evaluated 28 days after EAG or 7 and 14 days after I/R induction. Oral treatment with the optimized ATX-inhibitor lead to reduced retinal ganglion cell (RGC) loss in both glaucoma models. In the optic nerve, the protective effect of ATX inhibition was less effective compared to the retina and only a trend to a weakened neurofilament distortion was detectable. Taken together, these results provide evidence that the dysregulation of the ATX-LPA axis in the aqueous humor of glaucoma patients, in addition to the postulated outflow impairment, might also contribute to RGC loss. The observation that ATX-inhibitor treatment in both glaucoma models did not result in significant IOP increases or decreases after oral treatment indicates that protection from RGC loss due to inhibition of the ATX-LPA axis is independent of an IOP lowering effect.

  自动税脂酶-溶磷脂酸（ATX-LPA）信号通路在多种自身免疫性疾病中发挥作用，如类风湿性关节炎或神经退行性疾病。在青光眼患者的房水样本中发现ATX-LPA轴过度活跃，暗示了其与青光眼发病机制的联系。对这些样本的分析表明，ATX-LPA轴促进了纤维生成活性，并通过小梁网状结构对房水流出的抵抗。为了抑制或调节这一通路，我们开发了一系列含有新颖的双环和螺环结构基元的ATX抑制剂。一种有效的前导化合物（对ATX的IC50：6 nM）具有良好的体内PK、有利的体外特性和安全性概况。这种化合物在口服后能降低体内LPA水平。因此，它适用于两种青光眼啮齿动物模型的慢性口服治疗，即实验性自身免疫性青光眼（EAG）和缺血/再灌注模型。在EAG模型中，大鼠接种视神经抗原匀浆，而对照组接受氯化钠。通过将一只眼的眼压升至140 mmHg，保持60分钟，然后再灌注，诱导视网膜缺血/再灌注（I/R），而另一只未处理的眼睛作为对照。在EAG后的第28天或I/R诱导后的第7和第14天评估视网膜和视神经。优化的ATX抑制剂口服治疗可减少两种青光眼模型中视网膜神经节细胞（RGC）的丢失。在视神经中，ATX抑制的保护作用比在视网膜中效果较弱，只能观察到神经丝蛋白变形减弱的趋势。综上所述，这些结果表明，在青光眼患者的房水中ATX-LPA轴的失调，除了假设的流出障碍外，可能也导致RGC的丢失。在两种青光眼模型中使用ATX抑制剂治疗后，未观察到口服治疗后眼压显著增加或减少的情况，这表明由于抑制ATX-LPA轴而保护RGC免受损失的效果与降低眼压的效果无关。
• Pyrrolidine-3,4-dicarboxamide derivatives
  申请人：Anselm Lilli

  公开号：US20050215599A1

  公开（公告）日：2005-09-29

  The invention is concerned with novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I) wherein R 1 to R 9 and X are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhibit the coagulation factor Xa and can be used as medicaments

  该发明涉及式(I)的新型吡咯烷-3,4-二羧酰胺衍生物，其中R1至R9和X在说明书和权利要求书中定义，以及其生理上可接受的盐。这些化合物抑制凝血因子Xa，并可用作药物。
• PROCESSES FOR THE MANUFACTURE OF A PYRROLIDINE-3,4-DICARBOXAMIDE DERIVATIVE
  申请人：Adam Jean-Michel

  公开号：US20080214826A1

  公开（公告）日：2008-09-04

  The invention is concerned with processes for the manufacture of the pyrrolidine-3,4-dicarboxamide derivative of formula (I), and the intermediates useful for those processes of manufacture.

  该发明涉及制造式(I)的吡咯烷-3,4-二羧酰胺衍生物的工艺，以及用于这些制造工艺的中间体。