3-oxo-2-(2-oxoethyl)butyric acid ethyl ester | 1071783-27-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: 3-oxo-2-(2-oxoethyl)butyric acid ethyl ester
• 英文别名: ethyl 2-acetyl-4-oxobutanoate；ethyl 3-oxo-2-(2-oxoethyl)butanoate；3-Oxo-2-(2-oxo-ethyl)-butyric acid ethyl ester
• CAS: 1071783-27-1
• 化学式: C₈H₁₂O₄
• 分子量: 172.181
• InChiKey: ZGKZMAVPWWKLND-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  12
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  60.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-oxo-2-(2-oxoethyl)butyric acid ethyl ester 在 1,10-菲罗啉 、 copper(II) bis(trifluoromethanesulfonate) 、 一水合肼 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 18.5h， 生成 6-(4-methylbenzyl)-7-(4-methylphenyl)-7,8-dihydropyrido[4,3-c]pyridazin-5(6H)-one
  参考文献：
  名称：

  Cu(OTf)2催化微波辅助合成新型支架7-芳基-7,8-二氢吡啶并[4,3-c]哒嗪-5(6H)-one

  摘要：

  描述了新型 7-芳基-7,8-二氢吡啶并[4,3-c]哒嗪-5(6H)-酮的合成，包括一步曼尼希型反应，然后是乙基 3-甲基哒嗪的分子内闭环- 4-羧酸盐和醛亚胺，在微波加热下由路易斯酸Cu(OTf)2催化。这种合成开辟了使用这种未经探索的药物化学支架的可能性。

  DOI：

  10.3998/ark.5550190.p008.934
• 作为产物：
  描述：

  2-乙酰基-4-戊酸乙酯 在 臭氧 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 1.5h， 生成 3-oxo-2-(2-oxoethyl)butyric acid ethyl ester
  参考文献：
  名称：

  Cu(OTf)2催化微波辅助合成新型支架7-芳基-7,8-二氢吡啶并[4,3-c]哒嗪-5(6H)-one

  摘要：

  描述了新型 7-芳基-7,8-二氢吡啶并[4,3-c]哒嗪-5(6H)-酮的合成，包括一步曼尼希型反应，然后是乙基 3-甲基哒嗪的分子内闭环- 4-羧酸盐和醛亚胺，在微波加热下由路易斯酸Cu(OTf)2催化。这种合成开辟了使用这种未经探索的药物化学支架的可能性。

  DOI：

  10.3998/ark.5550190.p008.934

文献信息

• [EN] BENZOXAZINONE DERIVATIVES AND ANALOGUES THEREOF AS MODULATORS OF TNF ACTIVITY<br/>[FR] DÉRIVÉS DE BENZOXAZINONE ET LEURS ANALOGUES EN TANT QUE MODULATEURS DE L'ACTIVITÉ DU TNF
  申请人：UCB BIOPHARMA SPRL

  公开号：WO2016198400A1

  公开（公告）日：2016-12-15

  A series of substituted 3,4-dihydro-2H-.1,4-benzoxazin-3-one derivatives, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neuradegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

  一系列替代的3,4-二氢-2H-1,4-苯并噁嗪-3-酮衍生物及其类似物，作为人类TNFα活性的有效调节剂，因此对于治疗和/或预防各种人类疾病具有益处，包括自身免疫和炎症性疾病；神经和神经退行性疾病；疼痛和伤害感知性疾病；心血管疾病；代谢性疾病；眼部疾病；以及肿瘤性疾病。
• PYRIDAZINE-, PYRIDINE- AND PYRANE-DERIVATIVES AS GPBAR1 AGONISTS
  申请人：Arista Luca

  公开号：US20100048579A1

  公开（公告）日：2010-02-25

  A compound of formula (I) wherein the substituents have various meanings, optionally in salt and/or solvate form, and their use as pharmaceuticals.

  一种化合物，其化学式为（I），其中取代基具有不同的含义，可选为盐和/或溶剂化合物形式，并且可以用作药物。
• Substituted benzo[b][1,4]oxazines and pyrido[3,2-b][1,4]oxazines as modulators of tumor necrosis factor activity
  申请人：UCB Biopharma SPRL

  公开号：US10287299B2

  公开（公告）日：2019-05-14

  A series of substituted 3,4-dihydro-2H-.1,4-benzoxazin-3-one derivatives, and analogs thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neuradegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

  一系列取代的 3,4-二氢-2H-.1,4-苯并恶嗪-3-酮衍生物及其类似物是人类 TNFa 活性的强效调节剂，因此可用于治疗和/或预防各种人类疾病，包括自身免疫和炎症性疾病、神经和神经退行性疾病、疼痛和痛觉失调、心血管疾病、代谢性疾病、眼部疾病和肿瘤疾病。
• Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity
  作者：William Mahy、Mikesh Patel、David Steadman、Hannah L. Woodward、Benjamin N. Atkinson、Fredrik Svensson、Nicky J. Willis、Alister Flint、Dimitra Papatheodorou、Yuguang Zhao、Luca Vecchia、Reinis R. Ruza、James Hillier、Sarah Frew、Amy Monaghan、Artur Costa、Magda Bictash、Magnus W. Walter、E. Yvonne Jones、Paul V. Fish

  DOI：10.1021/acs.jmedchem.0c00660

  日期：2020.9.10

  The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
• G-Protein-Coupled Bile Acid Receptor 1 (GPBAR1, TGR5) Agonists Reduce the Production of Proinflammatory Cytokines and Stabilize the Alternative Macrophage Phenotype
  作者：Klemens Högenauer、Luca Arista、Niko Schmiedeberg、Gudrun Werner、Herbert Jaksche、Rochdi Bouhelal、Deborah G. Nguyen、B. Ganesh Bhat、Layla Raad、Celine Rauld、José M. Carballido

  DOI：10.1021/jm501052c

  日期：2014.12.26

  GPBAR1 (also known as TGR5) is a G-protein-coupled receptor (GPCR) that triggers intracellular signals upon ligation by various bile acids. The receptor has been studied mainly for its function in energy expenditure and glucose homeostasis, and there is little information on the role of GPBAR1 in the context of inflammation. After a high-throughput screening campaign, we identified isonicotinamides exemplified by compound 3 as nonsteroidal GPBAR1 agonists. We optimized this series to potent derivatives that are active on both human and murine GPBAR1. These agonists inhibited the secretion of the proinflammatory cytokines TNF-alpha and IL-12 but not the antiinflammatory IL-10 in primary human monocytes. These effects translate in vivo, as compound 15 inhibits LPS induced TNF-alpha and IL-12 release in mice. The response was GPBAR1 dependent, as demonstrated using knockout mice. Furthermore, agonism of GPBAR1 stabilized the phenotype of the alternative, noninflammatory, M2-like type cells during differentiation of monocytes into macrophages. Overall, our results illustrate an important regulatory role for GPBAR1 agonists as controllers of inflammation.