tert-butyl ((S)-4-diazo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate | 741267-61-8

• 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: tert-butyl ((S)-4-diazo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate
• 英文别名: tert-butyl N-[(2S)-4-diazo-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]carbamate
• CAS: 741267-61-8
• 化学式: C₁₃H₂₀N₄O₄
• 分子量: 296.326
• InChiKey: LCOCRBFRJNSSSJ-IUCAKERBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.28
• 重原子数：
  21.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  120.9
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  tert-butyl ((S)-4-diazo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate 在 N-甲基吗啉 、 盐酸 、 potassium carbonate 、 cesium fluoride 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.5h， 生成 N-((1S)-1-{[((1S)-3-hydroxy-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)amino]carbonyl}-3,3-dimethylbutyl)-4-methoxy-1H-indole-2-carboxamide
  参考文献：
  名称：

  Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

  摘要：

  The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL(pro)) in a post-translational processing step that is critical for coronavirus replication. The 3CL(pro) sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL(pro) employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CL(pro) with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.

  DOI：

  10.1021/acs.jmedchem.0c01063
• 作为产物：
  描述：

  N-叔丁氧羰基-L-谷氨酸二甲酯 在 N-甲基吗啉 、 甲醇 、 sodium tetrahydroborate 、 lithium hydroxide monohydrate 、 水 、 cobalt(II) chloride 、 lithium hexamethyldisilazane 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 生成 tert-butyl ((S)-4-diazo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate
  参考文献：
  名称：

  [EN] PROTEASE INHIBITORS FOR THE TREATMENT OF CORONAVIRUS INFECTIONS
  [FR] INHIBITEURS DE LA PROTÉASE POUR LE TRAITEMENT D'INFECTIONS À CORONAVIRUS

  摘要：

  该申请涉及(I)和(III)式化合物及其药学上可接受的盐和制药组合物。这些化合物是严重急性呼吸综合症冠状病毒2号(SARS-CoV-2)的主要蛋白酶(Mpro)的有效抑制剂，并可用于治疗或预防受COVID-19感染的个体。

  公开号：

  WO2022261473A1

文献信息

• [EN] INHIBITORS OF NOROVIRUS AND CORONAVIRUS REPLICATION<br/>[FR] INHIBITEURS DE LA RÉPLICATION DE NOROVIRUS ET DE CORONAVIRUS
  申请人：COCRYSTAL PHARMA INC

  公开号：WO2021206876A1

  公开（公告）日：2021-10-14

  Compounds of Formula (I) and methods of inhibiting the replication of viruses in a biological sample or patient, of reducing the amount of viruses in a biological sample or patient, and of treating a virus infection in a patient, comprising administering to said biological sample or patient an effective amount of a compound represented by Formula (I), a compound of Table A or B or a pharmaceutically acceptable salt thereof.

  公式（I）化合物及抑制生物样本或患者中病毒复制、减少生物样本或患者中病毒数量、以及治疗患者病毒感染的方法，包括向所述生物样本或患者投与由公式（I）表示的化合物、表A或B中的化合物或其药用可接受盐的有效量。
• Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Warhead
  作者：N. G. R. Dayan Elshan、Karen C. Wolff、Laura Riva、Ashley K. Woods、Gennadii Grabovyi、Katy Wilson、James Pedroarena、Sourav Ghorai、Armen Nazarian、Frank Weiss、Yuyin Liu、Wrickban Mazumdar、Lirui Song、Neechi Okwor、Jacqueline Malvin、Malina A. Bakowski、Nathan Beutler、Melanie G. Kirkpatrick、Amal Gebara-Lamb、Edward Huang、Vân T. B. Nguyen-Tran、Victor Chi、Shuangwei Li、Thomas F. Rogers、Case W. McNamara、Anil Kumar Gupta、Alireza Rahimi、Jian Jeffrey Chen、Sean B. Joseph、Peter G. Schultz、Arnab K. Chatterjee

  DOI：10.1021/acs.jmedchem.3c01938

  日期：2024.2.22

  we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (∼5× more potent in primary cells) and human in vitro clearance (>4× better microsomal clearance and >10× better hepatocyte clearance),

  仍然需要开发新型 SARS-CoV-2 治疗方案，通过提高反应稳健性、减少安全责任和全球可及性来改进现有疗法。SARS-CoV-2 的功能关键型病毒主蛋白酶 （Mpro， 3CLpro） 是一个有吸引力的靶标，因为它在新冠病毒家族内具有同源性，而对人类蛋白酶缺乏同源性。在本次披露中，我们概述了一种新型 SARS-CoV-2 3CLpro 抑制剂 CMX990 的出现，它带有前所未有的三氟甲氧基甲基酮弹头。与已上市的药物尼马曲韦（与利托那韦联合使用 = Paxlovid）相比，CMX990 具有明显的差异化效力（在原代细胞中效力 ∼ 5×）和人体外清除率（>4× 更好的微粒体清除率和 >10× 更好的肝细胞清除率），具有良好的体外与体内相关性。CMX990 凭借其引人注目的临床前特征和预计每天一次或两次的剂量，以支持人类的非加强口服治疗，作为 SARS-CoV-2 的口服候选药物进入 1 期临床试验。
• Structural variations in keto-glutamines for improved inhibition against hepatitis A virus 3C proteinase
  作者：Rajendra P Jain、John C Vederas

  DOI：10.1016/j.bmcl.2004.05.021

  日期：2004.7

  A series of keto-glutamine tetrapeptide analogs containing a 2-oxo-pyrrolidine ring as a glutamine side chain mimic were synthesized with both R and S configuration at the beta-carbon. Compounds bearing a phthalhydrazide moiety show improved reversible inhibition of HAV 3C proteinase in the low micromolar range. (C) 2004 Elsevier Ltd. All rights reserved.
• [EN] NOVEL AND HIGHLY SELECTIVE SARS-COV-2 MPRO INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS MPRO DU SARS-COV-2 HAUTEMENT SÉLECTIFS
  申请人：[en]THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY

  公开号：WO2023150790A2

  公开（公告）日：2023-08-10

  Disclosed herein are compounds of the formulas (I) as well as analogs thereof, wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used to inhibit Mpro proteases. Also provided are methods of administering compounds and compositions provided herein to a patient in need thereof, for example, for the treatment of diseases such as SARS-CoV-2 or a variant thereof.