tert-butyl ((S)-4-bromo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate | 741267-62-9

• 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-bromo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate
• 英文别名: tert-butyl N-[(2S)-4-bromo-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]carbamate
• CAS: 741267-62-9
• 化学式: C₁₃H₂₁BrN₂O₄
• 分子量: 349.225
• InChiKey: RAOCAZWSYKCCJT-IUCAKERBSA-N

物化性质

• 沸点：
  520.2±30.0 °C(Predicted)
• 密度：
  1.356±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  84.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl ((S)-4-bromo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate 在 sodium hydride 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.5h， 生成 2-[(S)-3-Amino-2-oxo-4-((S)-2-oxo-pyrrolidin-3-yl)-butyl]-2,3-dihydro-phthalazine-1,4-dione
  参考文献：
  名称：

  Structural variations in keto-glutamines for improved inhibition against hepatitis A virus 3C proteinase

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2004.05.021
• 作为产物：
  描述：

  (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid 在 N-甲基吗啉 、 氢溴酸 作用下， 以 四氢呋喃 为溶剂， 反应 2.5h， 生成 tert-butyl ((S)-4-bromo-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate
  参考文献：
  名称：

  CMX990 的发现：一种带有新型弹头的强效 SARS-CoV-2 3CL 蛋白酶抑制剂

  摘要：

  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。

  DOI：

  10.1021/acs.jmedchem.3c01938

文献信息

• [EN] ANTICORONVIRAL COMPOUNDS AND COMPOSITIONS, THEIR PHARMACEUTICAL USES AND MATERIALS FOR THEIR SYNTHESIS<br/>[FR] COMPOSES ET COMPOSITIONS ANTI-CORONAVIRUS, UTILISATIONS PHARMACEUTIQUES ASSOCIEES ET MATERIAUX POUR LA SYNTHESE DE CES COMPOSES ET COMPOSITIONS
  申请人：PFIZER

  公开号：WO2005113580A1

  公开（公告）日：2005-12-01

  The invention relates to methods of inhibiting SARS-related coronavirus viral replication activity comprising contacting a SARS-related coronavirus protease with a therapeutically effective amount of a SARS 3C like protease inhibitor of formula (I), and compositions comprising the same.

  本发明涉及一种抑制SARS相关冠状病毒病毒复制活性的方法，包括将SARS相关冠状病毒蛋白酶与公式（I）的治疗有效量的SARS 3C类蛋白酶抑制剂接触，并且包括相应的组合物。
• [EN] PROTEASE INHIBITORS FOR THE TREATMENT OF CORONAVIRUS INFECTIONS<br/>[FR] INHIBITEURS DE LA PROTÉASE POUR LE TRAITEMENT D'INFECTIONS À CORONAVIRUS
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2022261473A1

  公开（公告）日：2022-12-15

  The application relates to compounds of Formula (I) and (III), their pharmaceutically acceptable salts, and their pharmaceutical compositions. The compounds are potent inhibitors of the main protease (Mpro) of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), and they are useful in treating or preventing COVID-19 in a subject.

  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。
• Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19
  作者：Robert L. Hoffman、Robert S. Kania、Mary A. Brothers、Jay F. Davies、Rose A. Ferre、Ketan S. Gajiwala、Mingying He、Robert J. Hogan、Kirk Kozminski、Lilian Y. Li、Jonathan W. Lockner、Jihong Lou、Michelle T. Marra、Lennert J. Mitchell、Brion W. Murray、James A. Nieman、Stephen Noell、Simon P. Planken、Thomas Rowe、Kevin Ryan、George J. Smith、James E. Solowiej、Claire M. Steppan、Barbara Taggart

  DOI：10.1021/acs.jmedchem.0c01063

  日期：2020.11.12

  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.
• Synthesis and Evaluation of Keto-Glutamine Analogues as Potent Inhibitors of Severe Acute Respiratory Syndrome 3CL^pro
  作者：Rajendra P. Jain、Hanna I. Pettersson、Jianmin Zhang、Katherine D. Aull、Pascal D. Fortin、Carly Huitema、Lindsay D. Eltis、Jonathan C. Parrish、Michael N. G. James、David S. Wishart、John C. Vederas

  DOI：10.1021/jm0494873

  日期：2004.12.1

  The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the a-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC50 values ranging from 0.60 to 70 muM.
• [EN] PROTEASE INHIBITORS FOR THE TREATMENT OF CORONAVIRUS INFECTIONS<br/>[FR] INHIBITEURS DE PROTÉASE POUR LE TRAITEMENT D'INFECTIONS À CORONAVIRUS
  申请人：[en]THE SCRIPPS RESEARCH INSTITUTE

  公开号：WO2022266363A1

  公开（公告）日：2022-12-22

  Provided herein are compounds of Formula (I), their pharmaceutically acceptable salts, and their pharmaceutical compositions: wherein R1, R2, R3a, R3b, R4, R5, and A are defined in the present disclosure. The compounds are potent inhibitors of the main protease (MPRO) of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), and they are useful in treating or preventing COVID-19 in a subject.