(2S,5R)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,5R)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide
• 英文别名: (2S,5R)-1-((4-fluorophenyl)sulfonyl)-5-methyl-N-((6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)methyl)pyrrolidine-2-carboxamide；(2S,5R)-1-(4-fluorophenyl)sulfonyl-5-methyl-N-[[6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl]pyrrolidine-2-carboxamide
• 化学式: C₂₃H₂₁F₄N₅O₃S
• 分子量: 523.511
• InChiKey: BBCFRTHODCIVDP-VLIAUNLRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  1-tert-butyl 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate 在 溴化亚铜二甲硫醚 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.25h， 生成 (2S,5R)-1-[(4-fluorobenzene)sulfonyl]-5-methyl-N-([6-[6-(trifluoromethyl)pyridin-3-yl]pyrimidin-4-yl]methyl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  Discovery of a Potent (4R,5S)-4-Fluoro-5-methylproline Sulfonamide Transient Receptor Potential Ankyrin 1 Antagonist and Its Methylene Phosphate Prodrug Guided by Molecular Modeling

  摘要：

  Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an N-isopropylglycine sulfonamide lead (1) to a novel and potent (4R,SS)-4-fluoro-S-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy threedimensional conformations to guide ligand design. This effort led to compound 20, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited in vivo exposure. To improve solubility and in vivo exposure, we developed methylene phosphate prodrug 22, which demonstrated superior oral exposure and robust in vivo target engagement in a rat model of AITC-induced pain.

  DOI：

  10.1021/acs.jmedchem.8b00117

文献信息

• [EN] SUBSTITUTED HETEROCYCLIC SULFONAMIDE COMPOUNDS USEFUL AS TRPA1 MODULATORS<br/>[FR] COMPOSÉS DE SULFONAMIDE HÉTÉROCYCLIQUES SUBSTITUÉS UTILES COMME MODULATEURS DE TRPA1
  申请人：HOFFMANN LA ROCHE

  公开号：WO2015052264A1

  公开（公告）日：2015-04-16

  The invention is concerned with the compounds of formula I or II: and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

  本发明涉及式I或II的化合物及其盐。此外，本发明还涉及制备这些化合物的方法以及使用这些化合物的方法，以及含有这些化合物的药物组合物。这些化合物可能对治疗由TRPA1介导的疾病和状况，如疼痛，具有用途。
• [EN] 1-(HET)ARYLSULFONYL-(PYRROLIDINE OR PIPERIDINE)-2-CARBOXAMIDE DERIVATIVES AND THEIR USE AS TRPA1 ANTAGONISTS<br/>[FR] DÉRIVÉS DE 1-(HET)ARYLSULFONYLE- (PYRROLIDINE OU PIPÉRIDINE)-2-CARBOXAMIDE ET LEUR UTILISATION COMME ANTAGONISTES DE TRPA1
  申请人：HOFFMANN LA ROCHE

  公开号：WO2016128529A1

  公开（公告）日：2016-08-18

  The invention is concerned with the compounds of formula I and salts thereof and other compounds of formulas II-IX as disclosed herein. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formulas I-IX as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain or asthma.

  本发明涉及公式I的化合物及其盐，以及如本文所述的公式II-IX的其他化合物。此外，本发明还涉及制造和使用公式I-IX化合物的方法，以及含有这些化合物的药物组合物。这些化合物可能对治疗由TRPA1介导的疾病和状况，如疼痛或哮喘等有帮助。
• Exploring Electrochemical C(sp³)–H Oxidation for the Late-Stage Methylation of Complex Molecules
  作者：Luiz F. T. Novaes、Justin S. K. Ho、Kaining Mao、Kaida Liu、Mayank Tanwar、Matthew Neurock、Elisia Villemure、Jack A. Terrett、Song Lin

  DOI：10.1021/jacs.1c09412

  日期：2022.1.26

  targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C–C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the “magic methyl” effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to

  “神奇的甲基”效应，通过掺入单个甲基来显着提高生物活性化合物的效力，为药物化学家在药物发现过程中采用的简单而强大的策略提供了一种简单而强大的策略。尽管取得了重大进展，但能够对结构复杂的药物进行选择性 C(sp 3 )–H 甲基化的方法仍然非常有限。在这项工作中，我们公开了一种通过电化学氧化对受保护胺（即酰胺、氨基甲酸酯和磺酰胺）进行α-甲基化的模块化、高效和选择性策略。机理分析指导我们在经典的Shono氧化反应的基础上开发了一种改进的电化学方案，该反应具有反应范围广、官能团兼容性高、操作简单等特点。重要的是，该反应系统适合于药物活性剂中常见的含有碱性氮基团的复杂靶标的后期功能化。当与有机锌介导的 C-C 键形成相结合时，我们的方案能够实现多种胺衍生物的直接甲基化，包括那些先前已探索过的“神奇甲基”效应。因此，这种合成策略规避了目前获得此类化合物所必需的多步骤从头合成，并且有可能加速药物发现工作。
• SUBSTITUTED HETEROCYCLIC SULFONAMIDE COMPOUNDS USEFUL AS TRPA1 MODULATORS
  申请人：Genentech, Inc.

  公开号：US20160221945A1

  公开（公告）日：2016-08-04

  The invention is concerned with the compounds of formula I or II: and salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I or II as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

  本发明涉及公式I或II的化合物及其盐。此外，本发明还涉及制造和使用公式I或II化合物的方法，以及包含这些化合物的制药组合物。这些化合物可能有用于治疗由TRPA1介导的疾病和病况，如疼痛。
• SUBSTITUTED SULFONAMIDE COMPOUNDS
  申请人：Genentech, Inc.

  公开号：US20160264567A1

  公开（公告）日：2016-09-15

  The invention is concerned with the compounds of formula I: and salts thereof and other compounds of formulas II-IX as disclosed herein. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formulas I-IX as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain or asthma.

  本发明涉及以下式子的化合物：I，并且包括其盐和其他式子II-IX的化合物，如本文所述。此外，本发明涉及制造和使用式I-IX化合物的方法，以及含有这些化合物的药物组合物。这些化合物可能对治疗由TRPA1介导的疾病和状况，例如疼痛或哮喘，有用。