N-(2-乙酰基-4,6-二甲基苯基)-3-[[(3,4-二甲基-5-异恶唑基)氨基]磺酰基]-2-噻吩甲酰胺 | 349453-49-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-(2-乙酰基-4,6-二甲基苯基)-3-[[(3,4-二甲基-5-异恶唑基)氨基]磺酰基]-2-噻吩甲酰胺
• 英文名称: N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide
• 英文别名: TBC 3711；N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl)-amino]sulfonyl}-2-thiophene-carboxamide；N-(2-acetyl-4,6-dimethylphenyl)-3-(((3,4-dimethyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide；N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide；N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyI)amino]sulfonyI}-2-thiophenecarboxamide；N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)-thiophene-2-carboxamide；N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide；N-(2-acetyl-4,6-dimethylphenyl)-3-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxamide
• CAS: 349453-49-2
• 化学式: C₂₀H₂₁N₃O₅S₂
• 分子量: 447.536
• InChiKey: IAYNHDZSSDUYHY-UHFFFAOYSA-N

物化性质

• 密度：
  1.400
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  155
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarbonyl chloride 在 盐酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.0h， 生成 N-(2-乙酰基-4,6-二甲基苯基)-3-[[(3,4-二甲基-5-异恶唑基)氨基]磺酰基]-2-噻吩甲酰胺
  参考文献：
  名称：

  Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist

  摘要：

  Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (similar to100%) in rats, high potency (ETA IC50 = 0.08 nM), and optimal ETA/ETB selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).

  DOI：

  10.1021/jm030528p

文献信息

• SUBSTITUTED THIOPHENES
  申请人：Gant Thomas G.

  公开号：US20080255036A1

  公开（公告）日：2008-10-16

  Disclosed herein are substituted pyrimidine-based endothelin modulators of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

  本文揭示了一种基于嘧啶的Formula I内皮素调节剂的替代物，其制备方法，药物组合物以及使用方法。
• [EN] MODULATING FERROPTOSIS AND TREATING EXCITOTOXIC DISORDERS<br/>[FR] MODULATION DE LA FERROPTOSE ET TRAITEMENT DES TROUBLES EXCITOTOXIQUES
  申请人：UNIV COLUMBIA

  公开号：WO2015084749A1

  公开（公告）日：2015-06-11

  The present invention provides, inter alia, a compound having the structure of Formula (I). Also provided are compositions containing a pharmaceutically acceptable carrier and a compound according to the present invention. Further provided are methods for treating or ameliorating the effects of an excitotoxic disorder in a subject, methods of modulating ferroptosis in a subject, methods of reducing reactive oxygen species (ROS) in a cell, and methods for treating or ameliorating the effects of a neurodegenerative disease.

  本发明提供了一种具有式（I）结构的化合物。还提供了含有药用载体和根据本发明的化合物的组合物。此外还提供了用于治疗或改善受体内兴奋毒性障碍影响的方法，用于调节受体内铁死亡的方法，用于减少细胞内活性氧化物种（ROS）的方法，以及用于治疗或改善神经退行性疾病影响的方法。
• [EN] COMPOUNDS, COMPOSITIONS, AND METHODS FOR MODULATING FERROPTOSIS AND TREATING EXCITOTOXIC DISORDERS<br/>[FR] COMPOSÉS, COMPOSITIONS ET MÉTHODES DE MODULATION DE LA FERROPTOSE ET DE TRAITEMENT DE TROUBLES EXCITOTOXIQUES
  申请人：UNIV COLUMBIA

  公开号：WO2020113028A1

  公开（公告）日：2020-06-04

  The present disclosure provides, inter alia, a compound having the structure (1). Also provided are compositions containing a pharmaceutically acceptable carrier and one or more compounds according to the present disclosure. Further provided are methods for treating or ameliorating the effects of an excitotoxic disorder in a subject, methods of modulating ferroptosis in a subject, methods of reducing reactive oxygen species (ROS) in a cell, methods for treating or ameliorating the effects of a neurodegenerative disease, methods for alleviating side effects in a subject undergoing radiotherapy and/or immunotherapy, and methods for treating or ameliorating the effects of an infection associated with ferroptosis in a subject.

  本公开提供一种具有结构（1）的化合物。还提供了含有药用可接受载体和根据本公开披露的一个或多个化合物的组合物。此外，还提供了治疗或改善受体内兴奋毒性紊乱影响的方法，调节受体内铁死亡的方法，减少细胞内活性氧（ROS）的方法，治疗或改善神经退行性疾病影响的方法，缓解正在接受放射治疗和/或免疫治疗的受体的副作用的方法，以及治疗或改善与受体内铁死亡相关的感染影响的方法。
• Sulfonamides and derivatives thereof that modulate the activity of endothelin
  申请人：Texas Biotechnology Corporation

  公开号：US20010056183A1

  公开（公告）日：2001-12-27

  Thienyl-, furyl-, pyrrolyl- and phenylsulfonamides, formulations of pharmaceutically-acceptable derivatives thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides, N-(isoxazolyl)pyrrolylsulfonamides and N-(isoxazolyl)phenylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or pharmaceutically acceptable derivatives thereof that inhibit the activity of endothelin are also provided.

  提供了噻吩基、呋喃基、吡咯基和苯基磺酰胺，以及其药学上可接受的衍生物的配方和调节或改变内皮素家族肽活性的方法。具体而言，提供了N-(异噁唑基)噻吩基磺酰胺、N-(异噁唑基)呋喃基磺酰胺、N-(异噁唑基)吡咯基磺酰胺和N-(异噁唑基)苯基磺酰胺，以及这些磺酰胺的配方和使用这些磺酰胺通过与受体接触来抑制内皮素肽与内皮素受体的结合的方法。还提供了通过给予这些磺酰胺或药学上可接受的抑制内皮素活性的衍生物的有效量来治疗内皮素介导的疾病的方法。
• Processes for the preparation of N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide
  申请人：Encysive Pharmaceuticals, Inc.

  公开号：US07754892B2

  公开（公告）日：2010-07-13

  Provided are processes for the preparation of N-(2-acetyl-4,6-dimethylphenyl)-3-[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide, a compound useful for the treatment of endothelin-mediated disorders.

  提供了制备N-(2-乙酰基-4,6-二甲基苯基)-3-[(3,4-二甲基-5-异噁唑基)氨基]磺酰}-2-噻吩羧酰胺的过程，该化合物可用于治疗内皮素介导的疾病。