5-[N-methoxymethyl-(2-carbomethoxythienyl-3-sulfonyl)amino]-3,4-dimethylisoxazole | 205517-14-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 5-[N-methoxymethyl-(2-carbomethoxythienyl-3-sulfonyl)amino]-3,4-dimethylisoxazole
• 英文别名: Methyl 3-[(3,4-dimethyl-1,2-oxazol-5-yl)-(methoxymethyl)sulfamoyl]thiophene-2-carboxylate
• CAS: 205517-14-2
• 化学式: C₁₃H₁₆N₂O₆S₂
• 分子量: 360.412
• InChiKey: TXNCGAMKKXBESY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  136
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5-[N-methoxymethyl-(2-carbomethoxythienyl-3-sulfonyl)amino]-3,4-dimethylisoxazole 在 吡啶 、 sodium hydroxide 、 草酰氯 作用下， 以 四氢呋喃 、 二氯甲烷 、 氯仿 为溶剂， 反应 18.0h， 生成 3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarbonyl chloride
  参考文献：
  名称：

  Endothelin Antagonists:  Substituted Mesitylcarboxamides with High Potency and Selectivity for ET_A Receptors

  摘要：

  We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ETA-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz ct al. Circulation 1998, 98, Abstr. #3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation. 1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ETA selectivity by similar to 10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has similar to 10-fold higher ETA binding affinity than 1, high ETA/ETB selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.

  DOI：

  10.1021/jm9900063
• 作为产物：
  描述：

  溴甲基甲基醚 、 N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 8.0h， 生成 5-[N-methoxymethyl-(2-carbomethoxythienyl-3-sulfonyl)amino]-3,4-dimethylisoxazole
  参考文献：
  名称：

  Endothelin Antagonists:  Substituted Mesitylcarboxamides with High Potency and Selectivity for ET_A Receptors

  摘要：

  We have previously disclosed the discovery of 2,4-disubstituted anilinothiophenesulfonamides with potent ETA-selective endothelin receptor antagonism and the subsequent identification of sitaxsentan (TBC11251, 1) as a clinical development compound (Wu et al. J. Med. Chem. 1997, 40, 1682 and 1690). The orally active 1 has demonstrated efficacy in a phase II clinical trial of congestive heart failure (Givertz ct al. Circulation 1998, 98, Abstr. #3044) and was active in rat models of myocardial infarction (Podesser et al. Circulation. 1998, 98, Abstr. #2896) and acute hypoxia-induced pulmonary hypertension (Chen et al. FASEB J. 1996, 10 (3), A104). We now report that an additional substituent at the 6-position of the anilino ring further increases the potency of this series of compounds. It was also found that a wide range of functionalities at the 3-position of the 2,4,6-trisubstituted ring increased ETA selectivity by similar to 10-fold while maintaining in vitro potency, therefore rendering the compounds amenable to fine-tuning of pharmacological and toxicological profiles with enhanced selectivity. The optimal compound in this series was found to be TBC2576 (7u), which has similar to 10-fold higher ETA binding affinity than 1, high ETA/ETB selectivity, and a serum half-life of 7.3 h in rats, as well as in vivo activity.

  DOI：

  10.1021/jm9900063

文献信息

• N-heteroaryl aryl-substituted thienyl-furyl-and pyrrolyl-sulfonamides and derviatives thereof that modulate the activity of endothelin
  申请人：Texas Biotechnology Corporation

  公开号：US06420567B1

  公开（公告）日：2002-07-16

  Thienyl-, furyl- and pyrrolyl-sulfonamides, formulations of pharmaceutically-acceptable salts 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 and N-(isoxazolyl)pyrrolylsulfonamides, 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 prodrugs thereof that inhibit the activity of endothelin are also provided.

  噻吩基、呋喃基和吡咯基磺酰胺，以及它们的药物可接受盐的配方，以及调节或改变内皮素肽家族活性的方法。特别是，提供N-(异恶唑基)噻吩磺酰胺、N-(异恶唑基)呋喃磺酰胺和N-(异恶唑基)吡咯磺酰胺，它们的配方以及使用这些磺酰胺通过将受体与磺酰胺接触来抑制内皮素肽与内皮素受体结合的方法。还提供了通过给予有效量的一个或多个这些磺酰胺或抑制内皮素活性的前药来治疗内皮素介导的疾病的方法。
• 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。
• FORMULATIONS OF N-(2-ACETYL-4,6-DIMETHYLPHENYL)-3--2-THIOPHENECARBOXAMIDE
  申请人：Chen Jinling

  公开号：US20080317858A1

  公开（公告）日：2008-12-25

  Provided herein are intravenous and oral formulations of N-(2-acetyl-4,6-dimethylphenyl)-3-[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide. Also provided are methods of making and using the formulations.

  本文提供了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-噻吩羧酰胺的静脉和口服制剂。同时提供了制备和使用这些制剂的方法。
• SUBSTITUTED DEUTERIUM ENRICHED THIOPHENES FOR THE TREATMENT OF HYPERTENSION
  申请人：Auspex Pharmaceuticals, Inc.

  公开号：EP2144903A1

  公开（公告）日：2010-01-20
• US7863308B2
  申请人：——

  公开号：US7863308B2

  公开（公告）日：2011-01-04