3-{[N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxymethyl)amino]sulfonyl}-2-thiophenecarbonyl chloride | 205517-09-5

• 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: 3-{[N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxymethyl)amino]sulfonyl}-2-thiophenecarbonyl chloride
• 英文别名: N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonyl chloride；3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)-(methoxymethyl)sulfamoyl]thiophene-2-carbonyl chloride
• CAS: 205517-09-5
• 化学式: C₁₁H₁₀Cl₂N₂O₅S₂
• 分子量: 385.249
• InChiKey: CCEHEBCKDFZKIY-UHFFFAOYSA-N

物化性质

• 沸点：
  557.4±60.0 °C(Predicted)
• 密度：
  1.604±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  126
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-{[N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxymethyl)amino]sulfonyl}-2-thiophenecarbonyl chloride 在 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 2.75h， 生成 ethyl N-[(3-{[N'-(4-chloro-3-methyl-5-isoxazolyl)-N'-(methoxymethyl)amino]sulfonyl}-2-thienyl)carbonyl]-N-(3-acetoxy-2,4,6-trimethylphenyl)carbamate
  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：

  3-{[(4-氯-3-甲基-5-异噁唑)氨基]磺酰基}-2-噻吩羧酸甲酯 在 吡啶 、 sodium hydroxide 、 草酰氯 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 氯仿 为溶剂， 反应 26.0h， 生成 3-{[N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxymethyl)amino]sulfonyl}-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
• 作为试剂：
  描述：

  N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid 以 3-{[N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxymethyl)amino]sulfonyl}-2-thiophenecarbonyl chloride 为溶剂， 生成 3-{[N-(4-chloro-3-methylisoxazol-5-yl)(methoxymethyl)amino]sulfonyl}-5-methylthiophene-2-carbonyl chloride
  参考文献：
  名称：

  Sulfonamides for treatment of endothelin-mediated disorders

  摘要：

  提供了噻唑磺胺及其药用可接受衍生物、药物组合物、制造物品、组合物、冻干粉剂以及使用这些配方和磺胺类药物治疗内皮素疾病的方法。提供了一种制备疏水性磺胺类化合物的碱金属盐的过程。该过程包括将游离磺胺类化合物溶解在有机溶剂中，在饱和的碱金属盐溶液存在下，并从有机相中回收形成的磺胺类盐的步骤。

  公开号：

  US20020091270A1

文献信息

• [EN] SULFONAMIDES FOR TREATMENT OF ENDOTHELIN-MEDIATED DISORDERS<br/>[FR] SULFAMIDES POUR LE TRAITEMENT DES TROUBLES INDUITS PAR L'ENDOTHELINE
  申请人：TEXAS BIOTECHNOLOGY CORPORATION

  公开号：WO1998049162A1

  公开（公告）日：1998-11-05

  (EN) Thienyl-, furyl- and pyrrolyl-sulfonamides, pharmaceutically-acceptable salts of sulfonamides, formulations of salts and the sulfonamides, and methods for modulating or altering the activity of the endothelin family of peptides using the formulations and sulfonamides are provided. In particular, formulations of sodium salts of N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolylsulfonamides are provided. A process of preparing an alkali metal salt of a hydrophobic sulfonamide is provided. The process includes the step of dissolving a free sulfonamide in an organic solvent in the presence of a saturated alkali metal salt solution and recovering the formed sulfonamide salt from the organic phase.(FR) L'invention concerne des thiényl-, furyl- et pyrolylsulfamides, des sels pharmaceutiquement acceptables de sulfamides, des formulations de sels et des sulfamides, ainsi que des procédés visant à moduler ou altérer l'activité des peptides appartenant à la famille de l'endothéline au moyen des formulations et des sulfamides en question. En particulier, l'invention concerne des formulations de sels de sodium de N-(isoxazolyl)thiénylsulfamides, N-(isoxazolyl)furylsulfamides, et N-(isoxazolyl)pyrolylsulfamides. L'invention concerne aussi un procédé d'élaboration de sel de métal alcalin à partir d'un sulfamide hydrophobe. Ce procédé consiste à dissoudre un sulfamide libre dans un solvant organique, en présence d'un soluté salin de métal alcalin saturé, et à extraire de la phase organique le sel de sulfamide ainsi formé.

  提供了苯并噻唑基、呋喃基和吡咯基磺酰胺，磺酰胺的药用可接受盐，盐和磺酰胺的制剂，以及使用这些制剂和磺酰胺来调节或改变内皮素家族肽的活性的方法。特别提供了N-(异噁唑基)苯并噻唑磺酰胺、N-(异噁唑基)呋喃磺酰胺和N-(异噁唑基)吡咯磺酰胺的钠盐制剂。提供了一种制备疏水性磺酰胺的碱金属盐的方法。该方法包括在有饱和碱金属盐溶液存在的有机溶剂中溶解自由磺酰胺，并从有机相中回收形成的磺酰胺盐。
• Process for preparing alkali metal salts of hydrophobic sulfonamides
  申请人：ENCYSIVE PHARMACEUTICALS INC.

  公开号：EP1498419A1

  公开（公告）日：2005-01-19

  Thienyl-, furyl- and pyrrolyl-sulfonamides, pharmaceutically-acceptable salts of sulfonamides, formulations of salts and the sulfonamides, and methods of altering the activity of the endothelin family of peptides using the formulations and sulfonamides are provided. In particular, formulations of sodium salts of N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides and N-(isoxazolyl)pyrrolysulfonamides are provided. A process of preparing an alkali metal salt of a hydrophobic sulfonamide is provided. The process includes the step of dissolving a free sulfonamide in an organic solvent in the presence of a saturated alkali metal salt solution and recovering the formed sulfonamide salt from the organic plant.

  本发明提供了噻吩基、呋喃基和吡咯基磺酰胺类化合物、磺酰胺类化合物的药学上可接受的盐、盐和磺酰胺类化合物的制剂，以及使用这些制剂和磺酰胺类化合物改变内皮素族肽活性的方法。特别是提供了 N-(异恶唑基)噻吩基磺酰胺、N-(异恶唑基)呋喃基磺酰胺和 N-(异恶唑基)吡咯基磺酰胺的钠盐制剂。提供了一种制备疏水磺酰胺碱金属盐的工艺。该工艺包括在有饱和碱金属盐溶液存在的情况下，将游离磺酰胺溶解在有机溶剂中，并从有机植物中回收形成的磺酰胺盐。
• Discovery, Modeling, and Human Pharmacokinetics of <i>N</i>-(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
  作者：Chengde Wu、E. Radford Decker、Natalie Blok、Huong Bui、Tony J. You、Junmei Wang、Andree R. Bourgoyne、Vippra Knowles、Kurt L. Berens、George W. Holland、Tommy A. Brock、Richard A. F. Dixon

  DOI：10.1021/jm030528p

  日期：2004.4.1

  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%).
• SULFONAMIDES FOR TREATMENT OF ENDOTHELIN-MEDIATED DISORDERS
  申请人：ENCYSIVE PHARMACEUTICALS INC.

  公开号：EP0980369B1

  公开（公告）日：2005-03-30
• US6432994B1
  申请人：——

  公开号：US6432994B1

  公开（公告）日：2002-08-13