3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-5-methyl-2-thiophenecarboxylic acid | 446063-94-1

• 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-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-5-methyl-2-thiophenecarboxylic acid
• 英文别名: N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylic acid；3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]-5-methylthiophene-2-carboxylic acid
• CAS: 446063-94-1
• 化学式: C₁₀H₉ClN₂O₅S₂
• 分子量: 336.777
• InChiKey: WVNWTMVCRHCBCA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  146
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-5-methyl-2-thiophenecarboxylic acid 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 7.0h， 生成 3-{[N-(4-chloro-3-methylisoxazol-5-yl)(methoxymethyl)amino]sulfonyl}-5-methylthiophene-2-carbonyl chloride
  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
• 作为产物：
  描述：

  methoxymethyl N-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylate 在 sodium hydroxide 作用下， 生成 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-5-methyl-2-thiophenecarboxylic acid
  参考文献：
  名称：

  Sulfonamides for treatment of endothelin-mediated disorders

  摘要：

  提供了噻吩基、呋喃基和吡咯基磺胺类化合物，磺胺类化合物的药用盐，盐和磺胺类化合物的配方，以及使用这些配方和磺胺类化合物调节或改变内皮素家族肽的活性的方法。具体提供了N-(异噁唑基)噻吩磺胺类化合物、N-(异噁唑基)呋喃磺胺类化合物和N-(异噁唑基)吡咯磺胺类化合物的配方。提供了一种制备疏水性磺胺类化合物的碱金属盐的方法。该方法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。

  公开号：

  US06432994B1

文献信息

• SELECTIVE ALKYLATION/ACYLATION OF DI- OR TRIANIONS: EXPEDITIOUS DERIVATIZATION OF ENDOTHELIN ANTAGONISTS[1]
  作者：Chengde Wu、Natalie Blok、Wen Li、George W. Holland

  DOI：10.1081/scc-120004154

  日期：2002.1

  sodium (1, TBC11251Na) is an ETA selective endothelin antagonist under clinical development for pulmonary arterial hypertension and congestive heart failure. Second generation compounds, as exemplified by TBC2576 (2) are currently under development in our laboratories. To rapidly access analogs of 1 and 2, a route was developed for the selective alkylation or acylation of the corresponding di- or trianions

  摘要 SiTAxsenTAn sodium (1, TBC11251Na) 是一种 ETA 选择性内皮素拮抗剂，正在临床开发用于治疗肺动脉高压和充血性心力衰竭。我们的实验室目前正在开发第二代化合物，如 TBC2576 (2) 所示。为了快速获得 1 和 2 的类似物，开发了一条路线，用于选择性烷基化或酰化源自这两种高度官能化化合物的相应二阴离子或三阴离子。我们在此报告了这种简单而有效的程序，该程序包括用过量的亲电试剂处理双阴离子或三阴离子，然后快速淬灭。以这种方式，以令人满意的收率实现了 1 和 2 的选择性烷基化或酰化。
• [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。
• 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