N-(4,5-Dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide | 210891-12-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(4,5-Dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide
• 英文别名: N-(4,5-dimethyl-3-oxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide；N-(4,5-dimethyl-1,2-oxazol-3-yl)-2-[2-formyl-4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide
• CAS: 210891-12-6
• 化学式: C₂₁H₁₇N₃O₅S
• 分子量: 423.449
• InChiKey: DZDZLHPZRHZBTJ-UHFFFAOYSA-N

物化性质

• 沸点：
  668.7±65.0 °C(Predicted)
• 密度：
  1.386±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-(4,5-Dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide 在 sodium acetate 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 6.17h， 生成 N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide
  参考文献：
  名称：

  Biphenylsulfonamide Endothelin Receptor Antagonists. 4. Discovery of N-[[2‘-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1‘-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), A Highly Potent and Orally Active ET_A Selective Antagonist

  摘要：

  We have previously disclosed the selective ETA receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ETA receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent lleading to 16a (BMS-207940). Compound 16a is an extremely potent (ETAKi = 10 pM) and selective (80000-fold for ETA vs ETB) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 mumol/kg, 16a displays enhanced duration relative to 1.

  DOI：

  10.1021/jm020289q
• 作为产物：
  描述：

  2-溴苯磺酰氯 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 正丁基锂 、 sodium hydride 、 sodium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 、 正戊烷 为溶剂， 反应 10.17h， 生成 N-(4,5-Dimethyl-3-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide
  参考文献：
  名称：

  Biphenylsulfonamide Endothelin Receptor Antagonists. 4. Discovery of N-[[2‘-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1‘-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), A Highly Potent and Orally Active ET_A Selective Antagonist

  摘要：

  We have previously disclosed the selective ETA receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ETA receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent lleading to 16a (BMS-207940). Compound 16a is an extremely potent (ETAKi = 10 pM) and selective (80000-fold for ETA vs ETB) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 mumol/kg, 16a displays enhanced duration relative to 1.

  DOI：

  10.1021/jm020289q

文献信息

• Methods for the preparation of biphenyl isoxazole sulfonamides
  申请人：——

  公开号：US20020132838A1

  公开（公告）日：2002-09-19

  Methods for the preparation of biphenyl isoxazole sulfonamides and intermediates thereof. The present invention also relates to the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.

  本发明涉及制备联苯基异噁唑磺酰胺及其中间体的方法。本发明还涉及通过这些方法制备的新中间体。本发明所制备的联苯基异噁唑磺酰胺是内皮素拮抗剂，可用于治疗高血压等病症。
• [EN] ENDOTHELIN ANTAGONISTS: N-[[2'-[ [(4,5-DIMETHYL-3-ISOXAZOLYL) AMINO]SULFONYL]-4-(2-OXAZOLYL) [1,1'-BIPHENYL]-2-YL]METHYL] -N,3,3-TRIMETHYLBUTANAMIDE AND N-(4,5-DIMETHYL-3-ISOXAZOLYL) -2'-[(3,3-DIMETHYL-2-OXO-1-PYRROLIDINYL) METHYL] -4'-(2-OXAZOLYL)[1,1'-BIPHENYL]-2-SULFONAMIDE AND SALTS THEREOF<br/>[FR] ANTAGONISTES DE L'ENDOTHELINE: N-[[2'-[[4,5-DIMETHYL-3-ISOXAZOLYL)AMINO]SULFONYL]-4-(2-OXAZOLYL)[1,1'-BIPHENYL]-2-YL]METHYL]-N,3,3-TRIMETHYLBUTANAMIDE ET N-(4,5-DIMETHYL-3-ISOXAZOLYL)-2'-[3,3-DIMETHYL-2-OXO-1-PYRROLIDINYL)METHYL]-4'-(2-OXAZOLYL)[1,1'-BIPHENYL]-2-SULFONAMIDE ET LEURS SELS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：WO1998033780A1

  公开（公告）日：1998-08-06

  (EN) The compounds N-[[2'-[ [(4,5-dimethyl-3-isoxazolyl) amino]sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl]methyl]-N, 3,3-trimethylbutanamide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[ (3,3-dimethyl-2-oxo-1-pyrrolidinyl) methyl]-4'-(2-oxazolyl) [1,1'-biphenyl]-2-sulfonamide, and salts thereof, useful as endothelin antagonists.(FR) Les composés N-[[2'-[[4,5-diméthyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphényl]-2-yl]méthyl]-N,3,3-triméthylbutanamide et N-(4,5-diméthyl-3-isoxazolyl)-2'-[3,3-diméthyl-2-oxo-1-pyrrolidinyl)méthyl]-4'-(2-oxazolyl)[1,1'-biphényl]-2-sulfonamide, et leurs sels, sont utiles comme antagonistes de l'endothéline.

  这些化合物是N-[[2'-[[(4,5-二甲基-3-异噁唑基)氨基]磺酰]-4-(2-噁唑基)[1,1'-联苯基]-2-基]甲基]-N,3,3-三甲基丁酰胺和N-(4,5-二甲基-3-异噁唑基)-2'-[(3,3-二甲基-2-氧代-1-吡咯烷基)甲基]-4'-(2-噁唑基)[1,1'-联苯基]-2-磺酰胺，及其盐，可用作内皮素拮抗剂。
• ENDOTHELIN ANTAGONISTS: N- 2'- (4,5-DIMETHYL-3-ISOXAZOLYL) AMINO]SULFONYL]-4-(2-OXAZOLYL) 1,1'-BIPHENYL]-2-YL]METHYL] -N,3,3-TRIMETHYLBUTANAMIDE AND N-(4,5-DIMETHYL-3-ISOXAZOLYL) -2'- (3,3-DIMETHYL-2-OXO-1-PYRROLIDINYL) METHYL] -4'-(2-OXAZOLYL) 1,1'-BIPHENYL]-2-SULFONAMIDE AND SALTS THEREOF
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0996618B1

  公开（公告）日：2003-11-12
• J. Med. Chem. 2003, 46, 125-137
  作者：

  DOI：——

  日期：——
• EP0996618A4
  申请人：——

  公开号：EP0996618A4

  公开（公告）日：2000-05-03