N-(3,4-dimethyl-1,2-oxazol-5-yl)-N-(2-methoxyethoxymethyl)-2-[2-[[2-(methylamino)ethylamino]methyl]-4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide | 195447-68-8

• 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-(3,4-dimethyl-1,2-oxazol-5-yl)-N-(2-methoxyethoxymethyl)-2-[2-[[2-(methylamino)ethylamino]methyl]-4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide
• CAS: 195447-68-8
• 化学式: C₂₈H₃₅N₅O₆S
• 分子量: 569.682
• InChiKey: VYYYJXPKBMQEGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  40
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  140
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  N-(3,4-dimethyl-1,2-oxazol-5-yl)-N-(2-methoxyethoxymethyl)-2-[2-[[2-(methylamino)ethylamino]methyl]-4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide 在 盐酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 45.0h， 生成 N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[(2-oxo-3-methyl-1-imidazolidinyl)methyl][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'-(bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide 在 3 A molecular sieve 、 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 12.17h， 生成 N-(3,4-dimethyl-1,2-oxazol-5-yl)-N-(2-methoxyethoxymethyl)-2-[2-[[2-(methylamino)ethylamino]methyl]-4-(1,3-oxazol-2-yl)phenyl]benzenesulfonamide
  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

• SUBSTITUTED BIPHENYL ISOXAZOLE SULFONAMIDES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0921800B1

  公开（公告）日：2004-04-14