N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-piperidinyl)methyl]-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide | 195447-46-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-piperidinyl)methyl]-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide
• 英文别名: N-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[2-[(3,3-dimethyl-2-oxopiperidin-1-yl)methyl]-4-(1,3-oxazol-2-yl)phenyl]-N-(2-methoxyethoxymethyl)benzenesulfonamide
• CAS: 195447-46-2
• 化学式: C₃₂H₃₈N₄O₇S
• 分子量: 622.742
• InChiKey: HPTPEJUGKXGBEA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  44
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  137
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-piperidinyl)methyl]-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide 在 三甲基氯硅烷 、 sodium iodide 作用下， 以 乙腈 为溶剂， 反应 3.0h， 生成 N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-piperidinyl)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：

  N-(3,4-Dimethyl-5-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide 在 sodium tetrahydroborate 、 四溴化碳 、 sodium hydride 、 三苯基膦 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 N-(3,4-Dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-piperidinyl)methyl]-N-[(2-methoxyethoxy)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

文献信息

• Substituted biphenyl isoxazole sulfonamides
  申请人：Bristol-Myers Squibb Co.

  公开号：US05846990A1

  公开（公告）日：1998-12-08

  Compounds of the formula ##STR1## inhibit the activity of endothelin. The symbols are defined as follows: R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3 ; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) --C(O)H or --C(O)R.sup.5 ; (h) --CO.sub.2 H or --CO.sub.2 R.sup.5 ; (i) --Z.sup.4 --NR.sup.6 R.sup.7 ; (j) --Z.sup.4 --N(R.sup.10)--Z.sup.5 --NR.sup.8 R.sup.9 ; or (k) R.sup.3 and R.sup.4 together may also be alkylene or alkenylene, either of which may be substituted with Z.sup.1, Z.sup.2 and Z.sup.3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; and the remaining symbols are as defined in the specification.

  式子##STR1##的化合物能够抑制内皮素的活性。其中符号的定义如下：R.sup.1，R.sup.2，R.sup.3和R.sup.4直接连接在环状碳上，分别独立地表示：(a) 氢；(b) 烷基，烯基，炔基，烷氧基，环烷基，环烷基烷基，环烯基，环烯基烷基，芳基，芳氧基，芳基烷基或芳基烷氧基，其中任意一种可能用Z.sup.1，Z.sup.2和Z.sup.3替代；(c) 卤素；(d) 羟基；(e) 腈基；(f) 硝基；(g) --C(O)H或--C(O)R.sup.5；(h) --CO.sub.2H或--CO.sub.2R.sup.5；(i) --Z.sup.4--NR.sup.6R.sup.7；(j) --Z.sup.4--N(R.sup.10)--Z.sup.5--NR.sup.8R.sup.9；或(k) R.sup.3和R.sup.4也可以是烷基或烯基，其中任意一种可能用Z.sup.1，Z.sup.2和Z.sup.3替代，与它们连接的碳原子一起完成一个4-到8元饱和，不饱和或芳香环。其余符号如说明书中所定义。
• SUBSTITUTED BIPHENYL ISOXAZOLE SULFONAMIDES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0921800B1

  公开（公告）日：2004-04-14
• US5846990A
  申请人：——

  公开号：US5846990A

  公开（公告）日：1998-12-08
• Biphenylsulfonamide Endothelin Receptor Antagonists. 4. Discovery of <i>N</i>-[[2‘-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1‘-biphenyl]- 2-yl]methyl]-<i>N</i>,3,3-trimethylbutanamide (BMS-207940), A Highly Potent and Orally Active ET_A Selective Antagonist
  作者：Natesan Murugesan、Zhengxiang Gu、Steven Spergel、Marian Young、Ping Chen、Arvind Mathur、Leslie Leith、Mark Hermsmeier、Eddie C.-K. Liu、Rongan Zhang、Eileen Bird、Tom Waldron、Anthony Marino、Barry Koplowitz、W. Griffith Humphreys、Saeho Chong、Richard A. Morrison、Maria L. Webb、Suzanne Moreland、Nick Trippodo、Joel C. Barrish

  DOI：10.1021/jm020289q

  日期：2003.1.1

  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.