N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-3,3,3-trifluoro-N-methylpropanamide

• 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-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-3,3,3-trifluoro-N-methylpropanamide
• 英文别名: N-[2''-(3,4-Dimethyl-isoxazol-5-ylsulfamoyl)-4-oxazol-2-yl-biphenyl-2-ylmethyl]-3,3,3-trifluoro-N-methyl-propionamide；N-[[2-[2-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]methyl]-3,3,3-trifluoro-N-methylpropanamide
• 化学式: C₂₅H₂₃F₃N₄O₅S
• 分子量: 548.543
• InChiKey: TWNPZFARHUKPBV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  N-(3,4-dimethyl-5-isoxazolyl)-2'-formyl-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide 在 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 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 N-[[2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-3,3,3-trifluoro-N-methylpropanamide
  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.

  ##STR1##的化合物抑制内皮素的活性。符号定义如下：R.sup.1、R.sup.2、R.sup.3和R.sup.4分别直接与环碳键合，并且分别独立地为(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，其中任何一个可能被Z.sup.1、Z.sup.2和Z.sup.3取代；(c)卤素；(d)羟基；(e)氰基；(f)硝基；(g)--C(O)H或--C(O)R.sup.5；(h)--CO.sub.2 H或--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；或(k)R.sup.3和R.sup.4也可以一起是烷基或烯基，其中任何一个可能被Z.sup.1、Z.sup.2和Z.sup.3取代，与它们连接的碳原子一起形成4-至8-成员饱和、不饱和或芳香环；其余符号如规范中定义。
• [EN] SUBSTITUTED BIPHENYL ISOXAZOLE SULFONAMIDES<br/>[FR] BIPHENYL ISOXAZOLYL SULFONAMIDES, SUBSTITUES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：WO1997029748A1

  公开（公告）日：1997-08-21

  (EN) Compounds of formula (I) inhibit the activity of endothelin. The symbols are defined as follows: R1, R2, R3 and R4 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 Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) -C(O)H or -C(O)R5; (h) -CO2H or -CO2R5; (i) -Z4-NR6R7; (j) -Z4-N(R10)-Z5-NR8R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, 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.(FR) Les composés de la formule (I) inhibent l'activité de l'endothéline. Dans cette formule, chaque groupe R1, R2, R3 et R4 est lié directement à un carbone de cycle et représente, d'une manière indépendante : (a) un hydrogène; (b) un alkyle, alcényle, alcynyle, alcoxy, cycloalkyle, cycloalkyl-alkyle, cycloalcényle, cycloalcényl-alkyle, aryle, aryloxy, aralkyle ou aralcoxy, qui peuvent tous être substitués par Z1, Z2 et Z3: (c) halo; (d) hydroxyle; (e) cyano; (f) nitro; (g) -C(O)H ou -C(O)R5; (h) -CO2H ou -CO2R5; (i) -Z4-NR6R7; (j) -Z4-N(R10)-Z5-NR8R9; ou (k) R3 et R4 peuvent former ensemble un alkylène ou un alcénylène (éventuellement substitués par Z1, Z2 et Z3) formant avec les atomes de carbone auxquels il est fixé, un cycle à 4 - 8 éléments, saturé, insaturé ou aromatique. La signification des autres symboles est donnée dans la description.

  化合物式（I）的化合物能够抑制内皮素的活性。符号定义如下：R1、R2、R3和R4都直接结合在环碳上，且分别独立地表示：（a）氢；（b）烷基，烯基，炔基，氧烷基，环烷基，环烷基烷基，环烯基，环烯基烷基，芳基，芳氧基，芳基烷基或芳氧基烷基，其中任何一种都可以用Z1、Z2和Z3取代；（c）卤素；（d）羟基；（e）氰基；（f）硝基；（g）-C（O）H或-C（O）R5；（h）-CO2H或-CO2R5；（i）-Z4-NR6R7；（j）-Z4-N（R10）-Z5-NR8R9；或（k）R3和R4也可以相互结合成为烷基或烯基，其中任何一种都可以用Z1、Z2和Z3取代，与它们附着的碳原子一起形成4-8元饱和、不饱和或芳香环；其余符号如说明书所定义。
• EP0921800A4
  申请人：——

  公开号：EP0921800A4

  公开（公告）日：2000-12-06
• SUBSTITUTED BIPHENYL ISOXAZOLE SULFONAMIDES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0921800B1

  公开（公告）日：2004-04-14
• 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.