4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)-methyl][1,1'-biphenyl]-2-sulfonamide | 176961-30-1

• 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: 4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)-methyl][1,1'-biphenyl]-2-sulfonamide
• 英文别名: N-(3,4-dimethyl-5-isoxazolyl)-4'-bromomethyl-N-methoxyethoxymethyl-[1,1'-biphenyl]-2-sulfonamide；4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl] [1,1'-biphenyl]-2-sulfonamide；4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl][1,1'-biphenyl]-2-sulfonamide；4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl][1.1'-biphenyl]-2-sulfonamide；2-[4-(bromomethyl)phenyl]-N-(3,4-dimethyl-1,2-oxazol-5-yl)-N-(2-methoxyethoxymethyl)benzenesulfonamide
• CAS: 176961-30-1
• 化学式: C₂₂H₂₅BrN₂O₅S
• 分子量: 509.421
• InChiKey: PPWOJSFDJSQPSC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  90.2
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)-methyl][1,1'-biphenyl]-2-sulfonamide 在 盐酸 、 氢氧化钾 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 4'-[(5-Carboxy-2-n-propyl-4-ethylimidazol-1-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-[1,1'-biphenyl]-2-sulfonamide
  参考文献：
  名称：

  Discovery of 4′-[(Imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/Angiotensin II receptor antagonists

  摘要：

  A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ETA receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension. (C) 2603 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00018-0
• 作为产物：
  描述：

  2-溴苯磺酰氯 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 四(三苯基膦)钯 、 正丁基锂 、 四溴化碳 、 sodium carbonate 、 potassium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 32.25h， 生成 4'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)-methyl][1,1'-biphenyl]-2-sulfonamide
  参考文献：
  名称：

  Discovery of 4′-[(Imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/Angiotensin II receptor antagonists

  摘要：

  A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ETA receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension. (C) 2603 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00018-0

文献信息

• Discovery of <i>N</i>-Isoxazolyl Biphenylsulfonamides as Potent Dual Angiotensin II and Endothelin A Receptor Antagonists
  作者：Natesan Murugesan、John E. Tellew、Zhengxiang Gu、Bridgette L. Kunst、Leena Fadnis、Lyndon A. Cornelius、Rose Ann F. Baska、Yifan Yang、Sophie M. Beyer、Hossain Monshizadegan、Kenneth E. Dickinson、Balkrushna Panchal、Maria T. Valentine、Saeho Chong、Richard A. Morrison、Kenneth E. Carlson、James R. Powell、Suzanne Moreland、Joel C. Barrish、Mark C. Kowala、John E. Macor

  DOI：10.1021/jm020138n

  日期：2002.8.1

  both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension

  ET（A）受体拮抗剂（2）（N-（3,4-二甲基-5-异恶唑基）-4'-（2-恶唑基）-[1,1'-联苯] -2-磺酰胺，BMS-193884 ）与大量的AT（1）受体拮抗剂（包括厄贝沙坦（3））具有相同的联苯核心。因此，假设将2的结构元素与联苯AT（1）拮抗剂（例如厄贝沙坦）的结构元素合并将产生对两种受体均具有双重活性的化合物。这种策略导致设计，合成和发现（15）（4'-[（2-butyl-4-oxo-1,3-diazaspiro [4.4] non-1-en-3-yl）methyl]- N-（3,4-二甲基-5-异恶唑基）-2'-[（3,3-二甲基-2-氧代-1-吡咯烷基）甲基]-[1,1'-联苯] -2-磺酰胺，BMS -248360）作为AT（1）和ET（A）受体的有效和口服活性双重拮抗剂。化合物15代表了一种治疗高血压的新方法。
• N-Isoxazolyl-biphenylsulfonamide derivatives, their preparation and their use as endothelin antagonists
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0768305A1

  公开（公告）日：1997-04-16

  A compound of the formula I an enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein: one of X and Y is N and the other is O; R2,R3,R4 and R5 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)R6; (h) -CO2H or -CO2R6; (i) -SH, -S(O)nR6, -S(O)m-OH, -S(O)m-OR6, -O-S(O)m-R6, -O-S(O)mOH or -O-S(O)m-OR6; (j) -Z4-NR7R8; or (k) -Z4-N(R11)-Z5-NR9R10; R4 and R5 together are 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; G1 is (a) hydrogen; or (b) alkyl; G2 is (a) hydroxyalkyl; (b) -(CH2)mOR6; or (c) -(CH2)m-NR12R13; (d) mono- to hexa-halo substituted alkyl; or (e) -(CH2)nOR14; and the remaining symbols are as defined in the description. The compounds of formula I are antagonists of ET-1, ET-2 and /or ET-3 and are useful in treatment of conditions associated with increased ET levels (e.g., dialysis, trauma and surgery) and of all endothelin-dependent disorders. They are thus inter alia useful as antihypertensive agents.

  根据公式I，化合物为其对映体、非对映体或药用盐，其中：X和Y中的一个是N，另一个是O；R2、R3、R4和R5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)R6；(h) -CO2H或-CO2R6；(i) -SH、-S(O)nR6、-S(O)m-OH、-S(O)m-OR6、-O-S(O)m-R6、-O-S(O)mOH或-O-S(O)m-OR6；(j) -Z4-NR7R8；或(k) -Z4-N(R11)-Z5-NR9R10；R4和R5一起是烷基或烯基，其中任何一个都可以用Z1、Z2和Z3取代，与它们附着的碳原子一起形成4-至8-成员饱和、不饱和或芳香环；G1为(a)氢；或(b)烷基；G2为(a)羟基烷基；(b) -(CH2)mOR6；或(c) -(CH2)m-NR12R13；(d)单取代至六取代卤素烷基；或(e) -(CH2)nOR14；其余符号如描述中定义的那样。公式I的化合物是ET-1、ET-2和/或ET-3的拮抗剂，并且在治疗与增加的ET水平相关的病症（例如透析、外伤和手术）以及所有内皮素依赖性疾病方面具有用途。因此，它们也可作为降压药物。
• Design, synthesis and biological activity of 4′-[(benzimidazol-1-yl)methyl]biphenyl-2-sulphonamides as dual angiotensin II and endothelin A receptor antagonists
  作者：Li-Ping Hao、Wei-Zhe Xue、Xiao-Feng Han、Xing He、Jun Zhang、Zhi-Ming Zhou

  DOI：10.1039/c4md00499j

  日期：——

  A series of novel 4′-[(benzimidazol-1-yl)methyl]biphenyl-2-sulphonamides was designed, and their molecular model simulation fitting to a new HipHop 3D pharmacophore model was examined.

  一系列新型4'-[(苯并咪唑-1-基)甲基]联苯-2-磺酰胺被设计出来，并且它们的分子模型模拟与新的HipHop 3D药效团模型拟合进行了检验。
• Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists
  申请人：Bristol-Myers Squibb Company

  公开号：EP1741713A2

  公开（公告）日：2007-01-10

  Novel biphenyl sulfonamide compounds which are combined angiotensin and endothelin receptor antagonists are claimed along with methods of using such compounds in the treatment of conditions such as hypertension and other diseases, as well as pharmaceutical compositions containing such compounds.

  本发明公开了新型联苯磺酰胺化合物（血管紧张素和内皮素受体联合拮抗剂），以及使用此类化合物治疗高血压和其他疾病的方法和含有此类化合物的药物组合物。
• Substituted isoxazole sulfonamides and their use as endothelin antagonists
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0702012B1

  公开（公告）日：2003-10-15