4-(methylsulfonyl)-2-trifluoromethoxy-benzoic acid

• 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-(methylsulfonyl)-2-trifluoromethoxy-benzoic acid
• 英文别名: 4-(Methylsulfonyl)-2-(trifluoromethoxy)benzoic acid；4-methylsulfonyl-2-(trifluoromethoxy)benzoic acid
• 化学式: C₉H₇F₃O₅S
• 分子量: 284.213
• InChiKey: WKKRDFHLKXRMMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.69
• 重原子数：
  18.0
• 可旋转键数：
  3.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  80.67
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  N-环丙基-N-(哌啶-4-基)-3-(三氟甲基)苯磺胺 、 4-(methylsulfonyl)-2-trifluoromethoxy-benzoic acid 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以59%的产率得到N-cyclopropyl-N-(1-(4-(methylsulfonyl)-2-(trifluoromethoxy)benzoyl)piperidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide
  参考文献：
  名称：

  Improved Ca_v2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide

  摘要：

  We report the investigation of sulfonamide-derived Ca(v)2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)-benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Ca(v)2.2 potency without the liability of the circulating sulfonamide metabolite.

  DOI：

  10.1021/ml4002612
• 作为产物：
  描述：

  4-溴-2-(三氟甲氧基)碘苯 在 copper(l) iodide 、 正丁基锂 、 potassium hydroxide 作用下， 以 四氢呋喃 、 水 、 二甲基亚砜 为溶剂， 反应 0.5h， 生成 4-(methylsulfonyl)-2-trifluoromethoxy-benzoic acid
  参考文献：
  名称：

  Improved Ca_v2.2 Channel Inhibitors through a gem-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide

  摘要：

  We report the investigation of sulfonamide-derived Ca(v)2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)-benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Ca(v)2.2 potency without the liability of the circulating sulfonamide metabolite.

  DOI：

  10.1021/ml4002612

文献信息

• Improved Ca_v2.2 Channel Inhibitors through a <i>gem</i>-Dimethylsulfone Bioisostere Replacement of a Labile Sulfonamide
  作者：Pengcheng P. Shao、Feng Ye、Prasun K. Chakravarty、James B. Herrington、Ge Dai、Randal M. Bugianesi、Rodolfo J. Haedo、Andrew M. Swensen、Vivien A. Warren、McHardy M. Smith、Maria L. Garcia、Owen B. McManus、Kathryn A. Lyons、Xiaohua Li、Mitchell Green、Nina Jochnowitz、Erin McGowan、Shruti Mistry、Shu-Yu Sun、Catherine Abbadie、Gregory J. Kaczorowski、Joseph L. Duffy

  DOI：10.1021/ml4002612

  日期：2013.11.14

  We report the investigation of sulfonamide-derived Ca(v)2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)-benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Ca(v)2.2 potency without the liability of the circulating sulfonamide metabolite.