benzyl N-[3-benzyl-4-(2-ethyl-2-formylhexyl)sulfonylphenyl]carbamate | 865461-99-0

• 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: benzyl N-[3-benzyl-4-(2-ethyl-2-formylhexyl)sulfonylphenyl]carbamate
• CAS: 865461-99-0
• 化学式: C₃₀H₃₅NO₅S
• 分子量: 521.678
• InChiKey: DFCBSJALIIRFSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  37
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  97.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  benzyl N-[3-benzyl-4-(2-ethyl-2-formylhexyl)sulfonylphenyl]carbamate 在 N-甲基吗啉 、 三氟化硼乙醚 、 potassium tert-butylate 、 乙硫醇 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 114.0h， 生成 N-[(+/-)-(3S,4R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-5-phenyl-1-benzothiepin-7-yl]hexanamide
  参考文献：
  名称：

  Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 1)

  摘要：

  Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-l-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [C-14]taurocholate (TC) in H14 cells. A 3R,4.R,5R13S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.

  DOI：

  10.1021/jm040215+
• 作为产物：
  描述：

  2-氯-5-硝基二苯甲酮 在 palladium on activated charcoal 三乙基硅烷 、 lithium sulfide 、 三氟甲磺酸 、 氢气 、 potassium carbonate 、 间氯过氧苯甲酸 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 、 二甲基亚砜 、 甲苯 为溶剂， 20.0~80.0 ℃ 、689.47 kPa 条件下， 反应 135.5h， 生成 benzyl N-[3-benzyl-4-(2-ethyl-2-formylhexyl)sulfonylphenyl]carbamate
  参考文献：
  名称：

  Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 1)

  摘要：

  Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-l-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [C-14]taurocholate (TC) in H14 cells. A 3R,4.R,5R13S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.

  DOI：

  10.1021/jm040215+