2-((2-phenylmethyl-4-nitrophenylthio)methyl)-2-ethylhexanal | 178678-64-3

• 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: 2-((2-phenylmethyl-4-nitrophenylthio)methyl)-2-ethylhexanal
• 英文别名: 2-((2-benzyl-4-nitrophenylthio)methyl)-2-ethylhexanal；2-[(2-Benzyl-4-nitrophenyl)sulfanylmethyl]-2-ethylhexanal
• CAS: 178678-64-3
• 化学式: C₂₂H₂₇NO₃S
• 分子量: 385.527
• InChiKey: HTNLNYQXDQKJOF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  88.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-((2-phenylmethyl-4-nitrophenylthio)methyl)-2-ethylhexanal 在 palladium on activated charcoal N-甲基吗啉 、 三氟化硼乙醚 、 potassium tert-butylate 、 氢气 、 potassium carbonate 、 间氯过氧苯甲酸 、 乙硫醇 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 氯仿 、 甲苯 为溶剂， 20.0~55.0 ℃ 、689.47 kPa 条件下， 反应 171.5h， 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]acetamide
  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 三乙基硅烷 、 lithium sulfide 、 三氟甲磺酸 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 78.0h， 生成 2-((2-phenylmethyl-4-nitrophenylthio)methyl)-2-ethylhexanal
  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+

文献信息

• Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
  申请人：G.D. Searle & Co.

  公开号：US20020013476A1

  公开（公告）日：2002-01-31

  Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

  提供了新型苯并噻吩类化合物及其衍生物和类似物；含有它们的药物组合物；以及在医学中使用这些化合物和组合物的方法，特别是在哺乳动物中预防和治疗高脂血症状，如与动脉粥样硬化或高胆固醇血症相关的情况。
• Novel benzothiepines having activity as inhibitors of lleal bile acid transport and taurocholate uptake
  申请人：G.D. Searle & Co.

  公开号：US20040014803A1

  公开（公告）日：2004-01-22

  Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals.

  提供了新型苯硫杂吲哚类化合物及其衍生物和类似物；含有它们的药物组合物；以及在医学中使用这些化合物和组合物的方法，特别是在哺乳动物中预防和治疗高脂血症状，如与动脉粥样硬化或高胆固醇血症相关的情况。
• Novel mono- and di-fluorinated benzothiepine compouds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
  申请人：G.D. SEARLE, LLC

  公开号：US20040067872A1

  公开（公告）日：2004-04-08

  Mono-fluorinated and di-fluorinated benzothiepine apical sodium co-dependent bile acid transport (ASBT) inhibitors are disclosed together with methods of making the same, methods of using the same to treat hyperlipidemic conditions as well as pharmaceutical compositions containing the same compounds.

  本发明公开了单氟和二氟苯并噻吩顶部钠依赖性胆酸转运体（ASBT）抑制剂，以及制备这些抑制剂的方法，使用这些抑制剂治疗高脂血症的方法，以及含有这些化合物的药物组合物。
• Combination therapy employing ileal bile acid transport inhibiting benzothiepiens and HMG Co-A reductase inhibitors
  申请人：G.D. Searle & Co.

  公开号：US20030171426A1

  公开（公告）日：2003-09-11

  Provided are novel benzothiepines, derivatives, and analogs thereof; pharmaceutical compositions containing them; and methods of using these compounds and compositions in medicine, particularly in the prophylaxis and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia, in mammals. Also provided are compositions and methods for combination therapy employing ileal bile acid transport inhibitors and HMG Co-A reductase inhibitors for the treatment of hyperlipidemic conditions.

  提供了新型苯并噻吩、其衍生物和类似物；包含它们的药物组合物；以及在医学中使用这些化合物和组合物的方法，特别是在哺乳动物的预防和治疗高脂血症状况方面，例如与动脉粥样硬化或高胆固醇血症相关的情况。还提供了组合疗法的组合物和方法，采用回肠胆酸转运抑制剂和HMG Co-A还原酶抑制剂治疗高脂血症状况。
• Novel mono- and di-fluorinated beozothiepine copmunds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
  申请人：G.D. SEARLE, LLC

  公开号：US20040176438A1

  公开（公告）日：2004-09-09

  Mono-fluorinated and di-fluorinated benzothiepine apical sodium co-dependent bile acid transport (ASBT) inhibitors are disclosed together with methods of making the same, methods of using the same to treat hyperlipidemic conditions as well as pharmaceutical compositions containing the same compounds.

  本文披露了单氟和双氟苯并噻吩顶部钠依赖性胆汁酸转运体（ASBT）抑制剂的方法，以及制备这些抑制剂的方法，使用这些抑制剂治疗高脂血症状况的方法，以及含有这些化合物的制药组合物。