(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1lambda6-benzothiepin-4-ol

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫平类
• 英文名称: (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1lambda6-benzothiepin-4-ol
• 英文别名: (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1λ6-benzothiepin-4-ol
• 化学式: C₂₆H₃₈N₂O₃S
• 分子量: 458.665
• InChiKey: WIMIAOPXCGNHRQ-JWQCQUIFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  92
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1lambda6-benzothiepin-4-ol 在 lithium hydroxide 、 四丁基碘化铵 、 potassium carbonate 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 147.0h， 生成 {2-[3-((4R,5R)-3,3-Dibutyl-7-dimethylamino-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ⁶-benzo[b]thiepin-5-yl)-phenylamino]-acetylamino}-acetic acid
  参考文献：
  名称：

  Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

  摘要：

  In the preceding paper several compounds were reported as potent apical. sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

  DOI：

  10.1021/jm0402162
• 作为产物：
  描述：

  (4R,5R)-5-[3-(Benzhydrylidene-amino)-phenyl]-3,3-dibutyl-7-dimethylamino-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ⁶-benzo[b]thiepin-4-ol 在 盐酸羟胺 、 sodium acetate 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以8.64 g的产率得到(4R,5R)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2H-1lambda6-benzothiepin-4-ol
  参考文献：
  名称：

  Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

  摘要：

  In the preceding paper several compounds were reported as potent apical. sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

  DOI：

  10.1021/jm0402162

文献信息

• NOVEL 1,4-BENZOTHIEPIN-1, 1-DIOXIDE DERIVATIVES WITH IMPROVED PROPERTIES METHOD FOR PRODUCING THE SAME, DRUGS CONTAINING SAID COMPOUNDS AND THE USE THEREOF
  申请人：Glombik Heiner

  公开号：US20100035834A1

  公开（公告）日：2010-02-11

  This invention relates to Novel 1,4-benzothiepin-1,1-dioxide derivatives with improved properties, method for producing the same, drugs containing said compounds and use thereof.

  本发明涉及一种具有改进性能的新型1,4-苯并噻吩-1,1-二氧化物衍生物，制备方法，包含该化合物的药物以及其用途。
• US8106023B2
  申请人：——

  公开号：US8106023B2

  公开（公告）日：2012-01-31
• [EN] METHODS FOR TREATING CHOLESTASIS<br/>[FR] PROCÉDÉS DE TRAITEMENT DE LA CHOLESTASE
  申请人：MIRUM PHARMACEUTICALS INC

  公开号：WO2020167958A1

  公开（公告）日：2020-08-20

  Provided herein are methods for treating cholestasis in a subject having a liver disease. The method includes administering to the subject an Apical Sodium-dependent Bile Acid Transporter (ASBTI). More specifically, the present invention relates to methods for treating cholestasis in a subject where the method includes administering an ASBTI to a subject at a dose of at least 10 μg/kg/day.
• Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)
  作者：Horng-Chih Huang、Samuel J. Tremont、Len F. Lee、Bradley T. Keller、Andrew J. Carpenter、Ching-Cheng Wang、Shyamal C. Banerjee、Scott R. Both、Theresa Fletcher、Danny J. Garland、Wei Huang、Claude Jones、Kevin J. Koeller、Steve A. Kolodziej、James Li、Robert E. Manning、Matthew W. Mahoney、Raymond E. Miller、Deborah A. Mischke、Nigam P. Rath、Emily J. Reinhard、Michael B. Tollefson、William F. Vernier、Grace M. Wagner、Steve R. Rapp、Judy Beaudry、Kevin Glenn、Karen Regina、Joe R. Schuh、Mark E. Smith、Jay S. Trivedi、David B. Reitz

  DOI：10.1021/jm0402162

  日期：2005.9.1

  In the preceding paper several compounds were reported as potent apical. sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.