(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-(4-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2H-1λ6-benzothiepin-4-ol | 228113-64-2

• 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)-3,3-dibutyl-7-(dimethylamino)-5-(4-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2H-1λ6-benzothiepin-4-ol
• CAS: 228113-64-2
• 化学式: C₂₇H₃₉NO₄S
• 分子量: 473.677
• InChiKey: YYHTVXUCKQXZTF-CLJLJLNGSA-N

物化性质

• 熔点：
  134-135 °C
• 沸点：
  627.5±55.0 °C(Predicted)
• 密度：
  1.118±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  75.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-(4-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2H-1λ6-benzothiepin-4-ol 在 三溴化硼 、 sodium hydride 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (+)-(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-{4-[(5-bromopentyl)oxy]phenyl}-2,3,4,5-tetrahydro-1-benzothiepin-4-ol 1,1-dioxide
  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)-3,3-dibutyl-7-fluoro-5-(4-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2H-1lambda6-benzothiepin-4-ol 、 二甲胺 以 四氢呋喃 为溶剂， 以90.5%的产率得到(4R,5R)-3,3-dibutyl-7-(dimethylamino)-5-(4-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2H-1λ6-benzothiepin-4-ol
  参考文献：
  名称：

  Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides

  摘要：

  一种制备对映富集的四氢苯并噻吩氧化物的过程，包括环化对映富集的芳基-3-丙醛亚磺酸盐，其中芳基-3-丙醛亚磺酸盐的硫原子是手性中心。

  公开号：

  US06369220B1

文献信息

• Bile Acid Recycling Inhibitors for Treatment of Hypercholemia and Cholestatic Liver Disease
  申请人：Lumena Pharmaceuticals, Inc.

  公开号：US20130108573A1

  公开（公告）日：2013-05-02

  Provided herein are methods of treating or ameliorating hypercholemia or a cholestatic liver disease by administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

  本文提供了一种治疗或改善高胆固醇血症或胆汁淤积性肝病的方法，即通过向需要的个体施用治疗有效量的顶端钠依赖性胆酸转运蛋白抑制剂（ASBTI）或其药用可接受盐。还提供了一种治疗或改善肝病、降低血清胆酸或肝内胆酸水平、治疗或改善瘙痒、降低肝酶或减少胆红素的方法，即通过向需要的个体施用治疗有效量的ASBTI或其药用可接受盐。
• Bile Acid Recycling Inhibitors for Treatment of Pediatric Cholestatic Liver Diseases
  申请人：Lumena Pharmaceuticals, Inc.

  公开号：US20130109671A1

  公开（公告）日：2013-05-02

  Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.

  本文提供了一种通过非系统性给予需要治疗或改善儿童胆汁淤积性肝病的个体治疗的方法，该方法包括给予含有顶端钠依赖性胆酸转运体抑制剂（ASBTI）或其药学上可接受的盐的儿科制剂的治疗有效量。此外，还提供了一种治疗或改善儿童肝病、降低血清胆酸或肝胆酸水平、治疗或改善瘙痒、降低肝酶或减少胆红素的方法，该方法包括给予含有ASBTI或其药学上可接受的盐的儿科制剂的治疗有效量。
• BILE ACID RECYCLING INHIBITORS FOR TREATMENT OF PEDIATRIC CHOLESTATIC LIVER DISEASES
  申请人：Lumena Pharmaceuticals, Inc.

  公开号：US20140243281A1

  公开（公告）日：2014-08-28

  Provided herein are pediatric dosage forms for use in the treatment of a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of the pediatric dosage form comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are said pediatric dosage form for use in the treatment of a pediatric liver disease, for use in decreasing the levels of serum bile acids or hepatic bile acids, for use in the treatment of pruritis, for use in reducing liver enzymes or bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.

  本文提供了用于治疗儿童胆汁淤积性肝病的儿童剂型，通过非系统性给予需要治疗的个体含有顶端钠依赖性胆酸转运体抑制剂（ASBTI）或其药学上可接受的盐的治疗有效量的儿童剂型。还提供了该儿童剂型用于治疗儿童肝病，用于降低血清胆酸或肝胆酸水平，用于治疗瘙痒症，用于减少肝酶或胆红素的儿童制剂，通过非系统性给予需要治疗的个体含有ASBTI或其药学上可接受的盐的治疗有效量。
• Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
  申请人：Lumena Pharmaceuticals LLC

  公开号：US10512657B2

  公开（公告）日：2019-12-24

  Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.

  本文提供了治疗或改善小儿胆汁淤积性肝病的方法，其方法是向有需要的个体非系统地施用治疗有效量的儿科制剂，该制剂包含尖端钠依赖性胆汁酸转运体抑制剂（ASBTI）或其药学上可接受的盐。还提供了治疗或改善小儿肝病、降低血清胆汁酸或肝胆汁酸水平、治疗或改善瘙痒症、降低肝酶或胆红素的方法，包括向有需要的个体非系统地施用治疗有效量的包含ASBTI或其药学上可接受的盐的儿科制剂。
• Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 1)
  作者：Samuel J. Tremont、Len F. Lee、Horng-Chih Huang、Bradley T. Keller、Shyamal C. Banerjee、Scott R. Both、Andrew J. Carpenter、Ching-Cheng Wang、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、Theresa Fletcher、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/jm040215+

  日期：2005.9.1

  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.