(3R,4S)-1,4-二(4-甲氧基苯基)-3-(3-苯基丙基)氮杂环丁-2-酮 | 148260-92-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 中文名称: (3R,4S)-1,4-二(4-甲氧基苯基)-3-(3-苯基丙基)氮杂环丁-2-酮
• 英文名称: SCH 48461
• 英文别名: (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone；SCH48461；(3R-4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone；1,4-Bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone；(3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)azetidin-2-one
• CAS: 148260-92-8
• 化学式: C₂₆H₂₇NO₃
• 分子量: 401.505
• InChiKey: IMNTVVOUWFPRSB-JWQCQUIFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3R,4S)-1,4-二(4-甲氧基苯基)-3-(3-苯基丙基)氮杂环丁-2-酮 在 Crabtree catalyst 、 氘 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 生成 (3R,4S)-1-(2,6-dideuterio-4-methoxyphenyl)-4-(4-methoxyphenyl)-3-(3-phenylpropyl)azetidin-2-one
  参考文献：
  名称：

  Deuteration of acetanilides and other substituted aromatics using [Ir(COD)(Cy3P)(Py)]PF6 as catalyst

  摘要：

  研究了使用[Ir(COD)(Cy3P)(Py)]PF6作为催化剂和氘气对多种取代乙酰苯胺进行氘交换标记。在大多数情况下，获得的产物含有邻位苯胺基团的氘并具有高度富集。除一例外，没有发现间位、对位或苯胺甲基标记的证据。该催化剂还可有效用于苯乙酮、二苯甲酮和含 β-内酰胺化合物 Sch 48461 的邻位氘化。

  DOI：

  10.1002/jlcr.2580360514
• 作为产物：
  描述：

  rel-(3S,4S)-1-(4-methoxyphenyl)-3-(3-phenylpropyl)-4-(4-methoxyphenyl)-2-azetidinone 在 potassium tert-butylate 作用下， 以 四氢呋喃 为溶剂， 生成 (3R,4S)-1,4-二(4-甲氧基苯基)-3-(3-苯基丙基)氮杂环丁-2-酮
  参考文献：
  名称：

  胆固醇吸收抑制剂SCH 48461的不对称合成和绝对立体化学

  摘要：

  描述了胆固醇吸收抑制剂的第一个不对称合成，SCH 48461。使用Oppolzer的手性酯或相应的薄荷醇酯作为立体控制元素，由不对称的酯烯酸酯-亚胺缩合制备该化合物。从类似于文献实例，获得标题化合物的绝对立体化学被分配到3 - [R，4小号。

  DOI：

  10.1016/0040-4039(94)85308-8

文献信息

• BILE ACID RECYCLING INHIBITORS FOR TREATMENT OF GASTROINTESTINAL INFECTIONS
  申请人：Lumena Pharmaceuticals, Inc.

  公开号：US20150119345A1

  公开（公告）日：2015-04-30

  Provided herein are methods for treating or preventing gastrointestinal and/or liver infections utilizing bile acid transport inhibitors and/or enteroendocrine peptide enhancing agents and/or FXR agonists. Also provided herein are methods for increasing the levels of an enteroendocrine peptide or hormone in an individual suffering from a gastrointestinal infection or liver infection utilizing bile acid transport inhibitors and/or enteroendocrine peptide enhancing agents and/or FXR agonists.

  本文提供了利用胆汁酸转运抑制剂和/或肠内分泌肽增强剂和/或FXR激动剂治疗或预防胃肠和/或肝感染的方法。本文还提供了利用胆汁酸转运抑制剂和/或肠内分泌肽增强剂和/或FXR激动剂增加患有胃肠感染或肝感染的个体体内肠内分泌肽或激素水平的方法。
• Sulfur(VI) fluoride compounds and methods for the preparation thereof
  申请人：The Scripps Research Institute

  公开号：US10117840B2

  公开（公告）日：2018-11-06

  This application describes a compound represented by Formula (I): (I) wherein: Y is a biologically active organic core group comprising one or more of an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group, to which Z is covalently bonded; n is 1, 2, 3, 4 or 5; m is 1 or 2; Z is O, NR, or N; X1 is a covalent bond or —CH2CH2—, X2 is O or NR; and R comprises H or a substituted or unsubstituted group selected from an aryl group, a heteroaryl aryl group, a nonaromatic hydrocarbyl group, and a nonaromatic heterocyclic group. Methods of preparing the compounds, methods of using the compounds, and pharmaceutical compositions comprising the compounds are described as well.

  该应用描述了由式(I)表示的化合物：(I)其中：Y是一个生物活性有机核心基团，包括芳基、杂芳基、非芳香烃基和非芳香杂环基中的一个或多个，其中Z与之以共价键结合；n为1、2、3、4或5；m为1或2；Z为O、NR或N；X1为共价键或—CH2CH2—，X2为O或NR；R包括H或从芳基、杂芳基、非芳香烃基和非芳香杂环基中选择的取代或未取代基团。还描述了制备这些化合物的方法、使用这些化合物的方法以及包含这些化合物的药物组合物。
• Discovery of 1-(4-Fluorophenyl)-(3<i>R</i>)-[3-(4-fluorophenyl)-(3<i>S</i>)- hydroxypropyl]-(4<i>S</i>)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235):  A Designed, Potent, Orally Active Inhibitor of Cholesterol Absorption
  作者：Stuart B. Rosenblum、Tram Huynh、Adriano Afonso、Harry R. Davis、Nathan Yumibe、John W. Clader、Duane A. Burnett

  DOI：10.1021/jm970701f

  日期：1998.3.1

  (3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

  (3R)-(3-苯基丙基)-1,(4S)-双(4-甲氧基苯基)-2-氮杂环丁酮（2，SCH 48461），作为新型的肠道胆固醇吸收抑制剂，近期由Burnett等人提出，并已在人体中展现出降低总血浆胆固醇的效果。本研究考虑了化合物2的潜在代谢位点，并合成了最可能的代谢物。在胆固醇喂养的仓鼠模型中，评估了假设代谢物对血清总胆固醇和肝胆固醇酯降低的口服降胆固醇效力，相较于对照组。 基于对假设代谢物的结构-活性关系（SAR）分析，设计合成了SCH 58235（1，1-(4-氟苯基)-(3R)-[3-(4-氟苯基)-(3S)-羟基丙基]-(4S)-(4-羟基苯基)-2-氮杂环丁酮），旨在通过活性增强氧化来提升疗效，并在潜在有害代谢氧化的位置上进行阻断。同时，制备了一系列化合物2的类似物，引入了战略性放置的羟基和氟原子，以进一步探索2-氮杂环丁酮类胆固醇吸收抑制剂的SAR。 通过对化合物2系列假设代谢物的SAR分析，化合物1被靶向合成，并在胆固醇喂养的仓鼠模型中展现出显著效果，其降低肝胆固醇酯的ED50为0.04 mg/kg/day。
• 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。
• Trans diastereoselective synthesis of 3-alkyl substituted β-lactams via the acid chloride-imine reaction of nonactivated acid chlorides
  作者：Margaret Browne、Duane A. Burnett、Mary Ann Caplen、Lian-Yong Chen、John W. Clader、Martin Domalski、Sundeep Dugar、Pradeep Pushpavanam、Rosy Sher、Wayne Vaccaro、Monica Viziano、Hongrong Zhao

  DOI：10.1016/0040-4039(95)00338-d

  日期：1995.4

  New conditions for the acid chloride-imine reaction of nonactivated alkyl acid chlorides provide 3-alkyl substituted β-lactams in good yields with high trans selectivity.

  非活化烷基酰氯的酰氯-亚胺反应的新条件以高收率和高反式选择性提供了3-烷基取代的β-内酰胺。