(7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl]-(methyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid | 886041-60-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl]-(methyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid
• 英文别名: (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid；MK-3281；(10R)-19-cyclohexyl-10-[2-(dimethylamino)ethyl-methylamino]-8-oxa-12-azatetracyclo[10.7.0.02,7.013,18]nonadeca-1(19),2,4,6,13(18),14,16-heptaene-15-carboxylic acid
• CAS: 886041-60-7
• 化学式: C₂₉H₃₇N₃O₃
• 分子量: 475.631
• InChiKey: YQUCBFIQSJVCOR-JOCHJYFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  57.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl]-(methyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid 、 对甲苯磺酸 以 二氯甲烷 、 乙腈 为溶剂， 以5.346 kg的产率得到MK-3281 Toluenesulfonate
  参考文献：
  名称：

  Mitsunobu Inversion of a Secondary Alcohol with Diphenylphosphoryl azide. Application to the Enantioselective Multikilogram Synthesis of a HCV Polymerase Inhibitor

  摘要：

  The development of a practical synthesis of the hepatitis C virus polymerase inhibitor 1 was necessary to support preclinical safety and human clinical studies. Significant challenges face the process chemist in developing a route to 1 that is amenable to multikilogram operation. In particular, an efficient construction of the eight-membered dihydroindolobenzoxazocine ring and enantioselective synthesis of the secondary amine stereocenter are required. This article describes our process development of a Mitsunobu protocol to achieve the latter goal which uses diphenylphosphoryl azide at ambient temperature to invert a scalemic secondary alcohol, The hazard evaluation performed to establish the safety of this protocol and allow pilot-plant introduction at > 8.0 kg scale is discussed. Overall, an enantioselective synthesis of 1 by way of seven isolated intermediates in 32% overall yield was developed from commercially available materials. This allowed us to prepare over 3 kg of the targeted drug candidate.

  DOI：

  10.1021/op200002u
• 作为产物：
  描述：

  methyl (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl)-amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate 在 水 、 potassium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 (7R)-14-cyclohexyl-7-{[2-(dimethylamino)ethyl]-(methyl)amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid
  参考文献：
  名称：

  Discovery of (7R)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.

  DOI：

  10.1021/jm1013105

文献信息

• Development of a Scalable Chiral Synthesis of MK-3281, an Inhibitor of the Hepatitis C Virus NS5B Polymerase
  作者：Stefania Colarusso、Jörg Habermann、Immacolata Conte、Marcello Di Filippo、Caterina Ercolani、Angela Mackay、Maria Palumbi、Maria del Rosario Rico Ferreira、Ian Stansfield、Simone Zaramella、Frank Narjes

  DOI：10.1055/s-0030-1260790

  日期：2011.7

  The development of a scalable chiral synthesis for the HCV NS5B inhibitor MK-3281 is being reported. Several alternative routes were explored and are being described.

  本报告介绍了 HCV NS5B 抑制剂 MK-3281 的可扩展手性合成方法。对几种替代路线进行了探索，现予以介绍。
• Org. Process Res. Dev. 2011, 15, 1116-1123
  作者：

  DOI：——

  日期：——
• COMPOSITIONS USEFUL FOR THE TREATMENT OF VIRAL DISEASES
  申请人：Carroll Steven S.

  公开号：US20140328799A1

  公开（公告）日：2014-11-06

  The present invention is directed to compositions comprising inhibitors of hepatitis C virus (HCV) protease and one or more additional therapeutically effective agents. Uses of such compositions as HCV inhibitors and methods of treating infection by HCV by administration of such compositions are also disclosed.
• US7795247B2
  申请人：——

  公开号：US7795247B2

  公开（公告）日：2010-09-14
• Discovery of (7<i>R</i>)-14-Cyclohexyl-7-{[2-(dimethylamino)ethyl](methyl) amino}-7,8-dihydro-6<i>H</i>-indolo[1,2-<i>e</i>][1,5]benzoxazocine-11-carboxylic Acid (MK-3281), a Potent and Orally Bioavailable Finger-Loop Inhibitor of the Hepatitis C Virus NS5B Polymerase
  作者：Frank Narjes、Benedetta Crescenzi、Marco Ferrara、Jörg Habermann、Stefania Colarusso、Maria del Rosario Rico Ferreira、Ian Stansfield、Angela Claire Mackay、Immacolata Conte、Caterina Ercolani、Simone Zaramella、Maria-Cecilia Palumbi、Philip Meuleman、Geert Leroux-Roels、Claudio Giuliano、Fabrizio Fiore、Stefania Di Marco、Paola Baiocco、Uwe Koch、Giovanni Migliaccio、Sergio Altamura、Ralph Laufer、Raffaele De Francesco、Michael Rowley

  DOI：10.1021/jm1013105

  日期：2011.1.13

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral genome and has been a prime target for drug discovery efforts. Here, we report on the further development of tetracyclic indole inhibitors, binding to an allosteric site on the thumb domain. Structure-activity relationship (SAR) studies around an indolo-benzoxazocine scaffold led to the identification of compound 33 (MK-3281), an inhibitor with good potency in the HCV subgenomic replication assay and attractive molecular properties suitable for a clinical candidate. The compound caused a consistent decrease in viremia in vivo using the chimeric mouse model of HCV infection.