(1aR,12bS)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide | 958002-33-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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: (1aR,12bS)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide
• 英文别名: (8S,10R)-19-cyclohexyl-N-(dimethylsulfamoyl)-5-methoxy-10-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-12-azapentacyclo[10.7.0.02,7.08,10.013,18]nonadeca-1(19),2(7),3,5,13(18),14,16-heptaene-15-carboxamide
• CAS: 958002-33-0
• 化学式: C₃₆H₄₅N₅O₅S
• 分子量: 659.85
• InChiKey: ZTTKEBYSXUCBSE-VSBZUFFNSA-N

物化性质

• 密度：
  1.45±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO:30.0(最大浓度 mg/mL);45.46(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  47
• 可旋转键数：
  6
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  113
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 储存条件：
  2-8℃

制备方法与用途

Beclabuvir 是一种NS5B RNA依赖性RNA聚合酶抑制剂，也能抑制基因型1、2、4、5表达的NS5B蛋白活性，其抑制效果在数值上均小于28 nM。

反应信息

• 作为反应物：
  描述：

  (1aR,12bS)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide 在 盐酸 作用下， 生成 (1aR,12bS)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide hydrochloride
  参考文献：
  名称：

  Cyclopropyl Fused Indolobenzazepine HCV NS5B Inhibitors

  摘要：

  这项发明涵盖了公式I的化合物，以及使用这些化合物的组合物和方法。这些化合物对丙型肝炎病毒（HCV）具有活性，并可用于治疗感染HCV的患者。

  公开号：

  US20070270405A1
• 作为产物：
  描述：

  2-溴-3-环己基-1H-吲哚-6-羧酸甲酯 在 2-双环己基膦-2',6'-二甲氧基联苯 、 palladium diacetate 、 sodium hydride 、 potassium carbonate 、 caesium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 N,N'-羰基二咪唑 、 sodium hydroxide 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 52.08h， 生成 (1aR,12bS)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-11-methoxy-1a-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide
  参考文献：
  名称：

  Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

  DOI：

  10.1021/jm4016894

文献信息

• CYCLOPROPYL FUSED INDOLOBENZAZEPINE HCV NS5B INHIBITORS
  申请人：Bender John A.

  公开号：US20080146537A1

  公开（公告）日：2008-06-19

  The invention encompasses compounds of formula I as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.

  该发明涵盖了公式I的化合物，以及使用这些化合物的组合物和方法。这些化合物对丙型肝炎病毒（HCV）具有活性，并可用于治疗感染HCV的人。
• NOVEL METHODS AND INTERMEDIATES FOR THE PREPARATION OF (4bS,5aR)-12-CYCLOHEXYL-N-(N,N-DIMETHYLSULFAMOYL)-3-METHOXY-5a-((1R,5S)-3-METHYL-3,8-DIAZABICYCLO[3.2.1]OCTANE-8-CARBONYL)-4b,5,5a,6-TETRAHYDROBENZO [3,4]CYCLOPROPA[5,6]AZEPINO[1,2-A]INDOLE-9-CARBOXAMIDE
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20150133654A1

  公开（公告）日：2015-05-14

  The present invention provides methods and intermediates for the preparation of (1aR,12bS)-8-cyclohexyl-11-fluoro-N-((1-methylcyclopropyl)sulfonyl)-1a-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide (formula I), including pharmaceutically acceptable salts. The compound has activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.

  本发明提供了制备(1aR,12bS)-8-环己基-11-氟-N-((1-甲基环丙基)磺酰基)-1a-((3-甲基-3,8-二氮杂双环[3.2.1]辛-8-基)羰基)-1,1a,2,12b-四氢环丙并[2,1-a][2]苯并氮杂环己烷-5-羧酰胺（式I）的方法和中间体，包括药学上可接受的盐。该化合物对丙型肝炎病毒（HCV）具有活性，可能有助于治疗HCV感染者。
• COMBINATIONS OF HEPATITIS C VIRUS INHIBITORS
  申请人：Bristol-Myers Squibb Holdings Ireland

  公开号：EP2600835B1

  公开（公告）日：2018-05-30
• SOLUBILIZED CAPSULE FORMULATION OF 1,1-DIMETHYLETHYL [(1S)-1-{[(2S,4R)-4-(7-CHLORO-4METHOXYISOQUINOLIN-1-YLOXY)-2-({(1R,2S)-1-[(CYCLOPROPYLSULFONYL)CARBAMOYL]-2-ETHENYLCYCLOPROPYL}CARBAMOYL)PYRROLIDIN-1-YL]CARBONYL}-2,2-DIMETHYLPROPYL]CARBAMATE
  申请人：Bristol-Myers Squibb Holdings Ireland

  公开号：EP2846780B1

  公开（公告）日：2018-07-18
• METHODS AND INTERMEDIATES FOR THE PREPARATION OF (4BS,5AR)-12-CYCLOHEXYL-N-(N,N-DIMETHYLSULFAMOYL)-3- METHOXY-5A-((1R,5S)-3-METHYL-3,8-DIAZABICYCLO[3.2.1]OCTANE-8-CARBONYL)-4B,5,5A,6-TETRAHYDROBENZO [3,4]CYCLOPROPA[5,6]AZEPINO[1,2-A]INDOLE-9-CARBOXAMIDE
  申请人：Bristol-Myers Squibb Holdings Ireland

  公开号：EP2875030B1

  公开（公告）日：2016-10-26