[(3R,5S)-1-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-5-methoxycarbonylpyrrolidin-3-yl] 4-ethenyl-1,3-dihydroisoindole-2-carboxylate | 957475-36-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [(3R,5S)-1-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-5-methoxycarbonylpyrrolidin-3-yl] 4-ethenyl-1,3-dihydroisoindole-2-carboxylate
• CAS: 957475-36-4
• 化学式: C₃₀H₄₁N₃O₇
• 分子量: 555.671
• InChiKey: HOXBHKNJYRTPRD-VJTSUQJLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  40
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [(3R,5S)-1-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-5-methoxycarbonylpyrrolidin-3-yl] 4-ethenyl-1,3-dihydroisoindole-2-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以251 mg的产率得到[(3R,5S)-1-[(2S)-2-amino-2-cyclohexylacetyl]-5-methoxycarbonylpyrrolidin-3-yl] 4-ethenyl-1,3-dihydroisoindole-2-carboxylate
  参考文献：
  名称：

  Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

  摘要：

  Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and Cellular activity. Among these, Compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.

  DOI：

  10.1021/jm900524b
• 作为产物：
  描述：

  4-Vinyl-1,3-dihydro-isoindole-2-carboxylic acid 5-methoxycarbonyl-pyrrolidin-3-yl ester 、 Boc-L-环己基甘氨酸 在 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以80%的产率得到[(3R,5S)-1-[(2S)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]-5-methoxycarbonylpyrrolidin-3-yl] 4-ethenyl-1,3-dihydroisoindole-2-carboxylate
  参考文献：
  名称：

  Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement

  摘要：

  Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and Cellular activity. Among these, Compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.

  DOI：

  10.1021/jm900524b

文献信息

• Macrocyclic Compounds As Antiviral Agents
  申请人：Di Francesco Maria Emilia

  公开号：US20090258891A1

  公开（公告）日：2009-10-15

  The present invention relates to macrocyclic compounds of formula (I): wherein W, n, R 1 , R a , R b , R 3 , R 4 , M, Z, ring A and ring B are defined herein, and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, and their use for the treatment or prevention of infection by hepatitis C virus.

  本发明涉及式(I)的大环化合物： 其中W，n，R1，Ra，Rb，R3，R4，M，Z，环A和环B在此被定义，并且其药学上可接受的盐，包括它们的制药组合物，以及它们用于治疗或预防丙型肝炎病毒感染的用途。
• MACROCYCLIC COMPOUNDS AS ANTIVIRAL AGENTS
  申请人：MSD Italia S.r.l.

  公开号：EP2027144B1

  公开（公告）日：2015-04-29
• US8178520B2
  申请人：——

  公开号：US8178520B2

  公开（公告）日：2012-05-15
• Novel Macrocyclic Inhibitors of Hepatitis C NS3/4A Protease Featuring a 2-Amino-1,3-thiazole as a P4 Carbamate Replacement
  作者：M. Emilia Di Francesco、Gabriella Dessole、Emanuela Nizi、Paola Pace、Uwe Koch、Fabrizio Fiore、Silvia Pesci、Jillian Di Muzio、Edith Monteagudo、Michael Rowley、Vincenzo Summa

  DOI：10.1021/jm900524b

  日期：2009.11.26

  Our laboratories recently reported the discovery of P2-P4 macrocyclic inhibitors of HCV NS3/4A protease, characterized by high levels of potency and liver exposure. Within this novel class of inhibitors, we here describe the identification of a structurally diverse series of compounds featuring a 2-amino-1,3-thiazole as replacement of the carbamate in P4. Optimization studies focused on structural modifications in the P3, P2, and P1 regions of the macrocycle as well as on the linker chain and resulted in the discovery of several analogues characterized by excellent levels of enzyme and Cellular activity. Among these, Compound 59 displayed an attractive pharmacokinetic profile in preclinical species and showed sustained liver levels following oral administration in rats.