3-amino-4-cyclobutyl-2-hydroxy-N-prop-2-enylbutanamide | 856767-47-0

• 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: 3-amino-4-cyclobutyl-2-hydroxy-N-prop-2-enylbutanamide
• CAS: 856767-47-0
• 化学式: C₁₁H₂₀N₂O₂
• 分子量: 212.292
• InChiKey: QNMYEZZQRNTEHT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  15
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  75.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-amino-4-cyclobutyl-2-hydroxy-N-prop-2-enylbutanamide 、 (1R,2S,5S)-3-[(2S)-2-[[(2S)-1-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)-3,3-dimethylbutan-2-yl]carbamoylamino]-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease

  摘要：

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

  DOI：

  10.1021/jm801238q

文献信息

• [EN] SULFUR COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS NS3 SERINE PROTEASE<br/>[FR] COMPOSES SOUFRES EN TANT QU'INHIBITEURS DE LA PROTEASE SERINE NS3 DU VIRUS DE L'HEPATITE C
  申请人：SCHERING CORP

  公开号：WO2005087731A1

  公开（公告）日：2005-09-22

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

  本发明揭示了具有HCV蛋白酶抑制活性的新化合物，以及制备这些化合物的方法。在另一实施例中，本发明揭示了包含这些化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• [EN] CYCLOBUTENEDIONE GROUPS-CONTAINING COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS NS3 SERINE PROTEASE<br/>[FR] GROUPES CYCLOBUTENEDIONE CONTENANT DES COMPOSES SERVANT D'INHIBITEURS A LA SERINE PROTEASE NS3 DU VIRUS DE L'HEPATITE C
  申请人：SCHERING CORP

  公开号：WO2005085197A1

  公开（公告）日：2005-09-15

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

  本发明公开了具有HCV蛋白酶抑制活性的新化合物，以及制备这种化合物的方法。在另一实施方式中，本发明公开了包含这种化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• [EN] NOVEL KETOAMIDES WITH CYCLIC P4'S AS INHIBITORS OF NS3 SERINE PROTEASE OF HEPATITIS C VIRUS<br/>[FR] NOUVEAUX CETOAMIDES A P4 CYCLIQUES EN TANT QU'INHIBITEURS DE LA NS3 SERINE PROTEASE DU VIRUS DE L'HEPATITE C
  申请人：SCHERING CORP

  公开号：WO2005085242A1

  公开（公告）日：2005-09-15

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.

  本发明公开了具有HCV蛋白酶抑制活性的新化合物，以及制备这种化合物的方法。在另一实施方式中，该发明公开了包含这种化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile
  作者：Latha G. Nair、Mousumi Sannigrahi、Stephane Bogen、Patrick Pinto、Kevin X. Chen、Andrew Prongay、Xiao Tong、K.-C. Cheng、Viyyoor Girijavallabhan、F. George Njoroge

  DOI：10.1016/j.bmcl.2009.11.094

  日期：2010.1

  SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K-i* 15 nM, EC 90 = 70 nM) and pharmacokinetic properties (Rat AUC (PO) = 3.52 mu M h) compared to 1. (C) 2009 Elsevier Ltd. All rights reserved.
• Novel potent inhibitors of hepatitis C virus (HCV) NS3 protease with cyclic sulfonyl P3 cappings
  作者：Kevin X. Chen、Bancha Vibulbhan、Weiying Yang、Latha G. Nair、Xiao Tong、Kuo-Chi Cheng、F. George Njoroge

  DOI：10.1016/j.bmcl.2008.12.111

  日期：2009.2

  Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl- sultam cappings were selected for further SAR development. Modi. cation at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall pro. le in potency and PK profile: excellent K-i* of 5.3 nM and activity in replicon (EC90) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 mu Mh. (C) 2009 Elsevier Ltd. All rights reserved.