[2H]-Telaprevir

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: [2H]-Telaprevir
• 英文别名: (1S,3aR,6aS)-N-((S)-3-deutero-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide；d-telaprevir；d-VX-950；(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxo-3-deutero-hexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide；(3S,3aS,6aR)-2-[(2S)-2-[[(2S)-2-cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-3-deuterio-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxamide
• 化学式: C₃₆H₅₃N₇O₆
• 分子量: 680.852
• InChiKey: BBAWEDCPNXPBQM-FRYYVICASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  49
• 可旋转键数：
  14
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  180
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  [2H]-Telaprevir 生成 特拉匹韦
  参考文献：
  名称：

  Deuterated hepatitis C protease inhibitors

  摘要：

  一种氘代的α-酮氨基立体特异化合物，其化学式为其中D表示立体特异碳原子上的一个氘原子。

  公开号：

  US20070225297A1
• 作为产物：
  描述：

  (1S,3aR,6aS)-N-((S)-3-deutero-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxamide 在 sodium hypochlorite 、 2,2,6,6-四甲基哌啶氧化物 、 碳酸氢钠 作用下， 以 二氯甲烷 、 水 为溶剂， 以9.2 g的产率得到[2H]-Telaprevir
  参考文献：
  名称：

  In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats

  摘要：

  Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the alpha-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a similar to 13% increase of AUC for 1.

  DOI：

  10.1021/jm901023f

文献信息

• Process for preparing optically enriched compounds
  申请人：Vertex Pharmceuticals Incorporated

  公开号：EP2194039A1

  公开（公告）日：2010-06-09

  This invention relates to a process for preparing a compound of Formula 1 wherein: the carbon atoms alpha and beta to the carboxy group are stereocenters; R1 is independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; R'1 is deuterium such that the deuterium enrichment is at least 50%; R'2 is -NHR2 or -OE; R2 is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and E is C1-6 alkyl or benzyl; wherein the process comprises the steps of: a) forming a salt of a compound of Formula 1, and b) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.

  本发明涉及一种制备式 1 化合物的工艺 其中 羧基的碳原子α和β是立体中心； R1 独立地为 H、任选取代的脂肪族、任选取代的环脂族、任选取代的芳脂族、任选取代的杂脂族或任选取代的杂芳脂族； R'1 是氘，氘富集度至少为 50%； R'2 是-NHR2 或-OE； R2 是 H、任选取代的脂肪族、任选取代的环脂族、任选取代的芳脂族、任选取代的杂脂族或任选取代的杂芳脂族；以及 E 是 C1-6 烷基或苄基； 其中该工艺包括以下步骤 a) 形成式 1 化合物的盐，和 b) 结晶所述盐，得到对映体过量率大于 55%的化合物。
• DEUTERATED HEPATITIS C PROTEASE INHIBITORS
  申请人：Perni Robert B.

  公开号：US20110071074A1

  公开（公告）日：2011-03-24

  A deuterated α-ketoamido steric specific compound of the formula wherein D denotes a deuterium atom on a steric specific carbon atom.
• US8247532B2
  申请人：——

  公开号：US8247532B2

  公开（公告）日：2012-08-21
• Deuterated hepatitis C protease inhibitors
  申请人：Perni B. Robert

  公开号：US20070225297A1

  公开（公告）日：2007-09-27

  A deuterated α-ketoamido steric specific compound of the formula wherein D denotes a deuterium atom on a steric specific carbon atom.

  一种氘代的α-酮氨基立体特异化合物，其化学式为其中D表示立体特异碳原子上的一个氘原子。
• In Vitro and In Vivo Isotope Effects with Hepatitis C Protease Inhibitors: Enhanced Plasma Exposure of Deuterated Telaprevir versus Telaprevir in Rats
  作者：François Maltais、Young Chun Jung、Minzhang Chen、Jerry Tanoury、Robert B. Perni、Nagraj Mani、Leena Laitinen、Hui Huang、Shengkai Liao、Hongying Gao、Hong Tsao、Eric Block、Chien Ma、Rebecca S. Shawgo、Christopher Town、Christopher L. Brummel、David Howe、S. Pazhanisamy、Scott Raybuck、Mark Namchuk、Youssef L. Bennani

  DOI：10.1021/jm901023f

  日期：2009.12.24

  Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One of the major metabolites of 2 is its P1-(R)-diastereoisomer, 3 (VRT-394), containing an inversion at the chiral center next to the alpha-ketoamide on exchange of a proton with solvent. Compound 3 is approximately 30-fold less active against HCV protease. In an attempt to suppress the epimerization of 2 without losing activity against the HCV protease, the proton at that chiral site was replaced with deuterium (d). The compound 1 (d-telaprevir) is as efficacious as 2 in in vitro inhibition of protease activity and viral replication (replicon) assays. The kinetics of in vitro stability of 1 and 2 in buffered pH solutions and plasma samples, including human plasma, suggest that 1 is significantly more stable than 2. Oral administration (10 mg/kg) in rats resulted in a similar to 13% increase of AUC for 1.