2-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-ylmethylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-ylmethylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide
• 英文别名: 2-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl-methylsulphanyl)-1H-benzoimidazole 4-carboxylic acid amide radical
• 化学式: C₁₇H₂₁N₄O₂S
• 分子量: 345.445
• InChiKey: YWOIGKWRBXISJK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-ylmethylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide 在 铁粉 、 溶剂黄146 、 potassium carbonate 作用下， 以 水 为溶剂， 反应 0.5h， 以49%的产率得到2-(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-ylmethylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide
  参考文献：
  名称：

  New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine Nitroxides and Their Precursors

  摘要：

  4-Carboxamidobenzimidazoles were previously described as PARP inhibitor compounds. Here we report upon 4-carboxamido-1H-benzimidazoles substituted in the 2-position with nitroxides or their amine or hydroxylamine precursors. Among the new molecules, a highly active PARP inhibitor 4h (IC50 = 14 nM) was identified with antioxidant/radical scavenger activity. We concluded that in most cases sterically hindered amines are better PARP inhibitors than their oxidized form and structural changes in the 2-substituted 4-carboxamido-1H-benzimidazoles (such as N-substitution or changing the position of the carboxamide group) were detrimental to PARP inhibition activity but not to antioxidant activity. These results indicate the advantages of combining an antioxidant nitroxide or nitroxide precursor with a PARP inhibitor molecule to decrease or eliminate the deleterious processes initiated by reactive oxygen and reactive nitrogen species (ROS and RNS). The radical scavenging capability of 4h was demonstrated by EPR study of urine collected after drug administration.

  DOI：

  10.1021/jm801476y
• 作为产物：
  描述：

  2,3-二氢-2-硫氧代-1H-苯并咪唑-4-羧酰胺 、 3-(bromomethyl)-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-oxyl 在 氢氧化钾 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以45%的产率得到2-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-ylmethylsulfanyl)-1H-benzimidazole-4-carboxylic acid amide
  参考文献：
  名称：

  [EN] NEW ALICYCLIC-AMINE-SUBSTITUTED 4-CARBOXAMIDO-BENZIMIDAZOLES AS PARP-INHIBITORS AND ANTIOXIDANTS
  [FR] NOUVEAUX 4-CARBOXAMIDO-BENZIMIDAZOLES ALICYCLIQUES SUBSTITUES PAR UNE AMINE UTILISES COMME INHIBITEURS DE PARP ET COMME ANTIOXYDANTS

  摘要：

  公式(I)的化合物及其药用或技术上可接受的酸加成盐——其中，在公式中，R1代表氢、C(1-4)烷基或C(1-4)烷氧基；R2代表氢、C(1-4)烷基、羧基、C(1-4)烷氧羰基、羧酰胺、芳基或杂芳基；R3代表氢、C(1-4)烷基、芳基亚甲基或芳基；Y代表一个价键、一个直链或支链的C(1-4)烯烃、一个羰基氨基-C(1-4)烯烃或一个-S-(CH2)m-基团，其中上述所有烯烃基团可能由一个芳基烯基团隔开；n代表零或整数1；m代表整数1、2或3；Q代表氢、羟基或氧自由基(0)，或与相邻环的N原子一起形成一个+ N = O(氧肟酸)基团；Z代表一个单键或双键，以及它们的药用或技术上可用的盐，它们的制备方法以及它们作为PARP抑制剂和抗氧化剂的生物用途。

  公开号：

  WO2004096793A1

文献信息

• [EN] NEW ALICYCLIC-AMINE-SUBSTITUTED 4-CARBOXAMIDO-BENZIMIDAZOLES AS PARP-INHIBITORS AND ANTIOXIDANTS<br/>[FR] NOUVEAUX 4-CARBOXAMIDO-BENZIMIDAZOLES ALICYCLIQUES SUBSTITUES PAR UNE AMINE UTILISES COMME INHIBITEURS DE PARP ET COMME ANTIOXYDANTS
  申请人：HIDEG KALMAN

  公开号：WO2004096793A1

  公开（公告）日：2004-11-11

  Compounds of the formula (I) and their pharmaceutically acceptable or technically applicable acid salts - where in the formula R1 represents hydrogen, C(1-4) alkyl or C(1-4) alkoxy R2 represents hydrogen, C(1-4) alkyl, carboxyl, C(1-4) alkoxycarbonyl, carboxamido,aryl or hetero-aryl R3 represents hydrogen, C(1-4) alkyl, aryl-methylene, or aryl, Y is a valency bond, a straight or branched chain C(1-4) alkene, a carbonyl-amino- C(1-4) alkene, or a -S- (CH2)m- group, where all alkene groups above may be spaced by an arylene group, n represents zero or the integer 1 m represents the integer 1, 2 or 3 Q represents hydrogen, hydroxyl or the oxygen radical (0) or together with the N atom of the adjacent ring forms a +N=O (oxoimmonium) group Z represents a single or double bond and their pharmaceutically acceptable or technically useful salts, processes for their preparation and their biological use as PARP inhibitors and antioxidants.

  公式(I)的化合物及其药用或技术上可接受的酸加成盐——其中，在公式中，R1代表氢、C(1-4)烷基或C(1-4)烷氧基；R2代表氢、C(1-4)烷基、羧基、C(1-4)烷氧羰基、羧酰胺、芳基或杂芳基；R3代表氢、C(1-4)烷基、芳基亚甲基或芳基；Y代表一个价键、一个直链或支链的C(1-4)烯烃、一个羰基氨基-C(1-4)烯烃或一个-S-(CH2)m-基团，其中上述所有烯烃基团可能由一个芳基烯基团隔开；n代表零或整数1；m代表整数1、2或3；Q代表氢、羟基或氧自由基(0)，或与相邻环的N原子一起形成一个+ N = O(氧肟酸)基团；Z代表一个单键或双键，以及它们的药用或技术上可用的盐，它们的制备方法以及它们作为PARP抑制剂和抗氧化剂的生物用途。
• New Poly(ADP-ribose) Polymerase-1 Inhibitors with Antioxidant Activity Based on 4-Carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine Nitroxides and Their Precursors
  作者：Tamás Kálai、Mária Balog、Alíz Szabó、Gergely Gulyás、József Jekő、Balázs Sümegi、Kálmán Hideg

  DOI：10.1021/jm801476y

  日期：2009.3.26

  4-Carboxamidobenzimidazoles were previously described as PARP inhibitor compounds. Here we report upon 4-carboxamido-1H-benzimidazoles substituted in the 2-position with nitroxides or their amine or hydroxylamine precursors. Among the new molecules, a highly active PARP inhibitor 4h (IC50 = 14 nM) was identified with antioxidant/radical scavenger activity. We concluded that in most cases sterically hindered amines are better PARP inhibitors than their oxidized form and structural changes in the 2-substituted 4-carboxamido-1H-benzimidazoles (such as N-substitution or changing the position of the carboxamide group) were detrimental to PARP inhibition activity but not to antioxidant activity. These results indicate the advantages of combining an antioxidant nitroxide or nitroxide precursor with a PARP inhibitor molecule to decrease or eliminate the deleterious processes initiated by reactive oxygen and reactive nitrogen species (ROS and RNS). The radical scavenging capability of 4h was demonstrated by EPR study of urine collected after drug administration.