2-amino-8-methyl-4-(methylthio)-5H-indeno[1,2-d]pyrimidin-5-one | 1228035-28-6

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 2-amino-8-methyl-4-(methylthio)-5H-indeno[1,2-d]pyrimidin-5-one
• 英文别名: 2-Amino-8-methyl-4-methylsulfanylindeno[1,2-d]pyrimidin-5-one
• CAS: 1228035-28-6
• 化学式: C₁₃H₁₁N₃OS
• 分子量: 257.316
• InChiKey: MQESWRCGULWQSF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  94.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-amino-8-methyl-4-(methylthio)-5H-indeno[1,2-d]pyrimidin-5-one 在 4-二甲氨基吡啶 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 N-溴代丁二酰亚胺(NBS) 、 邻苯二甲酸二丁酯 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 2.0h， 生成 2-amino-8-(bromomethyl)-4-phenyl-5H-indeno[1,2-d]-pyrimidin-5-one
  参考文献：
  名称：

  Design and Characterization of Optimized Adenosine A_2A/A₁ Receptor Antagonists for the Treatment of Parkinson's Disease

  摘要：

  The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

  DOI：

  10.1021/jm201640m
• 作为产物：
  描述：

  盐酸胍 、 2-(bis(methylthio)methylene)-6-methyl-2,3-dihydro-1H-inden-1-one 在 potassium carbonate 、 盐酸胍 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以53%的产率得到2-amino-8-methyl-4-(methylthio)-5H-indeno[1,2-d]pyrimidin-5-one
  参考文献：
  名称：

  Design and Characterization of Optimized Adenosine A_2A/A₁ Receptor Antagonists for the Treatment of Parkinson's Disease

  摘要：

  The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

  DOI：

  10.1021/jm201640m

文献信息

• Methylene amine substituted arylindenopyrimidines as potent adenosine A2A/A1 antagonists
  作者：Brian C. Shook、Stefanie Rassnick、Daniel Hall、Kenneth C. Rupert、Geoffrey R. Heintzelman、Kristen Hansen、Devraj Chakravarty、James L. Bullington、Robert H. Scannevin、Brian Magliaro、Lori Westover、Karen Carroll、Lisa Lampron、Ronald Russell、Shawn Branum、Kenneth Wells、Sandra Damon、Scott Youells、Xun Li、Mel Osbourne、Keith Demarest、Yuting Tang、Kenneth Rhodes、Paul F. Jackson

  DOI：10.1016/j.bmcl.2010.03.042

  日期：2010.5

  A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally. (C) 2010 Elsevier Ltd. All rights reserved.
• In Vivo Characterization of a Dual Adenosine A_2A/A₁ Receptor Antagonist in Animal Models of Parkinson’s Disease
  作者：Brian C. Shook、Stefanie Rassnick、Melville C. Osborne、Scott Davis、Lori Westover、Jamie Boulet、Daniel Hall、Kenneth C. Rupert、Geoffrey R. Heintzelman、Kristin Hansen、Devraj Chakravarty、James L. Bullington、Ronald Russell、Shawn Branum、Kenneth M. Wells、Sandra Damon、Scott Youells、Xun Li、Derek A. Beauchamp、David Palmer、Mayra Reyes、Keith Demarest、Yuting Tang、Kenneth Rhodes、Paul F. Jackson

  DOI：10.1021/jm100971t

  日期：2010.11.25

  The in vivo characterization of a dual adenosine A(2A)/A(1) I receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of I from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K-i = 4.1 nM A(1) K-i = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
• Design and Characterization of Optimized Adenosine A_2A/A₁ Receptor Antagonists for the Treatment of Parkinson's Disease
  作者：Brian C. Shook、Stefanie Rassnick、Nathaniel Wallace、Jeffrey Crooke、Mark Ault、Devraj Chakravarty、J. Kent Barbay、Aihua Wang、Mark T. Powell、Kristi Leonard、Vernon Alford、Robert H. Scannevin、Karen Carroll、Lisa Lampron、Lori Westover、Heng-Keang Lim、Ronald Russell、Shawn Branum、Kenneth M. Wells、Sandra Damon、Scott Youells、Xun Li、Derek A. Beauchamp、Kenneth Rhodes、Paul F. Jackson

  DOI：10.1021/jm201640m

  日期：2012.2.9

  The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.