Tert-butyl 4-[5-(cyclopropylcarbamoyl)-2-methylphenyl]imino-5-methyl-6-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazine-3-carboxylate | 948842-81-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Tert-butyl 4-[5-(cyclopropylcarbamoyl)-2-methylphenyl]imino-5-methyl-6-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazine-3-carboxylate
• CAS: 948842-81-7
• 化学式: C₂₇H₃₄N₆O₄
• 分子量: 506.605
• InChiKey: XJQVSTBYRAHHQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Tert-butyl 4-[5-(cyclopropylcarbamoyl)-2-methylphenyl]imino-5-methyl-6-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazine-3-carboxylate 在 sodium iodide 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 丙酮 、 甲苯 为溶剂， 生成 (S)-((4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl 2-(benzyloxycarbonyl)propanoate
  参考文献：
  名称：

  Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor

  摘要：

  A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38 alpha inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and alpha-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of I. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.022
• 作为产物：
  描述：

  4-[[5-[(环丙基氨基)羰基]-2-甲基苯基]氨基]-5-甲基-N-丙基吡咯并[2,1-F][1,2,4]三嗪-6-甲酰胺 、 二碳酸二叔丁酯 在 4-二甲氨基吡啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以70%的产率得到Tert-butyl 4-[5-(cyclopropylcarbamoyl)-2-methylphenyl]imino-5-methyl-6-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazine-3-carboxylate
  参考文献：
  名称：

  Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor

  摘要：

  A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38 alpha inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and alpha-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of I. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.03.022

文献信息

• Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor
  作者：Chunjian Liu、James Lin、Gerry Everlof、Christoph Gesenberg、Hongjian Zhang、Punit H. Marathe、Mary Malley、Michael A. Galella、Murray Mckinnon、John H. Dodd、Joel C. Barrish、Gary L. Schieven、Katerina Leftheris

  DOI：10.1016/j.bmcl.2013.03.022

  日期：2013.5

  A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38 alpha inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and alpha-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of I. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates. (C) 2013 Elsevier Ltd. All rights reserved.