chloromethyl cyclopropyl(4-methyl-3-(5-methyl-6-(propylcarbamoyl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)benzoyl)carbamate | 948842-99-7

• 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: chloromethyl cyclopropyl(4-methyl-3-(5-methyl-6-(propylcarbamoyl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)benzoyl)carbamate
• 英文别名: chloromethyl N-cyclopropyl-N-[4-methyl-3-[[5-methyl-6-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzoyl]carbamate
• CAS: 948842-99-7
• 化学式: C₂₄H₂₇ClN₆O₄
• 分子量: 498.969
• InChiKey: MZPXHHSCMNHGCF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  chloromethyl cyclopropyl(4-methyl-3-(5-methyl-6-(propylcarbamoyl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)benzoyl)carbamate 、 monosodium fumarate 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 (E)-4-[[cyclopropyl-[4-methyl-3-[[5-methyl-6-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]benzoyl]carbamoyl]oxymethoxy]-4-oxobut-2-enoic acid
  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：

  3-硝基-N-环丙基-4-甲基-苯甲酰胺 在 氯化铵 、 lithium hexamethyldisilazane 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 chloromethyl cyclopropyl(4-methyl-3-(5-methyl-6-(propylcarbamoyl)pyrrolo[1,2-f][1,2,4]triazin-4-ylamino)benzoyl)carbamate
  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

• PYRROLOTRIAZINE ANILINE PRODRUG COMPOUNDS USEFUL AS KINASE INHIBITORS
  申请人：Liu Chunjian

  公开号：US20070213300A1

  公开（公告）日：2007-09-13

  Compounds having the Formula (I), including pharmaceutically acceptable salts thereof, wherein at least one of X 1 , X 2 or X 3 is and any remaining X 1 , X 2 or X 3 is hydrogen, which are useful as kinase inhibitors, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A 1 , A 2 and m are as described herein.

  具有化学式（I）的化合物，包括其药学上可接受的盐，其中X1、X2或X3中至少有一个是氢，其余的X1、X2或X3是氢，这些化合物可用作激酶抑制剂，其中R1、R2、R3、R4、R5、R6、A1、A2和m如本文所述。
• US7572795B2
  申请人：——

  公开号：US7572795B2

  公开（公告）日：2009-08-11
• [EN] PYRROLOTRIAZINE ANILINE PRODRUG COMPOUNDS USEFUL AS KINASE INHIBITORS<br/>[FR] COMPOSES DE PROMEDICAMENT DE PYRROLOTRIAZINE ANILINE UTILES EN TANT QU'INHIBITEURS DE LA KINASE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2007103839A2

  公开（公告）日：2007-09-13

  [EN] Compounds having the Formula (I), including pharmaceutically acceptable salts thereof, [INSERT CHEMICAL STRUCTURE HERE] (I), wherein at least one of X1, X2 or X3 is INSERT CHEMICAL STRUCTURE HERE] (i), and any remaining X1, X2 or X3 is hydrogen, which are useful as kinase inhibitors, wherein R1 , R2, R3, R4, R5, R6, A1, A2and m are as described herein.
  [FR] La présente invention concerne des composés répondant à la formule (I), incluant des sels pharmaceutiquement acceptables de ceux-ci, [INSERER LA FORMULE CHIMIQUE ICI] (I), dans laquelle au moins un élément choisi parmi X1, X2 ou X3 représente [INSERER LA FORMULE CHIMIQUE ICI] (i), et tout élément restant X1, X2 ou X3 est un atome d'hydrogène, qui sont utiles en tant qu'inhibiteurs de kinase, dans laquelle R1, R2, R3, R4, R5, R6, A1, A2 et m sont tels que décrits dans le présent document.
• 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.