5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carboxamide | 1456787-34-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carboxamide
• 英文别名: 5-(bromomethyl)-1-methyl-4-nitroimidazole-2-carboxamide
• CAS: 1456787-34-0
• 化学式: C₆H₇BrN₄O₃
• 分子量: 263.051
• InChiKey: LCSONNBNKPVRIG-UHFFFAOYSA-N

物化性质

• 沸点：
  472.4±53.0 °C(Predicted)
• 密度：
  2.06±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1,5-二甲基-4-硝基咪唑 在 1,1'-双(二苯基膦)二茂铁 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N-溴代丁二酰亚胺(NBS) 、 硫酸 、 水 、 溴 、 potassium carbonate 、 N,N-二异丙基乙胺 、 lithium bromide 、 锌 作用下， 以 四氢呋喃 、 氯仿 、 N,N-二甲基乙酰胺 、 水 、 乙腈 为溶剂， 反应 9.0h， 生成 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carboxamide
  参考文献：
  名称：

  Synthesis of substituted 5-bromomethyl-4-nitroimidazoles and use for the preparation of the hypoxia-selective multikinase inhibitor SN29966

  摘要：

  5-Bromomethyl-4-nitroimidazoles have utility as bioreductive trigger precursors for the preparation of hypoxia-selective prodrugs. Here we describe an efficient two-step synthesis of 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole, a preferred precursor, employing an N-bromosuccinimide mediated radical bromination. Use of this precursor to prepare SN29966, a promising hypoxia-selective irreversible pan-ErbB inhibitor is reported along with the preparation of four other prodrug candidates. 5-Bromomethyl-4-nitroimidazole analogues bearing electron-donating and electron-withdrawing substituents at the N-1 and C-2 positions are also described. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2013.08.037

文献信息

• KINASE INHIBITORS, PRODRUG FORMS THEREOF AND THEIR USE IN THERAPY
  申请人：Smaill Jeffrey Bruce

  公开号：US20120202832A1

  公开（公告）日：2012-08-09

  The invention provides kinase inhibitors of Formula I: wherein either: (1) R 1 is H, and (a) R 2 is (3-chlorobenzyl)oxy- and R 3 is chloro; (b) R 2 and R 3 , together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole; (c) R 2 is 2-pyridinylmethoxy and R 3 is chloro; (d) R 2 and R 3 are both chloro; (e) R 2 is chloro and R 1 is bromo; (f) R 2 and R 3 are both bromo; (g) R 2 is fluoro and R 3 is ethynyl; (h) R 2 is chloro and R 3 is ethynyl; (i) R 2 is bromo and R 3 is ethynyl; (j) other than when R 1 is in the 3-position in combination with R 3 , in the 4-position, R 2 is bromo and R 3 is fluoro; (k) R 2 is 2-pyridinylmethoxy and R 3 is fluoro; or (l) R 2 is 2-pyridinylmethoxy and R 1 is bromo; or (2) at least one of R 1 , R 2 and R 3 is selected from benzyloxy, 3-chlorobenzyloxy and 2-pyridinylmethoxy and when at least one of R 1 , R 2 and R 3 is not benzyloxy, 3-chlorobenzyloxy or 2-pyridinylmethoxy, each of the others is independently selected from H, halogen, and C 2 -C 4 alkynyl, with the proviso that when one of R 1 , R 2 and R 3 is benzyloxy or 2-pyridinylmethoxy, the other two of R 1 , R 2 and R 3 are not H; or (3) two of R 1 , R 2 and R 3 , together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole; and the other is selected from H, halogen and C 2 -C 4 alkynyl. Also provided are reductive prodrugs, comprising a kinase inhibitor as defined above and a reductive trigger linked directly or indirectly to a nitrogen of the kinase inhibitor. Further provided are pharmaceutical compositions, comprising the kinase inhibitors or the prodrugs, and the use of such compositions in therapy, in particular for treating cancer.

  本发明提供了式I的激酶抑制剂：其中：(1) R1为H，且(a) R2为(3-氯苯基)氧基，R3为氯；(b) R2和R3与它们连接的碳原子一起形成1-(3-氟苯基)-1H-吡唑；(c) R2为2-吡啶甲氧基，R3为氯；(d) R2和R3均为氯；(e) R2为氯，R1为溴；(f) R2和R3均为溴；(g) R2为氟，R3为乙炔基；(h) R2为氯，R3为乙炔基；(i) R2为溴，R3为乙炔基；(j) 当R1与R3组合时，R1在3位，R2在4位，R2为溴，R3为氟，除外；(k) R2为2-吡啶甲氧基，R3为氟；或(l) R2为2-吡啶甲氧基，R1为溴；或(2) R1、R2和R3中至少有一个选择自苄氧基、3-氯苯甲氧基和2-吡啶甲氧基，当R1、R2和R3中至少有一个不是苄氧基、3-氯苯甲氧基或2-吡啶甲氧基时，其他每个基团独立选择自H、卤素和C2-C4炔基，但当R1、R2和R3中有一个为苄氧基或2-吡啶甲氧基时，另外两个基团不为H；或(3) R1、R2和R3中的两个与它们连接的碳原子一起形成1-(3-氟苯基)-1H-吡唑；另外一个基团选择自H、卤素和C2-C4炔基。还提供了还原前药，包括定义如上的激酶抑制剂和直接或间接连接到激酶抑制剂的氮上的还原触发剂。还提供了制药组合物，包括激酶抑制剂或前药，以及在治疗中使用这种组合物，特别是用于治疗癌症。
• Kinase inhibitors, prodrug forms thereof and their use in therapy
  申请人：Smaill Jeffrey Bruce

  公开号：US09101632B2

  公开（公告）日：2015-08-11

  The invention provides kinase inhibitors of Formula I: wherein either: (1) R1 is H, and (a) R2 is (3-chlorobenzyl)oxy-and R3 is chloro; (b) R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole; (c) R2 is 2-pyridinylmethoxy and R3 is chloro; (d) R2 and R3 are both chloro; (e) R2 is chloro and R1 is bromo; (f) R2 and R3 are both bromo; (g) R2 is fluoro and R3 is ethynyl; (h) R2 is chloro and R3 is ethynyl; (i) R2 is bromo and R3 is ethynyl; (j) other than when R1 is in the 3-position in combination with R3, in the 4-position, R2 is bromo and R3 is fluoro; (k) R2 is 2-pyridinylmethoxy and R3 is fluoro; or (l) R2 is 2-pyridinylmethoxy and R1 is bromo; or (2) at least one of R1, R2 and R3 is selected from benzyloxy, 3-chlorobenzyloxy and 2-pyridinylmethoxy and when at least one of R1, R2 and R3 is not benzyloxy, 3-chlorobenzyloxy or 2-pyridinylmethoxy, each of the others is independently selected from H, halogen, and C2-C4 alkynyl, with the proviso that when one of R1, R2 and R3 is benzyloxy or 2-pyridinylmethoxy, the other two of R1, R2 and R3 are not H; or (3) two of R1, R2 and R3, together with the carbon atoms to which they are attached, form 1-(3-fluorobenzyl)-1H-pyrazole; and the other is selected from H, halogen and C2-C4 alkynyl. Also provided are reductive prodrugs, comprising a kinase inhibitor as defined above and a reductive trigger linked directly or indirectly to a nitrogen of the kinase inhibitor. Further provided are pharmaceutical compositions, comprising the kinase inhibitors or the prodrugs, and the use of such compositions in therapy, in particular for treating cancer.

  本发明提供了Formula I的激酶抑制剂：其中要么：（1）R1为H，且（a）R2为（3-氯苯基）氧基且R3为氯；（b）R2和R3与它们附着的碳原子一起形成1-（3-氟苯基）-1H-吡唑；（c）R2为2-吡啶甲氧基且R3为氯；（d）R2和R3均为氯；（e）R2为氯且R1为溴；（f）R2和R3均为溴；（g）R2为氟且R3为乙炔基；（h）R2为氯且R3为乙炔基；（i）R2为溴且R3为乙炔基；（j）当R1与R3相结合时，不在3位，而在4位时，R2为溴且R3为氟；（k）R2为2-吡啶甲氧基且R3为氟；或（l）R2为2-吡啶甲氧基且R1为溴；或（2）至少有一个R1，R2和R3选自苄氧基，3-氯苯甲氧基和2-吡啶甲氧基，当至少有一个R1，R2和R3不是苄氧基，3-氯苯甲氧基或2-吡啶甲氧基时，其他每个都独立地选自H，卤素和C2-C4炔基，但是当R1，R2和R3中有一个是苄氧基或2-吡啶甲氧基时，其他两个不是H；或（3）两个R1，R2和R3与它们附着的碳原子一起形成1-（3-氟苯基）-1H-吡唑；另外还提供了还原型前药，包括定义如上的激酶抑制剂和与激酶抑制剂的氮直接或间接连接的还原性触发剂。还提供了制药组合物，包括激酶抑制剂或前药，以及这种组合物在治疗中的应用，特别是用于治疗癌症。
• US9101632B2
  申请人：——

  公开号：US9101632B2

  公开（公告）日：2015-08-11