5-(hydroxymethyl)-1-methyl-4-nitro-1H-imidazole-2-carbonitrile | 1245555-97-8

• 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-(hydroxymethyl)-1-methyl-4-nitro-1H-imidazole-2-carbonitrile
• 英文别名: 5-(Hydroxymethyl)-1-methyl-4-nitroimidazole-2-carbonitrile
• CAS: 1245555-97-8
• 化学式: C₆H₆N₄O₃
• 分子量: 182.139
• InChiKey: CBOPTELTWRZNKT-UHFFFAOYSA-N

物化性质

• 沸点：
  437.3±53.0 °C(Predicted)
• 密度：
  1.58±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  108
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-(hydroxymethyl)-1-methyl-4-nitro-1H-imidazole-2-carbonitrile 在 硫酸 、 N,N-二异丙基乙胺 、 lithium bromide 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.5h， 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
• 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) 、 水 、 溴 、 potassium carbonate 、 锌 作用下， 以 氯仿 、 N,N-二甲基乙酰胺 、 乙腈 为溶剂， 反应 7.5h， 生成 5-(hydroxymethyl)-1-methyl-4-nitro-1H-imidazole-2-carbonitrile
  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：Auckland Uniservices Limited

  公开号：US20160031877A1

  公开（公告）日：2016-02-04

  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 3 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 2 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 3 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.

  本发明提供了化合物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与它们所连接的碳原子形成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，R3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R2与R3组合时，除非R2位于3-位且与R3位于4-位组合，否则R2为溴，R3为氟；(k) R2为2-吡啶甲氧基，R3为氟；或(l) R2为2-吡啶甲氧基，R3为溴；或(2) R1、R2和R3中至少有一个选择自苄氧基、3-氯苄氧基和2-吡啶甲氧基，且当R1、R2和R3中至少有一个不是苄氧基、3-氯苄氧基或2-吡啶甲氧基时，其余各自独立选择自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，其余两个不为H；或(3) R1、R2和R3中的两个，与它们所连接的碳原子一起形成1-(3-氟苯基)-1H-吡唑，另一个选择自H、卤素和C2-C4炔基。此外，还提供了还原型前药，包括上述激酶抑制剂和直接或间接与激酶抑制剂的氮原子相连的还原触发剂。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些组合物，特别是用于治疗癌症。
• PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY
  申请人：Auckland Uniservices Limited

  公开号：US20160002222A1

  公开（公告）日：2016-01-07

  The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R 1 is a group of the formula —(CH 2 ) n Tr, where Tr is an aromatic nitroheterocyde or aromatic nitrocarbocycle and —(CH 2 ) n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R 2 , R 3 and R 4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R 2 )(R 3 )(R 4 )N, or two of R 2 , R 3 , and R 4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R 2 , R 3 , and R 4 may be absent and two of R 2 , R 3 and R 4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

  本发明提供了新型的前药化合物，包括一种激酶抑制剂和一种还原活化的分裂芳香族硝基杂环或芳香族硝基碳杂环触发物，其中该化合物带有正电荷。在优选实施例中，该化合物的化学式为I：其中：X是任何带负电的反离子；R1是公式—（CH2）nTr的基团，其中Tr是一种芳香族硝基杂环或芳香族硝基碳杂环，而—（ ）nTr作为还原活化的分裂触发器；n是从0到6的整数；R2、R3和R4可以各自独立地选择来自三级胺激酶抑制剂（R2）（R3）（R4）N的脂肪族或芳香族基团，或者R2、R3和R4中的两个可以形成激酶抑制剂的脂肪族或芳香族杂环胺环，或者R2、R3和R4中的一个可以不存在，而R2、R3和R4中的两个可以形成激酶抑制剂的芳香族杂环胺环。本发明的化合物在治疗增殖性疾病如癌症方面是有用的。
• [EN] PRODRUG FORMS OF KINASE INHIBITORS AND THEIR USE IN THERAPY<br/>[FR] FORMES PROMÉDICAMENTS D'INHIBITEURS DE KINASE ET LEUR UTILISATION EN THÉRAPIE
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2010104406A8

  公开（公告）日：2011-10-06
• US9073916B2
  申请人：——

  公开号：US9073916B2

  公开（公告）日：2015-07-07
• US9101632B2
  申请人：——

  公开号：US9101632B2

  公开（公告）日：2015-08-11