2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile | 1450924-15-8

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile
• 英文别名: 2-(5-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-5-(trifluoromethyl)benzonitrile
• CAS: 1450924-15-8
• 化学式: C₁₆H₁₀F₄N₂O
• 分子量: 322.262
• InChiKey: GSQUVTFNZMCBNF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  36.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile 在 氯磺酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.75h， 生成 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
  参考文献：
  名称：

  The discovery of benzoxazine sulfonamide inhibitors of Na V 1.7: Tools that bridge efficacy and target engagement

  摘要：

  The voltage-gated sodium channel Na(V)1.7 has received much attention from the scientific community due to compelling human genetic data linking gain-and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na(V)1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat Na(V)1.7 versus human Na(V)1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse Na(V)1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.05.070
• 作为产物：
  描述：

  2-氰基-1-氟-4-(三氟甲基)苯 、 5-氟-3,4-二氢-2H-1,4-苯并恶嗪 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 2.08h， 以67%的产率得到2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile
  参考文献：
  名称：

  The discovery of benzoxazine sulfonamide inhibitors of Na V 1.7: Tools that bridge efficacy and target engagement

  摘要：

  The voltage-gated sodium channel Na(V)1.7 has received much attention from the scientific community due to compelling human genetic data linking gain-and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na(V)1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat Na(V)1.7 versus human Na(V)1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse Na(V)1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.05.070

文献信息

• [EN] DIHYDROBENZOXAZINE AND TETRAHYDROQUINOXALINE SODIUM CHANNEL INHIBITORS<br/>[FR] INHIBITEURS DES CANAUX SODIQUES DE TYPE DIHYDROBENZOXAZINE ET TÉTRAHYDROQUINOXALINE
  申请人：AMGEN INC

  公开号：WO2013122897A1

  公开（公告）日：2013-08-22

  The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

  本发明提供了式I的化合物或其药学上可接受的盐，这些化合物是电压门控钠通道的抑制剂，特别是Nav 1.7。这些化合物对于治疗可通过抑制钠通道治疗的疾病，如疼痛障碍，是有用的。还提供了含有本发明化合物的药物组合物。
• DIHYDROBENZOXAZINE AND TETRAHYDROQUINOXALINE SODIUM CHANNEL INHIBITORS
  申请人：AMGEN INC.

  公开号：US20150057271A1

  公开（公告）日：2015-02-26

  The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

  本发明提供了I式化合物或其药学上可接受的盐，其是电压门控钠通道的抑制剂，特别是Nav1.7。这些化合物对于治疗可通过钠通道抑制治疗的疾病如疼痛症状是有用的。还提供了含有本发明化合物的药物组合物。
• Dihydrobenzoxazine and tetrahydroquinoxaline sodium channel inhibitors
  申请人：AMGEN INC.

  公开号：US09346798B2

  公开（公告）日：2016-05-24

  The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

  本发明提供了I式化合物或其药学上可接受的盐，这些化合物是电压门控钠通道的抑制剂，特别是Nav 1.7。这些化合物对于治疗可通过抑制钠通道治疗的疾病，如疼痛障碍，是有用的。还提供了含有本发明化合物的制药组合物。
• US9346798B2
  申请人：——

  公开号：US9346798B2

  公开（公告）日：2016-05-24
• The discovery of benzoxazine sulfonamide inhibitors of Na V 1.7: Tools that bridge efficacy and target engagement
  作者：Daniel S. La、Emily A. Peterson、Christiane Bode、Alessandro A. Boezio、Howard Bregman、Margaret Y. Chu-Moyer、James Coats、Erin F. DiMauro、Thomas A. Dineen、Bingfan Du、Hua Gao、Russell Graceffa、Hakan Gunaydin、Angel Guzman-Perez、Robert Fremeau、Xin Huang、Christopher Ilch、Thomas J. Kornecook、Charles Kreiman、Joseph Ligutti、Min-Hwa Jasmine Lin、Jeff S. McDermott、Isaac Marx、David J. Matson、Stefan I. McDonough、Bryan D. Moyer、Hanh Nho Nguyen、Kristin Taborn、Violeta Yu、Matthew M. Weiss

  DOI：10.1016/j.bmcl.2017.05.070

  日期：2017.8

  The voltage-gated sodium channel Na(V)1.7 has received much attention from the scientific community due to compelling human genetic data linking gain-and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na(V)1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat Na(V)1.7 versus human Na(V)1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse Na(V)1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement. (C) 2017 Elsevier Ltd. All rights reserved.