(6-(4-tert-butylphenyl)pyrimidin-4-yl)-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl)methanone | 943997-63-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (6-(4-tert-butylphenyl)pyrimidin-4-yl)-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl)methanone
• 英文别名: [6-(4-Tert-butylphenyl)pyrimidin-4-yl]-(2,3-dihydro-1,4-benzodioxin-6-yl)methanone
• CAS: 943997-63-5
• 化学式: C₂₃H₂₂N₂O₃
• 分子量: 374.439
• InChiKey: XORKBHQYFQWMMQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  61.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6-(4-tert-butylphenyl)pyrimidin-4-yl)-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl)methanone 在 palladium on activated charcoal 吡啶 、 sodium tetrahydroborate 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 37.0h， 生成 4-(4-Tert-butylphenyl)-6-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)pyrimidine
  参考文献：
  名称：

  Novel Vanilloid Receptor-1 Antagonists:  1. Conformationally Restricted Analogues of trans-Cinnamides

  摘要：

  The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.

  DOI：

  10.1021/jm070189q
• 作为产物：
  描述：

  4-叔丁基苯硼酸 在 四(三苯基膦)钯 sodium hydride 、 1,3-二甲基咪唑 碘 、 potassium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 6.0h， 生成 (6-(4-tert-butylphenyl)pyrimidin-4-yl)-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl)methanone
  参考文献：
  名称：

  Novel Vanilloid Receptor-1 Antagonists:  1. Conformationally Restricted Analogues of trans-Cinnamides

  摘要：

  The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.

  DOI：

  10.1021/jm070189q

文献信息

• Novel Vanilloid Receptor-1 Antagonists:  1. Conformationally Restricted Analogues of <i>trans</i>-Cinnamides
  作者：Mark H. Norman、Jiawang Zhu、Christopher Fotsch、Yunxin Bo、Ning Chen、Partha Chakrabarti、Elizabeth M. Doherty、Narender R. Gavva、Nobuko Nishimura、Thomas Nixey、Vassil I. Ognyanov、Robert M. Rzasa、Markian Stec、Sekhar Surapaneni、Rami Tamir、Vellarkad N. Viswanadhan、James J. S. Treanor

  DOI：10.1021/jm070189q

  日期：2007.7.1

  The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats.