1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-hydroxynaphthalen-1-yl)-urea | 476010-14-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-hydroxynaphthalen-1-yl)-urea
• 英文别名: 1-[5-Tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-(4-hydroxynaphthalen-1-yl)urea
• CAS: 476010-14-7
• 化学式: C₂₅H₂₆N₄O₂
• 分子量: 414.507
• InChiKey: PZQAJEAIAYSEEM-UHFFFAOYSA-N

物化性质

• 沸点：
  537.8±50.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  79.2
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(2-氯乙基)哌啶盐酸盐 、 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-hydroxynaphthalen-1-yl)-urea 在 sodium hydroxide 、 苄基三丁基氯化铵 作用下， 以 二氯甲烷 为溶剂， 反应 8.0h， 以35%的产率得到3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-{4-[2-(piperidin-1-yl)ethoxy]naphthalen-1-yl}urea
  参考文献：
  名称：

  Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

  摘要：

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.

  DOI：

  10.1021/jm030121k
• 作为产物：
  描述：

  4-氨基-1-萘酚 在 4-二甲氨基吡啶 、 碳酸氢钠 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 为溶剂， 反应 48.25h， 生成 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-hydroxynaphthalen-1-yl)-urea
  参考文献：
  名称：

  Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

  摘要：

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.

  DOI：

  10.1021/jm030121k

文献信息

• Compounds useful as anti-inflammatory agents
  申请人：Boehringer Ingelheim Pharmaceuticals, Inc.

  公开号：US20030008868A1

  公开（公告）日：2003-01-09

  Disclosed are compounds useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.

  公开了一些化合物，可用于制备用于治疗涉及炎症的疾病或病理状况，如慢性炎症性疾病的药物组合物。还公开了制备这些化合物的方法。
• DIARYLUREA DERIVATIVES USEFUL AS ANTI-INFLAMMATORY AGENTS
  申请人：BOEHRINGER INGELHEIM PHARMACEUTICALS INC.

  公开号：EP1392661A1

  公开（公告）日：2004-03-03
• US6852717B2
  申请人：——

  公开号：US6852717B2

  公开（公告）日：2005-02-08
• [EN] DIARYLUREA DERIVATIVES USEFUL AS ANTI-INFLAMMATORY AGENTS<br/>[FR] DERIVES DE DIARYLUREE UTILISABLES EN TANT QU'AGENTS ANTI-INFLAMMATOIRES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2002092576A1

  公开（公告）日：2002-11-21

  Disclosed are diarylurea derivatives useful in pharmaceutic compositions for treating diseases or pathological conditions involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.
• Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-<i>tert</i>-Butyl-2-<i>p</i>-tolyl-2<i>H</i>-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)
  作者：John Regan、Alison Capolino、Pier F. Cirillo、Thomas Gilmore、Anne G. Graham、Eugene Hickey、Rachel R. Kroe、Jeffrey Madwed、Monica Moriak、Richard Nelson、Christopher A. Pargellis、Alan Swinamer、Carol Torcellini、Michele Tsang、Neil Moss

  DOI：10.1021/jm030121k

  日期：2003.10.1

  We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38alpha MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38alpha inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important pi-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38alpha by 16-17 degreesC translating into K-d values of 50-100 pM. Finally, we describe several compounds that potently inhibit TNF-alpha production when dosed orally in mice.