(4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl)carbamic acid tert-butyl ester | 499972-02-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl)carbamic acid tert-butyl ester
• 英文别名: 4-tert-butyloxycarbonylamino-1-(2-(thiomorpholin-4-yl)ethoxy)naphthalene；tert-butyl N-[4-(2-thiomorpholin-4-ylethoxy)naphthalen-1-yl]carbamate
• CAS: 499972-02-0
• 化学式: C₂₁H₂₈N₂O₃S
• 分子量: 388.531
• InChiKey: OJKMDTYEVWNJPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl)carbamic acid tert-butyl ester 在 sodium periodate 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 1-amino-4-(2-(1-oxothiomorpholin-4-yl)ethoxy)naphthalene
  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-羟基-1-萘)-氨基甲酸叔丁酯 在 potassium carbonate 、 N,N-二异丙基乙胺 、 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 为溶剂， 反应 64.0h， 生成 (4-(2-thiomorpholin-4-yl-ethoxy)naphthalen-1-yl)carbamic acid tert-butyl ester
  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

• AROMATIC HETEROCYCLIC COMPOUNDS AS ANTI-INFLAMMATORY AGENTS
  申请人：Boehringer Ingelheim Pharmaceuticals Inc.

  公开号：EP1163236B1

  公开（公告）日：2005-11-09
• US6297381B1
  申请人：——

  公开号：US6297381B1

  公开（公告）日：2001-10-02
• US6476023B1
  申请人：——

  公开号：US6476023B1

  公开（公告）日：2002-11-05
• [EN] AROMATIC HETEROCYCLIC COMPOUNDS AS ANTI-INFLAMMATORY AGENTS<br/>[FR] COMPOSES AROMATIQUES HETEROCYCLIQUES UTILISES EN TANT QU'AGENTS ANTI-INFLAMMATOIRES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2000055152A1

  公开（公告）日：2000-09-21

  Disclosed are novel aromatic heterocyclic compounds of formula (I) wherein Ar1,Ar2,L,Q and X are described herein. The compounds are useful in pharmaceutic compositions for treating diseases or pathological conditions. 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.