1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea
• 英文别名: 3-[3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-yl]-1-{4-[2-(morpholin-4-yl)ethoxy]naphthalen-1-yl}urea；1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea
• 化学式: C₃₀H₃₆N₆O₃
• 分子量: 528.654
• InChiKey: RIECGSRTVPSRCE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  93.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-甲基-5-硝基吡啶 在 palladium on activated charcoal 盐酸 、 氢气 、 碳酸氢钠 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 63.75h， 生成 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-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

文献信息

• 1,4-Benzofused urea compounds useful in treating cytokine mediated diseases
  申请人：Boehringer Ingelheim Pharmaceuticals, Inc.

  公开号：US20030232865A1

  公开（公告）日：2003-12-18

  Disclosed are 1,4-disubstituted benzo-fused urea compounds of formula (I): 1 wherein Ar, X, A, L, and Q of formula(I) are defined herein. The compounds inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

  披露了公式(I)的1,4-二取代苯并尿素化合物：1其中，公式(I)中的Ar、X、A、L和Q在本文中定义。这些化合物抑制参与炎症过程的细胞因子的产生，因此可用于治疗涉及炎症的疾病和病理状况，如慢性炎症疾病。还披露了制备这些化合物的方法以及包含这些化合物的药物组合物。
• Methods of treating cytokine mediated diseases
  申请人：Boehringer Ingelheim Pharmaceuticals, Inc.

  公开号：US20030130309A1

  公开（公告）日：2003-07-10

  Disclosed are methods of treating certain cytokine mediated diseases or conditions using novel aromatic heterocyclic compounds of the formula(I) wherein Ar 1 ,Ar 2 ,L,Q and X are described herein. 1

  披露了使用公式(I)中描述的新芳香杂环化合物治疗特定细胞因子介导的疾病或症状的方法，其中Ar1，Ar2，L，Q和X如下所述。
• Anticoagulant and fibrinolytic therapy uning p38 MAP kinase inhibitors
  申请人：Boehringer Ingelheim Pharmaceuticals, Inc.

  公开号：US20040033222A1

  公开（公告）日：2004-02-19

  Disclosed are methods for a treating a disease or condition relating to blood coagulation and fibrinolysis using p38 MAP kinase inhibitors.

  揭示了利用p38 MAP激酶抑制剂治疗与血液凝血和纤溶有关的疾病或症状的方法。
• Method of treating mucus hypersecretion
  申请人：Boehringer Ingelheim Pharma GmbH & Co. KG

  公开号：US20030220336A1

  公开（公告）日：2003-11-27

  The invention relates to the use of p38 kinase inhibitors for the preparation of a pharmaceutical composition suitable for inhalation for the treatment of mucus hypersecretion. Furthermore the invention is directed to pharmaceutical compositions suitable for inhalation comprising p38 kinase inhibitors and to methods for the preparation thereof.

  本发明涉及使用p38激酶抑制剂制备适用于治疗黏液过度分泌的吸入药物组合物。此外，本发明还涉及适用于吸入的含有p38激酶抑制剂的药物组合物以及其制备方法。
• [EN] AROMATIC HETEROCYCLIC COMPOUNDS AS ANTIINFLAMMATORY AGENTS<br/>[FR] COMPOSES HETEROCYCLIQUES AROMATIQUES UTILISES COMME AGENTS ANTI-INFLAMMATOIRES
  申请人：BOEHRINGER INGELHEIM PHARMA

  公开号：WO2000043384A1

  公开（公告）日：2000-07-27

  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 involving inflammation such as chronic inflammatory diseases. Also disclosed are processes of making such compounds.

  本发明揭示了一种新的芳香族杂环化合物，其化学式为（I），其中Ar1，Ar2，L，Q和X如本文所述。这些化合物在制备药物组合物中有用，用于治疗涉及炎症的疾病或病理条件，如慢性炎症性疾病。本发明还揭示了制备这种化合物的方法。