5-carbonitrile-4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(methylthio)pyrimidine | 898254-58-5

• 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: 5-carbonitrile-4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(methylthio)pyrimidine
• 英文别名: 4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile；4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-methylsulfanylpyrimidine-5-carbonitrile
• CAS: 898254-58-5
• 化学式: C₁₃H₉ClFN₃OS
• 分子量: 309.751
• InChiKey: AIZAZEHLXNRKTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  84.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-carbonitrile-4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(methylthio)pyrimidine 在 lithium hydroxide 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 sodium ethanolate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 N-tert-butyl-5-amino-4-(2-fluoro-3-methoxyphenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide
  参考文献：
  名称：

  Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thyroid Stimulating Hormone Receptors:  Structure−Activity Relationships and Selective Binding Patterns

  摘要：

  The substituted thieno[ 2,3-d] pyrimidine 3 ( Org 41841), a partial agonist for the luteinizing hormone/choriogonadotropin receptor ( LHCGR) and the closely related thyroid-stimulating hormone receptor ( TSHR), was fundamentally altered, and the resulting analogues were analyzed for their potencies, efficacies, and specificities at LHCGR and TSHR. Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores. Biochemical analysis of a specific modification to the chemical structure of 3 provides additional evidence of a H-bond between the ligand and a glutamate residue in transmembrane helix 3, which is conserved in both receptors. Several key interactions were surveyed to determine their respective biochemical roles in terms of both van der Waals dimensions and hydrogen bond capacity and the respective relationship to biological activity.

  DOI：

  10.1021/jm060247s
• 作为产物：
  描述：

  5-carbonitrile-1,6-dihydro-4-(2-fluoro-3-methoxyphenyl)-2-(methylthio)-6-oxopyrimidine 在 三氯氧磷 作用下， 以 1,4-二氧六环 为溶剂， 反应 3.0h， 生成 5-carbonitrile-4-chloro-6-(2-fluoro-3-methoxyphenyl)-2-(methylthio)pyrimidine
  参考文献：
  名称：

  Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thyroid Stimulating Hormone Receptors:  Structure−Activity Relationships and Selective Binding Patterns

  摘要：

  The substituted thieno[ 2,3-d] pyrimidine 3 ( Org 41841), a partial agonist for the luteinizing hormone/choriogonadotropin receptor ( LHCGR) and the closely related thyroid-stimulating hormone receptor ( TSHR), was fundamentally altered, and the resulting analogues were analyzed for their potencies, efficacies, and specificities at LHCGR and TSHR. Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores. Biochemical analysis of a specific modification to the chemical structure of 3 provides additional evidence of a H-bond between the ligand and a glutamate residue in transmembrane helix 3, which is conserved in both receptors. Several key interactions were surveyed to determine their respective biochemical roles in terms of both van der Waals dimensions and hydrogen bond capacity and the respective relationship to biological activity.

  DOI：

  10.1021/jm060247s

文献信息

• Inhibitors of TNFalpha, PDE4 and B-RAF, compositions thereof and methods of use therewith
  申请人：McKenna M. Jeffrey

  公开号：US20080004271A1

  公开（公告）日：2008-01-03

  Provided herein are compounds having TNFα and/or PDE4 and/or B-RAF inhibitory activity, and compositions thereof. In particular, provided herein are compounds of the formula I: and pharmaceutically acceptable salts, solvates, hydrates, clathrates, stereoisomers, polymorphs and prodrugs thereof, wherein Ar, R 1 , R 2 , R 3 , R 4 , n and Z are as described herein. Further provided herein are methods for treating or preventing various diseases and disorders by administering to a patient one or more TNFα and/or PDE4 and/or B-RAF inhibitors. In particular, provided herein are methods for preventing or treating cancer, inflammatory disorders, cognition and memory disorders and autoimmune disorders, or one or more symptoms thereof by administering to a patient one or more TNFα and/or PDE4 and/or B-RAF inhibitors.

  本文提供具有TNFα和/或PDE4和/或B-RAF抑制活性的化合物及其组合物。特别地，本文提供了式I的化合物：以及其药学上可接受的盐、溶剂化合物、水合物、包合物、立体异构体、多晶形和前药，其中Ar、R1、R2、R3、R4、n和Z如本文所述。此外，本文提供了通过向患者给予一种或多种TNFα和/或PDE4和/或B-RAF抑制剂来治疗或预防各种疾病和疾病的方法。特别地，本文提供了通过向患者给予一种或多种TNFα和/或PDE4和/或B-RAF抑制剂来预防或治疗癌症、炎症性疾病、认知和记忆障碍和自身免疫性疾病或其一种或多种症状的方法。
• [EN] INHIBITORS OF TNFa, PDE4 AND B-RAF, COMPOSITIONS THEREOF AND METHODS OF USE THEREWITH<br/>[FR] INHIBITEURS DE TNFa, DE PDE4 ET DE B-RAF, COMPOSITIONS COMPRENANT CES INHIBITEURS ET MÉTHODES D'UTILISATION ASSOCIÉES
  申请人：SIGNAL PHARM LLC

  公开号：WO2007084560A3

  公开（公告）日：2007-09-20
• INHIBITORS OF TNF ALPHA , PDE4 AND B-RAF, COMPOSITIONS THEREOF AND METHODS OF USE THEREWITH
  申请人：Signal Pharmaceuticals LLC

  公开号：EP1984377A2

  公开（公告）日：2008-10-29
• Evaluation of Small-Molecule Modulators of the Luteinizing Hormone/Choriogonadotropin and Thyroid Stimulating Hormone Receptors:  Structure−Activity Relationships and Selective Binding Patterns
  作者：Susanna Moore、Holger Jaeschke、Gunnar Kleinau、Susanne Neumann、Stefano Costanzi、Jian-kang Jiang、John Childress、Bruce M. Raaka、Anny Colson、Ralf Paschke、Gerd Krause、Craig J. Thomas、Marvin C. Gershengorn

  DOI：10.1021/jm060247s

  日期：2006.6.1

  The substituted thieno[ 2,3-d] pyrimidine 3 ( Org 41841), a partial agonist for the luteinizing hormone/choriogonadotropin receptor ( LHCGR) and the closely related thyroid-stimulating hormone receptor ( TSHR), was fundamentally altered, and the resulting analogues were analyzed for their potencies, efficacies, and specificities at LHCGR and TSHR. Chemical modification of the parent compound combined with prior mutagenesis of TSHR provided compelling experimental evidence in support of computational models of 3 binding to TSHR and LHCGR within their transmembrane cores. Biochemical analysis of a specific modification to the chemical structure of 3 provides additional evidence of a H-bond between the ligand and a glutamate residue in transmembrane helix 3, which is conserved in both receptors. Several key interactions were surveyed to determine their respective biochemical roles in terms of both van der Waals dimensions and hydrogen bond capacity and the respective relationship to biological activity.