(6-bromo-quinazolin-2-yl)(2-morpholin-4-yl-ethyl)amine | 882670-80-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (6-bromo-quinazolin-2-yl)(2-morpholin-4-yl-ethyl)amine
• 英文别名: 6-bromo-N-(2-morpholinoethyl)quinazolin-2-amine；6-bromo-N-[2-(morpholin-4-yl)ethyl]quinazolin-2-amine；6-bromo-N-(2-morpholin-4-ylethyl)quinazolin-2-amine
• CAS: 882670-80-6
• 化学式: C₁₄H₁₇BrN₄O
• 分子量: 337.219
• InChiKey: HHCYLXCWMOJFHU-UHFFFAOYSA-N

物化性质

• 沸点：
  499.4±55.0 °C(Predicted)
• 密度：
  1.487±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  50.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6-bromo-quinazolin-2-yl)(2-morpholin-4-yl-ethyl)amine 、 N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide 在 四(三苯基膦)钯 、 水 、 sodium carbonate 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 3.0h， 以58%的产率得到N-cyclopropyl-4-methyl-3-(2-((2-(4-morpholinyl)ethyl)amino)-6-quinazolinyl)benzamide
  参考文献：
  名称：

  Discovery of Highly Selective and Potent p38 Inhibitors Based on a Phthalazine Scaffold

  摘要：

  Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.

  DOI：

  10.1021/jm8005417
• 作为产物：
  描述：

  5-溴-2-氟苯甲醛 在 copper(l) iodide 、 二碘甲烷 、 N,N-二异丙基乙胺 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 异丙醇 为溶剂， 反应 4.5h， 生成 (6-bromo-quinazolin-2-yl)(2-morpholin-4-yl-ethyl)amine
  参考文献：
  名称：

  Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck:  Synthesis, SAR, and in Vivo Anti-Inflammatory Activity

  摘要：

  The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED50 of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.

  DOI：

  10.1021/jm0605482

文献信息

• Aryl nitrogen-containing bicyclic compounds and methods of use
  申请人：Patel F. Vinod

  公开号：US20070054916A1

  公开（公告）日：2007-03-08

  The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation, cancer and related conditions. The compounds have a general Formula I wherein A 1 , A 2 , A 3 , B, R 1 , R 2 , R 3 and R 4 are defined herein. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and treatment of kinase mediated diseases using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of compounds of the invention.

  这项发明涉及一类新的化合物，用于预防和治疗蛋白激酶介导的疾病，包括炎症、癌症和相关疾病。这些化合物具有一般的化学式I，其中A1、A2、A3、B、R1、R2、R3和R4在此有定义。因此，该发明还涉及包括该发明的化合物的药物组合物，使用该发明的化合物和组合物预防和治疗激酶介导的疾病的方法，以及用于制备该发明的化合物的中间体和方法。
• ARYL NITROGEN-CONTAINING BICYCLIC COMPOUNDS AND THEIR USE AS KINASE INHIBITORS
  申请人：AMGEN INC.

  公开号：EP1836174A2

  公开（公告）日：2007-09-26
• [EN] ARYL NITROGEN-CONTAINING BICYCLIC COMPOUNDS AND METHODS OF USE<br/>[FR] COMPOSES BICYCLIQUES AZOTES D'ARYLE ET LEURS PROCEDES D'UTILISATION
  申请人：AMGEN INC

  公开号：WO2006039718A2

  公开（公告）日：2006-04-13

  The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation, cancer and related conditions. The compounds have a general Formula I, wherein A1, A2, A3, B, R1, R2, R3 and R4 are defined herein. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and treatment of kinase mediated diseases using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of compounds of the invention.
• Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck:  Synthesis, SAR, and in Vivo Anti-Inflammatory Activity
  作者：Erin F. DiMauro、John Newcomb、Joseph J. Nunes、Jean E. Bemis、Christina Boucher、John L. Buchanan、William H. Buckner、Victor J. Cee、Lilly Chai、Holly L. Deak、Linda F. Epstein、Ted Faust、Paul Gallant、Stephanie D. Geuns-Meyer、Anu Gore、Yan Gu、Brad Henkle、Brian L. Hodous、Faye Hsieh、Xin Huang、Joseph L. Kim、Josie H. Lee、Matthew W. Martin、Craig E. Masse、David C. McGowan、Daniela Metz、Deanna Mohn、Kurt A. Morgenstern、Antonio Oliveira-dos-Santos、Vinod F. Patel、David Powers、Paul E. Rose、Stephen Schneider、Susan A. Tomlinson、Yan-Yan Tudor、Susan M. Turci、Andrew A. Welcher、Ryan D. White、Huilin Zhao、Li Zhu、Xiaotian Zhu

  DOI：10.1021/jm0605482

  日期：2006.9.1

  The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED50 of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
• Discovery of Highly Selective and Potent p38 Inhibitors Based on a Phthalazine Scaffold
  作者：Brad Herberich、Guo-Qiang Cao、Partha P. Chakrabarti、James R. Falsey、Liping Pettus、Robert M. Rzasa、Anthony B. Reed、Andreas Reichelt、Kelvin Sham、Maya Thaman、Ryan P. Wurz、Shimin Xu、Dawei Zhang、Faye Hsieh、Matthew R. Lee、Rashid Syed、Vivian Li、David Grosfeld、Matthew H. Plant、Bradley Henkle、Lisa Sherman、Scot Middleton、Lu Min Wong、Andrew S. Tasker

  DOI：10.1021/jm8005417

  日期：2008.10.23

  Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.