2-Chloro-5-[(2,2-difluoro-1,3-benzodioxole-5-carbonyl)amino]benzoic acid | 1018070-22-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-Chloro-5-[(2,2-difluoro-1,3-benzodioxole-5-carbonyl)amino]benzoic acid
• CAS: 1018070-22-8
• 化学式: C₁₅H₈ClF₂NO₅
• 分子量: 355.682
• InChiKey: LXYBAXLEJNTENV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N2-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,5-diamine 、 2-Chloro-5-[(2,2-difluoro-1,3-benzodioxole-5-carbonyl)amino]benzoic acid 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 以42%的产率得到N-(4-chloro-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenyl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide
  参考文献：
  名称：

  Structure-Guided Design of Aminopyrimidine Amides as Potent, Selective Inhibitors of Lymphocyte Specific Kinase: Synthesis, Structure–Activity Relationships, and Inhibition of in Vivo T Cell Activation

  摘要：

  The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED50 = 9.4 mg/kg).

  DOI：

  10.1021/jm7010996
• 作为产物：
  描述：

  2,2-二氟-1,3-苯并二恶茂-5-甲酰氯 、 5-氨基-2-氯苯甲酸 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.5h， 以62%的产率得到2-Chloro-5-[(2,2-difluoro-1,3-benzodioxole-5-carbonyl)amino]benzoic acid
  参考文献：
  名称：

  Structure-Guided Design of Aminopyrimidine Amides as Potent, Selective Inhibitors of Lymphocyte Specific Kinase: Synthesis, Structure–Activity Relationships, and Inhibition of in Vivo T Cell Activation

  摘要：

  The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED50 = 9.4 mg/kg).

  DOI：

  10.1021/jm7010996

文献信息

• Structure-Guided Design of Aminopyrimidine Amides as Potent, Selective Inhibitors of Lymphocyte Specific Kinase: Synthesis, Structure–Activity Relationships, and Inhibition of in Vivo T Cell Activation
  作者：Erin F. DiMauro、John Newcomb、Joseph J. Nunes、Jean E. Bemis、Christina Boucher、Lilly Chai、Stuart C. Chaffee、Holly L. Deak、Linda F. Epstein、Ted Faust、Paul Gallant、Anu Gore、Yan Gu、Brad Henkle、Faye Hsieh、Xin Huang、Joseph L. Kim、Josie H. Lee、Matthew W. Martin、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、Huilin Zhao、Li Zhu、Xiaotian Zhu

  DOI：10.1021/jm7010996

  日期：2008.3.1

  The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED50 = 9.4 mg/kg).