N-((2,2-dimethyl-2H-chromen-6-yl)methyl)aniline | 1342891-34-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: N-((2,2-dimethyl-2H-chromen-6-yl)methyl)aniline
• 英文别名: N-((2,2-Dimethyl-2H-chromen-6-yl)methyl)benzenamine；N-[(2,2-dimethylchromen-6-yl)methyl]aniline
• CAS: 1342891-34-2
• 化学式: C₁₈H₁₉NO
• 分子量: 265.355
• InChiKey: DYGNSQXXVACATJ-UHFFFAOYSA-N

物化性质

• 沸点：
  413.5±44.0 °C(Predicted)
• 密度：
  1.109±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  21.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N-((2,2-dimethyl-2H-chromen-6-yl)methyl)aniline 在 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 N-((2,2-dimethylchroman-6-yl)methyl)-4-methoxy-N-phenylbenzenesulfonamide
  参考文献：
  名称：

  Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway

  摘要：

  Many forms of solid tumor have a characteristic feature known as hypoxia, which describes a low or nonexistent presence of oxygen in the cellular microenvironment. This decrease in oxygen causes activation of the hypoxia inducible factor (HIF) pathway, which activates the transcription of many genes that cause cell proliferation, metastasis, increased glycolysis and angiogenesis. Increased HIF expression has been linked with poor patient prognosis, increased malignancy, and therapeutic resistance. Previous work in our lab has identified 1 and 2 as inhibitors of the HIF pathway, specifically as disrupters of the p300-HIF-1 alpha complex formation. A library of sulfonamide analogs has been designed and synthesized with the intent of examining the SAR of this series of compounds and improving potency and physicochemical properties as compared with lead compounds 1 and 2. At the end, we have achieved a thorough understanding of the structural features critical for future optimization work. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2017.02.073
• 作为产物：
  描述：

  6-formyl-2,2-dimethyl-2H-chromene 在 二异丁基氢化铝 、 对甲苯磺酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 生成 N-((2,2-dimethyl-2H-chromen-6-yl)methyl)aniline
  参考文献：
  名称：

  Structure–activity relationship of 2,2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, a novel small molecule hypoxia inducible factor-1 (HIF-1) pathway inhibitor and anti-cancer agent

  摘要：

  We have discovered that 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzene-sulfonamide, a novel small molecule HIF-1 pathway inhibitor, can antagonize tumor growth in animal models of cancer, but the treatment necessitates its delivery in a formulation, due to poor water solubility (<15 mu g/mL; pH 7.4), evidencing that the chemotype needs further exploration of its amenability to additional chemical modifications for ultimate optimization of function and pharmacology.As a first step towards this goal we investigated the structure-activity relationships of 15 lipophilic 2, 2-dimethyl-2H-chromene based arylsulfonamide analogs of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide to find out strategies of modification. A 3,4-dimethoxybenzenesulfonyl group in region 1 showed the strongest inhibition among five arylsulfonyl groups tested. The presence of propan-2-amine in region 2 conferred the strongest inhibitory effect of the compound on HIF-1 activated transcription in a reporter assay. These findings are important as they help define the structural motifs where the 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide can be chemically modified to improve its pharmacological properties towards development as a cancer therapeutic. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.04.064

文献信息

• Inhibitors of HIF and angiogenesis
  申请人：Van Meir Erwin G.

  公开号：US09062072B2

  公开（公告）日：2015-06-23

  Inhibitors of the Hypoxia Inducible Factor (HIF) and angiogenesis and their methods of use including the treatment of cancer, hypoxia related pathologies, disorders leading to ischemia, for example stroke and ischemic heart disease, and non-cancerous angiogenic diseases are provided.

  提供了抑制缺氧诱导因子（HIF）和血管生成的抑制剂及其使用方法，包括治疗癌症、与缺氧相关的病理学、导致缺血的疾病，例如中风和缺血性心脏病，以及非癌性血管生成性疾病。
• INHIBITORS OF HIF AND ANGIOGENESIS
  申请人：Van Meir Erwin G.

  公开号：US20130116275A1

  公开（公告）日：2013-05-09

  Inhibitors of the Hypoxia Inducible Factor (HIF) and angiogenesis and their methods of use including the treatment of cancer, hypoxia related pathologies, disorders leading to ischemia, for example stroke and ischemic heart disease, and non-cancerous angiogenic diseases are provided.

  本发明提供了针对缺氧诱导因子（HIF）和血管生成的抑制剂及其使用方法，包括用于治疗癌症、与缺氧相关的病理学、导致缺血的疾病（例如中风和缺血性心脏病）以及非癌性血管生成性疾病的治疗。
• Design and synthesis of benzopyran-based inhibitors of the hypoxia-inducible factor-1 pathway with improved water solubility
  作者：Jalisa H. Ferguson、Zeus De Los Santos、Saroja N. Devi、Stefan Kaluz、Erwin G. Van Meir、Sarah K. Zingales、Binghe Wang

  DOI：10.1080/14756366.2017.1347784

  日期：2017.1.1

  While progress has been made in treating cancer, cytotoxic chemotherapeutic agents are still the most widely used drugs and are associated with severe side-effects. Drugs that target unique molecular signalling pathways are needed for treating cancer with low or no intrinsic toxicity to normal cells. Our goal is to target hypoxic tumours and specifically the hypoxia inducible factor (HIF) pathway for the development of new cancer therapies. To this end, we have previously developed benzopyran-based HIF-1 inhibitors such as arylsulfonamide KCN1. However, KCN1 and its earlier analogs have poor water solubility, which hamper their applications. Herein, we describe a series of KCN1 analogs that incorporate a morpholine moiety at various positions. We found that replacing the benzopyran group of KCN1 with a phenyl group with a morpholinomethyl moiety at the para positions had minimal effect on potency and improved the water solubility of two new compounds by more than 10-fold compared to KCN1, the lead compound.
• [EN] INHIBITORS OF HIF AND ANGIOGENESIS<br/>[FR] INHIBITEURS DE HIF ET DE L'ANGIOGENÈSE
  申请人：UNIV EMORY

  公开号：WO2011133659A3

  公开（公告）日：2012-03-15
• Design and Synthesis of Novel Small-Molecule Inhibitors of the Hypoxia Inducible Factor Pathway
  作者：Suazette Reid Mooring、Hui Jin、Narra S. Devi、Adnan A. Jabbar、Stefan Kaluz、Yuan Liu、Erwin G. Van Meir、Binghe Wang

  DOI：10.1021/jm201018g

  日期：2011.12.22

  Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility, and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels but interfere with the ability of HIF-1 alpha/HIF-1 beta to interact with cofactors p300/CBP to form an active transcriptional complex.