N-((2,2-dimethyl-2H-chromen-6-yl)methyl)cyclobutanamine | 1391977-43-7

• 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)cyclobutanamine
• 英文别名: N-[(2,2-dimethylchromen-6-yl)methyl]cyclobutanamine
• CAS: 1391977-43-7
• 化学式: C₁₆H₂₁NO
• 分子量: 243.349
• InChiKey: FRLCFGXBJYZKSH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 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：

  3,5-二甲基异唑-4-磺酰氯 、 N-((2,2-dimethyl-2H-chromen-6-yl)methyl)cyclobutanamine 在 potassium carbonate 作用下， 以 二氯甲烷 为溶剂， 以43%的产率得到N-cyclobutyl-N-((2,2-dimethyl-2H-chromen-6-yl)methyl)-3,5-dimethylisoxazole-4-sulfonamide
  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：

  4-((2-methylbut-3-yn-2-yl)oxy)benzaldehyde 在 N-甲基吡咯烷酮 、 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)cyclobutanamine
  参考文献：
  名称：

  Design and in Vitro Activities of N-Alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, Novel, Small-Molecule Hypoxia Inducible Factor-1 Pathway Inhibitors and Anticancer Agents

  摘要：

  The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 mu M in water; log P-7.4 = 3.7). Here we describe the synthesis of 12 N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl)methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log P-7.4 values of 8 of the 12 new analogs ranged from 1.2-3.1. Aqueous solubilities of three analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl)pyridine-2-sulfonamide had an aqueous solubility of 80 mu M, e.g., a solubility improvement of similar to 9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC50 values at or below 5 mu M in our HIF-dependent reporter assay.

  DOI：

  10.1021/jm300752n

文献信息

• HYPOXIA INDUCIBLE FACTOR-1 PATHWAY INHIBITORS AND USES AS ANTICANCER AND IMAGING AGENTS
  申请人：EMORY UNIVERSITY

  公开号：US20130164218A1

  公开（公告）日：2013-06-27

  This disclosure relates to Hypoxia Inducible Factor-1 pathway inhibitors and uses as anticancer and imaging agents. In certain embodiments, the disclosure contemplates compounds and pharmaceutical compositions disclosed herein.

  本公开涉及缺氧诱导因子-1通路抑制剂及其作为抗癌和成像剂的用途。在某些实施方式中，本公开考虑了在此披露的化合物和药物组成物。
• 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.
• US9381260B2
  申请人：——

  公开号：US9381260B2

  公开（公告）日：2016-07-05