1-(2,2-dimethyl-2H-chromen-6-yl)-N-(propan-2-yl)methanimine | 1391727-48-2

• 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: 1-(2,2-dimethyl-2H-chromen-6-yl)-N-(propan-2-yl)methanimine
• 英文别名: 1-(2,2-dimethylchromen-6-yl)-N-propan-2-ylmethanimine
• CAS: 1391727-48-2
• 化学式: C₁₅H₁₉NO
• 分子量: 229.322
• InChiKey: CCFZWBOCLTZGID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  21.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-(2,2-dimethyl-2H-chromen-6-yl)-N-(propan-2-yl)methanimine 在 二异丁基氢化铝 作用下， 以 甲苯 为溶剂， 以111 mg的产率得到N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]propan-2-amine
  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
• 作为产物：
  描述：

  4-((2-methylbut-3-yn-2-yl)oxy)benzaldehyde 在 N-甲基吡咯烷酮 、 对甲苯磺酸 作用下， 以 二氯甲烷 为溶剂， 生成 1-(2,2-dimethyl-2H-chromen-6-yl)-N-(propan-2-yl)methanimine
  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

• 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
  作者：Jiyoung Mun、Adnan Abdul Jabbar、Narra Sarojini Devi、Yuan Liu、Erwin G. Van Meir、Mark M. Goodman

  DOI：10.1016/j.bmc.2012.04.064

  日期：2012.7

  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.