3-(3,5-dimethoxyphenyl)-7-(tritylamino)-1,6-naphthyridin-2-ylformamide | 311819-99-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 3-(3,5-dimethoxyphenyl)-7-(tritylamino)-1,6-naphthyridin-2-ylformamide
• 英文别名: N-[3-(3,5-dimethoxyphenyl)-7-(tritylamino)-1,6-naphthyridin-2-yl]formamide
• CAS: 311819-99-5
• 化学式: C₃₆H₃₀N₄O₃
• 分子量: 566.659
• InChiKey: JXULMSLXLYATAP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  85.4
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(3,5-dimethoxyphenyl)-7-(tritylamino)-1,6-naphthyridin-2-ylformamide 在 sodium hydroxide 、 silica gel 、 sodium hydride 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 52.53h， 生成 3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamine
  参考文献：
  名称：

  3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

  摘要：

  A series of 3-aryl-1,6-naphthyridine-2, 7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diamino-nicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropyl amino) analogue retained high FGFR potency (IC50 31 nM) and selectivity. Pairwise comparison of the 1,6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC50 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC50 0.01 nM) and Matrigel invasion (IC50 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.

  DOI：

  10.1021/jm000161d
• 作为产物：
  描述：

  三苯基氯甲烷 、 N,N-二甲基甲酰胺 、 3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamine 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.42h， 以13%的产率得到3-(3,5-dimethoxyphenyl)-7-(tritylamino)-1,6-naphthyridin-2-ylformamide
  参考文献：
  名称：

  3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and Related 2-Urea Derivatives Are Potent and Selective Inhibitors of the FGF Receptor-1 Tyrosine Kinase

  摘要：

  A series of 3-aryl-1,6-naphthyridine-2, 7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diamino-nicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropyl amino) analogue retained high FGFR potency (IC50 31 nM) and selectivity. Pairwise comparison of the 1,6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC50 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC50 0.01 nM) and Matrigel invasion (IC50 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.

  DOI：

  10.1021/jm000161d