3-(3,5-dimethoxyphenyl)-N⁷-trityl-1,6-naphthyridine-2,7-diamine | 311820-00-5

• 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)-N⁷-trityl-1,6-naphthyridine-2,7-diamine
• 英文别名: 3-(3,5-dimethoxyphenyl)-7-N-trityl-1,6-naphthyridine-2,7-diamine
• CAS: 311820-00-5
• 化学式: C₃₅H₃₀N₄O₂
• 分子量: 538.649
• InChiKey: OLGXYBITVKWZKZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  82.3
• 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)-N⁷-trityl-1,6-naphthyridine-2,7-diamine 在 silica gel 、 sodium hydride 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.03h， 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：

  3-(3,5-dimethoxyphenyl)-N²,N²-bis(4-methoxybenzyl)-N⁷-trityl-1,6-naphthyridine-2,7-diamine 在 silica gel 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 48.0h， 生成 3-(3,5-dimethoxyphenyl)-N⁷-trityl-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

文献信息

• 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
  作者：Andrew M. Thompson、Cleo J. C. Connolly、James M. Hamby、Stacey Boushelle、Brian G. Hartl、Aneesa M. Amar、Alan J. Kraker、Denise L. Driscoll、Randall W. Steinkampf、Sandra J. Patmore、Patrick W. Vincent、Bill J. Roberts、William L. Elliott、Wayne Klohs、Wilbur R. Leopold、H. D. Hollis Showalter、William A. Denny

  DOI：10.1021/jm000161d

  日期：2000.11.1

  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.