3-Phenyl-1,6-naphthyridine-2,7-diamine | 293301-08-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-Phenyl-1,6-naphthyridine-2,7-diamine
• CAS: 293301-08-3
• 化学式: C₁₄H₁₂N₄
• 分子量: 236.276
• InChiKey: IEGFEVXCKUNXSR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  77.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-Phenyl-1,6-naphthyridine-2,7-diamine 在 N-甲基吗啉 、 吡啶 、 三氯化铁 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 209.83h， 生成 N-[2-[[(tert-butylamino)carbonyl]amino]-3-phenyl-1,6-naphthyridin-7-yl]-N-[4-(diethylamino)butyl]acetamide
  参考文献：
  名称：

  可溶性7-取代的3-（3,5-二甲氧基苯基）-1,6-萘啶-2-胺和相关尿素作为成纤维细胞生长因子受体-1和血管内皮生长因子受体的双重抑制剂的合成及其与构效关系-2酪氨酸激酶。

  摘要：

  7位取代的3-芳基-1,6-萘啶-2,7-二胺和相关的2-脲是成纤维细胞生长因子受体1（FGFR-1）和血管内皮生长因子受体2（VEGFR-2）的抑制剂。3-（3,5-二甲氧基苯基）和3-苯基类似物由7-乙酰氨基-2-叔丁基脲通过苄基ω-碘烷基醚烷基化，脱苄基化和胺化，然后选择性裂解7-N-来制备。乙酰胺。通过用取代的烷基胺置换从7-氟-2-胺制备3-（2，6-二氯苯基）类似物，然后用烷基异氰酸酯选择性地酰化所得的取代的萘啶-2,7-二胺。3-（3,5-二甲氧基苯基）衍生物是FGFR和VEGFR的低纳摩尔抑制剂，相对于PDGFR和c-Src具有高度选择性（> 100倍）。7侧链碱基的碱基强度或空间位置的变化对效价（<5倍）或选择性（<20倍）的影响很小。3-（2,6-二氯苯基）-2-脲衍生物对VEGFR的活性略低，选择性较低，对PDGFR（约10倍）和c-Src（约500倍）更有效。通常，3-（3

  DOI：

  10.1021/jm0500931
• 作为产物：
  描述：

  苯乙腈 、 4,6-Diaminonicotinaldehyde hydrochloride 在 sodium methylate 作用下， 以 乙二醇乙醚 为溶剂， 反应 3.0h， 以59%的产率得到3-Phenyl-1,6-naphthyridine-2,7-diamine
  参考文献：
  名称：

  Synthesis of 7-substituted 3-aryl-1,6-naphthyridin-2-amines and 7-substituted 3-aryl-1,6-naphthyridin-2(1H )-ones via diazotization of 3-aryl-1,6-naphthyridine-2,7-diamines

  摘要：

  由3-芳基-1重氮化制备3-芳基-7-卤代-1,6-萘啶-2-胺和3-芳基-7-卤代-1,6-萘啶-2(1H)-酮报道了 ,6-萘啶-2,7-二胺。在各种溶剂（浓 HCl、50% HBF4、70% HF-吡啶、20% 和 90% H2SO4、稀 HCl 和纯 TFA）中研究了反应。通过适当选择溶剂和其他条件，可以获得目标化合物的良好产率，尽管在某些情况下也会产生各种不同的副产物。随后用烷基胺取代 7-卤素取代基提供了获得更复杂的 7-取代 1,6-萘啶衍生物的途径，这些衍生物是潜在的酪氨酸激酶抑制剂。

  DOI：

  10.1039/b002599m

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.
• Synthesis and Structure−Activity Relationships of Soluble 7-Substituted 3-(3,5-Dimethoxyphenyl)-1,6-naphthyridin-2-amines and Related Ureas as Dual Inhibitors of the Fibroblast Growth Factor Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinases
  作者：Andrew M. Thompson、Amy M. Delaney、James M. Hamby、Mel C. Schroeder、Teresa A. Spoon、Sheila M. Crean、H. D. Hollis Showalter、William A. Denny

  DOI：10.1021/jm0500931

  日期：2005.7.1

  5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl omega-iodoalkyl ethers, debenzylation, and amination, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2

  7位取代的3-芳基-1,6-萘啶-2,7-二胺和相关的2-脲是成纤维细胞生长因子受体1（FGFR-1）和血管内皮生长因子受体2（VEGFR-2）的抑制剂。3-（3,5-二甲氧基苯基）和3-苯基类似物由7-乙酰氨基-2-叔丁基脲通过苄基ω-碘烷基醚烷基化，脱苄基化和胺化，然后选择性裂解7-N-来制备。乙酰胺。通过用取代的烷基胺置换从7-氟-2-胺制备3-（2，6-二氯苯基）类似物，然后用烷基异氰酸酯选择性地酰化所得的取代的萘啶-2,7-二胺。3-（3,5-二甲氧基苯基）衍生物是FGFR和VEGFR的低纳摩尔抑制剂，相对于PDGFR和c-Src具有高度选择性（> 100倍）。7侧链碱基的碱基强度或空间位置的变化对效价（<5倍）或选择性（<20倍）的影响很小。3-（2,6-二氯苯基）-2-脲衍生物对VEGFR的活性略低，选择性较低，对PDGFR（约10倍）和c-Src（约500倍）更有效。通常，3-（3
• Synthesis of 7-substituted 3-aryl-1,6-naphthyridin-2-amines and 7-substituted 3-aryl-1,6-naphthyridin-2(1H )-ones via diazotization of 3-aryl-1,6-naphthyridine-2,7-diamines
  作者：Andrew M. Thompson、H. D. Hollis Showalter、William A. Denny

  DOI：10.1039/b002599m

  日期：——

  The preparation of 3-aryl-7-halo-1,6-naphthyridin-2-amines and 3-aryl-7-halo-1,6-naphthyridin-2(1H)-ones from the diazotization of 3-aryl-1,6-naphthyridine-2,7-diamines is reported. The reactions were investigated in various solvents (concentrated HCl, 50% HBF4, 70% HF–pyridine, 20% and 90% H2SO4, dilute HCl, and neat TFA). By appropriate choice of solvent and other conditions, good yields of the target compounds could be obtained, although in some cases a variety of different side products was also produced. Subsequent displacement of the 7-halogen substituents with alkylamines provides a route to more complex 7-substituted 1,6-naphthyridine derivatives that are potential tyrosine kinase inhibitors.

  由3-芳基-1重氮化制备3-芳基-7-卤代-1,6-萘啶-2-胺和3-芳基-7-卤代-1,6-萘啶-2(1H)-酮报道了 ,6-萘啶-2,7-二胺。在各种溶剂（浓 HCl、50% HBF4、70% HF-吡啶、20% 和 90% H2SO4、稀 HCl 和纯 TFA）中研究了反应。通过适当选择溶剂和其他条件，可以获得目标化合物的良好产率，尽管在某些情况下也会产生各种不同的副产物。随后用烷基胺取代 7-卤素取代基提供了获得更复杂的 7-取代 1,6-萘啶衍生物的途径，这些衍生物是潜在的酪氨酸激酶抑制剂。