6-(aminomethyl)pteridine-2,4-diamine | 172757-90-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 6-(aminomethyl)pteridine-2,4-diamine
• CAS: 172757-90-3
• 化学式: C₇H₉N₇
• 分子量: 191.195
• InChiKey: XBEUQVLNPDEQKL-UHFFFAOYSA-N

物化性质

• 熔点：
  >350 °C
• 沸点：
  524.3±60.0 °C(Predicted)
• 密度：
  1.580±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  6-(aminomethyl)pteridine-2,4-diamine 在 4-二甲氨基吡啶 、 ammonium hydroxide 作用下， 以 甲醇 为溶剂， 反应 50.0h， 生成 N-(2,4-Diamino-pteridin-6-ylmethyl)-isobutyramide
  参考文献：
  名称：

  Inhibition of Neuronal Nitric Oxide Synthase by 4-Amino Pteridine Derivatives:  Structure−Activity Relationship of Antagonists of (6R)-5,6,7,8-Tetrahydrobiopterin Cofactor

  摘要：

  The family of nitric oxide synthases (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in the pathophysiology of septic shock and inflammatory and neurodegenerative disease states. NOS can be maximally activated by the ubiquitous cofactor, (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), and antagonists of H(4)Bip may be of therapeutic importance to inhibit pathologically high NO formation. The 4-amino substituted analogue of H(4)Bip was reported to be a potent NOS inhibit-or. Therefore, we developed a series of novel 4-amino pteridine derivatives, antipterins, to pharmacologically target the neuronal isoform of nitric oxide synthase (NOS-I). To functionally characterize the pterin/anti-pterin interaction and establish a structure-activity relationship (SAR), we systematically altered the substituents in the 2-, 4-, 5-, 6-, and 7-position of the pteridine nucleus. Varying the substitution pattern in the 2-, 5-, and 7-position resulted in no significant inhibitory effect on enzyme activity. In contrast, bulky substituents in the B-position, such as phenyl, markedly increased the inhibitory potency of the reduced 4-amino-5,6,7,8-tetrahydropteridines, possibly as a consequence of hydrophobic interactions within NOS-I. However, this was not the case for the aromatic 4-amino pteridines. Interestingly, chemical modification of the 4-amino substituent by dialkyl/diaralkylation together with 6-arylation of the aromatic 2,4-diamino pteridine resulted in potent and efficacious inhibitors of NOS-I, suggesting possible hydrophilic and hydrophobic interactions within NOS-I. This SAR agrees with (a) the recently published crystal structure of the oxygenase domain of the inducible NOS isoform (NOS-II) and (b) the comparative molecular field analysis of selected NOS-I inhibitors, which resulted in a 3D-QSAR model of the pterin binding site interactions. Further optimization should be possible when the full length structure of NOS-I becomes available.

  DOI：

  10.1021/jm981129a
• 作为产物：
  描述：

  2,4-diamino-6-bromomethylpteridine*HBr*2-hydroxypropane 在 氨 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以60%的产率得到6-(aminomethyl)pteridine-2,4-diamine
  参考文献：
  名称：

  Inhibition of Neuronal Nitric Oxide Synthase by 4-Amino Pteridine Derivatives:  Structure−Activity Relationship of Antagonists of (6R)-5,6,7,8-Tetrahydrobiopterin Cofactor

  摘要：

  The family of nitric oxide synthases (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in the pathophysiology of septic shock and inflammatory and neurodegenerative disease states. NOS can be maximally activated by the ubiquitous cofactor, (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), and antagonists of H(4)Bip may be of therapeutic importance to inhibit pathologically high NO formation. The 4-amino substituted analogue of H(4)Bip was reported to be a potent NOS inhibit-or. Therefore, we developed a series of novel 4-amino pteridine derivatives, antipterins, to pharmacologically target the neuronal isoform of nitric oxide synthase (NOS-I). To functionally characterize the pterin/anti-pterin interaction and establish a structure-activity relationship (SAR), we systematically altered the substituents in the 2-, 4-, 5-, 6-, and 7-position of the pteridine nucleus. Varying the substitution pattern in the 2-, 5-, and 7-position resulted in no significant inhibitory effect on enzyme activity. In contrast, bulky substituents in the B-position, such as phenyl, markedly increased the inhibitory potency of the reduced 4-amino-5,6,7,8-tetrahydropteridines, possibly as a consequence of hydrophobic interactions within NOS-I. However, this was not the case for the aromatic 4-amino pteridines. Interestingly, chemical modification of the 4-amino substituent by dialkyl/diaralkylation together with 6-arylation of the aromatic 2,4-diamino pteridine resulted in potent and efficacious inhibitors of NOS-I, suggesting possible hydrophilic and hydrophobic interactions within NOS-I. This SAR agrees with (a) the recently published crystal structure of the oxygenase domain of the inducible NOS isoform (NOS-II) and (b) the comparative molecular field analysis of selected NOS-I inhibitors, which resulted in a 3D-QSAR model of the pterin binding site interactions. Further optimization should be possible when the full length structure of NOS-I becomes available.

  DOI：

  10.1021/jm981129a

文献信息

• US7390784B2
  申请人：——

  公开号：US7390784B2

  公开（公告）日：2008-06-24
• [EN] TREATMENT OF HYPERPROLIFERATIVE DISEASES WITH METHOTREXATE N-OXIDE AND ANALOGS<br/>[FR] TRAITMENT DE MALADIES HYPERPROLIFÉRATIVES AVEC DU N-OXIDE DE MÉTHOTREXATE ET DES ANALOGUES CORRESPONDANTS
  申请人：NOVACEA INC

  公开号：WO2007098089A2

  公开（公告）日：2007-08-30

  [EN] The present invention relates to methotrexate and analog N-oxides having activity for treating hyperproliferative disorders. Further, the invention relates to pharmaceutical compositions and methods of using methotrexate and analog N-oxides, alone or in combination with one or more other active agents or treatments, to treat hyperproliferative disorders.
  [FR] L'invention concerne des N-oxides de méthotrexate et d'analogues possédant une activité destinée à traiter des troubles hyperprolifératifs. L'invention concerne également des compositions pharmaceutiques et des procédés utilisant des N-oxides de méthotrexate et d'analogues, seul ou en combinaison avec un ou plusieurs autres agents ou traitements actifs, en vue de traiter des troubles hyperprolifératifs.