2,6-diamino-4-diethylamino-5-p-chlorophenylazopyrimidine | 247913-67-3

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2,6-diamino-4-diethylamino-5-p-chlorophenylazopyrimidine
• 英文别名: 5-[(4-chlorophenyl)diazenyl]-4-N,4-N-diethylpyrimidine-2,4,6-triamine
• CAS: 247913-67-3
• 化学式: C₁₄H₁₈ClN₇
• 分子量: 319.797
• InChiKey: QKAFIAUTZHKORN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  106
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2,6-diamino-4-diethylamino-5-p-chlorophenylazopyrimidine 在 镍 氨 、 氢气 作用下， 以 甲醇 、 水 为溶剂， 反应 48.0h， 生成 2,5,6-triamino-4-diethylaminopyrimidine
  参考文献：
  名称：

  N-substituted 4-aminopteridines, synthesis and use thereof as pharmaceutical agent

  摘要：

  公式（I）的化合物，其中最好：A=部分式（II）或（III）的桥，R1和R2=独立的（取代的）烷基，芳基或芳基烷基，或者一起形成杂环，R3=H，—CO-烷基，或—CO-芳基，R4=芳基，—CO—O-芳基或—CO-芳基和R5=H，是一种有效的NO合酶抑制剂，适用于作为预防和治疗与紊乱的NO代谢相关的疾病状态的药物。

  公开号：

  US06844343B1
• 作为产物：
  描述：

  对氯苯胺 、 alkaline earth salt of/the/ methylsulfuric acid 在 盐酸 、 sodium nitrite 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.25h， 生成 2,6-diamino-4-diethylamino-5-p-chlorophenylazopyrimidine
  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

• N-substituted 4-aminopteridines, synthesis and use thereof as pharmaceutical agent
  申请人：Pfleiderer Wolfgang

  公开号：US06844343B1

  公开（公告）日：2005-01-18

  Compounds of formula (I), where preferably: A=a bridge of partial formula (II) or (III), R 1 and R 2 =independently (substituted) alkyl, aryl or aralkyl, or together form a heterocycle, R 3 =H, —CO-Alkyl, or —CO-Aryl, R 4 =Aryl, —CO—O-Aryl or —CO-Aryl and R 5 =H, are potent inhibitors of NO-synthase and are suitable as pharmaceutical agents of prophylaxis and treatment of disease states associates with a disturbed NO metabolism.

  公式（I）的化合物，其中最好：A=部分式（II）或（III）的桥，R1和R2=独立的（取代的）烷基，芳基或芳基烷基，或者一起形成杂环，R3=H，—CO-烷基，或—CO-芳基，R4=芳基，—CO—O-芳基或—CO-芳基和R5=H，是一种有效的NO合酶抑制剂，适用于作为预防和治疗与紊乱的NO代谢相关的疾病状态的药物。
• Inhibition of Neuronal Nitric Oxide Synthase by 4-Amino Pteridine Derivatives:  Structure−Activity Relationship of Antagonists of (6<i>R</i>)-5,6,7,8-Tetrahydrobiopterin Cofactor
  作者：Lothar G. Fröhlich、Peter Kotsonis、Hermann Traub、Shahriyar Taghavi-Moghadam、Najim Al-Masoudi、Heinrich Hofmann、Hartmut Strobel、Hans Matter、Wolfgang Pfleiderer、Harald H. H. W. Schmidt

  DOI：10.1021/jm981129a

  日期：1999.10.1

  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.