N'-(4-butan-2-ylphenyl)ethane-1,2-diamine | 211558-25-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N'-(4-butan-2-ylphenyl)ethane-1,2-diamine
• CAS: 211558-25-7
• 化学式: C₁₂H₂₀N₂
• 分子量: 192.304
• InChiKey: NALYFRVRUMDTMQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  14
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  38
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N'-(4-butan-2-ylphenyl)ethane-1,2-diamine 在 碘甲烷 作用下， 以 乙醇 为溶剂， 反应 8.0h， 生成 N,1-bis(4-butan-2-ylphenyl)-4,5-dihydroimidazol-2-amine
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Conformationally Constrained Analogues of N,N‘-Diaryl- and N-Aryl-N-aralkylguanidines as Potent Inhibitors of Neuronal Na⁺ Channels

  摘要：

  In the present investigation, the rationale for the design, synthesis, and biological evaluation of potent inhibitors of neuronal Nai channels is described. N,N'-Diaryl- and N-aryl-N-aralkylguanidine templates were locked in conformations mimicking the permissible conformations of the flexible diarylguanidinium ion (AS(+), AA(+), SS+). The resulting set of constrained guanidines termed "lockamers" (cyclophane, quinazoline, aminopyrimidazolines, aminoimidazolines azocino- and tetrahydroquinolinocarboximidamides) was examined for neuronal Na+ channel blockade properties. Inhibition of [C-14]guanidinium ion influx in CHO cells expressing type IIA Na+ channels showed that the aminopyrimidazoline 9b and aminoimidazoline 9d, compounds proposed to lock the N,N'-diarylguanidinium in an SS+ conformation, were the most potent Na+ channel blockers with IC50's of 0.06 mu M, a value 17 times lower than that of the parent flexible compound 18d. The rest of the restricted analogues with 4-p-alkyl substituents retained potency with IC50 values ranging between 0.46 and 2.9 mu M. Evaluation in a synaptosomal Ca-45(2+) influx assay showed that 9b did not exhibit high selectivity for neuronal Na+ vs Ca2+ channels. The retention of significant neuronal Na+ blockade in all types of semirigid conformers gives evidence for a multiple mode of binding in this class of compounds and can possibly be attributed to a poor structural specificity of the site(s) of action. Compound 9b was also found to be the most active compound in vivo based on the high level of inhibition of seizures exhibited in the DBA/2 mouse model. The pK(a) value of 9b indicates that 9b binds to the channel in its protonated form, and log D vs pH measurements suggest that ion-pair partitioning contributes to membrane transport. This compound stands out as an interesting lead for further development of neurotherapeutic agents.

  DOI：

  10.1021/jm980124a
• 作为产物：
  描述：

  2-(4-Butan-2-ylanilino)acetonitrile 在 Ra-Ni ammonium hydroxide 、 氢气 作用下， 以 甲醇 为溶剂， 以60%的产率得到N'-(4-butan-2-ylphenyl)ethane-1,2-diamine
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of Conformationally Constrained Analogues of N,N‘-Diaryl- and N-Aryl-N-aralkylguanidines as Potent Inhibitors of Neuronal Na⁺ Channels

  摘要：

  In the present investigation, the rationale for the design, synthesis, and biological evaluation of potent inhibitors of neuronal Nai channels is described. N,N'-Diaryl- and N-aryl-N-aralkylguanidine templates were locked in conformations mimicking the permissible conformations of the flexible diarylguanidinium ion (AS(+), AA(+), SS+). The resulting set of constrained guanidines termed "lockamers" (cyclophane, quinazoline, aminopyrimidazolines, aminoimidazolines azocino- and tetrahydroquinolinocarboximidamides) was examined for neuronal Na+ channel blockade properties. Inhibition of [C-14]guanidinium ion influx in CHO cells expressing type IIA Na+ channels showed that the aminopyrimidazoline 9b and aminoimidazoline 9d, compounds proposed to lock the N,N'-diarylguanidinium in an SS+ conformation, were the most potent Na+ channel blockers with IC50's of 0.06 mu M, a value 17 times lower than that of the parent flexible compound 18d. The rest of the restricted analogues with 4-p-alkyl substituents retained potency with IC50 values ranging between 0.46 and 2.9 mu M. Evaluation in a synaptosomal Ca-45(2+) influx assay showed that 9b did not exhibit high selectivity for neuronal Na+ vs Ca2+ channels. The retention of significant neuronal Na+ blockade in all types of semirigid conformers gives evidence for a multiple mode of binding in this class of compounds and can possibly be attributed to a poor structural specificity of the site(s) of action. Compound 9b was also found to be the most active compound in vivo based on the high level of inhibition of seizures exhibited in the DBA/2 mouse model. The pK(a) value of 9b indicates that 9b binds to the channel in its protonated form, and log D vs pH measurements suggest that ion-pair partitioning contributes to membrane transport. This compound stands out as an interesting lead for further development of neurotherapeutic agents.

  DOI：

  10.1021/jm980124a

文献信息

• Design, Synthesis, and Pharmacological Evaluation of Conformationally Constrained Analogues of <i>N</i>,<i>N</i>‘-Diaryl- and <i>N</i>-Aryl-<i>N</i>-aralkylguanidines as Potent Inhibitors of Neuronal Na⁺ Channels
  作者：Michel C. Maillard、Michael E. Perlman、Oved Amitay、Deborah Baxter、David Berlove、Sonia Connaughton、James B. Fischer、Jun Qing Guo、Lain-Yen Hu、Robert N. McBurney、Peter I. Nagy、Katragadda Subbarao、Elizabeth A. Yost、Lu Zhang、Graham J. Durant

  DOI：10.1021/jm980124a

  日期：1998.7.1

  In the present investigation, the rationale for the design, synthesis, and biological evaluation of potent inhibitors of neuronal Nai channels is described. N,N'-Diaryl- and N-aryl-N-aralkylguanidine templates were locked in conformations mimicking the permissible conformations of the flexible diarylguanidinium ion (AS(+), AA(+), SS+). The resulting set of constrained guanidines termed "lockamers" (cyclophane, quinazoline, aminopyrimidazolines, aminoimidazolines azocino- and tetrahydroquinolinocarboximidamides) was examined for neuronal Na+ channel blockade properties. Inhibition of [C-14]guanidinium ion influx in CHO cells expressing type IIA Na+ channels showed that the aminopyrimidazoline 9b and aminoimidazoline 9d, compounds proposed to lock the N,N'-diarylguanidinium in an SS+ conformation, were the most potent Na+ channel blockers with IC50's of 0.06 mu M, a value 17 times lower than that of the parent flexible compound 18d. The rest of the restricted analogues with 4-p-alkyl substituents retained potency with IC50 values ranging between 0.46 and 2.9 mu M. Evaluation in a synaptosomal Ca-45(2+) influx assay showed that 9b did not exhibit high selectivity for neuronal Na+ vs Ca2+ channels. The retention of significant neuronal Na+ blockade in all types of semirigid conformers gives evidence for a multiple mode of binding in this class of compounds and can possibly be attributed to a poor structural specificity of the site(s) of action. Compound 9b was also found to be the most active compound in vivo based on the high level of inhibition of seizures exhibited in the DBA/2 mouse model. The pK(a) value of 9b indicates that 9b binds to the channel in its protonated form, and log D vs pH measurements suggest that ion-pair partitioning contributes to membrane transport. This compound stands out as an interesting lead for further development of neurotherapeutic agents.