[5-(4-Chloro-2-methoxy-phenyl)-1-methyl-1H-[1,2,4]triazol-3-yl]-(1-phenyl-butyl)-propyl-amine | 848648-99-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: [5-(4-Chloro-2-methoxy-phenyl)-1-methyl-1H-[1,2,4]triazol-3-yl]-(1-phenyl-butyl)-propyl-amine
• 英文别名: 5-(4-chloro-2-methoxyphenyl)-N-[1-(4-fluorophenyl)pentyl]-1-methyl-N-propyl-1,2,4-triazol-3-amine
• CAS: 848648-99-7
• 化学式: C₂₄H₃₀ClFN₄O
• 分子量: 444.98
• InChiKey: SYBPBURKXDRONN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  43.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [5-(4-Chloro-2-methoxy-phenyl)-1-methyl-1H-[1,2,4]triazol-3-yl]-(1-phenyl-butyl)-propyl-amine 生成 (R)-1-methyl-3-[N-{1-(4-fluorophenyl)pentyl}-N-propylamino]-5-(2-methoxy-4-chlorophenyl)-1H-[1,2,4]triazole 、 (S)-1-methyl-3-[N-{1-(4-fluorophenyl)pentyl}-N-propylamino]-5-(2-methoxy-4-chlorophenyl)-1H-[1,2,4]triazole
  参考文献：
  名称：

  Rational Design, Synthesis, and Structure−Activity Relationships of Aryltriazoles as Novel Corticotropin-Releasing Factor-1 Receptor Antagonists

  摘要：

  Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF1) (e.g., 1, K-i = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-acyl-S-methylisothioureas with alkylhydrazines or by cyclizations with hydrazine followed by alkylation. While members of this series showed potent binding affinity against CRF1 receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R-1 or R-2 side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(alpha-branched benzyl)-N-propylamino side chain were the most potent, followed by analogues such as 7a, with an N-bis(cyclopropyl)methyl-N-propylamino side chain, and analogues such as 7m, with an N-(alpha-branched aliphatic)-N-propylamino side chain. While the N-propyl group was crucial for high potency, we hypothesized that the terminal methyl mimicked the 5-methyl of pyrazolo[1,5-alpha]pyrimidines 3 and 4. Correlation of the low-energy conformers of compounds of type 3 and 7 generated by computational analyses was very good. The size and shape of the N-alkyl group dramatically changed the potency of the triazoles, which is in contrast to the SAR seen for bicyclic CRF1 antagonists. In general, the S-enantiomer was much more potent than the corresponding R-isomer. Furthermore, to a limited extent in the aryltriazole series the substituent on the 5-phenyl ring changed the potency up to 9-fold. (S)-1-Methyl-3-[N-(4-fluorophenylpentyl)-N-propyl]amino-5-(2-methoxy-4-dichlorophenyl)-1H-[1,2,4]triazole [(S)-7r] showed very potent binding affinity (K-i = 2.7 nM) to CRF1 receptors with an IC50 of 49 nM in a cAMP inhibition assay.

  DOI：

  10.1021/jm049339c
• 作为产物：
  描述：

  2-甲氧基-4-氯苯甲酰氯 在 sodium carbonate 作用下， 以 四氢呋喃 、 二氯甲烷 、 丙酮 为溶剂， 反应 0.17h， 生成 [5-(4-Chloro-2-methoxy-phenyl)-1-methyl-1H-[1,2,4]triazol-3-yl]-(1-phenyl-butyl)-propyl-amine
  参考文献：
  名称：

  Rational Design, Synthesis, and Structure−Activity Relationships of Aryltriazoles as Novel Corticotropin-Releasing Factor-1 Receptor Antagonists

  摘要：

  Following the discovery of the very high binding affinity of 4-anilinopyrimidines against corticotropin-releasing factor receptor-1 (CRF1) (e.g., 1, K-i = 2 nM), a new series of triazoles bearing different groups has been synthesized and evaluated. The compounds were prepared by cyclizations of N-acyl-S-methylisothioureas with alkylhydrazines or by cyclizations with hydrazine followed by alkylation. While members of this series showed potent binding affinity against CRF1 receptor, there were important differences between the different regio- (7 and 12) and stereoisomeric aryltriazoles where the R-1 or R-2 side chain in 7 has an asymmetric center. In terms of overall potency, aryltriazole analogues such as 7r bearing an N-(alpha-branched benzyl)-N-propylamino side chain were the most potent, followed by analogues such as 7a, with an N-bis(cyclopropyl)methyl-N-propylamino side chain, and analogues such as 7m, with an N-(alpha-branched aliphatic)-N-propylamino side chain. While the N-propyl group was crucial for high potency, we hypothesized that the terminal methyl mimicked the 5-methyl of pyrazolo[1,5-alpha]pyrimidines 3 and 4. Correlation of the low-energy conformers of compounds of type 3 and 7 generated by computational analyses was very good. The size and shape of the N-alkyl group dramatically changed the potency of the triazoles, which is in contrast to the SAR seen for bicyclic CRF1 antagonists. In general, the S-enantiomer was much more potent than the corresponding R-isomer. Furthermore, to a limited extent in the aryltriazole series the substituent on the 5-phenyl ring changed the potency up to 9-fold. (S)-1-Methyl-3-[N-(4-fluorophenylpentyl)-N-propyl]amino-5-(2-methoxy-4-dichlorophenyl)-1H-[1,2,4]triazole [(S)-7r] showed very potent binding affinity (K-i = 2.7 nM) to CRF1 receptors with an IC50 of 49 nM in a cAMP inhibition assay.

  DOI：

  10.1021/jm049339c