3-methylquinoline-8-sulfonic acid {4-(3-nitroguanidino)-1(S)-[4-(2-hydroxyethyl)piperidin-1-ylcarbonyl]butyl}amide | 252985-96-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 3-methylquinoline-8-sulfonic acid {4-(3-nitroguanidino)-1(S)-[4-(2-hydroxyethyl)piperidin-1-ylcarbonyl]butyl}amide
• 英文别名: 2-[(4S)-5-[4-(2-hydroxyethyl)piperidin-1-yl]-4-[(3-methylquinolin-8-yl)sulfonylamino]-5-oxopentyl]-1-nitroguanidine
• CAS: 252985-96-9
• 化学式: C₂₃H₃₃N₇O₆S
• 分子量: 535.624
• InChiKey: NDQQCGSUZMVOEY-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  204
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  溶剂黄146 、 3-methylquinoline-8-sulfonic acid {4-(3-nitroguanidino)-1(S)-[4-(2-hydroxyethyl)piperidin-1-ylcarbonyl]butyl}amide 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 20.0 ℃ 、100.0 kPa 条件下， 反应 92.0h， 生成 3(RS)-methyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid {4-guanidino-1(S)-[4-(2-hydroxyethyl)piperidin-1-ylcarbonyl]butyl}amide acetate salt
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209
• 作为产物：
  描述：

  3-methylquinoline-8-sulfonic acid {4-(3-nitroguanidino)-1(S)-[4-(2-acetoxyethyl)piperidin-1-ylcarbonyl]butyl}amide 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以55.7%的产率得到3-methylquinoline-8-sulfonic acid {4-(3-nitroguanidino)-1(S)-[4-(2-hydroxyethyl)piperidin-1-ylcarbonyl]butyl}amide
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209