(2R)-1-[benzyl-[4-[benzyl-[(2R)-4-(ethylamino)-2-hydroxybutyl]amino]butyl]amino]-4-(ethylamino)butan-2-ol | 177798-01-5

• 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: (2R)-1-[benzyl-[4-[benzyl-[(2R)-4-(ethylamino)-2-hydroxybutyl]amino]butyl]amino]-4-(ethylamino)butan-2-ol
• CAS: 177798-01-5
• 化学式: C₃₀H₅₀N₄O₂
• 分子量: 498.753
• InChiKey: URBSAJHSPGDODG-LOYHVIPDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  36
• 可旋转键数：
  21
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  71
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2R)-1-[benzyl-[4-[benzyl-[(2R)-4-(ethylamino)-2-hydroxybutyl]amino]butyl]amino]-4-(ethylamino)butan-2-ol 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以72%的产率得到(3R,12R)-N¹,N¹⁴-diethyl-3,12-dihydroxyhomospermine tetrahydrochloride
  参考文献：
  名称：

  Metabolically Programmed Polyamine Analogue Antidiarrheals

  摘要：

  The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N-1,N-14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N-1,N-14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)(2)DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)(2)DEHSPM would have a K-i for polyamine transport essentially identical with that of DEHSPM. The experimentally measured K-i and also the observed values of other biological properties of (HO)(2)DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)(2)DEHSPM, and (HO)(2)DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)(2)DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.

  DOI：

  10.1021/jm950827h
• 作为产物：
  描述：

  N1,N4-二(苯基甲基)-1,4-丁烷二胺 在 镍 lithium aluminium tetrahydride 、 18-冠醚-6 、 氨 、 氢气 、 magnesium sulfate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 25.0~65.0 ℃ 、344.73 kPa 条件下， 反应 109.0h， 生成 (2R)-1-[benzyl-[4-[benzyl-[(2R)-4-(ethylamino)-2-hydroxybutyl]amino]butyl]amino]-4-(ethylamino)butan-2-ol
  参考文献：
  名称：

  Metabolically Programmed Polyamine Analogue Antidiarrheals

  摘要：

  The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N-1,N-14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N-1,N-14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)(2)DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)(2)DEHSPM would have a K-i for polyamine transport essentially identical with that of DEHSPM. The experimentally measured K-i and also the observed values of other biological properties of (HO)(2)DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)(2)DEHSPM, and (HO)(2)DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)(2)DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.

  DOI：

  10.1021/jm950827h

文献信息

• Metabolically Programmed Polyamine Analogue Antidiarrheals
  作者：Raymond J. Bergeron、Guo Wei Yao、Hua Yao、William R. Weimar、Charles A. Sninsky、Brian Raisler、Yang Feng、Qianhong Wu、Fenglan Gao

  DOI：10.1021/jm950827h

  日期：1996.1.1

  The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N-1,N-14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N-1,N-14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)(2)DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)(2)DEHSPM would have a K-i for polyamine transport essentially identical with that of DEHSPM. The experimentally measured K-i and also the observed values of other biological properties of (HO)(2)DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)(2)DEHSPM, and (HO)(2)DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)(2)DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.