(4bS,8R,8aS,9aR,12aS,12bR)-1-((tert-butyldimethylsilyl)oxy)-7-(cyclopropylmethyl)-10-(((methylsulfonyl)oxy)methyl)-11-oxo-5,6,7,8,9,9a,10,11,12a,12b-decahydro-8aH-4,8-methanobenzofuro[3,2-e]furo[2,3-g]isoquinolin-8a-yl methanesulfonate | 96453-51-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: (4bS,8R,8aS,9aR,12aS,12bR)-1-((tert-butyldimethylsilyl)oxy)-7-(cyclopropylmethyl)-10-(((methylsulfonyl)oxy)methyl)-11-oxo-5,6,7,8,9,9a,10,11,12a,12b-decahydro-8aH-4,8-methanobenzofuro[3,2-e]furo[2,3-g]isoquinolin-8a-yl methanesulfonate
• CAS: 96453-51-9
• 化学式: C₃₁H₄₅NO₁₀S₂Si
• 分子量: 683.916
• InChiKey: NMLUFJISPJLRIN-RXHORLCFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.36
• 重原子数：
  45.0
• 可旋转键数：
  9.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  134.74
• 氢给体数：
  0.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  (4bS,8R,8aS,9aR,12aS,12bR)-1-((tert-butyldimethylsilyl)oxy)-7-(cyclopropylmethyl)-10-(((methylsulfonyl)oxy)methyl)-11-oxo-5,6,7,8,9,9a,10,11,12a,12b-decahydro-8aH-4,8-methanobenzofuro[3,2-e]furo[2,3-g]isoquinolin-8a-yl methanesulfonate 在 吡啶 、 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成 4,5α-epoxy-3,6α-dihydroxy-7α-(2-carboxyallyl)-8,14-dehydro-17-(cyclopropylmethyl)morphinan γ-lactone
  参考文献：
  名称：

  Opioid agonists and antagonists. 6-Desoxy-6-substituted lactone, epoxide, and glycidate ester derivatives of naltrexone and oxymorphone

  摘要：

  Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha-methylene-gamma-lactones (10a and 11a) were prepared. Related 6-desoxy-6-methylene 6 beta- and 6 alpha-oxides (12a,b and 13a) and glycidate esters 14a,b and 15a,b were also prepared with use of naltrexone (1a) and oxymorphone (1b) as starting material. Compounds in the N-cyclopropylmethyl (N-CPM) series were more potent than those in the N-Me series in displacing [3H]naltrexone in the opioid radioreceptor assay, usually by 2-16-fold in the absence of Na ion. The most potent N-CPM analogues were epoxides 12a and 13a and glycidate esters 14a and 15a, showing IC50's of 2-6 nM, similar to that of 5a. Of the N-Me analogues, 6 beta-oxide 12b was most active, with an IC50 of 8 nM in the absence of Na ion. For the N-CPM analogues, the Na ion ratios were generally less than 1, with two exceptions. The N-Me analogues showed expected larger Na ion effects of 7 or greater. None of the lactone analogues had irreversible effects when preincubated in the rat brain membrane preparation, even at 37 degrees C for 30 min, i.e., washing restored [3H]naltrexone binding to control levels. These results clearly show that the alpha-methylene-gamma-lactone moiety of 5a is required for irreversible effects, consistent with it serving as a conjugate addition acceptor of a nucleophilic group from a ligand at or near the receptor. The epoxides and glycidate esters also had no irreversible activity, indicating more electrophilic functional groups are needed and/or these electrophiles are not properly aligned to react with nucleophilic groups at or near the opioid receptor.

  DOI：

  10.1021/jm00145a018
• 作为产物：
  描述：

  4,5α-epoxy-3,6α,14-trihydroxy-7α-(carboxymethyl)-17-(cyclopropylmethyl)morphinan γ-lactone 在 咪唑 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 (4bS,8R,8aS,9aR,12aS,12bR)-1-((tert-butyldimethylsilyl)oxy)-7-(cyclopropylmethyl)-10-(((methylsulfonyl)oxy)methyl)-11-oxo-5,6,7,8,9,9a,10,11,12a,12b-decahydro-8aH-4,8-methanobenzofuro[3,2-e]furo[2,3-g]isoquinolin-8a-yl methanesulfonate
  参考文献：
  名称：

  Opioid agonists and antagonists. 6-Desoxy-6-substituted lactone, epoxide, and glycidate ester derivatives of naltrexone and oxymorphone

  摘要：

  Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha-methylene-gamma-lactones (10a and 11a) were prepared. Related 6-desoxy-6-methylene 6 beta- and 6 alpha-oxides (12a,b and 13a) and glycidate esters 14a,b and 15a,b were also prepared with use of naltrexone (1a) and oxymorphone (1b) as starting material. Compounds in the N-cyclopropylmethyl (N-CPM) series were more potent than those in the N-Me series in displacing [3H]naltrexone in the opioid radioreceptor assay, usually by 2-16-fold in the absence of Na ion. The most potent N-CPM analogues were epoxides 12a and 13a and glycidate esters 14a and 15a, showing IC50's of 2-6 nM, similar to that of 5a. Of the N-Me analogues, 6 beta-oxide 12b was most active, with an IC50 of 8 nM in the absence of Na ion. For the N-CPM analogues, the Na ion ratios were generally less than 1, with two exceptions. The N-Me analogues showed expected larger Na ion effects of 7 or greater. None of the lactone analogues had irreversible effects when preincubated in the rat brain membrane preparation, even at 37 degrees C for 30 min, i.e., washing restored [3H]naltrexone binding to control levels. These results clearly show that the alpha-methylene-gamma-lactone moiety of 5a is required for irreversible effects, consistent with it serving as a conjugate addition acceptor of a nucleophilic group from a ligand at or near the receptor. The epoxides and glycidate esters also had no irreversible activity, indicating more electrophilic functional groups are needed and/or these electrophiles are not properly aligned to react with nucleophilic groups at or near the opioid receptor.

  DOI：

  10.1021/jm00145a018