O3-(2-tetrahydrofuranyl)-4,5α-epoxy-3,14-dihydroxy-6-oxo-17-(cyclopropylmethyl)morphinan | 92398-25-9

• 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: O3-(2-tetrahydrofuranyl)-4,5α-epoxy-3,14-dihydroxy-6-oxo-17-(cyclopropylmethyl)morphinan
• 英文别名: O³-(2-tetrahydrofuranyl)-4,5α-epoxy-3,14-dihydroxy-6-oxo-17-(cyclopropylmethyl)morphinan
• CAS: 92398-25-9
• 化学式: C₂₄H₂₉NO₅
• 分子量: 411.498
• InChiKey: FXVZIOZNSHHYEC-JWLFCQOUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.34
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  68.23
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  O3-(2-tetrahydrofuranyl)-4,5α-epoxy-3,14-dihydroxy-6-oxo-17-(cyclopropylmethyl)morphinan 在 咪唑 、 正丁基锂 、 L-Selectride 、 六甲基二硅氮烷 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.58h， 生成 4,5α-epoxy-3-<(tert-butyldimethylsilyl)oxy>-6α,14-dihydroxy-7α-(carboxymethyl)-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：

  2-氯四氢呋喃 、 纳曲酮 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 O3-(2-tetrahydrofuranyl)-4,5α-epoxy-3,14-dihydroxy-6-oxo-17-(cyclopropylmethyl)morphinan
  参考文献：
  名称：

  纳曲酮和羟吗啡酮的非对映体6-脱氧-6-螺-α-亚甲基-γ-丁内酯衍生物。构象受限的迈克尔受体配体对阿片受体制剂中纳曲酮结合的选择性不可逆抑制。

  摘要：

  纳曲酮（4a和5a）和羟吗啡酮（4b和5b）的非对映体6-脱氧-6-螺-α-亚甲基-γ-丁内酯衍生物是由其母体酮制备的。非对映体4a和4b通过与由α-（溴甲基）丙烯酸甲酯制备的Reformatsky试剂反应，从纳曲酮（6a）和羟吗啡酮（6b）的3，14-二乙酸酯衍生物获得。用甲醇脱乙酰完成合成。非对映异构体5a和5b分别从肟酮8a和8b获得。使环氧乙烷酮与乙酰乙酸乙酯的钠盐反应，然后进行甲基化和脱保护，分别完成5a和5b的合成。化合物5a是在阿片样物质放射性受体测定中与[3H]纳曲酮竞争中测试的最有效的药物。在5 nM的浓度下，该化合物产生50％的结合抑制。这种抑制作用的大部分（30％）是不可逆的，即，即使在存在和不存在Na +的情况下彻底清洗膜制剂后，这种抑制作用仍然存在。纳洛酮可以防止这种不可逆的作用。数据表明受体亲核试剂（可能是巯基）位于可以加成5a的α，β-不饱和羰基系统的位置。

  DOI：

  10.1021/jm00378a032