Gergely A, Gyimesi-Forrás K, Horváth P, Hosztafi S, Kökösi J, Nagy P I, Szász Gy, Szentesi A
Department of Pharmaceutical Chemistry, Semmelweis University, H-1092 Budapest, Högyes E. u. 9. Hungary.
Curr Med Chem. 2004 Oct;11(19):2555-64. doi: 10.2174/0929867043364450.
The permanent therapeutic importance of morphine derivatives in pain treatment has inspired continual synthetic efforts to modify the rigid pentacyclic systems in search for new selective analgesic agents. As a result, several morphinane oximes have been synthesized recently, which have the additional advantage of possessing an oxime group that can provide a method for selective determination of opiate alkaloids in biological matrices. The oximes of hydrocodone and oxycodone have stronger analgesic effect than the parent ketones and they also proved to be effective in preventing the respiratory depressant and hypotensive actions of fentanyl. In this work a review is given on the present status of oxime pharmacology, chemistry and analysis and also the oxime and O-methyl oxime formation of 6-oxo-morphinanes with therapeutic interest (codeinone, oxycodone, hydrocodone and 14-OH-codeinone). The oxime formation was monitored by reversed-phase HPLC and the chromatographic properties of oxime isomers have been characterized. The assignation of the individual isomers isolated by preparative HPLC was performed by (1)H NMR spectroscopy based on the chemical shift differences of the 5-H signals. In this way the isomeric ratio in the oxime products could also be determined. It was found that in the case of Delta(7)-6-oxo-morphinanes, depending on the substituents, the formation of the Z-isomer highly dominates (73-96%) over that of the E-isomer. However, for the saturated 7,8-(dihydro) derivatives the E-isomer is definitely preferred (>98%). In conclusion of a survey on the theoretical background of oxime isomerism, the conformational differences between the saturated and unsaturated morphinane systems were found responsible for the different E/Z ratios. On the basis of the isomeric ratio and the on-line CD and UV spectra of the pure isomers, the molar ellipticities and absorbancies of the isomers were calculated by a parameter estimation method.
吗啡衍生物在疼痛治疗中具有长期的治疗重要性，这激发了人们不断进行合成研究，以修饰刚性五环系统，寻找新的选择性镇痛药。因此，最近合成了几种吗啡烷肟，它们还具有额外的优势，即拥有一个肟基，可为生物基质中阿片生物碱的选择性测定提供一种方法。氢可酮和羟考酮的肟比母体酮具有更强的镇痛作用，并且它们还被证明可有效预防芬太尼的呼吸抑制和降压作用。在这项工作中，对肟的药理学、化学和分析现状以及具有治疗意义的6-氧代吗啡烷（可待因酮、羟考酮、氢可酮和14-羟基可待因酮）的肟和O-甲基肟形成进行了综述。通过反相高效液相色谱监测肟的形成，并对肟异构体的色谱性质进行了表征。通过基于5-H信号化学位移差异的(1)H NMR光谱对通过制备型高效液相色谱分离的各个异构体进行了归属。通过这种方式，还可以确定肟产物中的异构体比例。结果发现，对于Δ(7)-6-氧代吗啡烷，根据取代基的不同，Z-异构体的形成比E-异构体占主导地位（73-96%）。然而，对于饱和的7,8-(二氢)衍生物，E-异构体绝对更受青睐（>98%）。在对肟异构现象理论背景的调查总结中，发现饱和和不饱和吗啡烷系统之间的构象差异是导致不同E/Z比例的原因。基于异构体比例以及纯异构体的在线圆二色光谱和紫外光谱，通过参数估计方法计算了异构体的摩尔椭圆率和吸光度。
