Holzgrabe U, Erciyas E
Pharmazeutisches Institut, Universität Bonn.
Arch Pharm (Weinheim). 1992 Oct;325(10):657-63. doi: 10.1002/ardp.19923251008.
The 2,4-di-2-pyridyl- substituted 7-methyl-3,7-diazabicyclo[3.3.1] nonan-9-one-1,5-diester shows a reasonable kappa-agonistic activity in the mouse vas deferens test. -To enhance the analgetic activity derivatives with m-Cl-, m-CH3-, m-OCH3-, m-OH-, and m-NO2 substituted phenyl residues at C-2/4 were synthesized: From the condensation of benzaldehydes, methylamine, and oxoglutarate isomeric mixtures of piperidones were obtained, containing cis-ketone and -enol and trans-enol; the isomerisation reactions of these piperidones were observed in CDCl3 and CD3OD. The bicyclus resulting from the reaction of the piperidones with HCHO and methylamine exhibits conformational rigidity because the free rotation of the 2,4-aryl groups is hindered. The rotational barrier around the C-2-aryl-bond was shown to be 18 kcal/mol by analysis of variable temp. 1H-NMR spectra.
2,4-二-2-吡啶基取代的7-甲基-3,7-二氮杂双环[3.3.1]壬烷-9-酮-1,5-二酯在小鼠输精管试验中显示出合理的κ-激动活性。为了增强镇痛活性，合成了在C-2/4处带有间氯、间甲基、间甲氧基、间羟基和间硝基取代苯基残基的衍生物：通过苯甲醛、甲胺和氧代戊二酸的缩合反应得到了含有顺式酮、顺式烯醇和反式烯醇的哌啶酮异构体混合物；在CDCl₃和CD₃OD中观察到了这些哌啶酮的异构化反应。哌啶酮与甲醛和甲胺反应生成的双环具有构象刚性，因为2,4-芳基的自由旋转受到阻碍。通过变温¹H-NMR光谱分析表明，C-2-芳基键周围的旋转势垒为18千卡/摩尔。
