Wünsch B, Höfner G, Bauschke G
Institut für Pharmazie und Lebensmittelchemie, Universität München.
Arch Pharm (Weinheim). 1993 Sep;326(9):513-8. doi: 10.1002/ardp.19933260904.
The bromoacetals 5a and 5b react with n-butyllithium and the piperidone 7 to yield the hydroxyacetals 8b and 8c, respectively. Cyclization of 8b and 8c followed by acid hydrolysis affords the spirocyclic hemiacetals 10b and 10c which are oxidized by PCC to give the spirocyclic prodine analogues 4b and 4c. The corresponding spirocyclic pethidine derivative 2 is prepared by alkylation of the 2-benzopyran-3-one 16 with N-Lost (17). In the mouse writhing test the spiropethidine 2 is not analgesic active up to a dose of 20 mg/kg body weight (bw). In the spirocyclic prodine series the methylated lactone 4c is the most active analgesic with an ED50-value (ED50 = 9.2 mg/kg bw) in the range of the ED50-value of tramadol.
溴代缩醛5a和5b与正丁基锂和哌啶酮7反应，分别生成羟基缩醛8b和8c。8b和8c环化后经酸水解得到螺环半缩醛10b和10c，它们被PCC氧化得到螺环普罗定类似物4b和4c。相应的螺环哌替啶衍生物2是通过2-苯并吡喃-3-酮16与N-Lost（17）烷基化制备的。在小鼠扭体试验中，螺环哌替啶2在高达20mg/kg体重（bw）的剂量下没有镇痛活性。在螺环普罗定系列中，甲基化内酯4c是活性最强的镇痛药，其半数有效剂量（ED50 = 9.2mg/kg bw）在曲马多的ED50值范围内。
