Bailey B R, Berlin K D, Holt E M, Scherlag B J, Lazzara R, Brachmann J, van der Helm D, Powell D R, Pantaleo N S, Ruenitz P C
J Med Chem. 1984 Jun;27(6):758-67. doi: 10.1021/jm00372a010.
The synthesis of the title ketone has been completed via a type of Mannich reaction starting from 4- thianone . An X-ray diffraction analysis has revealed that the solid system is a chair-boat conformer with the sulfur atom in the boat portion of the bicyclic ring compound. Wolff- Kishner reduction of the ketone group gave 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane, which was isolated as the hydroperchlorate . However, X-ray diffraction analysis of the salt showed this solid to be a chair-chair conformer. Addition of phenylmagnesium bromide to the ketone gave a tertiary alcohol with the C-C6H5 bond being equatorial with respect to the thiane ring and axial with respect to the piperidine ring. The reaction of the Grignard reagent with the ketone to give this alcohol seems to be very stereospecific. An X-ray analysis of the hydroperchlorate of the alcohol confirmed the system to be a chair-chair form in the solid. The title compounds were screened for antiarrhythmic activity in anesthetized mongrel dogs in which myocardial infarctions had been created when the left anterior descending coronary artery was ligated. Vagal-induced slowing of the sinus mode firing rate was used to determine the underlying ventricular automaticity in the dogs, which averaged 164 +/- 27 beats/min. Ventricular pacing was initiated to rates between 240 and 390/min. This technique resulted in the induction of rapid and sustained ventricular tachycardia. At doses of 3 and 6 mg/kg of body weight, 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane hydroperchlorate in alcohol (the solution was administered intravenously) was able to suppress markedly the induced ventricular tachycardia in five of six dogs. The compound also caused a 10-15% increase in blood pressure within a few minutes. The antiarrhythmic properties of this compound and others of related structure are discussed, and some comparison is made with the action of lidocaine in similar dog preparations.
从4-噻蒽酮出发，通过一种曼尼希反应完成了标题酮的合成。X射线衍射分析表明，该固体体系是一种椅式-船式构象体，硫原子位于双环环化合物的船式部分。酮基的沃尔夫-基什纳还原反应得到7-苄基-3-硫杂-7-氮杂双环[3.3.1]壬烷，其以高氯酸氢盐形式分离出来。然而，该盐的X射线衍射分析表明，这种固体是一种椅式-椅式构象体。向酮中加入苯基溴化镁得到一种叔醇，其中C-C6H5键相对于噻蒽环是平伏键，相对于哌啶环是直立键。格氏试剂与酮反应生成这种醇的反应似乎具有很高的立体选择性。该醇的高氯酸氢盐的X射线分析证实，在固体中该体系为椅式-椅式构象。在结扎左前降支冠状动脉造成心肌梗死的麻醉杂种犬中，对标题化合物进行了抗心律失常活性筛选。通过迷走神经诱导的窦性心律放电频率减慢来测定犬的潜在心室自律性，其平均为164±27次/分钟。开始进行心室起搏，频率在240至390次/分钟之间。该技术导致诱发快速且持续的室性心动过速。在体重剂量为3和6mg/kg时，7-苄基-3-硫杂-7-氮杂双环[3.3.1]壬烷高氯酸氢盐的乙醇溶液（静脉给药）能够显著抑制6只犬中5只犬诱发的室性心动过速。该化合物还能在几分钟内使血压升高10-15%。讨论了该化合物及其他相关结构化合物的抗心律失常特性，并与利多卡因在类似犬制剂中的作用进行了一些比较。
