Potentiality of Alkylthiofuropyridone for Exploitation of Cerebrovascular Agents

考虑到治疗阿尔茨海默病的脑血管药物和毒扁豆碱激动剂都有取代的哌啶作为共同的关键结构特征，我们研究了这两种药物的新合成策略的开发，使用双环杂环烷基硫代呋喃吡啶酮作为合成子。我们首次建立了一种有价值的合成子烷基硫代呋喃吡啶酮的有效合成路线，涉及烷基硫代烯胺的还原光环化反应。通过烷基硫基、烯醚和内酰胺羰基的合成反应评价了呋喃吡啶酮的潜力，这些官能团提供了一种新的碳-碳键形成和环转化反应。以羧酸、伯胺和呋喃甲酰氯为原料制备的烷基硫代烯胺在硼氢化钠的存在下顺利地进行了光环化反应，得到了两种类型的烷基硫代呋喃吡啶酮。呋喃吡啶酮通过内酰胺羰基烯醇烷基化得到了3，4-二取代的哌啶类化合物，它们被有效地转化为已知的M受体激动剂的类似物，也被转化为生物碱、替可曼宁(降血糖活性)、奎宁(抗疟疾药)、艾美汀(抗阿米巴药)和阿马利汀(肾上腺素能阻滞剂)。另一种呋喃并吡啶酮的消除加成反应得到了3，3-二取代哌啶类化合物，其中一些已被证明是合成eburnamine-vincamine生物碱、eburnamonine(脑血管药物)和Cuazine(抗心律失常、血管扩张和抗高血压活性)的常见中间体。

Considering that both cerebrovascular agents and muscarinic agonists for the treatment for Alzheimer's disease have the substituted piperidine as a common key structural feature, we have investigated the development of new synthetic strategy for both medicinals employing the bicyclic heterocycles, alkylthiofuropyridone, as a synthon.We first established an efficient synthetic route for a valuable synthon, alkylthiofuropyridone' via the route involving the reductive photocyclization of the alkylthio-enamides. Potentiality of the furopyridone has been evaluated by the synthetically useful reactions involving three functional groups, alkylthio, enolether, and lactam carbonyl groups which have provided a novel carbon-carbon bond formation and ring transformation reactions.Reductive photocyclization of alkylthio-enamides, prepared from the carboxylic acid, primary amine, and furoyl chloride, in the presence of sodium borohydride proceeded smoothly to give two types of alkylthiofuropyridones. Alkylation of the furopyridone via the lactam carbonyl-enolate gave the 3, 4-disubstituted piperidines which were efficiently converted into the analogues of the known muscarinic agonists and also into the biologically active alkaloids, tecomanine (hypoglycemic activity), quinine (antimalarial agent), emetine (antiamebic agent), and ajmalicine (adrenergic blocking agent). Elimination-addition reaction of another furopyridone gave the 3, 3-disubstituted piperidines, some of which have proved common intermediates for the synthesis of eburnamine-vincamine alkaloids, eburnamonine (cerebrovascular agent) and cuanzine (antiarrhythmic, vasodilatory, and antihypertensive activties).