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Potentiality of Alkylthiofuropyridone for Exploitation of Cerebrovascular Agents

烷基硫代呋喃并吡啶酮开发脑血管药物的潜力

基本信息

批准号：
01571171
负责人：
NAITO Takeaki
金额：
$ 1.34万
依托单位：
Kobe Women's College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

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).

考虑到用于治疗阿尔茨海默病的脑血管药和毒蕈碱激动剂都具有取代哌啶作为共同的关键结构特征，我们研究了以双环杂环烷基硫代呋喃吡啶酮为合成物的两种药物的新合成策略。我们首先建立了一种有效的合成路线，通过还原光环化的路线，有价值的合成物，烷基硫代呋喃吡啶酮。呋喃吡啶酮的潜力通过涉及烷基硫基、烯醚基和内酰胺羰基三个官能团的合成有用的反应来评价，这些反应提供了一种新的碳-碳键形成和环转化反应。以羧酸、伯胺和氟酰氯为原料，在硼氢化钠的存在下，对烷基硫代烯酰胺进行了还原性光环反应，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酯烷基化得到3,4 -二取代哌啶，这些哌啶有效地转化为已知毒蕈碱激动剂的类似物，也转化为生物活性生物碱，tecomanine（降糖活性），quinine（抗疟疾剂），emetine（抗阿米巴药物）和ajmalicine（肾上腺素能阻滞剂）。另一种呋喃吡啶酮的消除加成反应得到3,3 -二取代哌啶，其中一些已被证明是合成eburnamine-vincamine生物碱，eburnamonine（脑血管剂）和cuanzine（抗心律失常，血管扩张和降压活性）的常见中间体。