Studies on the Development of New Reaction Modes for the Synthesis of New Drugs

新药合成新反应模式开发研究

基本信息

批准号：
08457585
负责人：
NAGAO Yoshimitsu
金额：
$ 4.54万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

We are extensively carrying out the development of new reaction modes useful for the synthesis of seed and lead compounds of new drugs by utilizing the latent active species. Recently, we have disclosed several new reactions as follows. A new reagent, 3,3'- (phenylphosphoryl) -bis (1,3-thiazolidine-2-thione) was exploited for intramolecular dehydration of various beta-amino acids to give the coreresponding beta-lactams, which could be useful for the monobactam antibiotics. New beta-lactamase inhibitors, thienamonobactams were successfully synthesized by utilizing the latent [2+2] cycloaddition reaction of diketene with an imine derivative. A unique heterocyclic compound, mercaptobicyclotriazolium chloride as the pendant molecule of a remarkable 1beta-methylcarbapenem antibiotic "biapenem", was efficiently synthesized via the reaction cascade employing a pyrazolidine derivative and ethyl formimidate hydrochloride. New angiotensin II (Ag II) receptor antagonists, (acylimino) thiadiazolines were synthesized by exploiting the latent regioselective activation of the nitrogen atom in the heterocyclic moiety of 2-trifluoroacetamido-1,3,4-thiadiazoles. 1,5-Type intramolecular nonbonding S・・・O interaction was clarified by X-ray crystallographic analyzes and abinito MO calculation of the Ag II receptor antagonists and their simple model compounds. We have also developed several new reactions useful for the drug syntheses such as a chemoselective Dieckmann-type reaction mode toward the enantiodivergent process, the Horner-Wadsworth-Emmons reaction of aryl alkyl ketones using tin (II) -triflate and N-ethylpiperidine, and syntheses of new strained [6] and [7] metacyclophanes utilizing the latent conjugated allenyl ketone systems.

我们正在广泛地开发新反应模式，可通过利用潜在的活性物种来合成种子和新药的铅化合物。最近，我们披露了几种新反应，如下所示。一种新的试剂，3,3'-（苯基磷酸）-BIS（1,3-噻唑啉-2-硫代）被利用用于各种β-氨基酸的分子内脱水，从而使corer corser eperra corser eperer beta beta-lactams可用于Monobactam抗生素。新的β-内酰胺酶抑制剂，通过利用二基烯与亚胺衍生物的潜在[2+2]环载反应，成功合成了硫代氨基酰胺。一种独特的杂环化合物，胃咬霉菌二唑烷氯化物作为一个显着的1Beta-甲基甲基苯二甲酸抗生素抗生素“ Biapenem”的吊坠分子，是通过使用吡唑胺衍生物和乙基甲酰胺甲氯乙酰甲氯的反应级联反应有效合成的。新的血管紧张素II（AG II）受体拮抗剂，（酰基氨基）硫二唑啉是通过利用2-三氟乙酰胺1,3,4- thiadiazole的杂环部分中氮原子的潜在调节激活来合成的。通过X射线晶体学分析和ABINITO MO计算AG II受体拮抗剂及其简单模型化合物，通过X射线晶体学分析和ABINITO MO计算来阐明1,5型分子内无键S・・O的相互作用。我们还开发了几种新反应，可用于药物合成，例如化学选择性的Dieckmann-type反应模式，用于对映射过程，即使用TIN（II） - 三磷酸盐和N-乙基二皮苯和合成的N-乙基烷基烷基酮的Horner-Wadsworth-Emmons反应，芳基烷基酮的反应[6]共轭甲烯基酮系统。