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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.

我们正在广泛开展利用潜在活性物种合成新药种子化合物和先导化合物的新反应模式的开发。最近，我们披露了几个新的反应如下。开发了一种新试剂3，3‘-(苯基磷酰基)-双(1，3-噻唑烷-2-硫酮)，用于各种β-氨基酸的分子内脱水，得到了相应的β-内酰胺类药物，可用于单杆菌类抗生素。利用双乙烯酮与亚胺类化合物潜在的[2+2]环加成反应，成功地合成了新的β-内酰胺酶抑制剂。利用吡唑烷衍生物和甲酰亚胺盐酸乙酯的级联反应，高效地合成了一种独特的杂环化合物--硫代环三氮唑氯化物，它是一种引人注目的1β-甲基碳青霉烯类抗生素“biapenem”的侧链分子。利用2-三氟乙酰氨基-1，3，4-噻二唑杂环上氮原子潜在的区域选择性活化作用，合成了新的血管紧张素II受体拮抗剂(Acylimino)噻二唑类化合物。通过对AgII受体拮抗剂及其简单模型化合物的X-射线晶体分析和从头算，阐明了1，5型分子内非键S相互作用。我们还开发了几个用于药物合成的新反应，如针对对映体发散过程的化学选择性Dieckmann型反应模式，芳基烷基酮与三氟化锡和N-乙基哌啶的Horner-Wadsworth-Emmons反应，以及利用潜在的共轭烯丙基酮体系合成新的应变[6]和[7]偏环番化合物。