“优势结构”1，5-苯并杂（艹卓）类化合物的液相平行合成

【作者】 赵海燕；

【导师】 刘刚；

【作者基本信息】 中国协和医科大学 ， 药物化学， 2007， 博士

【摘要】 先导化合物的发现及优化是新药研究的重要基础。组合化学能够快速、高效合成大量具有分子多样性的化合物,在先导化合物的发现和优化过程中发挥着重要的作用。“优势结构”(privileged structure)是指一类能够与多种生物受体强烈结合或者作用的分子结构,它表现出“似先导化合物”、“似药”等性质。组合合成具有“优势结构”的化合物有助于提高发现先导化合物的概率。苯并硫氮杂(艹卓)和苯并二氮杂(艹卓)都具有很广泛的生物活性,都属于优势结构。本论文以1,5-二氟-2,4-二硝基苯(DFDNB)为起始原料,探索并优化了液相平行合成1,5-苯并硫氮杂(艹卓)-4-酮和1,5-苯并二氮杂(艹卓)-2-酮化学库的方法。1 1,5-苯并硫氮杂(艹卓)-4-酮经定量亲核取代、硫醚氧化、芳香间二硝基还原、皂化和分子内关环等反应合成了重要基本分子骨架1,5-苯并硫氮杂(艹卓)-4-酮和1,1-二氧-1,5-苯并硫氮杂(艹卓)-4-酮母环,进而以它们为基础,衍生出一系列“取代多样性”的二环骨架。所得化合物具有三个或四个多样性位点。苯并咪唑、苯并羰基咪唑和苯并硫代羰基咪唑都具有广泛的生物活性,将它们稠合到优势骨架1,5-苯并硫氮杂(艹卓)-4-酮中,有可能增加发现新先导化合物的机会。以中间体1,1-二氧-1,5-苯并硫氮杂(艹卓)-4-酮为原料,分别和醛、三光气、二硫化碳反应得到三类新的三环骨架。本文中合成了1,5-苯并硫氮杂(艹卓)-4-酮类化合物109个。对所合成的化合物进行初步药理活性筛选,结果表明:化合物B28具有维甲酸受体拮抗作用,B13、B22和B36具有抗流感病毒活性。因此我们对这些化合物进行优化,制备了一个含有42个纯化合物的亚库。其活性评价正在进行中。2 1,5-苯并二氮杂(艹卓)-2-酮利用各种伯氨与丙烯酸甲酯进行共轭加成得到β-氨基酸酯,再经亲核取代、硫醚的氧化、硝基的还原、皂化、缩合等反应,合成了5,7,8-三取代的1,5-苯并二氮杂(艹卓)-2-酮类化合物。此外,用取代的β-氨基酸来进行亲核取代,可以得到具有四个或五个多样性位点的1,5-苯并二氮杂(艹卓)-2-酮类化合物。利用这两种方法我们合成了含有55个纯化合物的1,5-苯并二氮杂(艹卓)-2-酮化学库。这类化合物的活性评价正在进行中。本论文中优化出的合成路线具有反应条件温和、反应速度快、收率高等特点,利用这些方法可以快速合成具有结构多样性的化合物库。所有合成的化合物均经MS(LC-MS或HRMS)及NMR确证结构。并对其中一个化合物通过X-单晶衍射的方法确认了精确结构。更多还原

【Abstract】 The number of lead compounds is the vital base for drug discovery. Combinatorial chemistry, which can rapidly provide large number of compounds, has been recognized as a powerful tool for both identification and optimization of lead compounds. Privileged structures, which have become a popular theme in medicinal chemistry recently, present a class of molecules capable of binding to or effect on multiple biological receptors with high affinity and demonstrate "drug-like" or "lead-like" properties. Therefore, the exploration of synthesis of privileged structures may provide more chances for discovery and optimization of novel lead compounds.Benzothiazepine and benzodiazepine are both privileged structures eliciting broad spectrum of biological activities. Practical and efficient new solution-phase parallel methods have been developed in this thesis for the synthesis of 1,5-benzothiazepin-4-ones and 1,5-benzodiazepin-2-ones with a large variety of substituents starting from 1,5-difluoro-2,4-dinitrobenzene (DFDNB).1. Solution-Phase Parallel Synthesis of 1,5-Benzothiazepin-4-onesThe synthetic route mainly includes quantitatively nucleophilic substitution, oxidation of sulfide, reduction of aromatic dinitro groups and cyclization, yielding two important scaffolds: 1,5-benzothiazepin-4-one and 1,1-dioxo-1,5-benzothiazepin-4-one. The benzothiazepine skeleton possesses three or four points of diversity and thus affords new opportunities for identification of hits in drug lead discovery and optimization.Bnezimidazole, benzimidazolone and thio-benzimidazole are all privileged structures too, which also possess extensively biological activities. Therefore, integrating one of these privileged pharmacophores with 1,5-benzothiazepin-4-one would benefit for the more opportunities to discover new lead compounds. Treatment of 1,1-dioxo-1,5-benzothiazepin-4-one with aldehydes, triphosgene or carbon disulfide eventurely, three novel tricycles were developed respectively.A library containing 109 single compounds were synthesized. Primary screening indicated that compound B28 elicit the retinoic acid receptor antagonist property and compounds B13, B22 and B36 exhibit anti flu property. A sub-library containing 42 pure compounds was then synthesized to optimize the activity. The data will be reported somewhere else soon.2. Solution-Phase Parallel Synthesis of 1,5-Benzodiazepin-2-onesThe requisiteβ-amino esters were gained after reaction of various primary amines with methyl acrylate. They, together with several commercial availableβ-amino acids, were then used herein to successfully explore a solution-phase parallel synthetic method of 1,5-benzodiazepin-2-ones with four or five diversity points. A library containing 55 individual compounds was prepared.These routes permit us to introduce a great molecular diversity at substitution level of 1,5-benzothiazepin-4-ones and 1,5-benzodiazepin-2-ones under mild reaction conditions. Large number of derivatives is able to be rapidly synthesized in excellent purity and high yield using these methods.All the compounds synthesized in this thesis were fully characterized by MS (LC-MS or HRMS) and NMR. One of them is further determined by X-ray diffraction.更多还原