The Preferred 1,5 - Benzo Miscellaneous (zhuo Lv) Compounds, Liquid Phase Parallel Synthesis

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.