Synthesis, Preliminary Bioactive Evaluation And New Synthetic Methods Of New Chiral Aryloxypoperazine Derivatives

Research backgroundAs the pace of aging in China, benign prostatic hyperplasia（BPH） is a commondisease agitating men in old age. According to deep research in this area, it had beenfound that α₁-AR is a good target for drug treatment. So that α₁-AR antagonist hasbecome a very effective drug for BPH. A group of aryloxypoperazine derivatives isrepresentative. NAF is one of aryloxypiperazine derivatives, which was made byBoehringer Mannheim company. It is a new type of α₁-AR antagonist drug.It has achiral center so it has two enantiomers. Comparing with prazosin, NAF not only hasthe same curative effect, but also has some dramatic characteristics: lighter untowardreaction, longer potency, convenience sume, no impact on weight while loweringblood fat. So that it can be used for the treatment of benign prostatic hyperplasia（BPH）and urinary incontinence.This paper is willing to design and synthesize a new group of aryloxypoperazinederivatives, based on well established research in our lab, which has effection ofα₁-AR antagonist. Then do preliminary bioactive research for these compounds andexplore new synthetic procedures for these compounds.Research Content1. To design and synthesize4group，totally12of new aryloxypoperazine derivatives,including their enantiomers. To use HPLC, ESI-MS, IR,¹HNMR to analyse theirconstruction.2. To use Dual-luciferase reporter gene detection method to do preliminary bioactiveresearch for these12compounds.3. Based on the chiral pool method of NAF, I try brand new methods forsynthesizing NAF and newly designed12compounds by using β-cyclodextrin andsilica gel as catalyst for solving the drawbacks of old procedures in our lab.4. Design new cascade reaction, try to optimize the basic parameters.Research result1. Synthesizing12compounds of new aryloxypoperazine derivatives, using HPLC, ESI-MS, IR,¹HNMR to analyse their constructions then find out the right absoluteconfigurations.2. This project use Dual-luciferase reporter gene detection method to preliminary testthe biological activity of12new derivatives. The results show that all12compounds have α₁A-AR antagonistic activities in varying degrees. Many of thesecompounds’ α₁A-AR antagonistic coefficients are larger than prazosin’s. Implyingthat they may be potential antagonists for α₁-AR receptor. In most of the targetcompounds, S–enantiomers have more bioactive than R-enantiomers, implyingthat the further verification of the target compounds’ chiral pharmacology,chiralpharmacokinetic and the other two α₁-AR subtypes selectivity studies are stillneeded.3. Using β-cyclodextrin and silica gel as catalyst, synthesize NAF and its twoenantiomers, good yield and high ee%are made. Then apply to12newcompounds, it is also a good methods.4. Finish a newly design cascade reaction, optimize its parameters.