The Synthesis Process Study Of Chiral NAF Utilizing Hydrolytic Kinetic Resolution And Synthesis , Biological Evaluation Of Chiral Aryloxy-Piperazine Derivatives

Background:As Chinese Population aging, benign prostatic hyperplasia ( BPH ) has become a common serious diseases that troubled middle-aged and old men in today's society. In recent years, with deep study onα1-adrenergic receptor (α1 - AR ),α1 - AR antagonists have become one of the most common first-line drugs on the application of non-surgical treatment of BPH. NAF is a new type of selective aryloxy-piperazinesα1A,D - AR antagonist, and its formula contained the structure of chiral secondary alcohol ,so it has a pair of optical enantiomers. Nowadays NAF is used with its racemic form in the market, however it was found that different selectivity and pharmacological activity exsited among the racemate and its two optical isomers in vitro animals organizations. By studying the differences of pharmacodynamic stereoselectivity and clarifying the differences of pharmacological activity between enantiomers, then the law of enantiomers'molecular structure and pharmacodynamics can be revealed in chiral drugs. Further study of chiral drug enantiomers'mechanism can provide a basis for positive prediction on the occurrence of interaction between chiral drugs and their toxicity, and have an significant point on providing basis for chiral drugs development and clinical rational administration.Research content:1. Research on the asymmetric synthetic technological study of chiral aryloxy- piperazine compounds S - NAF and R - NAF .2. compounds with better biological activity in vitro pre-screening ,we designed and synthesized a series of novel chiral aryloxy-piperazine compounds ,which contained 5 groups of raceme and its optical isomers together 15 goal compounds.3. Targeted at theα1 - receptor antagonists with better biological activity in preliminary screening , we further proceeded to design the structure and sythesis a series of newly chiral piperazine compounds which contained 5 groups of raceme and its optical isomers together 15 goal compounds.Research results:1.This paper established the best reaction conditions of S - NAF and R - NAF through the hydrolytic kinetic resolution technological study. Under the best condition, the target compounds were obtained with high yield and high, as ee values ( > 98 % ) after recrystallization.2. The method of chiral source was used to synthesize 5 groups aryloxy-piperazine derivatives, then their purity and structures were test using HPLC, UV, IR, 1HNMR, ESI-MS,and finally these synthetic compounds were determined as the target compounds.3. Preliminary isolated organizations studies showed that these compunds have better vitro inhibition activity on phenylephrine-induced contraction of rabbit isolated thoracic aorta, prostate muscle strips and bladder muscle strips of muscle. The results as follows:①The relative inhibitory response of thoracic aortic S - 01 > Control≈R - 01≈Rac - 01; R - 02≈Control > S - 02;R - 03≈Rac - 03≈S - 03≈Control; Rac - 04≈S - 04≈Control; R - 05≈Rac - 05≈S - 05 < Control.②The relative inhibitory response of prostate muscle strips S - 01≈Rac - 01≈Control,Control >R - 01;S - 02 > R - 02≈Control; R - 03≈Rac - 03≈S - 03≈Control; S - 04≈Rac - 04 > Control≈R - 04;S - 05≈Rac - 05 < Control.③S - 01≈Rac - 01≈Control > R - 01;R - 02≈Rac - 02≈Control;S - 03≈Rac - 03≈R - 03 < Control; S - 04≈Rac - 04≈R - 04 < Control;S - 05≈Rac - 05≈R - 05≈Control.Conclusions: This paper established the best reaction conditions of S - NAF and R - NAF through the hydrolytic kinetic resolution technological study . However, hydrolytic kinetic resolution technology is not suitable for the synthesis of 5 groups compounds. Maybe it is because of the huge carbazole structure in compounds that made greater steric hindrance ,and finally the catalyst can not make a recognition. The method of chiral source was used to synthesize 5 groups aryloxy-piperazine derivatives, which were identified as target compounds by using HPLC, UV, IR, 1HNMR, ESI-MS and optical rotation. Preliminary vitro activity studies showed that these synthetic compounds have better vitro inhibition activity, which implied that these compouds may become theα1-AR subtypes antagonists whic still needs further verification.