Synthesis Process Optimization Of NAF Enantiomers, Synthesis And Biological Evaluation Of Chiral Phenylpiperazine Derivatives

Background:Benign Prostatic Hyperplasia (BPH), has become a widely serious disease, which have troubled middle-aged people and the older in society today. In recent years, with our profund studying onα₁-adrenergic receptor (α₁-AR), it has becoming one of the most commonly first-line drugs on the application of non-surgical treatment of BPH. Naphtopidil(NAF) is a new type of selective aryloxy-piperazinesα_1A,D-AR antagonist, the formula of NAF contains the structures of chiral secondary alcohol, so it has a pair of optical enantiomers. Nowadays, NAF is used as its racemic form in the market. It has been found that different selectivity and pharmacological activity exist among the racemates and its two optical isomers upon in vitro organizations of animals.This thesis will be set up on the conducted basis of synthesis of chiral drugs, chiral pharmacology studies, chosing some compounds from the pre-design,synthesis of phenylpiperazine racemic compounds withα₁ receptor antagonist activity, in order to study asymmetric synthesis ways of such chiral drugs; to study the different effects of pharmacodynamics stereoselectivity betwwen optial isomers, and to provide a basis for the design and synthesis of novel and efficient chiral drug molecules.Research content:1. Research on the asymmetric synthetic technological study of chiral compounds S-NAF and R-NAF with chiral glycidyl tosylate and epichlorohydrin.2. Compounds with better biological activity in vitro pre-screening, we designed and synthesized 5 pairs of novel chiral aryloxy-piperazine compounds.3. Targeted at theα₁-receptor antagonists for better biological activity in preliminary screening, we further proceeds to design the structures and synthesis 3 pairs of newly chiral piperazine compounds. Research results:1. This paper established the best reaction conditions of S-NAF and R-NAF, through the chiral materials with technological study. Under the best condition, the target compounds were obtained with high yield (>50%) and high e.e.% values (>99%) after recrystallization.2. The chiral pool method is used to synthesize 3 pairs of aryloxy- piperazine derivatives, their purity and structures are tested by using 1HNMR, HPLC, ESI-MS , UV, IR. Finally those compounds are conformed as the target compounds.3. Studies of Preliminary isolated organizations have showed that these compounds have vitro activity of inhibition to phenylephrine-induced contraction of isolated thoracic aorta and inferior vena cava of a rabbit. The results are as follows: relative inhibitory response JL01≈NAF, JL02≤NAF, JL03≥NAF, all responses that conpare to vena cava are better than the thoracic aorta diastolic function; meanwhile the activity of R configuration is slightly lower than S configuration. And the studies of preliminary in vitro activity shows these synthetic compounds have some in vitro inhibition activities, which implies that these compounds may become potentialα₁-AR subtype's antagonists, further verification of which are still needed.