Design, Synthesis And Preliminary Biological Activity Evaluation Of Chiral Aryloxypiperazine Derivatives

Background:At present, the treatment of benign prostatic hyperplasia focus on two categories of drugs on the whole: one category is 5α-reductase inhibitors; the other is selectiveα1-blockers. Studies have shown that: the point for studyingα1 adrenergic receptor antagonists which used for treating benign prostatic hyperplasia is to look for a focus on drugs with high-selectiveα1 receptor subtypes and to avoidα1B adrenergic receptor subtypes which have cardiovascular antagonistic effect, in order to reduce orthostatic hypotension and reflex tachycardia and other side effects. It is found that someα1 receptor antagonist enantiomers showed different pharmacological activities in the treatment of benign prostatic hyperplasia, so by studying chiral drugs'different effects of pharmacodynamic stereoselectivity, 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. In the past ten years, our laboratory has made a research on the design,synthesis,metabolic products and structure-function relationship of piperazinesα1 adrenergic receptor antagonists, and also studied asymmetric synthesis,analysis and chiral pharmacology of their chiral isomers. As a result, we found that an difference of pharmacodynamics stereoselectivity was existed between enantiomers; preliminary pharmacokinetic study found that such compounds'optical isomers were different in stereoselective pharmacokinetic and in vivo process.In view of the research area of chiral drugs at home and abroad and the development foundation of our laboratory research in this field , this thesis will be set up on the conducted basis of synthesis of chiral drugs, chiral pharmacology studies, structure-activity relationships and pharmacokinetic studies, chosing better compounds from the pre-design,synthesis of phenylpiperazine racemic compounds withα1 receptor antagonist activity, to further design and synthesize a series of newly chiral piperazine compounds , in order to study asymmetric synthesis ways of such chiral drugs; to study the different effects of pharmacodynamics stereoselectivity betwwen optial isomers, as well as the law of enantiomers molecular structure and pharmacodynamics in such compounds; to provide a basis for the design and synthesis of novel and efficient chiral drug molecules.Research contents:1. A review on the asymmetric catalytic synthesis of chiral secondary alcohol compounds.2. Research on three asymmetric synthetical routes of chiral compound NAF :(1) Chiral Source Program: refer to Sharpless epoxidation reaction, (R/ S) - p-methyl benzenesulfonate glycidyl ether were used as chiral sources to react with 1- naphthol and then the key chiral intermediates (R/S) -1 - (α-naphthyl) glycidyl ether were obtained, followed by the reaction with displ-methoxyphenyl piperazine and finally S-NAF and R-NAF were synthesized;(2) Hydrolysis Kinetics Program: the Jacobsen catalyst - R, R-Salen-Co (III) OAc was used and water was used as a nucleophile to make an asymmetric ring-opening reaction on racemic terminal epoxide±1 - (α-naphthyl) glycidyl ether to obtain (S) -1 - (α-naphthyl) glycidyl ether and (2R) -3 -α-naphthoxy-1,2-propylene glycol. After that, Mitsunobu reaction was carried out on (2R) -3 -α-naphthoxy-1,2-propylene glycol to get (R) -1 - (α-naphthyl) glycidyl ether, and both chiral epoxide were further reacted with displ- methoxyphenyl piperazine and finally S-NAF and R-NAF could be obtained;(3) Asymmetric Aminolytic Kinetic Resolution Program: the Jacobsen catalyst R, R-Salen-Co (II) or analogues were used and displ-methoxyphenyl piperazine was used as a nucleophile to make an asymmetric ring-opening reaction on racemic terminal epoxide±1 - (α-naphthyl) glycidyl ether and wished to obtain (S) -1 - (α-naphthyl) glycidyl ether and R-NAF by one step.3. Choose an optimal synthetic route. 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.4. Initial vitro biological activity screening on new designed,synthetical novel chiral aryloxy-piperazine compounds: among the racemic compounds and its enantiomers, the vitro tissue biological function tests were carried out to test their activity and selectivity differences on the rabbit prostate, bladder muscle and thoracic aortic ring.Research Results:(1) The chiral source route showed mild reaction conditions, little pollution and has a good reproducibility and stability. When the reaction was occurred 8 hours, at 30℃in DMF, the yield of intermediat (S) -1 - (α-naphthyl) glycidyl ether could achieve to the highest as 84.33% with its stabile ee 90%. Followed by the reaction with (S) -1 - (α-naphthyl) glycidyl ether and displ-methoxyphenyl piperazine at 60℃, 10 hours in iso-propanol, targeted compound S-NAF c ould be obtained with the yield 78.46% and ee 89.43%. Ee of S-NAF could be improved to 99% after recrystallisation in dehydrated alcohol.(2) The hydrolysis kinetics route showed many advantages: it proved that R, R-Salen-Co (III) OAc was a catalyst with excellent function, the use of cheap water as a nucleophile was both environmentally-friendly and safe, and it was a more moderate reaction condition, without solvent, at room temperature ee 99.9% of (S) -1 - (α-naphthyl ) glycidyl ether was obtained, not only so, but also high enantioselectivity of (2R) -3 -α-naphthoxy-1,2-propylene glycol could be obtained, and then targted compound R-/S-NAF with high enantioselectivity could be obtained. However, there were also many disadvantages: cumbersome reaction steps with a more Mitsunobu reaction than chiral source route; domestic catalyst of poor stability made the hydrolysis kinetics reaction under poor reproducibility; the low recovery rate of catalyst and the cumbersome process after the reaction.(3) The asymmetric aminolytic kinetic resolution route showed an mild reaction conditions, simple operation, high yield and ee 99.9 % of (S) -1 - (α-naphthyl) glycidyl ether and ee 18 % ~ 20 % of R-NAF were obtained by one step using salen-Co complex. However, non obvious catalystic effect of salen-Fe,Mn,Cr complex were found.(4) The 15 neotype aryloxy-piperazine compounds including 5 raceme and its 10 corresponding enantiomers were synthesized and detected by the UV, IR, HPLC, 1HNMR and Optical Rotation finally were definited to have the same structures with target compounds. All compounds had 99 % purity and the ee values of all enantiomers were above 98 % detected by HPLC.(5) Among the target compounds , compounds R-04,rac-04,S-04 and R-05,rac-05,S-05 were chosed to proceed the vitrvo activity test. The results showed that: all these compounds have goodα1-receptor antagonistic effect, and compounds with difference configuration expressed obvious pharmo-activity diversity: the antagonistic effect order is S config. > rac config. > R config..Conclusions: An investigation on three synthetic routes of chiral compound NAF was made and finally we determined the source of chiral synthesis route as the best route in this paper. The synthetical compounds were consistent with the structure of target products by UV,IR,HPLC,ESI-MS,1HNMR and Optical Rotation. The preliminary results of vitro activity research showed that raceme 04, 05 and their enantiomers existed different pharmacology characteristics among them. In the relaxation experiment that aimed at phenylephrine-induced contraction effect of different rabbit vitro tissue effect, compounds S-04,S-05 showed good vitro activity and organization selectivity on urinary tract. It was suggested that S-04,S-05 may be two potentialα1-AR antagonists with good selectivity on urinary tract, which still needs to be verified by radioactive ligand binding experiments, relaxation effect of isolated organizations with single receptor subtype and overall animal models.Prospect: Next step on the basis of asymmetric synthesis study, we would study the differences on pharmacological properties of such compounds among enantiomers and racemes, to explore the law between efficacy and enantiomeric molecular structure of these compounds, for the purpose of design and explore single enantiomer more selectively and objectively. By studying the effort of such compounds through the pharmacokinetics and stereoselective differences in metabolism, and clarifying the process of enantiomeric differences in the mechanism of the body, through structural modification, we hope to target the process of change in a body to make compounds have higher efficiency, lower toxicity, and then provide a basis for the design and synthesis of novel, efficientα1A/D- subtype selective drug molecules.