Study On Synthesis And Activity Of New Timolol Analogues

Chiral drug timolol is known as the best fat soluble beta-adrenaline receptor blocker, and chemical name is1-tertbutyl amine-3-[(4-morpholinyl-1,2,5-thiadiazole oxadiazole3-yl)oxy]-2-propanol maleic acid salt. It has been given official approvalroved to apply on glaucoma treatment by FDA after a large clinical application, which is the unique drug that has already been proved to be safe and can be used for reducing glaucoma intraocular pressure. On Tokyo Twenty-third International Ophthalmic Glaucoma Thematic Conferences in Japan, chiral drug timolol has sucessfully been recommended as the first choice for treating glaucoma. Norwegian multi-center research group have proved chiral drug timolol could be used on the treatment and prevention of is chemic heart disease after a large number of clinical experiment too.In this paper, the structure and synthesis methods of timolol were analyzed. And then, two new compounds,1-tert-butyl amine base-3-[(1,3,4-thiadiazole-2-yl) oxygen]-2-propanol maleic acid salt and1-tert-butylamine base-3-[(5-phenyl-1,3,4-thiadiazole oxadiazole2-yl) oxy]-2-propanol maleic acid salt were designed and synthesized. We also optimized the synthetic process and discussed the biological activity. It is very important for the synthesis and development of new drug.This thesis includes four parts mainly:1. Synthetic route design of Timolol analogueOn the basis of discussing the Timolol’s structure and synthesis method, we design the synthetic route and methods of the1-tert-butylamine-3-[(1,3,4-thiadiazole oxadiazole2-yl) oxy]-2-propanol along maleic acid salt and1-tert-butyl amine-3-[(5-phenyl-1,3,4-thiadiazole-2-yl) oxy]-2-propanol maleic acid salt.2. The study on the synthesis of1-tert-butylamine-3-[(1,3,4-thiadiazole oxadiazole2-yl) oxy]-2-propanol along maleic acid salt and1-tert-butyl amine-3-[(5-phenyl-1,3,4-thiadiazole-2-yl)oxy]-2-propanol maleic acid salt.First,2-amino-1,3,4-thiadiazole was synthesized by formic acid and thiosemicarbazide through condensation and cyclization reaction, catalyzed by hydrochloric acid. Then2-amino-1,3,4-thiadiazole was made into2-bromo-1,3,4-thiadiazole through diazo reaction and then reacted with2-phenyl-3-tert-butyl-5-(hydroxymethyl) oxazolidine to get1-tert-butyl amine-3-[(1,3,4-thiadiazole-2-yl)oxy]-2-propanol maleic acid salt. 2-amino-5-phenyl-1,3,4-thiadiazol was synthesized by benzoic acid and thiosemicarbazide through condensation and cyclization reaction, catalyzed by phosphorus oxychloride. Then2-amino-5-phenyl-1,3,4-thiadiazol was made into2-bromo-5-phenyl-1,3,4-thiadiazole through diazo reaction and then reacted with2-phenyl-3-tert-butyl-5-(hydroxymethyl) oxazolidine to get1-tert-butylamine-3-[(5-phenyl-1,3,4-thiadiazole-2-yl) oxy]-2-propanol maleic acid salt.During the process, the structures of the intermediateis were confirmed by melting point and1H NMR. The target compounds were characterized by scanning electron microscopy(SEM), infrared spectroscopy(IR), thermogravimetric analysis(TGA), mass spectrometry(MS),1H NMR and13C NMR.3. The investigation of synthesis processThe synthesis process of every intermediate was discussed and analyzed. The influence of the type and concentration of catalyst, the mole ratio of reactants, reaction time and synthesis temperature was investigated. We obtained the optimum reaction conditions and the optimum process route. The yield was improved significantly.4. The investigation of biological activityThe bacteriostasis activities of the two synthetic target compounds have been studied in this paper. The results showed that1-tert-butylamine-3-[(1,3,4-thiadiazole oxadiazole2-yl) oxy]-2-propanol along maleic acid salt has bacteriostasis to the rhizoctonia solani, Inhibition increased as the concentration change trend;1-tert-butyl amine-3-[(5-phenyl-1,3,4-thiadiazole-2-yl)oxy]-2-propanol maleic acid salt has bacteriostasis to the enterococcus faecalis, Bacteriostatic diameter between8-12mm, With the increase of the content of liquid antibacterial effect without obvious changes, While other strains have almost no bacteriostatic action.