Study On The Synthesis And Anti-Inflamatory And Analgesic Activities Of The N-substituent Derivatives Of Acetyl Ilicifolius Alkaloids A

Objective:To improve the method of synthetic process of Ilicifolius alkaloids A(4-Hydroxy-2-benzoxazolone,HBOA)and Acetyl Ilicifolius alkaloids A(4-Acetoxy-2-benzoxazolone,AcO-BOA).Mainly to synthesize some N-substituent derivatives of AcO-BOA,to study their anti-inflammatory and analgesic activitives.Methods:2-nitroresorcinol was converted to HBOA by "one-pot-way".HBOA was converted to AcO-BOA using some others reaction solvent instead of acetone.According to the medicine chemistry design principles and some NSAIDs structure characteristics,some N-substituent derivatives were designed.Used alkyl,acyl,carboxylic and carboxylic derivatives,alkyl nitrate as the substituents to synthesize N-substituent derivatives of AcO-BOA,as well as some derivatives of stuctural combination with Aspirin on 3 or 4 position of HBOA.The structures of the derivatives were elucidated by IR,1H-NMR,13C-NMR and MS spectra analysis,and the melting point of the derivatives weredetermined with micro-melting point detector.The anti-inflammatory activities of the derivatives were screened by the carrag-eenan-induced paw edema model.The analgesic activities of the derivatives were screened by the acetic acid induced stretching test and hot-plate method.The influence of the derivatives upon the mice coagulation-time and bleeding-time were tested with the capillary method and measuring by cutting the tail of mice.Results:After improving synthetic processes,2-nitroresorcinol was the starting material,the yeild of HBOA was 71.69%,and the yeild of AcO-BOA was 83.76%by using DMF as the reaction solvent.Synthesized fifteen derivatives of HBOA,they were identified by IR,1H-NMR,13C-NMR and MS wave analysis.The wave information of them was matched with the target compounds.All the derivatives had inhibition effect of the analgesic activity by the acetic acid induced stretching test.Among them,AN-6 showed equal effect to Ibuprofen.AN-6,AN-10,and AN-16 showed stronger effect than Aspirin.AN-1,AN-2,AN-3,AN-5,AN-7,AN-8,AN-9,AN-11,and AN-13 showed equal effect to Aspirin.On the inhibition effect of the anti-inflammatory activity by the carrageenan-induced paw edema model,AN-16 showed stronger effect than Aspirin.AN-1,AN-2,AN-3,AN-4,AN-5,AN-10,and,AN-13 showed equal effect to Aspirin.AN-16 had best total activities of anti-inflammatory and analgesia,moreover,AN-16,AN-10,AN-6,AN-1,AN-13,AN-2 and AN-2,had a tendency of better total activities than Aspirin.The influence of the derivatives upon the mice coagulation-time and bleeding-time,AN-16 showed great extension,while AN-1,AN-4,AN-5,AN-6,AN-10,AN-11,AN-12,AN-13,AN-14,and AN-15 showed signification short.The total time of coagulation-bleeding of AN-2,AN-3,AN-7,AN-8,AN-9,and AN-16 showed great shorter than the large dose of Aspirin which showed short time.Conclusion:The improved synthetic processes of HBOA and AcO-BOA are suited to prepare in batches,the methods have simpler handling and higher yields.Among the fifteen derivatives,twelve compounds of AN-5,AN-6,AN-7,AN-8,AN-9,AN-10,AN-11,AN-12,AN-13,AN-14,AN-15,and AN-16 have not been reported.Seven derivatives AN-16,AN-10,AN-6,AN-1,AN-13,AN-3,and AN-2 have good anti-inflammatory and analgesia activities.AN-16 show prolong time of the derivative which has propanoic acid acetaminophen ester structure,yet ten derivatives AN-1,AN-4,AN-5,AN-6,AN-10,AN-11,AN-12,AN-13,AN-14,and AN-15 of AcO-BOA show procoagulant.