The Study Of Synthesis And Degradation Of Acetylation L-dopa Methyl Ester Ibuprofen

Objective:This paper design and synthesis the new L-DOPA (LD) conjugate (4-((2S)-2-(2-(4-isobutylphenyl)propanamido)-3-methoxy-3-oxopropyl)-1,2-phenylene diacetate)(IPPD) obtained by joining LD with ibuprofen, which has the potential to lower Parkinson’s disease (PD) risk. And study its degradation in vitro and preliminary pharmacological effects.Methods:IPPD was prepared by L-DOPA and ibuprofen as raw materials throwing esterification, acetylation and amidation. And the reactions were optimized.The structure of the conjugate was confirmed by UV, MS,1H-NMR,13C-NMR.The dynamics of its aqueous solutions were studied under the following conditions:(temperature:37℃) pH1.3, pH5.0, pH7.4. A HPLC method had been developed and validated for the determination of the prodrug IPPD.The method was used to study the pharmacokinetics of IPPD in rat plasma and human plasma, and determination of its apparent partition coefficient, we also study of its analgesic and anti-inflammatory preliminary pharmacological effects in mice.Results:The product is while with a purity exceed98%. The product structure is4-((2S)-2-(2-(4-isobutyl phenyl)propanamido)-3-methoxy-3-oxopropyl)-1,2-phenylene diacetate. The HPLC method was simple, rapid, accurate and was able to determinate the content of IPPD. The half lives of IPPD aqueous solutions at pH1.3,pH5.0,pH7.4(temperature:37℃) were21,238,5h, respectively. The degradation of IPPD is rapid in rat plasma and human plasma. Its apparent partition coefficient Log Papp≈1.4The analgesic and anti-inflammatory effects in mice shows it has the similar effects with ibuprofen.Conclusion:The structure of the product was consistent with the design one. The aqueous solutions of IPPD is stable under the condition of pH1.3,pH5.0,pH7.4(temperature:37℃), it shows that it is stable before entering the internal circulation. Log Papp of compound IPPD was determined as1.4thus suggesting that the synthesized product possesses adequate characteristics to permeate membranes.