The Synthesis, Oil/water Partition Coefficient And Antioxidant Ability Determination Of (S)-naproxen Reverse Esters

Objective:In order to find a novel drug, which has proper selectivity to COX-2to decrease the adverse reaction (ADR) possibility, a series of (S)-naproxen reverse esters((S)-2-(6-methoxy-2-naphthyl) propyl esters) was synthesized based on the structure and physiological difference between COX-1and COX-2. A prolonged side chain was introduced in, expecting to increase the selectivity to COX-2. To imitate the distribution of (S)-naproxen reverse esters in different location of the GI and to provide experimental data to the further pharmacokinetics study and invivo research, the oil/water partition coefficient in different pH buffer solutions and the anti-oxidative ability of (S)-naproxen reverse esters was determined. A series of indomethacin morpholine esters were synthesized before under the cooperation of our team and Hunan University, a DPPH· clearance determination was performed as (S)-naproxen reverse esters.Methods:(S)-naproxen was hydrogenated to (S)-2-(6-methoxy-2-naphthyl) propanol via the reduction of LiAlH4first, and different acyl chlorides, acid anhydrides and acids were used to react with it then, and a series of (S)-2-(6-methoxy-2-naphthyl) propyl esters were obtained. Different buffer solutions were used to imitate the environment of different location of GI in vivo, and the distribution of12(S)-naproxen reverse esters was balanced via flask-shaking method. At last, the oil/water partition coefficient was determined and compulated by the ultraviolet/visible spectrophotometer. The DPPH· clearance experiment was accomplished on the (S)-naproxen reverse esters and indomethacin morpholine. SPSS16.0was used to tell if the difference between target compound and the raw material were significant(P<0.05).Results:A series of new (S)-naproxen reverse esters were obtained, and their structure were confirmed via correlated spectrum graph.The oil/water partition coefficient of (S)-naproxen reverse esters under different pH solution was determined, and it shows that the1gP of12(S)-naproxen reverse esters differs in different pH, and varies from each other in the same pH solution, and all of them reaches maximum at pH2.5-5.8subacidity environment.The result of the clearance of DPPH· of (S)-naproxen reverse esters shows that the I%of2d,2e and2f increase significantly than before. The clearance of DPPH-(I%) grows gently after c>1600μmol·L-1. Among the indomethacin morpholine, s2and s8own significantly increased free radical clearance. The change trend of DPPH· clearance1%is similar with the (S)-naproxen reverse esters.Conclusions:The synthesis route and experience is provided for similar non-steroidal anti-inflammatory drugs.The lgP of (S)-naproxen reverse esters varies with different introduced groups, and it can be affected by many factors, environmental pH especially. All (S)-naproxen reverse esters reach the maximum of1gP in subacidty buffer solutions and satisfied liposolubility is kept. So we can presume that promoted absorption of (S)-naproxen reverse esters in GI is still possible at the same time of avoiding GI stimulus.I%varied with different introduced groups, and is also closed to the stereospecific blockade, electronic effect and introduced location. The compounds which contain electron donor, amino or hydroxyl group are usually proved to own higher free radical clearance. Phenolic hydroxyl and some similar electron donors with small stereospecific blockade could be considered to be introduced to increase the anti-oxidant ability.This article contains9graphs,13tables and35referances.