The Synthesis And Determination Of Apparent Oil/water Partition Coefficient And Activity Of A Series Of New Produrgs Of Indomethacin Morpholine Ester

ObjectiveIn order to find a proper drug that COX-2 inhibitory function is appropriately enhanced and 5-LOX is also inhibited, a series of new produrgs of indomethacin are synthetized based on the structural difference of isoenzyme of COX (COX-1 and COX-2). The attetion is mainly focused on the hydroxy of the indomethacin, hoping to find a satisfying drug that gastrointestinal and cadiovascular side effect can be reduced at the same time. Compared with celecoxib, a tropical COX-2 selective inhibitory drug, the inhibitory functions of COX-1 and COX-2 are determined to find an ideal prodrug with a better inhibit ritio of COX-1/COX-2. In order to ultivily provide meaningful data for it's further stability forcast and relative PK study, the ideal condition of the vivo environment is simulated to determine the apparent oil/water partition coefficient in buffer solvents under different pH.MethodsOxalyl chloride is used as chloroformylating agent to sustitude the hydroxyl of indomethacin into a more active acyl chloride in solvent of after-dried dichloromethane. And then, esterification between the product of last step and different substituted morpholinols is happened in polar aprotic solveni of tetrahydrofuran, obtaining a serious product of indomethacin 2-aryl morpholine ethyl ester. Considering celecoxin as referece substance, the macrophage inhibition ratios in mice enterocoelia of these optimized products are determined to see their inhibitory function to COX-land COX-2. Gastrointestinal environment in vivo under ideal condition is imulated via shaking flask method to determine the apparent oil/water partition coefficient of these optimized products by HPLC and ultraviolet spectrophotometer under different pH phosphate buffer solution systems.Results1 The synthesis methods of 9 indomethacin 2-aryl morpholine ethyl esters and relative muriatics are discussed, and their conformations are confirmed through'H-NMR structures.2 The inhibitory functions to COX-1 and COX-2 of these optimized compounds are determined, and the outcome shows that the IC50 COX-1/COX-2 ratio of indomethacin 2-[2-(4-butoxy phenyl morpholinyl] ethyl ester muriate and 2-[2-(2,4-Dichloro-5-phenyl fluoride) morpholinyl] ethyl ester muriate have a most close ratio to celecoxib.3 The result of apparent oil/water partition coefficient determining experiment suggest that these indomethacin 2-aryl morpholine ethyl esters own a highest partition coefficient in n-octanol/pH4 buffer solution system, and apparent oil/water partition coefficient increases along with structrural conformation and the molecular weight of inductive groups.Conclusions:1 New method is provided to other indomethacin derivatives and relative muriates through the synthesis experiment of indomethacin 2-aryl morpholine ethyl esters series.2 The compounds is found that IC50 COX-1/COX-2 ratio most close to celecoxib through activity inhibition experiment, which provide reference evidence to screen a ideal indomethacin morpholine esters further that suppress COX-1/COX-2 more reasonable.3 The apparent oil/water partition coefficient determining experiment of the series of indomethacin 2- aryl morpholine ethyl esters in n-octanol phosphate buffer system shown that logP depends on not only the molecular structure of the drug, but also molecular ratio under different pH and the conformation and molecular weight of inductiv groups.