Synthesis And Bioactivity Of (S)-2-(6-methoxynaphthalen-2-yl)Propyl Esters Of Acids And2-(2-arylmorpholino)Ethyl Esters Of Indomethacin

Nonsteroidal antiinflammatory drugs (NSAIDs) remain the most commonly used medications for treatment of symptoms of many chronic inflammatory diseases, including rheumatoid arthritis and osteoarthritis. However, the gastrointestinal (GI) side effects will be generated after long term use of NSAIDs and even the cardiovascular system will be greatly affected. Naproxen and indomethacin are two typical drugs of arylalkyl acids drugs. Clinical manifestations of gastric ulcers, gastroorrhagia and even worse perforation. After absorption, naproxen and indomethacin inhibit both COX-1and COX-2without selectivity in vivo leading to the synthesis of prostaglandins with GI protective function been inhibited. On the basis of the structure activity relationship of both drugs and the structure differences of COX-1and COX-2,(S)-2-(6-methoxynaphthalen-2-yl)propyl esters and2-(2-arylmorpholino)ethyl esters of indomethacin were synthesized. The results were shown as follows.Synthesis of (S)-2-(6-methoxynaphthalen-2-yl)propyl esters (S)-2-(6-methoxy-naphthalen-2-yl)propanol was prepared via the reduction of (S)-naproxen with LiAlH4and the yield was94%, then eighteen (S)-2-(6-methoxynaphthalen-2-yl)propyl esters were obtained after (S)-2-(6-methoxynaphthalen-2-yl)propanol reacting with acyl chlorides, acid anhydrides and acids with yields among70～93%.Through UV spectrometry method, the lipid-water partition coefficients of (S)-2-(6-methoxynaphthalen-2-yl)propanyl esters were tested in n-octyl-phosphate buffer solutions under nine pH values of2.5-8.0which are similar with the internal conditions of GI tract. The method has advantages of high accuracy rating, good reproducibility with relative standard deviation (RSD) less than2%and avoids the problems of chromatographic column detector jam using HPLC method instead. The lgP values all increases first and then decreased, the lgP(max) values appear in solutions of pH2.5-5.8.The COXs inhibitory activities of (S)-2-(6-methoxynaphthalen-2-yl)propyl esters were tested using Cox Inhibitor Screening Assay Kit (560131).(S)-2-(6-Methoxynaphthalen-2-yl) propyl esters of lauric acid and stearic acid show moderate COX-2selectivity with1.60and4.15respectively, which is larger than naproxen (less than1.00).2-(2-Arylmorpholino)ethyl esters of indomethacin2-Bromoketones reacted with2,2’-azanediyldiethanol in the molar ratio of1:4, then88%formic acid was added. Replacement, self-cyclization and reduction were finished in one pot. Indomethacin acid chloride was prepared with the reaction of indomethacin and oxalyl chloride at0℃for3hours with yield94%. through which the degradadtion of1-amine group using thionyl chloride as acyl chlorination reagent was avoided. Then indomethacin acid chloride was reacted with2-aryl-4-hydroxyethylmorpholines without purification in the presence of tetrahydrofuran (THF) and triethylamine to obtain the esters as an oily products, which were converted into hydrochloride derivatives as solid. All the compounds were characterized by1H NMR, ESI-MS, IR and elemental analyses spectra data.The lipid-water partition coefficients of2-(2-arylmorpholino)ethyl esters of indomethacin were tested following the method of testing (S)-2-(6-methoxynaphthalen-2-yl)propyl esters.. In n-octyl-phosphate buffer solution of pH5.0,1gP values of2-(2-arylmorpholino)ethyl esters of indomethacin were1.24～2.58, which are smaller than indomethacin (3.8), indicating that all of the compounds showed better water solubility. While in solutions of pH7.0and7.8,2-(2-arylmorpholino)ethyl esters of indomethacin showed1gP values of1.00～2.00which are larger than parent drug indomethacin (0.54), indicating better lipid solubility. The1gP values all increases first and then decreased, the lgP(max) values appear in solutions of pH4.0.The COXs inhibitory activities of2-arylmorpholinoethyl esters of indomethacin were obtained through testing the fluorescence intensity of reactive oxygene species (ROS) and showed moderate to good selective inhibitory among30～358.2-[4-(n-BuO)phenyl]-morpholinoethyl ester of indomethacin showed good COX-2selectivity inhibitory (SI182) which is comparatively with celecoxib (SI214).2-[2-(2,4-dichloro-5-fluorophenyl)-morpholino]ethyl ester of indomethacin showed greater COX-2selective inhibitory (SI358) than celecoxib.The Serotonin Transporter (SERT) inhibitory activity of2-arylmorpholine hydrochlorides,2-(2-arylmorpholino-4-yl)ethyl esters of indomethacin and ibuprofen were tested.2-[4-(Benzyloxy)phenyl]-4-(2-hydroxyethyl)-5-methylmorpholin-2-ol hydrochloride and4-benzyl-2-(7-ethoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)morpholin-2-ol hydro-chloride showed good inhibitory activity with the ratio of34.5%and33.9%respectively.2-[2-(4-(Benzyloxy)phenyl]-2-hydroxy-5-methylmorpholino)ethyl ester of ibuprofen hydrochloride and2-[2-(5-chloro-6-methoxynaphthalen-2-yl)morpholino]ethyl ester of ibuprofen hydrochloride showed good inhibitory activity in the ratio of49.9%and30.3%respectively.