The Synthesis, Bioactivity Of 2-aryl Propionic Acid 2-aryl Morpholine Esters And Reverse Esters

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. However, NSAIDs are associated with gastrointestinal and cardiovascular side effects.Especially patients suffering from chronic inflammatory diseases, which are under permanent treatment with NSAIDs, are exposed to a risk of gastrointestinal ulcerations and cardiovascular complications.Thus, there is a need for safer anti-inflammatory drugs.Ibuprofen and naproxen, typical NSAIDs with aryl propionic acid group, are mainly used for the treatment of rheumatic, rheumatoid arthritis and osteoarthritis. They are also associate with side effects such as ulcers, bleeding, gastric perforation in long-term use, which greatly limits their application.Three different classes of aryl propionic acid morpholine esters and reverse esters were designed and synthesized based on the structure and activity relationship (SAR) of NSAIDs. The compounds were characterized by1H NMR、and bioactivity test.The background of the thesis was introduced at the first charter. The history of NSAIDs and the development of the research of mechanism of inflammation and the latest research of NSAIDs were reviewed. There are three parts of the thesis:the design,synthesis,bioactive of ibuprofen 2-aryl morpholine esters、naproxen 2-aryl morpholine esters and naproxen reverse esters.The design of the new drugs based on:Inhibition of cyclooxygenase(COX), the enzyme that catalyzes arachidonic acid (AA) oxygenation, was initially considered to be responsible for the shared therapeutic benefits and gastrointestinal side effects of NSAIDs. Conventional NSAIDs are nonselective inhibitors of isozymes of cyclooxygenase (COX-1 and COX-2).COX-1 is expressed constitutively in most cell types and plays a role in gastric cytoprotection and in maintaining normal renal function. The COX-2 pathway involves an induction mechanism resulting in elevated expression in inflamed tissues. GI lesions induced by NSAIDs reflect mainly the suppression of constitutive formation of "housekeeping" PGs through COX-1 inhibition, whereas limiting PG production from COX-2 is largely sufficient for pain relief, which reduces reduce the signs and symptoms of inflammation. The other major route of arachidonic acid (AA) metabolism is the lipoxygenase pathway which generates leukotrienes (LTs). LTB4 and the cysteinyl-leukotrienes have powerful pro-inflammoatory properties and the inhibition of the metabolic pathway led to development of new therapeutic treatments for pathologies such as asthema, allergies and other inflammatory disorders Classical NSAIDs. Dual COX-2/5-LOX inhibitiors are described as potential new therapeutic agents for inflammatory diseases. 1.The synthesis, characterization and biological activity of 2-(2-arylmorpholino)ethyl esters of IbuprofenAccording to the structure and activity relationship (SAR),The carboxyl group of Ibuprofen was modified and the morpholine group which can insert into the "side pocket" of COX-2 was introduced. The biding of Arg120, Glu524 at the entrance was declined while the COX-2 selectivity was enforced. The morpholine ring has similar pharmacophore of 5-LOX inhibitor ZD22138,thus the same efficacy of 5-LOX to inhibit is expected. Ibuprofen 2-Aryl morpholine ethyl esters were designed as COX-2/5-LOX dual inhibitor to reduce the gastrointestinal side effects and the risk of cardiovascular disease.The 2-(2-arylmorpholino)ethyl esters of Ibuprofen were synthesized by the reaction of 2-aryl-4-(2-hydroxyethyl)morpholine with 2-(4-isobutylphenyl)propanoyl chloride,2-Aryl-4-(2-hydroxylethyl)morpholine intermediates were synthesized from arylethanones by bromination, amination and deoxidization. Their structures were confirmed by1H NMR.Their structures were confirmed by1H NMR. The crystals of 3f and 3o was determined by X-ray diffraction analysis.The morpholine ring is in a chair conformation and the chloride anion links with the morpholinonium cation through hydrogen boning.The crystal structure is further stabilized by van der Waals forces. The bioassays of compound 1j、1h、1i、1l showed better activity against COX-2 comparing than ibuprofen. The COX IC50 of compound 1j is 0.038μmol.L-1 and the COX-1/COX-2 selectivity of compound 1i is 158.1.The test of LOX inhibiting activity is in processing.2.The synthesis, characterization and biological activity of 2-(2-arylmorpholino)ethyl esters of naproxen.The 2-(2-arylmorpholino)ethyl esters of naproxen were designed and synthesized according to the SAR by the reaction of 2-aryl-4-(2-hydroxyethyl)morpholine with 2-(6-methoxy-2-naphthyl)propionyl chloride in yields of 24.2%～76.5%.Their structures were confirmed by 1H NMR.There are 1-2 chiral carbons in the marpholine ring of the new compounds, which plays an important role in the activity and toxicity of the medicine. Using (2R,3R)-dimethyl tartrate as chiral auxiliary, Br2 as brominating agent,2-methyl-2-aminopropanol as aminating agent, 2-arylmopholol hydrochloride was asymmetric synthesized via acetalization, asymmetric bromination, hydrolysis, amination, acidification.3.The synthesis, characterization of reverse esters of naproxen.Reverse esters of naproxen was designed for increasing the stability of COX-2 inhititor, The carboxyl of naproxen was taken place by hydroxyl and then esterified with acyl chloride derivatives.Naproxen was reductied to alcohol with LiAlH4 in anhydrous ether. Esterification of different acyl chloride derivatives with alcohol of naproxen in pyridine resulted in the formation of esters.Alcohol of naproxen was synthesized to a good yield (96%). 15 reverse esters of naproxen n were synthesized and all the new compounds were confirmed by1H NMR. To prepare Alcohol of naproxen, LiAlH4 was added as reducting agent at room temperature in anhydrous ether. The carboxyl of naproxen can be conveniently convert hydroxyl.Pyridine as solvent and acceptor of HCl, different acyl chloride derivatives were condensed with alcohol of naproxen.