Studies On Synthesis And Antiinflammatory Activity Of Selective COX-2 Inhibitor T614 And Its Analogues

The mechanism of the COX inhibitors, development of the selective COX-2 inhibitors and the studies on T614 were briefly reviewed.T614, which was certified by 'H-NMR, MS, was synthesized starting with commercially available 4-amino-3-nitroanisole via eight-step route including Sandmeyer reaction, Aromatic nucleophilic substitution, Reduction of nitre group, N-Methylsulfonylation, a-Chloroacetylation, Formylamination, Demethylation and Ring condensation. The synthetic process was optimized, resulting in decreasing the cost, simplifying the operation procedure, assuring safety, and the total yield was 34.8%.Two series of compounds were designed by modifying the lead compound, T614. One is Mannich base of 7-methanesulfonylamino-6-phenoxy-2, 3-dihydrochromone while the other is 7-methanesulfonylanuno-3-methylidene-6-phenoxy-2, 3-dihydrochromones. Nine new compounds of the second series were synthesized and identified by 1H-NMR, IR and MS.The target compounds were evaluated for antiinflammatory activity. Preliminary pharmacological tests showed that L5, L7 and L11 exerted potent antiinflammatory activity on xylene-induced ear edema in mice at the dose of 200mg/kg, equal or superior to Indomethacin at the dose of 10mg/kg, and that L1, L2, L9 and L10 at the dose of 200mg/kg were a bit less potent than Indomethacinat the dose of 10mg/kg. The preliminary structure-activity relationship of these compounds indicated that the substituted methylidene adherent to 2, 3-dihydrochromones at 3 position played an important role in the bioactivity of the target compounds. If substituted methylidene was benzylidene, electron-donating groups at meta or para position of benzene ring of benzylidene would benefit activity and those at ortho position would decrease activity. Activity of the compounds with electron-withdrawing groups on the benzene ring was relatively weak while with no groups, non-potent. Furane or thiophene ring substituted for benzene ring of benzylidene, activity of the compounds would be increased. Furthermore, the compounds containing hyper-conjugate skeleton were more potent.