Sinteza, karakterizacija i QSPR analiza amidnih derivata ketoprofena

Ketoprofen, 2-(3-benzoylphenyl)propionic acid, a non-steroidal anti-inflammatory drug (NSAID), was introduced into therapy in 1986 and so far has gained a wide acceptance. In addition to anti-inflammatory activity, ketoprofen also possesses analgesic and antipyretic properties. It is indicated in long-term management of rheumatoid arthritis and osteoarthritis, for mild to moderate pain and for primary dismenorrhea. Side effects of ketoprofen are similar to those of other NSAIDs, gastrointestinal irritation being the most frequent one. By modification of carboxylic moiety of ketoprofen to amide group it would be possible to avoid direct irritation of gastrointestinal tract, which was proven to be the main side effect. Some recent reports also indicate that amide type derivatives could be selective inhibitors of COX-2 enzyme. Amide derivatives were prepared by aminolysis of ketoprofen benzotriazolide, formed by simple synthetic procedure, which afforded intermediate in high yield (90%). The intermediate was easily converted to the corresponding amides using different amines, i.e., propylamine, diethylamine, cyclohehylamine, ethane-1, 2-diamine, 3-aminopropionic acid, 2-aminoethanol, 3-aminopropanol and 2-(2-hydroxyethylamine)-ethanol. The synthesized amides were characterized by means of FTIR, one- and two-dimensional, homo- and hetero-nuclear, 1H and 13C NMR correlation spectra. The structure-property relationship (QSPR) investigation showed a linear correlation between experimentally obtained and calculated parameters for lipophylicity logP and Rm (R2 = 0.80 – R2 = 0.91), while with other parameters (topological indices, W and X) the results of regression analyses were not statistically significant. (1) Kalgutkar, A. S., Crews, B. S., Rowlins, S. W., Marnett, A. B., Kozak, K. R., Remmel, R. P., Marnet, L. J., Proc. Natl. Acad. Sci USA 97 (2000) 925. (2) Kalgutkar, A. S., Marnett, A. B., Crews, B. C. Remmel, R. P., Marnet, L., J. Med. Chem. 43 (2000) 2860. (3) Woods, K. W., McCroskey, R. W., Michaelides, M. R., Wada, C. K., Hulkover, K. I., Bell, R. L., Bioorg. Med. Chem. 11 (2001) 1325.