Convenient synthesis of ibuprofen and naproxen aminoacyl, dipeptidoyl and ester derivatives

ORGN 674

Davit Jishkariani, davit@ufl.edu, Department of Chemistry, University of Florida, 127 Chemistry Research Building, University of Florida, Gainesville, FL 32611
DL-Ibuprofen and L-naproxen are among the most commonly prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for the management of inflammation and pain1. However, these drugs are associated with significant adverse side effects especially upper gastrointestinal (GI) ulcer complications2. Masking the carboxylic group of NSAIDs significantly reduces topical irritant action3. In our study ibuprofen and naproxen were coupled with amino acids and other bioactive compounds to provide ibuprofen and naproxen bioconjugates in 61-95 % yield as prodrugs or potential drug candidates4. Our two-step synthetic route consists of: (i) conversion of DL-ibuprofen and L-naproxen into their benzotriazolides (known as good acylating agents5) and (ii) the coupling of active benzotriazolides with the N-terminus of free amino acids and dipeptides, or the acylation of free OH groups of protected sugars and diverse steroids to provide potential anti-inflammatory drug candidates. References: 1. Dubois R. W., Melmed G. Y., Henning J. M., Laine L. (2004) Aliment Pharmacol Ther; 19: 197-208. 2. Hernandez-Diaz S., Rodriguez L. A. G. (2000) Arch Intern Med; 160: 2093-2099. 3. Zhao X., Tao X., Wei D., Song Q. (2006) European Journal of Medicinal Chemistry 41: 1352-1358 4. Jishkariani D., Narindoshvili T. Unpublished work. 5. Katritzky A. R., Suzuki K., Wang Z. (2005) Synlett.