Design and synthesis of non-steroidal diclofenac derivatives as anti-inflammatory drugs

Tae-Woo Kim; Tasneem Islam; Kang-Yeoun Jung

Journal of Industrial and Engineering Chemistry, Vol.16, No.3, 461-466, May, 2010

DOI10.1016/j.jiec.2010.01.050 Export Citation

Design and synthesis of non-steroidal diclofenac derivatives as anti-inflammatory drugs

Tae-Woo Kim, Tasneem Islam¹, and Kang-Yeoun Jung^†

Department of Environmental & Applied Chemical Engineering, Gangneung-Wonju National University, Gangneung, Gangwondo 210-702, Republic of Korea
¹Department of Biological, Chemical and Physical Sciences, Roosevelt University, Schaumburg, IL 60173, USA

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In the course of our studies directed towards the discovery of novel non-steroidal anti-inflammatory agents (NSAIDs), which are expected to have improved drug efficacy and better toxicity profile than diclofenac, we have synthesized new derivatives of diclofenac phosphonates. These phosphonate analogs were efficiently prepared from commercially available 2-hydroxymethylaniline in three steps. The 2-hydroxymethylaniline was converted to the azide in reasonable yield. Click chemistry with a variety of alkynes followed by Arbuzov reaction resulted in a series of triazole based phosphonate products. Our inhibitors are designed to reduce the gastrointestinal bleeding caused by diclofenac by substituting the carboxylic acid group with the phosphonate group and in addition replacing with the triazole ring would allow the flexibility to explore the importance of both hydrophilicity and hydrophobicity of the ring at the active site.

Keywords:Diclofenac phosphonates;Anti-inflammatory drug;NSAID;Triazole derivatives

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[Related Articles]

[1] Gottileb NL, Semin. Arthritis Rheum., (Suppl. 1), 15, 1 (1985)

[2] Moser P, Sallmann A, Wiesenberg I, J. Med. Chem., 33, 2358 (1990)

[3] Sallmann A, Am. J. Med., (Suppl. 4B), 80, 29 (1986)

[4] Fries JF, J. Musculoskelet. Med., 8, 21 (1991)

[5] Vane JR, Nat. (London), New Biol., 231, 232 (1971)

[6] Smolinsky GJ, J. Org. Chem., 26, 4108 (1961)

[7] Suh BC, Jeon H, Silverman SM, Posner GH, Tetrahedron Lett., 45, 4623 (2004)

[8] Chittaboina S, Xie F, Wang Q, Tetrahedron Lett., 46, 2331 (2005)

[9] Bae I, Han H, Chang S, J. Am. Chem. Soc., 127(7), 2038 (2005)

[10] Skowronska A, Pakulski M, Michalski J, Cooper D, Trippett S, Tetrahedron Lett., 21, 321 (1980)

[11] Michalski J, Pakulski M, Skowronska A, J. Chem. Soc., Perkin Trans., 1, 833 (1980)