Synthesis of Potential Selective COX‐2 Enzyme Inhibitors Derived from Ethyl Ester of 2‐Isothiocyanato‐5‐phenyl‐3‐thiophenecarboxylic Acid.

Abstract

Derivatives containing the thieno [2,3-d]pyrimidin-4-one system, potential selective COX-2 inhibitors, were prepared starting from ethyl ester of 2-isothiocyanato-5-phenyl-3-thiophenecarboxylic acid (2); their structural elucidation is also reported.J. Heterocyclic Chem., 40, 869 (2003).Derivatives containing the thienopyrimidine systems are reported to possess several important pharmacological properties [1]; in particular some derivatives of the 6-showed interesting anti-inflammatory and analgesic activities without ulcerogenic activity and with low acute toxicity.Recent developments in the research of non-steroidal anti-inflammatory drugs (NSAIDs) as selective inhibitors of COX-2 [3,4] have prompted us, on the basis of the above heterocyclic system [2] and structures of leads [3,4], to prepare new derivatives with the characteristic functional groups of selective COX-2 inhibitor drugs.In this paper we report the synthesis and the structural elucidation of a series of new derivatives containing the 6-phenyl-thieno[2,3-d]pyrimidin-4-one heterocyclic system as a stage of research of compounds with effective analgesic and anti-inflammatory activities as selective COX-2 inhibitors.The key compound was the ethyl ester of 2-isothiocyanato-5-phenyl-3-thiophenecarboxylic acid (2) prepared, without the production of pollutants, in acetone at room temperature from the reaction of amino ester 1 and thiophosgene with subsequent dilution in water (Scheme 1). The reaction at room temperature with hydrazine or with mesylhydrazine and treatment of the resulting

Synthesis, characterization, molecular modelling and biological evaluation of thieno‐pyrimidinone methanesulphonamide thio‐derivatives as non‐steroidal anti‐inflammatory agents

“…The synthetic route to prepare the new isomers thioaryl and thiocycloesyl derivatives of the heterocyclic system 6-phenylthieno [3,2] pyrimidinone by up-to-date method is reported in Figure 1. The several steps to synthetize the compounds are shown in Supplementary Data S1.…”

“…In previous papers, we demonstrated that thieno[2,3‐d]pyrimidinone methanesulfonamides thio‐derivatives show an interesting selective COX‐2 anti‐inflammatory activity without toxic effects on cells. These derivatives were designed by bioisosterically replacing the carbon‐carbon double bond as in the coxibs stilbene scaffold through a sulphur atom and molecular hybridization with the lead L‐745 337 and the thienopyrimidin‐4‐one moiety.…”

“…In addition, during the inflammatory processes, ROS and NO determinate induction of the PGE 2 synthesis, which contributes to synovial inflammation by increasing local blood flow, inhibiting chondrocyte growth and up-regulating IL-1β. 1 In previous papers, [2][3][4] we demonstrated that thieno [2,3-d]pyrimidinone methanesulfonamides thio-derivatives show an interesting selective COX-2 anti-inflammatory activity without toxic effects on cells. These derivatives were designed by bioisosterically replacing the carbon-carbon double bond as in the coxibs stilbene scaffold 5,6 through a sulphur atom and molecular hybridization with the lead L-745 337 and the thienopyrimidin-4-one moiety.…”