Derivatization of enolic OH of piroxicam: a comparative study on esters and sulfonates

Abstract

Vários ésteres e sulfonatos derivados da piroxicam foram preparados por acilação e sulfonação da hidroxila fenólica da piroxicam. Todos os compostos foram avaliados quanto à estabilidade química e às propriedades de inibição da ciclooxigenase. Os dados sugeriram que os ésteres poderiam ser o ponto de partida para o desenvolvimento de fármacos em potencial. Os sulfonatos derivados, preparados pela primeira vez, apresentaram estabilidade. Entre eles, um demonstrou uma moderada seletividade de inibição da COX-2 sobre a COX-1 e teria menor efeito colateral para o sistema gastrintestinal que a piroxicam devido ao grupo OH enólico mascarado. Um mecanismo plausível para o processo de acilação e sulfonação foi proposto, envolvendo a participação da porção da piridina presente na piroxicam. A estrutura molecular de um dos ésteres foi estabelecida, pela primeira vez, por meio de análise cristalográfica dos dados de raio-X de difração de pó.A number of ester and sulfonate derivatives of piroxicam were prepared via acylation/ sulfonation of the enolic OH of piroxicam. All the compounds were evaluated for their chemical stability and cyclooxygenase inhibiting properties. Data suggested that esters could be useful for the development of potential prodrugs. The sulfonate derivatives prepared for the first time were found to be stable. One of them showed a moderately selective COX-2 inhibition over COX-1 and would have lower gastrointestinal side effects than piroxicam due to the masked enolic OH group. A plausible mechanism for the acylation/sulfonation process has been proposed that involves participation of the pyridine moiety of piroxicam. Molecular structure of one of the ester was established for the first time by the crystal structure analysis from X-ray powder data. Keywords: piroxicam, esters, sulfonates, cyclooxygenase IntroductionPiroxicam (1, 1,2-benzothiazine-3-carboxamide-4-hydroxy-2-methyl-N-(2-pyridyl)-1,1-dioxide, Figure 1), 1 a nonsteroidal anti-inflammatory drug (NSAID) that belongs to the enol-carboxamide class, was developed prior to the discovery of cyclooxygenase-2 (COX-2, the second and inducible isoform of cyclooxygenase responsible for inflammation) on the basis of its anti-inflammatory activity and relative safety in animal models. In subsequent studies it was discovered that it possessed moderate COX-2 selectivity in compared to other COX-2 inhibitors. Several attempts were made to improve its pharmacological profile in addition to gastrointestinal side effects. For example, extensive SAR studies have been carried out in order to improve its COX-2/COX-1 selectivity profile which includes substitution at the 6-and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification.1 In another approach, the enolic OH group thought to be responsible for its COX-2 selectivity has been exploited as a "handle" for the preparation of various piroxicam derivatives. [2][3][4][5] These derivatives are inactive against cyclooxygenase but converted to piroxic...

Synthesis and structure analysis of cyclodehydration product of piroxicam: A metabolite detected in dogs and monkeys

“…Due to our continuing interest in the chemical modifications of existing cyclooxygenase inhibitors [4,5] we have recently reported synthesis and pharmacological evaluation of a number of piroxicam derivatives [6]. In this study when piroxicam was treated with a number of aliphatic and aromatic acyl chlorides to afford the Oacylated products formation of an unidentified side product was observed.…”

Synthesis and evaluation of novel mutual prodrugs of Piroxicam

“…6 The residue was purified by recrystallization from Chloroform-Ethyl acetate (1:1) to afford PA, PI, PM and PN. The synthesized compounds were purified by column chromatography using silica gel G as stationary phase.…”

“…5 Prodrugs of piroxicam is of profound interest for medicinal chemist as the enolic hydroxyl group can be derivatized easily and may results in diversified derivatives including ampiroxicam, one of the widely used agent. [6][7][8] Moreover, several prodrugs of selected NSAIDs were also reported. 9 As a part of extension of our work on mutual prodrugs, 10 and motivated by above findings, a new series of mutual prodrugs of piroxicam is designed by combining it with well known NSAIDs as aceclofenac, ibuprofen, mefenamic acid and naproxen as promoieties These therapeutic agents were selected so as to get active promoiety.…”

Predictions and correlations of structure activity relationship of some aminoantipyrine derivatives on the basis of theoretical and experimental ground

“…Owing to its low pK a value and small degree of plasma protein binding, antipyrine is distributed in total body water. In view of their high medicinal value and due to our interest in the synthesis of compounds of potential pharmacological interest (Pericherla et al, 2007;Pal et al, 2007;Jayaselli et al, 2008), we became interested in constructing a library based on pyrazolone scaffold. Azomethine belong to a widely used group of organic intermediates important for production of specialty chemicals, e.g., pharmaceuticals, or rubber additives (Macho et al, 2004) and as amino protective groups in organic synthesis (Bey and Vevert, 1977;Lucas et al, 1960;Bezas and Zervas, 1961).…”