Design and synthesis of stable N-[2-(Aryl/heteroaryl substituted)ethyl] propanamide derivatives of (S)-ketoprofen and (S)-ibuprofen as non-ulcerogenic anti-inflammatory and analgesic agents

The carboxylic acid groups of (S) ketoprofen and (S) ibuprofen were brought into reaction with substituted ethylamine derivatives to form (S)-2-(4-isobutylphenyl)- and (S)-2-(3-benzoylphenyl)-N-[2-(aryl/heteroaryl substituted) ethyl]propanamide derivatives. Then, these sets were evaluated in terms of their in vivo anti-inflammatory and analgesic properties using the carrageenan-induced paw edema and p-benzoquinone-induced writhing models. Among the synthesized compounds, (S)-2-(4-isobutylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]propanamide (4f) showed the highest activity at the 100mg/kg dose inducing no gastric lesions when compared to the parent compound, ibuprofen. In vitro studies on chemical stability revealed that the amide derivative with the highest activity (4f) was chemically stable in simulated gastric (pH 1.2) and intestinal fluids (pH 7.4). In 80% v/v human plasma, the amide derivative was found to be stable against plasma hydrolases over the experimental period. The most active compound, (S)-2-(4-isobutylphenyl)-N-[2-(pyrrolidin-1-yl)ethyl]propanamide, was also studied in 10% rat liver homogenate (pH 7.4) to identify its release pattern as a prodrug.