Diclofenac prodrug

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

FIGURE 16.1 Chemical structure of water-soluble morpholinoalkyl ester prodrugs of diclofenac. The subscript equals 2, 3, or 4. 

Tammara, V. K., M. M. Narurkar, A. M. Crider, and M. A. Khan. 1994. Morpholinoalkyl ester prodrugs of diclofenac synthesis vitro andin vivoevaluationJ. Pharm. Sci83 644-648. 

Because the sulfide may be reoxidized to the inactive prodrug in the kidney, sulindac may inhibit renal COX less than other NSAIDs, though reversible renal failure and nephrotic syndrome have been observed with this drug. Among the more severe reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. Like diclofenac, sulindac may have some propensity to cause elevation of serum aminotransferases it is also sometimes associated with cholestatic liver damage, which disappears or becomes quiescent when the drug is stopped. 

Tammara, V.K. Narurkar, M.M. Crider, A.M. Khan, M.A. Morpholinoalkyl ester prodrugs of diclofenac Synthesis, in vitro and in vivo evaluation. J.Pharm.Sci., 1994, 83, 644-648 [rat plasma mefenamic acid (IS)]... 

---