Synthesis and anti-phlogistic potency of some new non-proteinogenic amino acid conjugates of "Diclofenac".

In search for more potent, particularly less ulcerogenic gastritis that hopefully replace the universal NSAID "Diclofenac", (2-[(2,6-dichlorophenyl)amino]-phenylacetic acid, C.A.S. 15307-86-5), twelve new non-proteinogenic amino acid conjugates of the drug, namely that of sarcosine, beta-alanine, D-leucine and D-phenylalanine, were synthesized and biologically screened for their anti-inflammatory, analgesic and ulcerogenic activity in rats. "Diclofenac" amino acid esters (IIa-d), were synthesized via the corresponding HOSu or HOBt active esters. Alkaline hydrolysis (NaOH) followed by acidification (KHSO4) or thioamide formation (Lawsson's Reagent, C.A.S. 19172-47-5), afforded the corresponding free acids IIIa-d or the thioamides IVa-d respectively. Interestingly, in contrary to the parent "Diclofenac", the synthesized candidates (except IIId), were entirely nonulcerogenic in rats. Further, they considerably retained a generalized anti-phlogistic activity. The major "Diclofenac" irritating gastric side effect was thus eliminated. Particularly, the sarcosine conjugate IIa and its thiomimic IVa exhibit promising therapeutic perspectives.