Water-soluble salts of aminoacid esters of the anaesthetic agent Propofol

The glycinates 4, 5, acetates 6, 7, 10, propionate 8, butyrate 9 and carbonate 11 were synthesized and evaluated as potential water-soluble prodrugs of Propofol (2,6-diisopropylphenol) 1 suitable for parenteral administration. The 4–9 · HCl salts were also prepared and some of them (i.e. 4 · HCl and 6 · HCl) were found sufficiently soluble in aqueous solutions. The kinetics of hydrolysis of the esters 4–11 and 4–9 · HCl salts were studied in 0.05 M phosphate buffer pH 7.4, and a number of derivatives (4, 6, 7, and corresponding HCl salts) were examined for their stability in human plasma and brain homogenate. Our results indicated that the salts 4 · HCl and 6 · HCl, sufficiently soluble in water, are relatively stable in physiological media. Most of the examined compounds, in particular compound 6, were found to inhibit the binding of [35S]-tert-butylbicyclophosphorothionate ([35S]TBPS) demonstrating to possess affinity for the Propofol recognition site on GABAA receptors.