International Journal of Pharmaceutics, 47 (1988) 103-110 103 Elsevier IJP 01586 Prodrug forms for the sulfonamide group. II. Water-soluble acid derivatives of N-methylsulfonamides as possible prodrugs Jorn Drustrup Larsen a, Hans Bundgaard 1 and Vincent H.L. Lee 2 I The Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry A D, Copenhagen (Denmark and 2 University of Southern California, School of Pharmacy, Los Angeles, CA (U.S.A.) (Received 1 March 1988) (Accepted 9 April 1988) Key words: Prodrug; Sulfonamide; N-Acyl derivatives; Hydrolysis; Solubility; Lipophilicity Summary Various N-acyl derivatives (acetyl, benzoyl, N,N-diethylaminoacetyl and morpholinoacetyl) of the model sulfonamide N-m p-toluenesulfonamide were synthesized and evaluated as potential prodrug forms for the sulfonamide group occurring in e.g anhydrase inhibitors. The kinetics of hydrolysis of the derivatives were determined at 37 o C in the pH range 0-12 and in the of human plasma. Maximal stability was achieved at pH around 4. The N-acyl compounds were readily hydrolyzed enzymati yield the parent sulfonamide in quantitative amounts. The derivatives with an ionizable amino function in the acyl moiety po high water-solubility as well as adequate lipophilicity at physiological pH. Since various N-methylsulfonamides are known to demethylation in vivo a promising prodrug approach for a primary sulfonamide may be N-acylation of the corresponding N-methylsulfonamide. Introduction Carbonic anhydrase inhibitors such as acetazol- amide, ethoxzolamide and methazolamide are use- ful for the treatment of glaucoma. However, due to limited aqueous solubility and unfavourable lipophilicity they are not active when given topi- cally andmust be given orally or parenteraUy (Maren et al., 1983; Friedland and Maren, 1984; Maren, 1987). Systemic side effects severely limit this mode of therapy (Friedland and Maren, 1984) and consequently, great activities are presently Correspondence: H. Bundgaard, The Royal Danish School of Pharmacy, Department of Pharmaceutical Chemistry AD, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. going on to find a new carbonic anhydrase inhibi- tor that would readily penetrate the cornea and be active in lowering intraocular pressure when topi- cally administered to the eye (Maren et al., 1983, 1987; Maren, 1987; Schoenwald et al., 1984; Lewis et al., 1986; Sugrue et al., 1985; Maren and Jankowska, 1985; Duffel et al., 1986; Bar-Ilan et al., 1986; Katritzky et al., 1987; Putnam et al., 1987). An alternative approach to solve the delivery problems with these drugs, which all contain a primary sulfonamide group as the most prominent functional moiety, may be the development of prodrug derivatives possessing adequatewater solubility and lipophilicitycharacteristics com- bined with the ability to be reconverted to the parent active sulfonamide following corneal pas- sage. 0378-5173/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)