Synthesis and Pharmacological Activities of Novel Cyclic Disulfide and Cyclic Sulfide Derivatives as Hepatoprotective Agents

Abstract

In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure induced by Propionibacterium acnes-lipopolysaccharide in mice. Compounds 1 were synthesized by oxidative cyclization of the corresponding dithiol derivatives (3) with diethyl bromomalonate or iodine. Compounds 2 were prepared from the methyl esters of 1 by desulfurization with tris(diethylamino)phosphine followed by deprotection. Compounds 1 were generally found to be more active than compounds 2. Compound lb (SA3443) was found to exhibit potent protective activity. The synthesis and structure-activity relationships are discussed. © 1993, The Pharmaceutical Society of Japan. All rights reserved.