Synthesis of a Series of Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group and Pharmacological Evaluation on Isolated Rat Aortas

Abstract

As part of our research into new organic nitrates for the treatment of angina pectoris, we have investigated a series of hexitol and aminodeoxyhexitol mononitrate derivatives containing a sulfur group. Since the depletion of tissue stores of sulfhydryl groups appears to play an important role in the development of this phenomenon, the addition of a sulfur group to a nitrate derivative could prevent the development of nitrate tolerance during a long-term treatment. Before Organic nitrates, for example nitroglycerin, constitute the most widely used treatment for angina pectoris. Although not conclusively demonstrated [1] , it now seems well-documented that these compounds are transformed during the enzymatic or thiol-mediated metabolism as depicted in 933 studying the duration of action, and the possible influence on tolerance phenomenon, it was important to check the vasorelaxing effects of our compounds compared to those of commercial organic nitrates of similar structures such as isosorbide mononitrate or isosorbide dinitrate. All the compounds were tested on isolated rat aortas; some of these products exhibited an interesting activity.duces the development of tolerance which limits their efficiency. This has been explained by an intracellular depletion in thiol groups [7] . As it is known that the phenomenon can be avoided or reduced by simultaneous administration of -cysteine derivatives [8] [9] [10] , we have postulated that new compounds containing a nitrate moiety linked to cysteine, or masked cysteine, may provide the basis for structures devoid of tolerance development.For the design of new drugs, we have decided to combine the most easily obtained hexitol mononitrates 1, 2 and the aminodeoxyhexitol mononitrates 3, 4 with -cysteine derivatives (Figure 2). Due to the instability of the free SϪH group, protected or masked cysteines were used for the different syntheses.

Comparison of the Relaxant Effects of a New Oxime-nitrate Derived from Isosorbide-5-mononitrate and the Parent Drug

“…Although it was thought that tolerance might be less of a problem with IS-5-MN, tolerance has been seen with this agent as well [7,8]. On the other hand, the mononitrate, possessing a free hydroxyl group, offers a variety of possibilities for molecular modification of the pharmacologically "less active" site of the molecule and introduction of a new functionality which could change or improve its pharmacological properties [4,9,10].…”