O,O'-(1,4-XYLYLENE)BISPILOCARPIC ACID-ESTERS AS NEW POTENTIAL DOUBLE PRODRUGS OF PILOCARPINE FOR IMPROVED OCULAR DELIVERY .1. SYNTHESIS AND ANALYSIS

An analogue series representing novel diesters of bispilocarpic acid, O,O'-(1,4-xylylene) bispilocarpic acid esters, were synthesized as double prodrugs of pilocarpine in order to improve the ocular delivery characteristics of the drug. In previous studies, various bispilocarpic acid monoesters have been synthesized and evaluated as prodrugs of pilocarpine. However, these derivatives suffer from instability in aqueous solution and hence were not suitable as a pilocarpine prodrug. Based on earlier results, 1,4-xylylene bispilocarpate was selected as the starting material for the synthesis of diesters. Bispilocarpic acid diesters were prepared by esterifying the free hydroxyl groups of bispilocarpic acid monoesters. All the diesters formed a salt with 3 equivalents of fumaric acid. The yields of bispilocarpic acid diester fumarates varied from 48 to 99%. The identification of the compounds and evaluation of the purity of synthetic products were performed by liquid chromatography with UV detection, thermospray liquid chromatography mass spectrometry, electron impact ionization mass spectrometry and H-1-NMR spectroscopy. The elemental composition of each compound was determined on high-resolution mass spectrometry by measuring the accurate mass of the molecular ion.