Synthesis Of Isosorbide Mononitrate Derivatives And 4,4'-dihydroxybenzophenone

The approach to utilize the concept of a prodrug is limited to the improvement of only pharmaceutical properties with resperct to solubility and stability. We suggest herein the concept of conjugating two drugs having different pharmacological activites, termed 'mutual prodrug (chimera drugs)', to produce a chemical modification which might optimize drug delivery. This concept originates from the practice of co-adminsistering two drugs in order to enhance pharmacological activity or to prevent clinical side effects. If the absorption of the two drugs would take place at exactly the same time and in a constant ratio, then this would result in an optimal clinical situation.The purpose of the present study is to investigate the concept wihich involves the conjugation of two drugs having different pharmacological activities which is termed a 'chimera drug (mutual prodrug)', in drug delivery optimization using a chemical modification approach. The combination of ISMN, a nitric oxide donor, with NS AID or nicotinic acid were synthesized with a goal of reducing gastric mucosal damage coused by NSAID and the pharmacokinetic properties of Prodrug I . Prodrug II were examined. They are stable within in pH7.4 PBS at 3 7X3 and, however, were rapidly hydrolyzed in 10% buffered rabbit plasma (pH7.4) at 37 "C. In addition, they were found to be effective in reducing gastric erosion which is normally induced by aspirin with no changes in the anti-inflammatory effects.In addition, an efficient and practical approach to synthesize moderate to large amount of 4,4'-dihydroxybenzophenone (4,4'-DHP) is described. The key step in the synthesis is the regioselective introduction of a p-hydroxybenzoyl group at the C-4 position of phenol using methanesulfonic acid mediated Fries rearrangement carried out on phenyl 4-hydroxybenzoate. The five step synthetic procedure readily gave 4,4'-DHP in 65% over all yield.