CHELATING DRUG

AN ORALLY EFFECTIVE IRON CHELATING DRUG FOR USE IN THE TREATMENT OF CHRONIC IRON OVERLOAD IS BADLY NEEDED. THE PRINCIPLE AIM OF THIS PHASE I PROPOSAL IS TO DEVELOP A COST EFFECTIVE SYNTHESIS OF N,N'-BIS(O-HYDROXYBENZYL) ETHYLENEDIAMINE-N,N'-DIACETIC ACID (HBED), AN IRON CHELATINGAGENT WHICH HAS PROVEN TO BE HIGHLY ACTIVE IN ANIMAL MODELS OF IRON OVERLOAD. THE PUBLISHED SYNTHESES OF THIS COMPOUND ARE NOT SUITABLE FO PREPARING THE KILOGRAM QUANTITIES NEEDEDTOXICITY STUDIES AND SUBSEQUENT CLINICAL EVALUATION. THIS THIS INVESTIGATION FOCUSES ON NOVEL SYNTHETIC ROUTES TO HBEDUTILIZING METAL TEMPLATES. IN THIS WAY IT IS HOPED THAT THESIDE REACTIONS WHICH HAVE PLAGUED MOST PREVIOUSLY ATTEMPTED SYNTHESES OF THIS COMPOUND WILL BE AVOIDED AND ITS ISOLATIONAND PURIFICATION WILL BE FACILITATED. SPECIFIC EMPHASIS WILL BE PLACED ON USING LOW COST STARTING MATERIALS AND SYNTHETIC ROUTES WITH A MINIMUM NUMBER OF STEPS. ONCE A PRACTICAL SYNTHETIC ROUTE HAS BEEN ESTABLISHED, WE WILL INVESTIGATE ITS POTENTIAL FOR SCALE UP AS WELL AS THE CONVERSION OF HBED INTO THE CORRESPONDING METHYL ESTER (DMHBED), THE MOST ACTIVE DERIVATIVE OF HBED. THE HBED PREPARED IN THE COURSE OF THESE PILOT INVESTIGATIONS WILL BE USED IN PRELIMINARY SHORT TERM FEEDING STUDIES INVOLVING MICE AND RATS. THESE STUDIES WILL SERVE AS A GUIDE FOR DETERMINING THE SCOPE OF SUBSEQUENT TOXICITY EVALUATIONS. ASSUMING THAT THE RESULTS OF THE PHASE I STUDIES LOOK PROMISING, A PHASE II APPLICATION WILL BE SUBMITTED DEALING WITH THE SCALE UP AND MANUFACTURE OF HBED AND DMHBED FOR USE IN CHRONIC TOXICITY STUDIES AND CLINICAL EVALUATION.