Patent Evaluation: Phosphate esters of cyclohexapeptides

Summary

Novelty: A novel process for the preparation of phosphate esters of known natural cyclohexapeptides isolated from Zaleiron arbonicola is claimed. A process for the isolation of the compounds as the crystalline potassium salt and its conversion to other salts is also disclosed. In the novel phosphorylation process there is no need to protect the 5-position of the ornithine. The natural product is an antifungal agent and also controls parasitic Pneumocystis carinii infections.

Biology: The specified compound was evaluated in vivo in immunosuppressed Sprague-Dawley rats with Pneumocystitis carinii pneumonia infections. Elimination of cysts after four days (twice daily iv or ip injection) was evaluated and an ED₉₀ value of 0.6 mg/kg is given. The MFC values against strains of C. albicans, C. tropicalis and C. parapsilosis are between 1 and 4μg/ml for four of the five strains tested.

Chemistry: The process comprises the direct phosphorylation of the natural product with tetrabenzyl pyrophosphate in the presence of lithium hydroxide to obtain a dibenzyl phosphate ester followed by debenzylation by hydrogenolysis on palladium on carbon. The preparation of seventeen starting products, and phosphorylation of one of these to produce the specified compound, is described.