The present invention is directed towards novel cyclic phosph(oramid)ate
prodrugs of alcohol-, amine-, and thiol-containing drugs, their
preparation, their synthetic intermediates, and their uses. Another
aspect of the invention is the use of the prodrugs to treat diseases that
benefit from enhanced drug distribution to the liver and like tissues and
cells that express cytochrome P450, including hepatitis, cancer, liver
fibrosis, malaria, other viral and parasitic infections, and metabolic
diseases where the liver is responsible for the overproduction of the
biochemical end product, e.g. glucose (diabetes); cholesterol, fatty
acids and triglycerides (hyperlipidemia) (atherosclerosis) (obesity). In
one aspect, the invention is directed towards the use of the prodrugs to
enhance oral drug delivery. In another aspect, the prodrugs are used to
prolong pharmacodynamic half-life of the drug. In addition, the prodrug
methodology of the current invention is used to achieve sustained
delivery of the parent drug. In another aspect, the prodrugs are used to
increase the therapeutic index of the drug. In another aspect of the
invention, a method of making these prodrugs is described. In another
aspect, the prodrugs are also useful in the delivery of diagnostic
imaging agents to the liver.
