PRODRUGS OF PHOSPHATES AND PHOSPHONATES - NOVEL LIPOPHILIC ALPHA-ACYLOXYALKYL ESTER DERIVATIVES OF PHOSPHATE OR PHOSPHONATE CONTAINING DRUGS MASKING THE NEGATIVE CHARGES OF THESE GROUPS

Using phenyl phoshonate and phenyl phosphate as model compounds for dr ugs containing these moieties a new type of alpha-acyloxyalkyl ester d erivatives of the OH-groups are introduced. The derivatives both mask the negative charge of these compounds and at the same time are able t o release the parent phospho group in vivo in quantitative amounts. Th e compounds are degraded through a two-step reaction with intermediate production of the mono phospho ester with a negative charge. By intro ducing a spacer in the R-group it is possible to separate the site of esterase attack from this negative charge and thus accelerate the rele ase of the parent phosphate or phosphonate drug in plasma. It was show n that the more bulky and the more nucleophilic the substituents are, the faster will degradation occur in plasma. Thus, it was shown that c ompounds II and VII, where the R-group is (Bis([3-(2-acetoxyphenyl)pro pionyl]oxymethyl), were the most promising.