Developments in the synthesis of new functionalized bisphosphonate drug candidates such as cyclic prodrugs

A new series of bisphosphonic acids bearing nitrogen containing heterocycles and carbocycles has been designed and synthesized. The most potent novel bisphosphonates were shown to have lower mineral affinity but have better inhibition of farnesyl diphosphate synthase, than most clinically used bisphosphonates. However, the high polarity and charged nature of bisphosphonates result in very low oral bioavailability, resulting in highly variable absorption, especially when administered with food. To eliminate side effects and absorption issues while maintaining the bisphosphonate pharmacological activity, a series of novel potential prodrugs-cyclic esters of bisphosphonic acids was developed where the bisphosphonic acid functionality is masked as a cyclic ester. A new synthesis and the steric and structural isomerism of these novel cyclic bisphosphonates are discussed. The cyclic esters of bisphosphonates demonstrated better absorption, particularly in the presence of food when dosed orally. Also, several protected bisphosphonates were hydrolytically labile in vivo, thereby releasing the tetra-acid functionality of the bisphosphonates systemically after their oral absorption. [GRAPHICS] .