Alkaline and alkaline earth metal complexes of dianhydride derivatives of clodronate and their hydrolysis products.

Alkaline and alkaline earth metal complexes of P,P'-diacetyl- (L1(2-)); new P,P'-dipropanoyl- (L2(2-)) and P,P'-dibenzoyl(dichloromethylene)bisphosphonates (L3(2-)) and their hydrolysis products were prepared and characterized using the single-crystal X-ray diffraction technique and spectroscopy, with the intention of studying the hydrolysis and coordinating properties of these potential prodrugs of clodronate. Na(2)L1 and Na(2)L2 formed the first crystalline hydrolysis product of these dianhydrides, 3D polymeric trisodium clodronate, [Na(3){Cl(2)C(PO(3))(2)}(H(2)O)(4)](n) (1). The other metal complexes prepared comprised the polymeric Ba(2+) complex of L1(2-) ligand [Ba{Cl(2)C(PO(2)O(C(O)Me))(2)}(H(2)O)(3)](n) (2); the new Sr(2+) complex of clodronic acid [{Sr(2)(Cl(2)C(PO(3))(2))(H(2)O)(4)}.H(2)O](n) (3), and the K(+) complex of the L3(2-) ligand [{K(2)Cl(2)C(PO(2)O(C(O)C(6)H(5)))(2)}O](n) (4). In addition, these L1(2-)-L3(2-) ligands have formed the same, previously published [NaMgCl(2)CP(2)O(6)H)(H(2)O)(5)](n) (5) and [{Ca(2)(Cl(2)C(PO(3))(2))(H(2)O)(6)}.4.5H(2)O](n) (6) by using the hydrolysis method in a systematic way. This study revealed that the Na(2)L1 and Na(2)L2 hydrolyze quite fast to structure 1 or form hydrolyzed metal complexes of clodronic acid, and hence the absorption in the body may not be increased by the use of Na(2)L1-Na(2)L2 as prodrugs. Na(2)L3, in turn, has a longer hydrolysis time and generally forms crystalline polymeric metal complexes without undergoing hydrolyzation. In addition, the masking of the two phosphonic acid groups by esterification to form clodronic dianhydrides does not prevent the formation of 2D polymeric metal complexes, which methylenebisphosphonates form as drugs on the hydroxyapatite surface of bone. Clodronate, however, is able to extend the dimensionality to 3D by coordination or hydrogen bonding.