N-Arylaminomethylenebisphosphonates Bearing Fluorine Atoms: Synthesis and Antiosteoporotic Activity

A series of N-phenyl and N-pyridyl-aminomethylenebisphosphonates substituted in their aromatic rings with fluorine atoms or trifluoromethyl groups have been synthesized by a three component approach. They were screened for potential antiosteoporetic activity using mouse macrophage-like J774E cells. Most of the compounds appeared to be moderate inhibitors of macrophage cells proliferation compared to known the antiosteoporetic drug, Incandronate. Their potency was compared with their structural analogues, hydroxymethylene-bisphosphonate 2 and ethylidenebisphosphonates 3, which appeared to be equipotent. Although the aminomethylenebisphosphonates 1 show low stability in aqueous solutions, the most stable, i.e., N-(3-trifluoromethylphenyl)-aminomethylenebisphosphonic acid, was chosen for in vivo testing on sheep with induced osteoporosis. This compound had marginal influence on the bone structure recovery.