Pyrrolidine-Containing Bisphosphonates as Potential Anti-Resorption Bone Drugs

Bisphosphonates, particularly those with N-substituted groups, are currently the most popular drugs for the treatment of osteoporosis. However, their chemical structures are still rather simple and new synthetic methods are needed to expand their molecular complexity and also improve their specificity of action towards other targets as anticancer, antibacterial, and antimalarial drugs. Herein, we report a new class of potential antiresorption bisphosphonate drugs that have a pyrrolidine unit with different substituents, obtained through a simple dipolar cycloaddition reaction between azomethine ylides and vinylidenebisphosphonate derivatives as precursors. The methodology led to the efficient preparation of a wide range of (1-methylpyrrolidine-3,3-diyl)bis(phosphonic esters) derivatives with different substituents in position 4

Stereoselective Synthesis of Chiral Isatin Containing Bisphosphonates as Potential Anti-Resorption Bone Drugs

Bisphosphonates are currently the major class of drugs used for the treatment of osteoporosis, a disease that leads to bone fragility and increase in fracture risk that affects hundreds of million elderly individual worldwide. All commercially available bisphosphonates are achiral albeit their activity is demonstrated to be related to inactivation of specific enzymes. Cinchona alkaloid urea derivatives are efficient organocatalysts for the asymmetric aldol reaction of ketones to an isatin containing bisphosphonate precursor to provide a class of new chiral enantioenriched potentially anti-resorption bone drugs. High chemical yields were generally achieved in a wide array of substrates tested an

Copper-mediated 1,4-Conjugate Addition of Boronic Acids and Indoles to Vinylidenebisphosphonate leading to gem-Bisphosphonates as Potential Antiresorption Bone Drugs

A wide range of gem-bisphosphonate tetraethyl esters as precursors for bisphosphonic acids, which are potent inhibitors of bone resorption, bearing alkyl, aryl, and indole substituents in the β position were prepared through the CuII-catalyzed 1,4-conjugate addition of boronic acids and indoles to vinylidenebisphosphonate tetraethyl ester