Elmar Bosies

Synthesis of thioether phosphocholine analogues

The synthesis of thioether phospholipids, which represent a new class of antitumor agents, is reported here. In particular, the route of synthesis of 3-hexadecylmercapto-2-methoxymethylpropyl-2′-trimethylammonio-ethyl phosphate (BM 41.440, Ilmofosine), one of the most potent cytostatic/cytotoxic derivatives, is described in detail. Starting with diethylbis-hydroxymethylmalonate, ethyl 2-phenyl-1,3-dioxane-5-carboxylate is formed via diethyl 2-phenyl-1,3-dioxane-5,5-dicarboxylate and 5-ethoxycarbonyl-2-phenyl-1,3-dioxane-5-carboxylic acid. Reduction of ethyl 2-phenyl-1,3-dioxane-5-carboxylate with LiAlH4 affords 5-hydroxymethyl-2-phenyl-1,3-dioxane. Alkylation with dimethyl sulfate gives 5-methoxymethyl-2-phenyl-1,3-dioxane. The ring structure then is opened byN-bromosuccinimide, resulting in the formation of 3-bromo-2-methoxymethylpropyl benzoate. Reaction of 3-bromo-2-methoxymethylpropyl benzoate with the sodium salt of hexadecanethiol leads to 3-hexadecylmercapto-2-methoxy-methylpropanol, which is reacted with a cyclic chlorophosphate to give the corresponding phosphorylated 3-hexadecylmercapto-2-methoxymethylpropanol. Treatment with trimethylamine yields BM 41.440. This compound already has been tested in clinical phase I/II trials in West Germany.

Bisphosphonates and Novel Related Structural Classes for Bone Resorption Disorders

Bisphosphonates (BPs) are powerful inhibitors of bone resorption. They exert a strong affinity to bone mineral which allows the rapid and selective targeting to bone in vivo. We synthesized and evaluated two new classes of compounds: phosphono succinic acid (PSA) and phosphono glutaric acid (PGA) derivatives. In order to transfer the antiresorptive properties of bisphosphonates attempts have been made to elucidate the key elements of the putative BP pharmacophore. Whereas the new compounds revealed similar or better bone mineral affinity properties than BPs in vitro, the inhibition of endogenous bone resorption in vivo was less effective, but in contrast to BPs the effects were reversible after discontinuation of treatment, which suggests that these compounds are metabolically degradable.