Knut A. Jaeggi

S-[1-(2,3-diaminophenoxy)]-3′-(N-t-butylamino)propan-2′-ol-simplified asymmetric synthesis with CD and chiral HPLC analysis

Abstract S-[1-(2,3-Diaminophenoxy)]-3′-(N-t-butylamino)propan-2′-ol is important as a precursor in the radiosynthesis of a 11C-labelled radioligand (S-[carbonyl-11C]CGf 12177) for the study of β-receptors in living man. The asymmetric synthesis of this precursor has been simplified based on the reaction of readily available 2-amino-3-nitrophenol and the chiral auxiliary, S-glycidyl-3-nitrobenzenesulphonate, followed by treatment of the resultant S-epoxide with t-butylamine and reduction with hydrogen in the presence of palladium on carbon. Chiral HPLC methods have been successfully developed to monitor the enantiomeric purity of the chiral auxiliary and of all intermediates in the asymmetric synthesis. All intermediates and products have been studied by CD. It has been demonstrated by chiral HPLC that S-CGP 12177 can be prepared in > 98.4% e.e. from the synthesised S-precursor. R-CGP 12177 (e.e.>96.2%) was prepared analogously.

Synthesis and characterization of CGP-12177-NBD: a fluorescent β-adrenergic receptor probe

The synthesis and properties of a fluorescent derivative of the hydrophilic beta-adrenergic antagonist CGP-12177 are described. The fluorescence of the NBD derivative of CGP-12177 (CGP-NBD) is extremely sensitive to its environment, the quantum yield increasing 23-fold upon transfer from water to acetonitrile. This property of CGP-NBD was taken into account and a procedure was developed using quantitative chloroform extraction of ligand for the measurement of CGP-NBD bound specifically to beta-receptors on A431.E3 membranes. The fluorescent NBD-derivative of CGP-12177 bound strongly and specifically to A431 cells, a KD of 3.9 x 10(-10) M being measured; the specific binding represented 63% of the total binding at a concentration of 1 x 10(-8) M (256 x KD). A431.E3 cells were used for the binding studies since they gave consistently higher receptor numbers when compared with the native strain. A maximal number of 47,000 sites/cell and a KD of 100 pM were measured with CGP-12177 on adhered cells. The receptor number was strongly dependent upon cell density with only 3000 sites/cell being measured in suspension at confluence.

Amino-Substituted GEM-Bisphosphonates

In 1986, a chemistry program was initiated to discover a more potent bisphosphonate as a follow-up to pamidronate for the treatment of osteoporosis and metastatic bone disease. Three subclasses of bisphosphonates were investigated: 1) analogues of pamidronate with different alkyl and phenyl-X-alkyl-substituents (X = O, S) at the nitrogen (tables 1 and 2); 2) hydroxy bisphosphonates with a five-membered heteroaromatic substitutent linked via a methylene bridge to C1 (table III); 3) aminomethylene bisphosphonates with a five-membered heteroaromatic substitutent (table IV). Zoledronate was selected for development based on its high antiresorptive activity, good dissociation from inhibition of bone mineralization and excellent renal tolerability. Preliminary results from Phase I clinical trials have confirmed the compounds predicted profile.

A novel rearrangement in the series of GEM-bisphosphonic acids

Abstract Some bisphosphonic acids containing basic side chain sub-stituents are compounds of pharmaceutical interest which are undergoing clinical investigation as agents for the treatment of various bone diseases. 3-Amino-propane-l-hydroxy-1,l-bisphosphonic acid (pamidronic acid, APD) is a well known member of this series (1). When APD was subjected to trimethylsilylation and subsequent distillation at low pressure, a novel rearrangement was observed: