A convenient synthesis of bis(phosphino)methanes: Formation of a nickel(II) bis(phosphino)methane monoxide complex

The reaction of (trimethylsilyl)methyl phosphines R₂PCH₂SiMe₃ with chlorophosphines ${\mathrm{ClPR}}_2^{\prime }$ provides ready access to a range of symmetrical or non-symmetrical diphosphinomethanes ${\mathrm{R}}_2{\mathrm{PCH}}_2{\mathrm{PR}}_2^{\prime }$. The products are obtained cleanly and can be used directly in the synthesis of transition metal complexes. This is illustrated by the preparation and structural characterization of the corresponding NiCl₂(P–P) derivatives.     

Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of ${{\text{P}}_1}^{\prime }$, ${{\text{P}}_2}^{\prime }$ and P₃ portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.