Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323.

DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to intermediates which were easily purified without chromatography. Additionally, a one-pot, high yield process was developed to prepare the alkylating agent, 4-[(triphenylmethoxy)methyl]benzyl chloride from 1,4-benzenedimethanol.

Structural and rate studies of the 1,2-additions of lithium phenylacetylide to lithiated quinazolinones: influence of mixed aggregates on the reaction mechanism.

The 1,2-addition of lithium phenylacetylide (PhCCLi) to quinazolinones was investigated using a combination of structural and rate studies. (6)Li, (13)C, and (19)F NMR spectroscopies show that deprotonation of quinazolinones and phenylacetylene in THF/pentane solutions with lithium hexamethyldisilazide affords a mixture of lithium quinazolinide/PhCCLi mixed dimer and mixed tetramer along with PhCCLi dimer. Although the mixed tetramer dominates at high mixed aggregate concentrations and low temperatures used for the structural studies, the mixed dimer is the dominant form at the low total mixed aggregate concentrations, high THF concentrations, and ambient temperatures used to investigate the 1,2-addition. Monitoring the reaction rates using (19)F NMR spectroscopy revealed a first-order dependence on mixed dimer, a zeroth-order dependence on THF, and a half-order dependence on the PhCCLi concentration. The rate law is consistent with the addition of a disolvated PhCCLi monomer to the mixed dimer. Investigation of the 1,2-addition of PhCCLi to an O-protected quinazolinone implicates reaction via trisolvated PhCCLi monomers.

Synthesis, antiviral activity and pharmacokinetics of P1/P1' substituted 3-aminoindazole cyclic urea HIV protease inhibitors.

A series of P1/P1' substituted cyclic urea analogues were prepared in an attempt to increase the intra-cellular antiviral potency of the nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851. The effect of alkyl substitution of the P1/P1' residues on cellular antiviral potency, protein binding, resistance profile and pharmacokinetics are described.