Drug discovery efforts at Abbott Laboratories have led to the identification of influenza neuraminidase inhibitor A-315675 (1) as a candidate for development as an antiinfluenza drug. A convergent, stereoselective synthesis of this highly functionalized pyrrolidine is reported that utilizes pyrrolinone 2 as the key intermediate. The C5, C6 stereochemistry was established through a diastereoselective condensation of chiral imine compound 3 with silyloxypyrrole 4 to give pyrrolinone 2. The stereochemical outcome of this reaction depended critically on the choice of the imine functional group (FG), with tritylsulfenyl and (R)-toluenesulfinyl providing the desired products in good yields as crystalline intermediates. Conversion of pyrrolinone 2 into 1 was accomplished in seven subsequent steps, including Michael addition of cis-1-propenylcuprate at C4 and introduction of a cyano group as a carboxylic acid equivalent at C2.

We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However, oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.

No abstract

A novel reduced taxane, 13-acetyl-9(R)-dihydrobaccatin III (1) has been isolated from Taxus canadensis. The selective C-13 deacetylation of this isolate has allowed for the preparation of a wide variety of 9(R)-dihydrotaxane analogs. In general, this series has shown greater stability and water solubility than the 9-carbonyl series while retaining antimicrotubule and tumor cell cytotoxicity activities relative to taxol. Placement of polar functionalities at the C-7 position results in loss of activity whereas alkylation or acylation of either C-7 or C-9 hydroxyl groups ameliorate the activity.

No abstract