Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.

The synthesis of an anti-infective nucleoside intermediate was accomplished through direct iodine displacement at C-5′ by a tetrabutylammonium carboxylate. This approach constitutes a more efficient alternative to the traditional oxidative displacement.4′-Azidonucleosides have attracted much attention as experimental drugs in the therapy of HIV 1,2 and HCV 3-5 (hepatitis C virus). We were interested in developing a practical, economical, and robust synthesis of a novel class of anti-HCV agents, represented by 4′-azido-2′-deoxy-2′-C-methylcytidine and its diester prodrugs, 6 in order to support a clinical program.We have recently described a practical synthesis of (2′R)-2′-deoxy-2′-C-methyluridine. 7 This synthesis provided us with hundreds of kilograms of the key intermediate 1 (Scheme 1). Following the literature precedent, 1 was smoothly dehydrated to 2 in two steps. The functionalization of the double bond in 2 to our drug candidate 3 can be carried out according to two distinct methods (Scheme 2): A recent publication details the epoxidation of vinyl ether 2 followed by ring opening with TMSN 3 (path a). 8,9 This approach is scalable, but epoxide instability and the hazard associated with handling TMSN 3 make it challenging. 10 The second method (path b) begins with the regioand stereoselective addition of IN 3 to the vinyl ether double bond of 2a. This addition is described as proceeding with complete Markovnikov regioselectivity and a face selectivity of 9:1 in a similar substrate, 1 and we were therefore confident that we could achieve this step regioand stereoselectively. Indeed, our first attempts to adopt the published procedure to our substrate 2a led to 6 in 85-87% isolated yield. 11 We determined the diastereomeric ratio as 95:5 in solution. Isolation by crystallization led to 6 contaminated by only 2-3% of its C-4′ epimeric analogue 6′. 11