Chemical process synthesis of beta-amino acids and esters.

The importance of beta-amino acids and esters for the synthesis of potential therapeutic agents and biologically active compounds is well known and the subject of this special issue. This review outlines some of the recent approaches reported for the synthesis of both racemic and enantiomeric beta-amino acids and esters with emphasis on those used for large scale production. This compilation is written from a chemical process perspective focusing on the practical application of these processes for large scale synthesis. A survey of procedures described in patent publications as well as current advances from chemical process research groups and results from our laboratory are included with emphasis on asymmetric Michael-type additions, addition of metal enolates to imines/sulfinimines, classical and enzymatic resolutions, and reduction of enantiomeric enamines.

Synthesis of influenza neuraminidase inhibitors.

Influenza neuraminidase inhibitors provide a means to combat flu, a potentially very serious disease. For the first time, there is a way to treat influenza by blocking the influenza enzyme neuraminidase to stop or slow the progression of infection. The diverse structures and synthesis of several influenza neuraminidase inhibitors are discussed. Contributions from chemical process development groups are highlighted for those compounds that have reached the market, such as zanamivir and oseltamivir phosphate.

Piperazinylalkyl heterocycles as potential antipsychotic agents.

We recently reported on a series of pyrrole Mannich bases orally active in inhibiting the conditioned avoidance response (CAR) in rats. These compounds exhibit affinity for both D2 and 5-HT1A receptors, and some are noncataleptogenic. Such a profile suggests that they may be potential antipsychotic agents which lack the propensity for causing extrapyramidal side effects and tardive dyskinesias in humans. One of these compounds, 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]- 1-piperazinyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25730, 1), was chosen for further development but found to be unstable in dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethylene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substituted acyclic amide for lactam. In addition, we replaced the pyrrole segment with other heterocycles including thiophene, furan, isoxazole, isoxazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compounds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was significantly decreased or abolished, with the exception of 6. For the most part, the modifications to 1 resulted in the decrease or loss of D2 receptor binding. However, within this series, 5-HT1A receptor binding was greatly increased, with thiophene 40 exhibiting an IC50 of 0.07 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44-47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak or nonexistent D2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic active metabolites are responsible. Pyrrole 6 and furans 44 and 47 show promise as antipsychotic agents based on their CAR activity, receptor-binding profile, and solution stability.

Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic alpha1 receptors.

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.

Adhesion and cohesion in structures containing suspended microscopic polymeric films.

This paper presents a novel technique for the characterization of adhesion and cohesion in suspended micro-scale polymeric films. The technique involves push-out testing with probes that are fabricated using focused ion beam techniques. The underlying stresses associated with different probe tip sizes were computed using a finite element model. The critical force for failure of the film substrate interface is used to evaluate adhesion, while the critical force for penetration of the film determines cohesion. When testing a standard material, polycarbonate, a shear strength of approximately 70 MPa was calculated using the Mohr-Coulomb theory. This value was shown to be in agreement with the results in the literature. The technique was also applied to the measurement of adhesion and cohesion in a model drug-eluting stent (the Nevo™ Sirolimus Eluting Coronary Stent) containing suspended microscopic polymeric films in metallic Co-Cr alloy reservoirs. The cohesive strength of the formulation was found to be comparable with that of plastics such as those produced by reaction injection molding and high-density polyethylene.

Degradation and adhesive/cohesive strengths of a reservoir-based drug eluting stent.

This paper presents the results of loss of mechanical strengths due to the degradation that occurs in a model reservoir-based coronary stent, the NEVO(™) Sirolimus-eluting Stent (NEVO(™) SES). The adhesion of the formulation to the reservoir and cohesion within the formulation in the time course of hydrolysis were determined using a micro-testing system that was developed specifically for the measurements of the adhesive and cohesive strengths of suspended polymeric films. The strengths were measured after hydration, during degradation with gentle agitation, as well as degradation with pulsatile mechanical loading. The morphology and molecular weight changes in the time course of NEVO(™) SES formulation degradation were also studied using Scanning Electron Microscopy (SEM) and Gel Permeation Chromatography (GPC) techniques. Morphological changes, such as pore formation, lagged behind the decrease in the molecular weight of the formulation. In contrast, the adhesion/cohesion strengths showed that the mechanical integrity of the stents dropped significantly within a few hours of hydration, before reaching a plateau. Despite the significant molecular weight decrease and morphological changes, the plateau mechanical strengths reached were essentially the same during degradation, under both, mechanically unloaded and loaded conditions.

Quantitative spatial distribution of sirolimus and polymers in drug-eluting stents using confocal Raman microscopy.

Raman spectroscopy was used to differentiate each component found in the CYPHER Sirolimus-eluting Coronary Stent. The unique spectral features identified for each component were then used to develop three separate calibration curves to describe the solid phase distribution found on drug-polymer coated stents. The calibration curves were obtained by analyzing confocal Raman spectral depth profiles from a set of 16 unique formulations of drug-polymer coatings sprayed onto stents and planar substrates. The sirolimus model was linear from 0 to 100 wt % of drug. The individual polymer calibration curves for poly(ethylene-co-vinyl acetate) [PEVA] and poly(n-butyl methacrylate) [PBMA] were also linear from 0 to 100 wt %. The calibration curves were tested on three independent drug-polymer coated stents. The sirolimus calibration predicted the drug content within 1 wt % of the laboratory assay value. The polymer calibrations predicted the content within 7 wt % of the formulation solution content. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra from five formulations confirmed a linear response to changes in sirolimus and polymer content.

Unexpected antinociceptive effect of the N-oxide (RWJ 38705) of tramadol hydrochloride.

N-Oxides of centrally acting analgesics generally have minimal analgesic activity. However, the N-oxide of tramadol produced dose-related, long-lasting antinociception in the mouse abdominal irritant, 48 degrees C hot-plate, 55 degrees C hot-plate, and tail-flick tests (ED50 = 15.5, 84.7, 316.4 and 138.2 mg/kg, p.o., respectively). Tramadol N-oxide (T-N-O) (RWJ 38705) was also antinociceptive in the 51 degrees C hot-plate test in male (ED50 = 63.2 mg/kg, i.p.) and female (ED50 = 39.9 mg/kg, i.p.) rats. A characteristic feature of T-N-O was an extended duration of action in these tests (4-5 h). T-N-O had negligible affinity for opioid mu (Ki = 38.5 microM) delta. or kappa receptors (Ki > 100 microM) and, in contrast to tramadol, was essentially devoid of norepinephrine or serotonin neuronal reuptake inhibitory activity (Ki > 100 microM). However, T-N-O displayed tramadol-like characteristics in vivo. There were also significant amounts of tramadol in plasma after T-N-O administration, and the levels resulting from equal oral doses of T-N-O and tramadol were the same, suggesting that the conversion of T-N-O to tramadol was rapid and essentially quantitative. T-N-O was not readily metabolized to tramadol in rat hepatic S9 fraction (< 2%), implying that the conversion might occur in the gastrointestinal tract. Taken together, the results suggest that T-N-O acts as a prodrug for tramadol. T-N-O could offer the clinical benefits of an extended duration of action and a "blunted" plasma concentration spike, possibly leading to an enhanced side-effect profile.