Parkinson's Disease: Advances in Treatment and the Syntheses of Various Classes of Pharmaceutical Drug Substances.

An overview of Parkinson's disease (PD) prevalence, diagnosis, and currently available treatment options is provided. A comprehensive list of different classes of marketed pharmaceutical drug products and the syntheses of various drug substances are summarized based on published literature.

Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson's Disease.

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

Chemiluminescent acridinium-9-carboxamide boronic acid probes: application to a homogeneous glycated hemoglobin assay.

Chemiluminescent acridinium-9-carboxamide probes containing 1, 3, 9, and 27 phenylboronic acids were prepared and their chemiluminescent properties evaluated. The relative chemiluminescent signal from the probes varied from 4 to 0.83 x 10(19)counts/mol across the series, while the apparent affinity of the probes for the diabetes marker glycated hemoglobin increased from 211 to 0.43 microM. The dose-dependent modulation of the chemiluminescent intensity of the probes upon binding was used to demonstrate a homogeneous assay for glycated hemoglobin.

An efficient synthesis of a heterobifunctional coupling agent.

An efficient synthesis of 4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]-N-(6-[[6-([6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexyl]amino)-6-oxohexyl]amino]-6-oxohexyl)cyclohexanecarboxamide (12), a heterobifunctional coupling agent, was developed, which is critical for chemoselective conjugation of proteins and enzymes. The synthesis involved seven steps starting from 6-{[(benzyloxy)carbonyl]amino}hexanoic acid (1), and multigram quantities of coupling agent (12) were prepared using this protocol in excellent overall yield and 99.6% purity by reversed phase HPLC. The new method is suitable for the synthesis of coupling agent 12, consistently with purity >99%, and is useful for the preparation of other analogous coupling agents.

An efficient preparation of polyanionic affinity agent and its evaluation for the measurement of glycated hemoglobin.

An efficient method was developed for the preparation of polyanionic affinity agent (3), a key component in the measurement of glycated hemoglobin (GHb). Glycated hemoglobin is an important clinical marker for diagnosis of patients with diabetes and useful to monitor the management of disease. The affinity agent (3) was prepared based on coupling reaction between poly(acrylic acid) (1) and 3-aminophenylboronic acid (2) in water. The critical features of this polymeric affinity agent (3), such as size, boronic acid incorporation ratio and concentration, on the measurement of glycated hemoglobin were evaluated. It was found that the agent (3) prepared using poly(acrylic acid) (1) with 225 kDa molecular weight gave optimal GHb measurement. The performance test results demonstrated that the boronic acid incorporation ratio and concentration of affinity agent (3) play a critical role in the assay and determines the precision of glycated hemoglobin measurement.

Synthesis of a novel fluorescent probe for estrogen receptor.

A novel estradiol-mimetic fluorescent probe 5 was synthesized from diethylstilbestrol (DES, 1), which is useful for probing estrogen receptor (ERalpha), a prognostic indicator of estrogen-dependent cancers, and for developing a homogeneous fluorescence polarization (FP) assay to identify the ligands of estrogen receptor.

Asymmetric Synthesis and Properties of Sulfinimines (Thiooxime S-Oxides).

Enantiomerically pure sulfinimines (thiooxime S-oxides 10), important building blocks in the asymmetric synthesis of amine derivatives, are prepared in good to excellent yields in one step from aromatic, heteroaromatic, and aliphatic aldehydes. This protocol involves treating commercially available (R)- or (S)-menthyl p-toluenesufinate (Andersen reagent 4) with LiHMDS, followed by the aldehyde, affording (E)-10 exclusively. The sulfinimines 10 are formed via a Peterson-type olefination reaction of silylsulfinamide anion 13 with the aldehyde. Anion 13 is generated by reaction of lithium menthoxide (12a) with bis(trimethylsilyl)sulfinamide 11, which is formed in the reaction of 4 with LiHMDS. The other product formed is O-(trimethylsilyl)menthol (12c), which is isolated in >80% yield for recycling. Two other less efficient methods for the asymmetric synthesis of 10 are discussed: (i) the asymmetric oxidation of sulfenimines 6 with chiral nonracemic oxaziridines and (ii) the reaction of metal aldimines, prepared from nitriles, with 4. All of these protocols fail with ketones.