Marvin M. Hansen

A NOVEL PROTECTING GROUP FOR HINDERED PHENOLS

Boc2O and DMAP were used to protect hindered phenols as their Boc derivatives under mild conditions. Deprotection conditions were developed to suppress loss of a tert-butyl group from the aromatic ring, or alkylation of an additional tert-butyl group at an unsubstituted ortho or para position.

The assessment of impurities for genotoxic potential and subsequent control in drug substance and drug product

The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.

Synthesis and anticonvulsant activity of 3-aryl-5H-2,3-benzodiazepine ampa antagonists

A novel series of 3-aryl-5H-2,3-benzodiazepines with N-3 aromatic substituents has been synthesized. Good in vivo anticonvulsant activity of the new compounds has been demonstrated employing the maximal electroshock seizure test in mice. Evaluation of a subset of the compounds in the cortical wedge assay confirmed the new structures to be AMPA antagonists.

Substrate acidities and conversion times for reactions of amides with di-tert-butyl bicarbonate

Abstract The conversion time tor 4-dimethylaminopyndine catalysed reaction of amides with di- tert -butyl dicarbonate varies dramatically with substrate acidity. The pK a s in DMSO of some amides are determined to support correlation of reactivity with substrate acidity. Particularly acidic substrates, such as 4-thiazolidinone, readily react with a variety of dialkyl dicarbonates. Less acidic substrates react with Boc 2 O but other dialkyl dicarbonates decompose preferentially.

Synthesis of enantioenriched 4-thiazolidinone (−)-LY213829 by chemoselective benzylamide cleavage in the presence of a C-S bond

Abstract ( R )-2-Methylbenzylamine has been used to covalently “resolve” thiol acid 7 and assemble 4-thiazolidinone 8a in one step. Selective deprotection of the 2-methylbenzylamide using lithium in ammonia/THF has been achieved in the presence of a readily hydrogenolyzed C-S bond. Enantioenriched (−)-LY213829 ( 1 ) of 98% ee has been prepared by this five step route in 25% yield from aldehyde 2 .

Synthesis of 4-thiazolidinones from rhodanines by thiocarbonyl removal

Abstract A new procedure for synthesis of 4-thiazolidinones from readily available rhodanines is reported. Slow addition of the substrate to excess zinc dust in acetic acid at reflux affords the best yields. Identification of dimeric byproducts led to development of a procedure to suppress their formation.

Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M1 agonists

The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimers disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.

Selective methylphosphonylation of an echinocandin B analog derived from LY303366

Abstract Echinocandin B (ECB) analog 1c was methylphosphonylated with the new reagent dimethyldiphosphonate 7 . Selective functionalization of the phenol group was achieved in the presence of 11 other reactive alcohol and amide groups. The phosphonylation was best conducted in a mixture of THF and DMF using lithium t-butoxide as base. Methylphosphonate diester 1d was deprotected by hydrogenolysis to afford methylphosphonate monoester 1e , a potential prodrug for ECB analog 1c .