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A synthetic methodology for a protecting-group-free formation of 3-aryl-substituted 4-aminopyrazoles from acetophenones via a telescoped oximation and hydrazine condensation of 1,3-ketoaldehydes to generate nitrosopyrazoles, and copper-catalyzed NaBH4 reduction of the nitroso group, was demonstrated. The synthesis tolerates a broad scope of substrates with a variety of substituents on the phenyl ring to afford the desired products.

The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of ...

The crystallization-induced diastereomer transformation of a precursor to navoximod was investigated using online HPLC and optimized with inline racemization.

Micronization by air jet milling is often used to produce drug substance particles of acceptable respirable size for use in dry powder inhaler formulations. The energy from this process often induces surface disordered sites on the micronized particles with potential consequences for the long-term stability of the drug substance. In this study, two lots of the same drug substance were qualitatively determined to have different extents of disordered surface using dynamic vapor sorption and scanning electron microscopy. These differences led to observable divergences in particle size and morphology between lots of drug substances on long-term and accelerated stability. The studies investigate the contribution of temperature and humidity, morphology prior to milling, and stability behavior post-micronization. The results highlight the importance of controlling the crystallization solvents upstream of micronization and their contribution to a material's susceptibility to milling-induced disorder on long-term physical stability. Furthermore, this work proposes an accelerated technique useful in predicting stability behavior of micronized drug substances in days rather than months, especially in cases where small differences cannot be detected by standard solid-state techniques.

The concise early development route to the Nav1.7 inhibitor GDC-0310 is described. The active pharmaceutical ingredient (API) contains one stereocenter, which was obtained with high enantiomeric excess (>99:1) by using an SN2 displacement approach to connect two intermediates: a chiral benzyl alcohol and a piperidine. The synthesis of the piperidine building block proceeded via a regioselective SNAr reaction on 1-chloro-2,4-difluorobenzene by N-Boc-4-piperidinemethanol, followed by installation of the methyl ester group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into cleavage of the Boc group to provide the advanced piperidine intermediate. The key feature of the synthesis is the highly selective SN2 displacement of the chiral mesylate of (R)-1-(3,5-dichlorophenyl)ethan-1-ol with the piperidine intermediate, followed by a chiral purity upgrade via the corresponding (1S)-(+)-camphorsulfonic acid salt. After standard hydrolysis of the methyl ester and CDI mediated amidation to couple the resulting acid with methanesulfonamide, enantiomerically pure GDC-0310 was obtained in high overall yield (37%) on a 6.5 kilogram scale.

A highly regioselective Mg-catalyzed alkylation of 3-substituted pyrazoles has been developed to provide N2-alkylated regioisomers. Using α-bromoacetates and acetamides as alkylating agents, this new method was applied to a variety of 3-substituted and 3,4-disubstituted pyrazoles to produce the N2-alkylated products with high regioselectivities ranging from 76:24 to 99:1 and 44–90% yields.

The development of a redesigned and improved second-generation synthesis of the Nav1.7 inhibitor GDC-0276 based on experience gained from a fit-for-purpose first-generation synthesis will be described. The first-generation synthesis proceeded via a regioselective SNAr reaction on the advanced starting material t-butyl 5-chloro-2,4-difluorobenzoate with 1-adamantanemethanol. In the newly developed second-generation synthesis, the much improved regioselective SNAr reaction was performed on the readily available starting material 1-chloro-2,4-difluorobenzene, followed by installation of the carboxylate group by electrophilic aromatic bromination and a palladium-catalyzed alkoxycarbonylation. A subsequent Suzuki–Miyaura cross-coupling reaction was then telescoped directly into a phase-transfer-catalyzed ester hydrolysis. Amidation of the resulting acid intermediate with 1-azetidine sulfamide in turn provided GDC-0276 in high overall yield and purity on a 100 kg scale.

A practical convergent synthesis of PI3K inhibitor GDC-0908 (1) is described. The process features a dihydrobenzothienooxepine formation via palladium-catalyzed intramolecular direct C-H arylation and a Negishi coupling to construct the key C-C bonds. We further developed a general synthesis of dihydrobenzothienooxepines in good to excellent yields via palladium-catalyzed intramolecular direct C-H arylation, which tolerates both electronically and sterically diverse substituents on the phenyl ring.

Boronic acids and boronate esters are commonly used reagents in Suzuki–Miyaura coupling chemistry which are known to be weakly mutagenic in microbial assays. In this paper, we describe an inductively coupled plasma mass spectrometer method (ICP-MS) for the analysis of boron at low parts per million levels. Boronic acid and ester levels are then calculated stoichiometrically in a drug substance based on the determination of boron with good sensitivity (LOQ of 0.8 ppm). The paper outlines some of the important aspects of the method and instrument features such as use of organic diluent, spray chamber configuration, and its optimization which are critical for analysis of trace inorganic species in drug substances.

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals.

GENE-A, a Nav1.7 inhibitor compound with analgesic activity, was developed as a crystalline anhydrate, for which two polymorphic forms, I and II, were discovered. The two forms were found to possess very similar free energies as determined experimentally with Form II being thermodynamically stable above 25 °C based on solubility measurements. A detailed solid-state characterization was conducted to determine the relative stability of these solid forms, and both thermodynamic and kinetic pathways (slurry bridging and crystallization) were evaluated. Form II was obtained as the final form in competitive slurries at RT. The outcome of crystallization experiments in terms of the solid form obtained was complicated and yielded variable results depending on the form of the starting material and that of the seeds. Form II was reproducibly obtained as the end product in unseeded experiments and in those with Form II as seeds and starting material, while Form I was obtained in all other seeded experiments. On the basis of the experimental data, a controlled crystallization strategy was developed, wherein Form II was used both as starting material and seeds to reproducibly obtain the desired form upon scale-up.

A process leading to the multikilogram GMP synthesis of Chk1 inhibitor GDC-0425 (1) was developed. Highlights of the synthesis include protection of the pyrrole ring of a 1,7-diazacarbazole as propyl ethyl ether, an efficient Pd catalyzed cyanation of an aryl chloride, aryl ether formation by SNAr fluoride displacement, and development of a controlled crystallization providing the API with the required polymorphic form. The process delivered high-quality GDC-0425 with low levels of impurities and residual metals in five steps and 31% overall yield.

SummaryBackgroundIn the era of improving overall survival rates of malignant diseases, the impact of a previous malignancy (PM) on treatment and outcome of lung cancer (LC) remains unclear.MethodsWe reviewed all LC patients from our institution that were treated from 2004 to 2006 for the occurrence of LC with PM excluding patients with multiple primary LC.ResultsA total of 444 and 2698 LC patients with and without a history of a PM were identified (prevalence of 14.1%). PM were most often located in breast (15.5%), prostate (14.9%), bladder (9.0%) and kidney (8.8%). Compared to never smokers, patients with nicotine consumption had more often a cancer history of prostate, gastrointestinal, and the head-neck region. The median interval until diagnosis of LC was 72.2 months (range 0–537 months) with most LC diagnosed 5 years after PM diagnosis. With a similar distribution of histology, stage and localization compared to controls, NSCLC patients with PM and stage IV disease showed a favorable overall survival (p

Hexafluorophosphoric acid promotes 1,3,4-oxadiazolium hexafluorophosphate formation from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions. These 1,3,4-oxadiazolium hexafluorophosphates can be treated with cyanamide in propan-2-ol in the presence of triethylamine to generate 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good yields. This safe and scalable protocol displays a broad scope with respect to N-substitutions and N′-acyl protecting groups.

Patients with lung cancer are at risk of developing a second primary lung cancer (SPLC). However, the characteristics of patients at risk remain largely speculative. We reviewed 2816 lung cancer patients from our institution for the occurrence of SPLC. Any SPLC was categorised as synchronous when diagnosed within 2 years of the first primary lung cancer (FPLC) and after direct histological comparison of both tumours. All other SPLCs were considered as metachronous. 139 patients developed a second malignancy including 69 nonsmall cell lung cancer (NSCLC) and 9 small cell lung cancer. The median interval for diagnosis of metachronous SPLC (n=59) after FPLC occurrence was 72 months. SPLC detected within 5 years of FPLC diagnosis had a more favourable stage distribution (p=0.02). After diagnosis of SPLC, patients had a superior median overall survival compared to controls (57.7 versus 18.1 months; p

Ruthenium-catalyzed asymmetric homogeneous hydrogenation (AHH) is used as the key step of a multi-kilogram scale synthesis of an enantiomeric fluoropiperidine. The AHH of a tetrasubstituted β-fluoroenamide is carried out under mild conditions using a Ru/Josiphos catalyst with high ee (98%).

Suitable as highly effective polymerization catalysts is the new class of donor/acceptor metallocenes in which the rotation of the two pi ligands is restricted through the formation of a dative D(+)-->A(-) bond (see picture). Specifically optimized substitution patterns yield excellent properties for the synthesis of high-melting, highly crystalline thermoplastic materials, amorphous thermoplastic materials with high glass transition temperatures as well as polyolefin elastomers with low glass T(g).

The major product in the intramolecular Pauson-Khand reaction of 3,4-disubstituted 1,6-heptenynes to form bicyclo[3.3.0]octenones is highly dependent on the relative configurations of the two stereocenters of the substrate. For example, cycloaddition of the “syn,syn” stereoisomer of 3,5-dimethyl-4-propargyl-1,6-heptadiene gives predominantly an enone containing both substituents in more hindered endo orientations; the “syn,anti” stereoisomer, upon reaction across the “syn” linkage similarly gives mostly endo product, but upon reaction across the “anti” portion of the molecule affords almost exclusively an enone in which the C6 methyl group possesses exo stereochemistry. Parallel results obtain from enynes built upon cyclohexane frameworks. Calculated energies of pre-cycloaddition enynes, metallacycles presumed to be the penultimate intermediates in the cyclization mechanism, and the final products are examined in order to develop a reasonable predictive model.

Hexafluorophosphoric acid promotes 1,3,4-oxadiazolium hexafluorophosphate formation from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions. These 1,3,4-oxadiazolium hexafluorophosphates can be treated with cyanamide in propan-2-ol in the presence of triethylamine to generate 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good yields. This safe and scalable protocol displays a broad scope with respect to N-substitutions and N′-acyl protecting groups.

To complete the process of comprehensive growth-oriented brand management, this chapter deals with the unanswered questions addressed in Chap. 3 – how to develop your marketing and sales plan, calculate your return on marketing investment and monitor success. It also presents checklists and questions for successful use of the BGB model.

Before looking at the Brand Growth Barrier Model and its advantages, we need to understand the flaws in today’s popular approaches to brand management. This will help us identify the key requirements a model for growth-oriented brand management must meet. Several ideas presented in this chapter will strike you as new and inspiring. Some you may have thought about already, but not found a satisfying solution yet. If you come away from this chapter with the impression that your brand management challenges are even bigger than you thought – that’s fine. You will find answers to your (new) questions in the next chapter.

There are only three ways a company or its brand can go: up – growth; down – decline; neither nor – stagnation. And only one way satisfies everyone involved, especially owners and shareholders: going up, i.e. achieving growth. Theoretically, the sky’s the limit in terms of growth – you can always grow more. Even in economically hard times, you need to strive for growth because, sooner or later, you’ll have cut all the costs you can. The only other lever with which to increase profits is growth. So it’s all the more important to use that lever and create new growth – especially with the help of your brand. Even in a period of crisis when many potential customers focus on price, a strong brand can overcome that barrier and revive sales, turnover and profits.

The first step is to find out what you will need to focus on – in other words to identify the major challenges your brand is facing. This is done using the Brand Growth Barrier (BGB) model. The challenges can also be described as the conditions which are a barrier to the growth of a brand – hence the term “brand growth barriers”.

Whichever focus barrier you’re dealing with, you’ll always find a solution. And once you’ve done that, you have opened the door to new growth.

Now that we know which barriers are our focus barriers, the next task is to understand why they exist. This part of the model is called diagnostics. Like a doctor examining a painful knee and asking the patient questions, we study the barriers and, in many cases, also conduct interviews with our target group.

The optically active, facial complex Cr(CO)3(PP′P″) (1) with the tridentade ligand PP′P″ = (R)-(+)-1,2,4-tris (diphenylphosphino)butane has been synthesized and characterized. The complex Cr(CO)3(PP′)P″ (PP′ = (R)-(+)-prophos, P″ = PMe2Ph) forms two pairs of diastereomers, facial (3, 4) and meridional (5, 6), respectively, that can be separated by preparative column chromatography. Surprisingly, the CD spectra of Cr(CO)3(PP′P″) (1) and the facial diastereomer of Cr(CO)3(PP′P″ (3), which have the same configuration at the Cr atom, are dissimilar. The meridional configuration of the two isomers 5 and 6 of Cr(CO)3 (PP′)PMe2Ph is supported by the 31P and 1H NMR spectra of the optically inactive complex Cr(CO)3(PP′)P″ (PP′ = 1-[di (4-methoxyphenyl)phosphinol-2-(diphenylphosphino)ethane P″ = PMePh2) which forms the meridional isomers 9 and 10.

3-Thiabicyclo-[3,3,0]-oct-5-en-7-ones have been prepared by intramolecular Pauson-Khand reaction on allylpropargylsulfide cobalt complexes in benzene with dimethylsulfoxide as promoter and dimethylsulfide in 65-80% yield.

Falschungen sind Regelverletzungen, die das Strafrecht meist unter die Kategorie Betrug einordnet. Es gibt allerdings auch Lebensbereiche, in denen sie so haufig vorkommen, dass man sie als schon regelmasige Ausnahmen bezeichnen kann. Dazu gehort die Warenproduktion mit dem grosen Sortiment an Produktfalschungen: Gerade von einer Reise nach Peking zuruckgekehrt, kann selbst ein deutscher Universitatsprofessor seinen Kindern Luxusuhren der Marke „Lolex“ lassig als Souvenir prasentieren.

Um die ganzheitliche, wachstumsorientierte Markenfuhrung zum Abschluss zu bringen, werden nun im Nachfolgenden zum einen die drei noch offenen Markenfuhrungsfragen aus Kapitel 3 beantwortet (Marketing- und Vertriebsplan, Return on Marketing Investment und Erfolgskontrolle). Zum anderen werden die Checklisten und Fragelisten fur die erfolgreiche Anwendung des MWB-Modells zusammengefasst.

Bevor wir uns mit dem Modell der Markenwachstumsbarrieren und seinen Vorteilen beschaftigen, ist es wichtig, die Problematik der heute gangigen Markenfuhrung zu verstehen. Denn hieraus ergeben sich die wichtigsten Anforderungen an ein Modell, das eine wachstumsorientierte Markenfuhrung ermoglicht. Vieles in diesem Kapitel wird neu und inspirierend sein, mit manchen Fragestellungen werden Sie sich wiederholt und vielleicht nicht immer zufriedenstellend auseinandergesetzt haben. Sollte die Herausforderung fur Ihre Markenfuhrung am Ende dieses Kapitels noch groser erscheinen als zuvor – wunderbar. Erste Antworten auf Ihre (neuen) Fragen finden Sie bereits im folgenden Kapitel.

Es gibt genau drei Richtungen, in die es mit einem Unternehmen bzw. seiner Marke gehen kann: rauf – Wachstum; runter – Ruckgang; weder noch – Stagnation. Und nur eine Richtung stellt samtliche Beteiligte, insbesondere Eigentumer und Aktionare, zufrieden: rauf. Theoretisch ist nach oben hin alles offen – es gibt fur Wachstum keine wirkliche Grenze. Selbst in wirtschaftlich schwierigen Zeiten sollte man vom Streben nach Wachstum nicht abkommen. Denn irgendwann hat man alle Kosten gesenkt, die gesenkt werden konnen. Der einzig andere Hebel zur Gewinnsteigerung liegt im Wachstum. Umso wichtiger ist es also, diesen Hebel zu betatigen und neues Wachstum anzustreben – gerade mithilfe der Marke. Denn auch die in schwierigen Zeiten weit verbreitete Fokussierung der potenziellen Kunden auf den Preis kann mit einer starken Marke uberwunden werden, sodass Absatz, Umsatz und Gewinn neu angetrieben werden.

We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporo-occipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes II+III and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8(+) T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8(+) T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease.

3-Thiabicyclo-[3,3,0]-oct-5-en-7-ones have been prepared by intramolecular Pauson-Khand reaction on allylpropargylsulfide cobalt complexes in benzene with dimethylsulfoxide as promoter and dimethylsulfide in 65-80% yield.

Department of Chemistry and Division of Molecular Engineering and Chemistry, Korea University, Seoul 136-701, KoreaReceived September 16, 2004Key Words : Pauson-Khand reaction, Propargyl aldehyde dicobalt hexacarbonyl, Asymmetric addition,Bis(homoallyl)zincThe preparation of the optically active secondary prop-argyl alcohols has been a subject of intensive researches.