Synthese von 19-Hydroxyaldosteron Ueber Steroide 236. Mitteilung

Ausgehend von 19-Hydroxycorticosteron (IV), das unter Verwendung intramolekularer Radikalreaktionen (Barton-, bzw. Hypojodit- Reaktion) aus 19-unsubstituierten Vorlaufern zuganglich ist, wurde durch Photolyse des entsprechenden 11-Nitrits VI das 19- -Hydroxyaldosteron-diacetat (IX) erhalten. In einer analogen Sequenz entstand auch aus dem in 1,2-Stellung dehydrierten Nitrit xtu das 1-Dehydro-19-hydroxyaldosteron-diacetat (XVI). Der Angriff des in der Photolyse-Stufe interrnediar gebildeten 11jf-O-Radikals erfolgte in beiden Fallen selektivan der C(18)-Methylgruppe, Durch die formelle Einfiihrung einer zusatztichen Sauerstoff- Funktion in Stellung 19 von Aldosteron-Derivaten wurden sowohl die Bindung and den cytoplasmatischen Rezeptor wie auch die mineralocorticoide Wirkung stark reduziert

Concept and Development of a Potent Topical Corticosteroid

In a rational approach to identify an ultrapotent compound for the treatment of therapy-resistant dermatoses, Weirich's modification of McKenzie's skin vasoconstriction assay (HVK test) has been used as the essential selection criteria. In a primary phase, a quantitative relationship between the HVK activity of 25 derivatives of corticosterone substituted in various positions of the skeleton, and their lipophilicity (log P) was established. The specific lipophilicity-independent interactions were accounted for by the inclusion of 'indicator variables' into the regression analysis. The highly significant results allowed to localize an optimal log P range and to identify the influence of various substituents. In a next phase, the evidence of the first HVK analysis was refined by considering 28 additional compounds. On the basis of the confirmed facts, six 21-chloro-6α-fluoro compounds were specifically synthesized and submitted to dermatopharmacological testing. Finally, CGP 14458 (= 2l-chloro-6α,9-difluoro-11β-hydroxy-16β-methyl-3,20-dioxopregna-1,4-dien-17α-yl propionate) which was predicted to be the most potent representative of these series, whose synthesis is described in detail, showed indeed to be the most effective compound. Clinical trials with this compound – halobetasol propionate/Ultravate® (ulobetasol/Miracorten®) – confirmed its unique efficacy, especially in the treatment of severe, chronic plaque psoriasis

A (1,3) strain in cis- and trans-5, 6-dihydro-4, 6-dimethyl-4H, 8H-pyrido [3,2,1-de]phenanthridin-8-ones

The stereochemistry of trans- and cis-2, 4-dimethyl-tetrahydroquinolines, 6 and 7 were derived from <SUP>1</SUP>H-NMR. studies. These were converted respectively into trans- and cis-5, 6-dihydro-4, 6-dimethyl-4H, 8H-pyrido [3, 2, 1-dephenanthridin-8-ones 18 and 20 by a Pschorr reaction on the anthranilamides 10 and 15. Bromophenanthridones 19 and 21 were similarly prepared from bromoanthranilamides 12 and 17. Detailed <SUP>1</SUP>H-NMR. studies on 18 and 20 indicated axial disposition of the methyl groups at C(2) in both compounds in contrast to the situation in 6 and 7. This is presumably to avoid adverse CH<SUB>3</SUB>CO group interaction of the A (1, 3) type. The severity of this is gauged by the preference of 20 for a normally forbidding 1, 3-diaxial orientation of two methyl groups. X-ray crystallographic studies on 19 and 20 confirm the stereochemical assignments

A (1,3) Strain in cis- and trans-5, 6-dihydro-4, 6-dimethyl-4H, 8H-pyrido [3,2,1-de]phenanthridin-8-ones

The stereochemistry of trans- and cis-2, 4-dimethyl-tetrahydroquinolines, 6 and 7 were derived from 1H-NMR. studies. These were converted respectively into trans- and cis-5, 6-dihydro-4, 6-dimethyl-4H, 8H-pyrido [3, 2, 1-de]phenanthridin-8-ones 18 and 20 by a Pschorr reaction on the anthranilamides 10 and 15. Bromophenanthridones 19 and 21 were similarly prepared from bromoanthranilamides 12 and 17. Detailed 1H-NMR. studies on 18 and 20 indicated axial disposition of the methyl groups at C(2) in both compounds in contrast to the situation in 6 and 7. This is presumably to avoid adverse CH3CO group interaction of the A (1, 3) type. The severity of this is gauged by the preference of 20 for a normally forbidding 1, 3-diaxial orientation of two methyl groups. X-ray crystallographic studies on 19 and 20 confirm the stereochemical assignments

A Prototype Implementation of a TTP/C Controller

The SAE has classified automotive electronics into two major categories, body electronics and system electronics. The latter (SAE class C) comprises safety critical functions that are of vital importance for the movement of the vehicle. This paper presents a prototype implementation of TTP, a time-triggered communication system developed for this type of applications. The main purpose of the prototype is to provide a means for verifying the concepts of TTP

Triage and Allocation of Neurocritical Care Resources During the COVID 19 Pandemic - A National Survey

Objective: In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited. Methods: A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons). Results: Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98%), the state of health before admission (96%), SOFA-score (85%) and patient age (69%). Interestingly, other principles of allocation, such as a treatment of “youngest first” (61%) and members of the healthcare sector (50%) were also noted. While these were the most accepted parameters affecting the triage of patients, a “first-come, first-served” principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team. Conclusions: The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU

Biosphere-atmosphere interactions of ammonia with grasslands: Experimental strategy and results from a new European initiative

A new study to address the biosphere-atmosphere exchange of ammonia (NH3) with grasslands is applying a European transect to interpret NH3 fluxes in relation to atmospheric conditions, grassland management and soil chemistry. Micrometeorological measurements using the aerodynamic gradient method (AGM) with continuous NH3 detectors are supported by bioassays of the NH3 `stomatal compensation point' (s). Relaxed eddy accumulation (REA) is also applied to enable flux measurements at one height; this is relevant to help address flux divergence due to gas-particle inter-conversion or the presence of local sources in a landscape. Continuous measurements that contrast intensively managed grasslands with semi-natural grasslands allow a scaling up from 15 min values to seasonal means. The measurements demonstrate the bi-directional nature of NH3 fluxes, with typically daytime emission and small nocturnal deposition. They confirm the existence of enhanced NH3 emissions (e.g. 30 g N ha–1 d–1) following cutting of intensively managed swards. Further increased emissions follow fertilization with NH4NO3 (typically 70 g N ha–1 d–1). Measurements using REA support these patterns, but require a greater analytical precision than with the AGM. The results are being used to develop models of NH3 exchange. `Canopy compensation point' resistance models reproduce bi-directional diurnal patterns, but currently lack a mechanistic basis to predict changes in relation to grassland phenology. An advance proposal here is the coupling of s to dynamic models of grassland C–N cycling, and a relationship with modelled plant substrate-N is shown. Applications of the work include incorporation of the resistance models in NH3 dispersion modelling and assessment of global change scenarios