Syntheses of the New Indole Derivatives Related to Indomethacin

Syntheses and properties of the new indole derivatives 18-33, being potential antiinflammatoric agents, are described. 1-p-Chlorobenzoyl- 2-methyl-3-(2\u27-methyl-4\u27-nitroimidazol-1\u27-yl)-5-methoxyindole (32) have been found to possess pronounced antiinflammatoric activity and very low ulcerogenity. Attempting preparation of N-benzoylindole derivative 38 via sigmatropic rearrangement of the open chain precursor 35, as a model procedure for the new synthesis of indomethacin, very low yields on the desired cyclic product 38 have inevitably been obtained

Chiral 1,4-Benzodiazepines. VIII. Concerning the Rate of WD Exchange and Optical Stability of the Chiral Centre C(3).

Various chiral substituted 1,4-benzodiazepin-2-ones with 3- -acyloxy (general formula I), 3-hydroxy- and 3-alkoxy (general formula II), 3-alkyl (general formula III) and 3-quaternary ammonium (general formula IV) groups as substituents were subjected to C(3)-H-D exchange rate measurements in order to obtain information on the optical stability of the chiral centre and on the mechandsm of racemization. Only type IV compounds (IVa-j) exhibited H/D exchange, but acid catalyzed racemization took place in type I and II compounds, indkating some other mechani. sms in this process. Type III compounds as free bases (IIIa-c), N4-protonated acids, or N4-oxides (III, e; f) underwent no H/D exchange and are optically sfable as well. In cases whe,re deprotonation- reprotonation mechanism of racemization can be excluded two other mechanisms are discussed, i. e. acid-\u27catalyzed ring-chain tautomerism and identity substitution with alkoxide ion

N 1-Substitution in 2-Methyl-4(5)-Nitroimidazole. II.

During the syntheses of some new derivatives of 2-methyl-4(5)nitroimidazole with potential antitrichomonal activity, we have noticed that the substitution on N 1 did not always depend on the pH of the medium, as it has been stated by Pyman1- 4 and Grimison et al.5- 8 • Therefore, we have approached the syste matic investigations of the influence of pH on the formation of t h e 4-nitro and 5-nitroisomers of N1- s ubstituted 2-methyl-4(5)-nitroimidazole. The results obtained indicate that the conclusion of Pyman1- 4 is valid only when strongly alkylated agents are applied, e. g. dialkylsulphates and alkyl tosylates9, since, with other alkylated agents this conclusion could be applied only with restrictions· In addition, we have measured pK:i constants for some isomer pairs prepared, in order to apply the statem ent of Grimison et al.6 that the tautomer ratio, calculated from pKa values, determines the ratio of the isomers in the product mixture . In spite of the fact that the pKa measurements were in goo d accordance with some earlier perform e d6 ,10,15, N 1-substitution with a number of alkylating agents indicate that the statement of Grimison et al.5- 8 is of importance only for alkylation with dimethylsulphate under strictly d e termined conditions

Chiral 1,4-Benzodiazepines. X. Further Investigations of Configurational Stability of the Chiral Centre C(3)

For various at C(3)-chiral 1,4-benzodiazepin-2-ones rate determinations of racemisation (ka.- for C(3)-0CH3 derivative ( + )-1), degenerate nucleophilic exchange (k0 - for rac. 1 and rac. 2), and solvolysis (k5 - for C(3)-hemisuccinyl derivative 4) have been performed. These investigations revealed; (a) retention of .configuration during methanolysis of ( + )-3, (b) slow racemisation of ( + )-1 during solvolytic degenerate nucleophilic substitution (kefko. - - 4), (c} no participation of SNl retentive reaction, possible via intramolecular transfer of the methoxy group within intermediary compounds 4-6, (d) thermodi:namic parameters for racemisation of ( + )-1 between 20-40 °c; liH"" = 18.0 ± 0.8 kcal/moll**, liS"" = = - 7.2 ± 2.5 e. u.*** Mechanistic scheme is offered which accounts for all experimental results. The effect of the electrocyclic equilibrium on the electronic structure of N(4) protonated benzodiazepines, and its possible consequences for their mechanisms of biological activity on the central nervous system (CNS), have briefly been discussed

The effect of hot days on occupational heat stress in the manufacturing industry: implications for workers' well-being and productivity

Climate change is expected to exacerbate heat stress at the workplace in temperate regions, such as Slovenia. It is therefore of paramount importance to study present and future summer heat conditions and analyze the impact of heat on workers. A set of climate indices based on summer mean (Tmean) and maximum (Tmax) air temperatures, such as the number of hot days (HD: Tmax above 30 °C), and Wet Bulb Globe Temperature (WBGT) were used to account for heat conditions in Slovenia at six locations in the period 1981–2010. Observed trends (1961–2011) of Tmean and Tmax in July were positive, being larger in the eastern part of the country. Climate change projections showed an increase up to 4.5 °C for mean temperature and 35 days for HD by the end of the twenty-first century under the high emission scenario. The increase in WBGT was smaller, although sufficiently high to increase the frequency of days with a high risk of heat stress up to an average of a third of the summer days. A case study performed at a Slovenian automobile parts manufacturing plant revealed non-optimal working conditions during summer 2016 (WBGT mainly between 20 and 25 °C). A survey conducted on 400 workers revealed that 96% perceived the temperature conditions as unsuitable, and 56% experienced headaches and fatigue. Given these conditions and climate change projections, the escalating problem of heat is worrisome. The European Commission initiated a program of research within the Horizon 2020 program to develop a heat warning system for European workers and employers, which will incorporate case-specific solutions to mitigate heat stress.The work was supported by the European Union Horizon 2020 Research and Innovation Action (Project number 668786: HEATSHIELD)

The HEAT-SHIELD project — Perspectives from an inter-sectoral approach to occupational heat stress

Objectives: To provide perspectives from the HEAT-SHIELD project (www.heat-shield.eu): a multi-national, inter-sectoral, and cross-disciplinary initiative, incorporating twenty European research institutions, as well as occupational health and industrial partners, on solutions to combat negative health and productivity effects caused by working on a warmer world. Methods: In this invited review, we focus on the theoretical and methodological advancements developed to combat occupational heat stress during the last five years of operation. Results: We outline how we created climate forecast models to incorporate humidity, wind and solar radiation to the traditional temperature-based climate projections, providing the basis for timely, policy-relevant, industry-specific and individualized information. Further, we summarise the industry-specific guidelines we developed regarding technical and biophysical cooling solutions considering effectiveness, cost, sustainability, and the practical implementation potential in outdoor and indoor settings, in addition to field-testing of selected solutions with time-motion analyses and biophysical evaluations. All recommendations were adjusted following feedback from workshops with employers, employees, safety officers, and adjacent stakeholders such as local or national health policy makers. The cross-scientific approach was also used for providing policy-relevant information based on socioeconomic analyses and identification of vulnerable regions considered to be more relevant for political actions than average continental recommendations and interventions. Discussion: From the HEAT-SHIELD experiences developed within European settings, we discuss how this inter-sectoral approach may be adopted or translated into actionable knowledge across continents where workers and societies are affected by escalating environmental temperatures. © 202