Thia- and selenaheterocycles by a four-component reaction using elemental sulfur and selenium

The course of the four-component reactions of (2-benzimidazolyl) acetonitrile, carbondisulfide, isothiocyanate, and sulfur and selenium, respectively, is quite different. Whereas in the case of sulfur a tetracyclic [1,3]thiazolo[4 ,5 :4,5]pyrimido[1,6-a]benzimidazol-2(3H)-thione is formed, a zwitterionic 7-(benzimidazolium-2-yl)-[1,2]thiaselenolo[2,3-b][1,2,4]thiaselenazole-6-thiolate (an azaselenadithiapentalene) is the product in the case of selenium. The structures of the products have been established by X-ray crystallography, and reaction mechanisms for their formation are proposed

Application of diethyl ethynylphosphonate to the synthesis of 3‐phosphonylated β‐lactams via the Kinugasa reaction

Dedicated to Prof. Jacek Młochowski on the occasion of his 80th birthday.The easily available diethyl ethynylphosphonate reacts with diverse aldonitrones under Kinugasa reaction conditions at room temperature, providing 3‐phosphonylated β‐lactams in good yields. In all cases, the reaction led to the trans‐isomer exclusively. The trans‐configuration was assigned based on 1H‐NMR spectroscopic analysis.Authors acknowledge the National Science Center (PL-Cracow) for financial support (Grant OPUS–7 (UMO– 2014/13/B/ST5/04004))

Importance of single or blended polymer types for controlled in vitro release and plasma levels of a somatostatin analogue entrapped in PLA/PLGA microspheres.

The aim of the work was to develop biodegradable microspheres for controlled delivery of the somatostatin analogue vapreotide and maintenance of sustained plasma levels over 2–4 weeks after a single injection in rats. Vapreotide was microencapsulated into end-group capped and uncapped low molecular weight poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) by spray-drying and coacervation. Microspheres were prepared from single and blended (1:1) polymer types. The microparticles were characterized for peptide loading, in vitro release and pharmocokinetics in rats. Spray-drying and coacervation produced microspheres in the size range of 1–15 and 10–70 μm, respectively, and with encapsulation efficiencies varying between 46% and 87%. In vitro release of vapreotide followed a regular pattern and lasted more than 4 weeks, time at which 40–80% of the total dose were released. Microspheres made of 14-kDa end-group uncapped PLGA50:50 or 1:1 blends of this polymer with 35 kDa end-group uncapped PLGA50:50 gave the best release profiles and yielded the most sustained plasma levels above a pre-defined 1 ng/ml over approximately 14 days. In vitro/in vivo correlation analyses showed for several microsphere formulations a linear correlation between the mean residence time in vivo and the mean dissolution time (r=0.958) and also between the amount released between 6 h and 14 days and the AUC6h–14d (r=0.932). For several other parameters or time periods, no in vitro/in vivo correlation was found. This study demonstrates that controlled release of the vapreotide is possible in vivo for a duration of a least 2 weeks when administered i.m. to rats. These results constitute a step forward towards a twice-a-month or once-a-month microsphere-formulation for the treatment of acromegaly and neuroendocrine tumors

Generation and reactions of thiocarbonyl S-(2,2,2-trifluoroethanides). Synthesis of trifluoromethylated 1,3-dithiolanes, thiiranes and alkenes

The ‘in situ’ generated 1,1,1-trifluorodiazoethane reacts with thioketones as C=S dipolarophiles in a two-phase system (DCM/H$_2$O) at room temperature to yield trifluoromethylated 2,5-dihydro-1,3,4-thiadiazoles. Whereas stable crystalline products were obtained with cyclobutanethiones, the reaction with aromatic and heteroaromatic thioketones occured with spontaneous elimination of nitrogen. The formation of sterically crowded 4,4,5,5-tetrahetaryl-1,3-dithiolanes indicates that thiocarbonyl S-methanides are formed immediately and entered formal [3+2]-cycloaddition as diradical species with the starting thioketone. A protocol for the preparation of 3,3,3-trifluoropropene derivatives starting from corresponding thioketones and 1,1,1-trifluorodiazoethane is also presented

A novel access to 4-trifluoromethyl-1,3-thiazole derivatives via an intermediate thiocarbonyl ylide

A Lewis acid catalyzed reaction of trifluoroacetyldiazomethane (CF3COCHN2) with thiourea occurs in boiling THF solution in the presence of BF3·OEt2 yielding 2-amino-4-trifluoromethyl-1,3-thiazole in a fair yield. Analogous reactions with aromatic thioamides, performed in the presence of a mesylchloride/triethylamine mixture as a dehydrating agent led to the corresponding 2-aryl-4-trifluoromethyl-1,3-thiazoles. Aromatic thioamides also react with CF3COCHN2 under MW irradiation, and after 2 min, the corresponding 1,3-thiazoles were obtained in fair yields. The obtained fluorinated 2-amino-1,3-thiazole was used for the reactions with selected N-alkylating and N-acylating reagents to give trifluoromethylated analogues of commonly known pharmaceuticals with 1,3-thiazole structures (Fanetizole and Lotifazole)

In vitro and in vivo evaluation of a somatostatin analogue released from PLGA microspheres

The purpose of this study was to design poly(lactide-co-glycolide) (PLGA) microspheres for the continuous delivery of the somatostatin analogue, vapreotide, over 2–4 weeks. The microspheres were produced by spray-drying and the desired characteristics, i.e. high encapsulation efficiency and controlled release over 2–4 weeks, achieved through optimizing the type of polymer, processing solvent, and co-encapsulated additive. The in vitro release was tested in fetal bovine serum preserved with 0.02% of thiomersal. Furthermore, formulations were injected intramuscularly into rats to obtain pharmacokinetic profiles. Encapsulation efficiency was between 34 and 91%, depending on the particular formulation. The initial peptide release (within 6 h) was lowest, i.e. 1 ng/ml) over 21–28 days in rats was the one made with end-group uncapped PLGA 50:50, the solvent acetic acid and the additive polyethyleneglycol. In conclusion, the optimization of formulation parameters allowed us to produce vapreotide-loaded PLGA microspheres of suitable characteristics for therapeutic use

Frequency, course and correlates of alcohol use from adolescence to young adulthood in a Swiss community survey

BACKGROUND: Few studies have analyzed the frequency of alcohol use across time from adolescence to young adulthood and its outcome in young adulthood. A Swiss longitudinal multilevel assessment project using various measures of psychopathology and psychosocial variables allowed for the study of the frequency and correlates of alcohol use so that this developmental trajectory may be better understood. METHOD: Alcohol use was studied by a questionnaire in a cohort of N = 593 subjects who had been assessed at three times between adolescence and young adulthood within the Zurich Psychology and Psychopathology Study (ZAPPS). Other assessment included questionnaire data measuring emotional and behavioural problems, life events, coping style, self-related cognitions, perceived parenting style and school environment, and size and efficiency of the social network. RESULTS: The increase of alcohol use from early adolescence to young adulthood showed only a few sex-specific differences in terms of the amount of alcohol consumption and the motives to drink. In late adolescence and young adulthood, males had a higher amount of alcohol consumption and were more frequently looking for drunkenness and feeling high. Males also experienced more negative consequences of alcohol use. A subgroup of heavy or problem drinkers showed a large range of emotional and behavioural problems and further indicators of impaired psychosocial functioning both in late adolescence and young adulthood. CONCLUSION: This Swiss community survey documents that alcohol use is problematic in a sizeable proportion of youth and goes hand in hand with a large number of psychosocial problems

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis