Esters with imidazo [1,5-c] quinazoline-3,5-dione ring spectral characterization and quantum-mechanical modeling

1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione reacts with ethyl bromoacetate under mild conditions to give 2-(ethoxycarbonylmethyl)-1-phenyl-6H-imidazo[1,5-c]quinazoline-3,5-dione (MEPIQ) and next 2,6-bis(ethoxycarbonylmethyl)-1-phenylimidazo[1,5-c]quinazoline-3,5-dione (BEPIQ). The products were isolated at high yield and identified on the basis of IR, 1H- and 13C-NMR, UV spectroscopy, and X-ray crystallography. Diester (BEPIQ) can be presented by 16 possible pair of enantiomers. Only one pair of them is the most stable and crystallizes which is shown crystallographic research. Based on quantum-mechanical modeling, with the use of DFT method, which conformers of mono- and diester and why they were formed was explained. It was calculated that 99.93% of the monoester (MEPIQ) is formed at position No. 2 and one pair of the monoester conformers, from six possible, has the largest share (51.63%). These results afforded to limit the number of diester conformers to eight. Unfortunately, the quantum-mechanical calculations performed that their shares are similar. Further quantum-mechanical modeling showed that conformers are able to undergo mutual transformations. As a result only one pair of diester conformers forms crystals. These conformers have substituents in trans position and these substituents are located parallel to imidazoquinazoline ring. This allows for the denser packing of the molecules in the unit cell. © 2017, The Author(s).IGA/FT/2016/004, UTB, Univerzita Tomáše Bati ve ZlíněInterdisciplinary Centre for Mathematical and Computational Modelling in Warsaw [G49-12]; TBU in Zlin [IGA/FT/20017/005

Unprecedented reaction course of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione with 3-M excess of ethylene oxide

The reaction of 1-phenyl-2H,6H-imidazo[1,5-c]quinazolino-3,5-dione (4) with 3-molar excess ethylene oxide was described. The resulting product was characterized by spectroscopic techniques ( 1 H-, 13 C-NMR, IR, and UV) and by X-ray crystallography. It was expected to produce a product of the subsequent reaction in the hydroxyl groups of the initially formed diol—1-phenyl-2,6-bis(2-hydroxyethyl)imidazo[1,5-c]quinazoline-3,5-dione (7) with ethylene oxide (5). However, crystallographic studies revealed that the proper and only product of the reaction is 3-{2-[1,3-bis(2-hydroxyethyl)-2-oxo-4-phenylimidazolidin-5-yl]phenyl}-1,3-oxazolidin-2-one (8). This product was formed by quinazoline ring opening which occurred in the presence of more than 2-molar excess ethylene oxide. In the work, the exemplary reaction mechanism explaining the formation of the unexpected product was proposed. In order to understand the reasons of quinazoline ring opening, the quantum mechanical modeling was performed. Energy of transition states indicated that the reaction with the third mole of ethylene oxide was controlled by kinetics. © 2019, The Author(s).Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw [G49-12]; European Union from the European Regional Development Fund under the Operational Programme Innovative Economy, 2007-2013; DS budget; internal grant of TBU in Zlin [IGA/FT/2017/005

Linear polyurethanes with imidazoquinazoline rings: preparation and properties evaluation

Abstract: In this work, research concerning the synthesis and properties of linear polyurethanes (PUs) with the imidazoquinazoline rings was represented. Reaction conditions of 2,6-bis(2-hydroxyethyl)-1-phenylimida-zo[1,5-c]quinazoline-3,5-dione (BHPIQ) with 1,6-hexamethylene diisocyanate were determined and optimized. These conditions are adapted to reaction of BHPIQ with 4,4′-diphenylmethane diisocyanate and 2,4-toluene diisocyanate. New PUs with imidazoquinazoline rings were characterized by spectral methods ( 1 H-NMR and IR spectroscopies), which confirm their structures. Their molar masses and dispersity index were measured by size exclusion chromatography method. The wide-angle X-ray scattering and differential scanning calorimetry (DSC) studies have shown that all PUs based on BHPIQ are amorphous. Moreover, thermal properties of PUs were investigated by thermogravimetry analysis, standard DSC, and temperature-modulated DSC methods. During thermogravimetric measurements, the exhaust gases were analyzed by FTIR method. Incorporation of imidazoquinazoline ring into the PU chains escalates their glass transition temperature; thus, their heat resistance was enhanced. Furthermore, their degradation rate and the amount of released degradation products were reduced. The investigated properties of the obtained PUs with imidazoquinazoline rings were compared with those ones of suitable PUs based on 1,4-butanediol. Graphical abstract: Linear polyurethanes were obtained in reaction of 1-phenyl-2,6-bis(2-hydroxyethylimidazo[1,5-c]quinazoline-3,5-dione with hexamethylene 1,6-diisocyanate, 4,4′-diphenylmethane diisocyanate and toluene 2,4-diisocyanate. Their composition and structure were confirmed. The phase contents and thermal properties were investigated[Figure not available: see fulltext.]. © 2019, The Author(s).DS budge

Niewłaściwe przepisywanie zredukowanej dawki NOAC w praktyce klinicznej — wyniki Polskiego Rejestru Migotania Przedsionków (POL-AF) u hospitalizowanych pacjentów

Introduction. Prescribing non-vitamin K antagonist oral anticoagulants (NOACs) in a reduced or full dosage is important for providing patients with atrial fibrillation (AF) with efficacious and safe treatment. The study aimed to evaluate the administration frequency of reduced NOAC dosages against the guidelines and analysis of factors predisposing to such a choice in patients with AF included in the Polish Atrial Fibrillation (POL-AF) Registry. Material and methods. The study included 1003 patients with AF treated with reduced dosages of NOACs hospitalized in ten Polish cardiology centers from January to December 2019. The criteria for appropriately reduced NOAC dosages was a dosage reduction of individual NOAC from the clinical studies, which was the basis for their registration. Results. Among the 1003 patients who were treated with a reduced dosage of NOACs, inappropriately reduced dosages were observed in 242 patients (24.1%): in 120 patients (29.3%) treated with rivaroxaban, in 93 patients (33.8%) treated with apixaban and in 29 patients (9.1%) treated with dabigatran (p &lt; 0.0001). Independent predictors of the use of inappropriately reduced dosages of NOACs were heart failure (odds ratio [OR] 1.55, confidence interval [CI]: 1.08–2.22) and hospitalization due to cardiac implantable electronic device (CIED) implantations/reimplantations (OR 2.01, CI: 1.27–3.17). Factors diminishing the chances of using inappropriately reduced dosages of NOACs were age (OR 0.98, CI: 0.97–0.998), vascular disease (OR 0.29, CI: 0.21–0.40) and creatinine clearance (CrCl) &lt; 60 mL/min (OR 0.37, CI: 0.27–0.52). Conclusions. In the group of patients treated with a reduced dosage of NOAC, 24.1% of patients had an inappropriately reduced dosage prescription, most frequently the patients receiving apixaban and rivaroxaban. The factor predisposing to prescribing an inappropriately reduced dosage of NOAC was heart failure and hospitalization due to CIED implantation/reimplantation. Label adherence to NOAC dosage is important to improve clinical outcomes in AF patients, and further investigation is needed to assess the best dosage of NOACs in the AF population.Wstęp. Przepisywanie doustnych przeciwkrzepliwych leków niebędących antagonistami witaminy K (NOAC) w dawce zredukowanej lub pełnej jest istotne dla zapewnienia pacjentom z migotaniem przedsionków (AF) skutecznego i bezpiecznego leczenia. Celem badania było ocenienie częstości stosowania zredukowanych dawek NOAC w stosunku do wytycznych oraz analiza czynników predysponujących do takiego wyboru u pacjentów z AF zarejestrowanych w Polskim Rejestrze Migotania Przedsionków (POL-AF). Materiał i metody. Badanie obejmowało 1003 pacjentów z AF leczonych zredukowanymi dawkami NOAC, hospitalizowanych w 10 polskich ośrodkach kardiologicznych od stycznia do grudnia 2019 roku. Kryterium stosowania odpowiednio zredukowanych dawek NOAC była redukcja dawki indywidualnego leku NOAC na podstawie badań klinicznych, które były podstawą ich rejestracji. Wyniki. Spośród 1003 pacjentów leczonych zredukowanymi dawkami NOAC, nieodpowiednio zredukowane dawki zaobserwowano u 242 pacjentów (24,1%): u 120 pacjentów (29,3%) leczonych rywaroksabanem, u 93 pacjentów (33,8%) leczonych apiksabanem oraz u 29 pacjentów (9,1%) leczonych dabigatranem (p < 0,0001). Niezależnymi czynnikami predykcyjnymi stosowania nieodpowiednio zredukowanych dawek NOAC były: niewydolność serca (iloraz szans [OR] 1,55; przedział ufności [CI]: 1,08–2,22) oraz hospitalizacja związana z wszczepieniem/reimplantacją kardioelektronicznych urządzeń wszczepialnych (CIED) (OR 2,01; CI: 1,27–3,17). Czynnikiem zmniejszającym szanse na stosowanie nieodpowiednio zredukowanych dawek NOAC były: wiek (OR 0,98; CI: 0,97–0,998), choroba naczyniowa (OR 0,29; CI: 0,21–0,40) i klirens kreatyniny (CrCl) < 60 ml/min (OR 0,37; CI: 0,27–0,52). Wnioski. W grupie pacjentów leczonych zredukowaną dawką NOAC, 24,1% pacjentów miało nieodpowiednio przepisane dawki, najczęściej pacjenci otrzymujący apiksaban i rywaroksaban. Czynnikami predysponującymi do przepisywania nieodpowiednio zredukowanej dawki NOAC były niewydolność serca oraz hospitalizacja związana z wszczepieniem/reimplantacją CIED. Przestrzeganie zaleceń dotyczących dawek NOAC jest istotne dla poprawy wyników klinicznych u pacjentów z AF, konieczne jest również dalsze badanie w celu oceny optymalnej dawki NOAC w populacji z AF

Ostry zespół wieńcowy a epidemia COVID-19 — przypadek 85-letniej pacjentki ze świeżym zawałem ściany dolnej

85-year-old woman with a history of myocardial infarction treatedwith percutaneous left anterior descending intervention withdrug eluting stent (DES) implantation in 2004, was admitted tothe Department of Cardiology due to acute coronary syndrome.For about 10 days the patient has complained recurrent pain inthe right hypochondrium, radiating toward chest. Symptomswere accompanied by diarrhea. Moreover, the day beforehospital admission, patient developed fever up to 39˚C. Dueto the current epidemiological situation, the woman was afraidof coronavirus infection from the healthcare professionals aswell as other patients and she did not want see a doctor. Basedon the results of the additional tests, inferior wall myocardialinfarction was diagnosed. Coronary angiography revealed 90%stenosis within the right coronary artery, which was treatedwith angioplasty and DES implantation. There was no complicationsduring the procedure and the post-operative period.This clinical case shows a problem frequently encountered inthe recent months – patients’ fear of reporting to health carefacilities due to SARS-CoV-2 pandemic.Osiemdziesięciopięcioletnia pacjentka, po przebytym zawale serca, leczona angioplastyką gałęzi przedniej zstępującej z implantacją stentu DES w 2004 roku, została przyjęta do kliniki kardiologii z powodu ostrego zespołu wieńcowego. W wywiadzie chora podawała nasilające się od około 1,5 tygodnia bóle w prawym podżebrzu promieniujące do klatki piersiowej. Objawom towarzyszyła biegunka; ponadto dzień przed przyjęciem do szpitala pacjentka zagorączkowała do 39˚C. Z uwagi na panującą sytuację epidemiologiczną chora nie zgłaszała się do lekarza, obawiała się zakażenia koronawirusem od pracowników ochrony zdrowia oraz innych pacjentów. Na podstawie wyników badań dodatkowych rozpoznano świeży zawał ściany dolnej. W koronarografii uwidoczniono 90-procentowe zwężenie prawej tętnicy wieńcowej i jednoczasowo wykonano angioplastykę zwężonego naczynia z implantacją stentu uwalniającego lek. Zabieg i okres pozabiegowy przebiegły bez powikłań. Opisany przypadek kliniczny pokazuje często spotykany w ostatnich miesiącach problem – obawę pacjentów przed zgłaszaniem się do placówek ochrony zdrowia oraz zakażeniem SARS-CoV-2

New diols with imidazoquinazoline ring

The objective of these studies was to synthesize and characterize new diols with an imidazoquinazoline ring. New diols were obtained in reactions of 2,6-bis-(ethoxycarbonylmethyl)-1-phenylimidazo[1,5-c]quinazoline-3,5-dione with excess of ethylene glycol or in reaction of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione with 2-M excess of ethylene oxide. The products were isolated at high yield and characterized by instrumental methods (IR, 1H- and 13C-NMR, MS-ESI, UV, TGA). The structure of 2,6-bis(2-hydroxyethyl)-1-phenylimidazo[1,5-c]quinazoline-3,5-dione (BEFIQ) was also investigated by single-crystal X-ray diffraction. BEFIQ crystallizes in the monoclinic P21/n space group with two molecules in the asymmetric unit of the crystal lattice. The nature of the packing of molecules in the crystal lattice of BEFIQ was investigated by Hirshfeld surface analysis. The described methods enable the synthesis of new diols with an imidazoquinazoline ring. The new diols are quite soluble in typical organic solvents. Therefore, they can be used as raw materials for the synthesis of thermally stable polymers, and they can also have biological activity. © 2017 Elsevier B.V.ERDF, European Regional Development FundEuropean Union from European Regional Development Fund under Operational Programme Innovative Economy; DS budget; DS budget of Department of Organic Chemistry, Faculty of Chemistry, Rzeszow University of Technology; TBU in Zlin [IGA/FT/2017/005

Synthesis, spectroscopic characterization and DFT calculations of monohydroxyalkylated derivatives of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione

Synthesis of new derivatives with an imidazo[1,5-c]quinazoline-3,5-dione ring has been presented. Two new alcohols with the imidazo[1,5-c]quinazoline-3,5-dione ring were obtained and characterized by spectral (1H, 13C NMR, IR and UV) and crystallography methods. A reaction chemoselectivity has been observed with a formation of monohydroxyalkyl derivatives of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione substituted at the 2. nitrogen atom. The absence of derivatives substituted at the 6. nitrogen atom was proven experimentally. The synthesis with chemoselectivity over 99% without control of the substituent effect happens very rarely. The HOMO–LUMO mappings are reported which reveals the different charge transfer possibilities within the molecule of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione in the region of the 2. and the 6. nitrogen atoms. Quantum-mechanical DFT calculations proved to be very useful to explain the reason of selectivity reaction of 1-phenyl-2H,6H-imidazo[1,5-c]quinazoline-3,5-dione with oxiranes. © 2016 Elsevier B.V.Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw [G49-12]; TBU in Zlin [IGA/FT/2016/004

Hybrid nanobiocomposites based on poly(3-hydroxybutyrate) - characterization, thermal and mechanical properties

Poly(3-hydroxybutyrate) is a biopolymer which is used to production of implants in the human body. On the other hand, the physical and mechanical properties of poly(3-hydroxybutyrate) are compared to the properties of isotactic polypropylene what makes poly(3-hydroxybutyrate) possible substitute for polypropylene. Unfortunately, the melting point of poly(3-hydroxybutyrate) is almost equal to its degradation temperature what gives very narrow window of its processing conditions. Therefore, numerous attempts are being made to improve the poly(3-hydroxybutyrate) properties. In the present work, hybrid nanobiocomposites based on poly(3-hydroxybutyrate) as a matrix with the use of organic nanoclay-Cloisite 30B and linear polyurethane as a second filler have been manufactured. The linear polyurethane was based on diphenylmethane 4,4'-diisocyanate and diol with imidazoquinazoline rings. The obtained nanobiocomposites were characterized by X-ray diffraction, scanning and transmission electron microscopies, thermogravimetry, differential scanning calorimetry and their selected mechanical properties were tested. The resulting hybrid nanobiocomposites have intercalated/exfoliated structure. The nanobiocomposites characterize a higher thermal stability and a wider range of processing temperatures compared to the unfilled matrix. The plasticizing influence of nanofillers was also observed. In addition, the mechanical properties of the discussed nanobiocomposites were examined and compared with those ones of the unfilled poly(3-hydroxybutyrate). The new-obtained nanobiocomposites based on poly(3-hydroxybutyrate) containing 1% Cloisite 30B and 5% by mass of the linear of polyurethane characterized the highest improvement of processing conditions. They have the biggest difference between the temperature of degradation and the onset melting temperature, about 100°C. © 2020, Institute of Machine Design and Operation. All rights reserved

Antithrombotic therapy in elderly patients with atrial fibrillation: an analysis of non-treatment predisposing factors - results from the Polish Atrial Fibrillation (POL-AF) registry.

Wstęp: Podeszły wiek wiąże się ze współchorobowością. W większości badań wykazano korzyści leczenia przeciwzakrzepowego w zapobieganiu udarom mózgu u pacjentów w wieku ≥75 lat. Badania przeprowadzono ze względu na niedostateczną reprezentację pacjentów w podeszłym wieku w randomizowanych badaniach kontrolowanych. Celem pracy była ocena częstości stosowania doustnej terapii przeciwzakrzepowej (OAC) u pacjentów w wieku ≥75 lat oraz identyfikacja czynników predysponujących pacjentów z tej grupy do przerwania leczenia. Metody: Badanie opracowano na podstawie polskiego ,wielośrodkowego prospektywnego Polskiego Rejestru Migotania Przedsionków(POL-AF) obejmującego 10 szpitali kardiologicznych (ClinicalTrials.gov: NCT04419012). Rekrutacja trwała od 1 stycznia 2019 r do 1 grudnia 2019. Włączono i analizowano pacjentów w wieku ≥ 75 lat. Wyniki: Grupę badaną stanowiło 1731 pacjentów, z czego 1563 (90,3%) pacjentów otrzymywało OAC, 71 (4,1%) pacjentów otrzymywało lek przeciwpłytkowy, 54 (3,1%) pacjentów otrzymywało heparynę drobnocząsteczkową, a 43 (2,5%) pacjentów nie otrzymywało jakąkolwiek profilaktyki udaru. Średni wiek wynosił 82,2 (5,0) lat. Stworzono modele regresji logistycznej jednoczynnikowej wyboru OAC w porównaniu z brakiem leczenia OAC.Na tej podstawie wytypowano konkretne predyktory wyboru leczenia przeciwkrzepliwego OAC, które uwzgledniono w modelu wieloczynnikowym. Niezależnymi czynnikami predykcyjnymi braku leczenia przeciwkrzepliwego były: niedokrwistość (OR 0,14, 95% CI 0,06-0,35, pBackground: The elderly age is associated with numerous comorbidities. Benefits of antithrombotic treatment regarding the prevention of stroke in patients aged ≥75 were demonstrated in most studies. The studies were undertaken due to elderly patients being underrepresented in randomized controlled trials. The aim of this study was to assess the prevalence of oral anticoagulant (OAC) therapy in patients aged ≥75 and to identify factors that predispose patients in this group for discontinuation of treatment. Methods: The study was based on the multicenter prospective Polish Atrial Fibrillation (POL-AF) registry including patients from 10 cardiology centres in Poland. Recruitment lasted from 1 January 2019 to 1 December 2019. Included and analyzed in the study were patients aged ≥ 75 years. Results: The study group consisted of 1731 patients, with 1563 (90.3%) patients receiving OACs, 71 (4.1%) patients receiving antiplatelets drug, 54 (3.1%) patients receiving low molecular weight heparin, and 43 (2.5%) patients not receiving any stroke prevention. The mean age was 82.2 (5.0) years. Univariable logistic regression models were developed for the choice of OAC versus no treatment. On this basis, specific predictors for the choice of OAC treatment were selected for including in the multivariable model. Independent predictors of no OAC prescription were: anaemia (OR 0.14, 95%CI 0.06-0.35, p &lt; 0.001), history of bleeding(OR 0.26, 95% CI 0.14-0.5, p &lt; 0.001), renal dysfunction (OR 0.42, 95% CI 0.27-0.67, p &lt; 0.001), cancer (OR 0.54, 95% CI 0.3-0.97, p=0.04), and age (OR 0.79, 95% CI 0.67-0.94, p=0.006). Conclusions: Most elderly AF patients received OACs. The factors predisposing to non-use of OACs in these patients included conditions which significantly increased the risk of bleeding complications