Regioselective Synthesis of New Family of 2-Substituted 1,2,3-Triazoles and Study of Their Fluorescent Properties.

Modification of 5-aryl-4-trifluoroacetyltriazoles at the NH-moiety was investigated. Screening of the alkylation conditions revealed that using Na2CO3 as a base and DMF as a solvent of 2-substituted triazoles can be preferentially prepared in up to 86% yield. In the best cases, the amount of minor 1-alkyl isomer was less than 6%. SNAr reaction of the 5-aryl-4-trifluoroacetyltriazoles with aryl halides having electron-withdrawing groups led to regiospecific formation of 2-aryltriazoles isolated in good-to-high yields. Chan-Lam reaction of the 5-aryl-4-trifluoroacetyltriazoles with boronic acids afforded 2-aryltriazoles as single isomers in up to 89% yield. The subsequent reaction of the prepared 2-aryltriazoles with primary and secondary amines gave a set of amides of 4-(2,5-diaryltriazolyl)carboxylic acid. The fluorescent properties of the prepared 2-substituted derivatives of triazoles were investigated to demonstrate their utility as new efficient luminophores having more than 60% quantum yields.

Acid-Switchable Synthesis of Trifluoromethylated Triazoles and Isoxazoles via Reaction of CF3-Ynones with NaN3: DFT Study of the Reaction Mechanism.

A detailed study of the reaction of CF3-ynones with NaN3 was performed. It was found that the reaction permits the selective synthesis of either 4-trifluoroacetyltriazoles or 5-CF3-isoxazoles. The chemoselectivity of the reaction was switchable via acid catalysis. The reaction of CF3-ynones with NaN3 in EtOH produced high yields of 4-trifluoroacetyltriazoles. In contrast, the formation of 5-CF3-isoxazoles was observed under catalysis by acids. This acid-switchable procedure can be performed at sub-gram scale. The possible reaction mechanism was supported by DFT calculations. The synthetic utility of the prepared 4-trifluoroacetyltriazoles was demonstrated.

Synthesis and Reactions of 3-Halogenated 2-CF3-Indoles.

Halogenation of 2-trifluoromethylindole afforded 3-chloro-, 3-bromo- and 3-iodo derivatives in up to 98% yield. Methyl-, benzyl- and tosyl-groups can be installed at the nitrogen atom of prepared indoles in high yields by base catalyzed reaction with the corresponding alkylating (sulfonylating) reagents. A high synthetic utility of the prepared haloindoles in the reaction with various nucleophilies was shown. The reaction with 4-methylthiophenol and copper cyanide afforded the corresponding sulfides and nitriles in high yield. Palladium catalyzed cross-coupling with phenyl boronic acid and phenylacetylene gave the corresponding 3-phenyl-2-CF3-indoles and acetylenic derivatives in 72-98% yield.

α,ß-Disubstituted CF3-Enones as a Trifluoromethyl Building Block: Regioselective Preparation of Totally Substituted 3-CF3-Pyrazoles.

An efficient pathway toward a novel class of trifluoromethyl building blocks was elaborated. The reaction of α-CF3-enamines with arylaldehydes resulted in direct synthesis of α,ß-diaryl-CF3-enones isolated in up to 93% yield as E-isomers. The possible reaction mechanism was proposed using the Zimmerman-Traxler model. The reaction of α,ß-diaryl-CF3-enones with hydrazines opens a novel pathway to trifluoromethylated pyrazolines. Oxidation of pyrazolines with DDQ opened access to totally regioselective preparation of 3-CF3-pyrazoles isolated in high yield. Using this strategy, 4-arylated derivatives of known drugs Celebrex, Mavacoxib, and SC-560 can be synthesized.

Synthesis of 2-trifluoromethylated quinolines from CF3-alkenes.

α-CF3-enamines can be prepared by the reaction of pyrrolidine with the corresponding haloalkenes. The prepared enamines react with 2-nitrobenzaldehydes to give ortho-nitro-substituted α,ß-diaryl-CF3-enones highly stereoselectively in up to 88% yield. Subsequent reduction of the nitro-group by an Fe-AcOH system promotes intramolecular cyclization to afford 2-CF3-3-arylquinolines in up to 99% isolated yield. High synthetic utility of all synthetic steps of the sequence was shown. A one-pot procedure was developed to give the target trifluoromethylated quinolines directly from enamines or haloalkenes.

An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes.

The catalytic olefination reaction of 2-nitrobenzaldehydes with CF3CCl3 afforded stereoselectively trifluoromethylated ortho-nitrostyrenes in up to 88% yield. The reaction of these alkenes with pyrrolidine permits preparation of α-CF3-ß-(2-nitroaryl) enamines. Subsequent one pot reduction of nitro-group by Fe-AcOH-H2O system initiated intramolecular cyclization to afford 2-CF3-indoles. Target products can be prepared in up to 85% yields. Broad synthetic scope of the reaction was shown as well as some followed up transformations of 2- CF3-indole.

An Efficient Synthesis of 2-CF3-3-Benzylindoles.

The reaction of α-CF3-ß-(2-nitroaryl) enamines with benzaldehydes afforded effectively α,ß-diaryl-CF3-enones having nitro group. Subsequent reduction of nitro group by NH4HCO2-Pd/C system initiated intramolecular cyclization to give 2-CF3-3-benzylindoles. Target products can be prepared in up to quantitative yields. Broad synthetic scope of the reaction was shown. Probable mechanism of indole formation is proposed.

One-Pot Metal-Free Synthesis of 3-CF3-1,3-Oxazinopyridines by Reaction of Pyridines with CF3CO-Acetylenes.

The reaction of pyridines with trifluoroacetylated acetylenes was investigated. It was found that the reaction of various pyridines with two molecules of CF3CO-acetylenes proceeds under mild metal-free conditions. As a result, efficient stereoselective synthesis of 3-arylethynyl-3-trifluoromethyl-1,3-oxazinopyridines was elaborated. Target heterocycles can be prepared in up to quantitative yields.

Chord length sampling with memory effects for spatially heterogeneous Markov media: Application to the rod model.

In this work we propose a modified Chord Length Sampling (CLS) algorithm, endowed with two layers of "memory effects," aimed at solving particle transport problems in one-dimensional spatially nonhomogeneous Markov media. CLS algorithms are a family of Monte Carlo methods which account for the stochastic nature of the media by sampling on-the-fly the random interfaces between material phases during the particle propagation. The possibility for the particles to remember the last crossed interfaces increases the accuracy of these models with respect to reference solutions obtained by solving the Boltzmann equation on a large number of realizations of the Markov media. In previous investigations, CLS models with memory have been tested exclusively for spatially uniform stochastic media: in this paper we extend this class of Monte Carlo methods to the case of spatially nonhomogeneous configurations. The effectiveness and the robustness of the modified CLS are probed considering several benchmark problems with varying material cross sections and Markov media densities. The obtained results are a stepping stone towards a generalization to three-dimensional models.

Diagnostic predictivity of transtubular potassium gradient for primary hypoadrenocorticism in hyperkalemic dogs: a cross-sectional study.

OBJECTIVES: Transtubular potassium gradient has never been evaluated in the diagnosis of primary hypoadrenocorticism in dogs. The objective of this study is to evaluate the diagnostic utility of transtubular potassium gradient for the diagnosis of primary hypoadrenocorticism in dogs with serum K+ > 5.5 mol/L. MATERIALS AND METHODS: Cross-sectional study including dogs with primary hypoadrenocorticism and dogs with other disease. Differences in signalment and laboratory parameters between groups were assessed by binary logistic regression modelling. Variables significantly associated with primary hypoadrenocorticism were evaluated for their diagnostic accuracy of this condition by receiver operator characteristic curve analysis and by multivariable logistic regression analysis, respectively. RESULTS: Dogs with primary hypoadrenocorticism (n=39) were significantly younger than hyperkalemic dogs without primary hypoadrenocorticism (n=41). Moreover they had higher serum and urinary concentrations of Na+ and Na+ :K+ , but lower transtubular potassium gradient than hyperkalemic dogs without hypoadrenocorticism. Serum Na+ (sNa+ ) had the highest diagnostic accuracy (area under the curve [AUC]: 0.87, 95% confidence interval, 0.78 to 0.96), followed by the transtubular potassium gradient (AUC: 0.81, 0.72 to 0.91), however the accuracy of the two AUCs was not statistically different. The transtubular potassium gradient-sNa+ additive index (i.e. transtubular potassium gradient+sNa+ /10) had a greater accuracy (AUC: 0.88, 0.79 to 0.94) than transtubular potassium gradient or sNa+ , although it was not statistically superior to the latter. The multivariable logistic regression model showed that transtubular potassium gradient (adjusted odds ratio [aOR]: 0.51, 0.3 to 0.84), sNa+ (aOR: 0.86, 0.78 to 0.95) and spayed female (aOR: 24.96, 2.32 to 267.66) were associated with primary hypoadrenocorticism. CLINICAL SIGNIFICANCE: Transtubular potassium gradient-sNa+ additive index can contribute to decision-making on diagnosis of primary hypoadrenocorticism in dogs presenting with hyperkalaemia.

Collision-number statistics for transport processes.

Physical observables are often represented as walkers performing random displacements. When the number of collisions before leaving the explored domain is small, the diffusion approximation leads to incongruous results. In this Letter, we explicitly derive an explicit formula for the moments of the number of particle collisions in an arbitrary volume, for a broad class of transport processes. This approach is shown to generalize the celebrated Kac formula for the moments of residence times. Some applications are illustrated for bounded, unbounded and absorbing domains.

Modular Construction of Functionalized 2-CF3-Indoles.

The reaction of α-CF3-ß-(2-nitroaryl)enamines with benzaldehydes led to nitro-substituted α,ß-diaryl-CF3-enones in high yield. Subsequent reduction of the nitro-group to the amino moiety by the Pd/C-NH4HCO2 system resulted in intramolecular cyclization to form a 5-membered hemiaminal which is stabilized by the presence of a CF3-group. The reaction of this hemiaminal with various nucleophiles afforded functionalized 2-CF3-indoles isolated in up to quantitative yields. High efficiency and broad synthetic scope of all steps of the sequence were demonstrated. A possible mechanism of the reaction is discussed.

Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14-8.23; P<0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19-3.77; P=0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08-3.47; P=0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10-5.50; P=0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30-0.72; P=0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01-1.04; P<0.001) and age (OR, 1.17; 95% CI, 1.08-1.26; P<0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54-0.69) and a specificity of 0.63 (95% CI, 0.59-0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.

Continuous-time random-walk approach to normal and anomalous reaction-diffusion processes.

We study the dynamics of a radioactive species flowing through a porous material, within the continuous-time random-walk (CTRW) approach to the modeling of stochastic transport processes. Emphasis is given to the case where radioactive decay is coupled to anomalous diffusion in locally heterogeneous media, such as porous sediments or fractured rocks. In this framework, we derive the distribution of the number of jumps each particle can perform before a decay event. On the basis of the obtained results, we compute the moments of the cumulative particle distribution, which can be then used to quantify the overall displacement and spread of the contaminant species.

Low ratios of sodium to potassium in the serum of 238 dogs.

Serum sodium:potassium (Na:K) ratios are often reported in biochemical studies of dogs, although their value has not been assessed. The aims of this study were to identify diseases associated with a low Na:K ratio in dogs and to compare their prevalence with the prevalence in dogs from the same referral hospital with normal Na:K ratios. A total of 238 dogs with a Na:K ratio less than 27 were identified from medical records. Sample contamination with edta was suspected in 74 cases (31 per cent) and these and two cases that had been supplemented with potassium were removed from the analysis. The remaining 162 cases and 147 control dogs were divided into five categories depending on the organ system affected. Among the cases there were significantly more in the endocrine category than among the control dogs. Hypoadrenocorticism was the most single common cause of a low Na:K ratio and affected 27 (16.7 per cent) of the cases. Other clinical problems associated with low Na:K ratios included different urogenital, cardiorespiratory and gastrointestinal diseases.

Clinical and neurological characteristics of aortic thromboembolism in dogs.

OBJECTIVES: To characterise the clinical presentation and neurological abnormalities in dogs affected by aortic thromboembolism. METHODS: The medical records of 13 dogs diagnosed with aortic thromboembolism as the cause of the clinical signs, and where a complete neurological examination was performed, were reviewed retrospectively. RESULTS: The onset was acute in only four dogs, chronic in five dogs (with all of these presenting as exercise intolerance) or chronic with acute deterioration in four dogs. Dogs with an acute onset of clinical signs were more severely affected exhibiting neurological deficits, while dogs with a chronic onset of disease predominantly presented with the exercise intolerance and minimal deficits. The locomotor deficits included exercise intolerance with pelvic limb weakness (five of 13), pelvic limb ataxia (one of 13), monoparesis (two of 13), paraparesis (two of 13), non-ambulatory paraparesis (two of 13) and paraplegia (one of 13). There was an apparent male predisposition and the cavalier King charles spaniel was overrepresented. CLINICAL SIGNIFICANCE: The rate of onset of clinical signs appears to segregate dogs affected by aortic thromboembolism into two groups, with different clinical characteristics and outcomes. Dogs with an acute onset of the clinical signs tend to be more severely affected, while dogs with a chronic onset predominantly present with exercise intolerance. It is therefore important to consider aortic thromboembolism as a differential diagnosis in dogs with an acute onset of pelvic limb neurological deficits and in dogs with longer standing exercise intolerance.

Fractional Laplacian in bounded domains.

The fractional Laplacian operator -(-delta)(alpha/2) appears in a wide class of physical systems, including Lévy flights and stochastic interfaces. In this paper, we provide a discretized version of this operator which is well suited to deal with boundary conditions on a finite interval. The implementation of boundary conditions is justified by appealing to two physical models, namely, hopping particles and elastic springs. The eigenvalues and eigenfunctions in a bounded domain are then obtained numerically for different boundary conditions. Some analytical results concerning the structure of the eigenvalue spectrum are also obtained.

Association Between Pancreatitis and Immune-mediated Haemolytic Anaemia in Cats: A Cross-sectional Study.

In most cases, the underlying causes of feline pancreatitis and feline immune-mediated haemolytic anaemia (IMHA) remain unknown. Following the observation that some cats present with both diseases concurrently, the aim of this cross-sectional study was to investigate if the two disorders were associated statistically in this species. A residency case log of all cases seen at the Small Animal Hospital, University of Glasgow, Glasgow, UK, between July 2004 and December 2007, was used as the database for this study and an association between these two disorders was assessed by Fisher's exact test. Of the 155 sick cats included in the study, nine were diagnosed at the time of presentation with pancreatitis (prevalence of 5.8%) and 11 with IMHA (prevalence of 7.1%). In three of these cats both conditions were present concurrently at the time of presentation (prevalence of 1.9%). A significant association between these two disease was found (Odds Risk 8.63, exact 95% confidence interval 1.15-49.31, P = 0.0178). Two possible biological explanations for the statistical association found between these two diseases are that one of these conditions may represent the cause for the onset of the other or that an underlying disorder of the immune system may concurrently target feline red blood cells and the exocrine pancreas.

Hemostatic Findings in Ascitic Fluid: A Cross-Sectional Study in 70 Dogs.

BACKGROUND: Ascitic fluids of horses and humans have fibrinolytic activity, independent of the underlying mechanism of fluid formation. OBJECTIVE: To determine whether coagulation and fibrinogenolytic/fibrinolytic activity (ie, low fibrinogen and increased fibrin-fibrinogen degradation products [FDPs], D-dimer, or both) occur in all types of ascitic fluid in dogs. ANIMALS: A total of 70 client-owned dogs with ascites. METHODS: In this cross-sectional study, dogs were categorized based on the pathophysiology of fluid formation into 4 groups: transudates due to decreased osmotic pressure, transudates due to increased hydrostatic pressure, exudates, and hemorrhagic ascites. Fibrinogen, FDPs, and D-dimer concentrations were measured and then compared in both ascitic fluid and plasma. RESULTS: Ten dogs had transudates due to decreased colloid osmotic pressure, 18 had transudates due to increased hydrostatic pressure, 13 had exudates, and 29 had hemorrhagic ascites. Ascitic fibrinogen concentrations (n = 70) were significantly lower (median = 59 mg/dL; range: 59-122 mg/dL) than those in the plasma (median = 168 mg/dL, range: 59-879 mg/dL; P < .0001). Ascitic FDPs concentrations (n = 70) were significantly higher (<5 µg/mL: 3/70 dogs, ≥5 to <20 µg/mL: 11/70 dogs, ≥20 µg/mL: 56/70 dogs) than those in the plasma (<5 µg/mL: 17/70 dogs, ≥5 to <20 µg/mL: 28/70 dogs, ≥20 µg/mL: 25/70 dogs; P < .0001). Ascitic D-dimer concentrations (n = 70) were significantly higher (median = 3.98 µg/mL, range: 0.02-9.19) than those in the plasma (median = 0.11 µg/mL, range: 0.01-4.08; P < .0001). Analysis of the data for each of the 4 different types of ascites showed similar results to those of all the data analyzed together. CONCLUSIONS AND CLINICAL IMPORTANCE: Ascitic fluid of dogs has evidence of coagulation activation and fibrinogenolytic/fibrinolytic activity and that this phenomenon occurs independent of the underlying mechanism that leads to the formation of ascites.

Finite-size effects and percolation properties of Poisson geometries.

Random tessellations of the space represent a class of prototype models of heterogeneous media, which are central in several applications in physics, engineering, and life sciences. In this work, we investigate the statistical properties of d-dimensional isotropic Poisson geometries by resorting to Monte Carlo simulation, with special emphasis on the case d=3. We first analyze the behavior of the key features of these stochastic geometries as a function of the dimension d and the linear size L of the domain. Then, we consider the case of Poisson binary mixtures, where the polyhedra are assigned two labels with complementary probabilities. For this latter class of random geometries, we numerically characterize the percolation threshold, the strength of the percolating cluster, and the average cluster size.