Squaramide-catalyzed asymmetric regioselective allylic alkylation of 4-aminopyrazolones with Morita-Baylis-Hillman carbonates.

An efficient squaramide-catalyzed asymmetric allylic alkylation of 4-aminopyrazolones with various MBH carbonates via different pathways has been described. This method provides access to a series of pyrazolone derivatives bearing a nitrogen-containing quaternary stereocenter in high yields with excellent enantioselectivities and regioselectivities under mild conditions. In addition, we utilized the target products to construct a range of bi-heterocyclic skeletons through [3 + 2] cycloadditions. These novel hybrid heterocycles would be promising candidates for drug-discovery programs and chemical biology.

DMAP-Catalyzed [4+3] Spiroannulation of Pyrazolone-Derived Morita-Baylis-Hillman Carbonates with N-(o-Chloromethyl)aryl Amides to Forge Spiro[pyrazolone-azepine] Scaffolds.

A novel DMAP-catalyzed [4+3] spiroannulation of pyrazolone-derived Morita-Baylis-Hillman carbonates with N-(o-chloromethyl)aryl amides was developed. This reaction led to the assembly of medicinally relevant pyrazolone and azepine nuclei into a structurally new spirocyclic scaffold, and a diverse array of spiro[pyrazolone-azepine] products were afforded in good to excellent yields (up to 93%) with a wide substrate scope (23 examples) under mild conditions. Moreover, a gram-scale reaction and product transformations were conducted, which further increased the diversity of products.

Desymmetrization of Prochiral N-Pyrazolyl Maleimides via Organocatalyzed Asymmetric Michael Addition with Pyrazolones: Construction of Tri-N-Heterocyclic Scaffolds Bearing Both Central and Axial Chirality.

The desymmetrization of N-pyrazolyl maleimides was realized through an asymmetric Michael addition by using pyrazolones under mild conditions, leading to the formation of a tri-N-heterocyclic pyrazole-succinimide-pyrazolone assembly in high yields with excellent enantioselectivities (up to 99% yield, up to 99% ee). The use of a quinine-derived thiourea catalyst was essential for achieving stereocontrol of the vicinal quaternary-tertiary stereocenters together with the C-N chiral axis. Salient features of this protocol included a broad substrate scope, atom economy, mild conditions and simple operation. Moreover, a gram-scale experiment and derivatization of the product further illustrated the practicability and potential application value of this methodology.

Palladium-Catalyzed Stereoselective Construction of 1,3-Stereocenters Displaying Axial and Central Chirality via Asymmetric Alkylations.

The concurrent construction of 1,3-stereocenters remains a challenge. Herein, we report the development of stereoselective union of a point chiral center with allenyl axial chirality in 1,3-position by Pd-catalyzed asymmetric allenylic alkylation between racemic allenyl carbonates and indanone-derived ß-ketoesters. Various target products bearing a broad range of functional groups were afforded in high yield (up to 99%) with excellent enantioselectivities (up to 98% ee) and good diastereoselectivities (up to 13:1 dr).

Asymmetric [3+2] spiroannulation of pyrazolone-derived Morita-Baylis-Hillman carbonates with alkynyl ketones: facile access to spiro[cyclopentadiene-pyrazolone] scaffolds.

A tertiary amine-catalyzed asymmetric [3+2] spiroannulation reaction of pyrazolone-derived Morita-Baylis-Hillman carbonates with alkynyl ketones was achieved under mild conditions. This protocol offers a facile approach to chiral spiro[cyclopentadiene-pyrazolone] scaffolds in good to high yields (up to 92%) with good degrees of enantiocontrol (up to 98% ee). In addition, scale-up reaction and transformation of the products were performed to show the synthetic utility of this protocol.

C-4 benzofuranylation of pyrazolones by a metal-free catalyzed indirect heteroarylation strategy.

A metal-free catalyzed indirect heteroarylation of pyrazolones with 2-(3-hydroxy-3,3-diarylprop-1-yn-1-yl) phenols has been developed, and a series of novel 4-benzofuranyl substituted pyrazolone derivatives were obtained in moderate to excellent yields (up to 90%). The process has the salient features of metal-free catalysis, operational simplicity, good substrate compatibility and mild reaction conditions. In particular, the integration of the pyrazolone skeleton and benzofuran scaffold into a single molecule is expected to be of potential interest for medicinal research. In addition, the yield and efficiency are basically maintained in the gram-scale experiment, which makes the practical application of the process more prominent.

Construction of a spiro[pyrazolone-4,2'-pyridoindole] scaffold via a [3 + 3] cycloaddition of 2-indolylmethanol with a 4-aminopyrazolone-derived azomethine ylide.

This work reports a facile [3 + 3] cycloaddition sequence of two important heterocyclic pharmacophores, pyrazolone and 2-indolylmethanol, integrated into a polycyclic hybrid scaffold. In this process, an in situ generated azomethine ylide obtained from 4-aminopyrazolone and benzaldehyde reacts with 2-indolylmethanols to offer spiro[pyrazolone-pyridoindole] scaffolds in high yields with excellent diastereoselectivities. Remarkably, the reaction is carried out at room temperature without any catalyst and base.

The effect and prediction of diurnal temperature range in high altitude area on outpatient and emergency room admissions for cardiovascular diseases.

PURPOSE: Diurnal temperature range (DTR) is a meteorological indicator closely associated with global climate change. Thus, we aim to explore the effects of DTR on the outpatient and emergency room (O&ER) admissions for cardiovascular diseases (CVDs), and related predictive research. METHODS: The O&ER admissions data for CVDs from three general hospitals in Jinchang of Gansu Province were collected from 2013 to 2016. A generalized additive model (GAM) with Poisson regression was employed to analyze the effect of DTR on the O&ER admissions for all cardiovascular diseases, hypertension, ischemic heart disease (IHD) and stoke. GAM was also used to preform predictive research of the effect of DTR on the O&ER admissions for CVDs. RESULTS: There were similar positive linear relationships between DTR and the O&ER visits with the four cardiovascular diseases. And the cumulative lag effects were higher than the single lag effects. A 1 °C increase in DTR corresponded to a 1.30% (0.99-1.62%) increase in O&ER admissions for all cardiovascular diseases. Males and elderly were more sensitivity to DTR. The estimates in non-heating season were higher than in heating season. The trial prediction accuracy rate of CVDs based on DTR was between 59.32 and 74.40%. CONCLUSIONS: DTR has significantly positive association with O&ER admissions for CVDs, which can be used as a prediction index of the admissions of O&ER with CVDs.

An effect of 24-hour temperature change on outpatient and emergency and inpatient visits for cardiovascular diseases in northwest China.

Some studies suggested that 24-h temperature change (TC24) was one of the potential risk factors for human health. However, evidence of the short-term effect of TC24 on outpatient and emergency department (O&ED) visits and hospitalizations for cause-specific cardiovascular diseases (CVDs) is still limited. The aim of this study is to explore the short-term effects of TC24 on O&ED visits and hospitalizations for CVDs in northwest China which is an area with large temperature variation. The O&ED visits records for CVDs of 3 general hospitals and the inpatient records for CVDs of 4 general hospitals were collected from January 1, 2013, to December 31, 2016, in Jinchang City, northwest China. Meteorological and air pollution data were also obtained during the same study period from local meteorological monitoring station and environmental monitoring station, respectively. A generalized additive model (GAM) with Poisson regression was employed to analyze the effects of TC24 on O&ED visits and hospitalizations for CVDs. V-shaped relationship were found between TC24 and O&ED visits and hospitalizations for CVDs, including total CVD, hypertension, coronary heart disease (CHD) and stroke. Stratified analysis showed that men and patients over 65 years old were more susceptible to temperature changes. The estimates in non-heating months were higher than in full year. TC24 can affect the O&ED visits and hospitalizations for CVDs in this study. This study provides useful data for policy makers to better prepare local responses to the impact of changes in temperature on population health.

Corticosteroids Improve Renal Survival: A Retrospective Analysis From Chinese Patients With Early-Stage IgA Nephropathy.

Background: The efficacy and safety of corticosteroids and immunosuppressive therapy remain controversial for the treatment of immunoglobulin A nephropathy (IgAN). This study aimed to evaluate the effects of corticosteroid and immunosuppressant therapy in Chinese patients with early-stage IgAN whose estimated glomerular filtration rate (eGFR) was ≥45 ml/min/1.73 m2 and proteinuria was ≥1 g/24 h at biopsy. Methods: Patients with biopsy-proven IgAN were retrospectively enrolled from four study centers between 2007 and 2016. Patients were regularly followed up for at least 1 year or until the study end point. Patients were categorized into three treatment groups: supportive care (SC), steroids alone (CS), and steroids plus immunosuppressants (IT). The observed responses to therapy included complete remission (CR), partial remission (PR), no response (NR), and end-stage renal disease (ESRD). The primary end point of the current study was defined as a 50% decline in eGFR and/or ESRD. Results: A total of 715 patients (male 47% and female 53%) were recruited and followed up for 44.69 ± 24.13 months. The observed CR rate was 81.8% with corticosteroids alone (CS), 62.7% with corticosteroids + immunosuppresants (IT), and 37% with supportive care alone (SC). Renal outcomes were remarkably better in the CS group compared with the SC and IT groups (the percentage of patients reaching the end point in each group was 4.6 vs. 14.4 vs. 11.5%, respectively; p = 0.001). Moreover, 36 and 80-month renal survival were significantly better for the CS group (98.3 and 86.4%) than for the IT (94.2 and 82.4%) and SC (94.0 and 51.6%) groups. Early CKD stage also presented with better kidney survival (p < 0.001). Renal survival of CKD stage 1 patients was relatively good regardless of the specific treatment regimen. CS and IT treatment significantly improved renal survival for CKD stage 2 patients when compared with the SC group (p < 0.001 and 0.007, respectively). However, renal survival of CKD stage 3a patients was not impacted by any of the three treatment regimens. Subgroup analysis also showed that renal survival of patients with proteinuria >3.5 g, M1, E0, S1, T0, and C0 was significantly better in the CS group than in the SC and IT groups. A multivariate model showed that hypertension, serum creatinine, E1 lesion, and T1/T2 lesion remained independent predictors of poor renal survival. Conclusions: Immunosuppressive therapy does not have further benefit beyond that provided by steroids. Corticosteroids plus optimal supportive care may further be beneficial in treating early-stage IgAN patients in that it could significantly improve the short-term renal outcome.