Copper-Catalyzed Enantioselective 1,2-Allylation of Azadienes with Allylboronates.

Catalytic asymmetric 1,2-allylation of aurone-derived azadienes is very difficult to achieve due to the driving force for aromatization and the greater steric hindrance of 1,2-addition compared with 1,4-addition. By taking advantage of the ability of nitrogen ligated metal complexes, we successfully demonstrated the first example of copper-catalyzed 1,2-allylation of azadienes with allylboronates for the highly enantioselective synthesis of homoallylic amines. Meanwhile, the enantioenriched 1,4-addition products could also be obtained through a subsequent 3,3-sigmatropic rearrangement of the 1,2-addition products. Extensive DFT calculations were carried out to elucidate the origins of high regioselectivity (1,2- vs 1,4-) and enantioselectivity.

Copper-Catalyzed Asymmetric Allylation of N-Aryl Aldimines.

The copper-catalyzed enantioselective allylation reaction of N-aryl aldimines has been developed using a combination of Cu(OAc)2 and SPINOL-based phosphonamidite. This protocol significantly broadens the substrate scope, such that imines bearing various ortho-substituents on the N-aryl were converted smoothly into homoallylic amines in up to 99% yield and 98% ee. Taking advantage of the diversity of the N-aryl motif, three kinds of N-heterocyclic compounds were constructed, respectively, from the corresponding homoallylic amines in merely one step.

Nickel-Catalyzed Three-Component Alkylarylation of Alkenyl N-Heteroarenes.

A nickel-catalyzed three-component alkylarylation of alkenyl N-heteroarenes with α-bromocarboxylates and aryl boronic acids is reported. The protocol provides a new method to access a variety of N-heteroarene substituted diarylalkanes in moderate to good yields. It features mild reaction conditions, cheap nickel catalyst, readily available substrates, and broad substrate scope.

Synthesis of Cyclopenta[b]indoles via Sc(III)-Catalyzed Annulation of Vinyl Diazoacetates with Indole-Derived Unsaturated Imines.

A Lewis acid Sc(OTf)3-catalyzed annulation reaction of vinyl diazoacetates with in situ formed α,ß-unsaturated imines for the preparation of indole-fused tricyclic rings has been reported. This strategy involves a sequential addition/rebound addition process of vinyl diazoacetates and an in situ dedinitrogenation. This annulation protocol features low-cost catalysts, mild reaction conditions, and facilely prepared substrates.

Cyclization of Vinyl Diazo Compounds with Benzofuran-Derived Azadienes Enabled by NaBArF4.

An unprecedented cycloaddition of vinyl diazo compounds with benzofuran-derived azadienes catalyzed by rarely independently used NaBArF4 has been established. Benzofuran-fused hydropyridines were constructed with excellent yields and high diastereoselectivity via a Na+-catalyzed inverse-electron-demand aza-Diels-Alder reaction. Notably, this transformation also features good compatibility with a one-pot protocol to deliver the spiro[benzofuran-cyclopentene] skeleton, as well as perfect atom economy and simple reaction conditions.

Analysis of Chinese Medical Syndrome Features of Ischemic Stroke Based on Similarity of Symptoms Subgroup / 中国结合医学杂志

OBJECTIVE@#To derive the Chinese medicine (CM) syndrome classification and subgroup syndrome characteristics of ischemic stroke patients.@*METHODS@#By extracting the CM clinical electronic medical records (EMRs) of 7,170 hospitalized patients with ischemic stroke from 2016 to 2018 at Weifang Hospital of Traditional Chinese Medicine, Shandong Province, China, a patient similarity network (PSN) was constructed based on the symptomatic phenotype of the patients. Thereafter the efficient community detection method BGLL was used to identify subgroups of patients. Finally, subgroups with a large number of cases were selected to analyze the specific manifestations of clinical symptoms and CM syndromes in each subgroup.@*RESULTS@#Seven main subgroups of patients with specific symptom characteristics were identified, including M3, M2, M1, M5, M0, M29 and M4. M3 and M0 subgroups had prominent posterior circulatory symptoms, while M3 was associated with autonomic disorders, and M4 manifested as anxiety; M2 and M4 had motor and motor coordination disorders; M1 had sensory disorders; M5 had more obvious lung infections; M29 had a disorder of consciousness. The specificity of CM syndromes of each subgroup was as follows. M3, M2, M1, M0, M29 and M4 all had the same syndrome as wind phlegm pattern; M3 and M0 both showed hyperactivity of Gan (Liver) yang pattern; M2 and M29 had similar syndromes, which corresponded to intertwined phlegm and blood stasis pattern and phlegm-stasis obstructing meridians pattern, respectively. The manifestations of CM syndromes often appeared in a combination of 2 or more syndrome elements. The most common combination of these 7 subgroups was wind-phlegm. The 7 subgroups of CM syndrome elements were specifically manifested as pathogenic wind, pathogenic phlegm, and deficiency pathogens.@*CONCLUSIONS@#There were 7 main symptom similarity-based subgroups in ischemic stroke patients, and their specific characteristics were obvious. The main syndromes were wind phlegm pattern and hyperactivity of Gan yang pattern.

Palladium-Catalyzed Intermolecular Asymmetric Dearomative Annulation of Phenols with Vinyl Cyclopropanes.

Herein, we report the Pd(0)-catalyzed intermolecular asymmetric dearomative [3 + 2] annulation of phenols with vinyl cyclopropanes via in situ generated ortho-quinone methide intermediates. A series of highly functionalized spiro-[5,6] bicycles which bear three contiguous stereogenic centers including one all-carbon quaternary were obtained with excellent stereoselectivities. Density functional theory (DFT) calculations indicate that the reactions were controlled by thermodynamics.

CuH-Catalyzed Enantioselective Reductive Coupling of 1,3-Dienes and Trifluoromethyl Ketoimines or α-Iminoacetates.

The intermolecular addition of allylic copper species generated from diene and copper hydride remains elusive. Herein copper hydride catalyzed asymmetric cross reductive coupling of conjugated dienes and ketoimines including trifluoromethyl ketoimines and α-iminoacetates was first achieved using chiral Ph-BPE as the ligand, providing rapid access to structurally and optically enriched homoallylic amines containing two vicinal stereogenic centers with up to 95% yield, 99% ee, and 11:1 diastereoselectivities.

Enantioselective [3 + 2] Cycloaddition of Vinylcyclopropanes with Alkenyl N-Heteroarenes Enabled by Palladium Catalysis.

The first catalytic enantioselective [3 + 2] cycloaddition reaction between vinylcyclopropanes and alkenyl N-heteroarenes in the presence of LiBr and a Pd(0)/SEGPHOS complex was developed. LiBr plays a key role in improving the reactivity of alkenyl N-heteroarenes as a mild Lewis acid.

Research progress on the mechanism of cerebral blood flow regulation in hypoxia environment at plateau.

The plateau is a special environment with low air pressure and low oxygen content. The average altitude of Qinghai-Tibet is 3,500 m, and the atmospheric oxygen partial pressure in most areas is lower than 60% of that at sea level. In order to adapt to the plateau low-oxygen environment, the human body has developed corresponding physiological structure and functions adjust. In the present review, the regulation mechanism of cerebral blood flow (CBF) under high-altitude environments was elaborated in eight aspects: the arterial blood gas, endogenous substances in the nerve and blood, the cerebral neovascularization, the hematocrit, cerebral auto-regulation mechanism, cerebrovascular reactivity, pulmonary vasoconstriction, and sympathetic automatic regulation, aiming to further explore the characteristics of changes in brain tissue and cerebral blood flow in a hypoxic environment.

[Analysis on the Spatial Variability Mechanism of the Characteristic Water Quality Factors of Urban River Channel Reclaimed Water].

Due to the limitations of the treatment process of urban sewage treatment plants and the complexity of water sources, the rich inorganic nitrogen and trace persistent organic matter in the reclaimed water cause potential human health risks through lateral leakage or bioaccumulation during the replenishment process of rivers and lakes. Exploring the distribution law of different types of reclaimed water characteristic water quality factors and their formation in reclaimed water replenishment river channels is of great significance to river and lake management. This study takes the Beijing-Tianjin-Hebei section of the North Canal as the research area and explores the spatial variation characteristics of conventional physical parameters, full index, inorganic nitrogen, and salinity hydronium antibiotics in river water quality with the help of clustering, discrimination, principal components, and variance decomposition. The results showed that, although the spatial distribution patterns of different types of water quality factors were consistent, they all showed significant mid-upstream and downstream distribution; however, there were big differences in the degree of variation and the mechanism of variation. The spatial variation of inorganic nitrogen and antibiotics was the most obvious, whereas the variation in conventional physical parameters and the full index was the weakest, and the salinity hydronium showed moderate variation. The spatial variation mechanism of conventional physical parameters was mainly reflected in microbial degradation. The full index was the result of the combined effect of microorganisms, diffusion, the synergy of the two, and a certain degree of source-sink homogeneity. Diffusion was the main mechanism affecting the spatial variation in salinity hydronium. The spatial variation mechanism of inorganic nitrogen was mainly reflected in the source-sink homogenization and microbial degradation; as a secondary mechanism of the spatial variation of inorganic nitrogen, diffusion had a synergistic mode with microbial degradation. Antibiotics, which have great differences in chemical structural stability and biodegradability, showed high spatial variability and had the highest diffusion and microbial synergy mechanism. This research provides a quantitative analysis of the spatial variability mechanism of water quality based on variance decomposition, which has practical guiding significance for the causes of the spatial variability of river pollutants and river management.

Comparison of Clinical Efficacy and Safety of Metformin Sustained-Release Tablet (II) (Dulening) and Metformin Tablet (Glucophage) in Treatment of Type 2 Diabetes Mellitus.

Objectives: This study investigated the clinical efficacy and safety of metformin hydrochloride sustained-release (SR) tablet (II) produced by Dulening and the original metformin hydrochloride tablet produced by Glucophage in the treatment of type 2 diabetes mellitus (T2DM). Methods: This randomized, open and parallel controlled clinical trial consecutively recruited a total of 886 patients with T2DM in 40 clinical centers between May 2016 and December 2018. These patients were randomly assigned to the Dulening group (n=446), in which patients were treated with Dulening metformin SR tablets, and the Glucophage group (n=440), in which patients were treated with Glucophage metformin tablets, for 16 weeks. The changes in the levels of glycated hemoglobin (HbAc1) and fasting blood glucose (FBG) as well as weight loss were compared between these two groups. Also, the overall incidence of adverse drug reactions (ADRs) and the incidence of ADR of the gastrointestinal system observed in patients of these two groups were also compared. Results: There were no significant differences in demographic and basal clinical characteristics between these two groups. The Dulening and Glucophage groups showed comparable levels of decrease in HbA1c levels, FBG and weight loss after 12-week treatment (all p>0.05). The Dulening group had a significantly lower overall incidence of ADRs as well as gastrointestinal ADR than the Glucophage group. Conclusions: Metformin SR tablets (II) and the original metformin tablets exhibit similar therapeutic efficacy in the treatment of T2DM, but metformin SR tablets (II) has the significantly lower incidence of ADRs than the original metformin tablets.

Asymmetric Synthesis of 3-Methyleneindolines via Rhodium(I)-Catalyzed Alkynylative Cyclization of N-(o-Alkynylaryl)imines.

The first asymmetric synthesis of 3-methyleneindolines from alkynyl imines has been developed via a rhodium-catalyzed tandem process: regioselective alkynylation of the internal alkynes and subsequent intramolecular addition to the imines. The reaction proceeded with unconventional chemoselectivity and provided 3-methyleneindolines with good yields (up to 82% yield) and high enantioselectivities (up to 97% ee). Moreover, this transformation also features mild reaction conditions, perfect atom economy, and a broad substrate scope.

A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis.

BACKGROUND: Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis. METHODS: We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12. RESULTS: The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported. CONCLUSION: During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

Secukinumab demonstrates high efficacy and a favorable safety profile over 52 weeks in Chinese patients with moderate to severe plaque psoriasis.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease, affecting about 0.6% of the Chinese population. Many patients are not well controlled by conventional treatments, thus there is need for new treatment regimens. In this study, we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis. METHODS: This study was a 52-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 trial. A sub-population of study participants (≥18 years) of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab, or placebo. The co-primary endpoints were psoriasis area severity index (PASI) 75 and Investigator's Global Assessment (IGA) 0/1 at Week 12. RESULTS: A total of 441 Chinese patients were enrolled in this study. Co-primary outcomes were achieved; 300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75 (97.7% and 87.2% vs. 3.7%, respectively; P < 0.001), and IGA 0/1 (82.3% and 69.7% vs. 2.7%; P < 0.001) at Week 12. Treatment efficacy was maintained until Week 52. There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period. CONCLUSION: Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03066609; https://clinicaltrials.gov/ct2/show/record/NCT03066609.

Copper-catalyzed asymmetric silyl addition to alkenyl-substituted N-heteroarenes.

Asymmetric conjugate addition of PhMe2SiBPin to a wide range of N-heteroaryl alkenes proceeded in the presence of a copper catalyst coordinated with an easily accessible chiral phosphoramidite ligand to afford useful ß-silyl N-heteroarenes in high yields (up to 96%) and excellent enantioselectivities (up to 97% ee).

Consensus on Pre-examination and Triage in Clinic of Dermatology During Outbreak of COVID-19 From Chinese Experts.

The 2019 novel coronavirus infection has brought a great challenge in prevention and control of the national epidemic of coronavirus disease 2019 (COVID-19) in China. During the fight against the epidemic of COVID-19, properly carrying out pre-examination and triage for patients with skin lesions and fever has been a practical problem encountered in hospitals for skin diseases as well as clinics of dermatology in general hospitals. Considering that certain skin diseases may have symptom of fever, and some of the carriers of 2019 novel coronavirus and patients with COVID-19 at their early stage may do not present any symptoms of COVID-19, to properly deal with the visitors to clinics of dermatology, the Chinese Society of Dermatology organized experts to formulate the principles and procedures for pre-examination and triage of visitors to clinics of dermatology during the epidemic of COVID-19.

A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis / 中华医学杂志(英文版)

BACKGROUND@#Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.@*METHODS@#We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12.@*RESULTS@#The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.@*CONCLUSION@#During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

Secukinumab demonstrates high efficacy and a favorable safety profile over 52 weeks in Chinese patients with moderate to severe plaque psoriasis / 中华医学杂志(英文版)

BACKGROUND@#Psoriasis is a chronic inflammatory skin disease, affecting about 0.6% of the Chinese population. Many patients are not well controlled by conventional treatments, thus there is need for new treatment regimens. In this study, we assessed the efficacy and safety of secukinumab in Chinese patients with moderate to severe plaque psoriasis.@*METHODS@#This study was a 52-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 trial. A sub-population of study participants (≥18 years) of Chinese ethnicity were randomized to receive subcutaneous injections of 300 or 150 mg secukinumab, or placebo. The co-primary endpoints were psoriasis area severity index (PASI) 75 and Investigator's Global Assessment (IGA) 0/1 at Week 12.@*RESULTS@#A total of 441 Chinese patients were enrolled in this study. Co-primary outcomes were achieved; 300 and 150 mg secukinumab were superior to placebo as shown in the proportion of patients that achieved PASI 75 (97.7% and 87.2% vs. 3.7%, respectively; P < 0.001), and IGA 0/1 (82.3% and 69.7% vs. 2.7%; P < 0.001) at Week 12. Treatment efficacy was maintained until Week 52. There was no increase in overall adverse events with secukinumab relative to placebo throughout the 52-week period.@*CONCLUSION@#Secukinumab is highly effective and well tolerated in Chinese patients with moderate to severe plaque psoriasis.@*TRIAL REGISTRATION@#ClinicalTrials.gov, NCT03066609; https://clinicaltrials.gov/ct2/show/record/NCT03066609.

CuH-Catalyzed Asymmetric 1,6-Conjugate Reduction of p-Quinone Methides: Enantioselective Synthesis of Triarylmethanes and 1,1,2-Triarylethanes.

The first copper hydride (CuH)-catalyzed asymmetric 1,6-conjugate reduction of p-quinone methides is reported. This protocol provides a new method to access a variety of triarylmethanes and 1,1,2-triarylethanes in good yields with excellent enantioselectivities and broad functional group tolerance.