A green and efficient method for the synthesis of homodimeric (β-dicarbonyl) arylmethanes and dihydropyridine from dimedone in water

A direct method has been developed for the synthesis of the dihydropyridine ring system by means of Michael reaction. The reaction of dimedone with 1 .0 equiv. of amines in water provides intermediate product, which allowed dihydropyridine derivatives by intramolecular cyclization in various yields. Of particular interest is the use of the water as solvent of reaction and in absence of catalyst. Also these operating conditions protect the environment and economic points of view.Keywords: aqueous synthesis; bioactivity; dihydropyridine; dimedone; green method; selective condition

Synthesis of benzimidazole-cyclohexanone derivatives

This work reports the synthesis and characterization of new benzimidazole-cyclohexanone derivatives 3a-d, 4a-d and 5a-d under different reaction conditions. The intermediates and final compounds were purified and their  chemical structures were elucidated using 1H-NMR, 13C-NMR and mass spectral data.Keywords: Benzimidazole, Cyclohexanone, NMR, Reaction intermediate

Effectiveness of TOcilizumab in comparison to Prednisone In Rheumatoid Arthritis patients with insufficient response to disease-modifying antirheumatic drugs (TOPIRA): study protocol for a pragmatic trial

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, predominantly affecting joints, which is initially treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). In RA patients with insufficient response to csDMARDs, the addition of prednisone or tocilizumab, a biological DMARD (bDMARD), to the medication has been shown to be effective in reducing RA symptoms. However, which of these two treatment strategies has superior effectiveness and safety is unknown. METHODS: In this multicenter, investigator-initiated, open-label, randomized, pragmatic trial, we aim to recruit 120 RA patients meeting the 2010 ACR/EULAR classification criteria for RA, with active disease defined as a Clinical Disease Activity Index (CDAI) > 10 and at least one swollen joint of the 28 assessed. Patients must be on stable treatment with csDMARDs for ≥ 8 weeks prior to screening and must have been treated with ≥ 2 DMARDs, of which a maximum of one tumor necrosis factor inhibitor (a class of bDMARDs) is allowed. Previous use of other bDMARDs or targeted synthetic DMARDs is not allowed. Patients will be randomized in a 1:1 ratio to receive either tocilizumab (subcutaneously at 162 mg/week) or prednisone (orally at 10 mg/day) as an addition to their current csDMARD therapy. Study visits will be performed at screening; baseline; and months 1, 2, 3, 6, 9, and 12. Study medication will be tapered in case of clinical remission (CDAI ≤ 2.8 and ≤ 1 swollen joint at two consecutive 3-monthly visits) with careful monitoring of disease activity. In case of persistent high disease activity at or after month 3 (CDAI > 22 at any visit or > 10 at two consecutive visits), patients will switch to the other strategy arm. Primary outcome is a change in CDAI from baseline to 12 months. Secondary outcomes are additional clinical response and quality of life measures, drug retention rate, radiographically detectable progression of joint damage, functional ability, and cost utility. Safety outcomes include tocilizumab-associated adverse events (AEs), glucocorticoid-associated AEs, and serious AEs. DISCUSSION: This will be the first randomized clinical trial comparing addition of oral prednisone or of tocilizumab head to head in RA patients with insufficient response to csDMARD therapy. It will yield important information for clinical rheumatology practice. TRIAL REGISTRATION: This trial was prospectively registered in the Netherlands Trial Register on October 7, 2019 (NL8070). The Netherlands Trial Register contains all items from the World Health Organization Trial Registration Data Set

Synthesis of benzimidazole-cyclohexanone derivatives

International audienc

Synthesis of functionalized benzimidazole-butyrolactone dyads

A two-step procedure transformation starting from the reaction of ortho-phenylenediamines on 2-acetylbutyrolactone 1 yielded (Z)-3-(1-aminoethylidene)butyrolactones 2, which were treated with either N,N-dimethylformamide dimethyl acetal, triphosgene, or carbon disulfide under different reaction conditions to produce a new series of benzimidazole-, benzimidazolone-, or benzimidazole-2-thione-butyrolactone dyads 3-5, respectively. The structures of compounds 2-5 were established by NMR and mass spectrometry. The isolation of important reaction intermediates as single-crystals allowed the determination of the (Z)-configuration in the resulting conjugate heterocyclic systems 3-5 by X-ray diffraction studies. (C) 2015 Elsevier Ltd. All rights reserved

Sex-specific differences and how to handle them in early psoriatic arthritis

Objectives The prevalence of psoriatic arthritis (PsA) is the same in men and women; however, the latter experience a higher burden of disease and are affected more frequently by polyarthritis. Here, we performed an early PsA cohort analysis to assess sex-related differences in demographics, disease characteristics, and evolution over 1 year including applied treatment strategies. Methods Our study is embedded in the Dutch south-west Early Psoriatic Arthritis cohoRt. We described patient characteristics and treatment decisions. For the comparison across sexes and baseline and 1 year follow-up, appropriate tests depending on the distribution were used. Results Two hundred seventy-three men and 294 women with no significant differences in age and ethnicity were included. Women reported significantly longer duration of symptoms before diagnosis and significantly higher tender joint count, a higher disease activity, higher levels of pain, and lower functional capacity. Although minimal disease activity (MDA) rates increased over time for both sexes, MDA remained significantly more prevalent among men at 1 year (58.1% vs 35.7%, p < 0.00). Initially, treatment strategies were similar in both sexes with methotrexate being the most frequently used drug during the first year. Women received methotrexate for a shorter period [196 (93–364) vs 306 (157–365), p < 0.00] and therefore received a lower cumulative dose compared to men. Retention time was shorter for all DMARDs, and women had a delayed start on b-DMARDs. Conclusion After 1 year of standard-of-care treatment, women did not surpass their baseline disadvantages. Despite the overall improvement, they still presented higher disease activity, higher levels of pain, and lower functional capacity score than men. The nature of these findings may advocate a need for sex specific adjustment of treatment strategies and evaluation in early PsA patients