Explore the vast range of titles available.

An efficient \"one pot\" direct N-[alpha]-C(sp.sup.3)-H functionalization of arylmethylamines towards synthesis of substituted 2,4,6-triarylpyridines has developed. Fascinatingly, this method features O.sub.2 as an oxidant, metal-free simple reaction operation and the dual role of arylmethylamines. The self-oxidative coupling of readily available simple methylamines followed by their sequential deamination/cyclization cascade with arylmethylketones has accomplished anticipated 2,4,6-triarylpyridines (20 examples) up to 95% yield with good functional groups tolerance. The straightforward reaction condition in the presence of an oxidant O.sub.2 and generated H.sub.2O as a sole byproduct made this process environmentally friendly.

An efficient \"one pot\" direct N-[alpha]-C(sp.sup.3)-H functionalization of arylmethylamines towards synthesis of substituted 2,4,6-triarylpyridines has developed. Fascinatingly, this method features O.sub.2 as an oxidant, metal-free simple reaction operation and the dual role of arylmethylamines. The self-oxidative coupling of readily available simple methylamines followed by their sequential deamination/cyclization cascade with arylmethylketones has accomplished anticipated 2,4,6-triarylpyridines (20 examples) up to 95% yield with good functional groups tolerance. The straightforward reaction condition in the presence of an oxidant O.sub.2 and generated H.sub.2O as a sole byproduct made this process environmentally friendly. Graphical

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)[sub.3] as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C[sub.3]-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by [sup.1]H NMR, [sup.13]C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Reactions of the technetium(I) nitrosyl complex [Tc(NO)(Cp)(PPh[sub.3])Cl] with triphenylphosphine chalcogenides EPPh[sub.3] (E = O, S, Se), and Ag(PF[sub.6]) in a CH[sub.2]Cl[sub.2]/MeOH mixture (v/v, 2/1) result in an exchange of the chlorido ligand and the formation of [Tc(NO)(Cp)(PPh[sub.3])(EPPh[sub.3])](PF[sub.6]) compounds. The cationic acetonitrile complex [Tc(NO)(Cp)(PPh[sub.3])(NCCH[sub.3])][sup.+] is formed when the reaction is conducted in NCCH[sub.3] without additional ligands. During the isolation of the corresponding PF[sub.6] [sup.−] salt a gradual decomposition of the anion was detected in the solvent mixture applied. The yields and the purity of the product increase when the BF[sub.4] [sup.−] salt is used instead. The acetonitrile ligand is bound remarkably strongly to technetium and exchange reactions readily proceed only with strong donors, such as pyridine or ligands with ‘soft’ donor atoms, such as the thioether thioxane. Substitutions on the cyclopentadienyl ring do not significantly influence the ligand exchange behavior of the starting material. [sup.99]Tc NMR spectroscopy is a valuable tool for the evaluation of reactions of the complexes of the present study. The extremely large chemical shift range of this method allows the ready detection of corresponding ligand exchange reactions. The observed [sup.99]Tc chemical shifts depend on the donor properties of the ligands. DFT calculations support the discussions about the experimental results and provide explanations for some of the unusual findings.

In 6 to 10% of patients with acute myeloid leukemia, mutant isocitrate dehydrogenase 1 is thought to contribute to leukemogenesis. Ivosidenib is an oral inhibitor of mutant IDH1. In a randomized trial, event-free survival was significantly longer with ivosidenib and azacitidine than with placebo and azacitidine.

Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0·73 log IU/mL in group 1 (95% CI 0·17–1·31; p=0·03) and −1·54 log IU/mL in group 2 (1·21–1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r2=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

The ALK inhibitor crizotinib as first-line therapy was associated with a significantly better response rate, longer progression-free survival, and greater improvement in quality of life measures than standard chemotherapy in patients with ALK -positive lung cancer. Rearrangements of the anaplastic lymphoma kinase ( ALK ) gene are present in 3 to 5% of non–small-cell lung cancers (NSCLCs). 1 , 2 They define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that has adenocarcinoma histologic characteristics. 3 – 5 Crizotinib is an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases. 6 In phase 1 and 2 studies, crizotinib treatment resulted in objective tumor responses in approximately 60% of patients with ALK -positive NSCLC and in progression-free survival of 7 to 10 months. 7 – 9 In . . .

The first diastereoselective synthesis of (−)-1-epi-lentiginosine from a common chiral trans-epoxyamide derived from 2-pyridincarbaldehyde is reported. This methodology involves a sequential oxirane ring opening and intramolecular 5-exo-tet cyclization of tosylate trans-epoxyalcohol to afford a diastereomeric mixture of indolizinium salts in a one-pot fashion, followed by regio- and diastereospecific pyridinium ring reduction.

Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. NCT02342249, 2014-004068-39, and CR107745.

This preclinical, phase 2 report shows that VX-445, a CFTR potentiator when administered with tezacaftor and ivacaftor, improved lung function and reduced sweat chloride concentrations and symptoms in patients harboring one or two Phe508del alleles.