Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates.
TL;DR: The manufacturing route appears to follow the regioselective Cu catalyzed cycloaddtion of 2,6-difluro benzyl azide with or without isolated activated acetylenic esters in three steps that provide a good lead for new synthetic strategy for the rufinamide synthesis.
Abstract: Introduction: There is great potential in the synthetic development of rufinamide to treat childhood-onset epilepsy known as Lennox–Gastaut syndrome (LGS).Areas covered: 1,4-disubstituted triazole ...
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TL;DR: In this article, a new magnetic ligand fishing probe for discovery of DPP-IV inhibitory ligands was developed and it was tested as a proof of concept on the fruit extract of Vaccinium vitis-idaea (lingonberry).
Abstract: In this work, a new magnetic ligand fishing probe for discovery of DPP-IV inhibitory ligands was developed and it was tested as a proof of concept on the fruit extract of Vaccinium vitis-idaea (lingonberry). The ligands were shown to have appreciable dipeptidyl peptidase IV (DPP-IV) inhibitory activity (IC50: 31.8 μg mL-1).) Inhibition of DPP-IV is a well-known therapeutic approach for management of type 2 diabetes (T2D). DPP-IV was successfully immobilized onto magnetic beads and was shown to retain its catalytic activity and selectivity over a model mixture. A total of four ligands were successfully fished out and identified as cyanidin-3-galactoside (2), cyanidin-3-arabinoside (3), proanthocynidin A (4), and 10-carboxyl-pyranopeonidin 3-O-(6″-O-p-coumaroyl)-glucoside (5) using HPLC/HRMS.
5 citations
Patent•
13 Oct 2009
TL;DR: The present invention relates to a process for the preparation of lufinamide by reacting methyl 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid of formula (IV) with ammonia Obtaining amide.
Abstract: The present invention relates to a process for the preparation of lufinamide of formula (I), wherein the process comprises (i) 2,6-difluorobenzylhalide of formula (II), wherein X is chlorine, bromine, or Iodine) to react with azide to obtain 2- (azidomethyl) -1,3-difluorobenzene of formula (III); (ii) methyl 1- (2,6-difluorobenzyl) of formula (IV) by reacting 2- (azidomethyl) -1,3-difluorobenzene of formula (III) with methyl propiolate Obtaining -1H-1,2,3-triazole-4-carboxylic acid; And (iii) a rupee of formula (I) by reacting methyl 1- (2,6-difluorobenzyl) -1H-1,2,3-triazole-4-carboxylic acid of formula (IV) with ammonia Obtaining amide.
2 citations
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TL;DR: This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries by revealing through four selected examples the present state of the art in privileged scaffold library synthesis.
1,160 citations
TL;DR: Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox‐Gastaut syndrome and a positive correlation has been identified between reduction in seizure frequency and steady‐state plasma ruf inamide concentrations.
Abstract: Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V(d)/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of -13.7% in female children comedicated with vigabatrin to a maximum of -46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related.
203 citations
TL;DR: In the scenario of a continuous request for better drugs in shorter times, medicinal chemists must face the challenging task of preparing new patentable molecules, combining high activity and selectivity, drug-likeness and good pharmacokinetic properties.
153 citations
10 Dec 2013
TL;DR: This chapter discusses fragment-based approaches in drug discovery and their applications in medicine, as well as other areas of science, such as nanofiltration and materials science.
Abstract: Fragment-based approaches in drug discovery , Fragment-based approaches in drug discovery , کتابخانه دیجیتال جندی شاپور اهواز
106 citations
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TL;DR: Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs as mentioned in this paper, which is used for adjunctive therapy in patients with partial seizures and with Lennox-Gastaut syndrome (LGS).
Abstract: Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs. Rufinamide was profiled for anticonvulsant activity at the National Institutes of Health and showed broad-spectrum anticonvulsant properties at nontoxic doses in animal models. The principal mechanism of action of rufinamide is considered to be the modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide provides an efficacious and well-tolerated treatment option for use as adjunctive therapy in patients with partial seizures and with Lennox-Gastaut syndrome (LGS). In LGS, rufinamide is effective in controlling multiple seizure types and in reducing the severity of the seizures. The most commonly observed (≥10%) adverse experiences seen in association with rufinamide are headache, dizziness, fatigue, somnolence and nausea. Rufinamide is generally well tolerated, and its safety profile is well-established.
94 citations