106308-44-5 Usage
Description
Different sources of media describe the Description of 106308-44-5 differently. You can refer to the following data:
1. Rufinamide (licensed in 2007) is a third- generation AED known with the proprietary
brand name of Invelon?(Eisai, Hatfield) in the UK and USA.
2. Approximately 2.5 million people worldwide are afflicted with epilepsy, a
devastating neurological disorder diagnosed by the tendency toward recurrent,
unprovoked seizures, often of unknown etiology. Rufinamide has been launched primarily as adjunctive
therapy of LGS. Its proposed mechanism of action involves the limitation of
firing of sodium-dependent action potentials. The ultimate result is membrane
stabilization. Since it does not exhibit measurable binding to monoamine,
acetylcholine, histamine, glycine, AMPA/kainate, NMDA, or GABA receptors or
systems, these receptor-mediated pathways are not anticipated to be involved in
the exertion of rufinamide’s effects. Rufinamide displayed efficacy in several
electrical and chemical animal seizure models.
3. Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple seizure types. Rufinamide is an anticonvulsant. It inhibits the activation of voltage-gated sodium channel 1.1 (Nav1.1) when used at a concentration of 100 μM. Rufinamide inhibits Nav1.1, but not Nav1.2, Nav1.3, and Nav1.6, opening and increases the action potential threshold in primary rat hippocampal neurons. It is an inhibitor of carbonic anhydrase VA (CAVA; Ki = 343.8 nM) that is selective for CAVA over CAI and CAII (Kis = >10,000 nM for both). Rufinamide (100 μM) prolongs the preictal phase and reduces seizure-like event frequency in an in vitro model of epileptiform activity in rat hippocampal slices. It inhibits seizures induced by pentylenetetrazole in a mouse model of epilepsy (ED50 = 54 mg/kg, i.p.) and reduces kainic acid-induced neuronal cell death in the mouse hippocampal CA3 region when used at doses of 25, 50, and 100 mg/kg. Formulations containing rufinamide have been used in the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS).
Generic formulation
MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):
The need for continued supply of a particular manufacturer’s product should be based on clinical judgment and consultation with the patient and/ or carer taking into account factors such as seizure frequency and treatment history.
Indications
Epilepsy: Adjunctive treatment of Lennox– Gastaut syndrome; refractory tonic/ atonic seizures (unlicensed).
Dose titration
Epilepsy— adjunctive therapy (adults with body weight 30– 50 kg): 200 mg bd for at least 2 days, then increased by 200 mg bd every 2 or more days (max. 900 mg bd).
Epilepsy— adjunctive therapy (adults with body weight 50– 70 kg): 200 mg bd for at least 2 days, then increased by 200 mg bd every 2 or more days (max. 1200 mg bd).
Epilepsy— adjunctive therapy (adults with body weight above 70 kg): 200 mg bd for at least 2 days, then increased by 200 mg bd every 2 or more days (max. 1600 mg bd).
Interactions
With AEDs
Significant increases in rufinamide plasma concentrations may occur with coadministration of valproate.
With other drugs
Women of child- bearing age using hormonal contraceptives are advised to use an additional safe and effective contraceptive method as co- administration of rufinamide has been shown to decrease exposure to a combined oral contraceptives.
Rufinamide has been shown to induce the cytochrome P450 enzyme CYP3A4 and may, therefore, reduce the plasma concentrations of substances, which are metabolized by this enzyme (modest- to- moderate effect). It is therefore recommended that patients treated with substances that are metabolized by the CYP3A4 enzyme system are to be carefully monitored for 2 weeks at the start of or after the end of treatment with rufinamide, or after any marked change in the dose (a dose adjustment of the concomitantly administered medicinal product may need to be considered). These recommendations should also be considered when rufinamide is used concomitantly with substances with a narrow therapeutic window, such as warfarin and digoxin.
With alcohol/food
No data on the interaction of rufinamide with alcohol are available ? As a food effect was observed, rufinamide should be administered with food
Special populations
Hepatic impairment
Caution and careful dose titration in mild- to- moderate impairment
Avoid in severe impairment
Renal impairment
The pharmacokinetics of rufinamide does not appear to be altered in subjects with chronic and severe renal failure compared to healthy volunteers
Pregnancy
No clinical data are available on pregnancies exposed to rufinamide. Therefore, rufinamide should not be used during pregnancy or in women of childbearing age who are not using contraceptive measures, unless clearly necessary. Women of childbearing age must use contraceptive measures during treatment with rufinamide.
If women treated with rufinamide plan to become pregnant, the continued use of this product should be carefully weighed. In case of treatment with rufinamide, the dose should be monitored carefully during pregnancy and after birth, and adjustments made on a clinical basis.
It is not known if rufinamide is excreted in human breastmilk. Due to the potential harmful effects for the breastfed infant, breastfeeding should be avoided during maternal treatment with rufinamide.
Behavioural and cognitive effects in patients with epilepsy
For this third- generation agent, clinical experience is still limited, and little is known
about its positive and negative psychotropic properties, and their implications for
the management of behavioural symptoms in patients with epilepsy. There are
initial reports of anxiety, depression, irritability, and agitation. Reports of cognitive
effects are rare.
Psychiatric use
Rufinamide has no indications for the treatment of psychiatric disorders. There
is insufficient experience with rufinamide to draw any conclusion regarding its
psychotropic profile.
Chemical Properties
White Solid
Originator
Novartis (US)
Uses
Different sources of media describe the Uses of 106308-44-5 differently. You can refer to the following data:
1. Rufinamide, a triazole derivative, is an anticonvulsant medication. It is used in combination with other medication and therapy to treat Lennox–Gastaut syndrome and various other seizure disorders. Rufinamide is presumed to involve stabilization of the so
2. Labelled Rufinamide (R701552). Antiepileptic triazole derivative which decreases firing by neurons at sodium channels. Anticonvulsant.
3. Rufinamide has been used to test its analgesic effect on neuropathic pain in spared nerve injury (SNI) model.
Brand name
Inovelon
General Description
An antiepileptic drug and anticonvulsant, Rufinamide is approved for the treatment of partial seizures associated with Lennox-Gastaut syndrome in adults and children 4 years and older. Rufinamide is marketed as Banzel® in the US and Inovelon® in the EU.
Biological Activity
Board spectrum anticonvulsant. Prolongs the inactivation of sodium channels and limits the frequency of action potential firing in cultured and acutely isolated neurons. Displays anticonvulsive activity in a range of animal seizure models.
Biochem/physiol Actions
Broad-spectrum anticonvulsant.
Clinical Use
Adjunctive treatment of seizures in Lennox-Gastaut
syndrome
Side effects
Rufinamide was well tolerated with the most common adverse events including fatigue, somnolence, tremors, mild-to-moderate dizziness, nausea, headache, and diplopia. Since rufinamide is not metabolized by the CYP450 system, it is anticipated to have a low potential for interaction with drugs metabolized by the CYP isozymes. Rufinamide, however, does exhibit clinically relevant interactions with other antiepileptic drugs; concomitant treatment with valproate results in a reduction in rufinamide clearance while concomitant treatment with phenytoin, primidone, phenobarbital, carbamazepine, or vigabatrin causes an increase in rufinamide clearance. In these situations, rufinamide dosage adjustment may be required.
Synthesis
While rufinamide may be prepared by several related routes, the preferred starting material is 2,6-difluorobenzyl azide. Reaction with either 2-propynoic acid or 2-chloroacrylonitrile affords 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid or 1-(2,6-difluorobenzyl)- 1H-1,2,3-triazole-4-carbonitrile, respectively. For the carboxylic acid Shridhar Hegde and Michelle Schmidt intermediate, treatment with thionyl chloride followed by concentrated aqueous ammonium hydroxide or conversion to its methyl ester (methanol/sulfuric acid) with subsequent ammonolyis provides rufinamide.
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: antagonism of anticonvulsant effect
(convulsive threshold lowered); avoid with St John’s
wort.
Antimalarials: mefloquine antagonises
anticonvulsant effect.
Antipsychotics: antagonism of anticonvulsant effect
(convulsive threshold lowered).
Oestrogens and progestogens: metabolism
accelerated by rufinamide - reduced contraceptive
effect.
Orlistat: possibly increased risk of convulsions with
orlistat.
Ulipristal: possibly reduces contraceptive effect.
Metabolism
Almost exclusively eliminated by metabolism
via hydrolysis of the carboxylamide group to the
pharmacologically inactive acid derivative CGP 47292.
Cytochrome P450-mediated metabolism is very minor.
The formation of small amounts of glutathione conjugates
cannot be completely excluded. 84.7% was excreted by the
renal route.
References
1) Hakimian et al. (2007), Rufinamide: a new anti-epileptic medication; Expert Opin. Pharmacother. 8 1931
2) Gilchrist et al. (2014), Nav1.1 Modulation by a Novel Triazole Compound Attenuates Epileptic Seizures in Rodents; ACS Chem. Biol. 9 1204
3) Chen et al. (2018), Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB; Chem. Biol. Interact. 286 71
Check Digit Verification of cas no
The CAS Registry Mumber 106308-44-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,6,3,0 and 8 respectively; the second part has 2 digits, 4 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 106308-44:
(8*1)+(7*0)+(6*6)+(5*3)+(4*0)+(3*8)+(2*4)+(1*4)=95
95 % 10 = 5
So 106308-44-5 is a valid CAS Registry Number.
InChI:InChI=1/C10H8F2N4O/c11-7-2-1-3-8(12)6(7)4-16-5-9(10(13)17)14-15-16/h1-3,5H,4H2,(H2,13,17)
106308-44-5Relevant articles and documents
An efficient ruthenium(iv) catalyst for the selective hydration of nitriles to amides in water under mild conditions
Tomás-Mendivil, Eder,Suárez, Francisco J.,Díez, Josefina,Cadierno, Victorio
, p. 9661 - 9664 (2014)
A Ru(iv) catalyst able to promote the selective hydration of nitriles to amides in water, at low metal loadings and under mild conditions, is presented. This journal is the Partner Organisations 2014.
An efficient synthesis of rufinamide, an antiepileptic drug
Mudd, Whitney H.,Stevens, Erland P.
, p. 3229 - 3231 (2010)
A two-step, one-pot synthesis of rufinamide, an antiepileptic drug, has been developed. 2,6-Difluorobenzyl azide reacts with methyl 3-methoxyacrylate followed by methanolic ammonia to afford rufinamide in 89% yield. The new method generates less waste and uses reagents that are both less expensive and less toxic than other reported syntheses.
Novel Cu(I)-catalyzed one-pot multicomponent synthesis of the antiepileptic drug rufinamide
Meena,Rao, R. Nishanth,Maiti, Barnali,Chanda, Kaushik
, p. 4711 - 4717 (2017)
Abstract: This work represents a new synthesis of the antiepileptic drug rufinamide, through a one-pot multicomponent approach employing a Cu(I) as a catalyst. In this methodology, 2,6-difluoro benzyl bromide reacts with NaN3 and propiolamide i
Aerobic oxidation of primary amines to amides catalyzed by an annulated mesoionic carbene (MIC) stabilized Ru complex
Yadav, Suman,Reshi, Noor U Din,Pal, Saikat,Bera, Jitendra K.
, p. 7018 - 7028 (2021/11/17)
Catalytic aerobic oxidation of primary amines to the amides, using the precatalyst [Ru(COD)(L1)Br2] (1) bearing an annulated π-conjugated imidazo[1,2-a][1,8]naphthyridine-based mesoionic carbene ligand L1, is disclosed. This catalytic protocol is distinguished by its high activity and selectivity, wide substrate scope and modest reaction conditions. A variety of primary amines, RCH2NH2 (R = aliphatic, aromatic and heteroaromatic), are converted to the corresponding amides using ambient air as an oxidant in the presence of a sub-stoichiometric amount of KOtBu in tBuOH. A set of control experiments, Hammett relationships, kinetic studies and DFT calculations are undertaken to divulge mechanistic details of the amine oxidation using 1. The catalytic reaction involves abstraction of two amine protons and two benzylic hydrogen atoms of the metal-bound primary amine by the oxo and hydroxo ligands, respectively. A β-hydride transfer step for the benzylic C-H bond cleavage is not supported by Hammett studies. The nitrile generated by the catalytic oxidation undergoes hydration to afford the amide as the final product. This journal is
Continuous synthesis method of lulaninamide
-
Paragraph 0048-0087, (2020/11/11)
The invention provides a continuous rufinamide synthesizing method. The continuous rufinamide synthesizing method comprises, with existence of acid-binding agent, continuously inputting 1, 2, 3-triazole-4-methyl carboxylate and 2, 6-difluorobenzyl chloride into a first continuous reaction device for continuous condensation reaction to obtain continuous condensation products, and continuously discharging the continuous condensation products; continuously inputting the continuous condensation products and ammonia gas or ammonia-containing solution into a second continuous reaction device for ammonolysis reaction to obtain rufinamide, and continuously discharging the rufinamide. The continuous rufinamide synthesizing method not only avoids production of isomers during cyclization of conventional routes to simplify the purification process of finished products, but also effectively reduces the process costs and shortens the reaction route; meanwhile, compared with batch equipment, the continuous rufinamide synthesizing method is implemented in a continuous reaction device; due to the facts the reaction system is small and heat exchange speed is high, reaction conditions can be more intense but safer.
Organic synthesis in a modular robotic system driven by a chemical programming language
Steiner, Sebastian,Wolf, Jakob,Glatzel, Stefan,Andreou, Anna,Granda, Jaros?aw M.,Keenan, Graham,Hinkley, Trevor,Aragon-Camarasa, Gerardo,Kitson, Philip J.,Angelone, Davide,Cronin, Leroy
, (2018/12/14)
The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.
