Flumazenil

Flumazenil Basic information
Product Name:Flumazenil
Synonyms:ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate;FLUMAZENIL;FluMazenil USP;8-FLUORO-5,6-DIHYDRO-5-METHYL-6-OXO-4H-IMIDAZO[1,5-A][1,4]BENZO-DIAZEPINE-3-CARBOXYLIC ACID ETHYL ESTER;8-FLUORO-5,6-DIHYDRO-5-METHYL-6-OXO-4H-IMIDAZO[1,5-A][1,4]BENZODIAZEPINE-3-CARBOXYLIC ACID ETHYL EST;4H-IMIDAZO[1,5-A][1,4]BENZODIAZEPINE-3-CARBOXYLIC ACID, 8-FLUORO-5,6-DIHYDRO-5-METHYL-6-OXO-, ETHYL ESTER;RO 15-1788;FLUMAZENIL;RO 15-1788; RO15-1788;
CAS:78755-81-4
MF:C15H14FN3O3
MW:303.29
EINECS:616-650-9
Product Categories:Other APIs;ZEBETA;Active Pharmaceutical Ingredients;GABA/Glycine receptor;antagonist;API;GABA;Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;78755-81-4
Mol File:78755-81-4.mol
Flumazenil Structure
Flumazenil Chemical Properties
Melting point 201-203°C
Boiling point 528.0±50.0 °C(Predicted)
density 1.39±0.1 g/cm3(Predicted)
storage temp. Sealed in dry,2-8°C
solubility Soluble in DMSO to 25mM
form solid
pka0.86±0.20(Predicted)
color white
Water Solubility 128 mg/L
Merck 14,4135
Stability:Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
CAS DataBase Reference78755-81-4(CAS DataBase Reference)
NIST Chemistry ReferenceFlumazenil(78755-81-4)
Safety Information
Hazard Codes Xi
Risk Statements 36/37/38
Safety Statements 26-27-36/37/39
WGK Germany 2
RTECS NI2922170
HS Code 2933997500
ToxicityLD50 in mice, rats (mg/kg): 4000, 1360 i.p.; 4300, 6000 orally (Hunkeler)
MSDS Information
ProviderLanguage
Flumazenil English
SigmaAldrich English
Flumazenil Usage And Synthesis
DescriptionFlumazenil is a benzodiazepine antagonist useful as a fast-acting antidote in the treatment of benzodiazepine intoxication, and in reversing the central sedative effects of benzodiazepines during anesthesia.
Chemical PropertiesFlumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions.
OriginatorHoffmann-La Roche (Switzerland)
UsesFlumazenil is an imidazodiazepine which selectively blocks the central effects of classic benzodiazepines. It is used as benzodiazepine antagonist sedation reversal drug.
DefinitionChEBI: Flumazenil is an organic heterotricyclic compound that is 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine which is substituted at positions 3, 5, 6, and 8 by ethoxycarbonyl, methyl, oxo, and fluoro groups, respectively. It is used as an antidote to benzodiazepine overdose. It has a role as a GABA antagonist and an antidote to benzodiazepine poisoning. It is an ethyl ester, an organofluorine compound and an imidazobenzodiazepine.
PreparationThe Synthesis of Flumazenil
Synthesis of Flumazenil
Starting with 4-fluoroaniline (15) the isatin 17 is synthesized via the Sandmeyer synthesis; isatin is then oxidized with peracetic acid to the isatoic anhydride 18. Reaction with sarcosine in DMF leads to the benzodiazepine-2,5-dione 19. This is converted to the iminochloride by reaction with POCI3 . In the key step the imidazoester is built up by reaction with deprotonated ethyl isocyanoacetate [8]. Since ethyl isocyanoacetate is not very stable, an alternative synthesis based on the synthesis of midazolam was developed for large scale-production. Tnthis synthesis diethylmalonate is used. The diester 21 is then transformed to the monoester 22 hy deethoxycarbonylation. Nitrosation and catalytic reduction lead to the amino compound 23. The final carbon atom is introduced by reaction with the orthoester.
Brand nameRomazicon (Roche);Anexate.
Therapeutic FunctionBenzodiazepine receptor antagonist, Anticonvulsant
Biological ActivityFlumazenil is a GABAA receptor antagonist with non-selective for α 1, α 2, α 3 or α 5 (IC50 = 2 nM in a radioligand binding assay using rat cortical synaptosomes). Flumazenil also acts as a partial agonist of GABAA receptors, decreasing the amplitude of electrically stimulated population spikes in rat hippocampal CA1 pyramidal neurons. It increases the number of entries into the open arms of the elevated plus maze in high-anxiety BALB/c, but not C57BL/6, mice when administered at doses ranging from 0.1 to 1,000 μg/kg. Flumazenil (5 and 10 mg/kg) prevents a reduction in burying behavior induced by the GABAA receptor positive allosteric modulator allopregnanolone in ovariectomized rats when administered at doses of 5 and 10 mg/kg. Formulations containing flumazenil have been used to reverse sedation induced by benzodiazepines and in the treatment of benzodiazepine overdose or withdrawal.
PharmacokineticsFlumazenil is a competitive antagonist at the GA BAA benzodiazepine binding site for all other ligands. I t rapidly reverses the CN S and dangerous physiological effects of benzodiazepines following iatrogenic overdose or deliberate self-harm. I t has no effect on benzodiazepine metabolism. Flumazenil is rapidly cleared from plasma and metabolised by the liver and has a very short elimination half-life (<1h). Its duration of action depends on the dose administered and the duration of action of the drug to be antagonised; repeated administration or infusions may be necessary.
Clinical UseReversal of sedative effects of benzodiazepines in anaesthetic, intensive care, and diagnostic procedures
Veterinary Drugs and TreatmentsFlumazenil may be useful for the reversal of benzodiazepine effects after either therapeutic use or overdoses. Flumazenil may be of benefit in the treatment of encephalopathy in patients with severe hepatic failure.
MetabolismFlumazenil is extensively metabolised in the liver. The carboxylic acid metabolite is the main metabolite in plasma (free form) and urine (free form and its glucuronide). This main metabolite showed no benzodiazepine agonist or antagonist activity in pharmacological tests.Flumazenil is almost completely (99%) eliminated by non-renal routes. Practically no unchanged flumazenil is excreted in the urine, suggesting complete metabolic degradation of the drug. Elimination of radiolabelled drug is essentially complete within 72 hours, with 90-95% of the radioactivity appearing in urine and 5-10% in the faeces.
storage+4°C (desiccate)
Mode of actionFlumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. In animal experiments the effects of compounds showing no affinity for the benzodiazepine receptor, e.g. barbiturates, ethanol, meprobamate, GABA mimetics, adenosine receptor agonists and other agents were not affected by flumazenil, but those of nonbenzodiazepine agonists of benzodiazepine receptors, such as cyclopyrrolones (e.g. zopiclone) and triazolopyridazines were blocked.
ReferencesFlumazenil in benzodiazepine overdose
DOI:10.1503/cmaj.160357
Pharmacological uses of flumazenil in benzodiazepine use disorders: a systematic review of limited data
DOI:10.1177/0269881120981390
Methylparaben Paraquat dichloride Methyl N-[(3-fluorophenyl)methyl]ethanamine 1-Methylimidazole Acetonitrile Ethyl formate Triethyl orthoformate Urethane 1-(4-FLUOROPHENYL)IMIDAZOLE Basic Violet 1 Ethyl chloroformate Kresoxim-methyl Methanol Methyl acrylate fluoro jade Dihydromyrcenol Flumazenil

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