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Flumazenil 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.

Colourless crystals

Hoffmann-La Roche (Switzerland)

A benzodiazepine antagonist

benzodiazepine antagonist sedation reversal drug

beta-blocker, antihypertensive

Imidazodiazepine which selectively blocks the central effects of classic benzodiazepines. It is used as benzodiazepine antagonist.

ChEBI: 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 ntidote to benzodiazepine overdose.

The 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.

24 g (132.5 mmol) of 5-fluoroisatoic acid anhydride are dissolved in 140 ml of dimethyl sulphoxide and treated with 11.8 g (132.5 mmol) of sarcosine. The solution is stirred at 100°C until the gas evolution ceases (duration: ca 1.5 h) and subsequently poured into ca 1.2 L of water. After stirring for 10 min, a solid crystallizes out. The crystals are filtered off under suction, washed with 1 L of water and dried. There is obtained 7-fluoro-3,4-dihydro-4-methyl-2H-1,4- benzodiazepine-2,5(1H)-dione of melting point 262°-263°C.
A solution of 6.5 g (32 mmol) of 7-fluoro-3,4-dihydro-4-methyl-2H-1,4- benzodiazepine-2,5(1H)-dione in 30 ml of dry dimethylformamide is treated with 4.3 g (38 mmol) of potassium t-butylate under an argon atmosphere. The temperature thereby rises to 35°C. After 10 min, the mixture is cooled to -30°C and 5.8 g (34 mmol) of diethylchlorophosphate are added dropwise thereto at -30°C to -20°C. The solution is subsequently stirred at -200°C for 10 min.
Separately, 4 g (35 mmol) of potassium tert-butylate are dissolved in 10 ml of dimethylformamide and treated at ca. -40°C with 4 g (35 mmol) of ethyl isocyanoacetate. This solution is added dropwise at -10°C to -20°C to the mixture obtained according to the preceding paragraph. The resulting mixture is then stirred without cooling for 1 h, 3.2 ml of glacial acetic acid are added thereto, the mixture is poured into ca. 400 ml of water and extracted three times with 150 ml of ethyl acetate each time. The combined organic extracts are washed five times with 200 ml of water each time, dried over magnesium sulfate and evaporated. From the oily residue there is obtained, by column chromatography on silica gel and subsequent recrystallisation from ethyl acetate and ether, ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylate of melting point 199°-200°C.

Romazicon (Roche);Anexate.

Benzodiazepine receptor antagonist, Anticonvulsant

Benzodiazepine antagonist, non-selective for α 1, α 2, α 3 or α 5-containing GABA A receptors. Centrally active upon systemic administration in vivo .

Flumazenil 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.

Reversal of sedative effects of benzodiazepines in anaesthetic, intensive care, and diagnostic procedures

Flumazenil 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.

Potentially hazardous interactions with other drugs
None known

Flumazenil 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.

+4°C (desiccate)

Flumazenil, 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.

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