Basic information
- Standard SMILES
CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2- InChIKey
OFBIFZUFASYYRE-UHFFFAOYSA-N- Molecular formula
- C15H14FN3O3
- Average molar mass
- 303.29 g/mol
- Monoisotopic mass
- 303.10191953
Overview
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 imidazobenzodiazepine, an ethyl ester and an organofluorine compound.
Names & identifiers
- Preferred name
- Flumazenil
- IUPAC
- ethyl 8-fluoro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
- English name
- Flumazenil
- Molecular formula
- C15H14FN3O3
- Molecular weight
- 303.29
Names & synonyms
Show more names
Database identifiers
- CAS
78755-81-4- PubChem CID
- 3373
- DTXSID
DTXSID2023064- ChEMBL
CHEMBL407- ChEBI
CHEBI:5103- UNII
- 40P7XK9392
- EC Number
- 616-650-9
- Nikkaji
- J23.594F
Properties
Computed structural properties
- XLogP
- 1
- Topological polar surface area
- 64.4 Ų
- Hydrogen bond donors
- 0
- Hydrogen bond acceptors
- 5
- Rotatable bonds
- 3
- Heavy atoms
- 22
- Formal charge
- 0
- Complexity
- 461
Experimental & physicochemical properties
Drugs
Pharmaceuticals -> Listed in ZINC15
Pharmaceuticals -> Various
LogP
1.9
1.26
Human Drugs
Breast Feeding; Lactation; Milk, Human; Antidotes; GABA Modulators; Benzodiazepines
FDA approved drugs -> Active ingredient
FDA approved drugs -> Active ingredient
Melting Point
201-203 °C
201 - 203 °C
Collision Cross Section
164.31 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
165.6 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
165.8 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]
Physicochemical properties
- Melting point
- 201 · 201-203°C
- Boiling point
- 528 · 528.0±50.0 °C(Predicted)
- Density
- 1.39 · 1.39±0.1 g/cm3(Predicted)
- storage temp.
- 2 · Sealed in dry,2-8°C
- solubility
- 25 mM · Soluble in DMSO to 25mM
- form
- solid
- pka
- 0.86 · 0.86±0.20(Predicted)
- color
- white
- Water Solubility
- 128 mg/L · 128 mg/L
- Merck
- 14 · 14,4135
- Stability
- 2 years · Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
- Major Application
- pharmaceutical (small molecule)
- InChI
- InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3
- InChIKey
- OFBIFZUFASYYRE-UHFFFAOYSA-N
- SMILES
- N12C=NC(C(OCC)=O)=C1CN(C)C(=O)C1=CC(F)=CC=C12
- CAS DataBase Reference
- 78755 · 78755-81-4(CAS DataBase Reference)
- FDA UNII
- 40 P7XK9392 · 40P7XK9392
- ATC code
- 3 AB25 · V03AB25
- NIST Chemistry Reference
- Flumazenil(78755-81-4)
- UNSPSC Code
- 41116107 · 41116107
- NACRES
- 77 · NA.77
- Protein binding
- 50 % · 50%
- Excreted unchanged in urine
- 0.1 % · <0.1%
- Volume of distribution
- 0.6 · 0.6-1.1
- Biological half-life
- 0.7 · 0.7-1.3 / Unchanged
- Symbol(GHS)
- 7 · GHS07
- Signal word
- Warning
- Hazard statements
- 303 · H303
- Precautionary statements
- 270 · P270-P301+P312-P403-P501c
- Hazard Codes
- Xi
- Risk Statements
- 36 · 36/37/38
- Safety Statements
- 26 · 26-27-36/37/39
- WGK Germany
- 2 · 2
- RTECS
- 2922170 · NI2922170
- HS Code
- 2933997500 · 2933997500
- Storage Class
- 11 · 11 - Combustible Solids
- Toxicity
- 50 in · LD50 in mice, rats (mg/kg): 4000, 1360 i.p.; 4300, 6000 orally (Hunkeler)
Safety & regulation
GHS classification
GHS Classification
This chemical does not meet GHS hazard criteria for 20% (1 of 5) of reports.
Warning
H302 (80%): Harmful if swallowed [Warning Acute toxicity, oral]
P261, P264, P270, P271, P301+P317, P304+P340, P317, P330, and P501 (click each P-code to see the statement)
Aggregated GHS information provided per 5 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
Hazard information
Toxicology
Drug Induced Liver Injury
Drug Induced Liver Injury Rank (DILIrank 2.0)
Flumazenil
vNo-DILI-concern
0
No match
DOI:10.1016/j.drudis.2016.02.015
Safety data
- wgk
- 2
- rtecs
- NI2922170
- hs_code
- 2933997500
- Toxicity
- LD50 in mice, rats (mg/kg): 4000, 1360 i.p.; 4300, 6000 orally (Hunkeler)
- risk_code
- 36/37/38
- Signal word
- Warning
- Symbol(GHS)
- GHS07
- hazard_code
- Xi
- safety_code
- 26-27-36/37/39
- Storage Class
- 11 - Combustible Solids
- Hazard statements
- H303
- Precautionary statements
- P270-P301+P312-P403-P501c
Chemistry & industry
Pharmacology
ATC Code
V - Various
QV - Various
Pharmacodynamics
Flumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
Mechanism of Action
Flumazenil, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist. It competitively inhibits the benzodiazepine binding site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
Biological Half-Life
Initial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).
FDA Pharmacological Classification
40P7XK9392
FLUMAZENIL
Established Pharmacologic Class [EPC] - Benzodiazepine Antagonist
Flumazenil is a Benzodiazepine Antagonist.
FLUMAZENIL
Benzodiazepine Antagonist [EPC]
MeSH Pharmacological Classification
Agents counteracting or neutralizing the action of POISONS.
Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.
Absorption, Distribution and Excretion
Flumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.
0.9 to 1.1 L/kg
1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]
Applications
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.
UsesFlumazenil is an imidazodiazepine which selectively blocks the central effects of classic benzodiazepines. It is used as benzodiazepine antagonist sedation reversal drug.
Preparation methods
PreparationThe Synthesis of FlumazenilStarting 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.
Upstream & downstream products
Upstream raw materials
Downstream products
Suppliers50 total
Additional notes
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.
Related reactions
Linked notes
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