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Flumazenil

HCID 3373
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Grundinformationen

CAS
78755-81-4
Standard-SMILES
CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
InChIKey
OFBIFZUFASYYRE-UHFFFAOYSA-N
Summenformel
C15H14FN3O3
Durchschnittliche Molmasse
303,29 g/mol
Monoisotopische Masse
303,10191953

Überblick

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.

Namen und Bezeichner

Bevorzugter Name
Flumazenil
IUPAC
ethyl 8-fluoro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
Englischer Name
Flumazenil
Summenformel
C15H14FN3O3
Molmasse
303.29

Namen und Synonyme

flumazenil78755-81-4AnexateFlumazepilRomaziconLanexatMaziconRo-15-1788FlumazenilumFlumazeniloDTXSID2023064Ro 151788
Weitere Namen anzeigen
FMZethyl 8-fluoro-5-Methyl-6-oxo-5,6-dihydro-4H-benzo[f]iMidazo[1,5-a][1,4]diazepine-3-carboxylateYM-684Ro 1722RO 15-1788
RO-151788NSC-759193DTXCID703064Ro 15-1788/000Ro-15-1788/0004H-Imidazo(1,5-a)(1,4)benzodiazepine-3-carboxylic acid, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-, ethyl ester40P7XK9392RO-1722

Datenbank-Bezeichner

CAS
78755-81-4
PubChem CID
3373
DTXSID
DTXSID2023064
ChEMBL
CHEMBL407
ChEBI
CHEBI:5103
UNII
40P7XK9392
EC Number
616-650-9
Nikkaji
J23.594F

Eigenschaften

Berechnete Struktureigenschaften

XLogP
1
Polarare Oberfläche (TPSA)
64,4 Ų
H-Brücken-Donoren
0
H-Brücken-Akzeptoren
5
Frei drehbare Bindungen
3
Schwere Atome
22
Formalladung
0
Komplexität
461

Experimentelle und physikochemische Eigenschaften

Drugs · 2 Einträge

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Various

LogP · 2 Einträge

1.9

1.26

Solubility1.04e+00 g/L
Human Drugs · 3 Einträge

Breast Feeding; Lactation; Milk, Human; Antidotes; GABA Modulators; Benzodiazepines

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Melting Point · 2 Einträge

201-203 °C

201 - 203 °C

Physical DescriptionSolid
Collision Cross Section · 3 Einträge

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)]

Sicherheit und Regulatorisches

Sicherheitsangaben dienen nur zur Orientierung und ersetzen weder das Sicherheitsdatenblatt (SDB) des Lieferanten noch geltende Vorschriften oder eine fachliche Bewertung.

GHS-Klassifizierung

GHS Classification · 5 Einträge

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.

Gefahrenhinweise

Hazard Classes and CategoriesAcute Tox. 4 (80%)

Toxikologische Informationen

Adverse EffectsSerious Adverse Events
Toxicity SummaryFlumazenil has some associations with the precipitation of seizures in patients with benzodiazepine dependency with a history of seizures. However, flumazenil overdose is extremely rare.
Drug Induced Liver Injury · 6 Einträge

Drug Induced Liver Injury Rank (DILIrank 2.0)

Flumazenil

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

Effects During Pregnancy and Lactation◉ Summary of Use during Lactation

Sicherheitsdaten

wgk
2
hs_code

Chemie und Industrie

Pharmakologische Informationen

ATC Code · 2 Einträge

V - Various

QV - Various

Protein BindingProtein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.
Pharmacodynamics · 1 Eintrag

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 · 1 Eintrag

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 · 1 Eintrag

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).

Metabolism/MetabolitesHepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.
FDA Pharmacological Classification · 6 Einträge

40P7XK9392

FLUMAZENIL

Established Pharmacologic Class [EPC] - Benzodiazepine Antagonist

Flumazenil is a Benzodiazepine Antagonist.

FLUMAZENIL

Benzodiazepine Antagonist [EPC]

MeSH Pharmacological Classification

Zugehörige Reaktionen

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Physikochemische Eigenschaften

Schmelzpunkt
201 · 201-203°C
Siedepunkt
528 · 528.0±50.0 °C(Predicted)
Dichte
1.39 · 1.39±0.1 g/cm3(Predicted)
storage temp.
2 · Sealed in dry,2-8°C
Löslichkeit
25 mM · Soluble in DMSO to 25mM
Aggregatzustand
solid
pka
0.86 · 0.86±0.20(Predicted)
Farbe
white
Wasserlöslichkeit
128 mg/L · 128 mg/L
Merck
14 · 14,4135
Stabilität
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 Datenbank
78755 · 78755-81-4(CAS DataBase Reference)
NIST chemische Informationen
Flumazenil(78755-81-4)
2933997500
RTECS-Nr.
NI2922170
risk_code
36/37/38
Toxizität
LD50 in mice, rats (mg/kg): 4000, 1360 i.p.; 4300, 6000 orally (Hunkeler)
hazard_code
Xi
safety_code
26-27-36/37/39
Speicherklasse
11 - Combustible Solids
· 2 Einträge

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 · 3 Einträge

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]

Cellular LocationsMembrane

Anwendungen

BeschreibungFlumazenil 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.

VerwendenFlumazenil is an imidazodiazepine which selectively blocks the central effects of classic benzodiazepines. It is used as benzodiazepine antagonist sedation reversal drug.

Darstellung · 1 Eintrag

synthetischeThe 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.

Vor- und nachgelagerte Produkte

Vorgelagerte Rohstoffe

6-Fluoroisatoic anhydrideWasserstoffperoxid5-FluoroisatinN,N-Dimethyl-anilinNatrium-2-methylpropan-2-olatAnthranilic acidSarkosinEthylcyanacetatKaliumacetat

Nachgelagerte Produkte

4H-Imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-
Ergänzende Hinweise · 1 Eintrag

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.