12-chloro-9-(2-fluorophenyl)-3-methyl-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,8,11,13-hexaene

• ChemBase ID: 565
• Molecular Formular: C18H13ClFN3
• Molecular Mass: 325.7673232
• Monoisotopic Mass: 325.07820333
• SMILES: Clc1cc2c(n3c(CN=C2c2c(F)cccc2)cnc3C)cc1
• Canonical SMILES: Clc1ccc2c(c1)C(=NCc1n2c(C)nc1)c1ccccc1F
• InChI: InChI=1S/C18H13ClFN3/c1-11-21-9-13-10-22-18(14-4-2-3-5-16(14)20)15-8-12(19)6-7-17(15)23(11)13/h2-9H,10H2,1H3
• InChIKey: DDLIGBOFAVUZHB-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 12-chloro-9-(2-fluorophenyl)-3-methyl-2,4,8-triazatricyclo[8.4.0.0^{2,6}]tetradeca-1(10),3,5,8,11,13-hexaene; 12-chloro-9-(2-fluorophenyl)-3-methyl-2,4,8-triazatricyclo[8.4.0.0^2,^6]tetradeca-1(14),3,5,8,10,12-hexaene; 12-chloro-9-(2-fluorophenyl)-3-methyl-2,4,8-triazatricyclo[8.4.0.0^2,^6]tetradeca-1(10),3,5,8,11,13-hexaene
• IUPAC Traditional name: midazolam
• Brand Name: Dormicum; Versed
• Synonyms: Dea No. 2884; Midazolam Base; Midazolam Hcl; Midazolamum [INN-Latin]; Midazolam; 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5a][1,4]benzodiazepine hydrochloride; Midazolam hydrochloride; Midanium; Midazolam; Midosed; Rohipnol; Sumianxin; 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine; Dazolam; Dormicum

Database IDs

• CAS Number: 59467-96-8; 59467-70-8
• EC Number: 261-776-6
• MDL Number: MFCD00864445
• PubChem SID: 46507611; 160964028; 24724654
• PubChem CID: 4192

CALCULATED PROPERTIES

JChem

• H Acceptors: 2
• H Donor: 0
• LogD (pH = 5.5): 2.4297755
• LogD (pH = 7.4): 3.2779806
• Log P: 3.3348
• Molar Refractivity: 99.4297 cm^3
• Polarizability: 33.933826 Å^3
• Polar Surface Area: 30.18 Å^2
• Rotatable Bonds: 1
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 3.89
• LOG S: -4.52
• Solubility (Water): 9.87e-03 g/l

PROPERTIES

Physical Property

• Solubility: 0.024 mg/mL [Thorsteinn Loftsson and Dagny Hreinsdóttir, 2006]; Chloroform; DiMSO; Methanol
• Apperance: white to off-white solid; White to Off-White Solid
• Melting Point: 161-164°C

Safety Information

• Storage Condition: Controlled Substance, -20°C Freezer
• RTECS: NI2922250
• German water hazard class: 3
• Personal Protective Equipment: Eyeshields, Gloves, type N95 (US), type P1 (EN143) respirator filter
• Drug Control: USDEA Schedule IV; Home Office Schedule 3; psychotrope; kontrollierte Droge in Deutschland; regulated under CDSA - not available from Sigma-Aldrich Canada
• Storage Temperature: 2-8°C

Pharmacology Properties

• Gene Information: human ... ABCB1(5243), CYP3A4(1576)mouse ... Abcb1a(18671), Abcb1b(18669)rat ... Gabbr1(81657), Gabra1(29705)

Product Information

• Empirical Formula (Hill Notation): C18H13ClFN3 · HCl

DETAILS

DrugBank - DB00683

• Drug Groups: illicit; approved
• Description: A short-acting hypnotic-sedative drug with anxiolytic and amnestic properties. It is used in dentistry, cardiac surgery, endoscopic procedures, as preanesthetic medication, and as an adjunct to local anesthesia. The short duration and cardiorespiratory stability makes it useful in poor-risk, elderly, and cardiac patients. It is water-soluble at pH less than 4 and lipid-soluble at physiological pH. [PubChem] Midazolam is a schedule IV drug in the United States.
• Indication: For use as a sedative perioperatively.
• Pharmacology: Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities. Benzodiazepine pharmacologic effects appear to result from reversible interactions with the (gamma)-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist, flumazenil.
• Toxicity: LD₅₀=825 mg/kg (Orally in rats). Signs of overdose include sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and deleterious effects on vital signs.
• Affected Organisms: Humans and other mammals
• Biotransformation: Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, (alpha)-hydroxymidazolam, and 4-hydroxymidazolam.
• Absorption: Rapidly absorbed after oral administration (absolute bioavailability of the midazolam syrup in pediatric patients is about 36%, and intramuscular is greater than 90%).
• Half Life: 2.2-6.8 hours
• Protein Binding: 97%
• Elimination: Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, α-hydroxymidazolam, followed by glucuronidation of the α–hydroxyl metabolite which is present in unconjugated and conjugated forms in human plasma. The α- hydroxymidazolam glucuronide is then excreted in urine. No significant amount of parent drug or metabolites is extractable from urine before beta-glucuronidase and sulfatase deconjugation, indicating that the urinary metabolites are excreted mainly as conjugates.
• Distribution: * 1.24 to 2.02 L/kg [pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam,]
• Clearance: * 9.3 to 11 mL/min/kg [pediatric patients (6 months to <16 years old)]
• References: Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. [Pubmed] ; Isojarvi JI, Tokola RA: Benzodiazepines in the treatment of epilepsy in people with intellectual disability. J Intellect Disabil Res. 1998 Dec;42 Suppl 1:80-92. [Pubmed] ; Garratt JC, Gent JP, Feely M, Haigh JR: Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential? Eur J Pharmacol. 1988 Jan 5;145(1):75-80. [Pubmed] ; Tokunaga S, Takeda Y, Shinomiya K, Hirase M, Kamei C: Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats. J Pharmacol Sci. 2007 Feb;103(2):201-6. Epub 2007 Feb 8. [Pubmed] ; Vermeeren A: Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs. 2004;18(5):297-328. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Sigma Aldrich - UC429

Biochem/physiol Actions
Sedative/hypnotic; ligand for the GABAA receptor benzodiazepine modulatory site; CYP3A4 substrate.
Other Notes
Tandem Mass Spectrometry data independently generated by Scripps Center for Metabolomics is available to view or download in PDF. UC429.pdf Tested metabolites are featured on Scripps Center for Metabolomics METLIN Metabolite Database. To learn more, visit sigma.com/metlin.

Toronto Research Chemicals - M343000

Anesthetic; anticonvulsant; sedative; hypnotic.

REFERENCES

• Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. Pubmed
• Isojarvi JI, Tokola RA: Benzodiazepines in the treatment of epilepsy in people with intellectual disability. J Intellect Disabil Res. 1998 Dec;42 Suppl 1:80-92. Pubmed
• Garratt JC, Gent JP, Feely M, Haigh JR: Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential? Eur J Pharmacol. 1988 Jan 5;145(1):75-80. Pubmed
• Tokunaga S, Takeda Y, Shinomiya K, Hirase M, Kamei C: Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats. J Pharmacol Sci. 2007 Feb;103(2):201-6. Epub 2007 Feb 8. Pubmed
• Vermeeren A: Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs. 2004;18(5):297-328. Pubmed
• Dundee, J. W., et al.: Drugs, 28, 519 (1984)
• Lahat, E., et al.: Br. Med. J., 321, 83 (1984)