Brotizolam

Identification

Name
Brotizolam
Accession Number
DB09017
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

Brotizolam is a sedative-hypnotic thienodiazepine drug which is a benzodiazepine analog. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to short-acting benzodiazepines such as triazolam. It is used in the short term treatment of severe or debilitating insomnia. Brotizolam is an extremely potent drug and it is rapidly eliminated with an average half-life of 4.4 hours (range 3.6 - 7.9 hours).

Brotizolam is not approved for sale in the UK, United States or Canada. It is approved for sale in the Netherlands, Germany, Spain, Belgium, Austria, Portugal, Israel, Italy and Japan.

Structure
Thumb
Synonyms
  • Brotizolam
  • Brotizolamum
External IDs
SID144207150 / WE 941 / WE 941-BS / WE-941 / WE-941-BS
International/Other Brands
Amnezon (Nisshin Seiyaku) / Bondormin (Rafa) / Brometon (Mylan Seiyaku) / Brotizolam M (Sannova) / Dormex (Recalcine) / Eurimolan (Choseido Pharmaceutical) / Goodmin (Tanabe Mitsubishi Pharma) / Lendorm (Boehringer Ingelheim) / Lendormin (Boehringer Ingelheim) / Lindormin (Boehringer Ingelheim) / Nestrom (Tatsumi Kagaku) / Noctilan (Boehringer Ingelheim) / Noxtal (Alfresa Pharma) / Ronfleman (Kyowa Yakuhin) / Sintonal (Europharma) / Sorentmin (Taisho Yakuhin) / Zestromin (Towa Yakuhin)
Categories
UNII
5XZM1R3DKF
CAS number
57801-81-7
Weight
Average: 393.689
Monoisotopic: 391.949807384
Chemical Formula
C15H10BrClN4S
InChI Key
UMSGKTJDUHERQW-UHFFFAOYSA-N
InChI
InChI=1S/C15H10BrClN4S/c1-8-19-20-13-7-18-14(9-4-2-3-5-11(9)17)10-6-12(16)22-15(10)21(8)13/h2-6H,7H2,1H3
IUPAC Name
4-bromo-7-(2-chlorophenyl)-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0²,⁶]trideca-2(6),4,7,10,12-pentaene
SMILES
CC1=NN=C2CN=C(C3=C(SC(Br)=C3)N12)C1=CC=CC=C1Cl

Pharmacology

Indication

Brotizolam is indicated for the short-term treatment (2-4 weeks) of severe or debilitating insomnia.

Pharmacodynamics
Not Available
Mechanism of action
Not Available
Absorption

The plasma concentration profile of brotizolam can be described as a one compartmental open model with first-order absorption.

Volume of distribution

0.63 l/kg.

Protein binding

The mean value of the free fraction (%): 8.4 ± 0.7.

Metabolism

There are two primary metabolites: 1-methyl-hydroxy- and the 4-hydroxy-derivatives (Eberts et al., 1981; Boehringer Ingelheim, product information). The 4-hydroxymetabolites have a pharmacological activity which is far less than that of the parent drugs, but the 1-methyl-hydroxymetabolites probably have comparable activity (Gall et al., 1978; Jochemsen et al., 1982; Sethy & Harris, 1982; Jochemsen et al., unpublished results). These active compounds are, however, not present in plasma in measurable amounts following a single dose of brotizolam to young healthy subjects (Jochemsen et al., 1982; Jochemsen et al., unpublished results).

Route of elimination
Not Available
Half life

4.4 hours.

Clearance

Total clearance: 109 ml/min.

Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Brotizolam.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Brotizolam.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Brotizolam.
AcetazolamideThe risk or severity of adverse effects can be increased when Brotizolam is combined with Acetazolamide.
AdipiplonThe risk or severity of adverse effects can be increased when Adipiplon is combined with Brotizolam.
AgomelatineThe risk or severity of adverse effects can be increased when Agomelatine is combined with Brotizolam.
AlaproclateThe risk or severity of adverse effects can be increased when Brotizolam is combined with Alaproclate.
AlfaxaloneThe risk or severity of adverse effects can be increased when Brotizolam is combined with Alfaxalone.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Brotizolam.
AlimemazineThe risk or severity of adverse effects can be increased when Brotizolam is combined with Alimemazine.
Food Interactions
Not Available

References

Synthesis Reference

Brotizolam synthesis: Weber, K. H.; Bauer, A.; Danneberg, P.; Kuhn, F. J.; 1978, U.S. Patent 4,094,984.

General References
  1. Jochemsen R, Wesselman JG, van Boxtel CJ, Hermans J, Breimer DD: Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects. Br J Clin Pharmacol. 1983;16 Suppl 2:291S-297S. [PubMed:6140948]
External Links
KEGG Drug
D01744
PubChem Compound
2451
PubChem Substance
310264974
ChemSpider
2357
BindingDB
50011875
ChEBI
31308
ChEMBL
CHEMBL32479
Drugs.com
Drugs.com Drug Page
Wikipedia
Brotizolam
ATC Codes
N05CD09 — Brotizolam
MSDS
Download (316 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers3
3CompletedTreatmentSleep Initiation and Maintenance Disorders1
3Not Yet RecruitingPreventionSleeplessness1
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4094984No1974-03-021994-03-02Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)211-213U.S. Patent 4,094,984.
Predicted Properties
PropertyValueSource
Water Solubility0.058 mg/mLALOGPS
logP3.28ALOGPS
logP2.68ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)18.49ChemAxon
pKa (Strongest Basic)3.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area43.07 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity101.93 m3·mol-1ChemAxon
Polarizability34.99 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Download (85.7 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Mass Spectrum (Electron Ionization)MSsplash10-0006-6559000000-7456ba6570cdfa674b63
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as thienodiazepines. These are heteropolycyclic containing a thiophene ring fused to a diazepine ring. Thiophene is 5-membered ring consisting of four carbon and one sulfur atoms. Diazepine is a 7-membered ring consisting of five carbon and two nitrogen atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thienodiazepines
Sub Class
Not Available
Direct Parent
Thienodiazepines
Alternative Parents
2,3,5-trisubstituted thiophenes / Chlorobenzenes / 1,4-diazepines / Aryl chlorides / Aryl bromides / Triazoles / Heteroaromatic compounds / Ketimines / Propargyl-type 1,3-dipolar organic compounds / Azacyclic compounds
show 4 more
Substituents
Thieno-para-diazepine / 2,3,5-trisubstituted thiophene / Para-diazepine / Chlorobenzene / Halobenzene / Aryl bromide / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Benzenoid
show 17 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Drug created on June 23, 2014 14:43 / Updated on October 01, 2018 14:45