Sunday, 13 July 2014

BROMAZEPAM SYNTHESIS

Bromazepam.svg

Bromazepam
Bromazepam-from-xtal-3D-balls.png
Systematic (IUPAC) name
7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one
Clinical data
Trade namesLexotan, Lexotanil
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy cat.D (USA)
Legal statusSchedule IV(US)
RoutesOral
Pharmacokinetic data
Bioavailability84%
MetabolismHepatic
Half-life12-20 hours
ExcretionRenal
Identifiers
CAS number1812-30-2 Yes
ATC codeN05BA08
PubChemCID 2441
DrugBankDB01558
ChemSpider2347 Yes
UNIIX015L14V0O Yes
KEGGD01245 Yes
ChEMBLCHEMBL277062 Yes
Chemical data
FormulaC14H10BrN3O 
Mol. mass316.2

Chemical  Synthesis Of Bromazepam






Synthesis

anthranilamide + P4O10 Phosphorus pentoxide → anthranilonitrile + 2-pyridyllithium → 2-(2-Aminobenzoyl)pyridine.

Bromazepam synthesis.[60]


Bromazepam
Use: tranquilizer
 7- bromo- 1 ,3- di hydro- 5- (2- pyridinyl)- 2 H- 1 ,4- benzo diazepine- 2- one
 MW: 316.16 MF: C14H10BrN3O
 LD50: 879 mg/kg (M, p.o.);1950 mg/kg (R, p.o.)
Bromazepam Reference(s):
 US 3 100 770 (Roche; 13.8.1963; appl. 11.8.1961).
US 3 182 065 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963).
US 3 182 066 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963).
US 3 182 067 (Roche; 4.5.1965; appl. 9.4.1964).
Fryer, R.I. et al.: J. Pharm. Sci. (JPMSAE) 53, 264 (1964).

modified methods:
DAS 2 233 483 (Roche; appl. 7.7.1972; GB-prior. 8.7.1971, 7.10.1971).
DOS 2 252 378 (Roche; appl. 25.10.1972; CH-prior. 18.11.1971).


alternative synthesis of 2-(2-amino-5-bromobenzoyl)pyridine:
DAS 2 256 614 (Roche; appl. 17.11.1972).
DAS 1 813 241 (Roche; appl. 6.12.1968; J-prior. 8.12.1967, 9.12.1967, 12.12.1967,
25.4.1968).

combination with sulpiride:
DAS 2 342 214 (Roche; appl. 21.8.1973; CH-prior. 21.9.1972).

A white or yellowish crystalline powder. M.p. 237° to 238.5° with decomposition.
Practically insoluble in water, sparingly soluble in alcohol and in dichloromethane.

Bromazepam Dissociation Constant.

pKa2.9, 11.0.

Partition Coefficient.

Log P(octanol/water), 2.05.

Colour Test.

Formaldehyde–Sulfuric Acid—yellow.

Bromazepam Thin–layer Chromatography.

System TA—Rf 61; system TB—Rf 6; system TC—Rf 41; system TD—Rf 13; system TE—Rf 63; system TF—Rf 18; system TL—Rf 53; system TAD—Rf 47; system TAE—Rf 73; system TAF—Rf 69; system TAJ—Rf 34; system TAK—Rf 04; system TAL—Rf 63.

Bromazepam Gas Chromatography.

System GA—bromazepam RI 2665, M (3-OH-) RI 2470; system GB—bromazepam RI 2760, bromazepam-TMS RI 2702; M (3-OH-)-TMS2 RI 2650; system GG—RI 3280.
Column: DB-17 (30 m × 0.32 mm i.d., 0.25 μm film thickness). Column temperature: 150°, held for 1 min, ramp to 230°, held for 5 min, ramp to 300° held for 9 min at 10°/min. Injector and detector temperatures: 270° and 300°, respectively. Carrier gas: helium (pre–column pressure, 80 kPa). Detection: ECD. Retention time: 18.0 min. [F. Guan et al.,J. Anal. Toxicol.,1999, 23, 54–61.]
Column: HP5-MS (5% phenyl:95% siloxane, 30 m × 0.25 mm, 0.25 μm film thickness). Column temperature: 60° held for 1 min, ramp to 295° at 30°/min, held for 6 min. Injector temperature: 250°. Carrier gas: helium, flow rate 1 mL/min. MS detection (NCI mode). Retention time: 9.7 min. [P. Kintz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 700, 119–129.]

Bromazepam High Performance Liquid Chromatography.

System HI—k 2.32; system HK—k 2.99; system HX—RI 397; system HY—RI 331; system HZ—retention time 3.0 min; system HAA—retention time 14.7 min; system HAF—retention time 6.6 min (tailing peak); system HAX—retention time 5.8 min; system HAY—retention time 5.1 min; system HBH—k 1.63; system HBI—k 0.80; system HAL—retention time 8.1 min; system HAM—not detected.
Column: RP C18 (150 × 3.9 mm i.d., 5 μm). Mobile phase: water:acetonitrile:triethylamine (700:300:4), adjusted to pH 7.4 with phosphoric acid, flow rate 2 mL/min. UV detection (λ = 240 nm). Retention time: bromazepam, 2.1 min,α-hydroxytriazolam (IS), 3.2 min. [Le Solleu et al.,J. Pharm. Biomed. Anal.,1993, 11, 771–775.]

Bromazepam Ultraviolet Spectrum.

Aqueous acid—239, 345 nm; aqueous alkali—237 nm (A11=920b), 348 nm; methanol—233 nm (A11=1050b), 320 nm (A11=61b).

Bromazepam Infra–red Spectrum.

Principal peaks at wavenumbers 1685, 825, 750, 802, 1315, 1230 cm−1.

Bromazepam Mass Spectrum.

Principal ions at m/z 236, 317, 315, 288, 316, 286, 208, 78; 3–hydroxybromazepam 79, 78, 52, 105, 304, 314, 316, 51.

Quantification.

Gas chromatography.

In plasma: limit of detection 5 μg/L, ECD—U. Klotz,J. Chromatogr.,1981, 222(21) B Biomed. Appl., 501–506. In plasma or blood: bromazepam and other benzodiazepines, ECD and NPD—P. Lillsunde and T. Seppala,J. Chromatogr.,1990, 533, 97–110. In hair: limit of detection, 20 pg/mg hair, MS (NCI mode)—P. Kintz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 700, 119–129. In urine: bromazepam and other benzodiazepines, limit of detection for bromazepam 160 μg/L, ECD—F. Guan et al.,J. Anal. Toxicol.,1999, 23, 54–61.

Bromazepam Gas chromatography–mass spectrometry.

In tissue: limit of quantification, 50 ng/g tissue, SIM—X.X. Zhang et al.,J. Chromatogr.,1996, 677 B Biomed. Appl., 111–116. In urine: bromazepam, diazepam, and nordazepam, TOF–MS, comparison with MS and ECD—B. Aebi et al.,Forensic Sci. Int.,2002, 128, 84–89.

Bromazepam High performance liquid chromatography.

In plasma: limit of detection 5 μg/L, UV detection—H. Hirayama et al.,J. Chromatogr.,1983, 277(28) B Biomed. Appl., 414–418. In plasma: limit of detection 3 μg/L, UV detection—A. Boukhabza et al.,Analyst,1989, 114, 639–641. In plasma: limit of detection, 50 μg/L, UV detection—H. Le Solleu et al.,J. Pharm. Biomed. Anal.,1993, 11, 771–775. In serum: bromazepam and other benzodiazepines, UV detection—E. Tanaka et al.,J. Chromatogr.,1996,682 B Biomed Appl., 173–178 and E. Tanaka et al.,J. Chromatogr. B Biomed. Sci. Appl.,1998, 709, 324.

Bromazepam Disposition in the Body.

Well absorbed after oral administration and peak plasma concentrations are usually achieved within 2 h. About 70% of a dose is excreted in the urine in 72 h, including about 2% of the dose as unchanged bromazepam, about 27% as the glucuronide of 3–hydroxybromazepam, about 40% as the glucuronide of 2–amino–5–bromo–3–hydroxybenzoylpyridine, and less than 1% as 2-(2–amino–5–bromobenz–oyl)-pyridine.

Bromazepam Therapeutic concentration

After a single oral dose of 12 mg, administered to 10 subjects, peak plasma concentrations of 0.11 to 0.17 mg/L (mean 0.13) were attained in 1 to 4 h. Steady–state concentrations of 0.08 to 0.15 mg/L (mean 0.12) were measured during dosing of 6 subjects with 9 mg daily. [S. A. Kaplan et al.,J. Pharmacokinet. Biopharm.,1976, 4, 1–16.]
Administration of bromazepam as a slow–release formulation to 24 healthy subjects after an overnight fast resulted in peak plasma concentrations of 9.09 to 13.00 μg/L (mean 11.05 μg/L) attained in 4 to 16 h (mean 8 h); the corresponding values for a conventional–release preparation administered as 2 separate 1.5 mg doses, 12 h apart, were 8.91 to 11.50 μg/L (mean 10.21 μg/L) in 2 to 8 h (mean 8 h). [F. E. Lerner et al.,Arzneimittelforschung,2001,51, 955–958.]

Toxicity

In a 68–year–old woman who was found unconscious and barely breathing, bromazepam intoxication was discovered to be the cause (a serum level of 6 mg/L was detected); normal functions were restored 12 days after the ingestion. [J. Rudolf et al.,Dtsch. Med. Wochenschr.,1998, 123, 832–834.]
A 42–year–old woman ingested 420 mg bromazepam in a suicide attempt and survived despite being found unconscious outdoors in a state of semi–undress and suffering from hypothermia. About 12 h after the ingestion the blood concentration of bromazepam was 7.7 mg/L. [K. Michaud et al.,Forensic Sci. Int.,2001, 124, 112–114.]

Bromazepam Half–life.

Plasma half–life, 8 to 19 h (mean 12).

Bromazepam Volume of distribution.

About 0.9 L/kg.

Bromazepam Protein binding.

In plasma, 70%.

Bromazepam Dose.

Usually 3 to 18 mg daily; up to a maximum of 60 mg daily in divided doses has been given to hospitalised patients.
tags-synthesis of drugs,method of preparation of Bromazepam,molecular weight Bromazepam, molecular formula of  Bromazepam,structure of Bromazepam,A1%1 cm Bromazepam

Bromazepam (marketed under several brand names, including Lectopam, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil,Bromaze, Somalium and Lexotanil)[1] is a benzodiazepine derivative drug, patented by Roche in 1963[2] and developed clinically in the 1970s.[3][4] It has mainly an anti-anxiety agent with similar side effects to diazepam (Valium). In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets.[5] Bromazepam is contraindicated and should be used with caution in women who are pregnant, the elderly, patients with a history of alcohol or other substance abuse disorders and children. Prolonged use of bromazepam causes tolerance and may lead to both physical and psychological dependence on the drug, and as a result, it is a medication which is controlled by international law.

Indications

Side-effects

Bromazepam causes similar side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation,ataxia, memory impairment, and dizziness.[8] Impairments to memory functions are common with bromazepam and include a reducedworking memory and reduced ability to process environmental information.[9][10][11] A 1975 experiment on healthy, male college students exploring the effects of four different drugs on learning capacity observed that taking Bromazepam alone at 6 mg 3 times daily for 2 weeks impaired learning capacities significantly. In combination with alcohol impairments in learning capacity became even more pronounced.[12] Impaired memory, visual information processing and sensory data and impaired psychomotor performance.[13][14][15] Deterioration of cognition including attention capacity and impaired co-ordinative skills.[16][17] Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as lorazepam.[18] Impaired reactive and attention performance, which can impair driving skills.[19]
Drowsiness and decrease in libido.[20][21] On occasion, benzodiazepines can induce extreme alterations in memory such asanterograde amnesia and amnesic automatism, which may have medico-legal consequences. Such reactions occur usually only at the higher dose end of the prescribing spectrum.[22]
Very rarely, dystonia can develop.[23]
Up to 30% treated on a long-term basis develop a form of dependence, i.e. these patients cannot stop the medication without experiencing physical and/or psychological benzodiazepine withdrawal symptoms.
Leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have additionally been seen; the original manufacturer Roche recommends regular laboratory examinations to be performed routinely.
Ambulatory patients should be warned that bromazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.

Tolerance, dependence and withdrawal

Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological dependence and/or physical dependence.[24][25] A withdrawal study demonstrated both psychological dependence and physical dependence on bromazepam including marked rebound anxiety after 4 weeks chronic use. Those whose dose was gradually reduced experienced no withdrawal.[26]
Patients treated with bromazepam for generalised anxiety disorder were found to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms when abruptly withdrawn bromazepam.[27] Abrupt or over rapid withdrawal from bromazepam after chronic use even at therapeutic prescribed doses can lead to a severe withdrawal syndrome including status epilepticus and a condition resembling delerium tremens.[28][29][30]
Animal studies have shown that chronic administration of diazepam or bromazepam causes a decrease in spontaneous locomotor activity, decreased turnover of noradrenalineand dopamine and serotonin, increased activity of tyrosine hydroxylase and increased levels of the catecholamines. During withdrawal of bromazepam or diazepam a fall in tryptophan, serotonin levels occurs as part of the benzodiazepine withdrawal syndrome.[31] Changes in the levels of these chemicals in the brain can cause headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia.[32][33]

Contraindications and special precautions

Benzodiazepines require special precaution if used in elderly, pregnant, child, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[34]

Special populations[

  • Bromazepam may affect driving and ability to operate machinery.[36]

Interactions

Cimetidine, fluvoxamine and propranolol causes a marked increase in the elimination half-life of bromazepam leading to increased accumulation of bromazepam.[39][40][41]

Pharmacology


50 Pills of Lexotanil (containing 6 mg of Bromezepam apiece) as sold byHoffmann-La Roche in Germany
Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam,nitrazepam, flurazepam, and clorazepate.[42] Its molecular structure is composed of a diazepine connected to a benzene ring and apyridine ring, the benzene ring having a bromine atom attached to it.[43] It is a 1,4-benzodiazepine, which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.
Bromazepam binds to the GABA receptor GABAA, causing a conformational change and increasing the inhibitory effects of GABA. Bromazepam is a long-acting benzodiazepine and is lipophilic and metabolised hepatically via oxidative pathways.[44] It does not possess any antidepressant or antipsychotic qualities.[45]
After night time administration of bromazepam a highly significant reduction of gastric acid secretion occurs during sleep followed by a highly significant rebound in gastric acid production the following day.[46]
Bromazepam alters the electrical status of the brain causing an increase in beta activity and a decrease in alpha activity in EEG recordings.[47]

Pharmacokinetics

Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the Cytochrome P450 family of enzymes. In 2003, a team led by Dr. Oda Manami at Oita Medical University reported that CYP3A4, a member of the Cytochrome P450 family, was not the responsible enzyme since itraconazole, a known inhibitor of CYP3A4, did not affect its metabolism.[48] In 1995, J. van Harten at Solvay Duphar B.V.'s Department of Clinical Pharmacology inWeesp reported that fluvoxamine, which is a potent inhibitor of CYP1A2, a less potent CYP3A4 inhibitor, and a negligible inhibitor of CYP2D6, does inhibit its metabolism.[41]
The active metabolite of bromazepam is hydroxybromazepam, which has a half-life approximately equal to that of bromazepam.[citation needed]

Overdose

Main article: Benzodiazepine overdose
Bromazepam is commonly involved in drug overdoses.[49] A severe bromazepam benzodiazepine overdose may result in an alpha pattern coma type.[50] The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotic drugs.[51] Bromazepam is the most common benzodiazepine involved in intentional overdoses in France.[52] Bromazepam has also been responsible for accidental poisonings in companion animals. A review of benzodiazepine poisonings in cats and dogs from 1991-1994 found bromazepam to be responsible for significantly more poisonings than any other benzodiazepine.[53]

Drug misuse

See also: Benzodiazepine drug misuse
Bromazepam has a similar misuse risk as other benzodiazepines such as diazepam.[54] In France car accidents involving psychotropic drugs in combination found benzodiazepines, mainly diazepam, nordiazepam, and bromazepam, to be the most common drug, almost twice that of the next-most-common drug cannabis.[55] Bromazepam has also been used for serious criminal offences including robbery, homicide, and sexual assault.[56][57][58]

Legal status

Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[59]

Synthesis

anthranilamide + P4O10 Phosphorus pentoxide → anthranilonitrile + 2-pyridyllithium → 2-(2-Aminobenzoyl)pyridine.

Bromazepam synthesis.[60]

See also

References

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  59. Jump up^ List of psychotropic substances under international control (PDF). International Narcotics Control Board.
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