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| | Diazapam Basic information |
| | Diazapam Chemical Properties |
| | Diazapam Usage And Synthesis |
| Chemical Properties | Diazepam is a yellow crystalline powder. | | Chemical Properties | Light Yellow Crystalline Solid | | Originator | Valium,Roche,Italy,1962 | | Uses | Diazepam is an anxiolytic; muscle relaxant (skeletal); anticonvulsant.
Diazepam is a controlled substance (depressant). | | Uses | Anxiolytic; muscle relaxant (skeletal); anticonvulsant.
Controlled substance (depressant). | | Uses | Anxiolitic; muscle relaxant (skeletal); anticonvulsant.
Controlled substance (depressant) | | Definition | ChEBI: Diazepam is a 1,4-benzodiazepinone that is 1,3-dihydro-2H-1,4-benzodiazepin-2-one substituted by a chloro group at position 7, a methyl group at position 1 and a phenyl group at position 5. It has a role as a xenobiotic, an environmental contaminant, an anxiolytic drug, an anticonvulsant and a sedative. It is a 1,4-benzodiazepinone and an organochlorine compound. | | Manufacturing Process | Into a stirred, cooled (10°-15°C) solution of 26.2 grams (0.1 mol) of 2-amino5-chlorobenzophenone β-oxime in 150 ml of dioxane were introduced in small portions 12.4 grams (0.11 mol) of chloracetyl chloride and an equivalent
amount of 3 N sodium hydroxide. The chloracetyl chloride and sodium
hydroxide were introduced alternately at such a rate so as to keep the
temperature below 15°C and the mixture neutral or slightly alkaline. The
reaction was completed after 30 minutes. The mixture was slightly acidified
with hydrochloric acid, diluted with water and extracted with ether. The ether
extract was dried and concentrated in vacuum. Upon the addition of ether to
the oily residue, the product, 2-chloroacetamido-5-chlorobenzophenone βoxime, crystallized in colorless prisms melting at 161°-162°C.
20 ml of 1 N sodium hydroxide were added to a solution of 6.4 grams (20
mmol) of 2chloroacetamido-5-chlorobenzophenone β-oxime. After 15 hours
the mixture was diluted with ice cold 1 N sodium hydroxide and extracted with
ether. The ether extract was discarded. The alkaline solution was acidified with
hydrochloric acid and extracted with methylene chloride. The methylene
chloride solution was concentrated to a small volume and then diluted with
petroleum ether to obtain 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one
4-oxide.
To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-1,4-
benzodiazepin-2(1H)-one 4-oxide in approximately 150 ml of methanol was
added in portions an excess of a solution of diazomethane in ether. After
about one hour, almost complete solution had occurred and the reaction
mixture was filtered. The filtrate was concentrated in vacuum to a small
volume and diluted with ether and petroleum ether. The reaction product, 7-
chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide,
crystallized in colorless prisms. The product was filtered off and recrystallized
from acetone, MP 188°-189°C.
A mixture of 3 grams (0.01 mol) of 7-chloro-1-methyl-5-phenyl-3H-1,4-
benzodiazepin-2(1H)-one 4-oxide, 30 ml of chloroform and 1 ml of
phosphorus trichloride was refluxed for one hour. The reaction mixture was
then poured on ice and stirred with an excess of 40% sodium hydroxide
solution. The chloroform was then separated, dried with sodium sulfate,
filtered and concentrated in vacuo. The residue was dissolved in methylene
chloride and crystallized by the addition of petroleum ether. The product, 7-
chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one, was recrystallized
from a mixture of acetone and petroleum ether forming colorless plates
melting at 125°-126°C.
The manufacturing procedure above is from US Patent 3,136,815. Purification
of diazepam is discussed in US Patent 3,102,116. | | Brand name | Diastat (Valeant); Dizac (Pharmacia & Upjohn); Q-Pam (Quantum Pharmics); Valium (Roche). | | Therapeutic Function | Tranquilizer | | Synthesis Reference(s) | Journal of Heterocyclic Chemistry, 5, p. 731, 1968 DOI: 10.1002/jhet.5570050528 | | General Description | Diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one .Like chlordiazepoxide, repeated administration of diazepamleads to accumulation of an active nordazepam,which can be detected in the blood for more than 1 weekafter discontinuation of the drug. This drug is a long actingfor the same reason. Diazepam is metabolized to nordazepamby CYP2C19 and CYP3A4. Cimetidine, by inhibitingCYP3A4, decreases the metabolism and clearanceof diazepam. Thus, drugs that affect the activityof CYP2C19 or CYP3A4 may alter diazepam kinetics.Because diazepam clearance is decreased in the elderlyand in patients with hepatic insufficiency, a dosage reductionmay be warranted. It is widely used for several anxietystates and has an additional wide range of uses (e.g., asan anticonvulsant, a premedication in anesthesiology, andin various spastic disorders). | | General Description | Diazepam is given orally (Valium) or rectally (Diastat) as anadjunctive treatment in patients with generalized tonic–clonicstatus epilepticus (i.e., an acute and potentially fatal seizure)or in patients with refractory epilepsy in combination withother AEDs.For details on diazepam (Valium), see its discussionunder anxiolytics and sedative–hypnotic agents. | | General Description | Off-white to yellow crystalline powder. Practically odorless. Tasteless at first with a bitter aftertaste. | | Air & Water Reactions | Hydrolysis occurs in aqueous solutions with a maximum stability around pH 5. . Insoluble in water. | | Fire Hazard | Flash point data for Diazapam are not available; however, Diazapam is probably combustible. | | Biological Activity | Ligand at the GABA A receptor benzodiazepine modulatory site. Anxiolytic, anticonvulsant and sedative/hypnotic agent. | | Pharmacokinetics | The second group of antispastic drugs to be developed were the benzodiazepines, typified by
diazepam. Diazepam exerts its skeletal muscle relaxant effect by binding as an agonist at the
benzodiazepine receptor of the GABAA receptor complex, which enhances GABA potency to increase chloride
conductance. The muscle relaxant properties of classical benzodiazepines,
such as diazepam, appear to be mediated mainly by the GABAA α2 and α3 subunits. The
result is neuronal hyperpolarization, probably at both supraspinal and spinal sites for spasmolytic
activity. Its actions are sufficient to relieve spasticity in patients with lesions affecting the spinal
cord and in some patients with cerebral palsy. | | Clinical Use | Benzodiazepine:
Perioperative sedation (IV)
Anxiolytic
Muscle relaxant
Status epilepticus | | Side effects | Few high-quality clinical trials have evaluated
diazepam as a muscle relaxant, but these few suggest that diazepam is no more efficacious than,
for example, carisoprodol, cyclobenzaprine, or tizanidine (i.e., efficacy is marginal).
Moreover, diazepam produces drowsiness and fatigue in most patients at doses required to
significantly reduce muscle tone. | | Safety Profile | Poison by ingestion,
parenteral, subcutaneous, intravenous, and
intraperitoneal routes. Moderately toxic by
skin contact. Questionable carcinogen with
experimental tumorigenic data. Human
systemic effects: dermatitis, effect on
inflammation or mediation of inflammation,
change in cardiac rate, somnolence,
respiratory depression, and other respiratory
changes, visual field changes, diplopia
(double vision), change in motor activity,
muscle contraction or spasticity, ataxia (loss
of muscle coordination), an antipsychotic
and general anesthetic. Human reproductive
effects by ingestion and intravenous routes
causing developmental abnormalities of the
fetal cardiovascular (circulatory) system and
postnatal effects. Experimental teratogenic
and reproductive effects. Human mutation
data reported. An allergen. A drug for the
treatment of anxiety. When heated to
decomposition it emits very toxic fumes of
Cl and NOx. | | Drug interactions | Potentially hazardous interactions with other drugs
Antibacterials: metabolism enhanced by rifampicin;
metabolism inhibited by isoniazid.
Antifungals: concentration increased by fluconazole
and voriconazole - risk of prolonged sedation.
Antipsychotics: increased sedative effects;
increased risk of hypotension, bradycardia and
respiratory depression with parenteral diazepam
and IM olanzapine; risk of serious adverse effects in
combination with clozapine
Antivirals: concentration possibly increased by
ritonavir.
Sodium oxybate: enhanced effects of sodium oxybate
- avoid. | | Metabolism | Diazepam is rapidly and completely absorbed after oral administration. Maximum peak blood concentration occurs in
2 hours, and elimination is slow, with a half-life of approximately 20 to 50 hours. As with chlordiazepoxide, the major
metabolic product of diazepam is N-desmethyldiazepam, which is pharmacologically active and undergoes even
slower metabolism than its parent compound. Repeated administration of diazepam or chlordiazepoxide leads to
accumulation of N-desmethyldiazepam, which can be detected in the blood for more than 1 week after
discontinuation of the drug. Hydroxylation of N-desmethyldiazepam at the 3-position gives the active metabolite
oxazepam. | | storage | Store at RT | | Shipping | UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical
Name Required. UN3249 Medicine, solid, toxic, n.o.s.,
Hazard Class: 6.1; Labels: 6.1-Poisonous materials. |
| | Diazapam Preparation Products And Raw materials |
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