439-14-5

Usage

Uses

Used in Pharmaceutical Industry:
Diazepam is used as an anxiolytic for treating anxiety disorders and reducing anxiety symptoms. It helps in calming the nervous system and promoting relaxation.
Diazepam is used as a muscle relaxant (skeletal) for alleviating muscle spasms and tension, particularly in conditions like muscle strains or sprains.
Diazepam is used as an anticonvulsant to control seizures, especially in cases of generalized tonic-clonic status epilepticus, an acute and potentially fatal seizure. It is also used as an adjunctive treatment in patients with refractory epilepsy in combination with other antiepileptic drugs (AEDs).
Diazepam is used as a premedication in anesthesiology to induce sedation and relaxation before surgery.
Diazepam is used in the treatment of various spastic disorders, helping to reduce muscle stiffness and improve mobility.

Originator

Valium,Roche,Italy,1962

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.

Therapeutic Function

Tranquilizer

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 5, p. 731, 1968 DOI: 10.1002/jhet.5570050528

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)AnxiolyticMuscle relaxantStatus 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 drugsAntibacterials: 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 clozapineAntivirals: 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.

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.

InChI:InChI=1/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3

Upstream product

• 4637-24-5 N,N-dimethyl-formamide dimethyl acetal 
• 1088-11-5 desmethyldiazepam 
• 54960-29-1 7-chlor-1-methyl-2-chloromethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin 
• 6021-21-2 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone 
• 77-78-1 dimethyl sulfate 
• 1022-13-5 5-chloro-2-(methylamino)benzophenone 
• 5680-79-5 glycine ethyl ester hydrochloride 
• 98-80-6 phenylboronic acid 
• 719-59-5 5-chloro-2-aminobenzophenone 
• 29176-44-1 benzyl (2-((2-benzoyl-4-chlorophenyl)(methyl)amino)-2-oxoethyl)carbamate 
• 60067-08-5 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide hydrobromide 
• 30189-36-7 N,N'-di-t-butyloxycarbonyl-(S)-lysine N-hydroxysuccinimide ester 
• 22118-09-8 2-bromoacetyl chloride 
• 1007-19-8 4-chloro-N-methyl-N-nitrosoaniline 

Downstream Products

• 42915-41-3 10-chloro-7,11b-dihydro-7-methyl-11b-phenyl-thiazolo<3,2-d><1,4>benzodiazepine-3,6(2H,5H)-dione 
• 39683-94-8 3-benzoyl-10-chloro-7-methyl-11b-phenyl-7,11b-dihydro-benzo[f][1,2,4]oxadiazolo[4,5-d][1,4]diazepin-6-one 
• 39683-97-1 3-tert-butyl-10-chloro-7-methyl-11b-phenyl-7,11b-dihydro-benzo[f][1,2,4]oxadiazolo[4,5-d][1,4]diazepin-6-one 
• 78498-85-8 3-benzylidene-7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 142427-86-9 7-Chloro-3-[1-(4-methoxy-phenyl)-meth-(Z)-ylidene]-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 98826-18-7 10-chloro-3,11b-diphenyl-7-methyl-1-(4-nitrophenyl)-5,6,7,11b-tetrahydro-1H-s-triazolo<4,3-d><1,4>benzodiazepin-6-one 
• 213753-76-5 7-Chloro-3-(2-hydroxy-ethyl)-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 17311-35-2 4'-Hydroxy-Diazepam 
• 1088-11-5 desmethyldiazepam 
• 604-75-1 oxazepam 
• 846-50-4 temazepam 
• 50882-52-5 7-Chloro-1,3-dimethyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one 
• 201230-82-2 carbon monoxide 

Relevant academic research and scientific papers

Intranasal coadministration of a diazepam prodrug with a converting enzyme results in rapid absorption of diazepam in rats

Intranasal administration is an attractive route for systemic delivery of small, lipophilic drugs because they are rapidly absorbed through the nasal mucosa into systemic circulation. However, the low solubility of lipophilic drugs often precludes aqueous nasal spray formulations. A unique approach to circumvent solubility issues involves coadministration of a hydrophilic prodrug with an exogenous converting enzyme. This strategy not only addresses poor solubility but also leads to an increase in the chemical activity gradient driving drug absorption. Herein, we report plasma and brain concentrations in rats following coadministration of a hydrophilic diazepam prodrug, avizafone, with the converting enzyme human aminopeptidase B. Single doses of avizafone equivalent to diazepam at 0.500, 1.00, and 1.50 mg/kg were administered intranasally, resulting in 77.8% 6 6.0%, 112% 6 10%, and 114% 6 7% bioavailability; maximum plasma concentrations 71.5 6 9.3, 388 6 31, and 355 6 187 ng/ml; and times to peak plasma concentration 5, 8, and 5 minutes for each dose level, respectively. Both diazepam and a transient intermediate were absorbed. Enzyme kinetics incorporated into a physiologically based pharmacokinetic model enabled estimation of the first-order absorption rate constants: 0.0689 6 0.0080 minutes21 for diazepam and 0.122 6 0.022 minutes21 for the intermediate. Our results demonstrate that diazepam, which is practically insoluble, can be delivered intranasally with rapid and complete absorption by coadministering avizafone with aminopeptidase B. Furthermore, even faster rates of absorption might be attained simply by increasing the enzyme concentration, potentially supplanting intravenous diazepam or lorazepam or intramuscular midazolam in the treatment of seizure emergencies.

COMPOSITIONS AND METHODS FOR REDUCING TACTILE DYSFUNCTION, ANXIETY, AND SOCIAL IMPAIRMENT

The present invention provides novel peripherally-restricted benzodiazepines with reduced blood brain barrier permeability and methods of use thereof for reducing tactile dysfunction, social impairment, and anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett syndrome, Phelan McDermid syndrome, or Fragile X syndrome.

Photopotentiation of the GABAA receptor with caged diazepam

As the inhibitory γ-aminobutyric acid–ergic (GABAergic) transmission has a pivotal role in the central nervous system (CNS) and defective forms of its synapses are associated with serious neurological disorders, numerous versions of caged GABA and, more recently, photoswitchable ligands have been developed to investigate such transmission. While the complementary nature of these probes is evident, the mechanisms by which the GABA receptors can be pho-tocontrolled have not been fully exploited. In fact, the ultimate need for specificity is critical for the proper synaptic exploration. No caged allosteric modulators of the GABAA receptor have been reported so far; to introduce such an investigational approach, we exploited the structural motifs of the benzodiazepinic scaffold to develop a pho-tocaged version of diazepam (CD) that was tested on basolateral amygdala (BLa) pyramidal cells in mouse brain slices. CD is devoid of any intrinsic activity toward the GABAA receptor before irradiation. Importantly, CD is a photoreleasable GABAA receptor-positive allosteric modulator that offers a different probing mechanism compared to caged GABA and photoswitchable ligands. CD potenti-ates the inhibitory signaling by prolonging the decay time of postsynaptic GABAergic currents upon photoactivation. Additionally, no effect on presynaptic GABA release was recorded. We developed a photochemical technology to individually study the GABAA receptor, which specifically expands the toolbox available to study GABAergic synapses.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

Multistep Flow Synthesis of Diazepam Guided by Droplet-Accelerated Reaction Screening with Mechanistic Insights from Rapid Mass Spectrometry Analysis

Electrospray and Leidenfrost droplet accelerated reactions were used as a predictive tool for estimating the outcome of microfluidic synthesis as demonstrated by Wleklinski et al. Rapid analysis by electrospray-mass spectrometry (ESI-MS) also provided immediate feedback on reaction outcomes in flow reactions. Significant reaction acceleration was observed in electrospray relative to the corresponding bulk reaction. This rapid reaction screening and analysis method has allowed for the detection of previously unreported outcomes in the reaction between 5-chloro-2-(methylamino)benzophenone and haloacetyl chloride (halo = Cl or Br) in the continuous synthesis of diazepam. In our current study, a more detailed extension of the previous work, we report acceleration factors that are solvent dependent; additional byproducts that were observed on the microfluidic scale that were absent in the droplet reactions. Gaining insight from this combined droplet and microfluidic screening/rapid ESI-MS analysis approach, we have helped guide the synthesis of diazepam and showcased the potential of this method as a reaction optimization and discovery tool. Informed by these new insights, diazepam was synthesized in a high-yield two-step continuous flow process.

Denitrogenative Suzuki and carbonylative Suzuki coupling reactions of benzotriazoles with boronic acids

Unprecedented palladium-catalyzed denitrogenative Suzuki and carbonylative Suzuki coupling reactions of benzotriazoles with boronic acids have been realized, which afforded structurally diverse ortho-amino-substituted biaryl and biaryl ketone derivatives. The key to this success is due to the development of a rationally designed strategy to achieve the ring opening of benzotriazoles with a synergistic activating-stabilizing effect, which enables the in situ generation of the corresponding ortho-amino-arenediazonium species. The present work opens up a new avenue to utilize benzotriazoles as synthetic equivalents of ortho-amino-arenediazoniums, which otherwise could not be directly accessed by existing synthetic methods.

Thermolysis and radiofluorination of diaryliodonium salts derived from anilines

Aniline-derived diaryliodonium salts were synthesized and functionalized in good to excellent yields by judicious utilization of electron-withdrawing protecting groups. This simple approach opens another route to radiolabeling amino arenes in relatively complex molecules, such as flutemetamol.

THERAPEUTIC COMPOUNDS AND FORMULATIONS FOR INTRANASAL DELIVERY

Certain embodiments of the invention provide a formulation suitable for nasal administration comprising water, a prodrug of a therapeutic agent, and an enzyme that is suitable for intranasal conversion of the prodrug to the therapeutic agent, as well as methods of use thereof.

New and mild method for the synthesis of alprazolam and diazepam and computational study of their binding mode to GABAA receptor

A new method for the synthesis of 8-chloro-1-methyl-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine (alprazolam) and 7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) from 2-amino-5-chloro benzophenone was described under mild conditions. Most of the synthetic steps were carried out under solvent-free conditions, and the products were obtained in high yield and purity. The products were characterized by comparison of physical properties with authentic samples and also by IR, 1H NMR and 13C NMR. Three-dimensional (3D) model of GABAA was constructed using X-ray crystal structure of homopentameric caenorhabditis elegans glutamate-gated chloride channel (GluCl) (3RHW) at 3.3?? as the template based on sequence comparison and homology modeling method. The homology modeling and MD simulation studies predicted the 3D structure of receptor in a water environment. The resulted conformation of the receptor was used for docking of the alprazolam and diazepam. Docking studies indicated many important interactions of the drugs with the receptor. Furthermore, the complex of GABA with drugs was used in MD simulation to realize the conformation changes of the complex.

On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.