604-75-1

Basic information

• Product Name: OXAZEPAM
• Synonyms: 1,3-dihydro-7-chloro-3-hydroxy-5-phenyl-2h-1,4-benzodiazepin-2-one;2H-1,4-Benzodiazepin-2-one, 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-;2h-1,4-benzodiazepin-2-one,7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-[qr];7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one;7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2h-1,4-benzodiazepin-2-one[qr];7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine-2-one;7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2h-1,4-benzodiazepine-2-one[qr];7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2h-4-benzodiazepin-2-one
• CAS NO: 604-75-1
• Molecular Formula: C₁₅H₁₁ClN₂O₂
• Molecular Weight: 286.71
• EINECS: 210-076-9
• Product Categories: API;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;+8618031153937;Oxazepam ada@tuskwei.com whatsapp
• Mol File: 604-75-1.mol

Chemical Properties

• Melting Point: 205-206°
• Boiling Point: 506.5oC at 760 mmHg
• Flash Point: 11 °C
• Appearance: /
• Density: 1.3052 (rough estimate)
• Vapor Pressure: 4.4E-11mmHg at 25°C
• Refractive Index: 1.5200 (estimate)
• Storage Temp.: −20°C
• Solubility: Practically insoluble in water, slightly soluble in ethanol (96 per cent).
• PKA: pKa 1.6/11.6(5% MeOH in H2O,t =20,I=0.15) (Uncertain)
• Water Solubility: 20mg/L(22 oC)
• CAS DataBase Reference: OXAZEPAM(CAS DataBase Reference)
• NIST Chemistry Reference: OXAZEPAM(604-75-1)
• EPA Substance Registry System: OXAZEPAM(604-75-1)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 40-39/23/24/25-23/24/25-11
• Safety Statements: 7-16-36/37-45
• RIDADR: UN 1230 3/PG 2
• WGK Germany: 3
• RTECS: DF1400000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 604-75-1(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Oxazepam is used as an anxiolytic for the short-term relief of anxiety symptoms. It acts as a muscle relaxant for skeletal muscles, providing relief from muscle spasms and tension. Additionally, it serves as an anticonvulsant, helping to prevent and control seizures. Oxazepam also functions as a ligand for the GABAA receptor benzodiazepine modulatory site, enhancing the effects of GABA and promoting relaxation.
Used in Controlled Substances:
Oxazepam is classified as a controlled substance (depressant) due to its potential for dependency and abuse. It is important to use this medication under the supervision of a healthcare professional and follow the prescribed dosage to minimize the risk of dependency.

Originator

Serax,Wyeth,US,1965

Manufacturing Process

(A) Suspend 10 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2one 4-oxide in 150 ml of acetic anhydride and warm on a steam bath with stirring until all the solid has dissolved. Cool and filter off crystalline, analytically pure 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4benzodiazepin-2-one, melting point 242°C to 243°C. (B) Add to a suspension of 3.4 g of 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl2H-1,4-benzodiazepin-2-one in 80 ml of alcohol.6 ml of 4 N sodium hydroxide. Allow to stand after complete solution takes place to precipitate a solid. Redissolve the solid by the addition of 80 ml of water. Acidify the solution with acetic acid to give white crystals. Recrystallize from ethanol to obtain 7chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, melting point 203°C to 204°C.

Therapeutic Function

Tranquilizer

Air & Water Reactions

Insoluble in water.

Reactivity Profile

OXAZEPAM is stable in light and is non hygroscopic. OXAZEPAM is stable in neutral solution. OXAZEPAM is hydrolyzed by acids and bases.

Fire Hazard

Flash point data for OXAZEPAM are not available; however, OXAZEPAM is probably combustible.

Pharmacokinetics

The half-life of oxazepam is approximately 4 to 8 hours, and cumulative effects with chronic therapy are much less than with long-acting benzodiazepines, such as chlordiazepoxide and diazepam. Lorazepam is the 2′-chloro derivative of oxazepam and has a similarly short half-life (2–6 hours) and pharmacological activity.

Clinical Use

Oxazepam

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: metabolism possibly increased by rifampicin. Antipsychotics: enhanced sedative effects; risk of serious adverse effects in combination with clozapine. Antivirals: possibly increased concentration with ritonavir. Sodium oxybate: enhanced effects of sodium oxybate - avoid. Ulcer-healing drugs: metabolism inhibited by cimetidine.

Metabolism

Oxazepam is an active metabolite of both chlordiazepoxide and diazepam and is marketed separately, as a shortacting anxiolytic agent. Oxazepam is rapidly inactivated to glucuronidated metabolites that are excreted in the urine.

InChI:InChI=1/C15H11ClN2O2/c16-10-6-7-12-11(8-10)13(9-4-2-1-3-5-9)18-15(20)14(19)17-12/h1-8,15,20H,(H,17,19)/t15-/m1/s1

Upstream product

• 439-14-5 diazepam 
• 1824-74-4 l-oxazepam acetate 
• 1824-74-4 d-oxazepam acetate 
• 1824-74-4 l-oxazepam acetate 
• 1824-74-4 d-oxazepam acetate 
• 4016-85-7 5-chloro-2-(chloroacetylamino)benzophenone 
• 719-59-5 5-chloro-2-aminobenzophenone 
• 2888-63-3 2-Chloracetamino-5-chlor-benzophenon-α-oxim 
• 963-39-3 demoxepam 
• 18097-52-4 2-amino-5-chlorobenzophenone oxime 
• 17977-76-3 2-chloro-N-{4-chloro-2-[(hydroxyimino)(phenyl)methyl]phenyl}acetamide 
• 846-50-4 temazepam 
• 1088-11-5 desmethyldiazepam 
• 4700-56-5 Oxazepam hemisuccinate 

Downstream Products

• 18878-19-8 3-O-methyloxazepam 
• 91254-23-8 7-Chloro-3-hydroxy-1-hydroxymethyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 4951-07-9 3-O-ethyloxazepam 
• 67-56-1 methanol 
• 130753-94-5 2-Methyl-3-nitro-benzoic acid 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 128014-58-4 9H-β-Carboline-3-carboxylic acid 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 71107-56-7 oxazepam β-phenyl-propionate 
• 719-59-5 5-chloro-2-aminobenzophenone 
• 604-75-1 (+)-Oxazepam 
• 604-75-1 (-)-Oxazepam 
• 5958-05-4 6-chloro 4-phenyl quinazoline 2 carboxaldehyde 
• 60628-57-1 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one 

Relevant articles and documents

Oxazepam-Dopamine Conjugates Increase Dopamine Delivery into Striatum of Intact Rats

The neurotransmitter dopamine (DA) was covalently linked to oxazepam (OXA), a well-known positive allosteric modulator of γ-aminobutyric acid type-A (GABAA) receptor, through a carbamate linkage (4) or a succinic spacer (6). These conjugates were synthesized with the aim of improving the delivery of DA into the brain and enhancing GABAergic transmission, which may be useful for the long-term treatment of Parkinson disease (PD). Structure-based permeability properties, in vitro stability, and blood-brain barrier (BBB) permeability studies led to identify the OXA-DA carbamate conjugate 4a as the compound better combining sufficient stability and ability to cross BBB. Finally, in vivo microdialysis experiments in freely moving rats demonstrated that 4a (20 mg/kg, i.p.) significantly increases extracellular DA levels into striatum, with a peak (more than 15-fold increase over the baseline) at about 80 min after a single administration. The stability and delivery data proved that 4a may be a promising candidate for further pharmacological studies in animal models of PD.

In vivo evaluation of substituted 3-amino-1,4-benzodiazepines as anti-depressant, anxiolytic and anti-nociceptive agents

Oxazepam (CAS 604-75-1) 4 a served as building block in the synthesis of substituted 3-amino-l,4-benzodiazepines, which were subsequently tested in various CNS animal models. The hydroxy group of oxazepam was either activated as a chloride (Method A) or as a phos- phor-oxy derivative (Method B) giving the desired 3-amino-l,4-benzodiapines 6 a- 6r in high yields with primary and secondary amines in a typical nucleophilic substitution reaction. Eighteen 3-substi- tuted 1,4-benzodiazepines were prepared and served as new chemical entities and for lead structure discovery. The mixed cholecystokinin (CCK) antagonist 6 e showed anxiolytic and antidepressant effects from 10μg/kg in mice in the elevated x-maze test and the forced swimming test. The CCK 1 antagonist 6 g has shown antidepressant effects from the same dose, but lacked anxiolytic properties. Both compounds potentiated at a dose of 0.5 mg/kg morphine antinocicep- tion with a maximum possible effect (MPE) about 35 %. By assessing initially the MPE of antinocipection for the 18 newly synthesised benzodiazepines in the tail-flick test, 4 other benzodiazepines were found active. In further in vivo evaluation the cyclohexyl derivative 6 i displayed anxiolytic, antidepressant and antinociceptive properties as single agent at a dose of 5 mg/kg without toxicity. The benzodiazepines 6i and 6p, which initially showed a higher MPE in terms of morphine potentiation (43/44%) showed analgesic effects as single agents, without having anxiolytic or antidepressant properties. The amino-piperidinyl derivative 6 p displayed a similar dose-response relationship to morphine, but was 3 times more potent. ECV Editio Cantor Verlag, Aulendorf (Germany).

Efficient synthesis of 3-hydroxy-1,4-benzodiazepines oxazepam and lorazepam by new acetoxylation reaction of 3-position of 1,4-benzodiazepine ring

Simple, efficient, and scalable syntheses of 3-hydroxy-1,4-benzodiazepines, oxazepam (1), and lorazepam (2) were developed. The syntheses are based on the new acetoxylation reaction of the 3-position of the 1,4-benzodiazepine ring. The reaction involves iodine (20-50 mol %)-catalyzed acetoxylation in the presence of potassium acetate (2 equiv) and potassium peroxydisulfate (1-2 equiv) as a stoichiontetric oxidant affording the corresponding 3-acetoxy-1,4- benzodiazepines in good-to-high yields. The latter were converted by selective saponification to 3-hydroxy-1,4-benzodiazepines of very high purity (>99.8%) in an overall yield of 83% (oxazepam) and 64% (lorazepam).

Synthesis of substituted 3-anilino-5-phenyl-1,3-dihydro-2H-1,4- benzodiazepine-2-ones and their evaluation as cholecystokinin-ligands

3-Amino-1,4-benzodiazepines as well as chemically related diverse amines were prepared from oxazepam and subsequently screened on the cholecystokinin receptor in a radiolabel binding assay. Oxazepam 2 was activated via its 3-chloro-1,4-benzodiazepine intermediate 3 and was reacted with a large series of aliphatic and aromatic amines. The substituted 3-anilino-1,4-benzodiazepine structure was identified as lead structure in a diverse series of 3-amino-1,4-benzodiazepines 4-38 and the full SAR (structure-activity relationship) optimisation provided 3-anilinobenzodiazepines 16-38 with CCK 1 receptor selectivity to CCK2. The compounds 18, 24, 28 and 33 have shown affinities at the CCK1 receptor of 11, 10, 11 and 9 nM, respectively. These equipotent CCK1 ligands were fully evaluated in behaviour pharmacological essays. An antidepressant effect was identified in the tail suspension- and the Porsolt swimming-test. The ED50 values for 24 and 28 were determined in these assays as 0.46 and 0.49 mg/kg. The mixed antagonist 37 showed in addition to the antidepressant effects anxiolytic properties.

NOVEL 3-SUBSTITUTED-1,4-BENZODIAZEPINES

The present invention relates to compounds of formula (I). The invention also relates to methods for preparing the compounds and their uses as CCK receptor ligands and CCK antagonists.

Process for catalyzing the oxidation of organic compounds

Oxidation of organic compounds is catalyzed by addition of a catalytic amount of a metalloporphyrin in a non-reactive aprotic solvent.

Concentration-dependent metabolism of diazepam in mouse liver

Previous mouse liver studies with diazepam (DZ), N-desmethyldiazepam (NZ), and temazepam (TZ) confirmed that under first-order conditions, DZ formed NZ and TZ in parallel. Oxazepam (OZ) was generated via NZ and not TZ despite that preformed NZ and TZ were both capable of forming OZ. In the present studies, the concentration-dependent sequential metabolism of DZ was studied in perfused mouse livers and microsomes, with the aim of distinguishing the relative importance of NZ and TZ as precursors of OZ. In microsomal studies, the K(m)s and V(max)s, corrected for binding to microsomal proteins, were 34 μM and 3.6 nmole/min per mg and 239 μM and 18 nmole/min per mg, respectively, for N-demethylation and C3-hydroxylation of DZ. The K(m)s and V(max)s for N-demethylation and C3-hydroxylation of TZ and NZ, respectively, to form OZ, were 58 μM and 2.5 nmole/min per mg and 311 μM and 2 nmole/min per mg, respectively. The constants suggest that at low DZ concentrations, NZ formation predominates and is a major source of OZ, whereas at higher DZ concentrations, TZ is the important source of OZ. In livers perfused with DZ at input concentrations of 13 to 35 μM, the extraction ratio of DZ (E→DZ←) decreased from 0.83 to 0.60. NZ was the major metabolite formed although its appearance was less than proportionate with increasing DZ input concentration. By contrast, the formation of TZ increased disproportionately with increasing DZ concentration, whereas that for OZ decreased and paralleled the behavior of NZ. Computer simulations based on a tubular flow model and the in vitro enzymatic parameters provided a poor in vitro-organ correlation. The E→DZ←, appearance rates of the metabolites, and the extraction ratio of formed NZ (E→NZ,DZ←) were poorly predicted; TZ was incorrectly identified as the major precursor of OZ. Simulations with optimized parameters improved the correlations and identified NZ as the major contributor of OZ. Saturation of DZ N-demethylation at higher DZ concentrations increased the role of TZ in the formation of OZ. The poor aqueous solubility (limiting the concentration range of substrates used in vitro), avid tissue binding and the coupling of enzymatic reactions in liver, favoring sequential metabolism, are possible explanations for the poor in vitro-organ correlation. This work emphasizes the complexity of the hepatic intracellular milieu for drug metabolism and the need for additional modeling efforts to adequately describe metabolite kinetics.

Kinetics of diazepam metabolism in rat hepatic microsomes and hepatocytes and their use in predicting in vivo hepatic clearance

The rates of diazepam (DZ) metabolism to the primary metabolites 3-hydroxydiazepam, 4'-hydroxydiazepam and nordiazepam were studied in vitro using rat hepatic microsomes and hepatocytes. 4'-hydroxydiazepam had the largest intrinsic clearance (V(max)/K(m) ratio, CL(int)) in both microsomes and hepatocytes representing 49 and 70% of total metabolism respectively. Whereas the contribution of 3-hydroxydiazepam was similar in both systems (21-24%), the N-demethylation pathway was greater in microsomes (27%) than hepatocytes (9%). The pharmacokinetics of DZ were determined in vivo using the intraportal route to avoid blood flow limitations due to the high clearance of DZ. No dose dependency was observed in either clearance or steady state volume of distribution, which were estimated to be 38 ml/min/SRW (where SRW is a standard rat weight of 250g) and 1.3 L/SRW respectively. Blood binding of DZ was concentration independent, the unbound fraction being 0.22. Scaling factors were used to relate the in vitro CL(int) to the in vivo unbound clearance. Hepatocytes (123 ml/min/SRW) produced a more realistic prediction for the in vivo value (174ml/min/SRW) than microsomes (41 ml/min/SRW). This situation is believed to arise from the quantitative differences in the three metabolic pathways in the two in vitro systems. It is speculated that end product inhibition is responsible for reduced total metabolism in microsomes whereas hepatocytes operate kinetically in a manner close to in vivo.

Racemization kinetics of enantiomeric oxazepams and stereoselective hydrolysis of enantiomeric oxazepam 3-acetates in rat liver microsomes and brain homogenate.

Enantiomers of oxazepam and of 3-O-acyl, 1-N-acyl-3-O-acyl, and 3-O-methyl ether derivatives of oxazepam were resolved on HPLC columns packed with Pirkle's chiral stationary phases [CSP; (R)-N-(3,5-dinitrobenzoyl)phenylglycine or (S)-N-(3,5-dinitrobenzoyl)leucine] bonded either ionically or covalently to spherical particles of gamma-aminopropylsilanized silica, and on a column packed with poly-N-acryloyl-(S)-phenylalanine ethyl ester bonded covalently to silica gel (Chiraspher). Resolution was achieved, with several mobile phases of different solvent compositions and with varying chromatographic resolutions, on all of the chiral stationary phases tested. Resolved enantiomers of oxazepam undergo racemization, whereas enantiomers of 3-O-acyl and 3-O-methyl derivatives are stable. Racemization half-lives of oxazepam enantiomers were determined by monitoring changes in ellipticity as a function of time on a spectropolarimeter immediately (within 30 s) following resolution of enantiomers and were found to substantially vary, depending on the solvents used. Rates of hydrolysis of racemic and enantiomeric 3-O-acyl-oxazepams by esterases in liver microsomes and brain homogenate of rats were determined by a simple and sensitive CSP-HPLC method. The relative rate of hydrolysis was 3R greater than racemate much greater than 3S by rat liver microsomes and 3S greater than racemate much greater than 3R by rat brain homogenate.