846-50-4

Basic information

• Product Name: TEMAZEPAM
• Synonyms: Planum;Remestan;Restoril;Ro 5-5345;ro5-5345;Ro-5-5354;Signopam;WY 2917
• CAS NO: 846-50-4
• Molecular Formula: C₁₆H₁₃ClN₂O₂
• Molecular Weight: 300.74
• EINECS: 212-688-1
• Product Categories: Heterocycles;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Isotope Labeled Compounds;Heterocycles, Metabolites & Impurities, Pharmaceuticals, Intermediates & Fine Chemicals;pharmaceutical intermediate
• Mol File: 846-50-4.mol

Chemical Properties

• Melting Point: 119-121°C
• Boiling Point: 211°C (rough estimate)
• Flash Point: 11 °C
• Appearance: /
• Density: 1.2682 (rough estimate)
• Vapor Pressure: 6.33E-13mmHg at 25°C
• Refractive Index: 1.5200 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in ethanol (96 per cent).
• PKA: pKa 1.6 (Uncertain)
• CAS DataBase Reference: TEMAZEPAM(CAS DataBase Reference)
• NIST Chemistry Reference: TEMAZEPAM(846-50-4)
• EPA Substance Registry System: TEMAZEPAM(846-50-4)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 22-39/23/24/25-23/24/25-11
• Safety Statements: 16-36/37-45-7
• RIDADR: UN 1230 3/PG 2
• WGK Germany: 3
• RTECS: DF1225000
• Hazardous Substances Data: 846-50-4(Hazardous Substances Data)

Usage

Chemical Properties

Crystalline Solid

Originator

Levanxol,Carlo Erba,Italy,1970

Uses

Different sources of media describe the Uses of 846-50-4 differently. You can refer to the following data:
1. Pharmacologically active metabolite of Diazepam. Controlled substance (depressant). Sedative, hypnotic
2. Pharmacologically active labelled metabolite of Diazepam. Controlled substance (depressant). Sedative, hypnotic
3. Temazepam, is pharmacologically active metabolite of Diazepam (D416855). It is Sedative, and hypnotic. Controlled substance (depressant).

Manufacturing Process

According to British Patent 1,022,645 3.4 g of 3-acetoxy-7-chloro-1-methyl-5- phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one suspended in 80 ml alcohol was treated with 6 ml of 4 N NaOH. After complete solution had taken place, a solid precipitated; this solid was redissolved by the addition of 80 ml of water. The solution was acidified with acetic acid to give white crystals which were recrystallized from alcohol to yield 7-chloro-3-hydroxy-5-phenyl-1- methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, MP 119° to 121°C.

Brand name

Restoril (Tyco); Temaz (Quantum Pharmics).

World Health Organization (WHO)

Temazepam is a widely used benzodiazepine derivative. As with other drugs in this class, cases of misuse and drug dependence are known.

General Description

Temazepam, 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl -2H-1,4-benzodiazepine-2-one(Restoril), also occurs as a minor metabolite of diazepam.It can be visualized as N-methyl oxazepam, and indeed, asmall amount of N-demethylation occurs slowly. However,metabolism proceeds mainly through glucuronidationof the 3-hydroxyl group, thus, it is intermediate acting andmarketed as a hypnotic said to have little or no residualeffect.

Clinical Use

Benzodiazepine: Insomnia (short-term use) Pre-med anxiolytic prior to minor procedures

Drug interactions

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

Metabolism

Temazepam is metabolised mainly in the liver. It is excreted mainly in the urine in the form of its inactive glucuronide conjugate together with small amounts of the demethylated derivative, oxazepam, also in conjugated form.

InChI:InChI=1/C16H13ClN2O2/c1-19-13-8-7-11(17)9-12(13)14(18-15(20)16(19)21)10-5-3-2-4-6-10/h2-9,15,20H,1H3

Upstream product

• 94959-00-9 3-O-ethyltemazepam 
• 439-14-5 diazepam 
• 2888-64-4 diazepam 4-oxide 
• 18818-64-9 3-acetoxy-7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 

Downstream Products

• 130753-91-2 Benzoic acid 7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 94959-00-9 3-O-ethyltemazepam 
• 67-56-1 methanol 
• 130753-95-6 2-Methyl-3-nitro-benzoic acid 7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 719-59-5 5-chloro-2-aminobenzophenone 
• 1022-13-5 5-chloro-2-(methylamino)benzophenone 
• 60628-55-9 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one 
• 18818-64-9 3-acetoxy-7-chloro-1-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 28986-84-7 (+/-)-Temazepam glucuronide 
• 604-75-1 oxazepam 
• 201230-82-2 carbon monoxide 

Relevant articles and documents

NOVEL POLYMORPHIC FORMS OF TEMAZEPAM AND PROCESSES FOR PREPARING THE SAME

Disclosed herein are novel crystalline polymorphic forms Form I, Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X and amorphous form of temazepam characterized by X-ray powder diffraction patterns, DSC, TGA and IR. In addition, the invention describes processes for the preparation of the various polymorphic forms.

ORALLY DISINTEGRATING TABLET COMPOSITIONS OF TEMAZEPAM

The compositions of the present invention are orally disintegrating tablet compositions comprising a therapeutically effective amount of at least one drug such as temazepam, 0.5-3% of an ODT binder polymer, a sugar alcohol and/or saccharide, and a disintegrant.

Prediction of metabolic clearance using fresh human hepatocytes: Comparison with cryopreserved hepatocytes and hepatic microsomes for five benzodiazepines

1. Predictions of in vivo intrinsic clearance from cryopreserved human hepatocytes may be systematically low. In the current study, the metabolite kinetics of a series of CYP3A4 substrates (benzodiazepines) in fresh human hepatocytes from five donors, via a major UK supplier, were investigated and compared with those previously reported (by the authors' laboratory) for cryopreserved human hepatocytes and hepatic microsomes. 2. A high incidence of autoactivation (up to tenfold) and heteroactivation (by testosterone, up to 14-fold) among the major pathways was observed. CYP capacity (Vmax) was marginally lower and 'affinity' constants (KM, S50) were marginally greater compared with cryopreserved hepatocytes. 3. Average intrinsic clearance (based on maximal clearance, CLmax) was sevenfold lower than in cryopreserved hepatocytes (reflecting sensitivity of intrinsic clearance estimation in vitro to mechanistic parameter values, particularly those involving atypical kinetics), but scaled intrinsic clearances for fresh (and cryopreserved) hepatocytes were within the range previously determined in hepatic microsomes. 4. There was no evidence from this series of studies that fresh hepatocytes provide quantitatively improved estimates of intrinsic clearance over cryopreserved hepatocytes.

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.

Comparative study of the metabolism of drug substrates by human cytochrome P450 3A4 expressed in bacterial, yeast and human lymphoblastoid cells

1. The aim was to compare the metabolic activity of human CYP3A4 expressed in bacteria (E. coli), yeast (S. cerevisiae) and human lymphoblastoid cells (hBl), with the native CYP3A4 activity observed in a panel of human livers. 2. Three CYP3A4 substrates were selected for study: dextromethorphan (DEM), midazolam (MDZ) and diazepam (DZ). The substrate metabolism in each of the four systems was characterized by deriving the kinetic parameters Km or S50, Vmax and intrinsic clearance (CLint) or maximum clearance (CLmax) from the kinetic profiles; the latter differing by 100-fold across the three substrates. 3. The Km or S50 for the formation of metabolites 3-methoxymorphinan (MEM), 1′-hydroxymidazolam (1′-OH MDZ) and 3-hydroxydiazepam (3HDZ) compared well in all systems. For CYP3A4-mediated metabolism of DEM, MDZ and DZ, the Vmax for hB1 microsomes were generally 2-9-fold higher than the respective yeast and human liver microsomes and E. coli membrane preparations, resulting in greater CLint or CLmax. In the case of 3HDZ formation, non-linear kinetics were observed for E. coli, hBl microsomes and human liver microsomes, whereas the kinetics observed for S. cerevisiae were linear. 4. The use of native human liver microsomes for drug metabolic studies will always be preferable. However, owing to the limited availability of human tissues, we find it is reasonable to use any of the recombinant systems described herein, since all three recombinant systems gave good predictions of the native human liver enzyme activities.

Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: Role of CYP2B6, 2C19 and the 3A subfamily

1. We have examined the metabolism of diazepam by ten human cytochrome P450 forms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5) expressed in HepG2 cells using a recombinant vaccinia virus system. 2. Among the P450 forms tested, diazepam was significantly demethylated by CYP2B6, 2C9, 2C19, 3A4 and 3A5, with 2C19 exhibiting the highest rate at concentrations 0.1 mM, and hydroxylated only by the latter three enzymes, with 3A5 being the most active. The N-demethylation activity of diazepam by 2C19 at a concentration of 20 μM was six times of that by 3A4. However, that by 2C9 was detected at only a trace level. 3. CYP2C19, 3A4 and 3A5 of the ten human P450s catalysed the 3-hydroxylation of nordiazepam, and 2B6, the 2C subfamily and the 3A subfamily catalysed the N-demethylation of temazepam. CYP3A4 exhibited the highest activity of nordiazepam 3-hydroxylation and temazepam N-demethylation. 4. Diazepam N-demethylation by human liver microsomes correlated with diazepam 3-hydroxylation, but not S-mephenytoin 4'-hydroxylation. 5. Our results suggest that in the human liver, the metabolism of diazepam to nordiazepam is mediated by CYP3A4, which has been reported as the most abundant P450 form in human liver as well as 2C19, which has been reported as a polymorphic enzyme.

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.

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.

Acid-catalyzed ethanolysis of temazepam in anhydrous and aqueous ethanol solutions

The benzodiazepines are a family of anxiolytic and hypnotic drugs. When taken concurrently with ethanol, a pharmacological interaction may occur, potentiating the central nervous system depression produced by either drug. In addition to this pharmacological interaction, this report describes a novel chemical reaction between temazepam (a 3-hydroxy-1,4-benzodiazepine) and ethanol under acidic conditions similar to those found in vivo, resulting in a 3-ethoxylated product. Optimal conditions, kinetics, equilibrium, and the mechanism of this acid-catalyzed ethanolysis are reported. The results raise the possibility that the ethanolysis reaction may occur in the stomach of people who consume alcohol and 3-hydroxy-1,4-benzodiazepine on a regular basis. The acid-catalyzed ethanol-drug reaction is a relatively unexplored area and may alter the pharmacological action of some drugs.

3-FLUOROBENZODIAZEPINES

Benzodiazepines that bear a fluorine substituent in the metabolically active C-3 position were prepared by the reaction of diethylaminosulfur trifluoride (DAST) with the corresponding 3-hydroxybenzodiazepines.These products are surprisingly stable to hydrolysis and possess potent antianxiety and muscle-relaxing properties.