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
• Article Data: 10

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

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

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 
• 604-75-1 oxazepam 
• 201230-82-2 carbon monoxide 
• 23433-96-7 3,7-dichloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one 

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.

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.

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.