22316-47-8 Usage
Description
Clobazam, also known as 7-Chloro-1H-1,5-benzodiazepine-2,4(3H,5H)-dione, is a first-generation antiepileptic drug (AED) with a chemical structure that features a methyl group attached to the nitrogen at position 1 and a phenyl group attached to the other nitrogen. It is a white solid and is classified as a controlled substance due to its depressant effects. Clobazam is used for the short-term management of acute anxiety and as an adjunct in the treatment of epilepsy in combination with other antiepileptics. It is known under the proprietary brand names Frisium (Sanofi, Paris) in the UK and Onfi (Lundbeck, Copenhagen) in the USA.
Uses
Used in Pharmaceutical Industry:
Clobazam is used as a benzodiazepine psychotherapeutic agent for the short-term management of acute anxiety and as an adjunct in the treatment of epilepsy in association with other antiepileptics. It has proven efficacy against multiple seizure types, making it a valuable addition to the treatment of various neurological conditions.
Used in Mental Health Applications:
Clobazam is used as an anxiolytic agent for the treatment of acute anxiety. Its benzodiazepine properties help alleviate symptoms of anxiety and promote a sense of calm and relaxation in patients experiencing acute stress or anxiety disorders.
Used in Epilepsy Treatment:
Clobazam is used as an antiepileptic drug in combination with other antiepileptics for the treatment of epilepsy. Its efficacy against multiple seizure types makes it a valuable tool in managing the complex and varied symptoms associated with epilepsy.
Indications
Epilepsy: adjunctive therapy of focal and generalized seizures.
Recommendations summarized from NICE (2012)
Seizure types: adjunctive (generalized tonic- clonic seizures, focal seizures), on referral to tertiary care (absence seizures, myoclonic seizures).
Epilepsy types: adjunctive (epilepsy with generalized tonic- clonic seizures only), on referral to tertiary care (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy):?
Psychiatry— short-term relief (2–4 weeks) of severe, disabling, or unacceptably distressing anxiety, occurring alone or in association with insomnia, or shortterm psychosomatic, organic, or psychotic illness (adjunctive treatment in patients with psychotic illness).
Dose titration
Epilepsy—adjunctive therapy: 20– 30 mg daily (max. 60 mg daily in divided doses).
Anxiety (short-term use): 20– 30 mg nocte or in divided doses (max. 60 mg daily, in divided doses).
The effectiveness of clobazam may decrease significantly after weeks or months of continuous therapy.
Cautions
Patients with dependent/ avoidant/ obsessive– compulsive personality disorder (may increase risk of dependence).
Patients with organic brain damage.
Patients with muscle weakness.
Interactions
With AEDs
Phenytoin and carbamazepine may cause an increase in the metabolic conversion of clobazam to the active metabolite N- desmethyl clobazam.
With other drugs
With administration of clobazam (especially at higher doses), an enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics, hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anticonvulsant drugs, anaesthetics, and sedative antihistamines.
If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced (possibly leading to increased psychological dependence).
The effects of muscle relaxants, analgesics and nitrous oxide may be enhanced by concomitant use of clobazam.
Dosage adjustment of clobazam may be necessary when co- administered with strong (e.g. fluconazole, fluvoxamine, ticlopidine) or moderate (e.g. omeprazole) CYP2C9 inhibitors, which may result in increased exposure to N- desmethyl clobazam, the active metabolite of clobazam.
Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, nebivolol, paroxetine, and pimozide) may be necessary, as clobazam is a weak CYP2D6 inhibitor.
With alcohol/food
There is an increased sedative effect when clonazepam or clobazam are given with alcohol, and it is recommended that patients abstain from drinking alcohol during treatment with these drugs.
Special populations
Hepatic impairment
Start with smaller initial dose or reduce maintenance dose.
Avoid in severe impairment.
Renal impairment
Start with smaller dose in significant impairment.
Pregnancy
As a precautionary measure, it is preferable to avoid the use of Clobazam during pregnancy. Clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Administration Clobazam in the last trimester of pregnancy or during labour can result in hypothermia, hypotonia, respiratory depression, and feeding difficulties in the neonate.
Infants born to mothers who have taken Clobazam during the later stages of pregnancy may develop physical dependence, and may be at risk for developing withdrawal symptoms in the postnatal period.
Clobazam, like all benzodiazepines, are present in milk and should be avoided if possible during breastfeeding.
Behavioural and cognitive effects in patients with epilepsy
Behavioural effects include sleepiness, poor coordination, and agitation with paradoxical aggression/ disinhibition (usually dose- dependent). Long- term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. In addition to seizure exacerbation, abrupt discontinuation of benzodiazepines can be accompanied by changes in mental status, including anxiety, agitation, confusion, depression, psychosis, and delirium. Benzodiazepines are more frequently associated with adverse cognitive effects than most other AEDs. Among cognitive domains, attention and language appear to be more significantly affected in patients treated with clobazam (mainly at high doses).
Psychiatric use
In addition to its role as an AED, clobazam has an indication for short-term relief (2– 4 weeks) of acute anxiety in patients who have not responded to other drugs, with or without insomnia, and without uncontrolled clinical depression.
Originator
Urbanyl,Diamant,France,1975
Manufacturing Process
1.65 g of N-phenyl-N-(2-amino-5-chlorophenyl)-malonic acid ethyl ester
amide of MP 108° to 109°C are added to a sodium ethoxide solution, prepared
from 20 ml of absolute alcohol and 150 mg of sodium. The solution is allowed
to rest for 5 hours at room temperature. Then 1 ml of methyl iodide is added
and the reaction mixture is refluxed for 7 hours. After evaporation of the
solution in vacuo it is mixed with water and the solution is shaken with
methylene chloride. The methylene chloride phase is dried and evaporated. By
treatment of the residue with ethyl acetate/charcoal are isolated 500 mg of 7-
chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione of MP
180° to 182°C. The yield amounts to 34% of theory
Therapeutic Function
Tranquilizer
Clinical Use
Benzodiazepine:
Anticonvulsant
Anxiolytic
Safety Profile
Poison by ingestion and
intraperitoneal routes. Moderately toxic by
subcutaneous route. Human systemic effects
by ingestion: wakefulness, withdrawal,
nausea and vomiting. An experimental
teratogen. Other experimental reproductive
effects. A tranquhzer. When heated to
decomposition it emits very toxic fumes of
NOx and Cl-. See also DIAZEPAM.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: metabolism possibly increased by
rifampicin.
Antipsychotics: increased sedative effects; serious
adverse events reported with clozapine and
benzodiazepines.
Antivirals: concentration possibly increased by
ritonavir.
Disulfiram: metabolism of clobazam inhibited;
increased sedative effects.
Sodium oxybate: enhanced effects of sodium oxybate
- avoid.
Metabolism
Clobazam is metabolised in the liver by demethylation
and hydroxylation; the cytochrome P450 isoenzyme
CYP2C19 plays a role in its metabolism. Unlike the
1,4-benzodiazepines such as diazepam, clobazam, a
1,5-benzodiazepine, is hydroxylated at the 4-position
rather than the 3-position.Clobazam is excreted unchanged and as its main active
metabolite, N-desmethylclobazam, mainly in the urine.
Check Digit Verification of cas no
The CAS Registry Mumber 22316-47-8 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,2,3,1 and 6 respectively; the second part has 2 digits, 4 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 22316-47:
(7*2)+(6*2)+(5*3)+(4*1)+(3*6)+(2*4)+(1*7)=78
78 % 10 = 8
So 22316-47-8 is a valid CAS Registry Number.
InChI:InChI=1/C16H13ClN2O2/c1-18-13-8-7-11(17)9-14(13)19(16(21)10-15(18)20)12-5-3-2-4-6-12/h2-9H,10H2,1H3
22316-47-8Relevant articles and documents
Method for industrially producing clobazam
-
, (2021/05/01)
The invention discloses a method for industrially producing clobazam, and belongs to the technical field of medicine synthesis. According to the method, 5-chloro-2-nitrobenzidine is used as a raw material, and a clobazam bulk drug is prepared through processes of acylation, reduction ring closing, methylation and refining. According to the invention, the problems that reagents with high toxicity are used in the prior art, the pollution is serious, and potential safety hazards exist in the pressurized hydrogenation reaction are solved, the production cost is reduced, and the product quality and economic benefits are improved.
PROCESS FOR PREPARING CLOBAZAM USING NOVEL INTERMEDIATES
-
, (2016/12/22)
Processes for preparation of 7-chloro-1-methyl-5-phenyl-1,5-dihydro- benzo[b][1,4]diazepine-2,4-dione (Clobazam) are provided. The present invention also relates to the novel intermediates and its use in preparation of clobazam.
AN IMPROVED PROCESS FOR THE PREPARATION OF CLOBAZAM AND ITS INTERMEDIATE
-
Page/Page column 10; 20, (2016/10/11)
The present invention provides an improved process for the preparation of 8-chloro-1-phenyl- 1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (hereafter referred to as the compound (IV)), which is useful as a key intermediate for the synthesis of Clobazam (referred to as the compound (I)) 7-chloro-1-methyl-5-phenyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione. The process of the present invention further involves transformation of the compound (IV) into Clobazam (I), comprising (a) reacting the compound (II) (as described herein) with monoalkyl malonate in the presence of a coupling agent to obtain the compound (III) (as described herein); followed by the cyclization using a base; (b) reacting the compound-IV (as described herein) obtained from step (a) with methylating agent. The process of the present invention involves formation of novel intermediates methyl 3-((4- chloro-2-(phenylamino)phenyl)amino)-3-oxopropanoate (IlIa) and 3-((4-chloro-2- (phenylamino)phenyl)amino)-3-oxopropanoic acid (V).
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