Chemical Properties
Tan Solid
Originator
Rivotril,Roche,France,1973
Uses
Antiepileptic agent with anxiolytic and antimanic properties. Anticonvulsant.
This is a controlled substance (depressant)
Definition
ChEBI: 1,3-Dihydro-2H-1,4-benzodiazepin-2-one in which the hydrogens at positions 5 and 7 are substituted by 2-chlorophenyl and nitro groups, respectively. It is used in the treatment of all types of epilepsy and seizures, as well as myoclonus
nd associated abnormal movements, and panic disorders. However, its use can be limited by the development of tolerance and by sedation.
Manufacturing Process
The following description is taken from US Patent 3,116,203. A stirred solution
of 75 g of 2-amino-2'-nitrobenzophenone in 700 ml of hot concentrated
hydrochloric acid was cooled to 0°C and a solution of 21.5 g of sodium nitrite
in 50 ml of water was added in the course of 3 hours. The temperature of the
suspension was kept at 2° to 7°C during the addition. The resulting clear
solution was poured into a stirred solution of 37 g of cuprous chloride in 350
ml of hydrochloric acid 1:1. The solid which had formed after a few minutes
was filtered off, washed with water and recrystallized from ethanol. Crystals of
2-chloro-2'-nitrobenzophenone melting at 76° to 79°C were obtained.
A solution of 20 g of 2-chloro-2'-nitrobenzophenone in 450 ml of ethanol was
hydrogenated at normal pressure and room temperature with Raney nickel.
After uptake of about 6 liters of hydrogen the catalyst was filtered off, and the
alcohol then removed in vacuo. The residue was distilled in a bulb tube at 0.4
mm and a bath temperature of 150° to 165°C giving a yellow oil. The oil was
dissolved in alcohol, and on addition of water, needles of 2-amino-2'-
chlorobenzophenone melting at 58° to 60°C were obtained.
To a solution of 42 g of 2-amino-2'-chlorobenzophenone in 500 ml of benzene,
19 ml of bromoacetyl bromide was added dropwise. After refluxing for 2
hours, the solution was cooled, washed with 2 N sodium hydroxide and
evaporated. The residue was recrystallized from methanol giving crystals of 2-
bromo-2'-(2-chlorobenzoyl)acetanilide melting at 119° to 121°C.
To a solution of 14.5 g of 2-bromo-2'-(2-chlorobenzoyl)acetanilide in 100 ml
of tetrahydrofuran, an excess of liquid ammonia (ca 150 ml) was added. The
ammonia was kept refluxing with a dry-ice condenser for 3 hours after which
time the ammonia was allowed to evaporate and the solution was poured into
water. Crystals of 2-amino-2'-(2-chlorobenzoyl)acetanilide were collected,
which after recrystallization from ethanol melted at 162° to 164°C.
A solution of 3 g of 2-amino-2'-(2-chlorobenzoyl)acetanilide in 50 ml of
pyridine was refluxed for 24 hours after which time the pyridine was removed
in vacuo. The residue was recrystallized from methanol and a mixture of
dichloromethane and ether giving crystals of 5-(2-chlorophenyl)-3H-1,4-
benzodiazepin-2(1H)-one melting at 212° to 213°C.
To a solution of 13.5 g of 5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one
in 60 ml of concentrated sulfuric acid, a solution of 5.5 g of potassium nitrate
in 20 ml concentrated sulfuric acid was added dropwise. The solution then was
heated in a bath at 45° to 50°C for 2.5 hours, cooled and poured on ice. After
neutralizing with ammonia, the formed precipitate was filtered off and boiled
with ethanol. A small amount of white insoluble material was then filtered off.
The alcoholic solution on concentration yielded crystals of 7-nitro-5-(2-
chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one which, after recrystallization
from dichloromethane, melted at 238° to 240°C.
Brand name
Klonopin (Roche).
Therapeutic Function
Anticonvulsant
General Description
Clonazepam is useful in absence seizures and in myoclonicseizures. Tolerance to the anticonvulsant effect of the clonazepamoften developed rather quickly, and it is a commonproblem with the BZDs. Metabolism involves hydroxylationof the C-3 position, followed by glucuronidation andnitro group reduction, followed by acetylation.
Clinical Use
Benzodiazepine:
Anticonvulsant
Anxiolytic
Restless leg syndrome
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: metabolism possibly increased by
rifampicin.
Antipsychotics: increased sedative effects; increased
risk of hypotension, bradycardia and respiratory
depression with parenteral clonazepam and IM
olanzapine; risk of serious adverse effects in
combination with clozapine.
Antivirals: concentration possibly increased by
ritonavir.
Disulfiram: metabolism inhibited, increased sedative
effects.
Sodium oxybate: enhanced effects of sodium oxybate
- avoid.
Metabolism
Clonazepam is extensively metabolised in the liver, its
principal metabolite being 7-aminoclonazepam, which
has no antiepileptic activity; minor metabolites are the
7-acetamido- and 3-hydroxy-derivatives.
It is excreted mainly in the urine almost entirely as its
metabolites in free or conjugated form.
