| Identification | More | [Name]
Clomipramine | [CAS]
303-49-1 | [Synonyms]
[3-(3-CHLORO-10,11-DIHYDRO-DIBENZO[B,F]AZEPIN-5-YL)-PROPYL]-DIMETHYL-AMINE
3-chloro-10,11-dihydro-n,n-dimethyl-5h-dibenz[b,f]azepine-5-propanamine
3-CHLORO-10,11-DIHYDRO-N,N-DIMETHYL-5H-DIBENZ[B,F]AZEPINE-5-PROPANAMINE HYDROCHLORIDE
ANAFRANIL
ANAFRANIL HYDROCHLORIDE
AURORA KA-7606
CHLORIMIPRAMINE
CHLORIMIPRAMINE HYDROCHLORIDE
CHLOROIMIPRAMINE HYDROCHLORIDE
CLOMIPRAMINE
CLOMIPRAMINE HCL
CLOMIPRAMINE HYDROCHLORIDE
RARECHEM AX KI 5027
3-(3-Chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethyl-1-propanamine
3-Chloro-5-(3-(dimethylamino)propyl)-10,11-dihydro-5H-dibenz(b,f)azepine
3-Chloroimipramine
5H-Dibenz(b,f)azepine, 10,11-dihydro-3-chloro-5-(3-(dimethylamino)propyl)-
5H-Dibenz[b,f]azepine, 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-
5H-Dibenz[b,f]azepine-5-propanamine, 3-chloro-10,11-dihydro-N,N-dimethyl-
Anafranil (free base) | [EINECS(EC#)]
206-144-2 | [Molecular Formula]
C19H24Cl2N2 | [MDL Number]
MFCD00069234 | [Molecular Weight]
351.31 | [MOL File]
303-49-1.mol |
| Hazard Information | Back Directory | [Originator]
Anafranil,Ciba Geigy,Switz.,1968 | [Uses]
Antidepressan. | [Definition]
ChEBI: A dibenzoazepine that is 10,11-dihydro-5H-dibenzo[b,f]azepine which is substituted by chlorine at position 3 and in which the hydrogen attached to the nitrogen is replaced by a 3-(dimethylamino)propyl group. One of the more sedating tricyclic antidepressan
s, it is used as the hydrochloride salt for the treatment of depression as well as obsessive-compulsive disorder and phobias. | [Manufacturing Process]
22.9 parts of 3-chloroiminodibenzyl are dissolved in 300 parts by volume of
xylene, and 4 parts of sodium amide, pulverized and suspended in toluene,are added thereto while stirring and maintaining the whole under a nitrogen
atmosphere. The xylene solution immediately turns dark colored, but upon
crystallization of the sodium salt therefrom it becomes again light-colored. The
reaction mixture is stirred for about 2 hours at 80°C until the development of
ammonia has terminated. A solution of γ-dimethylaminopropyl chloride in
toluene, prepared by setting free a corresponding amount of the free base
from 17.4 parts of its hydrochloride salt by addition of aqueous sodium
hydroxide solution in about 10% excess, extraction with toluene and drying
for 2 hours over anhydrous sodium sulfate is added to the xylene solution
containing the sodium salt mentioned above and the whole is stirred under
reflux for 15 hours. Precipitated sodium chloride is filtered off and the filtrate
is concentrated. The residue is diluted with ether, and the hydrochloride of 3-
chloro-5-(γ-dimethylaminopropyl)-iminodibenzyl is precipitated by introducing
dry, gaseous hydrogen chloride. It is filtered off under suction and purified by
repeated recrystallization from acetone; the pure substance melts at 191.5°C
to 192°C. | [Brand name]
Anafranil (Tyco). | [Therapeutic Function]
Antidepressant | [Mechanism of action]
Clomipramine is different from the other TCAs, exhibiting preferential selectivity for inhibiting the reuptake of
5-HT at the presynaptic neuronal membrane. Its antidepressant mechanism of action as an inhibitor of the
5-HT transporter is reduced in vivo, however, because of the formation of its active metabolite,
N-desmethylclomipramine, which inhibits the reuptake of NE. As a result of its common structure with the
other TCAs, clomipramine shares the pharmacological and adverse-effect profile of the other TCAs.
The efficacy of clomipramine relative to the other TCAs in the treatment of obsessive-compulsive disorder
may be related to its potency in blocking 5-HT reuptake at the presynaptic neuronal membrane, suggesting a
dysregulation of 5-HT for the pathogenesis of obsessive-compulsive disorder. Clomipramine appears to
decrease the turnover of 5-HT in the CNS, probably because of a decrease in the release and/or synthesis of
5-HT.
Although in vitro studies suggest that clomipramine is approximately four times more potent than fluoxetine as
a 5-HT reuptake inhibitor, in vivo studies suggest the opposite. This difference has been attributed to the
relatively long elimination half-lives for fluoxetine and its principal serotonergic metabolite norfluoxetine. In
addition, metabolism of clomipramine to its N-desmethyl secondary amine metabolite decreases the potency
and selectivity of 5-HT -reuptake inhibition of clomipramine, but not fluoxetine. | [Pharmacokinetics]
Clomipramine appears to be well absorbed from the GItract following oral administration, with an oral
bioavailability of approximately 50%, suggesting some first-pass metabolism. Food does not
appear to substantially affect its bioavailability. Clomipramine and its active metabolite,
N-desmethylclomipramine, exhibit nonlinear pharmacokinetics at 25 to 150 mg daily. At dosages exceeding
150 mg daily, their elimination half-lives may be considerably prolonged, allowing plasma concentrations of
both to accumulate, which may increase the incidence of plasma concentration-dependent adverse effects,
particularly seizures. Because of the relatively long elimination half-lives of clomipramine and
N-desmethylclomipramine, their steady-state plasma concentrations generally are achieved within
approximately 1 to 2 weeks. Plasma concentrations of N-desmethylclomipramine generally are greater than
those for chlomipramine at steady-state conditions. Clomipramine crosses the placenta and is distributed into
breast milk.
Clomipramine is primarily metabolized by CYP2D6 N-dealkylation to its pharmacologically active metabolite,
the 2- and 8-hydroxylated metabolites and their glucuronides, and clomipramine N-oxide.
N-dealkylation also involves CYP3A4, CYP2C19, CYP2C9, and CYP1A2. Like all the other secondary amine
TCAs, N-desmethylclomipramine is significantly more potent as an inhibitor of NE reuptake than clomipramine
is. Although N-desmethylclomipramine is pharmacologically active, its efficacy in obsessive-compulsive
disorder is not known. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine also are
pharmacologically active, but their clinical importance remains unknown. The hydroxylation and
N-demethylation of clomipramine highlight CYP2D6 polymorphism in healthy adults who were phenotyped as either extensive metabolizers or poor metabolizers of clomipramine. Interindividual variation in plasma
concentrations may be caused by genetic differences in the metabolism of the drug. In addition, CYP1A2 ring
hydroxylates clomipramine. Less than 1% of an oral dose of clomipramine was excreted unmetabolized into
the urine, with 8-hydroxyclomipramine glucuronide as the principal metabolite found in the urine. The effects
of renal clearance suggest that clomipramine and desmethylclomipramine should be decreased in patients
with renal impairment. | [Clinical Use]
Clomipramine is considered to be the most powerful antidepressant ever made. This dihydrodibenzazepine
TCA, with actions on both the NE and 5-HT transporters, was the last of the major TCAs to come to market.
Initially, the U.S. FDA regarded it as another “me-too” drug, and accordingly, they did not license it.
Subsequently, however, it was licensed for the treatment of obsessive-compulsive disorders. Clomipramine
differs from imipramine only by the addition of a 3-chloro group. | [Side effects]
Male patients taking clomipramine should be informed of sexual dysfunction as a side effect associated with
antidepressants having significant serotonergic activity. Sexual dysfunction in men appears as ejaculatory incompetence, ejaculatory retardation, decreased
libido, or inability to obtain or maintain an erection. Sexual dysfunction is dose-related and may be treated by
simply lowering the drug dose. |
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