303-49-1 Usage
Description
Clomipramine, a dibenzoazepine derivative, is a tricyclic antidepressant (TCA) characterized by its 10,11-dihydro-5H-dibenzo[b,f]azepine structure. It is substituted by a chlorine atom at position 3 and features a 3-(dimethylamino)propyl group replacing the hydrogen attached to the nitrogen. Clomipramine is one of the more sedating TCAs and is known for its effectiveness in treating various mental health conditions.
Uses
Used in Pharmaceutical Industry:
Clomipramine is used as an antidepressant for the treatment of depression, obsessive-compulsive disorder (OCD), and phobias. It functions by inhibiting the reuptake of serotonin and norepinephrine in the brain, thereby increasing the levels of these neurotransmitters and improving mood and reducing anxiety.
Used in Mental Health Treatment:
Clomipramine is used as a therapeutic agent for patients suffering from depression, OCD, and phobias. Its sedating properties make it a suitable choice for individuals who may experience insomnia or restlessness as a result of their mental health conditions. The drug's ability to regulate neurotransmitter levels helps alleviate symptoms and improve overall well-being.
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.
Check Digit Verification of cas no
The CAS Registry Mumber 303-49-1 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 3,0 and 3 respectively; the second part has 2 digits, 4 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 303-49:
(5*3)+(4*0)+(3*3)+(2*4)+(1*9)=41
41 % 10 = 1
So 303-49-1 is a valid CAS Registry Number.
InChI:InChI=1/C19H23ClN2/c1-21(2)12-5-13-22-18-7-4-3-6-15(18)8-9-16-10-11-17(20)14-19(16)22/h3-4,6-7,10-11,14H,5,8-9,12-13H2,1-2H3
303-49-1Relevant articles and documents
Enhancing Reactivity and Selectivity of Aryl Bromides: A Complementary Approach to Dibenzo[b,f]azepine Derivatives
Casnati, Alessandra,Fontana, Marco,Coruzzi, Giovanni,Aresta, Brunella Maria,Corriero, Nicola,Maggi, Raimondo,Maestri, Giovanni,Motti, Elena,Della Ca', Nicola
, p. 4346 - 4352 (2018)
Dihydrodibenzo[b,f]azepines and dibenzo[b,f]azepines can be efficiently synthesized from aryl bromides, o-bromoanilines and norbornene or norbornadiene by means of palladium catalysis. This protocol gives access to dibenzo[b,f]azepine core containing a variety of electron-withdrawing substituents on both aromatic rings and complements the previously reported methodology where electron rich aryl iodides were preferentially used. The presence of KI, even in sub-stoichiometric amount, is crucial for this three-component reaction. The proper addition of iodide anions has a dramatic effect on reaction rate and selectivity. A formal three-step synthesis of the tricyclic antidepressant Clomipramine (Anafranil) is also described.
Discovery of 5-{2-[5-Chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl}-4-methoxypyridine-2-carboxylic Acid, a Highly Selective in Vivo Useable Chemical Probe to Dissect MCT4 Biology
Heinrich, Timo,Sala-Hojman, Ada,Ferretti, Roberta,Petersson, Carl,Minguzzi, Stefano,Gondela, Andrzej,Ramaswamy, Shivapriya,Bartosik, Anna,Czauderna, Frank,Crowley, Lindsey,Wahra, Pamela,Schilke, Heike,B?pple, Pia,Dudek, ?ukasz,Le?, Marcin,Niedziejko, Paulina,Olech, Kamila,Pawlik, Henryk,W?oszczak, ?ukasz,Zuchowicz, Karol,Suarez Alvarez, Jose Ramon,Martyka, Justyna,Sitek, Ewa,Mikulski, Maciej,Szcz??niak, Joanna,J?ckel, Sven,Krier, Mireille,Król, Marcin,Wegener, Ansgar,Ga??zowski, Micha?,Nowak, Mateusz,Becker, Frank,Herhaus, Christian
supporting information, p. 11904 - 11933 (2021/09/02)
Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient lactate transport to avoid intracellular lactate accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a lactate transporter that plays a central role in tumor pH modulation. The discovery and optimization of a novel class of MCT4 inhibitors (hit 9a), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound 18n with the cytosolic domain of MCT4 was shown after solubilization of the GFP-tagged transporter by fluorescence cross-correlation spectroscopy and microscopic studies. In vitro treatment with 18n resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of 18n allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus, 18n represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.
Field-induced single-ion magnets exhibiting tri-axial anisotropy in a 1D Co(ii) coordination polymer with a rigid ligand 4,4′-(buta-1,3-diyne-1,4-diyl)dibenzoate
C. Silva, Henrique,Ferreira, Glaucio B.,Guedes, Guilherme P.,Matos, Catiúcia R. M. O.,Nunes, Wallace C.,Ronconi, Célia M.,Sarmiento, Charlie V.
, p. 15003 - 15014 (2021/11/17)
Herein a 1D Co(ii) coordination polymer of formula [Co(η1-L1)(η2-L1)(py)2(H2O)]n (CoCP) has been synthesised using the rigid H2L1 proligand, containing a long spacer bearing two triple bonds. Single-crystal X-ray diffraction showed that Co(ii) adopts a distorted octahedral geometry. The state-averaged complete active self-consistent field (SA-CASSCF) calculation showed that the ground state of CoCP is a high spin quartet with a highly multiconfigurational character of its electronic structure. Due to the large intra- and intermolecular distances between the spin carriers, the magnetic interactions are negligible and the zero-field splitting (ZFS) effects of cobalt(ii) ions are predominant. This behavior was confirmed by direct current (DC) magnetic measurements and theoretical calculations using the broken-symmetry approach. Quantum chemical calculations indicate that CoCP has a negative axial component possessing mixed tri-axial anisotropy. The DC magnetic susceptibility data were fitted with a Griffith-Figgis Hamiltonian and the obtained parameters are in good agreement with those simulated by the ab initio calculation. Alternating current (AC) magnetic measurements showed a field induced slow magnetic relaxation in CoCP, which is attributed to the hyperfine interaction effects.
