303-49-1 Usage
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.
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.
BODIPY compounds containing 8-(diphenylethynyl)-ester groups as well as synthesis and application thereof
-
Paragraph 0034; 0042-0044, (2021/02/06)
The invention discloses BODIPY compounds containing 8-(diphenylethynyl)-ester groups as well as a preparation method and application thereof. The BODIPY compounds have a structure A. According to theinvention, BODIPY is used as a matrix, a diphenylacetylene rigid structure and an ester-based alkyl chain flexible structure are introduced to the No. 8 site through the Sonogashira coupling reaction,and a series of 8-(diphenylethynyl)-ester-based BODIPY dichroic dyes are designed and synthesized. The maximum emission wavelength of the compounds in dichloromethane is concentrated at about 518 nm,green fluorescence is shown, and good dichroic ratio and ordered parameters are shown in a liquid crystal E7; and the liquid crystal compounds provided by the invention have a liquid crystal mesophase within a temperature range of 50-100 DEG C, can be used for manufacturing liquid crystal display products, and particularly can be used as guest body dyes for guest-host mode liquid crystal displays; and when the compounds are added into the E7 liquid crystal and used in a guest-host display mode, response time can be prolonged, and the effect of quick response is achieved.
Design, synthesis and antitumor evaluations of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors
Sun, Qinsheng,Dai, Qiuzi,Zhang, Cunlong,Chen, Yan,Zhao, Lei,Yuan, Zigao,Jiang, Yuyang
supporting information, p. 2479 - 2483 (2021/03/08)
DNA methyltransferase (DNMT) and histone deacetylase (HDAC) are well recognized epigenetic targets for discovery of antitumor agents. In this study, we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors. MTT assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels, inducing hypomethylation of p16 and hyperacetylation of histones H3K9 and H4K8. Besides, 204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest. Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC. Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes. Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.
