5786-21-0 Usage
Uses
Used in Psychiatry:
Clozapine is used as an antipsychotic for treating acute and chronic schizophrenia. It is effective in managing both positive and negative symptoms of the disorder, including agitation, hallucinations, delusions, and emotional instability. Clozapine is particularly useful for patients who have not responded well to standard neuroleptics.
Used in Treatment of Mania and Sleep Disorders:
Clozapine is used as a mood stabilizer and sedative for treating acute and chronic mania, as well as severe sleep disorders. It helps in stabilizing emotions and alleviating symptoms such as vagrancy, sleep disorder, sadness, panic, tiredness, sudden violence, and anger.
Used in Treatment of Mental Retardation-Caused Behavioral Disorders:
Clozapine is used as a behavioral intervention for treating mental retardation-caused behavioral disorders. It helps in managing symptoms such as linguistic disorder, poor presentation ability, poor thought and mental ability, lack of abstraction, low perception, narrow attention range, poor memory, naive behavior, emotional instability, lack of self-control, and impulsiveness.
Used in Treatment of Drug or Alcohol-Dependence Withdrawal Syndrome:
Clozapine is used as a therapeutic agent for treating drug or alcohol-dependence withdrawal syndrome. It helps in managing symptoms such as acute tremors, agitation, being easy to get startled, nausea, vomiting, and sweating. It can also alleviate short delusions, hallucinations, and visual distortion associated with withdrawal.
Used as a Depigmentor:
Clozapine is used as a depigmenting agent in certain applications, although this use is not directly mentioned in the provided materials.
Pharmacological effects
1. Antipsychotic effects: Clozapine has good efficacy on treating various types of acute and chronic psychiatric disease. It can alleviate symptoms like excitement, agitation, hallucinations, delusion, thought disorder, depersonalization, and strange movements. The mechanism may be associated with its blocking effect on the dopamine receptor of mesolimbic system, but does not affect the dopamine receptors in the striatum, so this product rarely produces extrapyramidal reactions.
2. Sedative and hypnotic effects: This product can inhibit the spontaneous activity when applied in low-dose. High dose can increase automatic activity. Clozapine can directly inhibit the brain ascending reticular activating system.
3. Anti-cholinergic, anti-histamine and anti-adrenergic effects: The product has a strong anti-acetylcholine effect, and also has suppressing effect on histamine, norepinephrine and epinephrine.
Pharmacodynamics
This product is a kind of major tranquilizer which has well therapeutic effect on treating acute and chronic schizophrenia. Its mechanism of action is probably playing a pharmacological effect on central dopamine nerve. It can selectively block dopamine receptors in the limbic system with small effect on nigrostriatal dopamine receptor, so it has a strong anti-psychotic effect. The extrapyramidal side effects are rare. Its function also has no dependence on the activity of adenylate cyclase.
Pharmacokinetics
Its absorption through oral administration happens quickly and completely. There is no food effect on the rate and extent of absorption. It is widely distributed to various organizations after rapid absorption and there are large individual differences in bioavailability with an average deviation of about 50% to 60%. It also has hepatic first-pass effect. The plasma concentration reaches peak 3.2 hours (1-4 hours) after taking drugs and has an elimination half-life (t1/2β) about 9 hours. The apparent volume of distribution (Vd) is 4.04~13.78L/kg. It has a high tissue binding rate. After being metabolized by the liver, 80% of it is in the form of metabolites presented in urine and feces. Its major metabolites include N-demethylated clozapine, and the N-oxidant of clozapine. Under the same dose and a constant body weight, serum drug concentrations of female patients are significantly higher than that of male patients. Smoking can accelerate the metabolism of this product. Drug metabolism and renal clearance are significantly lower in the elderly. This product can be secreted from the milk, and can penetrate through the blood-brain barrier.
The above information is edited by the lookchem of Dai Xiongfeng.
Synthetic route
Use 2,5-dichloro-nitrobenzene (2) and anthranilic acid (3) to react in DMF to generate 2-(4-chloro-2-nitro) dimethylbenzene (4), dimethylbenzene undergoes hydrazine hydrate/ferric chloride catalytic reduction to produce 2-(2-amino-4-chlorophenyl) dimethylbenzene (5), dimethylbenzene goes through cyclization reaction with the catalysis of polyphosphoric acid to obtain 8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4]-dinitrogen-11-one (6). Product in step 6 is condensed together with N-methylpiperazine in the effect of titanium tetrachloride to get the final product.
Figure 1 the synthesis route of clozapine
Precautions
1. Induction of the decrease of neutropenia or its development into agranulocytosis is the most serious side effects of this product. So do not take drugs which causes leukopenia simultaneously while taking clozapine, especially avoid taking the traditional antipsychotic or antidepressant drugs or long-acting antipsychotics. Leukocyte count should be performed before treatment in order to understand the patient to return to normal polymorphonuclear leukocytes index. After the start of treatment, weekly leukocyte count should be performed for 18 consecutive weeks. Then the test should be done at least once a month. Do the same things during long-term medication. At each time of consultation, remind the patients to seek medical treatment immediately when infection or fever occurs. When there is an infection or WBC is less than 3.5 × 109/L or be much lower compared to the initial measured index, the white blood cell count should be reviewed immediately. If the absolute value of leukocyte reduced to 3 × 109/L or less and/or neutrophil polymorphonuclear leukocytes have an absolute value being less than 1.5 × 109/L, should be immediately discontinued.
2. For patients with a history of seizures or cardiovascular, renal, hepatic insufficiency, apply a lower initial dose and should increase the dose more gradually.
3. For patients with non-serious liver disease, clinical monitoring and regularly check of liver function is necessary.
4. Remind the patient that this product has the role of triggering drowsiness. So do not drive and operate machinery while taking the drug.
5. It has interaction with the central sedative and antipsychotic drugs, so be cautious when taking medicine.
6. Lactating women should not be breastfeeding upon medication.
7. Disable who are allergic to clozapine.
8. Patients with neutropenia, agranulocytosis or an apparent history of blood disease; Be cautious for patients of alcohol and drug-induced psychosis, poisoning and coma, severe heart, liver, kidney diseases, angle-closure glaucoma, and prostatic hypertrophy-caused urinary tract disease.
Side effects
Common adverse reactions include salivation (significantly during sleeping), nausea, vomiting, and abdominal distension. Occasionally fever, neutropenia, and a long-term drug addiction occur.
Side effects
A serious drawback to the use of clozapine, however, is the potentially fatal agranulocytosis that
is reported to occur in 1 to 2% of unmonitored patients, necessitating weekly white blood cell counts for at
least the first 6 months of pharmacotherapy.
Contraindications
Children under 16 years of age, patients of angle-closure glaucoma, prostatic hyperplasia, spastic disorders or with a history of epilepsy and severe cardiovascular disease should take with caution. Disable it for patients with significantly inhibited central nervous system and with a history of myelosuppression or abnormal blood cells.
Production methods
2-amino-4-chloro-diphenylamine-2'-carboxylic acid (4''-methyl) piperazine reacts with phosphorus oxychloride to get clozapine.
Originator
Leponex,Wander,W. Germany,1974
Manufacturing Process
7.4 g of 2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4"-methyl)
piperazide and 35 ml of phosphoroxychloride are heated for 3 hours under
reflux in the presence of 1.4 ml of N,N-dimethylaniline. Upon concentration of
the reaction mixture in vacuo as far as possible, the residue is distributed
between benzene and ammonia/ice water. The benzene solution is extracted
with dilute acetic acid. The acid extract is clarified with charcoal and treated
with concentrated ammonia water to precipitate the alkaline substance, which
is dissolved in ether. The ethereal solution is washed with water and dried
over sodium sulfate. The residue obtained yields, after recrystallization from
ether/petroleum ether 2.9 g (41% of the theoretical yield) of 8-chloro-11-(4-
methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine in the form of yellow
grains of melting point 182° to 184°C (from acetone/petroleum ether).
Therapeutic Function
Tranquilizer
World Health Organization (WHO)
Clozapine, a tricyclic neuroleptic, was introduced in 1972 for the
treatment of psychosis. In 1975 its use was associated with cases of
agranulocytosis, particularly in Finland. These cases, which included several
fatalities, resulted in the withdrawal of the drug in some countries. However,
clozapine remains available in at least 30 countries, in some cases only on special
request, for the treatment of severe psychotic disorders unresponsive to other
neuroleptics provided that close monitoring of the blood count is feasible. In 1989,
it was introduced in the United States for the treatment of severe schizophrenia.
Lately, the use of clozapine in the United Kingdom has been associated with
convulsions.
(Reference: (WHODIB) WHO Drug Information Bulletin, 2: 10, , 1977)
Biological Activity
Atypical antipsychotic drug, with a much lower tendency to cause extrapyramidal side effects than conventional neuroleptics. Displays a broad range of pharmacological actions; the antipsychotic effects are thought to be mediated principally by 5-HT 2A/2C and dopamine receptor blockade (K i values are 21, 170, 170, 230 and 330 nM for D 4 , D 3 , D 1 , D 2 and D 5 receptors respectively).
Biochem/physiol Actions
Atypical antipsychotic compound. Selective antagonist for D4-dopamine receptor. Antagonist at 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 serotonin receptors.
Clinical Use
Although clozapine demonstrates a favorable pharmacologicalprofile compared with typical antipsychotics, its useis restricted by a relatively high incidence of agranulocytosis.The exact mechanism for the cause of agranulocytosishas not been confirmed, but a highly reactive nitrenium ionthat is formed by the action of hepatic enzymes appears tobe involved.The mean elimination half-life of clozapine following a single 75-mg dose is 8 hours. Because of severaladverse effects, clozapine is only used in refractory casesof schizophrenia. Individuals with a history of seizures orpredisposed to seizures should be cautioned when takingclozapine. Similar to other atypical antipsychotic agents,clozapine causes an increased risk of mortality in elderly individualswith dementia-related psychoses.
Synthesis
Clozapine, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e] [1,4]diazepine (6.5.7) is synthesized by two methods. According to the first, 4-chloro-2-nitroaniline in the presence of copper filings is acylated by the o-chlorobenzoic acid methyl ester, forming the corresponding diphenylamine (6.5.4). By reacting this with N-methyl piperazine, the ester group in the resulting polyfunctional diphenylamine is transformed into the amide (6.5.5). The nitro group in the resulting 4-chloro-2- nitro-2′-carb-(N′-methyl piperazino)amide (6.5.5) is further reduced into an amine group by hydrogen in the presence of Raney nickel. Reacting the resulting product (6.5.6) with phosphorous oxychloride yields in heterocyclization into the desired dibenzodiazepine, clozapine (6.5.7).
The other way of synthesis of clozapine is from 8-chloro-10,11-dihydro-5H-dibenzo[b,e]1, 4-diazepin-11-thione, which is alkylated at the sulfur atom of the dibenzodiazepine ring by 4-nitrobenzylchloride in the presence of potassium tert-butoxide, giving N-methyl derivative (6.5.8). Reaction of this with N-methylpiperazine gives the desired clozapine (6.5.7).
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: increased risk of convulsions with
tramadol; enhanced hypotensive and sedative
effects with opioids; increased risk of ventricular
arrhythmias with methadone.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with anti-arrhythmics that prolong
the QT interval; increased risk of arrhythmias with
flecainide.
Antibacterials: concentration possibly increased
by erythromycin (possible increased risk
of convulsions); concentration increased by
ciprofloxacin; concentration possibly reduced
by rifampicin; avoid with chloramphenicol and
sulphonamides (increased risk agranulocytosis).
Antidepressants: concentration possibly increased
by citalopram, fluoxetine, fluvoxamine, paroxetine,
sertraline and venlafaxine (increased risk of toxicity);
possibly increased CNS effects of MAOIs; possibly
increased antimuscarinic effects with tricyclics;
increased concentration of tricyclics.
Antiepileptics: antagonises anticonvulsant effect;
metabolism accelerated by carbamazepine, phenytoin
and possibly phenobarbital; avoid with drugs known
to cause agranulocytosis; concentration possibly
increased or decreased by valproate.
Antimalarials: avoid with artemether/lumefantrine.
Antipsychotics: avoid with depot formulations
(cannot be withdrawn quickly if neutropenia occurs);
possible increased risk of ventricular arrhythmias
with risperidone - avoid.
Antivirals: concentration increased by ritonavir -
avoid; increased risk of ventricular arrhythmias with
saquinavir - avoid.
Anxiolytics and hypnotics: increased sedative effects;
adverse reports with clozapine and benzodiazepines.Atomoxetine: increased risk of ventricular
arrhythmias.
Cytotoxics: increased risk of agranulocytosis - avoid;
increased risk of ventricular arrhythmias with arsenic
trioxide.
Lithium: increased risk of extrapyramidal side effects
and possibly neurotoxicity.
Penicillamine: increased risk of agranulocytosis -
avoid.
Ulcer-healing drugs: effects possibly enhanced
by cimetidine; concentration possibly reduced by
omeprazole.
Metabolism
Clozapine is orally active and metabolized mainly by CYP3A4 to
inactive desmethyl, hydroxyl, and N-oxide derivatives, with a half-life of approximately 12 hours. Clozapine has relatively low affinity for brain dopamine D1 and D2 receptors (moderate affinity for D4) in comparison to its affinity
at adrenergic α1 and α2, histamine H1, muscarinic M1 and serotonin 5-HT2A receptors.
References
1) Seeman and Van Tol (1994),?Dopamine receptor pharmacology;? Trends Pharmacol. Sci.,?15?264
2) Ellenbroek?et al. (1991),?The involvement of dopamine D1 and D2 receptors in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine;? Eur. J. Pharmacol.,?196?103
3) Canton?et al.?(1990),?Binding of the typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites;? Eur. J. Pharmacol.,?191?93
4) Kuoppamaki?et al.?(1993),?Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists;? Eur. J. Pharmacol., 245?179
Check Digit Verification of cas no
The CAS Registry Mumber 5786-21-0 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 5,7,8 and 6 respectively; the second part has 2 digits, 2 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 5786-21:
(6*5)+(5*7)+(4*8)+(3*6)+(2*2)+(1*1)=120
120 % 10 = 0
So 5786-21-0 is a valid CAS Registry Number.
InChI:InChI=1/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3
5786-21-0Relevant articles and documents
Aminimides as potential CNS acting agents. I. Design, synthesis, and receptor binding of 4′-aryl aminimide analogues of clozapine as prospective novel antipsychotics
Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Neve, Juliette E.,Taylor, David A.
, p. 673 - 684 (2007)
A series of substituted 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)- 1-methylhexahydropyrazin-1-ium]-1-aminimide derivatives were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized as potential antipsychotic agents for the treatment of schizophrenia. The target compounds were readily prepared in two steps from clozapine (8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine) and involved N-acylation of a common hydrazinium salt intermediate by an acyl chloride or activated ester in the presence of a strong base. The aminimides were tested for in vitro activity at the dopamine D4 and serotonin 5-HT2A receptors and were found to possess modest affinity for both receptor systems. CSIRO 2007.
NOVEL and IMPROVED SYNTHESIS OF ANTIPSYCHOTIC DRUG
-
Page/Page column 15, (2020/01/08)
The present invention relates to novel as well as improved process for the preparation of Clozapine of Formula I which involves anti-narcotic and highly cost effective raw materials.
Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives
Tryniszewski, Micha?,Bujok, Robert,Cmoch, Piotr,Gańczarczyk, Roman,Kulszewicz-Bajer, Irena,Wróbel, Zbigniew
, p. 2277 - 2286 (2019/05/16)
A class of dialkylamino-substituted dibenzodiazepines and their hetero analogues was synthesized by the intramolecular aza-Wittig condensation of the amido group with iminophosphoranes. The one-pot, two-step procedure includes reductive synthesis of the intermediate iminophosphoranes from the corresponding nitroamides and tributylphosphine.
Palladium-catalysed regioselective: N -arylation of anthranilamides: A tandem route for dibenzodiazepinone synthesis
Laha, Joydev K.,Manral, Neelam,Hunjan, Mandeep Kaur
, p. 7339 - 7343 (2019/05/24)
A palladium-catalyzed domino approach to the synthesis of 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones from 2-aminobenzamides and 1,2-dihaloarenes has been developed. Our strategy integrating double N-arylations (inter- and intra-molecular) of 2-aminobenzamides with 1,2-dihaloarenes under palladium-catalyzed conditions is clearly distinct from the current literature available for the synthesis of dibenzodiazepinones. Unlike a previous report described for regioselective N-arylation of 2-aminobenzamide at the amine group, our mechanistic studies support the regioselective N-arylation of 2-aminobenzamide occurring first primarily at the amide group. The translational application of our protocol may be demonstrated in the synthesis of a marketed drug, clozapine.
Applications of TiCl3 as a Diagnostic Reagent for the Detection of Nitro- and N-Oxide-Containing Compounds as Potentially Mutagenic Impurities Using Ultrahigh-Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry
Yang, Rong-Sheng,Beard, Adam,Sheng, Huaming,Zhang, Li-Kang,Helmy, Roy
, p. 59 - 64 (2016/01/30)
The ICH has strict guidelines for limiting the presence of potentially mutagenic impurities (PMIs) in marketed drugs. Therefore, it is important to fully characterize and quantitate all possible PMIs that could arise during the process of synthesizing and developing a drug. Two important and prevalent examples of PMIs are compounds containing N-oxide and nitro functional groups. TiCl3 derivatization is an established method for determining the presence or absence of N-oxide metabolites by reduction to the corresponding amine. In this study, we demonstrate a novel application of TiCl3 reduction combined with high-resolution UHPLC/HRMS to analyze PMIs. The results indicate that a variety of N-oxide- and nitro-containing compounds can be readily characterized by this facile platform method. In addition, we show that this chemical derivatization method can be utilized to enhance the ionization of nitro-containing compounds for LC/MS analysis.
The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs
Chen, Xin,Choo, Hyunah,Huang, Xi-Ping,Yang, Xiaobao,Stone, Orrin,Roth, Bryan L.,Jin, Jian
, p. 476 - 484 (2015/03/30)
Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10000-fold selectivity for hM3Dq over hM3.
Synthesis and oxidant properties of phase 1 benzepine N-oxides of common antipsychotic drugs
Koerber, Jochen,Loeffler, Stefan,Schollmeyer, Dieter,Nubbemeyer, Udo
, p. 2875 - 2887 (2013/10/22)
There is increasing evidence that cell constituents are oxidized by widely used antipsychotic drugs but until now the underlying chemistry has remained unclear. It is well known that such drugs readily undergo N-oxidation as a first key metabolic step. To gain insight into the problem, the tertiary phase 1 N-oxides of clozapine, olanzapine, quetiapine, and zotepine were synthesized, together with the N,S-dioxides of quetiapine and zotepine. These N-oxides were then subjected to well-established chemical transformations to test their oxidant properties in group VIII transition-metal-catalyzed reactions. In the osmium tetroxide catalyzed dihydroxylation of styrene or cinnamyl alcohol and in the tetrapropylammonium perruthenate catalyzed oxidation of cinnamyl alcohol, the benzepine N-oxides could be used as replacements for the standard oxidant, N-methylmorpholine N-oxide (NMO) with varying degrees of efficiency. From a chemical point of view, clozapine N-oxide displayed a comparable oxidation power to NMO, characterizing the benzepines as oxygen carriers. Moreover, quetiapine was found to be an excellent double oxygen acceptor, undergoing initial N-oxidation and subsequent S-oxidation. It is therefore worthwhile considering whether oxidative damage to the human body might be related to the potential redox properties of common antipsychotic drugs. Georg Thieme Verlag Stuttgart ? New York.
Bifunctional solid catalysts for chemoselective hydrogenation-cyclisation- amination cascade reactions of relevance for the synthesis of pharmaceuticals
Leyva-Pérez, Antonio,Cabrero-Antonino, Jose R.,Corma, Avelino
supporting information; experimental part, p. 8203 - 8209 (2010/11/05)
The benzodiazepines olanzapine and clozapine are nowadays manufactured by a three-step process with a final yield below 50%. An approach to environmentally-friendly intensive processes consists in the development of multifunctional solid catalyst able to catalyze multistep reactions. Here, a bifunctional metal-acid solid catalyst has been prepared and is able to carry out hydrogenation-cyclisation-amination reactions in a cascade process. The catalytic system is illustrated for the synthesis of these important antipsychotics, being an alternative for the current industrial process that requires three steps batch reactions, using mineral acids and bases, and stoichiometric amounts of SnCl2.
DIBENZO[b,e][1,4]DIAZEPINE MODULATORS OF DOPAMINE RECEPTORS, SEROTONIN RECEPTORS, ADRENERGIC RECEPTORS, ACETYLCHOLINE RECEPTORS, AND/OR HISTAMINE RECEPTORS
-
, (2010/07/08)
The present invention relates to new dibenzo[b,e][1,4]diazepine modulators of dopamine receptors, serotonin receptors, adrenergic receptors, acetylcholine receptors, and/or histamine receptors, pharmaceutical compositions thereof, and methods of use thereof.
AMINO SUBSTITUTED DIARYL[A,D]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS
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Page/Page column 64, (2008/06/13)
Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.
