129722-12-9 Usage
Uses
Used in Antipsychotic Applications:
Aripiprazole is used as an antipsychotic agent for the treatment of schizophrenia and related psychotic disorders. It provides significant improvement in both positive and negative syndrome scale (PANSS) total scores in shortand long-term evaluations, with a low incidence of extrapyramidal symptoms and minimal impact on total cholesterol levels and fasting blood sugar.
Used in Bipolar Disorders:
Aripiprazole is used as a mood stabilizer for the treatment of bipolar disorders, demonstrating great efficacy in managing the symptoms of the condition.
Used in Dopamine Receptor Modulation:
Aripiprazole is used as a selective dopamine D2-receptor antagonist with dopamine autoreceptor agonist activity, offering a novel mechanism of action as a partial D2 receptor agonist.
Used in Cerebral Vasodilation and Antimotion:
Aripiprazole is used as a cerebral vasodilator and antimotion agent, providing relief from symptoms related to restricted blood flow and motion sickness.
Used in Deuterated Version:
A deuterated version of Aripiprazole is used in research and development for its potential benefits in terms of stability, solubility, and pharmacokinetics.
Outline
Aripiprazole is a new kind of highly lipid soluble quinoline derivatives, its pharmacological effects characteristic is that it is not only the postsynaptic dopamine D 2 receptor antagonist, but also the presynaptic dopamine D 2 receptor agonist,it can also excite D 1, D 3, D 4 receptors ; it has dual effect of partial activation or receptor antagonistic on 5-HT 1A receptor ; it has a completely antagonistic action on the 5-HT 2A receptor. This feature is different from the first generation, and atypical antipsychotics which belong to the second-generation antipsychotic drugs, and therefore it is called dopamine system stabilizer or third generation antipsychotic. Since it is sold in the market, it is mainly used in clinical schizophrenia, treatment of affective disorders and other psychiatric disorders. According to the literature, aripiprazole has significant effects on schizophrenia positive and negative symptoms and anxiety, depression, cognitive function , while higher safety. It was also reported that the drug can also treat other mental disorders, such as mood disorders manic episodes, senile dementia associated with mental disorders, anxiety disorders, children's behavioral disorders, depression.
EU approves aripiprazole for treatment of schizophrenia
Nowadays,Bristol-Myers Squibb and Otsuka Pharmaceutical Company announced that the European Union has approved Abilify (aripiprazole) in the treatment of schizophrenia listing application.
Schizophrenia affects 1% of the global population, and more in young adults. Schizophrenia affects thinking, emotional control and decision-making ability of the patient. Schizophrenia-positive patients will have symptoms such as hallucinations and delusions, patients with negative symptoms are social withdrawal, lack of emotional changes.
In 2002 the FDA approved Abilify for the treatment of schizophrenia, which has five dosage strengths: 5 mg, 10 mg, 15 mg, 20 mg and 30 mg, since its approval, in the United States ,a 1.8 million Abilify prescriptions have opened. aripiprazole approved by The EU has four sizes: 5 mg, 10 mg, 15mg and 30 mg.
Aripiprazole as an kind of antipsychotic drugs, in rare cases it may be associated with life-threatening neuroleptic malignant syndrome induced (NMS), also be associated with tardive dyskinesia (TD) have some relevance. Studies have shown that atypical antipsychotics may lead to hyperglycemia, although the study did not examine aripiprazole, but the relationship between hyperglycemia and aripiprazole remains uncertain, therefore, patients in treatment should be carried out blood glucose monitoring.
Patients before receiving aripiprazole treatment should be inform the doctor the physical condition and current drug situation . Aripiprazole should be used with caution in patients with a history of epilepsy aripiprazole.
In short-term clinical studies, the most common adverse reactions of aripiprazole compared with placebo groups are: headache (32%: 25%), anxiety (25%: 24%), insomnia (24%: 19%), nausea (14%: 10%), vomiting (12%: 7%), somnolence (11%: 8%), lightheadedness (11%: 7%), restlessness (10%: 7%) and constipation (10% :8%). A double-blind 26-week clinical study showed that there was higher incidence of tremor in aripiprazole group , it is 9%, only 1% while in the placebo group, slight tremor but tolerable , but also often led to discontinuation.
Metabolize
Metabolic pathway of aripiprazole is mainly through three kinds of biotransformation: dehydrogenation, hydroxylation and N-dealkylation. In vitro studies have shown, CYP3A4 and CYP2D6 are the two enzymes of the metabolism of the product , CYP3A4 and CYP2D6 are responsible for dehydrogenation and hydroxylation, and N-dealkylation is caused by CYP3A4 catalysis. Thus, when there is presence affecting two enzymatic activities and number of drugs, the amount of aripiprazole should be adjusted . In the steady state, pharmacokinetics of the product is proportional to dose. Single oral dose of 14C-labeled product showed that 55% of metabolites excreted through the feces, 25% excreted in urine and 18% of the original drug from the feces, 1% of the original drug excreted in the urine.
The above information is edited by the lookchem of Tian Ye.
Toxicity
Long-term toxicity: long-term toxicity study at a dose of 60 mg/kg for 26 weeks and 2-year carcinogenicity study at dose of 40 and 60mg/kg showed that this product caused retinal degeneration in rats. It showed no evidence of retinal degeneration in mice and monkey trials. Its mechanism of action has not been further researched, it is not shown that these findings is associated with human risks .
Carcinogenicity: In female mice, the daily 3~30mg/kg dose (based on surface area, respectively, is 0.5 to 5 times the MRHD; calculated by AUC, respectively, MRHD plasma concentrations of 0.1 to 0.9 times) leads to increasing incidence of pituitary tumors, breast cancer and skin cancer adenoacanthoma ; in female rats, the daily 10mg/kg dose (based on surface area is 3 times the MRHD; calculated by AUC, is MRHD plasma concentrations 0.1 times) causes increasing incidence of breast fibrous tumor ,daily 60mg/kg dose (based on surface area, is 19 times the MRHD; calculated by AUC, is MRHD plasma concentrations 14 times) causes increasing incidence of adrenocortical cancer and adrenal tumors .
Mutagenicity: in vitro bacterial reverse mutation assay, in vitro bacterial DNA recovery test, mouse lymphoma cells in vitro gene mutation test, Chinese hamster lung cells in vitro chromosomal aberration test, in vivo micronucleus test in mice and rats Unscheduled DNA synthesis test mutagenicity of this product. As a result, there is a positive response in the mouse micronucleus test in vivo, however, the positive reaction is considered to be independent to the mechanism of human .
Drug Interactions
1.It should be used with caution in combination with drugs acting on the central nervous system and alcohol.
2. aripiprazole has possibility of enhancing the role of certain antihypertensive drugs.
3. CYP3A4 inducer will result in elevated aripiprazole clearance and lower blood concentration, CYP3A4 inhibitor azole) or CYP2D inhibitors can inhibit aripiprazole elimination, increase plasma concentration.
Adverse reactions
The most common adverse reactions during treatment are headache, anxiety and insomnia. Rare adverse reactions are child blood sugar, even hyperglycemia.
Originator
Otsuka (Japan)
Manufacturing Process
To a solution of 4.06 g of K2CO3 with 400 ml of water was added 40 g of 7-
hydroxy-3,4-dihydrocarbostyril [1] and 158 g of 1,4-dibrombutane. The
mixture was refluxed for 3 hours. Then it was extracted with dichloremethane,
dried with anhydrous MgSO4, the solvent was removed by evaporation. The
residue was purified by means of silica gel chromatography (eluent:
dichloromethane) and recrystallized from n-hexane-ethanol to yield 50 g of 7-
(4-bromobutoxy)-3,4-dihydrocarbostyril, mp 110.5°-110.0°C.
47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of NaJ in 600 ml of
acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of
1-(2,3-dichlorophenyl)piperazine (it was prepareted from 2,3-chloroaniline and
di(2-bromoethyl)amine [1]) and 33 ml of triethylamine. The mixture was
refluxed for 3 hours. After removing of the solvent, the residue was dissolved
in chloroform, washed with water and dried with anhydrous MgSO4. The
solvent was removed by evaporation, and residue was recrystallized from
ethanol twice to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-
butoxy}-3,4-dihydrocarbostyril. Melting point: 139.0°-139.5°C.
Therapeutic Function
Antipsychotic
Hazard
A poison.
Biochem/physiol Actions
Aripiprazole is a second generation atypical antipsychotic and anti-depressant with partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Ki values are 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively, for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors. Aripiprazole is used in the treatment of schizophrenia.
Clinical Use
Atypical antipsychotic:
Treatment of schizophrenia
Depression in bipolar disorder
Safety Profile
A poison by intravenous route.When heated to decomposition it emits toxic vapors ofNOx and Cl-.
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.
Antihypertensives: may enhance antihypertensive
effect.
Alcohol and other CNS drugs: increased sedation
and other related side effects.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with anti-arrhythmics that prolong the
QT interval.
Antibacterials: concentration possibly reduced
by rifabutin and rifampicin - increase dose of
aripiprazole.
Antidepressants: fluoxetine and paroxetine possibly
inhibit metabolism - reduce dose of aripiprazole;
concentration possibly reduced by St John’s wort -
increase aripiprazole dose; increased concentration of
tricyclics.
Antiepileptics: antagonises anticonvulsant effect;
concentration reduced by carbamazepine and
possibly reduced by fosphenytoin, phenytoin,
phenobarbital and primidone - increase dose of
aripiprazole.
Antifungals: metabolism inhibited by ketoconazole
and possibly by itraconazole - reduce dose of
aripiprazole.
Antimalarials: avoid with artemether/lumefantrine.
Antipsychotics: possible increased risk of ventricular
arrhythmias with risperidone.
Antivirals: metabolism possibly inhibited by
atazanavir, darunavir, fosamprenavir, indinavir,
lopinavir, ritonavir, saquinavir and tipranavir -
reduce dose of aripiprazole; concentration possibly reduced by efavirenz and nevirapine - increase dose
of aripiprazole.
Anxiolytics and hypnotics: increased sedative effects.
Atomoxetine: increased risk of ventricular
arrhythmias.
Cytotoxics: increased risk of ventricular arrhythmias
with arsenic trioxide.
Metabolism
Aripiprazole is extensively metabolised by the liver
primarily by three biotransformation pathways:
dehydrogenation, hydroxylation, and N-dealkylation.
Based on in vitro studies, CYP3A4 and CYP2D6
enzymes are responsible for dehydrogenation and
hydroxylation of aripiprazole, and N-dealkylation is
catalysed by CYP3A4. Aripiprazole is the main active
moiety in systemic circulation. At steady state, dehydroaripiprazole, the active metabolite, represents about 40%
of aripiprazole AUC in plasma.
Following a single oral dose of [14C]-aripiprazole,
approximately 27% of the administered radioactivity
was recovered in the urine and approximately 60% in
the faeces. Less than 1% of unchanged aripiprazole
was excreted in the urine and approximately 18% was
recovered unchanged in the faeces.
References
1) Green et al. (2004), Focus on aripiprazole; Curr. Med. Res. Opin., 20 207
2) Kikuchi et al. (1995), 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity; J. Pharmacol. Exp. Ther., 274 329
3) Madhusoodanan et al. (2008), Management of psychosis in patients with Alzheimer’s disease: focus on aripiprazole; Clin. Interv. Aging, 3 491
4) Feltenstein et al. (2007), Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse; Biol. Psychiatry, 61 582
Check Digit Verification of cas no
The CAS Registry Mumber 129722-12-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,9,7,2 and 2 respectively; the second part has 2 digits, 1 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 129722-12:
(8*1)+(7*2)+(6*9)+(5*7)+(4*2)+(3*2)+(2*1)+(1*2)=129
129 % 10 = 9
So 129722-12-9 is a valid CAS Registry Number.
InChI:InChI=1/C23H27Cl2N3O2/c24-19-4-3-5-21(23(19)25)28-13-11-27(12-14-28)10-1-2-15-30-18-8-6-17-7-9-22(29)26-20(17)16-18/h3-6,8,16H,1-2,7,9-15H2,(H,26,29)
129722-12-9Relevant articles and documents
Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole
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Paragraph 0035; 0054; 0135-0143, (2021/08/07)
The invention discloses a synthesis method of high-purity aripiprazole and a preparation method of hydrate particles of aripiprazole. The method comprises the following steps: step (1), carrying out Williamson etherification on 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-dibromobutane under the action of potassium carbonate to obtain 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone; step (2), synthesizing 2,3-dichlorophenyl piperazine hydrochloride from 2,3-dichloroaniline and bis(2-chloroethyl) amine hydrochloride; step (3), carrying out an alkylation coupling reaction of nitrogen on 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 1-(2,3-dichlorophenyl) piperazine hydrochloride, so as to prepare aripiprazole; (4) refining: recrystallizing aripiprazole by using ethyl acetate to obtain high-purity anhydrous aripiprazole; and (5) preparation of aripiprazole hydrate particles: refluxing and dissolving anhydrous aripiprazole in an ethanol-water system, and controlling the stirring rate and the cooling rate to obtain the aripiprazole hydrate particles.
The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH
Chen, Kaixuan,Jiang, Zhenzhou,Liu, Shuwen,Xi, Baomin,Yang, Fubiao,Zeng, Li-Yan,Zeng, Yunong
, (2020/09/18)
Based on the SAR of both α1-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C6min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α1-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.
Preparation method of aripiprazole
-
Paragraph 0068-0074, (2019/10/01)
The invention discloses a preparation method of aripiprazole. The method comprises the following steps: dissolving 1-(2,3-dichlorophenyl)piperazine or a salt thereof in a polar solvent, adding 1,4-dibromobutane and an acid binding agent, carrying out a reaction under a first heating condition, performing first cooling and first filtration to obtain a first filtrate, distilling the solvent out of the first filtrate, adding a weakly polar solvent for crystallization, performing second filtration to obtain a second filtrate, performing drying to obtain 1-(2,3-dichlorophenyl)piperazine azacyclopentamine salt, adding the 1-(2,3-dichlorophenyl)piperazine azacyclopentamine salt, 7-hydroxyl-3,4-dihydroquinolone, and an alcohol base in an anhydrous alcohol, carrying out a reaction under a second heating condition, performing second cooling, performing dispersing by pouring the cooled system into ice water, performing third filtration, performing washing with water, and performing crystallization to obtain aripiprazole. According to the provided method, the process raw materials are easy to obtain, the route is simple and short, and the high-purity target product can be obtained. Compared with a method of the prior art, the method optimizes the process conditions, reduces the production cost, has good product quality, has high yield, and is favorable for industrialized production.
Preparation method of aripiprazole crystal form B
-
Paragraph 0064-0066, (2019/10/01)
The invention discloses a preparation method of an aripiprazole crystal form B. The preparation method comprises the following steps: dissolving an aripiprazole crude product in dichloromethane, and carrying out refluxing and separating water to obtain a dichloromethane solution of aripiprazole; and dropwise adding the dichloromethane solution of aripiprazole into n-hexane, evaporating out dichloromethane, then evaporating out a part of the solvent, stopping performing distillation, and carrying out cooling, filtering and drying to obtain the aripiprazole crystal form B. According to the preparation method provided by the invention, purification and crystallization of the aripiprazole crude product are completed in one step, operation is simple and convenient, the process is stable, the quality is good, the yield is high, purity of aripiprazole is further improved, and the impurity content is further reduced. The obtained crystal form meets the requirement of medicinal-grade purity, has good stability, and facilitates industrial production.
Synthesis method of aripiprazole
-
Paragraph 0027; 0032-0043, (2019/02/04)
The invention discloses a synthesis method of aripiprazole. 7-(4-hydroxybutyloxy)-3,4-dihydro-2(1H)-quinolone as a raw material is subjected to reaction with 1-(2,3-dichlorophenyl)piperazine hydrochloride in the presence of (cyanomethyl)trialkylphosphonium iodide and diisopropylethylamine to generate aripiprazole. Alkyl in (cyanomethyl)trialkylphosphonium iodide can be any one of methyl, ethyl, propyl or butyl. The raw materials and reagents in the method are cheap and commercially available, and high-quality aripiprazole can be obtained by two-step reaction. The process has good reaction selectivity and does not produce dimer by-products; intermediates in all the steps can be purified by recrystallization, and single impurities can reach the intermediate index of raw material drugs; the total yield of the finally prepared qualified-purity raw material drug can reach 60-70%, the process is obviously improved, and the synthesis method has a good industrial application prospect.
Preparation method of aripiprazole
-
, (2019/01/21)
The invention relates to a preparation method of aripiprazole, and belongs to the technical field of preparation of raw material medicines. The preparation method comprises the following steps: carrying out a coupling reaction on 2,3-dichlorobromobenzene ued as a starting material and bis(2-chloroethyl)amine, carrying out a cyclization reaction on the obtained coupling reaction product and 4-amino-1-butanol, carrying out a substitution reaction on the obtained cyclization reaction product and thionyl chloride to obtain a chlorobutyl-substituted intermediate III, and further reacting the intermediate III with 3,4-dihydro-7-hydroxyl-2(1H)-quinolinone to form the aripiprazole. The preparation method has great advantages in reducing the use equivalent of every material and controlling the formation of a dimer, so the finished aripiprazole product with a high purity is well obtained.
Method for synthesizing aripiprazole
-
, (2019/01/16)
The invention discloses a method for synthesizing aripiprazole. The method comprises making 4-halogenated-3-nitrophenol react with an ethylenation reagent under palladium catalysis conditions to obtain 3-nitro-4-vinylphenol; making the 3-nitro-4-vinylphenol and 1,4-dihalogenated butane reacting with alkali to obtain 4-(4-halobutoxy)-2-nitro-1-styrene; making the 4-(4-halobutoxy)-2-nitro-1-styreneand 1-(2,3-dichlorophenyl)piperazine salt reacting with the alkali to obtain 1-(2,3-dichlorophenyl)-4-(4-(3-nitro-4-vinylphenoxy)butyl)piperazine; making the 1-(2,3-dichlorophenyl)-4-(4-(3-nitro-4-vinylphenoxy)butyl)piperazine reacting with CO to form the aripiprazole. The method for synthesizing the aripiprazole has the total yield of up to 77% and is simple in post treatment.
Enabling CO Insertion into o-Nitrostyrenes beyond Reduction for Selective Access to Indolin-2-one and Dihydroquinolin-2-one Derivatives
Yang, Li,Shi, Lijun,Xing, Qi,Huang, Kuo-Wei,Xia, Chungu,Li, Fuwei
, p. 10340 - 10348 (2018/10/20)
The transition metal-catalyzed reductive cyclization of o-nitrostyrene in the presence of carbon monoxide (CO) has been developed to be a general synthetic route to an indole skeleton, wherein CO was used as a reductant to deoxidize nitroarene into nitrosoarene and/or nitrene with CO2 release, but the selective insertion of CO into the heterocyclic product with higher atom economy has not yet been realized. Herein, the Pd-catalyzed reduction of o-nitrostyrene by CO and its regioselective insertion were efficiently achieved to produce synthetically useful five- and six-membered benzo-fused lactams. Detailed investigations revealed that the chemoselectivity to indole or lactam was sensitive to the nature of the counteranions of Pd2+ precursors, whereas ligands significantly decided the carbonylative regioselectivity by different reaction pathways. Using PdCl2/PPh3/B(OH)3 (condition A), an olefin hydrocarboxylation was primarily initiated followed by partial reduction of the NO2 moiety and cyclization reaction to give N-hydroxyl indolin-2-one, which was further catalytically reduced by CO to afford the indolin-2-one as the final product with up to 95% yield. When the reaction was conducted under the Pd(TFA)2/BINAP/TsOH·H2O system (condition B), complete deoxygenation and carbonylation of the NO2 group occurred initially to yield the corresponding isocyanate followed by internal hydrocyclization to generate 3,4-dihydroquinolin-2-one with up to 98% yield. Importantly, the methodology could be efficiently applied in the synthesis of marketed drug Aripiprazole.
Novel Polymorphic DH Form of Aripiprazole Anhydride and Preparing Method of the Same
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Paragraph 0047-0049, (2018/08/22)
The present invention relates to novel polymorphism of aripiprazole, which are DH-1, DH-2, and DH-3. The present invention further relates to a method for producing the polymorphism. The novel polymorphism of aripiprazole provided in the present invention ensures excellent physicochemical properties such as stability and non-hygroscopicity, and can be useful for producing aripiprazole-containing drugs.COPYRIGHT KIPO 2018
A process for preparing aripiprazole crystalline B method
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Paragraph 0025; 0026; 0027, (2017/08/25)
A method of preparing a B-type aripiprazole crystal is provided. The method includes heating to dissolve aripiprazole into dichloromethane, cooling for crystallizing, filtering and drying to obtain the B-type aripiprazole crystal. The method is simple and convenient in operation and stable in process. The prepared product has characteristics of good crystal form oneness, easy drying and good crystal form stability and is suitable for industrial production.
