152459-95-5 Usage
Uses
Used in Oncology:
Imatinib is used as an antineoplastic agent for the treatment of chronic myelogenous leukemia (CML) with positive symptoms of the Philadelphia chromosome (Ber-Abl). It is particularly suitable for adult patients in the acute transformation phase, accelerated phase, and chronic phase who have experienced treatment failure with interferon. CML is a hematopoietic stem cell disease caused by DNA abnormalities in bone marrow stem cells, leading to an increase in white blood cell count. Imatinib has also demonstrated effectiveness in treating gastrointestinal stromal tumors with an efficiency of about 50%.
Used in Psychiatry:
Imatinib is utilized as an atypical antipsychotic, offering potential benefits in the treatment of certain psychiatric disorders.
Used in Pharmaceutical Research:
Imatinib impurity is employed in the development and research of new pharmaceutical compounds, contributing to the advancement of medical treatments.
Used in Drug Formulation:
As an orally bioavailable drug, Imatinib is used in the formulation of medications aimed at treating the specified conditions, providing a convenient and effective means of administration for patients.
Approved indications in Europe, the United States and other countries
Novartis's imatinib (imatinib, Glivec) had been approved in Switzerland for being used as first-line drug for the treatment of early-stage adult chronic myelogenous leukemia and can also be applied to patients with various types of chronic granulocytic leukemia. Switzerland is the first countries which had approved to additionally include the above two indications of this drug.
On July 28, 2006, the European Agency for the Evaluation of Medicinal Products (EMEA) had recommended the imatinib (Gleevec) of the Novartis Company for the treatment of two new indications-dermatofibrosarcoma protuberans (DFSP) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). These final approvals of these two indications still need to wait the decision of the European Food and Drug Administration.
In addition, Novartis has announced that the application of imatinib in treating hypereosinophilic syndrome and systemic mastocytosis is still in the approval process of FDA and EMEA.
The drug has currently been approved in Europe, the United States and other countries for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph + CML) and gastrointestinal stromal tumors.
The above information is edited by the lookchem of Dai Xiongfeng.
Precautions
When combined with Ketoconazole, itraconazole, erythromycin, clarithromycin, the Cmax of this drug can (the maximum plasma concentration after the first drug administration) be increased by an average of 26% with the AUC being increased by 40%.
The inducers of the metabolizing enzyme of hepatic drugs such as dexamethasone, phenytoin, carbamazepine, rifampicin and barbiturates can significantly reduce blood concentration of the drug.
When the CYP3A4 metabolized substrates such as simvastatin, cyclosporine, pimozide, etc. were used in combined with imatinib, the plasma concentration of those drugs can be increased due to its competing with the drug enzyme.
Indications
Bcr-Abl inhibitor imatinib (Gleevec(R), Novartis) was approved in 2001 by the FDA. Although fasudil was approved in 1995, imatinib is widely perceived as the first approved SMKI mainly owing to the fact that fasudil's kinase inhibitory mechanism was unknown at the time of approval, and efforts to gain approval of fasudil have been unsuccessful in the United States and Europe.
The field of kinase inhibitor development has evolved rapidly since the approval of imatinib. Some of the key discoveries and events include (i) the discovery of MAPK/ERK inhibitors, for example, CI-1040 (PD184352), as the first series of type III inhibitors in 2003; (ii) the approval of first dual tyrosine kinase and serine/threonine kinase inhibitor sorafenib in 2005; (iii) the description of the first series of allosteric type IVkinase inhibitor, that is,GNF-2 and analogues that inhibit Bcr–Abl through an allosteric non-ATP-competitivemode, by Gray and coworkers in 2006; (iv) the approval of the first type III inhibitor trametinib in 2013; (v) the approval of the first covalent kinase inhibitors, afatinib and ibrutinib, in 2013; and (vi) the approval of the first lipid kinase inhibitor, that is, the PI3K inhibitor idelalisib, in 2014.
By December 2016, kinase inhibitor drug discovery can leverage the structures of over 200 human kinases and 5000 kinases of all types, over 1 million publications, clinical data from more than 200 molecules currently in phase I–III trials, and post-marketing results from the approved 38 drugs.
Indications
Imantinib mesylate (Gleevec) is a rationally designed
inhibitor of the tumor-specific bcr-abl kinase. The
Philadelphia chromosome, present in nearly all patients
with chronic myelogenous leukemia (CML), is produced
by a chromosomal rearrangement linking the bcr
and the abl genes. The bcr-able kinase is therefore a
unique drug target in leukemic cells, and imantinib selectively
and potently inhibits this kinase. Remissions in
CML patients are achieved with high frequency and
very low toxicity, and this compound may become a
front-line agent for treating this cancer. Unfortunately,
drug resistance has already been observed in the clinic
as a result of mutations in the bcr-abl kinase, and this
magic bullet does not appear to be curative for CML
patients. Extension of the use of imantinib to other tumor
types with overexpression of c-kit kinase or
platelet-derived growth factor kinase is undergoing development
because of its observed activity against these
kinases.
Biological Activity
imatinib is an inhibitor of protein-tyrosine kinase with ic50 values of 0.1, 0.1 and 0.025μm, respectively against pdgf receptor, c-kit and abl [1].the type 3 group of receptor tyrosine kinases includes pdgfr, csf-1r, flt-3, c-kit and so on. pdgfrs are found in normal tissues, cells as well as some tumors. it is associated with several nonmalignant proliferative diseases. in vitro assays show that imatinib can inhibit both pdgf-aa and pdgf-bb stimulated pdgf receptor phosphorylation. imatinib is also found to inhibit the phosphorylation of c-kit, another kinase which mediates the growth of a number of tumors. imatinib inhibits the phosphorylation of these kinases without effecting the expression of them. some other kinases of the type 3 group (such as fms and flt-3) can’t be inhibited by imatinib, suggesting a selectivity of imatinib. in addition, imatinib is shown to significantly inhibit the bcr-abl tyrosine kinase both in cell-based assay and in vitro kinase assay. moreover, as a downstream pathway of pdgf-mediated signals, map kinase activation can also be effected in rat a10 smooth muscle cells [1].
Clinical Use
Tyrosine kinase inhibitor, antineoplastic agent:
Treatment of chronic myeloid leukaemia
Treatment of metastatic malignant gastrointestinal
stromal tumours
Treatment of acute lymphoblastic leukaemia
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Anticoagulants: enhanced anticoagulant effect of
warfarin, replace with heparin.
Antidepressants: concentration reduced by St. Johns
Wort - avoid.
Antiepileptics: concentration reduced by
carbamazepine, fosphenytoin, oxcarbazepine and
phenytoin - avoid; absorption of phenytoin possibly
reduced.
Antipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis).
Antivirals: avoid with boceprevir.
Ciclosporin: may increase ciclosporin levels.
Cytotoxics: possibly increases bosutinib
concentration - avoid or reduce bosutinib dose;
concentration of everolimus and possibly ibrutinib
increased - reduce dose of everolimus and ibrutinib.
Tacrolimus: may increase tacrolimus levels.
Metabolism
The main circulating metabolite in humans is the
N-demethylated piperazine derivative, which shows
similar in vitro potency to the parent. Imatinib and the
N-demethyl metabolite together accounted for about
65% of the circulating radioactivity (AUC(0-48h)). The
remaining circulating radioactivity consisted of a number
of minor metabolites. In vitro results showed that
CYP3A4 was the major human P450 enzyme catalysing
the biotransformation of imatinib. Based on the recovery
of compound(s) after an oral [14C]-labelled dose of
imatinib, approximately 81% of the dose was recovered
within 7 days in faeces (68% of dose) and urine (13% of
dose). Unchanged imatinib accounted for 25% of the dose
(5% urine, 20% faeces), the remainder being metabolites.
references
[1] elisabeth buchdunger, catherine l. cioffi, norman law, david stover, sayuri ohno-jones, brian j. druker and nicholas b. lydon. abl protein-tyrosine kinase inhibitor sti571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. the journal of pharmacology and experimental therapeutics. 2000, 295(1): 139-145.
Check Digit Verification of cas no
The CAS Registry Mumber 152459-95-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,2,4,5 and 9 respectively; the second part has 2 digits, 9 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 152459-95:
(8*1)+(7*5)+(6*2)+(5*4)+(4*5)+(3*9)+(2*9)+(1*5)=145
145 % 10 = 5
So 152459-95-5 is a valid CAS Registry Number.
InChI:InChI=1/C29H31N7O.CH4O3S/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36;1-5(2,3)4/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34);1H3,(H,2,3,4)
152459-95-5Relevant articles and documents
Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: Synthesis of Imatinib
Heo, Yumi,Hyun, Dajung,Kumar, Manian Rajesh,Jung, Hyun Min,Lee, Sunwoo
, p. 6657 - 6661 (2012)
CuO nanoflakes bound on polystyrene beads (PS-CuO) were prepared through the oxidation of copper(I) bromide in a suspension of polystyrene. The use of PS-CuO as a catalyst in the presence of KOtBu in the coupling reactions of aryl bromides and amines afforded the coupled products with a yield range of 15-89%. This catalytic system also afforded the key fragment in good yield for the synthesis of Imatinib (Gleevec).
Microwave-assisted solid phase synthesis of Imatinib, a blockbuster anticancer drug
Leonetti, Francesco,Capaldi, Carmelida,Carotti, Angelo
, p. 3455 - 3458 (2007)
An expeditious, high yield and convenient synthesis of Imatinib was carried out on an aldehydic, super acid-sensitive resin, through an efficient, microwave-assisted synthetic protocol. The high versatility of the reaction scheme may enable the straightforward preparation of libraries of potential protein kinase inhibitors endowed with large molecular diversity.
Synthesis of imatinib: A convergent approach revisited
Ivanov, Andrey S.,Shishkov, Sergey V.
, p. 619 - 623 (2009)
A classical convergent approach for the synthesis of the anticancer drug imatinib has been substantially improved. Imatinib was assembled by coupling the amine and carboxylic acid precursors by using N,N′-carbonyldiimidazole (CDI) as a condensing agent. Both intermediates have been synthesized by novel efficient methods.
A PROCESS FOR PREPARATION OF IMATINIB BY USING VILSMEIER REAGENT
-
, (2021/07/17)
The present invention relates to a process of preparation of Imatinib, wherein said process comprises one or more steps of converting benzoic acid intermediate (formula 8) into Imatinib in presence of Vilsmeier reagent preferably under basic condition. Vilsmeier reagent in the present invention is prepared by reaction of chlorinating agent and catalyst. In a preferred embodiment Chlorinating agent is thionyl chloride and catalyst is dimethyl formamide.
SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE
-
Page/Page column 39-40, (2021/04/23)
Processes and useful intermediates for the synthesis of the tyrosine kinase inhibitors Formula (II) nilotinib and Formula (IV) imatinib. Key intermediates, method for their synthesis and their use in a divergent synthesis, making use of a Curtius rearrangement, to nilotinib and imatinib are described.
Synthesis of imatinib, a tyrosine kinase inhibitor, labeled with carbon-14
Kang, Julie,Lee, Jun Young,Park, Jeong-Hoon,Chang, Dong-Jo
, p. 174 - 182 (2020/02/13)
Imatinib (Gleevec) is a multiple tyrosine kinase inhibitor that decreases the activity of the fusion oncogene called BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog) and is clinically used for the treatment of chronic myelogenous leukemia and acute lymphocytic leukemia. Small molecule drugs, such as imatinib, can bind to several cellular proteins including the target proteins in the cells, inducing undesirable effects along with the effects against the disease. In this study, we report the synthetic optimization for 14C-labeling and radiosynthesis of [14C]imatinib to analyze binding with cellular proteins using accelerator mass spectroscopy. 14C-labeling of imatinib was performed by the synthesis of 14C-labeld 2-aminopyrimidine intermediate using [14C]guanidine·HCl, which includes an in situ reduction of an inseparable byproduct for easy purification by HPLC, followed by a cross-coupling reaction with aryl bromide precursor. The radiosynthesis of [14C]imatinib (specific activity, 631 MBq/mmol; radiochemical purity, 99.6%) was achieved in six steps with a total chemical yield of 29.2%.
Synthesis method of imatinib and imatinib mesylate
-
, (2020/05/02)
The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
Preparation method of imatinib mesylate
-
, (2020/12/05)
The invention discloses a preparation method of imatinib mesylate. The method comprises the following steps: chlorinating imatinib acid[4-(4-methylpiperazine-1-ylmethyl)benzoic acid dihydrochloride] with thionyl chloride to generate an imatinib mesylate intermediate I; condensing the imatinib mesylate intermediate I with imatinib amine [N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine] toobtain an imatinib mesylate intermediate II, and finally salifying the imatinib mesylate intermediate II with methanesulfonic acid to obtain imatinib mesylate. According to the invention, the raw materials imatinib acid and imatinib amine used in the method are common medical intermediates, other raw materials and reagents used in the process are convenient and easy to obtain, the reaction process and post-treatment operation are simple and convenient, the yield is high, and the production cost is effectively reduced through process optimization.
Synthesis method of imatinib free base (by machine translation)
-
Paragraph 0033; 0041-0048, (2021/01/04)
The invention relates to a synthetic method of imatinib free base. [N - (5 - amino -2 - methylphenyl) -4 - (pyridin -3 -yl) pyrimidine -2 - amine and 1 - [(4 - bromophenyl) methyl] -4 - methylpiperazine are used as raw materials to generate imatinib under the catalysis of palladium acetate and ligand 4,5 - bis (triphenylphosphine -9, 9 -dimethylxanthene) in 1 atm carbon monoxide atmosphere. The synthetic route of the invention is simple and effective, avoids the use of highly contaminated reagents such as thionyl chloride or phosphorus oxychloride, and has the advantages of cheap and easily available starting materials and wide market supply. The method is simple to operate. The method is mild in process condition, low in pollution and suitable for industrial production. (by machine translation)
Synthesis of Imatinib by C-N Coupling Reaction of Primary Amide and Bromo-Substituted Pyrimidine Amine
Wang, Cuiling,Bai, Xiao,Wang, Rui,Zheng, Xudong,Ma, Xiumei,Chen, Huan,Ai, Yun,Bai, Yajun,Liu, Yifeng
, p. 1918 - 1925 (2019/09/07)
A new method for imatinib synthesis is described by using the C-N coupling reaction of 4-(4-methylpiperazine-1-methyl)benzamide with N-(5-bromo-2-tolyl)-4-(3-pyridyl)pyrimidin-2-amine to form imatinib. In this synthetic route, the high efficiency and high selectivity of nano-ZnO as a catalyst is key to the mild hydrolysis of 4-(4-methylpiperazine-1-methyl)benzonitrile into the corresponding amide. The total imatinib yield was 51.3%, and the purity was 99.9%. This simple and effective synthetic pathway avoids gene-impurity production (as classified by the FDA Center for Drug Evaluation and Research), and the synthesis is environmentally friendly with a short reaction time.
