641571-10-0 Usage
Uses
Used in Pharmaceutical Industry:
Nilotinib is used as an anti-cancer agent for the treatment of chronic myeloid leukemia (CML) in patients with Philadelphia chromosome-positive (Ph+) disease who are resistant or intolerant to imatinib mesilate. It selectively inhibits the tyrosine kinase Bcr-Abl, which is a key factor in the pathogenesis of CML.
Additionally, Nilotinib-d6, the labeled analogue of Nilotinib, might be useful in the treatment of chronic myelogenous leukemia.
Furthermore, Nilotinib (AMN-107) is a Bcr-Abl inhibitor with an IC50 less than 30 nM, indicating its potency in inhibiting the target enzyme.
Clinical trials are also underway for the treatment of acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumors (GISTs), expanding its potential applications in the medical field.
Nilotinib for the treatment of chronic myeloid leukemia
Nilotinib is a novel drug for targeted cancer therapy and belongs to tyrosine kinase inhibitors for the treatment of patients of chronic myelogenous leukemia (CML) which is resistant to the Gleevec (imatinib) with an excellent efficacy. Gleevec is the primary-choice drug developed by Novartis Company for the treatment of chronic myelogenous leukemia (CML) . Nilotinib is the developed through the improvement of the molecular structure of imatinib with a stronger selectivity on the BCR-ABL kinase activity. The inhibitory effect of nilotinib on the tyrosine kinase is 30 times as high as that of imatinib. It is capable of suppressing the activity of the imatinib-resistant BCR-ABL mutant kinase while also being able to inhibit the activity of KIT and PDGFR kinase. With administration twice daily, nilotinib can targeted to the Bcr-Abl protein, interact with it and inhibit the emergence of cancer cells containing abnormal chromosomes. Bcr-Abl protein is produced by cells containing the abnormal Philadelphia chromosome. For patients of CML, this protein is considered to be an important factor for causing the excessive proliferation of cancer-causing white blood cells.Approved Uses: TASIGNA? (nilotinib) capsules is a prescription medicine used to treat:Adults with newly diagnosed Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phaseAdults with Ph+ CML in chronic phase and accelerated phase who no longer benefit...https://www.novartis.us
Mechanism of Action
Nilotinib is a selective tyrosine kinase inhibitor active against Bcr-Abl kinase Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. Nilotinib is 30-fold more potent than imatinib.
Absorption, Fate, and Excretion
Nilotinib is rapidly absorbed and reaches its peak concentration in 3 hours. Nilotinib AUC was increased by 82% when given 30 minutes after a high-fat meal compared with a fasting state. Its elimination half-life is approximately 17 hours. It is metabolized by oxidation and hydroxylation as well as undergoing metabolism by CYP3A4. None of the nilotinib metabolites have significant pharmacologic activity.
Drug Interactions
Nilotinib is a competitive inhibitor of cytochrome P-450 (CYP) isoenzymes 3A4, 2C8, 2C9, and 2D6 and has the potential to increase concentrations of drugs metabolized by these enzymes. Nilotinib plasma concentration is increased during concomitant use with potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Decreased nilotinib plasma concentration occurs during concomitant use with potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort). Drugs that increase the pH of the upper gastrointestinal tract may decrease the solubility of nilotinib and reduce its bioavailability. The oral administration of esomeprazole resulted in a 34% reduction in the AUC of nilotinib.
Side effects
Nilotinib may cause anemia, neutropenia and thrombocytopenia. Prolonged QT interval and sudden death has occurred. Pruritus, rash, and nausea are common. Also seen with nilotinib are arthralgias and myalgias. Cough has also been associated with nilotinib.
Clinical evaluation
Nilotinib is the other second-generation Abl kinase inhibitor approved for treatment of patients with CML. Nilotinib has increased affinity for the Abl kinase compared with imatinib, binding with an improved topologic fit to the kinase site in its inactive form.Nilotinib is active in chronic and accelerated phase CML patients who have developed resistance to imatinib. As with dasatinib, nilotinib was compared with imatinib in a phase III randomized trial as initial therapy for chronic phase CML patients, with nilotinib achieving higher rates of complete cytogenetic and major molecular responses and with fewer cases of disease progression or clonal evolution in the nilotinib-treated cohorts. Survival outcomes were similar in all arms. Common adverse events with nilotinib included rash, gastrointestinal disturbances (nausea, vomiting, diarrhea), neutropenia, and thrombocytopenia. Pleural effusion and peripheral edema are less common than with dasatinib. In addition, QT prolongation and a risk of pancreatitis are serious side effects of nilotinib.
Clinical Use
Tyrosine kinase inhibitor:
Treatment of chronic myelogenous leukaemia
(CML)
Synthesis
The first step in the synthesis of nilotinib involves the nucleophilic aromatic substitution of 3-fluoro-5-(trifluoromethyl)benzonitrile with 2-methylimidazole. The nitrile is then hydrolyzed with sodium hydroxide in aqueous dioxane. A Curtius rearrangement employing diphenylphosphoryl azide in tert-butanol affords the tert-butyl carbamate. Deprotection of the Boc group provides the 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)aniline piece for the convergent synthesis. Construction of the other half begins with the condensation of 3-amino-4- methylbenzoic acid methyl ester with cyanamide in refluxing ethanolic HCl to generate the 3-guanidinobenzoate. An enamino ketone, prepared by a Claisen condensation of 3-acetylpyridine with ethyl formate in the presence of sodium metal in hot toluene, is then cyclized with the guanidine to yield the pyridylpyrimidine. Following saponification of the ethyl ester, the resultant 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]benzoic acid is finally coupled with the aniline utilizing diethyl cyanophosphate to provide nilotinib.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: avoid with clarithromycin, rifampicin
(concentration reduced) and telithromycin.
Antifungals: avoid with itraconazole, ketoconazole
(concentration increased) and voriconazole.
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Antivirals: avoid with boceprevir and ritonavir
(concentration possibly increased).
Grapefruit juice: avoid concomitant administration.
Avoid concomitant use with other inhibitors or
inducers of CYP3A4. Dose alterations may be
required.
Metabolism
Nilotinib is metabolised in the liver via oxidation and
hydroxylation, in which cytochrome P450 isoenzyme
CYP3A4 plays an important role.
Most of an oral dose is eliminated unchanged in the faeces
within 7 days.
References
1) Weisberg?et al.?(2006),?AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL; Br J. Cancer,?94?1765
2) Verstovsek?et al.?(2006),?Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells; Ann. Neurol.,?75?209
Check Digit Verification of cas no
The CAS Registry Mumber 641571-10-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 6,4,1,5,7 and 1 respectively; the second part has 2 digits, 1 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 641571-10:
(8*6)+(7*4)+(6*1)+(5*5)+(4*7)+(3*1)+(2*1)+(1*0)=140
140 % 10 = 0
So 641571-10-0 is a valid CAS Registry Number.
InChI:InChI=1/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)
641571-10-0Relevant articles and documents
SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE
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Page/Page column 40-41, (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.
High-yield synthesis method of nilotinib
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, (2020/03/17)
The invention discloses a high-yield synthesis method, of nilotinib, and relates to the technical field, of pharmaceutical organic synthesis, and 3 - and, of intermediates 3 - (4 - and) - 5 - are obtained through a closed-loop reaction to obtain the intermediate I, and the intermediate I of the present invention as a starting material II, through an acid addition reaction and a synthesis method for synthesizing meso II intermediate 3 - with the monocyanamide through an acid addition reaction and reducing the cost input) - 2 - and reducing the three-waste generation amount. to obtain the intermediate 70% . The raw material is easy to obtain, through a closed-loop. reaction to obtain a nilotinib, as a starting material by a closed-loop reaction.
Preparation method and intermediate of nilotinib
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, (2019/05/02)
The invention discloses a nilotinib preparation method and an intermediate of nilotinib. The preparation method comprises: in a solvent, carrying out a reaction defined in the specification on a compound D or a hydrochloride salt thereof, and a compound SM3 under the action of an inorganic base to obtain the compound E nilotinib. According to the present invention, the preparation method has characteristics of simple reaction, easy operation, safe and environmentally friendly reagent, less side reaction and short reaction time. The reaction formula is defined in the specification.
AN IMPROVED PROCESS FOR 3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL) ANILINE
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, (2019/07/17)
The present invention relates to an improved process for the preparation of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) aniline of Formula (I).
PROCESS FOR THE PREPARATION OF PURE NILOTINIB AND ITS SALT
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Paragraph 0125; 0126, (2018/12/04)
Object of the present invention is a process for the preparation of the pharmaceutical active ingredient Nilotinib free base or Nilotinib dihydrochloride dihydrate by means of an improved crystallization procedure.
A 3 - (4 - methyl - 1H - imidazole -1 - yl) -5 - trifluoromethyl aniline single hydrochloride crystalline form and application thereof (by machine translation)
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Paragraph 0101-0102, (2018/10/11)
The invention relates to a 3 - (4 - methyl - 1 H - imidazole - 1 - yl) - 5 - trifluoromethyl aniline single hydrochloride crystalline form and its application. In particular, the invention discloses 3 - (4 - methyl - 1 H - imidazole - 1 - yl) - 5 - trifluoromethyl aniline single hydrochloride anhydrous crystalline form A, crystalline form A preparation method of synthesizing [...] and this crystalline form in the application. The crystalline form of the present invention A has good stability and purity, can be directly used for the preparation of [...] in production. The invention of the preparation method [...] operation is simple and easy, with comparatively high industrial application value. (by machine translation)
METHOD FOR PREPARING NILOTINIB
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Paragraph 0098, (2018/06/09)
A method for preparing nilotinib includes the following steps: performing an aminocarbonylation reaction on a compound A and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) aniline to obtain an amination product; and performing deprotection treatment of an R group on the amination product to obtain the nilotinib, wherein the compound A has a structure shown in formula I, and in formula I, an R group is selected from benzyl, —COCF3, —CHO or —CO2R′, where an R′ group is C1?C10 alkyl, C1?C3 alkoxy ethyl or C7?C19 aralkyl.
Preparation method of high-purity nilotinib
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Paragraph 0019-0027, (2017/08/28)
The invention discloses a preparation method of high-purity nilotinib. The method includes two steps of synthesizing and purifying nilotinib. The purification further includes extraction, silica gel column chromatography, secondary extraction, re-crystallization, etc. The nilotinib is more than 99.5% in purity, is less than 0.1% in content of single impurity and is more than 65% in yield. The preparation method is suitable for industrial production in the scale of active pharmaceutical ingredients.
The preparation method of the [...]
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Paragraph 0060; 0063; 0064; 0066; 0067; 0069; 0107-00109, (2017/11/16)
The invention provides a preparation method for nilotinib. The preparation method comprises the following steps: producing a carbonyl insertion amination reaction of a compound A and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)phenylamine, and obtaining an amination product; performing R group deprotection treatment on the amination product, and obtaining nilotinib, wherein the compound A has a structure as shown in a formula I, in the formula I, R is selected from benzyl, -COCF3, -CHO or -CO2R', and R' is C1-C10 alkyl, C1-C3 alkoxy ethyl or C7-C19 aralkyl. The preparation method is short in synthetic route and mild in reaction condition, and due to the adoption of special raw materials, the preparation method reduces the process cost while increasing the carbonyl yield.
An optimized approach in the synthesis of imatinib intermediates and analogues
Kinigopoulou,Filippidou,Gogou,Giannousi,Fouka,Ntemou,Alivertis,Georgis,Brentas,Polychronidou,Voulgari,Theodorou,Skobridis
, p. 61458 - 61467 (2016/07/12)
We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt 4, one of the key steps to the imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of nilotinib and its analogues intermediates.
