Nilotinibhydrochlorid

Katalognummer: B1258797

CAS-Nummer: 923288-95-3

Molekulargewicht: 566.0 g/mol

InChI-Schlüssel: VTGGYCCJUPYZSX-UHFFFAOYSA-N

Achtung: Nur für Forschungszwecke. Nicht für den menschlichen oder tierärztlichen Gebrauch.

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Übersicht

1. Beschreibung

8. Eigenschaften

2. Wissenschaftliche Forschungsanwendungen

9. Synthesis routes and methods I

3. Wirkmechanismus

10. Synthesis routes and methods II

4. Biochemische Analyse

11. Synthesis routes and methods III

5. Vorbereitungsmethoden

12. Retrosynthesis analysis

6. Analyse chemischer Reaktionen

13. Haftungsausschluss

7. Vergleich mit ähnlichen Verbindungen

Beschreibung

Nilotinib hydrochloride is a medication primarily used to treat chronic myelogenous leukemia (CML) that is positive for the Philadelphia chromosome. It is a second-generation tyrosine kinase inhibitor developed to overcome resistance to imatinib, another tyrosine kinase inhibitor. Nilotinib hydrochloride is marketed under the brand name Tasigna and is known for its efficacy in treating both newly diagnosed and imatinib-resistant CML .

Wissenschaftliche Forschungsanwendungen

Nilotinibhydrochlorid hat mehrere Anwendungen in der wissenschaftlichen Forschung:

Chemie: Wird als Modellverbindung verwendet, um die Synthese und Stabilität von Tyrosinkinase-Inhibitoren zu untersuchen.

Biologie: Untersucht wegen seiner Auswirkungen auf zelluläre Signalwege und seinem Potenzial, andere Kinasen zu hemmen.

Medizin: Wird hauptsächlich zur Behandlung der chronisch-myeloischen Leukämie eingesetzt. .

Industrie: Wird bei der Entwicklung von pharmazeutischen Formulierungen und als Referenzstandard in der analytischen Chemie eingesetzt.

5. Wirkmechanismus

This compound übt seine Wirkung aus, indem es die Tyrosinkinase-Aktivität des BCR-ABL-Proteins hemmt, das vom Philadelphia-Chromosom produziert wird. Es bindet an die ATP-Bindungsstelle des BCR-ABL-Proteins und verhindert so dessen Phosphorylierungsaktivität. Diese Hemmung blockiert die nachgeschalteten Signalwege, die für das Überleben und die Proliferation von Leukämiezellen entscheidend sind .

Wirkmechanismus

Biochemische Analyse

Biochemical Properties

Nilotinib hydrochloride plays a crucial role in biochemical reactions by inhibiting the activity of several tyrosine kinases, including BCR-ABL, c-KIT, and platelet-derived growth factor receptor (PDGFR). It binds to the ATP-binding site of these kinases, preventing their phosphorylation and subsequent activation. This inhibition disrupts the signaling pathways that promote cell proliferation and survival . Nilotinib hydrochloride also interacts with other biomolecules such as EPHA3, EPHA8, DDR1, DDR2, MAPK11, and ZAK, further contributing to its anti-leukemic effects .

Cellular Effects

Nilotinib hydrochloride exerts significant effects on various cell types and cellular processes. In leukemic cells, it inhibits the BCR-ABL kinase, leading to reduced cell proliferation and increased apoptosis. This compound also affects cell signaling pathways, including those mediated by c-KIT and PDGFR, which are involved in cell growth and differentiation . Additionally, nilotinib hydrochloride influences gene expression and cellular metabolism, contributing to its therapeutic efficacy in CML .

Molecular Mechanism

The molecular mechanism of action of nilotinib hydrochloride involves its binding to the ATP-binding site of the BCR-ABL kinase, stabilizing its inactive conformation. This binding prevents the phosphorylation of downstream signaling proteins, thereby inhibiting the proliferation of leukemic cells . Nilotinib hydrochloride also inhibits other tyrosine kinases, such as c-KIT and PDGFR, by a similar mechanism, further contributing to its anti-cancer effects .

Temporal Effects in Laboratory Settings

In laboratory settings, the effects of nilotinib hydrochloride have been observed to change over time. The compound is relatively stable, but its efficacy can decrease due to degradation and the development of resistance in leukemic cells . Long-term studies have shown that continuous exposure to nilotinib hydrochloride can lead to sustained inhibition of BCR-ABL kinase activity and prolonged survival of treated cells . Resistance mechanisms, such as mutations in the BCR-ABL gene, can reduce its effectiveness over time .

Dosage Effects in Animal Models

In animal models, the effects of nilotinib hydrochloride vary with different dosages. At therapeutic doses, it effectively inhibits the proliferation of leukemic cells and reduces tumor burden . At higher doses, nilotinib hydrochloride can cause toxic effects, including hepatotoxicity and cardiotoxicity . Studies have shown that there is a threshold dose above which the adverse effects outweigh the therapeutic benefits .

Metabolic Pathways

Nilotinib hydrochloride is primarily metabolized in the liver through oxidation and hydroxylation, mainly by the enzyme CYP3A4 . The main circulating component in the serum is the parent drug, with its metabolites contributing minimally to its pharmacological activity . The metabolic pathways of nilotinib hydrochloride involve interactions with various enzymes and cofactors, affecting metabolic flux and metabolite levels .

Transport and Distribution

Within cells and tissues, nilotinib hydrochloride is transported and distributed through various mechanisms. It is highly protein-bound in the plasma, with a protein binding rate of approximately 98%. The compound is also an inhibitor of the OATP-1B1 transporter, which affects its distribution and accumulation in specific tissues . The distribution coefficient (D) for nilotinib hydrochloride in n-octanol/0.1 N HCl buffer at 37°C is 0.08, indicating its hydrophilic nature .

Subcellular Localization

Nilotinib hydrochloride is localized within specific subcellular compartments, influencing its activity and function. Studies have shown that it can be internalized by cells and distributed within the cytoplasm and nucleus . The subcellular localization of nilotinib hydrochloride is crucial for its therapeutic effects, as it needs to reach its target kinases to exert its inhibitory action .

Vorbereitungsmethoden

Synthesewege und Reaktionsbedingungen: Die Synthese von Nilotinibhydrochlorid umfasst mehrere Schritte, beginnend mit der Herstellung der Kernstruktur, die ein Benzamid-Derivat umfasst. Der Prozess beinhaltet typischerweise die folgenden Schritte:

Bildung der Kernstruktur: Die Kernstruktur wird durch Reaktion von 4-Methyl-3-nitrobenzoesäure mit 4-Methyl-1H-imidazol in Gegenwart eines Kupplungsmittels synthetisiert.

Reduktion: Die Nitrogruppe wird zu einem Amin reduziert, wobei typischerweise eine katalytische Hydrierung mit Raney-Nickel in einem Methanolmedium eingesetzt wird.

Bildung des Hydrochloridsalzes: Der letzte Schritt beinhaltet die Umwandlung der Zwischenverbindung in this compound durch Reaktion mit Salzsäure.

Industrielle Produktionsverfahren: Die industrielle Produktion von this compound folgt einem ähnlichen Syntheseweg, der jedoch für die großtechnische Produktion optimiert ist. Der Prozess stellt sicher, dass eine stabile kristalline Form von this compound gebildet wird, die für seine pharmazeutische Formulierung unerlässlich ist .

Analyse Chemischer Reaktionen

Arten von Reaktionen: Nilotinibhydrochlorid unterliegt verschiedenen chemischen Reaktionen, darunter:

Oxidation: this compound kann unter bestimmten Bedingungen oxidiert werden, was zur Bildung von Abbauprodukten führt.

Reduktion: Die Nitrogruppe in der Zwischenverbindung wird während der Synthese zu einem Amin reduziert.

Substitution: Die Synthese beinhaltet Substitutionsreaktionen, um funktionelle Gruppen in die Kernstruktur einzuführen.

Häufige Reagenzien und Bedingungen:

Katalytische Hydrierung: Raney-Nickel in Methanol wird für den Reduktionsschritt verwendet.

Salzsäure: Wird zur Bildung des Hydrochloridsalzes verwendet.

Hauptprodukte, die gebildet werden:

This compound: Das Hauptprodukt, das aus der Synthese entsteht.

Abbauprodukte: Werden während der Oxidation und anderer Stressbedingungen gebildet

Vergleich Mit ähnlichen Verbindungen

Imatinib: The first-generation tyrosine kinase inhibitor used to treat CML. Nilotinib hydrochloride was developed to overcome resistance to imatinib.

Dasatinib: Another second-generation tyrosine kinase inhibitor used to treat CML.

Bosutinib: A third-generation tyrosine kinase inhibitor used for CML treatment.

Uniqueness of Nilotinib Hydrochloride: Nilotinib hydrochloride is unique due to its higher potency and specificity for the BCR-ABL protein compared to imatinib. It is also effective against several imatinib-resistant BCR-ABL mutations, making it a valuable option for patients who do not respond to imatinib .

Eigenschaften

IUPAC Name	4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide;hydrochloride	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C28H22F3N7O.ClH/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);1H	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	VTGGYCCJUPYZSX-UHFFFAOYSA-N	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	CC1=C(C=C(C=C1)C(=O)NC2=CC(=CC(=C2)C(F)(F)F)N3C=C(N=C3)C)NC4=NC=CC(=N4)C5=CN=CC=C5.Cl	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C28H23ClF3N7O	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

DSSTOX Substance ID	DTXSID60238968	Source
Record name	Nilotinib hydrochloride anhydrous
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID60238968
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight	566.0 g/mol	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

CAS No.	923288-95-3	Source
Record name	Nilotinib hydrochloride anhydrous
Source	ChemIDplus
URL	https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0923288953
Description	ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system.

Record name	Nilotinib hydrochloride anhydrous
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID60238968
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Record name	4-Methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide hydrochloride
Source	European Chemicals Agency (ECHA)
URL	https://echa.europa.eu/information-on-chemicals
Description	The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness.
Explanation	Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.

Record name	NILOTINIB HYDROCHLORIDE ANHYDROUS
Source	FDA Global Substance Registration System (GSRS)
URL	https://gsrs.ncats.nih.gov/ginas/app/beta/substances/K37N7BYX3X
Description	The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions.
Explanation	Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.

Synthesis routes and methods I

Procedure details

To a 1 liter reactor was added Nilotinib-base (20 g, 0.04 mol), absolute ethanol (9.4 vol) and HCl solution (13.77% in ethanol abs., 10 g, 0.04 mol). The resulting slurry was heated to reflux, and dissolution occurred during the stirring. The solution was filtered under reduced pressure. The filtrate was fed back to the reactor and heated back to reflux temperature. At 76.6° C. the solution was seeded with 0.2 g of dry Nilotinib HCl form T17. A solid precipitate was formed, and the mixture was maintained at reflux for 1 hour. The mixture was then cooled over 2 h to 6° C. At 6° C., absolute ethanol (15 vol) was added and the resulting slurry was stirred at 5° C. for 30 minutes. The slurry was then filtered, and the separated solid was washed with absolute ethanol, and dried overnight at 70° C. in a vacuum oven to yield Nilotinib-HCl form T17 (18.4 g, 83% yield)

Name

Nilotinib

Quantity

20 g

Type

reactant

Reaction Step One

Name

HCl

Quantity

10 g

Type

reactant

Reaction Step One

Name

ethanol

Quantity

0 (± 1) mol

Type

solvent

Reaction Step One

Name

ethanol

Quantity

0 (± 1) mol

Type

solvent

Reaction Step Two

Name

Nilotinib HCl

Yield

83%

Details

Synthesis routes and methods II

Procedure details

To a 1 Liter reactor was added Nilotinib-base form A (20 g, 0.04 mol), absolute ethanol (200 ml), and HCl 32% solution in water (6.45 g, 0.04 mol). A slurry was formed. The slurry was heated to reflux, dissolution occurred during the stirring, and the solution was then filtered under reduced pressure. The filtrate was fed to a second reactor and heated back to reflux. At 76.0° C. the solution was seeded with 0.2 g of a dry material obtained by the process of example 23. Precipitation was observed. Then, the mixture was maintained at reflux for 0.5 h, followed by cooling over 2 h to 5° C. During cooling at 20° C. absolute ethanol was added (100 ml) and the slurry was stirred till it cooled to 5° C. The cooled slurry was then filtered, and the collected solid was washed with absolute ethanol, and dried over night at 70° C. in a vacuum oven to yield Nilotinib-HCl form T17 (16.3 g, 73% yield).

Name

Nilotinib

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

HCl

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

water

Quantity

6.45 g

Type

reactant

Reaction Step One

Name

ethanol

Quantity

200 mL

Type

solvent

Reaction Step One

Name

Nilotinib HCl

Yield

73%

Details

Synthesis routes and methods III

Procedure details

Nilotinib base form A (0.2 g, 0.38 mmol) was added to a 25 mL vial and the open vial was placed in a plastic sealed flask which contained 10 ml of HCl (12.04% in abs. ethanol) and this assembly was maintained at room temperature for 120 hours. The resulting solid was dried in a vacuum oven at 90° C. overnight to yield form T29.

Name

Nilotinib

Quantity

0 (± 1) mol

Type

reactant

Reaction Step One

Name

HCl

Quantity

10 mL

Type

reactant

Reaction Step Two

Name

Nilotinib Hydrochloride

Details

Retrosynthesis Analysis

AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.

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Strategy Settings

Precursor scoring	Relevance Heuristic
Min. plausibility	0.01
Model	Template_relevance
Template Set	Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph	6

Feasible Synthetic Routes

Reactant of Route 1

Nilotinib hydrochloride

Reactant of Route 2

Nilotinib hydrochloride

Reactant of Route 3

Nilotinib hydrochloride

Reactant of Route 4

Nilotinib hydrochloride

Reactant of Route 5

Nilotinib hydrochloride

Reactant of Route 6

Nilotinib hydrochloride

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