Nilotinib hydrochloride

Cat. No.: B1258797

CAS No.: 923288-95-3

M. Wt: 566.0 g/mol

InChI Key: VTGGYCCJUPYZSX-UHFFFAOYSA-N

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Overview

1. Description

8. Comparison with similar compounds

2. Scientific research applications

9. Properties

3. Mechanism of action

10. Synthesis routes and methods I

4. Safety and hazards

11. Synthesis routes and methods II

5. Biochemical analysis

12. Synthesis routes and methods III

6. Preparation methods

13. Retrosynthesis analysis

7. Chemical reactions analysis

14. Disclaimer

Description

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. This compound is marketed under the brand name Tasigna and is known for its efficacy in treating both newly diagnosed and imatinib-resistant CML .

Scientific Research Applications

Nilotinib hydrochloride has several scientific research applications:

Chemistry: Used as a model compound to study the synthesis and stability of tyrosine kinase inhibitors.

Biology: Investigated for its effects on cellular signaling pathways and its potential to inhibit other kinases.

Medicine: Primarily used to treat chronic myelogenous leukemia. .

Industry: Used in the development of pharmaceutical formulations and as a reference standard in analytical chemistry.

Mechanism of Action

Safety and Hazards

Nilotinib hydrochloride is considered hazardous by the 2012 OSHA Hazard Communication Standard (29 CFR 1910.1200). It causes damage to organs through prolonged or repeated exposure. It may cause long-lasting harmful effects to aquatic life.

Biochemical Analysis

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 . This compound also interacts with other biomolecules such as EPHA3, EPHA8, DDR1, DDR2, MAPK11, and ZAK, further contributing to its anti-leukemic effects .

Cellular Effects

This compound 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, this compound influences gene expression and cellular metabolism, contributing to its therapeutic efficacy in CML .

Molecular Mechanism

The molecular mechanism of action of this compound 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 . This compound 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 this compound 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 this compound 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 this compound vary with different dosages. At therapeutic doses, it effectively inhibits the proliferation of leukemic cells and reduces tumor burden . At higher doses, this compound 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

This compound 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 this compound involve interactions with various enzymes and cofactors, affecting metabolic flux and metabolite levels .

Transport and Distribution

Within cells and tissues, this compound 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 this compound in n-octanol/0.1 N HCl buffer at 37°C is 0.08, indicating its hydrophilic nature .

Subcellular Localization

This compound 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 this compound is crucial for its therapeutic effects, as it needs to reach its target kinases to exert its inhibitory action .

Preparation Methods

Synthetic Routes and Reaction Conditions: The synthesis of nilotinib hydrochloride involves multiple steps, starting from the preparation of the core structure, which includes a benzamide derivative. The process typically involves the following steps:

Formation of the Core Structure: The core structure is synthesized by reacting 4-methyl-3-nitrobenzoic acid with 4-methyl-1H-imidazole in the presence of a coupling agent.

Reduction: The nitro group is reduced to an amine using catalytic hydrogenation, typically with Raney nickel in a methanol medium.

Formation of the Hydrochloride Salt: The final step involves converting the intermediate compound into this compound by reacting it with hydrochloric acid.

Industrial Production Methods: Industrial production of this compound follows a similar synthetic route but is optimized for large-scale production. The process ensures the formation of a stable crystalline form of this compound, which is essential for its pharmaceutical formulation .

Chemical Reactions Analysis

Types of Reactions: Nilotinib hydrochloride undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized under specific conditions, leading to the formation of degradation products.

Reduction: The nitro group in the intermediate compound is reduced to an amine during synthesis.

Substitution: The synthesis involves substitution reactions to introduce functional groups into the core structure.

Common Reagents and Conditions:

Catalytic Hydrogenation: Raney nickel in methanol is used for the reduction step.

Hydrochloric Acid: Used to form the hydrochloride salt.

Major Products Formed:

This compound: The primary product formed from the synthesis.

Degradation Products: Formed during oxidation and other stress conditions

Comparison with Similar Compounds

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 this compound: this compound 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 .

Properties

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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Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.

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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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.

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