ニロチニブ塩酸塩

カタログ番号: B1258797

CAS番号: 923288-95-3

分子量: 566.0 g/mol

InChIキー: VTGGYCCJUPYZSX-UHFFFAOYSA-N

注意: 研究専用です。人間または獣医用ではありません。

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概要

1. 説明

8. 特性

2. 科学的研究の応用

9. Synthesis routes and methods I

3. 作用機序

10. Synthesis routes and methods II

4. 生化学分析

11. Synthesis routes and methods III

5. 準備方法

12. Retrosynthesis analysis

6. 化学反応の分析

13. 免責事項

7. 類似化合物との比較

説明

ニロチニブ塩酸塩は、フィラデルフィア染色体陽性の慢性骨髄性白血病（CML）の治療に主に用いられる医薬品である。これは、もう1つのチロシンキナーゼ阻害剤であるイマチニブへの耐性を克服するために開発された第2世代チロシンキナーゼ阻害剤である。ニロチニブ塩酸塩は、タシグナという商品名で販売されており、新規診断されたCMLとイマチニブ耐性CMLの両方の治療における有効性で知られている .

2. 製法

合成ルートと反応条件： ニロチニブ塩酸塩の合成は、ベンザミド誘導体を含むコア構造の調製から始まる複数ステップを伴う。このプロセスは通常、以下のステップを含む。

コア構造の形成： コア構造は、カップリング剤の存在下で4-メチル-3-ニトロ安息香酸と4-メチル-1H-イミダゾールを反応させることによって合成される。

還元： ニトロ基は、典型的にはメタノール媒体中でラネーニッケルを使用して、触媒的ハイドロジェネーションによってアミンに還元される.

塩酸塩の形成： 最後のステップは、中間体を塩酸と反応させてニロチニブ塩酸塩に変換することを含む.

工業的製造方法： ニロチニブ塩酸塩の工業的製造は、同様の合成ルートに従うが、大規模製造に最適化されている。このプロセスは、製薬製剤に不可欠なニロチニブ塩酸塩の安定な結晶形を形成することを保証する .

科学的研究の応用

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.

作用機序

ニロチニブ塩酸塩は、フィラデルフィア染色体によって生成されるBCR-ABLタンパク質のチロシンキナーゼ活性を阻害することでその効果を発揮する。それはBCR-ABLタンパク質のATP結合部位に結合し、そのリン酸化活性を阻害する。この阻害は、白血病細胞の生存と増殖に不可欠な下流のシグナル伝達経路をブロックする .

類似化合物：

イマチニブ： CMLの治療に使用される第1世代チロシンキナーゼ阻害剤。ニロチニブ塩酸塩は、イマチニブへの耐性を克服するために開発された。

ダサチニブ： CMLの治療に使用されるもう1つの第2世代チロシンキナーゼ阻害剤。

ボスチニブ： CML治療に使用される第3世代チロシンキナーゼ阻害剤。

ニロチニブ塩酸塩の独自性： ニロチニブ塩酸塩は、イマチニブと比較して、BCR-ABLタンパク質に対するより高い効力と特異性があるため、ユニークである。また、いくつかのイマチニブ耐性BCR-ABL変異に対しても効果的であるため、イマチニブに反応しない患者にとって貴重な選択肢となっている .

生化学分析

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 .

準備方法

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 nilotinib hydrochloride by reacting it with hydrochloric acid.

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

化学反応の分析

反応の種類： ニロチニブ塩酸塩は、以下を含むさまざまな化学反応を受ける。

酸化： ニロチニブ塩酸塩は、特定の条件下で酸化され、分解生成物を生成する可能性がある。

還元： 合成中に、中間体化合物のニトロ基はアミンに還元される。

置換： 合成には、コア構造に官能基を導入するための置換反応が含まれる。

一般的な試薬と条件：

触媒的ハイドロジェネーション： 還元ステップには、メタノール中のラネーニッケルが使用される。

塩酸： 塩酸塩を形成するために使用される。

主要な生成物：

ニロチニブ塩酸塩： 合成から生成される主な生成物。

分解生成物： 酸化およびその他のストレス条件下で生成される

4. 科学研究への応用

ニロチニブ塩酸塩には、いくつかの科学研究への応用がある。

化学： チロシンキナーゼ阻害剤の合成と安定性を研究するためのモデル化合物として使用される。

生物学： 細胞シグナル伝達経路に対するその影響と、他のキナーゼを阻害する可能性について調査されている。

医学： 主に慢性骨髄性白血病の治療に使用される。 .

産業： 製薬製剤の開発と、分析化学における参照標準として使用される.

類似化合物との比較

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 .

特性

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.

One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.

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

試験管内研究製品の免責事項と情報

BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。

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