molecular formula C28H23ClF3N7O B1258797 Nilotinib hydrochloride CAS No. 923288-95-3

Nilotinib hydrochloride

货号: B1258797
CAS 编号: 923288-95-3
分子量: 566.0 g/mol
InChI 键: VTGGYCCJUPYZSX-UHFFFAOYSA-N
注意: 仅供研究使用。不适用于人类或兽医用途。
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描述

尼洛替尼盐酸盐是一种主要用于治疗费城染色体阳性的慢性髓性白血病 (CML) 的药物。它是一种第二代酪氨酸激酶抑制剂,旨在克服对伊马替尼(另一种酪氨酸激酶抑制剂)的耐药性。 尼洛替尼盐酸盐以商品名 Tasigna 出售,以其在治疗新诊断的和伊马替尼耐药性 CML 中的疗效而闻名 .

作用机制

尼洛替尼盐酸盐通过抑制费城染色体产生的 BCR-ABL 蛋白的酪氨酸激酶活性发挥作用。它与 BCR-ABL 蛋白的 ATP 结合位点结合,阻止其磷酸化活性。 这种抑制阻断了对白血病细胞存活和增殖至关重要的下游信号通路 .

类似化合物:

    伊马替尼: 用于治疗 CML 的第一代酪氨酸激酶抑制剂。尼洛替尼盐酸盐旨在克服对伊马替尼的耐药性。

    达沙替尼: 另一种用于治疗 CML 的第二代酪氨酸激酶抑制剂。

    波舒替尼: 用于 CML 治疗的第三代酪氨酸激酶抑制剂。

尼洛替尼盐酸盐的独特性: 尼洛替尼盐酸盐与伊马替尼相比,具有更高的效力和对 BCR-ABL 蛋白的特异性,这一点是独一无二的。 它对几种伊马替尼耐药性 BCR-ABL 突变也有效,使其成为对伊马替尼无反应的患者的宝贵选择 .

生化分析

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 . 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 .

准备方法

合成路线和反应条件: 尼洛替尼盐酸盐的合成涉及多个步骤,从核心结构的制备开始,包括苯甲酰胺衍生物。该过程通常包括以下步骤:

工业生产方法: 尼洛替尼盐酸盐的工业生产遵循类似的合成路线,但针对大规模生产进行了优化。 该过程确保形成稳定的尼洛替尼盐酸盐晶体形式,这对于其药物制剂至关重要 .

化学反应分析

反应类型: 尼洛替尼盐酸盐经历各种化学反应,包括:

    氧化: 尼洛替尼盐酸盐在特定条件下可以被氧化,导致形成降解产物。

    还原: 在合成过程中,中间体化合物中的硝基被还原为胺。

    取代: 合成涉及取代反应,将官能团引入核心结构。

常见试剂和条件:

    催化加氢: 雷尼镍在甲醇中用于还原步骤。

    盐酸: 用于形成盐酸盐。

形成的主要产物:

科学研究应用

尼洛替尼盐酸盐有几种科学研究应用:

相似化合物的比较

    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 .

属性

IUPAC Name

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

InChI Key

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

Molecular Formula

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

DSSTOX Substance ID

DTXSID60238968
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 PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

CAS No.

923288-95-3
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)
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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)
Quantity
20 g
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10 g
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Yield
83%

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).
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6.45 g
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200 mL
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Reaction Step One
Yield
73%

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.
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0 (± 1) mol
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10 mL
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Retrosynthesis Analysis

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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

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