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Imatinib, also known as mesylate, is a small molecule protein kinase inhibitor, particularly a tyrosine kinase inhibitor, that has the ability to block one or more protein kinases. It is a white crystalline powder, CAS 152459-95-5, molecular formula C29H31N7O, while the chemical formula of mesylate is C30H35N7O4S, which is its methanesulfonate salt form. Both in vitro and in vivo, it strongly inhibits the activity of ABL tyrosine kinase, specifically suppressing the expression of ABL and the proliferation of BCR-ABL cells.
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Chemical Formula |
C29H31N7O |
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Exact Mass |
493 |
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Molecular Weight |
494 |
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m/z |
493 (100.0%), 494 (31.4%), 495 (2.7%), 494 (2.6%), 495 (2.0%) |
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Elemental Analysis |
C, 70.56; H, 6.33; N, 19.86; O, 3.24 |
In addition, it can also inhibit tyrosine kinases of platelet-derived growth factor (PDGF) and stem cell factor (SCF) receptors, thereby suppressing biochemical reactions mediated by these factors. It has the effects and functions of inhibiting tyrosine kinase, inhibiting cell proliferation, inhibiting tumor growth, prolonging survival, and improving patients' quality of life. It can block key steps in the signaling pathway, thereby inhibiting cell proliferation. Inhibiting cell proliferation by interfering with the activity of cell cycle regulatory factors to achieve therapeutic goals. The terminal drug of this product can selectively inhibit the function of specific proteins, thereby controlling the growth of tumor cells. This product is for laboratory use only and is strictly prohibited for any other purposes.
Imatinib, also known as imatinb mesylate, is an important anti-tumor drug that plays a crucial role in the treatment of leukemia. As a novel protein tyrosine kinase inhibitor, it can specifically block signal transduction in leukemia cells, thereby achieving therapeutic goals.
CML is a cancer that affects the generation of bone marrow blood cells, characterized by an abnormal increase in white blood cells in the bone marrow. It is a commonly used first-line treatment for CML, mainly by inhibiting the tyrosine kinase activity of BCR-ABL fusion protein.
The BCR-ABL fusion protein is produced by Philadelphia chromosome abnormalities and plays a crucial role in the pathogenesis of CML. Imatinb can bind to the BCR-ABL kinase domain, block its tyrosine kinase activity, prevent sustained activation of signal transduction, and thus inhibit the growth and division of malignant cells.
In the treatment of positive acute lymphoblastic leukemia (ALL)
It also has certain therapeutic effects. Especially for refractory ALL patients carrying specific fusion genes, such as RCSD1-ABL1 fusion gene, imatinb can inhibit the activity of BCR-ABL kinase, reduce the proliferation and survival of positive ALL cells, thereby improving the disease progression and prognosis of patients.
There are case reports showing that the use of imatinb monotherapy can provide partial relief to patients with refractory ALL, creating opportunities for subsequent treatment. In addition, imatinb can also be used in combination with other treatment methods, such as chimeric antigen receptor T-cell therapy (CAR-T), to enhance therapeutic efficacy.
It also has certain application value. GIST is a tumor originating from the mesenchymal tissue of the gastrointestinal tract, and imatinb can be used as a first-line treatment for GIST. It reduces tumor cell proliferation and survival by inhibiting the activity of two tyrosine kinases, KIT and PDGFRA, thereby controlling tumor size and delaying disease progression. Imatinb is an effective treatment option for malignant GIST patients who cannot undergo surgical resection or have already developed distant metastasis.
However, it is worth noting that imatinb may also cause some side effects in the treatment of leukemia. Common side effects include nausea, vomiting, diarrhea, rash, fatigue, etc. In addition, imatinb may also cause bone marrow suppression, leading to decreased white blood cells and platelets. Therefore, before using imatinb, it is advisable to consult a doctor and follow their instructions for medication. At the same time, patients need to undergo regular hematological, molecular, and cytogenetic monitoring to timely evaluate treatment efficacy and detect potential side effects.
In addition, with the in-depth research on leukemia and its treatment, the application of imatinb is constantly expanding and optimizing. For example, scientists are developing novel tyrosine kinase inhibitors (TKIs) to overcome imatinb resistance and optimize treatment efficacy. At the same time, the combined use of different types of TKIs or other anti-cancer drugs can also enhance treatment efficacy and delay the occurrence of drug resistance. In addition, personalized treatment strategies are gradually becoming possible. By analyzing the patient's gene mutation spectrum and drug metabolism characteristics, doctors can customize the most suitable treatment plan for each patient.
Application in Dermatofibrosarcoma Protuberans (DFSP)
Imatinib is an important targeted drug for the treatment of dermatofibrosarcoma protuberans (DFSP). Its core indications include patients with unresectable, recurrent, or metastatic DFSP, especially those who are ineligible for surgery due to large tumor size, invasion of critical structures, or high risks of cosmetic or functional impairment. Clinical studies have demonstrated that treatment with imatinib at a daily dose of 400–800 mg can achieve partial tumor response or disease stabilization in some patients, with no significant difference in efficacy between the two dose levels.
In addition, it can be used as neoadjuvant therapy preoperatively to reduce tumor volume, thereby creating surgical opportunities for patients who were initially unresectable. It should be noted that imatinib must be used under the guidance of a physician, and adverse reactions should be monitored during treatment. Its use has significantly improved the prognosis of patients with advanced DFSP and has become a key therapeutic modality beyond surgery.
Imatinib, also known as Gleevec, is an important anti-tumor drug primarily used to treat chronic myeloid leukemia (CML) and certain types of acute lymphoblastic leukemia (ALL). The commercial synthesis route involves multiple complex chemical steps. The following is a detailed overview of the synthesis steps, but due to space limitations, the specific chemical equations will only provide illustrations of the key steps.
Overview of the Commercial Synthesis Route of Gleevec
The synthesis of gleevec usually starts from specific starting materials, goes through the synthesis and transformation of multiple intermediates, and finally obtains the target product. The following is a brief description of a typical synthesis route and its key steps:
► Selection of starting materials and preliminary reactions
Chemical equation diagram (taking acetylacetone as an example):
4-methyl-3-nitroaniline+acetylacetone+base catalyzed → nitroaniline derivatives
Starting materials:
Common starting materials include 4-methyl-3-nitroaniline, 3-acetylpyridine, N, N-dimethylformamide formaldehyde, etc. Different synthesis routes may choose different starting materials.
Preliminary reaction:
Taking 4-methyl-3-nitroaniline as an example, it may first undergo condensation reaction and react with appropriate carbonyl compounds (such as acetylacetone) to generate nitroaniline derivatives. This step may involve alkaline catalysis, such as using potassium carbonate or sodium hydroxide.
► Reduction reaction
Chemical equation diagram: nitroaniline derivative+iron powder/HCl+reduction → amino aniline derivative
Objective:
To reduce nitro to amino, which is one of the key steps in the synthesis of Gleevec.
Reaction conditions:
Usually carried out in the presence of metal catalysts such as iron powder, stannous chloride, or platinum carbon, using acidic or alkaline media.
► Ring reaction
Chemical equation diagram (taking hypothetical intermediate as an example): Aminoaniline derivative+appropriate carbonyl compound+cyclization → pyrimidine ring intermediate
Purpose:
To form a pyrimidine ring, which is the core part of the molecular structure of Gleevec.
Reaction conditions:
Usually require heating and appropriate catalysts such as sulfuric acid or phosphoric acid.
► Acylation reaction
Chemical equation diagram: pyrimidine ring intermediate+acyl chloride+base catalysis → acylation intermediate
Objective:
To introduce acyl groups on the pyrimidine ring in preparation for subsequent reactions.
Reaction conditions:
Use acyl chloride or anhydride under alkaline conditions.
► Condensation and substitution reactions
Chemical equation schematic: Acylation intermediate+N-methylpiperazine+condensation/substitution → Gleevec skeleton
Objective:
To condense acylated intermediates with amine compounds such as N-methylpiperazine and perform substitution reactions at appropriate positions to form the skeletal structure of Gleevec.
Reaction conditions:
Usually heated in a solvent, catalyst may be required.
► Salt formation reaction
Chemical equation diagram: Gleevec skeleton+methanesulfonic acid+salt formation → Gleevec methanesulfonate
Objective:
To convert the skeletal structure of Gleevec into its methanesulfonate form, namely Gleevec methanesulfonate, which is a clinically used form.
Reaction conditions:
Carried out through acid-base reaction in the presence of methanesulfonic acid.
A synthesis method of imatinib.
The synthesis method uses 4-hydroxymethyl-N-[4-methyl-3-aminophenyl] benzamide as raw material and cyanamide addition to obtain intermediate 4-hydroxymethyl-N-(3-guanidino-4-methylphenyl) benzamide (II). Intermediate (II) is condensed with 3-(3-dimethylaminopropynyl) pyridine to obtain intermediate 4-hydroxymethyl-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide (III). Intermediate (III) reacts with substituted benzenesulfonyl chloride to obtain intermediate 4-[substituted benzenesulfonyl methyl]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide. Finally, intermediate (IV) reacts with methyl piperazine to obtain Gleevec (V). This route has a simple process, mild conditions, high product purity, high yield, low cost, and is conducive to industrial production
Detailed steps and chemical equations for the synthesis of Gleevec
Raw material: 4-hydroxymethyl-N-[4-methyl-3-aminophenyl] benzamide
Reagent: Monocyanamide
Condition: Usually, an appropriate amount of acid (such as hydrochloric acid) is added as a catalyst in an aqueous solution, and heated to a suitable temperature (such as 60-80 ° C) for the reaction.
Reaction description: In this step, the amino group of 4-hydroxymethyl-N-[4-methyl-3-aminophenyl] benzamide undergoes an addition reaction with the cyanide group of cyanamide, forming a guanidine group.
Chemical equation:
4-Hydroxymethyl-N-[4-methyl-3-aminophenyl] benzamide+melamine → 4-hydroxymethyl-N-(3-guanidino-4-methylphenyl) benzamide+water
Raw Material: 4-Hydroxymethyl-N-(3-Guanidino-4-methylphenyl) benzamide (Intermediate II)
Reagent: 3-(3-dimethylamino-allyl) pyridine
Condition: Add an appropriate base (such as triethylamine) as a catalyst in an inert solvent (such as N, N-dimethylformamide DMF) and heat the reaction under reflux.
Reaction description: The guanidine group of intermediate II undergoes a condensation reaction with the allyl group of 3-(3-dimethylamino-allyl) pyridine to form a pyrimidine ring.
Chemical equation: 4-hydroxymethyl-N-(3-guanidino-4-methylphenyl) benzamide+3-(3-dimethylaminopropynyl) pyridine → 4-hydroxymethyl-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide+byproduct
Note: The by-products here may include dimethylamine, water, etc., depending on the reaction conditions and the choice of catalyst.
Raw material: 4-hydroxymethyl-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide (intermediate III)
Reagent: substituted benzenesulfonyl chloride (such as 4-chlorobenzenesulfonyl chloride)
Condition: Add an appropriate amount of base (such as triethylamine or pyridine) as an acid binding agent in an inert solvent (such as dichloromethane), control the reaction temperature in an ice salt bath, and gradually raise the temperature to room temperature or slightly higher.
Reaction description: The hydroxymethyl group of intermediate III undergoes a substitution reaction with the sulfonyl chloride group of substituted benzenesulfonyl chloride, forming a methyl sulfonate group.
Chemical equation: 4-hydroxymethyl-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide+substituted benzenesulfonyl chloride → 4-[substituted benzenesulfonic acid methyl ester]-N-[4-methyl-3-[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide+hydrogen chloride
Raw material: 4-[substituted benzenesulfonic acid methyl ester]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide (intermediate IV)
Reagent: Methylpiperazine
Condition: Heat and reflux the reaction in a suitable solvent (such as ethanol or isopropanol), while adding a small amount of acid (such as hydrochloric acid) for catalysis.
Reaction description: The sulfonic acid methyl ester group of intermediate IV is hydrolyzed under acidic conditions to form a sulfonic acid group, which then undergoes a salt formation reaction with the amino group of methyl piperazine to obtain Gleevec.
Chemical equation: 4-[substituted benzenesulfonate methyl ester]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl] benzamide+methylpiperazine+acid catalyst → Gleevec salt+methanol+byproduct
Advantages of Imatinib Synthesis Method
Mild reaction conditions
Throughout the entire synthesis process, most reactions are carried out under relatively mild conditions, such as room temperature to moderate temperature range, without the need for extreme high temperature or high pressure conditions. This is not only beneficial for controlling the reaction process and reducing the generation of by-products, but also helps to protect the stability of reactants and intermediates.
High purity products
Through precise synthesis steps and appropriate purification methods such as crystallization, recrystallization, column chromatography, etc., high-purity products can be obtained. High purity products are crucial for the efficacy and safety of drugs.
Flexibility
This synthetic route has a certain degree of flexibility and can be adjusted appropriately according to market demand and production scale. For example, Gleevec derivatives with different substituents can be synthesized by changing the type of substituted benzenesulfonyl chloride to meet different therapeutic needs.
Pharmacological effects:
This product is a derivative of phenylalanine and belongs to a novel tyrosine kinase inhibitor. About 95% of chronic myeloid leukemia (CML) patients are pH chromosome positive, meaning that the oncogene ABL on chromosome 9 is ectopic to a segment of the oncogene on chromosome 22 called the breakpoint clustering region (BCR). The two genes recombine to produce the fusion protein p-210, which has higher tyrosine kinase activity compared to the normal C-ABL protein p-150 and can stimulate leukocyte proliferation, leading to leukemia. This product strongly inhibits the activity of ABL tyrosine kinase both in vitro and in vivo, specifically suppressing the expression of ABL and the proliferation of BCR-ABL cells, making it suitable for the treatment of CML. In addition, this product can also inhibit the tyrosine kinases of platelet-derived growth factor (PDGF) and stem cell factor (SCF) receptors, and can inhibit the biochemical reactions mediated by PDGF and SCF, but does not affect the signal transduction of other stimulating factors such as epidermal growth factor.
Drug interactions
► Drugs that can alter the plasma concentration of Gleevec
CYP3A4 inhibitor: After taking a single dose of ketoconazole (CYP3A4) inhibitor in healthy subjects, the drug exposure to Gleevec significantly increased (mean maximum plasma concentration (Cmax) and area under the Gleevec curve (AUC) increased by 26% and 40%, respectively). There is no experience of co administration with other CYP3A4 inhibitors such as itraconazole, erythromycin, and clarithromycin.
CYP3A4 inducer: After healthy volunteers took rifampicin, the clearance of Gleevec increased by 3.8 times (90% confidence interval=3.5-4.3 times), but Cmax, AUC (0-24), and AUC (0-8) decreased by 54%, 68%, and 74%, respectively. In clinical studies, it has been found that simultaneous administration of phenytoin leads to a decrease in plasma concentration of Gleevec, resulting in reduced efficacy. Similar results were observed in malignant glioma patients treated with enzyme induced anti epileptic deus (EIAEs) such as carbamazepine, oxcarbazepine, phenytoin, phosphophenytoin, phenobarbital, and phenobarbital. Compared with taking EIAEDs at different times, the AUC of Gleevec decreased to 73%. Other CYP3A4 inducers such as dexamethasone, ketamine, phenobarbital, etc. may have similar problems, so simultaneous use of Gleevec and CYP3A4 inducers should be avoided. In two published studies, the combination of Gleevec and St John wort extract formulations resulted in a 30-32% decrease in AUC of the product.
► Imatinib mesylate alters plasma concentrations of the following drugs
It increased the average Cmax and AUC of simvastatin (CYP3A4 substrate) by 2-fold and 3.5-fold, respectively. It should be noted that Gleevec increases the plasma concentration of other drugs metabolized by CYP3A4, such as benzodiazepines, dihydropyridine, calcium channel antagonists, and other HMG CoA reductase inhibitors. Therefore, caution should be exercised when taking both this medication and CYP3A4 substrates with narrow treatment windows (such as cyclosporine and pembrozil) simultaneously.
At concentrations similar to those that inhibit CYP3A4 activity, it can also inhibit CYP2D6 activity in vitro. Therefore, when taken simultaneously with Gleevec mesylate, it may increase the system's exposure to CYP2D6 substrates. Although no specific studies have been conducted, caution is recommended.
It can also inhibit the activity of CYP2C9 and CYP2C19 in vitro, and prolonged prothrombin time can be observed after taking warfarin. Therefore, when starting or changing the dosage of Gleevec mesylate treatment, short-term monitoring of prothrombin time should be conducted if dual coumarin is also used.
The inhibitory effect of iGleevec 400 mg twice a day on CYP2D6 induced metoprolol metabolism is weak, with a Cmax and AUC increase of approximately 23% for metoprolol. The combination of Gleevec and CYP2D6 inducers such as metoprolol seems to have no risk factors for drug interactions and does not require dose adjustment.
FAQ
What is the prognosis for imatinib patients?
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Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response.
How long do patients take imatinib?
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To reduce the recurrence and improve the long-term survival, we suggest that patients with high-risk GIST receive imatinib treatment for at least 5 years.
What to avoid when taking imatinib?
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Grapefruit or grapefruit juice may interact with imatinib; avoid eating or drinking these during your treatment with imatinib. Talk with your care provider or pharmacist before taking new medications or supplements, or receiving any vaccines. Handle imatinib with care.
How successful is imatinib?
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Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response.
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