Targeted therapeutic drug for lung cancer cells and preparation method therefor

Abstract

A targeted therapeutic drug for lung cancer cells and a preparation method therefor, relating to the technical field of drugs for treating cancer. The targeted therapeutic drug has a benzimidazole core structure, at least one fluoropyridine group linked to the benzimidazole core by means of an amide bond, and at least one trifluoromethylsulfonyl-substituted long-chain alkane group linked to the benzimidazole core. The preparation method comprises the following steps: preparing an intermediate A, the intermediate A being an N-chloroacetyl derivative of benzimidazole; preparing a raw material B, the raw material B comprising a fluoropyridine group and a trifluoromethylsulfonyl-substituted long-chain alkane group; performing an amidation reaction on the intermediate A and the key raw material B to obtain a crude product of EG20-XIN; and purifying the crude product to obtain high-purity EG20-XIN. In the present invention, EG20-XIN is efficiently prepared, microwave and ultrasonic technology is used to improve yield and purity, and costs are reduced. Isotope labeling is used to study metabolic kinetics and biodistribution. The pharmaceutical composition is diverse and has enhanced solubility and stability and an improved therapeutic effect.

Description

Lung cancer cell targeted therapy drug and preparation method thereof TECHNICAL FIELD

[0001] The present application relates to the field of tunnel engineering, in particular to a lung cancer cell targeted therapy drug and preparation method thereof. BACKGROUND

[0002] In the field of lung cancer treatment, especially for non-small cell lung cancer (NSCLC) treatment, molecular targeted therapy has become an important treatment method. Among them, epidermal growth factor receptor (EGFR) gene mutation is one of the most critical driver genes in NSCLC, and the drug research targeting this target has made significant progress. However, among the various mutation types of EGFR, the treatment of exon 20 insertion mutation (EGFR 20 ins) still faces great challenges.

[0003] Currently, the targeted drugs for EGFR mutations are mainly divided into several generations of tyrosine kinase inhibitors (TKIs). First-generation TKIs such as gefitinib, erlotinib and icotinib, and second-generation TKIs such as afatinib and dacomitinib, show good efficacy in treating common EGFR mutations (such as exon 19 deletion and exon 21 point mutation). However, the therapeutic effect of these drugs for EGFR 20 ins patients is not ideal, with low objective response rate (ORR) and overall survival (OS), and drug resistance is prone to occur.

[0004] In recent years, with the in-depth study of the mechanism of EGFR 20 ins, some new targeted drugs have gradually entered the clinical trial stage. For example, osimertinib as a third-generation TKI shows certain anti-tumor activity in some EGFR 20 ins patients, but its efficacy is still controversial and needs to be further verified by large sample clinical trials. In addition, Mobocertinib (TAK 788), poziotinib, Amivantamab (JNJ 6372) and other new drugs also show treatment potential for EGFR 20 ins patients, but their efficacy, safety and patient tolerance still need to be further evaluated.

[0005] It is worth noting that although these new drugs provide new treatment options for EGFR 20 ins patients, their efficacy is not completely satisfactory and has many limitations. Therefore, developing a new targeted drug with high selectivity and efficacy for EGFR 20 ins is still a hot and difficult point in current clinical research. SUMMARY

[0006] The present application aims to provide a lung cancer cell-targeted therapeutic drug and a preparation method thereof, and aims to solve the problems of low efficacy, drug resistance, safety and tolerance, and brain activity of the EGFR 20 ins mutation mentioned in the prior art.

[0007] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0008] A lung cancer cell-targeted therapeutic drug is a drug compound EG20-XIN,

[0009] A benzimidazole core structure; the N-1 position is protected by chloroacetyl as an active site for subsequent reactions;

[0010] At least one fluoropyridine group connected to the benzimidazole core by an amide bond;

[0011] At least one long-chain alkane group substituted by a trifluoromethylsulfonyl group connected to the benzimidazole core; another substitutable position connected to the benzimidazole core by an ester bond or an amide bond, enhancing the membrane penetration and stability of the drug;

[0012] The chemical structure is as follows,

[0013]

[0014] Wherein, R1 is a fluoropyridine group, R2 is a trifluoromethylsulfonyl group, and [benzene ring] and [imidazole ring] represent the backbone structure of benzimidazole.

[0015] In a preferred technical solution, the fluoropyridine group is a fluoropyridine-3-yl group. The N-3 position of the benzimidazole core is connected by an amide bond, providing specific binding ability with the EGFR 20ins mutation site.

[0016] In a preferred technical solution, the lung cancer cell-targeted therapeutic drug further comprises at least one isotope-labeled atom for drug metabolism kinetics research or biological distribution imaging, and the isotope includes but is not limited to deuterium, carbon-14 or fluorine-18.

[0017] A preparation method of a lung cancer cell-targeted therapeutic drug comprises the following steps,

[0018] Step 1: preparing an intermediate A, which is an N-chloroacetyl derivative of benzimidazole;

[0019] Step 2: preparing a key raw material B, which contains a fluoropyridine group and a long-chain alkane group substituted by a trifluoromethylsulfonyl group, obtained by multi-step organic synthesis;

[0020] Step three: under the condition of 10-50 MPa high pressure, the intermediate A and the key raw material B are subjected to amidation reaction under alkaline condition to obtain the crude product of EG20-XIN;

[0021] Step four: the crude product is purified by column chromatography and recrystallization to obtain the high-purity EG20-XIN.

[0022] Preferably, the specific operation of step one is that: the benzimidazole is reacted with chloroacetyl chloride in the presence of an alkaline catalyst in an anhydrous solvent to obtain the intermediate A, which is purified after post-treatment and used.

[0023] The specific operation of step two is: including a Grignard reaction step, the fluoro-pyridine is converted into a corresponding Grignard reagent, which is then reacted with an acyl chloride to obtain an amide acid, which is further converted into the required key raw material B, which is used after purification.

[0024] The targeted therapeutic drug "EG20-XIN" is used for preparing a pharmaceutical composition for treating or preventing EGFR 20 exon insertion mutant lung cancer.

[0025] A composition containing a lung cancer cell targeted therapeutic drug, which is a pharmaceutically acceptable carrier or excipient, and further contains one or more auxiliary materials for enhancing drug solubility, stability or targeting, which is one or more of cyclodextrin inclusion, liposome or nanoparticle.

[0026] A composition containing a lung cancer cell targeted therapeutic drug, which is used for treating or preventing EGFR 20 exon insertion mutant lung cancer.

[0027] Compared with the prior art, the beneficial effects of the present application are:

[0028] Highly specific targeting:

[0029] The EG20-XIN drug compound provides specific binding ability to the EGFR 20 exon insertion mutation (EGFR 20ins) site through its unique chemical structure design, especially the fluoro-pyridine group connected to the N-3 position of the benzimidazole core through an amide bond. This specific binding enables EG20-XIN to accurately target and inhibit EGFR 20ins mutant lung cancer cells, while having no significant inhibitory effect on wild-type cell lines, thereby improving the therapeutic effect and reducing side effects.

[0030] Enhanced membrane penetration and stability:

[0031] The introduction of trifluoromethylsulfonyl-substituted long-chain alkane groups into the drug molecule, connected to another substitutable position of the benzimidazole core through an ester or amide bond, not only enhances the drug's membrane penetration, but also improves its stability. This design helps the drug molecule to better penetrate the cell membrane, reach the target site, and maintain its activity, thereby improving the treatment efficiency.

[0032] Efficient drug preparation method:

[0033] The use of microwave-assisted or ultrasonic-promoted chloroacetylation reaction and amide reaction under high pressure conditions significantly improves the yield and purity of intermediate A and key raw material B, and also facilitates the synthesis of EG20-XIN. This efficient and controllable preparation method helps to reduce production costs, improve product quality, and provides strong support for large-scale production of drugs.

[0034] Pharmacokinetic and biodistribution studies:

[0035] Isotopically labeled atoms, including but not limited to deuterium, carbon-14, or fluorine-18, are provided in EG20-XIN drug variants. These isotopically labeled drugs can be used for pharmacokinetic studies and biodistribution imaging, helping to better understand the absorption, distribution, metabolism, and excretion of drugs in the body, providing important references for the clinical application of drugs.

[0036] Diversity and enhanced effects of drug compositions:

[0037] Drug compositions containing EG20-XIN are provided, which can contain pharmaceutically acceptable carriers or excipients, as well as one or more adjuvants that enhance drug solubility, stability, or targeting. These adjuvants, such as cyclodextrin inclusion complexes, liposomes, or nanoparticles, can further improve the bioavailability and therapeutic effect of the drug, meeting the treatment needs of different patients. DETAILED DESCRIPTION

[0038] The technical solutions in the embodiments of the present application will be described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0039] In order to facilitate understanding of the present application, the present application will be described more fully below. Several embodiments of the present application are given. However, the present application can be realized in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present application more thorough and comprehensive.

[0040] A lung cancer cell-targeted therapy drug, namely the drug compound EG20-XIN.

[0041] A benzimidazole core structure; its N-1 position is protected by a chloroacetyl group, which serves as the active site for subsequent reactions;

[0042] At least one fluoropyridine group is attached to the benzimidazole core via an amide bond;

[0043] At least one long-chain alkane group substituted with a trifluoromethylsulfonyl group is attached to the benzimidazole core; and is attached to another substituted position of the benzimidazole core via an ester bond or an amide bond to enhance the membrane permeability and stability of the drug.

[0044] The chemical structural formula is as follows:

[0045]

[0046] Wherein, R1 is a fluoropyridine group, R2 is a trifluoromethylsulfonyl group, and [benzene ring] and [imidazolium ring] represent the skeleton structure of benzimidazole.

[0047] The fluoropyridine group is fluoropyridine-3-yl. It is linked to the N-3 position of the benzimidazole core via an amide bond, providing specific binding ability to the EGFR 20ins mutation site.

[0048] A lung cancer cell-targeting therapy drug further includes at least one isotope-labeled atom for drug metabolism kinetic studies or biodistribution imaging, wherein the isotope includes, but is not limited to, deuterium, carbon-14, or fluorine-18.

[0049] A method for preparing a lung cancer cell-targeted therapy drug includes the following steps:

[0050] Step 1: Prepare intermediate A, which is an N-chloroacetyl derivative of benzimidazole; use microwave-assisted or ultrasound-promoted chloroacetylation reaction to improve the yield and purity of intermediate A (N-chloroacetyl derivative of benzimidazole); the reaction formula is as follows:

[0051] [benzimidazole] + ClCH2COCl → [benzimidazole-N-chloroacetyl] + HCl

[0052] In an anhydrous solvent (such as dichloromethane), benzimidazole is reacted with chloroacetyl chloride under alkaline conditions (such as in the presence of triethylamine) to give chloroacetylbenzimidazole (intermediate A).

[0053] Step 2: Prepare key raw material B, which contains fluoropyridine groups and trifluoromethylsulfonyl substituted long-chain alkane groups, obtained through multi-step organic synthesis; the reaction formula is as follows:

[0054] [fluoropyridine] → [fluoropyridine Grignard reagent] → [fluoropyridine amido acid]

[0055] Firstly, the fluoropyridine is converted into the corresponding Grignard reagent by Grignard reaction, and then reacted with acyl chloride to obtain amido acid, and the key raw material B is obtained after purification (the specific reaction conditions need to be optimized in detail).

[0056] Step three: under the condition of 10-50 MPa high pressure, the amide reaction of intermediate A and key raw material B is carried out under alkaline condition to obtain the crude product of EG20-XIN; high boiling point solvent and special catalyst (such as chiral catalyst) are used to promote the amide reaction of key raw material B (complex amido acid containing fluoropyridine and trifluoromethylsulfonyl) and intermediate A, so as to obtain high stereoselectivity of EG20-XIN; the reaction formula is as follows:

[0057] [intermediate A] + [key raw material B] → EG20-XIN + by-product

[0058] Step four: the crude product is purified by column chromatography, recrystallization and other methods to obtain high purity EG20-XIN.

[0059] The specific operation of step one is: in anhydrous solvent, benzimidazole is reacted with chloroacetyl chloride in the presence of alkaline catalyst to obtain intermediate A, which is used after post-treatment and purification.

[0060] The specific operation of step two is: including Grignard reaction step, the fluoropyridine is converted into the corresponding Grignard reagent, and then reacted with acyl chloride to obtain amido acid, which is further converted into the required key raw material B, and used after purification.

[0061] The application of the targeted therapeutic drug "EG20-XIN" in the preparation of a pharmaceutical composition for treating or preventing EGFR 20 exon insertion mutant lung cancer.

[0062] A composition containing a lung cancer cell targeted therapeutic drug, which is a pharmaceutically acceptable carrier or excipient, and further contains one or more auxiliary materials for enhancing drug solubility, stability or targeting, which is one or more of cyclodextrin inclusion, liposome or nanoparticle.

[0063] A composition containing a lung cancer cell targeted therapeutic drug for treating or preventing EGFR 20 exon insertion mutant lung cancer.

[0064] The following is the specific preparation process of the examples and the corresponding parameter table:

[0065] Preparation table of intermediate A

[0066] Preparation table of raw material B

[0067] Synthesis and characterization of EG20-XIN

[0068]

[0069] In vitro activity test table

[0070]

[0071] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely divergences and that many variations, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the application. The scope of the application is defined by the appended claims and their equivalents.

Claims

1. A lung cancer cell-targeting therapeutic drug, characterized by, A pharmaceutical compound EG20-XIN, A benzimidazole core structure; At least one fluoro-pyridine group connected to the benzimidazole core through an amide bond; At least one trifluoromethylsulfonyl-substituted long-chain alkane group connected to the benzimidazole core; The chemical structure is as follows, 2. Wherein, R1 is a fluoro-pyridine group, R2 is a trifluoromethylsulfonyl group, and [benzene ring] and [imidazole ring] represent the backbone structure of benzimidazole.

3. The lung cancer cell-targeting therapy drug according to claim 1, characterized in that: The fluoro-pyridine group is a fluoro-pyridine-3-yl group.

4. The lung cancer cell-targeting therapy drug according to claim 1, characterized in that: It also includes at least one isotopically labeled atom for pharmacokinetic studies or biodistribution imaging, and the isotope includes but is not limited to deuterium, carbon-14 or fluorine-18.

5. The preparation method of lung cancer cell targeting therapeutic drug according to claim 1, characterized in that: The method comprises the following steps, Step 1: preparation of intermediate A, which is an N-chloroacetyl derivative of benzimidazole; Step 2: preparation of key raw material B, which contains a fluoro-pyridine group and a trifluoromethylsulfonyl-substituted long-chain alkane group, obtained by multi-step organic synthesis; Step 3: under the condition of 10-50 MPa high pressure, intermediate A and key raw material B are subjected to amidation reaction under alkaline condition to obtain the crude product of EG20-XIN; Step 4: purify the crude product by column chromatography and recrystallization method to obtain high-purity EG20-XIN.

6. The preparation method of claim 4, wherein the lung cancer cell targeting therapeutic drug is prepared by the following steps: 1) preparing a lung cancer cell targeting peptide; 2) preparing a drug carrier; 3) conjugating the lung cancer cell targeting peptide and the drug carrier to obtain the lung cancer cell targeting therapeutic drug. The specific operation of step 1 is: in anhydrous solvent, benzimidazole is reacted with chloroacetyl chloride in the presence of an alkaline catalyst to obtain intermediate A, which is purified after post-treatment and used.

7. The method for preparing a lung cancer cell-targeted therapy drug according to claim 4, characterized in that: The specific operation of step 2 is: it includes a Grignard reaction step, in which fluoro-pyridine is converted into the corresponding Grignard reagent, which is then reacted with acyl chloride to obtain amide acid, which is further converted into the desired key raw material B, which is used after purification. 8.The preparation method of the lung cancer cell targeting therapeutic drug according to claim 4, characterized in that: The targeted therapeutic drug "EG20-XIN" is used in the preparation of a pharmaceutical composition for treating or preventing EGFR 20 exon insertion mutant lung cancer.

9. A composition comprising the lung cancer cell-targeting therapeutic agent of claim 1, characterized in that: A pharmaceutically acceptable carrier or excipient, which further contains one or more adjuvants that enhance drug solubility, stability or targeting, and the adjuvant is one or more of cyclodextrin inclusion, liposome or nanoparticle.

10. The composition of claim 8, wherein: For treating or preventing EGFR 20 exon insertion mutant lung cancer.

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