Preparation and anti-tumor effect of an aminoquinazoline compound

Abstract

The present invention relates to the preparation and application of aminoquinazoline compounds that dual-target EGFR and ACK1, and belongs to the technical field of anti-tumor pharmaceuticals. The technical problem addressed by the present invention is to provide a compound that acts as a dual-target EGFR and ACK1 inhibitor. The compound includes the compounds shown below, or pharmaceutically acceptable salts thereof. The compounds of the present invention, or pharmaceutically acceptable salts thereof, can act as inhibitors of EGFR and ACK1, exhibit anti-tumor activity, and can effectively inhibit the growth of tumor cells. The compounds of the present invention are preferably anti-tumor compounds targeted to tumor types characterized by overexpression of EGFR and ACK1.

Description

Technical Field

[0001] The present invention relates to the preparation and application of an aminoquinazoline compound dual-targeting EGFR and ACK1, belonging to the technical field of anti-tumor medicine. Background Art

[0002] Cancer is one of the most serious diseases that currently affects human health and threatens human life. Lung cancer is currently one of the leading causes of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the five-year survival rate for NSCLC patients is relatively low. Most patients will develop locally advanced or metastatic disease. In the past decade, scientists have made significant progress in understanding the different molecular and genetic subgroups of NSCLC, which has greatly transformed the clinical evaluation and treatment of patients.

[0003] The epidermal growth factor receptor (EGFR), a product of the proto-oncogene c-erbB-1, is a transmembrane tyrosine kinase receptor widely expressed in many normal tissues and solid tumors. Studies have shown that it plays an important role in cell survival, autophagy, proliferation, tumor invasion, and migration by influencing downstream signaling pathways such as AKT and ERK. EGFR has also been identified as a key target for non-small cell lung cancer. Since its approval for the treatment of NSCLC in 2003, EGFR inhibitors have achieved some efficacy, but the emergence of drug resistance has made it difficult to achieve the desired anti-tumor effect.

[0004] Activated Cdc42-related tyrosine kinase 1 (ACK1), also known as TNK2, is a structurally unique non-receptor tyrosine kinase belonging to the VIII tyrosine kinase family. ACK1 integrates RTK signals from different cell types and is activated by EGF. It interacts with EGFR and promotes EGFR internalization and lysosomal degradation. ACK1 mutations and overexpression have been observed in many cancers, including breast, lung, and prostate cancers. Furthermore, ACK1 phosphorylation serves as a diagnostic, predictive, and prognostic marker for certain cancers, such as pancreatic and breast cancer. High levels of ACK1 phosphorylation have been observed in tumors resistant to third-generation EGFR inhibitors, leading to apoptosis inhibition through sustained activation of the downstream AKT pathway.

[0005] This study designed and synthesized a quinazoline inhibitor targeting EGFR and ACK1. This inhibitor selectively inhibits EGFR, ACK1, and downstream signaling pathways, and exhibits strong antiproliferative activity in corresponding tumor cells. Dual-targeted EGFR-ACK1 inhibitors offer a potential strategy for overcoming drug resistance in the treatment of non-small cell lung cancer and hold broad research potential. Summary of the Invention

[0006] The technical problem solved by the present invention is to provide a compound as a novel dual-targeting EGFR and ACK1 inhibitor.

[0007] The present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0008]

[0009] The present invention also provides use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of anti-tumor drugs.

[0010] Furthermore, the anti-tumor drug is preferably an inhibitor drug that dual-targets EGFR and ACK1.

[0011] The anti-tumor drug is preferably an anti-tumor drug, and the corresponding tumor is a tumor with the characteristics of excessive activation of EGFR and ACK1.

[0012] The compounds prepared by the present invention or their pharmaceutically acceptable salts can be used as dual-targeting EGFR and ACK1 inhibitors, have certain anti-tumor activity, and can effectively inhibit the growth of cancer cells. The compounds of the present invention have significant inhibitory effects on various tumor cells, especially lung cancer cell lines. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 These are the test results of the anti-proliferative activity of the compound represented by formula I on NCI-H3255 and HCC827 cells. DETAILED DESCRIPTION

[0014] The present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0015]

[0016] The present invention also provides use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of anti-tumor drugs.

[0017] Furthermore, the anti-tumor drug is preferably an inhibitor drug that dual-targets EGFR and ACK1.

[0018] The anti-tumor drug is preferably an anti-tumor drug, and the corresponding tumor is a tumor with the characteristics of excessive activation of EGFR and ACK1.

[0019] The present invention also provides a pharmaceutical composition, which is a preparation containing an effective dose of the above compound or a pharmaceutically acceptable salt thereof.

[0020] The compounds of the present invention can be formulated into the following forms by methods known in the art: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders for inhalation or aerosols or sprays, sterile aqueous or oily solutions or suspensions, or sterile emulsions for parenteral administration (including intravenous, intramuscular, or infusion). Liquid preparations can be prepared using sterile water or water-propylene glycol solutions as solvents, and the active ingredient can also be formulated in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavorings, stabilizers, and thickeners as needed. Aqueous suspensions for oral administration can be prepared by dispersing the finely divided active ingredient in water along with a viscous substance, such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other suspending agents known in the pharmaceutical art.

[0021] The pharmaceutical composition can be in unit dosage form. In these forms, the composition is divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as boxed tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet, or any of these packaged forms can be an appropriate number.

[0022] The active ingredient of the pharmaceutical composition of the present invention may be the compound of the present invention alone, or it may be combined with other anti-tumor compounds as the active ingredient.

[0023] In the treatment of tumors, the pharmaceutical composition of the present invention can be used in combination with other anti-tumor drugs, for example, anti-proliferative / antitumor drugs, cell growth inhibitors, anti-invasion drugs, growth factor function inhibitors, anti-angiogenic agents, vascular damage agents, etc. used in medical oncology.

[0024] In the treatment of tumors, such combination therapy can be achieved by administering the various therapeutic components simultaneously, sequentially or separately. Such combination products utilize the compounds of this invention within their effective dosage ranges and the other pharmaceutically active agents within their approved dosage ranges.

[0025] The specific embodiments of the present invention are further described below in conjunction with examples, but the present invention is not limited to the scope of the examples.

[0026] Example 1 Synthesis of Preferred Compounds

[0027] The preferred compound is synthesized using the following reaction formula:

[0028]

[0029] Reaction conditions and reagents were: (a) m-nitroaniline, DIPEA, isopropanol, 80°C; (b) N₂H₄·H₂O, Renay-Ni, methanol, 0°C; (c) acryloyl chloride, TEA, THF, 0°C; and (d) 1-methyl-1H-pyrazol-4-amine, TFA, sec-butanol, 80°C.

[0030] 1. Synthesis of Intermediates 1-3

[0031] 2. 4-Dichloroquinazoline was dissolved in isopropanol (100 mL), and then 3-nitroaniline (1.11 g, 8.0 mmol) and diisopropylethylamine (6.61 mL, 40.0 mmol) were added and heated to 80°C for reaction. When TLC showed that the reaction of 3-nitroaniline was complete, the mixture was filtered under reduced pressure and the filter cake was purified by column chromatography (petroleum ether / ethyl acetate, 2 / 1) to obtain intermediate 1.

[0032] Intermediate 1 (4.0 mmol), hydrazine hydrate (497 μL, 16.0 mmol), and Raney nickel (0.47 g, 8.0 mmol) were added to methanol and reacted in an ice bath. When TLC detection showed that the reaction of intermediate 1 was complete, the mixture was filtered under reduced pressure, concentrated, and purified by column chromatography to obtain intermediate 2.

[0033] Acryloyl chloride (304 μL, 4.0 mmol) and TEA (834 μL, 6.0 mmol) were added to a solution of Intermediate 2 (2.0 mmol) in tetrahydrofuran (15 mL). The reaction was stirred in an ice bath. TLC analysis showed that the reaction of Intermediate 2 was complete. The mixture was concentrated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate, 2 / 1) to obtain Intermediate 3.

[0034] 2. Synthesis of Compound 1

[0035] Intermediate 3 (0.5 mmol), 4-(1H-pyrazol-1-yl)aniline (0.06 g, 0.4 mmol) and TFA (111 μL, 1.5 mmol) were added to sec-butanol, and the reaction was stirred at 80°C. The reaction was monitored by TLC. When the reaction of 3 was complete, the target compound 1 was obtained by column chromatography.

[0036] Compound 1, yellow solid, yield 43%; 1H NMR (400MHz, DMSO-d6) δ10.23 (s, 2H), 9.07 (s, 1H), 8.41 (d, J = 8.3Hz, 1H), 7.89 (d, J = 132.0Hz, 3H), 7.51 (s, 3H) , 7.44-7.21 (m, 3H), 6.49 (dd, J=17.0, 10.1Hz, 1H), 6.28 (d, J=17.1Hz, 1H), 5.78 (d, J=12.1Hz, 1H), 3.57 (s, 3H). 13 C NMR (100MHz, DMSO-d6) δ163.7, 159.2, 158.9, 139.9, 132.3, 130.7, 129.6, 129.4, 127.5, 121.9, 119.1, 116.1, 66.8, 39.1; HR-ESI-MS[M+H] + :m / z 386.1724.

[0037] Test Example 1 Antiproliferation test of compound 1 on NCI-H3255 and HCC827 cells

[0038] Antiproliferative activity assay in NCI-H3255 and HCC827 cells:

[0039] NCI-H3255 and HCC827 cells in the logarithmic growth phase were seeded in 96-well plates (approximately 5×10 cells per well). 3 Cells were cultured for 24 hours. After the cells attached and grew, the indicated concentrations of compound 1 were added and incubated for 24 hours. MTT was dissolved in PBS to a final concentration of 0.5%, and 20 μL of MTT solution was added to each well. The cells were incubated in a dark incubator at 37°C and 5% CO₂ for 3-4 hours. The culture medium was then discarded, and 150 μL of DMSO was added to each well. The OD values ​​at a wavelength of 490 nM were measured using a microplate reader. The effects of the compounds on cell proliferation were analyzed using SPSS. The half-maximal inhibitory concentration (50%) for different tumor cell lines was determined to evaluate the antiproliferative activity of each compound.

[0040] See the results Figure 1 ,from Figure 1 It can be clearly seen that the compound has significant and strong anti-proliferative activity against cells overexpressing EGFR and ACK1, with the half-maximal inhibitory concentrations for NCI-H3255 and HCC827 cells being 5.01±0.13 μM and 3.53±0.22 μM, respectively.

[0041] Based on the above experiments, we have obtained inhibitors that can effectively inhibit the anti-cancer effects of EGFR and ACK1. This type of inhibitor can provide a good method for treating tumors with overexpression of EGFR and ACK1. The development of this type of inhibitor has broad research prospects.

Claims

1. An aminoquinazoline compound for dual targeting of EGFR and ACK1, characterized by: Provided are the following compound structures or pharmaceutically acceptable salts thereof:

2. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

3. The use according to claim 2, characterized in that: The anti-tumor drug is an inhibitor drug that dual-targets EGFR and ACK1.

4. The use according to claim 2, characterized in that: The anti-tumor drug is a drug for treating tumors characterized by overactivation of EGFR and ACK1.

5. A pharmaceutical composition, characterized in that: The invention relates to a preparation comprising an effective dose of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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