CN118063441A - Preparation of aminoquinazoline compound and anti-tumor effect - Google Patents

Abstract

The invention relates to preparation and application of an amino quinazoline compound of dual-targeting EGFR and ACK1, and belongs to the technical field of anti-tumor pharmacy. The technical problem solved by the invention is to provide a compound serving as a dual-targeting EGFR and ACK1 inhibitor. The compound includes a compound shown below or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof can be used as an inhibitor of EGFR and ACK1, has anti-tumor activity, and can effectively inhibit the growth of tumor cells. The compounds of the invention are preferably anti-tumor compounds, and the corresponding tumor types are characterized by EGFR and ACK1 overexpression.

Description

Preparation of aminoquinazoline compound and anti-tumor effect

Technical Field

The invention relates to preparation and application of an amino quinazoline compound of dual-targeting EGFR and ACK1, and belongs to the technical field of antitumor pharmacy.

Background

Cancer is one of the important diseases which seriously affects human health and threatens human life at present, and lung cancer is one of the cancers which causes the greatest number of deaths of cancer patients worldwide at present. Wherein non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and NSCLC patients have a lower 5-year survival rate, most patients will develop locally advanced or other metastatic disease. In the last decade scientists have made significant progress in the study of different molecular and genetic sub-populations of NSCLC and have greatly altered the clinical assessment and treatment of patients.

The epidermal growth factor receptor (EPITHELIAL GROWTH FACTOR RECEPTOR, EGFR) is an expression product of a proto-oncogene c-erbB-1, is a transmembrane tyrosine kinase receptor, and is widely expressed in many normal tissues and solid tumors. Studies show that the cell-mediated apoptosis inhibitor plays an important role in the processes of cell survival, autophagy, proliferation, tumor invasion, migration and the like by influencing downstream signal pathways such as AKT, ERK and the like. EGFR has also been identified as a key target for non-small cell lung cancer, and inhibitors thereof have achieved a certain efficacy since being approved for the treatment of NSCLC in 2003, but the emergence of resistance has made it difficult to exert an ideal antitumor effect.

Activated Cdc 42-related tyrosine kinase 1 (ACK 1), also known as TNK2, is a structurally unique non-receptor tyrosine kinase belonging to the VIII tyrosine kinase family. ACK1 is capable of integrating RTK signals of different cell types and is capable of being activated by EGF and is capable of interacting with EGFR and promoting EGFR internalization and lysosomal degradation. Mutations and overexpression of ACK1 are observed in many cancers, including breast, lung, prostate. In addition, phosphorylation of ACK1 can be used as a marker for diagnosis, prognosis and prognosis of certain cancers (e.g., pancreatic and breast cancers). Apoptosis inhibition by continued activation of the downstream AKT pathway by high phosphorylation levels of ACK1 was observed in resistant tumors of third generation EGFR inhibitors.

The invention designs and synthesizes a quinazoline inhibitor targeting EGFR and ACK 1. The inhibitor can selectively inhibit EGFR, ACK1 and downstream signal channels and has good antiproliferative activity in corresponding tumor cells. The dual-targeting EGFR-ACK1 inhibitor provides a potential strategy for overcoming drug resistance for the treatment of non-small cell lung cancer, and has wide research prospect.

Disclosure of Invention

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

The present invention provides a compound as shown below or a pharmaceutically acceptable salt thereof:

The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing antitumor drugs.

Further, the antitumor drug is preferably an inhibitor drug for dual targeting EGFR and ACK 1.

The antitumor drug is preferably an antitumor drug, and the corresponding tumor is a tumor with EGFR and ACK1 overactivation characteristics.

The compound or the pharmaceutically acceptable salt thereof prepared by the invention can be used as a dual-targeting EGFR and ACK1 inhibitor, has a certain antitumor activity, and can effectively inhibit the growth of cancer cells. The compound has obvious inhibition effect on various tumor cells, especially lung cancer cell lines.

Drawings

FIG. 1 shows the results of antiproliferative activity of compounds of formula I on NCI-H3255, HCC827 cells.

Detailed Description

The present invention provides a compound as shown below or a pharmaceutically acceptable salt thereof:

The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing antitumor drugs.

Further, the antitumor drug is preferably an inhibitor drug for dual targeting EGFR and ACK 1.

The antitumor drug is preferably an antitumor drug, and the corresponding tumor is a tumor with EGFR and ACK1 overactivation characteristics.

The present invention also provides a pharmaceutical composition which is a formulation comprising an effective amount of the above compound or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may be prepared by methods known in the art in the form of: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or sprays for inhalation, sterile aqueous or oily solutions or suspensions for parenteral (including intravenous, intramuscular or infusion) or sterile emulsions. Sterile water or water-propylene glycol solutions may be used as solvents to prepare liquid formulations, and the active ingredient may also be formulated in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions for oral use can be prepared by dispersing the finely divided active component in water together with viscous materials such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose and other suspending agents known in the pharmaceutical arts.

The pharmaceutical composition may be in unit dosage form. In these forms, the composition is divided into unit doses containing appropriate amounts of the active component. The unit dosage form may be a packaged formulation, including discrete amounts of formulation, such as a boxed tablet, capsule, and powder in a vial or ampoule. The unit dosage form may also be a capsule, cachet or tablet or it may be the appropriate number of any of these packaged forms.

The active ingredients of the pharmaceutical composition of the present invention may be only the compound of the present invention, or may be combined with other antitumor compounds as active ingredients.

In the course of treatment of tumors, the pharmaceutical composition of the present invention may be used in combination with other antineoplastic agents. For example, in combination with antiproliferative/antineoplastic agents for medical oncology, cytostatic agents, anti-invasive agents, inhibitors of growth factor function, antiangiogenic agents, vascular damaging agents, etc.

In the treatment of tumors, such combination therapy may be achieved by simultaneous, sequential or separate administration of the various therapeutic ingredients. Such combination products employ the compounds of the invention in an effective dosage range and other pharmaceutically active agents in a permitted dosage range.

The following describes the invention in more detail with reference to examples, which are not intended to limit the invention thereto.

EXAMPLE 1 Synthesis of preferred Compounds

Preferred compounds are synthesized using the following reaction scheme:

The reaction conditions and reagents are (a)m-nitroaniline,DIPEA,isopropanol,80℃;(b)N2H4·H2O,Renay-Ni,methanol,0℃;(c)acryloyl chloride,TEA,THF,0℃;(d)1-methyl-1H-pyrazol-4-amine,TFA,sec-butanol,80℃.

1. Synthesis method of intermediates 1-3

2 Dissolving 4-dichloroquinazoline in isopropanol (100 mL), adding 3-nitroaniline (1.11 g,8.0 mmol), heating diisopropylethylamine (6.61 mL,40.0 mmol) to 80 ℃ for reaction, carrying out vacuum filtration when TLC shows that the 3-nitroaniline is reacted, and purifying a filter cake by column chromatography (petroleum ether/ethyl acetate, 2/1) to obtain an intermediate 1.

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 under ice bath conditions, TLC detection showed intermediate 1 was reacted completely, filtered under reduced pressure, concentrated and purified by column chromatography to give intermediate 2.

To a solution of intermediate 2 (2.0 mmol) in tetrahydrofuran (15 mL) was added acryloyl chloride (304. Mu.L, 4.0 mmol) and TEA (834. Mu.L, 6.0 mmol), and the reaction was stirred under ice-bath conditions, and TLC detection showed complete reaction of intermediate 2. Concentrated under reduced pressure and isolated as intermediate 3 by column chromatography (petroleum ether/ethyl acetate, 2/1).

2. Synthesis method of compound 1

Intermediate 3 (0.5 mmol), 4- (1H-pyrazol-1-yl) aniline (0.06 g,0.4 mmol) and TFA (111. Mu.L, 1.5 mmol) were added to sec-butanol and the reaction was stirred at 80℃and monitored by TLC, when the reaction was complete, the title compound 1 was isolated as a white solid by column chromatography.

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).¹³C 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.

Test example 1 Compound 1 anti-proliferation assay against NCI-H3255, HCC827 cells

Anti-dereferencing Activity assay in NCI-H3255, HCC827 cells:

NCI-H3255 in logarithmic growth phase, HCC827 cells were inoculated into 96-well plates (approximately 5X 10 ³ cells per well), respectively. After culturing for 24 hours, the specified concentration of compound 1 was added separately after the cell attachment growth, and incubated for 24 hours. MTT was dissolved to a final concentration of 0.5% using PBS, followed by the addition of 20. Mu.L of MTT solution per well. Incubate in a 5% CO2 cell incubator at 37℃for 3-4 hours in the absence of light, then discard the existing medium, add 150. Mu.L of DMSO per well, and detect the corresponding OD at 490nM wavelength by an ELISA reader. The effect of the SPSS assay compound on cell proliferation was used to determine the median inhibitory concentration for different tumor cells and to evaluate the antiproliferative activity of each compound.

As a result, as is apparent from FIG. 1, the compound has significantly stronger antiproliferative activity on EGFR and ACK1 overexpressed cells, and half-maximal inhibitory concentrations on NCI-H3255 and HCC827 cells are 5.01+ -0.13 μM and 3.53+ -0.22 μM, respectively.

By combining the experiments, the inhibitor capable of effectively inhibiting EGFR and ACK1 to play an anticancer role is obtained, and the inhibitor can provide a good method for treating tumors over-expressed by EGFR and ACK1, and has a very wide research prospect aiming at the development of the inhibitor.

Claims (6)

1. An aminoquinazoline compound for dual targeting EGFR and ACK1, characterized in that: providing a compound of the general structural formula or a pharmaceutically acceptable salt thereof as shown below:

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the structural formula is shown as formula I.

3. Use of a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the manufacture of an antitumor medicament.

4. Use according to claim 3, characterized in that: the antitumor drug is an inhibitor drug for dual targeting EGFR and ACK 1.

5. Use according to claim 4, characterized in that: the antitumor drug is a drug for treating tumor types with EGFR and ACK1 overactivation characteristics.

6. A pharmaceutical composition characterized by: a formulation comprising an effective amount of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.