CN115124480A - Preparation of 2, 4-disubstituted quinazoline compound and anti-tumor application thereof - Google Patents
Preparation of 2, 4-disubstituted quinazoline compound and anti-tumor application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention belongs to the technical field of antitumor medicine, and particularly relates to a 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor), a preparation method and application thereof, wherein the 2, 4-disubstituted quinazoline compound serving as a 2, 4-disubstituted quinazoline compound targeting EGFR L858R/T790M comprises the following compounds or pharmaceutically acceptable salts thereof. The compound or the pharmaceutically acceptable salt thereof has the activity of inhibiting EGFR L858R/T790M, can be used as an inhibitor of EGFR L858R/T790M, has antitumor activity, and can effectively inhibit the growth of tumor cells.
Description
Technical Field
The invention belongs to the technical field of antitumor pharmacology, and particularly relates to a 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor), a preparation method and application thereof.
Background
Epidermal Growth Factor Receptor (EGFR) is one of the HER family members. EGFR is an expression product of proto-oncogene c-erbB-1 and is a transmembrane tyrosine kinase receptor. EGFR plays an important role in physiological processes such as growth, proliferation and differentiation of cells by influencing downstream signaling pathways such as PI 3K/AKT. Loss of function or abnormal activity of EGFR can cause development of tumors, diabetes, immunodeficiency and cardiovascular diseases. In particular, EGFR has also been identified as a key target for non-small cell lung cancer.
Existing EGFR tyrosine kinase inhibitors have been developed into third generation inhibitors having advantages of combining EGFR sensitive mutation and T790M mutation site, but the emergence of drug resistance makes it difficult to exert ideal antitumor effect. The invention designs and synthesizes a 2, 4-disubstituted quinazoline inhibitor targeting EGFR L858R/T790M. The inhibitor can selectively inhibit EGFR L858R/T790M protein and downstream signal paths, and shows good antiproliferative activity in corresponding tumor cells.
The specification of Chinese patent CN 201010179803.X describes a 2, 4-disubstituted quinazoline compound, a preparation method thereof, a pharmaceutical composition and application thereof, wherein the compound, a precursor thereof, a stereoisomer thereof and a physiologically acceptable salt thereof are represented by a general formula (I):
mainly inhibits the Pin1 enzyme.
The Pin1 inhibitor usually targets the C-terminal catalytic domain, which can specifically isomerize the pSer/Thr-Pro amide bond, inducing changes in the conformation and function of the protein, and thus, such inhibitors can disrupt the function of Pin 1. Another class of inhibitors targets the N-terminal WW domain of Pin1, which renders the WW domain unable to bind to a substrate containing the pSer/Thr-Pro peptide fragment, thereby disabling the action of Pin 1.
Whereas EGFR inhibitors generally target the kinase domain located inside the cell, which is closely related to the kinase activity itself, such compounds affect downstream signaling pathways and related functions by inhibiting EGFR phosphorylation by targeting ATP binding sites or allosteric sites therein.
The inhibitor targeting domains of the Pin1 inhibitor and the EGFR inhibitor are different, the Pin1 inhibitor targets the catalytic domain and WW domain of the Pin1 protein, and the EGFR targets the kinase domain of EGFR, which is a transmembrane protein, inside the cell. In addition, these two classes of inhibitors work in different ways, with the Pin1 inhibitor acting by disabling Pin1 from binding to the substrate or disrupting the function of its isomerized pSer/Thr-Pro substrate, whereas the EGFR inhibitor inactivates the EGFR by inhibiting its phosphorylation, thereby disabling activation of downstream substrates.
Thus, inhibitors that inhibit the effects of EGFR are needed.
Disclosure of Invention
In order to solve the technical problems, the invention provides a 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor), a preparation method and application thereof, and the compound is used as a 2, 4-disubstituted quinazoline inhibitor targeting EGFR L858R/T790M. Shows good anti-proliferative activity in corresponding tumor cells highly expressing EGFR L858R/T790M,
the present invention provides a compound shown below or a pharmaceutically acceptable salt thereof:
the invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Furthermore, the anti-tumor drug is preferably an inhibitor drug targeting EGFR L858R/T790M.
The anti-tumor medicine is preferably an anti-tumor medicine, and the corresponding tumor is a tumor with the characteristic of EGFR L858R/T790M overexpression.
The compound or the pharmaceutically acceptable salt thereof prepared by the invention can be used as an inhibitor targeting EGFR L858R/T790M, has antitumor activity, and can effectively inhibit the growth of cancer cells. The compound has an inhibition effect on tumor cells with the characteristic of overexpression of EGFR L858R/T790M, and particularly has a good inhibition effect on non-small cell lung cancer.
Drawings
FIG. 1 shows the results of the anti-proliferative activity test of the compounds of formula I on NCI-H1975, HCC827, A549, A431 cells
Detailed Description
The present invention provides a compound shown below or a pharmaceutically acceptable salt thereof:
the invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Furthermore, the antitumor drug is preferably an inhibitor drug targeting EGFR L858R/T790M.
The anti-tumor medicine is preferably an anti-tumor medicine, and the corresponding tumor is a tumor with the characteristic of EGFR L858R/T790M overexpression.
The present invention also provides a pharmaceutical composition which is a preparation comprising an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof.
The compounds of the invention can be prepared in 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 or aerosols or sprays for inhalation, sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral (including intravenous, intramuscular or infusion). The liquid formulations can be prepared using sterile water or water-propylene glycol solutions as solvents, or the active ingredient can be formulated in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents 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 quantities of the active ingredient. The unit dosage form may be a packaged preparation, the package including discrete quantities of the preparation, for example, tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet or it can be the appropriate number of any of these packaged forms.
The active ingredient of the pharmaceutical composition of the present invention may be only the compound of the present invention, or may be combined with other anti-tumor compounds as an active ingredient.
In the process of treating tumors, the pharmaceutical composition can be used for combined treatment with other antitumor drugs. For example, it is used in combination with antiproliferative/antitumor agents, cytostatic agents, anti-invasive drugs, growth factor function inhibitors, antiangiogenic agents, vascular damaging agents, etc. for medical oncology.
In the treatment of tumors, such combination therapy may be achieved by the simultaneous, sequential or separate administration of the various therapeutic ingredients. Such combinations employ the compounds of the present invention in an effective dosage range and the other pharmaceutically active agents in a permitted dosage range.
The following examples are provided to further illustrate the embodiments of the present invention and are not intended to limit the scope of the present invention.
Synthesis of the Compound of example 1
The compound is synthesized by adopting the following reaction formula:
(i)DIPEA，i-PrOH，80℃；(ii)TEA，THF，0-25℃；(iii)TFA，2-butanol，80℃；(iv)K 2 CO 3 ，DMF，80℃；(v)Ranny-Ni，Hydrazine hydrate，MeOH，0-25℃；(vi)TEA，THF，0-25℃。
1. general Synthesis of intermediates 1 to 5
2, 4-dichloroquinazoline (1.99g, 10.0mmol) was dissolved in 60mL of isopropanol and stirred at room temperature, followed by the addition of p-phenylenediamine (0.86g, 8.0mmol) and DIPEA (6.61mL, 40.0 mmol). Then, the reaction solution was heated to 80 ℃ to react for four hours. After TLC detection reaction is completed, vacuum filtration is carried out to obtain yellow solid. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate, 2/1) to yield intermediate 1(2.11g, 78% yield).
Intermediate 1(2.11g, 7.8mmol) was dissolved in 30mL tetrahydrofuran and stirred in an ice bath, p-fluorophenylacetyl chloride (1.88g, 10.9mmol) was added, and triethylamine (1.58g, 15.6mmol) was added dropwise. Then the temperature is increased to 25 ℃ for reaction for 2 hours, and after the TLC detection, the reaction is completely carried out and then the concentration is carried out under reduced pressure. The crude product was isolated by column chromatography (petroleum ether/ethyl acetate, 2/1) to give intermediate 2(1.78g, 56% yield).
Intermediate 2(0.41g, 1mmol), 4-fluoro-3-nitroaniline (0.12g, 0.8mmol) and trifluoroacetic acid (222 μ L, 3mmol) were dissolved in sec-butanol (6 mL). Then, the reaction solution was heated to 80 ℃ and stirred to react for 4 hours. When TLC showed the reaction was complete, intermediate 3(0.29g, 56% yield) was isolated using column chromatography (dichloromethane/methanol, 200/1).
Intermediate 3(0.29g, 0.56mmol), N-methylpiperazine (0.07g, 0.73mmol) and potassium carbonate (0.28g, 2mmol) were dissolved in sec-butanol (6 mL). Then, the reaction solution was heated to 100 ℃ and stirred to react for 12 hours. When TLC showed the reaction was complete, intermediate 4(0.27g, 80% yield) was isolated using column chromatography (dichloromethane/methanol, 100/1).
Adding the intermediate 4(0.27g, 0.46mmol), hydrazine hydrate (58 mu L, 1.87mmol) and Raney nickel (0.06g, 0.94mmol) into methanol, reacting under ice bath condition, reducing pressure and filtering, concentrating and purifying by column chromatography to obtain intermediate 5(0.22g) as yellow solid with the yield of 82% when TLC detection shows that the 5a reaction is finished.
2. Synthesis method of compound 1
To a solution of intermediate 5(0.22g, 0.38mmol) in tetrahydrofuran (4mL) was added acryloyl chloride (58. mu.L, 0.76mmol) and TEA (158. mu.L, 1.14mmol), the reaction was stirred under ice-bath conditions and TLC indicated complete reaction. Concentrated under reduced pressure, and separated by column chromatography (dichloromethane/methanol, 100/1) to give compound 1(0.17g, yield 70%) as a yellow solid.
Compound 1, yellow solid, yield 70%; 1 H NMR(400MHz，DMSO-d 6 )δ10.20(s，1H)，9.49(s，1H)，9.10(s，1H)，9.02(s，1H)，8.47(s，1H)，8.37(d，J＝8.2Hz，1H)，7.92(d，J＝8.6Hz，2H)，7.76(d，J＝6.2Hz，1H)，7.63(dd，J＝11.4，8.1Hz，3H)，7.46(d，J＝8.3Hz，1H)，7.40(dd，J＝8.5，5.7Hz，2H)，7.25(t，J＝7.6Hz，1H)，7.17(t，J＝8.9Hz，2H)，7.10(d，J＝8.8Hz，1H)，6.59(dd，J＝17.0，10.3Hz，1H)，6.24(d，J＝15.2Hz，1H)，5.76(d，J＝11.9Hz，1H)，3.66(s，2H)，3.30(dd，J＝8.3，2.8Hz，4H)，2.79(t，J＝4.7Hz，4H)，2.25(s，3H). 13 C NMR(101MHz，DMSO)δ169.2，162.8，160.4，158.4，156.9，152.1，137.8，135.4，135.2，133.3，132.7，132.6，131.5，131.4，126.8，126.1，122.8，122.1，120.2，119.7，115.6，115.3，112.3，55.5，52.2，46.3，42.7.
test example 1 Compound 1 cell antiproliferation test for NCI-H1975, HCC827, A549, A431
The anti-proliferative activity assays were carried out in NCI-H1975, HCC827, A549, A431 cells:
h1975, HCC827, a549, a431 cells were seeded in 96-well plates (approximately 5 × 103 cells per well) in logarithmic growth phase, respectively. After 24 hours of culture, the compounds were added at the indicated concentrations (0-40. mu.M) separately and incubated for 24 hours after adherent growth of the cells. MTT was dissolved using PBS to a final concentration of 0.5%, followed by addition of 20. mu.L of MTT solution per well. Incubating at 37 ℃ in a cell culture box with 5% CO2 for 3-4 hours in the dark, then discarding the existing culture medium, adding 150 mu L of DMSO into each well, detecting the corresponding OD value at 490nM wavelength by a microplate reader, analyzing the influence of each compound on cell proliferation by SPSS, and evaluating the anti-proliferation activity of each compound.
NCI-H1975, HCC827, A549, A431 cells were treated with the compound 1 of the present invention, and the median inhibitory concentrations on various tumor cells were determined. And measuring the corresponding OD value by using a microplate reader, and evaluating the antiproliferative activity by using an MTT method.
The results are shown in FIG. 1, and it is evident from FIG. 1 that the compound has significantly strong antiproliferative activity on cells expressing EGFR L858R/T790M, and has half-inhibitory concentrations of 2.76. + -. 0.32. mu.M, 3.66. + -. 0.13. mu.M, 15.0. + -. 1.45. mu.M and 14.1. + -. 1.02. mu.M on NCI-H1975, HCC827, A549 and A431 cells, respectively.
By combining the experiments, the inhibitor capable of effectively inhibiting EGFR L858R/T790M from playing an anticancer role is obtained, the inhibitor can provide a good method for treating various tumors which over-express EGFR L858R/T790M and comprise non-small cell lung cancer, and the inhibitor has a wide research prospect aiming at the development of the inhibitor.
Claims (6)
1. A 2, 4-disubstituted quinazoline compound for use in the inhibition of EGFR, characterized in that: the structural general formula of the compound shown as the following or pharmaceutically acceptable salt thereof is provided:
2. the 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 preparation of an anti-tumor medicament.
4. Use according to claim 3, characterized in that: the anti-tumor drug is an inhibitor drug targeting EGFR L858R/T790M.
5. Use according to claim 4, characterized in that: the anti-tumor drug is a drug for treating tumors with the characteristic of EGFR L858R/T790M overexpression.
6. A pharmaceutical composition characterized by: a formulation comprising an effective amount of a compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof.
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