CN106831711B

CN106831711B - Benzo [ e ] [1,2,4] triazine-1-oxy derivatives, and compositions and uses thereof

Info

Publication number: CN106831711B
Application number: CN201611260249.1A
Authority: CN
Inventors: 郭子扬; 褚延军; 田新芳; 裴海龙; 聂晶; 吴安庆; 李冰燕; 张健; 马季; 陈卫强; 周光明
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2016-12-30
Filing date: 2016-12-30
Publication date: 2021-08-24
Anticipated expiration: 2036-12-30
Also published as: CN106831711A

Abstract

The invention relates to 3- [ (7-chloroquinoline-4-amino) butylamine shown as a formula (1)]-7-substituted-benzo [ e][1,2,4]Triazine-1-oxo derivatives, pharmaceutically acceptable salts, esters, solvates thereof:

R¹selected from hydrogen, hydroxy, C₁‑C₆Alkyl, fluoro, chloro and bromo; r²Selected from hydrogen, C₁‑C₁₂Alkyl or hydroxy; r³Selected from hydrogen, C₁‑C₁₂Alkyl or hydroxy. The invention also provides a composition which comprises the 3- [ (7-chloroquinoline-4-amino) butylamine group shown as the formula (1)]-7-substituted-benzo [ e][1,2,4]Triazine-1-oxo derivatives, pharmaceutically acceptable salts, esters, solvates and pharmaceutically acceptable adjuvants thereof:

wherein R is¹Selected from hydrogen, hydroxy, C₁‑C₆Alkyl, fluoro, chloro or bromo; r²Selected from hydrogen, C₁‑C₁₂Alkyl or hydroxy; r³Selected from hydrogen, C₁‑C₁₂Alkyl or hydroxy. The invention also claims 3- [ (7-chloroquinoline-4-amino) butylamine]-7-substituted-benzo [ e][1,2,4]Triazine-1-oxygen derivatives, and pharmaceutically acceptable salts, esters and solvates thereof are applied to preparation of tumor treatment medicines.

Description

Benzo [ e ] [1,2,4] triazine-1-oxy derivatives, and compositions and uses thereof

Technical Field

The invention relates to the field of pharmacy, in particular to a benzo [ e ] [1,2,4] triazine-1-oxygen derivative, a composition and an application thereof.

Background

Cancer seriously harms human life and health, and is one of the biggest public health problems in the world. More than 1400 million cancer patients are newly added every year around the world, and more than 820 million people die every year due to cancer. The number of cancer diseases and deaths exceeds 430 million and 280 million respectively every year in China, and the situation is severe. Malignant tumors (also called cancers) are diseases that interfere with normal cellular functions mainly due to dysregulation of cell proliferation mechanisms, and may locally invade normal tissues and metastasize to other sites via the lymphatic system, the systemic circulatory system. Has the characteristics of insensitivity to growth signal inhibition, unlimited proliferation without being controlled by growth signal, and has the capabilities of resisting apoptosis and promoting angiogenesis, invasion and migration.

Autophagy is the process by which a cell degrades its own organelles (e.g., endoplasmic reticulum, mitochondria, etc.) or protein aggregates to maintain its own energy and metabolism of substances under conditions of nutrient deprivation or external stress. In mammalian cells, the general molecular mechanisms that induce autophagy are: under starvation or ambient pressure conditions, the convergence of various signals at mTORC1 causes mTORC1 to dissociate from the ULK complex, allowing hyperphosphorylation of ULK, followed by phosphorylation of Ambra1, allowing the Beclin1-Ambra1-PIK3C3 complex to migrate from microtubules to the endoplasmic reticulum, constituting the core of the autophagosome. The Atg5-Atg12 complex and LC3 then complete the extension of the autophagic vacuole, and the mature autophagic vacuole is associated with lysosomes to complete the degradation. Autophagy is generally considered to be an effective response of cells to environmental changes, plays a crucial role in survival and death of cells, and current research shows that autophagy is closely related to various diseases of human beings, especially malignant tumors.

The relationship between autophagy and tumor cell death is not yet fully understood. Autophagy has been shown to be a mode of cell death, similar to apoptosis, and is termed type ii programmed cell death. Inhibition of autophagy will induce apoptosis and thereby inhibit tumor development.

Chloroquine is an anti-malarial drug which is widely used, and research shows that chloroquine is an autophagy inhibitor by increasing the pH value of a lysosome, inhibiting fusion of an autophagosome and the lysosome and degradation of proteins in the autophagosome. Amaradi et al found that 5. mu. mol/L chloroquine can inhibit autophagy degradation mechanism and promote p 53-mediated tumor cell apoptosis (J.Clin. invest.2007,117: 326-336); maclean et al believe that high concentrations of chloroquine (50. mu. mol/L) directly cause tumor cell death (J Clin Invest,2008,118: 79-88); the Chaachouay study found that the radiation sensitivity can be improved by using 3-methyladenine (3-MA) and chloroquine to inhibit radiation-resistant breast cancer cells MDA-MB-231 (radiotherOncol, 2011,99: 287-292). Chloroquine as an autophagy inhibitor has been combined with various chemotherapeutic drugs to form a combined therapeutic drug and has entered clinical I/II experimental stage.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide a benzo [ e ] [1,2,4] triazine-1-oxygen derivative, a composition and an application thereof, wherein benzo [ e ] [1,2,4] triazine-1-oxide is used for generating free radicals in cells to activate autophagy of the cells, and a chloroquine autophagy inhibitor is combined to inhibit an autophagy signal pathway of the cells, so that apoptosis is triggered, and the aims of killing tumor cells and inhibiting tumor growth are fulfilled.

In one aspect, the present invention provides a 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxy derivative represented by formula (1), a pharmaceutically acceptable salt, an ester, or a solvate thereof:

wherein R is¹Selected from hydrogen, hydroxy, C₁-C₆Alkyl, fluoro, chloro or bromo;

R²selected from hydrogen, C₁-C₁₂Alkyl or hydroxy;

R³selected from hydrogen, C₁-C₁₂Alkyl or hydroxy.

Further, in one embodiment, R¹Is hydrogen, R²Is hydrogen, R³Is hydrogen, and has the following structural formula:

further, in another embodiment, R¹Is methyl, R²Is hydrogen, R³Is hydrogen, and has the following structural formula:

further, in one embodiment, R¹Is chlorine, R²Is hydrogen, R³Is hydrogen, and has the following structural formula:

in another aspect, the present invention provides a composition comprising a 3- [ (7-chloroquinolin-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazin-1-oxy derivative of formula (1), a pharmaceutically acceptable salt, ester, solvate or pharmaceutically acceptable excipient thereof:

R²selected from hydrogen, C₁-C₁₂Alkyl or hydroxy;

R³selected from hydrogen, C₁-C₁₂Alkyl or hydroxy.

Further, the auxiliary materials are one or more of starch, pregelatinized starch, dextrin, sucrose, dry starch, sodium hydroxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrant and crospovidone.

In another aspect, the invention also claims the application of the 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxygen derivative, and pharmaceutically acceptable salts, esters and solvates thereof in preparing tumor treatment medicines.

Further, the tumor is a solid tumor.

Further, the tumor is non-small cell lung cancer, head and neck cancer, liver cancer, prostate cancer, bone and soft tissue sarcoma, rectal cancer, malignant melanoma, brain tumor, pancreatic cancer, esophageal cancer, carcinoma of large intestine, breast cancer, uterine cancer, ovarian cancer or cancer of major peritoneum.

Further, the tumor treatment medicine is in the dosage form of tablets, capsules, pills, suppositories, aerosols, granules, powder, mixtures, syrups, oral liquids, injections, syrups, medicated liquors, tinctures, lotions or films.

Further, the administration mode of the tumor therapeutic drug is oral administration, injection, implantation, external application, spraying or inhalation.

The invention adopts an autophagy inhibitor chloroquine as a parent molecule, and introduces a benzo [ e ] [1,2,4] triazine-1-oxygen unit into a branched chain part of the autophagy inhibitor chloroquine. Benzo [ e ] [1,2,4] triazine-1-oxygen can be reduced by cytochrome C in cells to generate hydroxyl free radicals, and the hydroxyl free radicals further induce the occurrence of DNA chain breakage, so that autophagy is initiated; due to the existence of the chloroquine parent structure, the cell autophagy signal pathway is inhibited, cell apoptosis is triggered, and the aims of killing tumor cells and inhibiting tumor growth are fulfilled.

By the scheme, the invention at least has the following advantages:

compared with the current chloroquine drugs used in clinic, the 3- [ (7-chloroquinoline-4-amino) butylamine group of the invention]-7-substituted-benzo [ e][1,2,4]The triazine-1-oxygen derivative has higher cytotoxicity to A549, and can kill lung cancer cells more obviously; the result of a cytotoxicity experiment shows that under the condition that the parent compound is nontoxic to the non-small cell lung cancer, the chloroquine derivative disclosed by the invention has ID of A549 cells₅₀Around 25 μ M, while being relatively less toxic to normal cells; the acute and subacute experimental results of mice show that the chloroquine derivative has small acute and long-term toxicity to animals.

The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.

Description of the reference numerals

FIG. 1 shows the results of cytotoxicity test of the compound of the present invention against Calu-1 cells;

FIG. 2 shows the results of the cytotoxicity test of the compounds of the present invention against Beas-2B cells;

FIG. 3 shows the results of cytotoxicity tests of the compounds of the present invention against A549 cells;

FIG. 4 shows the results of acute toxicity test of drug using Compound 3 in mice;

FIG. 5 shows the results of a drug sub-acute toxicity test performed on mice using Compound 3;

FIG. 6 shows the results of the Westernblotting experiment for the compounds of the present invention.

Detailed Description

The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

The synthetic route of the 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxygen derivative is as follows:

in the preparation method, 4, 7-dichloroquinoline is used as a raw material to react with a butanediamine derivative at high temperature to generate a 4- (aminobutyl) amino-7-chloroquinoline derivative (A); the 4- (aminobutyl) amino-7-chloroquinoline derivative (A) reacts with 7-substituted-3-chloro-1, 2, 4-benzotriazole-1-oxide in the presence of triethylamine to generate the required product (I).

Example 13- [ (7-chloroquinolin-4-amino) butylamine group]-benzo [ e ]][1,2,4]Preparation of triazine-1-oxygen (R)¹＝H)

Weighing (1g, 5.05mmol)4, 7-dichloroquinoline, placing in a 50mL three-necked bottle, adding 1.74g butanediamine under the protection of argon, heating at 110 ℃ for 6-8h, cooling to room temperature after the reaction is finished, adding dichloromethane, spin-drying the solvent, adding ethyl acetate, performing suction filtration to obtain a light yellow solid, and performing column chromatography purification, wherein Me of DCM is 20:1 to obtain 1.13g of the compound 4- (aminobutyl) amino-7-chloroquinoline, and the yield is 86%. The results of the nuclear magnetic tests are as follows:

¹H NMR(400MHz，DMSO-d6)δ＝8.40(d，J＝5.4Hz,1H)，8.35(d，J＝9.0Hz，1H)，7.78(d，J＝2.0Hz，1H)，7.44(dd，J＝9.0，2.0Hz,1H),6.49(d，J＝5.4Hz，1H),3.30(t，J＝5.9Hz，2H),2.82(t，J＝6.8Hz，2H)，1.70(s，4H)。

3-chloro-1, 2, 4-benzotriazole-1-oxide (50mg, 0.275mmol) and 4- (aminobutyl) amino-7-chloroquinoline (68mg, 0.275mmol) were weighed out into a 50mL single-neck flask, 10mL of DME and 0.5mL of triethylamine were added, and the mixture was heated under reflux at 80 ℃ for 5 hours. After the reaction, the solvent, dichloromethane and water were extracted by spin-drying, and the organic layer was washed with saturated brine and anhydrous sodium sulfate. After spin-drying, purification was performed by column chromatography to obtain 80mg of 3- [ (7-chloroquinolin-4-amino) butylamino ] -benzo [ e ] [1,2,4] triazine-1-oxy (hereinafter referred to as compound 1) in 78% yield, from PE: EA ═ 5:1-2: 1. The results of nuclear magnetic and mass spectrometry are as follows:

¹H NMR(400MHz,DMSO-d6)δ＝9.58(s,1H),8.67(d,J＝9.1Hz,1H),8.50(d,J＝7.0Hz,1H),8.08(dd,J＝14.3,5.2Hz,2H),7.99(s,1H),7.75(t,J＝7.2Hz,1H),7.68(dd,J＝9.1,1.8Hz,1H),7.54–7.37(m,1H),7.31(t,J＝7.5Hz,1H),6.87(d,J＝7.1Hz,1H),3.61–3.53(m,2H),3.40(d,J＝5.5Hz,2H),1.85–1.67(m,4H)。

MS：[M+1]+：395.27(100％)。

example 23- [ (7-chloroquinolin-4-amino) butylamine group]-7-methyl-benzo [ e [ ]][1,2,4]Preparation of triazine-1-oxygen (R)¹＝CH₃)

Weighing (1g, 5.05mmol)4, 7-dichloroquinoline, placing in a 50mL three-necked bottle, adding 1.74g butanediamine under the protection of argon, heating at 110 ℃ for 6-8h, cooling to room temperature after the reaction is finished, adding dichloromethane, spin-drying the solvent, adding ethyl acetate, performing suction filtration to obtain a light yellow solid, and performing column chromatography purification, wherein Me is DCM 20:1 to obtain 1.13g 4- (aminobutyl) amino-7-chloroquinoline.

3-chloro-7-methyl-1, 2, 4-benzotriazole-1-oxide (50mg, 0.275mmol) and the above 4- (aminobutyl) amino-7 chloroquinoline (68mg, 0.275mmol) were weighed out into a 50mL single-necked flask, 10mL of DME and 0.5mL of triethylamine were added, and the mixture was heated under reflux at 80 ℃ for 5 hours. After the reaction, the solvent, dichloromethane and water were extracted by spin-drying, and the organic layer was washed with saturated brine and anhydrous sodium sulfate. After spin-drying, purification was performed by column chromatography to obtain 80mg of 3- [ (7-chloroquinolin-4-amino) butylamino ] -7-methyl-benzo [ e ] [1,2,4] triazine-1-oxy (hereinafter referred to as compound 2) in 79% yield, where EA was 5:1-2: 1. The results of nuclear magnetic and mass spectrometry are as follows:

¹H NMR(400MHz,DMSO-d₆)δ＝8.43(t,J＝7.1Hz,2H),8.34(s,1H),7.94–7.78(m,3H),7.59(d,J＝8.5Hz,1H),7.52(d,J＝8.0Hz,1H),7.42(d,J＝8.6Hz,1H),6.64(d,J＝6.1Hz,1H),3.43(d,J＝5.8Hz,1H),3.39(d,J＝5.9Hz,1H).,2.43(s,2H),1.74(s,4H)。¹³C NMR(100MHz,DMSO-d₆)δ159.16(s),152.74(s),148.28(s),145.00(s),138.08(s),135.65(s),135.00(s),130.04(s),126.20(s),125.42(s),124.23(s),118.92(s),117.03(s),99.04(s),45.75(s),42.85(s),34.16(s),31.74(s),26.41(s),25.53(s),21.15(s)。

MS：[M+1]⁺：409.27(100％)。

example 33- [ (7-chloroquinolin-4-amino) butylamine group]-7-chloro-benzo [ e][1,2,4]Preparation of triazine-1-oxygen (R)¹＝Cl)

3, 7-dichloro-1, 2, 4-benzotriazole-1-oxide (50mg, 0.275mmol) and the above 4- (aminobutyl) amino-7 chloroquinoline (68mg, 0.275mmol) were weighed out into a 50mL single-neck flask, 10mL of DME and 0.5mL of triethylamine were added, and the mixture was heated under reflux at 80 ℃ for 5 hours. After the reaction, the solvent, dichloromethane and water were extracted by spin-drying, and the organic layer was washed with saturated brine and anhydrous sodium sulfate. After spin-drying, purification was performed by column chromatography to obtain 80mg of 3- [ (7-chloroquinolin-4-amino) butylamino ] -7-chloro-benzo [ e ] [1,2,4] triazine-1-oxy (hereinafter referred to as compound 3) in 73% yield, where EA was 5:1-2: 1. The results of nuclear magnetic and mass spectrometry are as follows:

¹H NMR(400MHz,DMSO-d₆)δ＝9.01(s,1H),8.57(d,J＝9.1Hz,1H),8.47(d,J＝6.7Hz,1H),8.12(dd,J＝9.4,2.3Hz,2H),7.98(d,J＝2.1Hz,1H),7.76(dd,J＝9.0,2.4Hz,1H),7.66(dd,J＝9.0,2.0Hz,1H),7.55(d,J＝9.0Hz,1H),6.75(d,J＝6.7Hz,1H),,3.45(d,J＝5.8Hz,2H),3.41(d,J＝5.9Hz,2H).,2.43(m,2H),1.74(m,2H)。¹³C NMR(100MHz,DMSO-d₆)δ159.50(s),154.49(s),145.12(s),141.44(s),137.19(s),136.40(s),128.47(s),126.40(s),126.07(s),121.33(s),119.39(s),116.36(s),98.91(s),45.71(s),42.65(s),34.15(s),31.34(s),25.23(s),21.19(s)。

MS：[M+1]⁺：429.30(100％)。

example 4

1 equivalent of 3- [ (7-chloroquinoline-4-amino) butylamino ] -benzo [ e ] [1,2,4] triazine-1-oxide and 2 equivalents of formaldehyde aqueous solution are condensed into imine salt in a weak alkaline environment, and then the imine salt is further reduced by Pd/C hydrogen to obtain corresponding R2 and R3 methyl products, wherein the structural formula is as follows:

wherein R is¹Is hydrogen, R²Is methyl, R³Is methyl.

Example 5

1 equivalent of 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-methyl-benzo [ e ] [1,2,4] triazine-1-oxygen and 2 equivalents of aqueous formaldehyde solution are condensed into imine salt in a weak alkaline environment, and then the imine salt is reduced by Pd/C hydrogen to obtain corresponding R2 and R3 methyl products, wherein the structural formula is as follows:

wherein R is¹Is methyl, R²Is methyl, R³Is methyl.

Example 6

1 equivalent of 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-chloro-benzo [ e ] [1,2,4] triazine-1-oxygen and 2 equivalents of aqueous formaldehyde solution are condensed into imine salt in a weak alkaline environment, and then the imine salt is reduced by Pd/C hydrogen to obtain corresponding R2 and R3 methyl products, wherein the structural formula is as follows:

wherein R is¹Is chlorine, R²Is methyl, R³Is methyl.

Example 7

Cytotoxicity tests were carried out on Calu-1 and Beas-2B, A549 cells using compound 1, compound 2 and compound 3 synthesized in examples 1 to 3, respectively, and the results are shown in fig. 1 to 3. FIG. 1a shows the cytotoxicity test of Calu-1, the test results show that the cytotoxicity of compound 1, compound 2 and compound 3 is significantly increased and the cytotoxicity of compound 3 is the maximum, compared with the blank control group; FIG. 1b shows the cytotoxicity test of Calu-1, and the test results show that the cytotoxicity of Compound 3 is significantly higher than that of Compound 2 at different drug concentrations. Ctrl in FIG. 1a represents a blank control group, and C in the figure represents clinically commonly used chloroquine. FIG. 2a is a toxicity test of Bease-2B cells, and the test results show that the cytotoxicity of compound 1, compound 2 and compound 3 is significantly increased and the cytotoxicity of compound 3 is the highest compared with that of the blank control group; FIG. 2B is a cytotoxicity experiment of Bease-2B, and the experimental results show that the cytotoxicity of Compound 3 is significantly higher than that of Compound 2 at different drug concentrations. Ctrl in FIG. 2a represents a blank control group, and C in the figure represents clinically commonly used chloroquine. Fig. 3a is a549 cytotoxicity test, and the test results show that the cytotoxicity of compound 1, compound 2 and compound 3 is significantly increased and the cytotoxicity of compound 3 is the greatest compared with that of the blank control group; fig. 3b is a cytotoxicity experiment of a549, and the experimental result shows that the cytotoxicity of the compound 3 is obviously higher than that of the compound 2 under different drug concentrations, Ctrl in fig. 3a represents a blank control group, and C in the figure represents clinically common chloroquine. As can be seen from the figure, compared with the common clinical medication chloroquine, the 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxy derivative has strong killing power on non-small cell lung cancer cells Calu-1 and A549, wherein the compound 3 has the highest cytotoxicity on the lung cancer cells.

Acute drug toxicity tests were performed on male (male) and female (female) mice using compound 3, and the results are shown in figure 4. Ctrl (female) in the figure represents a female mouse physiological saline negative control group, and DMSO (male) in the figure represents a male mouse DMSO gastric lavage group. From the figure, it can be seen that the compound 3 in the novel chloroquine drug can reduce the organ index of the mice, but has no obvious influence on the survival rate of the mice compared with the mice in the normal saline and DMSO groups, which indicates that the drug has little acute toxicity to the mice.

The subacute toxicity test was performed on the mice using compound 3, and the mice were treated by various methods such as gastric lavage and tail vein injection with compound 3, and the results are shown in fig. 5. The results show that compound 3 has little effect on the survival of mice, indicating that the drug has no significant long-term toxicity to mice.

Western blotting experiments were carried out on mice using Compound 1, Compound 2 and Compound 3 synthesized in examples 1 to 3, respectively, and the results are shown in FIG. 6. In FIG. 6, Ctrl group is a blank control group, a starvation group is a positive control group, a starvation + compound 3 represents a starvation treatment group +3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxy derivative, group A represents benzo [ e ] [1,2,4] triazine-1-oxide, and group C represents a chloroquine gavage group. Compared with chloroquine, the 3- [ (7-chloroquinoline-4-amino) alkylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxygen derivative has obvious inhibition effect on autophagy. The medicine can activate the autophagy of cells by adopting benzo [ e ] [1,2,4] triazine-1-oxide to generate free radicals in the cells, and induce apoptosis by combining the inhibition of chloroquine autophagy inhibitor on autophagy pathways of the cells, thereby achieving the purpose of killing tumor cells and achieving the effect of inhibiting tumors.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims

1. A3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxy derivative represented by formula (1), and a pharmaceutically acceptable salt thereof:

wherein R is¹Is chlorine, R²And R³Is hydrogen.

2. A composition characterized by: comprises 3- [ (7-chloroquinoline-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazine-1-oxygen derivative shown as a formula (1), pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary materials thereof:

wherein R is¹Is chlorine, R²And R³Is hydrogen.

3. The composition of claim 2, wherein: the auxiliary materials are one or more of starch, dextrin, sucrose, sodium hydroxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrant and crospovidone.

4. The use of a 3- [ (7-chloroquinolin-4-amino) butylamino ] -7-substituted-benzo [ e ] [1,2,4] triazin-1-oxy derivative according to claim 1, a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of tumors; the tumor is non-small cell lung cancer.

5. Use according to claim 4, characterized in that: the tumor treatment medicine is in the dosage form of tablets, capsules, pills, suppositories, aerosols, granules, powder, mixtures, syrup, oral liquid, injections, syrups, medicated wine, tinctures, lotions or films.

6. Use according to claim 4, characterized in that: the administration mode of the tumor treatment drug is oral administration, injection, implantation, external application, spraying or inhalation.