CN102153508B - 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs - Google Patents

Abstract

The invention discloses 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumor drugs. The 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compound can be obtained by Claisen-Schimidt reaction of aromatic aldehyde and N-cyclopropyl-4-piperidine ketone. The 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone compound can obviously restrain the proliferation of various tumor cells and can be used for preparing drugs for treating leukocythemia, colorectal cancer, lover cancer, skin cancer, gastric cancer, breast cancer, prostatic cancer or other malignant tumor.

Description

3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one and its application in the preparation of antitumor drugs

Technical field:

The present invention relates to the synthesis of anti-tumor drugs and their preparation methods, in particular to the synthesis of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds and their application in the preparation of anti-tumor drugs . the

Background technique:

Using 4-piperidone as an intermediate and condensing aromatic aldehydes to obtain a series of compounds with anti-tumor, anti-inflammatory, antibacterial and other activities, the representative compound EF-24 (structural formula is as follows) has good anti-tumor activity in vivo and in vitro [Document ^{1 , 2} ]. However, there is no literature report on the synthesis of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds and their application in the preparation of antitumor drugs.

Chemical structural formula of EF-24

references

1. Subramaniam D, May R, Sureban SM, et al. Diphenyl difluoroketone: a curcumin derivative with potent in vivo anticancer activity. [J]. Cancer Res., 2008, 68(6): 1962-1969.

2. Adams BK, Ferstl EM, Davis MC, et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents[J]. Bioorg Med Chem, 2004, 12(14): 3871-3883. 

Invention content:

One of the objectives of the present invention is to provide a 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin 4-one compound. the

3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compound general formula of the present invention is as follows:

The present invention can also use a therapeutically effective amount of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin 4-one compound and a pharmaceutically acceptable carrier to form a composition. The group represented by Ar in formula (I) is: substituted phenyl or heterocyclic ring, the substituent on the phenyl can be at least one non-hydrogen substitution in R ₁ , R ₂ , R ₃ , R ₄ , R ₅ If all are hydrogen, the substituted phenyl is phenyl (see Example 7), or there are two substituents such as R ₁ , R ₃ , or three substituents such as R ₃ , R ₄ , R ₅ , There can be up to five substituents R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ can be the same group or different groups, For example, R ₁ = R ₂ , or R ₁ ≠ R ₂ , the substituents are preferably alkyl, alkoxy, halogen, haloalkyl or nitro, most preferably methoxy, with 1-4 carbons Alkyl, fluoro, trifluoromethyl or nitro; most preferred substituents on phenyl are 2-methoxy (see Example 5); 2,5-dimethoxy (see Example 4); 3,4-dimethoxy (see Example 3); 2,4,5-trimethoxy (see Example 1); 2-fluoro (see Example 2); 2-chloro (see Example 9) 2-bromo (see Example 8); 4-methyl (see Example 12); 2-trifluoromethyl (see Example 6); 3,4-methylenedioxy (see Example 10) ; Substituted phenyl Ar is 2-naphthylene (see Example 11). The heterocycle is preferably pyridyl, pyrrolyl or furyl, most preferably 3-pyridyl.

The second object of the present invention is to provide a preparation method of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds. Compound 3 of the present invention, 5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-ketone compound can be obtained by Claisen-Schimidt reaction of aromatic aldehyde and N-cyclopropyl-4-piperidinone . The reaction equation is shown as follows:

The third object of the present invention is to provide the application of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds and their compositions in the preparation of antitumor drugs. the

The 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compound of the present invention can be used, but not limited to, as a preparation for the treatment of leukemia, colon cancer, skin cancer, gastric cancer, liver cancer , breast or prostate cancer drugs. the

The present invention provides a pharmaceutical composition for treating anti-tumor, which contains a therapeutically effective amount of the compound according to any one of claims 1-5 and a pharmaceutically acceptable carrier. The therapeutically effective dose is the lowest pharmaceutical dose that has a clinical therapeutic effect. the

The present invention provides a pharmaceutical composition for treating autemia, colon cancer, skin cancer, gastric cancer, liver cancer, breast cancer, and prostate cancer, which contains a therapeutically effective amount of any one of the compounds in claims 1 to 5 and pharmaceutically acceptable carrier. The therapeutically effective dose is the lowest pharmaceutical dose that has a clinical therapeutic effect. the

According to an embodiment of the present invention, the medicine or composition of the 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compound for treating cancer described in the present invention can treat Examples of cancer include, but are not limited to, leukemia, colon cancer, skin cancer, stomach cancer, liver cancer, breast cancer, prostate cancer. the

The beneficial effects of the present invention are: the 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one class of compounds of the present invention can significantly inhibit the proliferation of various human tumor cells in vitro, see Table 1: Oral administration in vivo Taking compound 2 as an example and adding 100 mg·Kg ^-1 ·d ^-1 amount can achieve 48.4% tumor inhibition rate on H22 liver cancer xenograft mice, see Table 2, Fig. 1, illustrate 3 of the present invention , 5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds can be used as a preparation for the treatment of leukemia, colon cancer, liver cancer, skin cancer, gastric cancer, breast cancer or prostate cancer, etc. Drug.

And the preparation method of the present invention is different from the EF-24 compound preparation method in the background technology, and the EF-24 compound preparation method can not be used for the preparation of the present invention, and EF-24 synthesis is to make the glacial acetic acid etc. of saturated HCl as catalyst and reaction solvent , the reaction time is generally 2d. The target compound of the present invention, 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one is catalyzed by base, and ethanol is used as solvent, and the reaction time is obviously shortened, generally in 30min-1d, separation The purification is simple, and the solvent is non-corrosive, green and safe. The preparation time of the present invention is short, the efficiency is high, the preparation process is simple, and the yield is high, reaching more than 60%, and the highest can reach 88%. the

Description of drawings:

Fig. 1 is the inhibitory action figure of compound 2 of the present invention to mouse H22 ascites liver cancer xenograft tumor,

The upper row in the figure is the shape diagram of liver cancer xenograft tumor without adding compound 2, and the lower row in the figure is the inhibition shape diagram of liver cancer xenograft tumor after adding compound 2. Compared with the upper and lower diagrams, it can be seen that the mice after adding compound 2 H22 ascites liver cancer xenografts were significantly inhibited. the

Detailed ways:

The present invention is described in detail below in conjunction with embodiment:

Melting point was determined by Shanghai Precision Instrument Factory X-4 Microscopic Melting Point Apparatus, and the temperature was not corrected. ^{The 1} H and ¹³ C NMR spectra were measured by a Bruker Avance III nuclear magnetic resonance instrument (400 MHz), and TMS was used as an internal standard. The mass spectrum was determined by Agilent 1100LC/MSD Trap ion trap liquid mass spectrometer. The raw materials 1-cyclopropyl 4-piperidone and aromatic aldehyde were purchased from Alfa Aisha (Tianjin) Chemical Co., Ltd., and sodium hydroxide, absolute ethanol, concentrated hydrochloric acid and acetic acid were purchased from Sinopharm Chemical Reagent Company.

3,5-(E)-dibenzylidene-N-cyclopropylpiperidin 4-one synthetic general method

N-cyclopropyl-4-piperidone 348mg (2.5mmol), sodium hydroxide 20mg (0.5mmol), absolute ethanol 20mL, after mixing, stir at room temperature, add aromatic aldehyde (5mmol) after clarification, and react at room temperature for 0.5 h ~ 24h, there is solid precipitation. Suction filtration, the filter cake was washed with absolute ethanol, and dried in vacuum. Various aromatic aldehydes (its molar number is 5mmol) adopted in this example, see as follows: the chemical structural formula of the 1～12 compound that embodiment one～twelve is synthesized is as follows:

That is, the chemical structural formula of 1-12 kinds of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds is:

1-12 kinds of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-ketone compounds are measured by melting point apparatus, nuclear magnetic resonance apparatus and mass spectrometer, and the measured values are as follows:

Embodiment 1. When the aromatic aldehyde is 2,4,5-trimethoxybenzaldehyde, 3,5-(E)-bis(2,4,5-trimethoxybenzylidene)-N-ring Propylpiperidin-4-one (Compound 1), orange-red powder, yield 60%, mp150～153℃, ESI-MS: 496.3 (M+1); ¹ H-NMR (CDCl ₃ , ppm)δ : 8.02 (2H, s, -CH=), 6.82 (2H, s, Ar-H), 6.55 (2H, s, Ar-H), 4.63 (4H, s, -CH ₂ -), 3.86 (18H, s, -OCH ₃ ), 1.93 (s, 1H, -N-CH(CH ₂ ) ₂ ), 0.44-0.39 (m, 4H, -CH(CH ₂ ) ₂ ). δ: 87.99, 154.18, 151.13, 142.54 , 131.93, 116.36, 114.32, 109.17, 97.27, 56.86, 56.35, 56.21, 55.19, 37.42, 6.67

Example 2. When the aromatic aldehyde is 2-fluorobenzaldehyde, 3,5-(E)-bis(2-fluorobenzylidene)-N-cyclopropylpiperidin-4-one (compound 2) is obtained , as light yellow powder, yield 88%, mp169～172°C, ESI-MS: 352.3 (M+1); ¹ H-NMR (CDCl ₃ , ppm) δ: 7.88 (2H, s, -CH=), 7.39～7.31(4H, m, Ph-H), 7.22～7.11(4H, m, Ph-H), 3.86(s, 4H, -CH ₂ -), 1.90(s, 1H, -N-CH(CH _{2 ) . _} ^_ _{_} 123.25, 115.82, 54.98, 37.70, 6.77.

Example three, when the aromatic aldehyde is 3,4-dimethoxybenzaldehyde, 3,5-(E)-bis(3,4-dimethoxybenzylidene)-N-cyclopropyl is obtained Piperidin-4-one (compound 3), yellow powder, yield 66%, mp195～198°C, ESI-MS: 436.3 (M+1); ¹ H-NMR (CDCl ₃ , ppm) δ: 7.75 ( 2H, s, -CH=), 7.06 (2H, d, J=8Hz, Ar-H), 6.97 (2H, s, Ar-H), 6.93 (2H, d, J=8Hz, Ar-H), 4.01 (4H, s, -CH ₂ -), 3.92 (12H, s, -OCH ₃ ), 1.97 (s, 1H, -N-CH(CH ₂ ) ₂ ), 0.53-0.48 (m, 4H, -CH (CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 187.16, 150.01, 148.86, 136.26, 128.40, 124.04, 123.89, 114.04, 111.13, 55.99, 55.75, 55.12, 37.90, 6.73

Embodiment four, when the aromatic aldehyde is 2,5-dimethoxybenzaldehyde, 3,5-(E)-bis(2,5-dimethoxybenzylidene)-N-cyclopropyl is obtained Piperidin-4-one (compound 4), golden yellow powder, yield 77%, mp138～141℃, ESI-MS: 436.3 (M+1); ¹ H-NMR (CDCl ₃ , ppm) δ: 7.99 (2H, s, -CH=), 6.91-6.84 (4H, m, Ar-H), 6.81 (2H, s, Ar-H), 3.89 (4H, s, -CH ₂ -), 3.80 (12H, s, -OCH ₃ ), 1.89 (s, 1H, -N-CH(CH ₂ ) ₂ ), 0.43-0.37 (m, 4H, -CH(CH2)2). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 187.43, 152.99, 152.96, 133.70, 132.14, 125.38, 116.34, 114.88, 111.89, 56.17, 55.87, 55.05, 37.59, 6.77

Example five, when the aromatic aldehyde is 2-dimethoxybenzaldehyde, 3,5-(E)-bis(2-methoxybenzylidene)-N-cyclopropylpiperidine-4- Ketone (compound 5), pale yellow needle-like crystal, yield 80%, mp178～181℃, ESI-MS: 476.3 (M+1); ¹ H NMR (CDCl ₃ , ppm) δ: 8.05 (2H, s , -CH=), 7.36 (2H, t, J=8Hz, Ar-H), 7.25 (2H, d, J=8Hz, Ar-H), 6.99 (2H, t, J=8Hz, Ar-H) , 6.92 (2H, d, J=8Hz, Ar-H), 3.88 (4H, s, -CH ₂ -), 3.85 (6H, s, -OCH ₃ ), 1.88 (s, 1H, -N-CH ( CH ₂ ) ₂ ), 0.42-0.35 (m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100 MHz, CDCl ₃ , ppm) δ: 187.56, 158.52, 133.40, 132.19, 130.39, 130.31, 124.63 , 120.09, 110.82, 55.52, 55.15, 37.67, 6.72

Embodiment 6. When the aromatic aldehyde is 2-trifluoromethylbenzaldehyde, 3,5-(E)-bis(2-trifluoromethylbenzylidene)-N-cyclopropylpiperidine-4 is obtained - Ketone (compound 6), yellow needle crystal, yield 60%, mp152～154°C, ESI-MS: 452.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ: 8.04 (2H , s, -CH=), 7.75 (2H, d, Ph-H, J=7.6Hz), 7.59 (2H, t, Ph-H, J=7.6Hz), 7.48 (2H, t, Ph-H, J = 7.6Hz), 7.30 (2H, d, Ph-H, J = 7.6Hz), 3.73 (s, 4H, -CH ₂ -), 1.86 (s, 1H, -N CH(CH ₂ ) ₂ ), 0.39-0.33 (m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 186.11, 162.22, 159.72, 135.09, 130.76, 129.25, 123.99, 123.25, 115.82, 54.05 , 36.65, 6.62.

Example 7. When the aromatic aldehyde is benzaldehyde, 3,5-(E)-bis(2-benzylidene)-N-cyclopropylpiperidin-4-one (compound 7) is obtained, light yellow powder , yield 80%, mp 156～159℃, ESI-MS: 316.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ7.80 (2H, s, -CH=), 7.46～ 7.35(10H, m, Ph-H), 3.99(s, 4H, -CH ₂ -), 1.97～1.92(m, 1H, -N-CH(CH ₂ ) ₂ ), 0.50-0.38(m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 187.54, 136.26, 135.37, 133.50, 13 0.49, 128.97, 128.59, 128.23, 127.25, 55.18, 38.03, 6.81

Embodiment 8. When the aromatic aldehyde is 2-bromobenzaldehyde, 3,5-(E)-bis(2-bromobenzylidene)-N-cyclopropylpiperidin 4-one (compound 8) is obtained. Yellow powder, yield 77%, mp 130～135°C, ESI-MS: 492.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ: 7.94 (2H, s, -CH=), 7.66 (2H, d, Ph-H, J=8Hz), 7.37 (2H, t, Ph-H, J=7.6Hz), 7.27～7.21 (4H, q, Ph-H, J=7.2Hz), 3.82( s, 4H, -CH ₂ -), 1.88 (s, 1H, -N-CH(CH ₂ ) ₂ ), 0.44-0.37 (m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz , CDCl ₃ , ppm) δ: 186.81, 136.30, 135.52, 134.25, 133.19, 130.32, 130.09, 127.10, 125.24, 54.51, 37.49, 6.74

Example 9. When the aromatic aldehyde is 2-chlorobenzaldehyde, 3,5-(E)-bis(2-chlorobenzylidene)-N-cyclopropylpiperidin 4-one (compound 9) is obtained. Pale yellow powder, yield 74%, mp 152～155°C, ESI-MS: 384.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ: 7.99 (2H, s, -CH=) , 7.34～7.26(8H, m, Ph-H), 3.83(s, 4H, -CH ₂ -), 1.88(m, 1H, -N-CH(CH ₂ ) ₂ ), 0.45-0.35(m, 4H , -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 186.81, 135.21, 134.63, 133.89, 133.74, 130.34, 129.97, 129.95, 126.47, 54.67, 37.58, 6.76

Embodiment 10. When the aromatic aldehyde is piperonal, 3,5-(E)-bis(3,4-methylenedioxybenzylidene)-N-cyclopropylpiperidin-4-one ( Compound 10), yellow powder, yield 68%, mp215～218°C, ESI-MS: 404.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ: 7.68 (2H, s, -CH =), 6.97 (2H, d, Ph-H, J=8Hz), 6.93 (2H, s, Ph-H), 6.88 (2H, d, Ph-H, J=8Hz), 6.03 (4H, s, O-CH2-O), 3.94(s, 4H, -CH ₂ -), 1.95(m, 1H, -N-CH(CH ₂ ) ₂ ), 0.54-0.40(m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 187.24, 148.38, 147.91, 135.93, 132.02, 129.62, 126.09, 110.06, 108.61, 101.48, 55.26, 38.14, 6.87

Embodiment 11. When the aromatic aldehyde is 2-naphthaldehyde, 3,5-(E)-bis(2-naphthylene)-N-cyclopropylpiperidin 4-ketone (compound 11) is obtained. Yellow powder, yield 82%, mp 199～202°C, ESI-MS: 416.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ: 7.99 (2H, s, -CH=), 7.92～7.98(4H, m, Ph-H), 7.88～7.85(4H, m, Ph-H), 7.56～7.51(6H, m, Ph-H), 4.14(s, 4H, -CH ₂ -) , 2.02 (m, 1H, -N-CH(CH ₂ ) ₂ ), 0.50-0.40 (m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 136.61 , 133.76, 133.26, 133.14, 132.93, 130.58, 128.58, 128.23, 127.72, 127.50, 127.13, 126.58, 55.19, 37.91, 6.85

Embodiment twelve, when the aromatic aldehyde is 4-methylbenzaldehyde, 3,5-(E)-bis(4-methylbenzylidene)-N-cyclopropylpiperidin-4-ketone ( Compound 12), light yellow powder, yield 88%, mp 196～199°C, ESI-MS: 344.3 (M+1); ¹ H-NMR (400MHz, CDCl ₃ , ppm) δ: 7.76 (2H, s, -CH=), 7.33 (4H, d, Ph-H, J=8Hz), 7.24 (4H, d, Ph-H, J=8Hz), 3.99 (s, 4H, -CH ₂ -), 2.40 (s , 6H, Ph-CH ₃ ) 1.95 (m, 1H, -N-CH(CH ₂ ) ₂ ), 0.45-0.35 (m, 4H, -CH(CH ₂ ) ₂ ). ¹³ C-NMR (100MHz, CDCl ₃ , ppm) δ: 187.49, 139.27, 136.22, 132.78, 132.62, 130.60, 129.36, 55.22, 38.01, 21.45, 6.78

Embodiment Thirteen

Detection of anti-tumor activity in vitro:

The tumor cell lines used are: human chronic myelogenous leukemia blast cell K562, human myeloid leukemia cell HL60, human colon cancer cell SW480, and human colon cancer cell SW1116. The above cells are all from the Shanghai Cell Bank of the Chinese Academy of Sciences. the

The cells were cultured in RPMI1640 supplemented with 10% calf serum at 37°C in a 5% CO ₂ incubator, and the cells in the logarithmic growth phase were used for experiments.

A certain number of cells in the logarithmic growth phase were inoculated in a 96-well plate at a certain density (after the adherent cells were adhered to the wall). The experimental group was added with different concentrations of the test drug, and the control group was added with the same concentration of solvent. For the blank group (medium only, no cells), set three parallel wells for each group, culture at 37°C for 48h, add 5mg/ml MTT solution 20ul/well, continue to culture for 4h, centrifuge to discard the supernatant, add DMSO 150ul, Shake for 10 min, and after fully lysing, use an automatic microplate reader (produced by BIO-RAD, USA) to detect the absorbance at 570 nm (OD570). The cell growth inhibition rate was calculated according to the absorbance. Cell growth inhibition rate=[OD control-OD experiment]/[OD control-OD blank]×100%. the

The dose-response curve can be obtained by plotting the inhibitory rate of tumor cell growth at different concentrations of the same drug, and the concentration at which the drug inhibits cell growth by 50%, that is, the half inhibitory concentration IC ₅₀ , is calculated according to the linear regression equation. The results are shown in Table 1. Compound numbers 1-12 in Table 1 represent the compounds synthesized in Examples 1-12, and EF-24 was used as a control. It can be seen from Table 1 that compound 2 has stronger inhibitory activity on HL60 cells than EF-24, compound 7 has stronger inhibitory activity on K562 cells than EF-24, compound 3 and compound 9 have stronger inhibitory activity on SW1116 cells than EF-24, indicating that 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds can significantly inhibit the proliferation of various human tumor cells. The scope of protection of the present invention is not limited to the embodiments described above.

Table 13, IC ₅₀ (μmol·L ^-1 ) of 5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds on tumor cells cultured in vitro

Compound No. K562 HL60 SW480 SW1116 1 12.5 33.6 134 49.5 2 4.22 5.13 25.8 17.25 3 8.90 the the 2.60 4 18.6 19.7 32.3 14.9 5 17.8 44.0 49.1 35.6 6 24.0 the the 38.6 7 0.559 the the 74.0 8 6.86 the the 14.1 9 14.2 the the 10.4 10 37.2 the the 61.0 11 412 the the 89.6 12 417 the the 37.9 EF-24 1.58 11.2 10.0 11.7

＊The blank is the cell line that the compound has not been used for

Example 14 Effect of compound 2 on the growth of mouse H22 ascites type liver cancer cells

Tumor cells were inoculated according to conventional methods: take the milky white ascites that had grown well after 6-8 days in the peritoneal cavity, diluted it with normal saline to 1×10 ⁷ cells/mL, and inoculated 0.2 mL under the skin of the right axilla of the mice. After the inoculation, the animals were randomly divided into groups. The experiment was divided into two groups, 10 rats in each group, the negative control group (administered with the same amount of solvent), and the compound 2100 mg/kg group (compound 2 was prepared as a solid dispersion with poloxamer). 24 hours after inoculation, intragastric administration was performed once a day for 7 consecutive days. On the 8th day, the body weight was weighed, and the animals were sacrificed by cervical dislocation. The tumor tissue was stripped off, blotted dry with filter paper and weighed. Tumor inhibition rate was calculated.

Tumor inhibition rate = (1-experimental group tumor weight/negative control group tumor weight) × 100%

Compound 2 has a significant inhibitory effect on H22 ascites-type subcutaneous transplanted tumors in mice, and the inhibition rate of 100 mg/kg/d intragastric administration is 48.4%, and the difference is significant (P<0.01) (results are shown in Table 2 and Figure 1). the

Table 2 Inhibitory effect of compound 2 on mouse H22 ascites liver cancer xenografts

**: p<0.01, *: p<0.05 vs control.t test

Claims (8)

1. The compound of following general formula (I):

in:

At least one of the substituents R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ on the phenyl in the above formula is a non-hydrogen substituent; each of the non-hydrogen substituents is independently selected from methoxy, Alkyl of 1-4 carbons, fluorine, chlorine, bromine substituent, trifluoromethyl. 2. The compound according to claim 1, characterized in that the substituent on the phenyl group is 2-methoxy; 2,5-dimethoxy; 3,4-dimethoxy; 2,4,5 - Trimethoxy; 2-fluoro; 2-chloro; 2-bromo; 4-methyl; 2-trifluoromethyl. 3. The following compounds:

4. A pharmaceutical composition for treating anti-tumor, which contains a therapeutically effective amount of the compound according to any one of claims 1-3 and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition for the treatment of leukemia, colon cancer, skin cancer, gastric cancer, liver cancer, breast cancer or prostate cancer, which contains a therapeutically effective amount of any one of the compounds in claims 1 to 3 and a pharmaceutically acceptable carrier. 6. The application of the pharmaceutical composition according to claim 4 in the preparation of medicines for treating leukemia, colon cancer, skin cancer, stomach cancer, liver cancer, breast cancer or prostate cancer. 7. Use of the compound according to any one of claims 1 to 3 in the preparation of antitumor drugs. 8. The use according to claim 7, characterized in that the tumor is leukemia, colon cancer, skin cancer, stomach cancer, liver cancer, breast cancer or prostate cancer.

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