An anti-tumor compound, an anti-tumor drug, a preparation method and an application thereof

Abstract

The present invention provides an anti-tumor compound, an anti-tumor drug, a preparation method and an application thereof, belonging to the technical field of pharmaceutical preparation. The general structural formula of the compound provided by the present invention is #imgabs0#. In vitro anti-tumor activity tests of this type of compound found that it has an obvious inhibitory effect on the growth of human prostate cancer cell PC3. Among them, compound D17 has significant anti-tumor activity against five human prostate cancer cells (PC3, DU145, C42B, LNCAP, 22RV1) and shows concentration dependence, and can be used as a lead compound or a candidate compound for the development of anti-tumor drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and particularly relates to an anti-tumor compound, an anti-tumor drug, a preparation method and an application thereof. Background Art

[0002] At present, the treatment methods for tumors are still traditional surgical treatment, radiotherapy and drug treatment, but to a large extent, drug treatment is still the main method. Therefore, the research and development of novel anti-tumor drugs have important clinical significance for the treatment of malignant tumors. Summary of the Invention

[0003] In view of this, the purpose of the present invention is to provide an anti-tumor compound, an anti-tumor drug, a preparation method and an application thereof. The compound provided by the present invention has an obvious inhibitory effect on the growth of human prostate cancer cells.

[0004] To achieve the above purpose, the present invention provides the following technical solutions: An anti-tumor compound has the structure shown in Formula Ι:

[0005]

[0006] In the formula, is

[0007] selected from

[0008] Preferably, the compound is selected from the structures shown in D1-D21:

[0009]

[0010] The present invention also provides a preparation method of the compound according to the above technical solution, including the following steps:

[0011]

[0012] (1) Dissolve compound A and compound B in toluene, add benzoic acid and piperidine, and carry out a reflux reaction to prepare intermediate C.

[0013] In the present invention, after the reflux reaction is completed, the reaction solution is also subjected to extraction, drying with a desiccant, and concentration steps; the extraction is first carried out with water and then with saturated brine, and the number of extraction times is 3 times; the desiccant is any one or a mixture of two of anhydrous sodium sulfate, anhydrous magnesium sulfate, silica gel, and molecular sieve, and the drying time is 12 hours.

[0014] (2) Add intermediate C and aromatic aldehyde derivatives containing different aromatic rings into an organic solvent, and react at 40 - 120 °C for 6 - 12 h under alkaline conditions to obtain the target compound.

[0015] In the present invention, a purification step is further included, specifically: filter the reaction solution after the reaction by suction, concentrate it under reduced pressure to dryness, add ethyl acetate to dissolve it completely, extract the ethyl acetate organic layer with water three times, extract it with saturated brine three times, dry it with a desiccant for 12 hours, and elute it by column chromatography to obtain the target compound; the desiccant is any one or a mixture of two of anhydrous sodium sulfate, anhydrous magnesium sulfate, silica gel, and molecular sieve; the eluent is a mixture of ethyl acetate and petroleum ether; the volume ratio of ethyl acetate to petroleum ether is: ethyl acetate / petroleum ether = 10 / 1 - 13 / 1.

[0016] In some embodiments, the compound B is 4 - methoxypropiophenone or 4 - hydroxy - 3 - methoxypropiophenone.

[0017] In some embodiments, the aromatic aldehyde derivatives containing different aromatic rings are 4 - bromo - 2 - methylbenzaldehyde, 3 - fluoro - 4 - methoxybenzaldehyde, 4 - fluorobenzaldehyde, quinoline - 2 - carbaldehyde, 4 - methoxybenzaldehyde, 2 - fluorobenzaldehyde, 5 - bromo - 2 - pyridinecarbaldehyde, 6 - bromo - 3 - pyridinecarbaldehyde, thiophene - 2 - carbaldehyde, 3 - methyl - 2 - thiophenecarbaldehyde, 2 - formyl - 6 - methoxypyridine, 4 - bromobenzaldehyde, 2 - chlorobenzaldehyde, 5 - chlorothiophene - 2 - carbaldehyde, benzaldehyde or 3,5 - difluorobenzaldehyde.

[0018] In some embodiments, the reflux reaction temperature in step (1) is 110 °C and the reaction time is 8 h.

[0019] In some embodiments, the organic solvent in step (2) is selected from at least one of methanol, ethanol, n - propanol, isopropanol, n - butanol, dichloromethane, chloroform, toluene, 1,4 - dioxane, acetone, tetrahydrofuran, acetonitrile, and ethyl acetate.

[0020] In some embodiments, the pH of the alkaline condition in step (2) is 8 - 13. In the present invention, at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium phosphate dodecahydrate, sodium methoxide, sodium phosphate, potassium bicarbonate, potassium carbonate, potassium hydroxide, potassium phosphate, potassium tert - butoxide, potassium ethoxide, calcium hydroxide, pyridine, triethylamine, diethylamine, and ammonia monohydrate is used to adjust the pH.

[0021] The present invention also provides the application of the compound described in the above technical solution in the preparation of anti - tumor drugs, and the tumor is preferably prostate cancer.

[0022] The present invention also provides an anti-tumor drug, which comprises a compound having the structure described in the above technical solution and a pharmaceutically acceptable carrier or excipient.

[0023] Advantageous technical effects:

[0024] 1. In the in vitro anti-tumor activity test of the compound provided by the present invention, it is found that the compound with the above structure has an obvious inhibitory effect on the growth of human prostate cancer cell PC3. Among them, compound D17 has significant anti-tumor activity against five human prostate cancer cells (PC3, DU145, C42B, LNCAP, 22RV1) and shows concentration dependence, indicating that this kind of novel structure compound can be used as a lead compound or candidate compound for the development of anti-tumor drugs.

[0025] 2. The preparation method provided by the present invention is simple and has a high yield. The total yield of preparing target compounds D1 - D21 from intermediate C reaches more than 70%. Description of the drawings

[0026] Figure 1 It is the 1H-NMR spectrum of the compound (D1) obtained in Example 1;

[0027] Figure 2 It is the growth inhibition curve of compound (D17) against five tumor cells in a concentration-dependent manner. Detailed implementation manners

[0028] In order to better understand the present invention, the content of the present invention will be further clarified below in conjunction with examples. However, the content of the present invention is not limited only to the following examples.

[0029] It should be understood that the terms described in the present invention are only for describing particular embodiments and are not used to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the range.

[0030] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0031] Without departing from the scope or spirit of the present invention, various modifications and variations can be made to the specific embodiments of the description of the present invention, which are obvious to those skilled in the art. Other embodiments obtained from the description of the present invention are obvious to those skilled in the art. The description and examples of this application are merely exemplary.

[0032] Regarding the use of "comprising", "including", "having", "containing", etc. in this article, they are all open-ended terms, meaning including but not limited to.

[0033] The technical solutions described in the present invention, unless otherwise specified, are all conventional solutions in the art. The reagents or raw materials used, unless otherwise specified, are all purchased from commercial channels or are publicly available.

[0034] Example 1

[0035] Preparation of Compound (D1)

[0036] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. Water was added for extraction 3 times (20 ml each time), saturated brine was added for extraction 3 times (20 ml each time), dried over anhydrous sodium sulfate for 12 hours, filtered by suction, and the toluene organic layer was concentrated to prepare intermediate C;

[0037] 2) In ethanol (40 ml), intermediate C, 4-bromo-2-methylbenzaldehyde (8 mmol) and sodium bicarbonate (8 mmol) were added, and the reaction was carried out at 80 °C for 8 hours. Filtered by suction, concentrated under reduced pressure to dryness, dissolved completely in ethyl acetate (50 ml), the ethyl acetate organic layer was extracted with water three times (20 ml each time), extracted with saturated brine three times (20 ml each time), dried over anhydrous magnesium sulfate for 12 hours, and eluted by column chromatography to prepare compound D1. The eluent was selected as ethyl acetate: petroleum ether = 10:1, and the yield was 76.5%.

[0038] Example 2

[0039] Preparation of Compound (D2)

[0040] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. Water was added for extraction 3 times (20 ml each time), saturated brine was added for extraction 3 times (20 ml each time), dried over anhydrous sodium sulfate for 12 hours, filtered by suction, and the toluene organic layer was concentrated to prepare intermediate C;

[0041] 2) In methanol (40 ml), add intermediate C, 3-fluoro-4-methoxybenzaldehyde (8 mmol) and sodium hydroxide (8 mmol), and react at 65 °C for 10 hours. Filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with molecular sieve for 12 hours, and elute by column chromatography to prepare the novel structure compound D2. The eluent is selected as ethyl acetate: petroleum ether = 11:1, and the yield is 70.2%.

[0042] Example 3

[0043] Preparation of compound (D3)

[0044] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0045] 2) In acetonitrile (40 ml), add intermediate C, 4-fluorobenzaldehyde (8 mmol) and sodium methoxide (8 mmol), react at 85 °C for 7 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous magnesium sulfate for 12 hours, and elute by column chromatography to prepare the novel structure compound D3. The eluent is selected as ethyl acetate: petroleum ether = 10:1, and the yield is 82.5%.

[0046] Example 4

[0047] Preparation of compound (D4)

[0048] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0049] 2) In tetrahydrofuran (40 ml), intermediate C, quinoline-2-carbaldehyde (8 mmol), and potassium tert-butoxide (8 mmol) were added, and the reaction was carried out at 66 °C for 11 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and then extracted with saturated brine three times (20 ml each time). It was dried over anhydrous sodium sulfate for 12 hours, and compound D4 with a novel structure was prepared by column chromatography elution. The eluent was selected as ethyl acetate: petroleum ether = 12:1, and the yield was 80.7%.

[0050] Example 5

[0051] Preparation of Compound (D5)

[0052] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. It was extracted with water 3 times (20 ml each time), and then extracted with saturated brine 3 times (20 ml each time). It was dried over anhydrous sodium sulfate for 12 hours, and after suction filtration, the toluene organic layer was concentrated to prepare intermediate C;

[0053] 2) In 1,4-dioxane (40 ml), intermediate C, 4-methoxybenzaldehyde (8 mmol), and potassium hydroxide (8 mmol) were added, and the reaction was carried out at 100 °C for 6 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and then extracted with saturated brine three times (20 ml each time). It was dried over silica gel for 12 hours, and compound D5 with a novel structure was prepared by column chromatography elution. The eluent was selected as ethyl acetate: petroleum ether = 13:1, and the yield was 83.2%.

[0054] Example 6

[0055] Preparation of Compound (D6)

[0056] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. It was extracted with water 3 times (20 ml each time), and then extracted with saturated brine 3 times (20 ml each time). It was dried over anhydrous sodium sulfate for 12 hours, and after suction filtration, the toluene organic layer was concentrated to prepare intermediate C;

[0057] 2) In n-butanol (40 ml), add intermediate C, 2-fluorobenzaldehyde (8 mmol), and potassium bicarbonate (8 mmol), react at 120 °C for 6 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, and elute by column chromatography to prepare the novel structure compound D6. The eluent is selected as ethyl acetate: petroleum ether = 11:1, and the yield is 87.6%.

[0058] Example 7

[0059] Preparation of Compound (D7)

[0060] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-hydroxy-3-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0061] 2) In tetrahydrofuran (40 ml), add intermediate C, 4-bromo-2-methylbenzaldehyde (8 mmol), and potassium ethoxide (8 mmol), react at 70 °C for 10 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with silica gel for 12 hours, and elute by column chromatography to prepare the novel structure compound D7. The eluent is selected as ethyl acetate: petroleum ether = 10:1, and the yield is 73.0%.

[0062] Example 8

[0063] Preparation of Compound (D8)

[0064] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0065] 2) In n-propanol (40 ml), add intermediate C, 5-bromo-2-pyridinecarboxaldehyde (8 mmol) and calcium hydroxide (4 mmol), react at 100 °C for 6 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous magnesium sulfate for 12 hours, and elute by column chromatography to prepare novel-structured compound D8. The eluent is selected as ethyl acetate: petroleum ether = 10:1, and the yield is 76.6%.

[0066] Example 9

[0067] Preparation of compound (D9)

[0068] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0069] 2) In toluene (40 ml), add intermediate C, 6-bromo-3-pyridinecarboxaldehyde (8 mmol) and pyridine (8 mmol), react at 110 °C for 6 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, and elute by column chromatography to prepare novel-structured compound D9. The eluent is selected as ethyl acetate: petroleum ether = 10:1, and the yield is 81.6%.

[0070] Example 10

[0071] Preparation of compound (D10)

[0072] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0073] 2) In acetonitrile (40 ml), intermediate C, thiophene-2-carboxaldehyde (8 mmol), and sodium phosphate dodecahydrate (8 mmol) were added, and the reaction was carried out at 85 °C for 8 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and extracted with saturated brine three times (20 ml each time). It was dried with molecular sieve for 12 hours, and compound D10 with a novel structure was prepared by column chromatography elution. The eluent was selected as ethyl acetate: petroleum ether = 12:1, and the yield was 79.3%.

[0074] Example 11

[0075] Preparation of compound (D11)

[0076] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. It was extracted with water 3 times (20 ml each time), extracted with saturated brine 3 times (20 ml each time), dried with anhydrous sodium sulfate for 12 hours, filtered by suction, and the toluene organic layer was concentrated to prepare intermediate C;

[0077] 2) In toluene (40 ml), intermediate C, 3-methyl-2-thiophenecarboxaldehyde (8 mmol), and potassium hydroxide (8 mmol) were added, and the reaction was carried out at 110 °C for 6 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and extracted with saturated brine three times (20 ml each time). It was dried with anhydrous sodium sulfate for 12 hours, and compound D11 with a novel structure was prepared by column chromatography elution. The eluent was selected as ethyl acetate: petroleum ether = 13:1, and the yield was 83.6%.

[0078] Example 12

[0079] Preparation of compound (D12)

[0080] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. It was extracted with water 3 times (20 ml each time), extracted with saturated brine 3 times (20 ml each time), dried with anhydrous sodium sulfate for 12 hours, filtered by suction, and the toluene organic layer was concentrated to prepare intermediate C;

[0081] 2) In isopropanol (40 ml), add intermediate C, 2-formyl-6-methoxypyridine (8 mmol) and sodium hydroxide (8 mmol), react at 85 °C for 8 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely. Extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous magnesium sulfate for 12 hours, and elute by column chromatography to prepare a compound D12 with a novel structure. The eluent is selected as ethyl acetate: petroleum ether = 11:1, and the yield is 78.2%.

[0082] Example 13

[0083] Preparation of compound (D13)

[0084] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0085] 2) In ethyl acetate (40 ml), add intermediate C, 4-bromobenzaldehyde (8 mmol) and triethylamine (5 mmol), react at 80 °C for 9 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely. Extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with molecular sieve for 12 hours, and elute by column chromatography to prepare a compound D13 with a novel structure. The eluent is selected as ethyl acetate: petroleum ether = 10:1, and the yield is 70.8%.

[0086] Example 14

[0087] Preparation of compound (D14)

[0088] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0089] 2) In acetonitrile (40 ml), add intermediate C, 2-chlorobenzaldehyde (8 mmol) and calcium hydroxide (4 mmol), and react at 85 °C for 7 hours. Filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely. The ethyl acetate organic layer is extracted with water three times (20 ml each time), and extracted with saturated brine three times (20 ml each time), dried with anhydrous magnesium sulfate for 12 hours, and eluted by column chromatography to prepare compound D14 with a novel structure. The eluent is selected as ethyl acetate: petroleum ether = 11:1, and the yield is 87.9%.

[0090] Example 15

[0091] Preparation of compound (D15)

[0092] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0093] 2) In toluene (40 ml), add intermediate C, 5-chlorothiophene-2-carboxaldehyde (8 mmol) and sodium hydroxide (8 mmol), react at 110 °C for 6 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely. The ethyl acetate organic layer is extracted with water three times (20 ml each time), and extracted with saturated brine three times (20 ml each time), dried with anhydrous sodium sulfate for 12 hours, and eluted by column chromatography to prepare compound D15 with a novel structure. The eluent is selected as ethyl acetate: petroleum ether = 10:1, and the yield is 75.0%.

[0094] Example 16

[0095] Preparation of compound (D16)

[0096] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux and react at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0097] 2) In acetonitrile (40 ml), intermediate C, benzaldehyde (8 mmol), and sodium methoxide (8 mmol) were added. The reaction was carried out at 85 °C for 9 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and then extracted with saturated brine three times (20 ml each time). It was dried over anhydrous sodium sulfate for 12 hours, and then eluted by column chromatography to prepare the compound D16 with a novel structure. The eluent was selected as ethyl acetate: petroleum ether = 13:1, and the yield was 90.7%.

[0098] Example 17

[0099] Preparation of Compound (D17)

[0100] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml). Benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added. The reaction was refluxed at 110 °C for 8 hours. It was extracted with water 3 times (20 ml each time), and then extracted with saturated brine 3 times (20 ml each time). It was dried over anhydrous sodium sulfate for 12 hours, and then suction filtered. The toluene organic layer was concentrated to prepare intermediate C;

[0101] 2) In toluene (40 ml), intermediate C, 3,5-difluorobenzaldehyde (8 mmol), and potassium bicarbonate (8 mmol) were added. The reaction was carried out at 110 °C for 6 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and then extracted with saturated brine three times (20 ml each time). It was dried over molecular sieve for 12 hours, and then eluted by column chromatography to prepare the compound D17 with a novel structure. The eluent was selected as ethyl acetate: petroleum ether = 10:1, and the yield was 72.3%.

[0102] Example 18

[0103] Preparation of Compound (D18)

[0104] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-hydroxy-3-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml). Benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added. The reaction was refluxed at 110 °C for 8 hours. It was extracted with water 3 times (20 ml each time), and then extracted with saturated brine 3 times (20 ml each time). It was dried over anhydrous sodium sulfate for 12 hours, and then suction filtered. The toluene organic layer was concentrated to prepare intermediate C;

[0105] 2) In n-butanol (40 ml), add intermediate C, 3-fluoro-4-methoxybenzaldehyde (8 mmol) and sodium bicarbonate (8 mmol), react at 120 °C for 6 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous magnesium sulfate for 12 hours, and elute by column chromatography to prepare the novel structure compound D18. The eluent is selected as ethyl acetate: petroleum ether = 11:1, and the yield is 80.6%.

[0106] Example 19

[0107] Preparation of compound (D19)

[0108] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-hydroxy-3-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0109] 2) In dichloromethane (40 ml), add intermediate C, 3-methyl-2-thiophenecarboxaldehyde (8 mmol) and potassium ethoxide (8 mmol), react at 40 °C for 12 hours, filter by suction, concentrate under reduced pressure to dryness, add ethyl acetate (50 ml) to dissolve completely, extract the ethyl acetate organic layer with water three times (20 ml each time), extract with saturated brine three times (20 ml each time), dry with anhydrous magnesium sulfate for 12 hours, and elute by column chromatography to prepare the novel structure compound D19. The eluent is selected as ethyl acetate: petroleum ether = 12:1, and the yield is 85.7%.

[0110] Example 20

[0111] Preparation of compound (D20)

[0112] 1) Dissolve 3,4,5-trimethoxybenzaldehyde (8 mmol) and 4-hydroxy-3-methoxypropiophenone (8 mmol) in toluene (40 ml), add benzoic acid (1.6 mmol) and piperidine (2.4 mmol), reflux at 110 °C for 8 hours, extract with water 3 times (20 ml each time), extract with saturated brine 3 times (20 ml each time), dry with anhydrous sodium sulfate for 12 hours, filter by suction, and concentrate the toluene organic layer to prepare intermediate C;

[0113] 2) In acetonitrile (40 ml), intermediate C, 4-bromobenzaldehyde (8 mmol), and potassium tert-butoxide (8 mmol) were added, and the reaction was carried out at 85 °C for 7 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and then extracted with saturated brine three times (20 ml each time), and dried over anhydrous sodium sulfate for 12 hours. Column chromatography was used for elution to prepare the novel-structured compound D20. The eluent was selected as ethyl acetate: petroleum ether = 10:1, and the yield was 72.7%.

[0114] Example 21

[0115] Preparation of Compound (D21)

[0116] 1) 3,4,5-Trimethoxybenzaldehyde (8 mmol) and 4-hydroxy-3-methoxypropiophenone (8 mmol) were dissolved in toluene (40 ml), benzoic acid (1.6 mmol) and piperidine (2.4 mmol) were added, and the reaction was refluxed at 110 °C for 8 hours. After extraction with water 3 times (20 ml each time), and then extracted with saturated brine 3 times (20 ml each time), and dried over anhydrous sodium sulfate for 12 hours. After suction filtration, the toluene organic layer was concentrated to prepare intermediate C;

[0117] 2) In 1,4-dioxane (40 ml), intermediate C, 4-fluorobenzaldehyde (8 mmol), and sodium hydroxide (8 mmol) were added, and the reaction was carried out at 100 °C for 6 hours. After suction filtration, it was concentrated under reduced pressure to dryness. Ethyl acetate (50 ml) was added to dissolve it completely. The ethyl acetate organic layer was extracted with water three times (20 ml each time), and then extracted with saturated brine three times (20 ml each time), and dried over anhydrous sodium sulfate for 12 hours. Column chromatography was used for elution to prepare the novel-structured compound D21. The eluent was selected as ethyl acetate: petroleum ether = 12:1, and the yield was 86.6%.

[0118] Antitumor Activity Assay of Test Compounds

[0119] Weighed 2 mg of the compound sample and placed it in an EP tube, and then prepared a 10 mM solution with biograde dimethyl sulfoxide and stored it at 4 °C. Logarithmic growth phase human prostate cancer cells PC3 were inoculated into a 96-well plate. After culturing for 24 h, the culture medium was discarded. The compound was diluted with the culture medium to different concentrations and added to the 96-well plate. After the drug acted for 48 h, 20 μL of MTT was added to each well, and after continuing to culture for 4 h, the liquid was aspirated, 100 μL of biograde dimethyl sulfoxide was added, and it was shaken evenly. The absorbance value was detected at 490 nm by an enzyme-linked immunosorbent assay (ELISA) reader, and the half-inhibitory concentration of the compound against tumor cells was calculated. The antitumor drug 5-fluorouracil (5-Fu) was used as a reference substance, and the experimental results are shown in Table 1.

[0120] Table 1 Antitumor Activity of Compounds

[0121] Compound <![CDATA[PC3(IC 50 , μM)]]> D1 8.34 D2 7.78 D3 5.27 D4 1.18 D6 7.94 D7 3.92 D8 1.53 D9 1.62 D12 2.88 D13 3.70 D15 6.17 D16 5.41 D17 1.09 5-Fu 15.62

[0122] As can be seen from Table 1, compounds D1, D2, D3, D4, D6, D7, D8, D9, D12, D13, D15, D16, D17 have obvious anti-tumor growth inhibitory effects on human prostate cancer cell line PC3. The anti-PC3 cell activities of these compounds are significantly superior to the control drug 5-fluorouracil, indicating that these compounds can be used as candidate or lead compounds for further development and applied to the preparation of anti-tumor drugs. Among them, compounds D10, D11 and D18-D21 have obvious inhibitory effects on the growth of human prostate cancer cell line PC3, but their activities are weaker than 5-fluorouracil, so they are no longer listed in Table 1.

[0123] Among them, compound D17 has significant anti-tumor growth inhibitory effects on human prostate cancer cell line PC3, and its anti-tumor activity is further evaluated. Weigh compound D17 and place it in an EP tube, then prepare a 10 mM solution with biological-grade dimethyl sulfoxide and store it at 4 °C. Five human prostate cancer cell lines (PC3, DU145, C42B, LNCAP, 22RV1) in the logarithmic growth phase are inoculated into 96-well plates. After culturing for 24 h, the culture medium is discarded, and compound D17 is diluted with the culture medium to different concentrations and added to the 96-well plates. After the drug acts for 48 h, 20 μL of MTT is added to each well. After continuing to culture for 4 h, the liquid is aspirated, 100 μL of biological-grade dimethyl sulfoxide is added, and it is shaken evenly. The absorbance value is detected at 490 nm by an enzyme-linked immunosorbent assay (ELISA) reader, and the survival rates of the five tumor cells under the intervention of compound D17 are calculated. A growth inhibition curve of compound D17 against the five tumor cells is plotted, and the results are shown in Figure 2 . The experimental results show that compound D17 inhibits the growth of the five tumor cells in a concentration-dependent manner.

[0124] The above is only the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. An anti-tumor compound having the structure shown in Formula Ι: In the formula, is Selected from 2. The compound according to claim 1, characterized in that, The compound is selected from the structures shown in D1 - D21:

3. A process for preparing the compound according to claim 1 or 2, characterized in that, Comprising the following steps: (1) Dissolve compound A and compound B in toluene, add benzoic acid and piperidine, and carry out a reflux reaction to prepare intermediate C; (2) Add intermediate C and aromatic aldehyde derivatives containing different aromatic rings in an organic solvent, and react at 40 - 120 °C for 6 - 12 h under alkaline conditions to obtain the target compound; The structural formulas of compound A, compound B, and intermediate C are shown as follows: Compound B is 4 - methoxypropiophenone or 4 - hydroxy - 3 - methoxypropiophenone; The aromatic aldehyde derivatives containing different aromatic rings are 4 - bromo - 2 - methylbenzaldehyde, 3 - fluoro - 4 - methoxybenzaldehyde, 4 - fluorobenzaldehyde, quinoline - 2 - carbaldehyde, 4 - methoxybenzaldehyde, 2 - fluorobenzaldehyde, 5 - bromopyridine - 2 - carbaldehyde, 6 - bromopyridine - 3 - carbaldehyde, thiophene - 2 - carbaldehyde, 3 - methylthiophene - 2 - carbaldehyde, 2 - formyl - 6 - methoxypyridine, 4 - bromobenzaldehyde, 2 - chlorobenzaldehyde, 5 - chlorothiophene - 2 - carbaldehyde, benzaldehyde, or 3,5 - difluorobenzaldehyde.

4. The preparation method according to claim 3, characterized in that, The reflux reaction temperature in step (1) is 110 °C, and the reaction time is 8 h.

5. The preparation method according to claim 3, characterized in that, The organic solvent in step (2) is selected from at least one of methanol, ethanol, n - propanol, isopropanol, n - butanol, dichloromethane, chloroform, toluene, 1,4 - dioxane, acetone, tetrahydrofuran, acetonitrile, and ethyl acetate.

6. The preparation method according to claim 3, characterized in that, The pH of the alkaline condition in step (2) is 8 - 13.

7. Use of the compound according to claim 1 or 2 in the preparation of a medicament for treating anti - tumor, wherein the tumor is prostate cancer.

8. An anti-tumor drug, characterized in that, A compound comprising the structure according to claim 1 or 2 and a pharmaceutically acceptable carrier or excipient.

Images