Aryl compound, preparation method thereof and application of aryl compound in preparation of anti-inflammatory and anti-tumor drugs

Abstract

The invention belongs to the technical field of medicines and synthesis, and particularly relates to an aryl compound, a preparation method thereof and application of the aryl compound in preparation of anti-inflammatory and anti-tumor medicines. A natural anti-inflammatory active compound containing phenylboronic acid is connected through a covalent bond to construct a new compound with anti-inflammatory and anti-tumor curative effects, the new compound can be used as a medicine for treating liver cancer, and the anti-cancer curative effect of an inflammation regulator is improved through the addition effect of the inflammation regulator and an organic boric acid compound with tumor activity. The preparation method provided by the invention has the advantages of simple steps, convenience in operation, good feasibility, large-scale industrial application potential and wide market prospect. The invention also provides an application of the aryl compound provided by the scheme or the aryl compound obtained by the preparation method provided by the scheme in preparation of anti-inflammatory and anti-tumor drugs. The aryl compound provided by the invention has a good anti-cancer curative effect, can be used for preparing anti-inflammatory and anti-tumor drugs, and has good social benefits.

Description

Technical Field

[0001] The invention belongs to the field of medicine and synthesis technology, and specifically relates to an aromatic compound and a preparation method thereof and application in the preparation of anti-inflammatory and anti-tumor drugs. Background Art

[0002] Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world, with high morbidity and mortality. In the past decade, some molecular targeted drugs have been approved by the FDA for the treatment of advanced HCC patients (such as kinase inhibitor sorafenib, angiogenesis inhibitor monoclonal antibody drugs). Although these drugs have been shown to be effective as adjuvant therapy, their efficacy is not great. For some patients, they can only extend survival by a few months. Therefore, there is an increasing need for the development of low-toxic and high-efficiency drugs for the treatment of liver cancer.

[0003] Natural compounds derived from plants are consistently considered to be a reliable and consistent source for anti-cancer lead drug research. Natural products are generally safer. Cinnamic acid (CA) and its derivative ferulic acid (FA) are biologically active chemicals. They are a phenolic acid commonly found in plants and have been shown to have anti-inflammatory and antibacterial activities. Indole-3-acetic acid, also known as indoleacetic acid (IA), is a plant growth hormone. A study reported the effect of oral IA in a diet-induced non-alcoholic fatty liver disease (NAFLD) mouse model. The results showed that IA was significantly effective in reducing fatty degeneration and inflammation. IA may become a safe treatment option for NAFLD.

[0004] Innate immunity and adaptive immunity in inflammatory response play an important role in tumor occurrence, progression and metastasis. Therefore, the inflammatory response induced by treatment also affects the clinical treatment effect of tumors to varying degrees. However, it is clear that common anti-inflammatory drugs have limited efficacy in treating tumors and cannot completely inhibit tumor development and elimination. Summary of the invention

[0005] The purpose of the present invention is to provide an aromatic compound and a preparation method thereof and application in the preparation of anti-inflammatory and anti-tumor drugs. The aromatic compound provided by the present invention has good anti-inflammatory and anti-tumor efficacy.

[0006] In order to achieve the above object, the present invention provides the following technical solutions: The present invention provides an aromatic compound, the structure of which is shown in Formula CA-1, Formula FA-1 or Formula IA-1: ; In formula CA-1, formula FA-1 or formula IA-1, R is a group of formula a, a group of formula b or a group of formula c (the five-pointed star is the attachment site); .

[0007] Preferably, the aromatic compound comprises one of the compounds of formula CA-1a, CA-1b, CA-1c, FA-1a, FA-1b, FA-1c, IA-1a, IA-1b and IA-1c; .

[0008] The present invention also provides a method for preparing the aromatic compound described in the above scheme, comprising the following steps: The raw material drug, 1-hydroxybenzotriazole, carbodiimide and a poor solvent are mixed for esterification reaction to obtain a solution A containing an intermediate compound, the structure of the intermediate compound is shown in Formula Z: ; The solution A and the solution B are mixed to perform an amidation reaction to obtain the aromatic compound; the solution B comprises a base catalyst, a benzene derivative and a good solvent; the benzene derivative is m-aminophenylboronic acid, m-aminobenzyl alcohol, m-aminobenzoic acid methyl ester, aniline or benzylamine; The bulk drug includes a compound of formula CA, a compound of formula FA or a compound of formula IA; .

[0009] Preferably, the mass ratio of the bulk drug to 1-hydroxybenzotriazole is 200-1000: 180-1200.

[0010] Preferably, the mass ratio of the bulk drug to carbodiimide is 200-1000:210-1400.

[0011] Preferably, the mass volume ratio of the API to the poor solvent is (200-1000) mg:(4-20) mL.

[0012] Preferably, the concentration of the benzene derivative in the solution B is 9.5-465 mg / mL.

[0013] Preferably, the mass ratio of the bulk drug to the benzene derivative in solution B is 50-2000:60-2400.

[0014] Preferably, the reaction time of the amidation reaction is 20 to 36 h; and the amidation reaction is carried out under stirring conditions.

[0015] The present invention also provides the use of the aromatic compound described in the above scheme or the aromatic compound obtained by the preparation method described in the above scheme in the preparation of anti-inflammatory and anti-tumor drugs.

[0016] The present invention provides an aromatic compound. The present invention connects a natural anti-inflammatory active compound containing phenylboronic acid by covalent bonds to construct a new compound with anti-inflammatory and anti-tumor efficacy, which can be used as a drug for liver cancer treatment. The inflammation regulator improves the anti-cancer efficacy through the additive effect with the organic boronic acid compound with tumor activity.

[0017] The present invention also provides a method for preparing the aromatic compound of the above scheme. The preparation method provided by the present invention has simple steps, convenient operation, good feasibility, potential for large-scale industrial application, and broad market prospects.

[0018] The present invention also provides the use of the aryl compound described in the above scheme or the aryl compound obtained by the preparation method described in the above scheme in the preparation of anti-inflammatory and anti-tumor drugs. The aryl compound provided by the present invention has good anti-cancer efficacy, can be used to prepare anti-inflammatory and anti-tumor drugs, and has good social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0020] Figure 1 The compound of formula CA-1a prepared in Example 1 of the present invention 1 H NMR spectrum; Figure 2 The compound of formula CA-1b prepared in Example 2 of the present invention 1 H NMR spectrum; Figure 3 The compound of formula CA-1c prepared in Example 3 of the present invention 1 H NMR spectrum; Figure 4 The compound of formula FA-1a prepared in Example 4 of the present invention 1 H NMR spectrum; Figure 5 The compound of formula FA-1b prepared in Example 5 of the present invention 1 H NMR spectrum; Figure 6 The compound of formula FA-1c prepared in Example 6 of the present invention 1 H NMR spectrum; Figure 7 The compound of formula IA-1a prepared in Example 7 of the present invention 1 H NMR spectrum; Figure 8 The compound of formula IA-1b prepared in Example 8 of the present invention 1 H NMR spectrum; Fig. 9 The compound of formula IA-1c prepared in Example 9 of the present invention 1 H NMR spectrum; Fig.10 The MS spectrum of the compound of formula CA-1a prepared in Example 1 of the present invention; Fig.11 The MS spectrum of the compound of formula CA-1b prepared in Example 2 of the present invention; Fig.12 The MS spectrum of the compound of formula CA-1c prepared in Example 3 of the present invention; Fig.13 The MS spectrum of the compound of formula FA-1a prepared in Example 4 of the present invention; Fig.14 The MS spectrum of the compound of formula FA-1b prepared in Example 5 of the present invention; Fig.15 The MS spectrum of the compound of formula FA-1c prepared in Example 6 of the present invention; Fig.16 The MS spectrum of the compound of formula IA-1a prepared in Example 7 of the present invention; Fig.17 The MS spectrum of the compound of formula IA-1b prepared in Example 8 of the present invention; Fig.18 The MS spectrum of the compound of formula IA-1c prepared in Example 9 of the present invention; Fig.19 Determination of the antitumor activity of cinnamic acid and the compounds prepared in Examples 1 to 3; Fig. 20 Determination of the antitumor activity of ferulic acid and the compounds prepared in Examples 4 to 6; Fig.21 The antitumor activity of indole-3-acetic acid and the compounds prepared in Examples 7 to 9 was determined. DETAILED DESCRIPTION

[0021] The present invention provides an aromatic compound, the structure of which is shown in Formula CA-1, Formula FA-1 or Formula IA-1: ; In formula CA-1, formula FA-1 or formula IA-1, R is a group of formula a, a group of formula b or a group of formula c (the five-pointed star is the attachment site); .

[0022] In the present invention, the aromatic compound preferably includes one of the compounds of formula CA-1a, CA-1b, CA-1c, FA-1a, FA-1b, FA-1c, IA-1a, IA-1b and IA-1c; .

[0023] The present invention also provides a method for preparing the aromatic compound described in the above scheme, comprising the following steps: The raw material drug, 1-hydroxybenzotriazole, carbodiimide and a poor solvent are mixed for esterification reaction to obtain a solution A containing an intermediate compound, the structure of the intermediate compound is shown in Formula Z: ; The solution A and the solution B are mixed to carry out an amidation reaction to obtain the aromatic compound; the solution B comprises a base catalyst, a benzene derivative and a good solvent; the benzene derivative is m-aminophenylboronic acid, m-aminobenzyl alcohol, m-aminobenzoic acid methyl ester, aniline or benzylamine.

[0024] In the present invention, a raw material drug, 1-hydroxybenzotriazole (HOBT), carbodiimide and a poor solvent are mixed (referred to as mixed A) for esterification reaction to obtain a solution A containing an intermediate compound.

[0025] In the present invention, the drug substance preferably includes a compound of formula CA, a compound of formula FA or a compound of formula IA; .

[0026] In the present invention, the mass ratio of the bulk drug to 1-hydroxybenzotriazole is preferably 200-1000: 180-1200, more preferably 300-900: 180.2-1181.2, further preferably 400-700: 199.8-998.9, and further preferably 500-600: 236.2-901.2. The present invention improves the reaction rate of the intermediate after DCC activation by 1-hydroxybenzotriazole.

[0027] In the present invention, the mass ratio of the bulk drug to the carbodiimide is preferably 200-1000:210-1400, more preferably 200-1000:212.2-1390.4, further preferably 200-1000:235.2-1175.95, and further preferably 200-1000:278.1-1060.8. The present invention activates the carboxyl group by carbodiimide, increases the O-terminal leaving property, makes the urea derivative leave more easily, and thus promotes the formation of amide bonds or ester bonds.

[0028] In the present invention, the poor solvent preferably includes one or more of tetrahydrofuran and N,N-dimethylformamide.

[0029] In the present invention, the mass volume ratio of the drug substance to the poor solvent is preferably (200-1000) mg: (4-20) mL, more preferably (400-800) mg: (8-15) mL, and further preferably (500-700) mg: (10-12) mL.

[0030] In the present invention, the mixing A is preferably: adding the raw material drug to tetrahydrofuran and mixing (referred to as the first mixing) to obtain a premixed solution, then adding 1-hydroxybenzotriazole to the premixed solution and mixing (referred to as the second mixing) to obtain a mixed solution, and then adding carbodiimide to the mixed solution while stirring at 500-700 rpm and mixing (referred to as the third mixing).

[0031] In the present invention, the first mixing is preferably stirring mixing; the rotation speed of the stirring mixing is preferably 500-700 rpm, more preferably 550-650 rpm, further preferably 600 rpm, and the mixing time is preferably 20-60 s, more preferably 30-50 s, further preferably 40 s.

[0032] In the present invention, the second mixing is preferably carried out in an ice bath; the second mixing is preferably stirring mixing; the stirring mixing speed is preferably 500-700 rpm, more preferably 550-650 rpm, and further preferably 600 rpm, until 1-hydroxybenzotriazole is dissolved.

[0033] In the present invention, the third mixing is preferably carried out in an ice bath; the third mixing is preferably stirring mixing; the rotation speed of the stirring mixing is preferably 500-700 rpm, more preferably 550-650 rpm, further preferably 600 rpm, and the mixing time is preferably 20-60 min, more preferably 25-45 min, further preferably 30 min.

[0034] In the present invention, the esterification reaction is preferably carried out in an ice bath, and the reaction time is preferably within 30 min, more preferably 20 to 30 min.

[0035] In the present invention, in solution B, the base catalyst is preferably nitrogen-methylmorpholine.

[0036] In the present invention, in solution B, the good solvent preferably includes one or more of dioxane, tetrahydrofuran and N,N-dimethylformamide.

[0037] In the present invention, the concentration of the benzene derivative in the solution B is preferably 9.5-465 mg / mL, more preferably 15-400 mg / mL, further preferably 50-300 mg / mL, and further preferably 150-200 mg / mL.

[0038] In the present invention, the preparation method of the solution B is preferably: mixing a base catalyst and a good solvent to obtain a premixed solution, and then adding a benzene derivative to the premixed solution for mixing (referred to as mixed B). The present invention uses a base catalyst to provide an alkaline environment, activates the amino group in the benzene derivative, interacts with the substrate through proton transfer, is conducive to the formation of an amide bond, accelerates the rate of the chemical reaction, and thus improves the efficiency of the condensation reaction.

[0039] In the present invention, the mixture B is preferably stirred and mixed; the rotation speed of the stirring and mixing is preferably 500-700 rpm, more preferably 550-650 rpm, the mixing time is preferably 10-60 min, more preferably 30 min; the temperature of the mixture B is preferably room temperature.

[0040] After obtaining solution A, the present invention mixes the solution A and solution B to perform an amidation reaction to obtain the aryl compound. In the present invention, the mass ratio of the bulk drug to the benzene derivative in solution B is preferably 50-2000:60-2400, more preferably 100-1500:120-1800, and further preferably 200-1000:240-1200.

[0041] In the present invention, the temperature of the amidation reaction is preferably room temperature, the reaction time is preferably 20 to 36 h, more preferably 24 to 32 h, and further preferably 27 to 30 h; the amidation reaction is preferably carried out under stirring conditions; the stirring speed is preferably 500 to 700 rpm, more preferably 550 to 650 rpm, and further preferably 600 rpm. In the present invention, whether the reaction is complete is detected by TLC (ethyl acetate: petroleum ether = 1:1 to 2).

[0042] In the present invention, after the amidation reaction, the obtained reaction product is preferably subjected to solid-liquid separation and solid purification in sequence.

[0043] In the present invention, the solid-liquid separation is preferably vacuum distillation after filtration; the pressure of the vacuum distillation is preferably 50-200 mbar, more preferably 80-150 mbar, further preferably 100-120 mbar, and the temperature is preferably 25-50°C, more preferably 30-45°C, further preferably 40°C. The present invention removes dicyclohexylurea (DCU) and tetrahydrofuran through solid-liquid separation.

[0044] In the present invention, the solid purification preferably includes washing and recrystallization in sequence.

[0045] In the present invention, the cleaning is preferably: dissolving the solid and then washing it, recovering the ethyl acetate layer, drying it, and then filtering and concentrating the filtrate in sequence.

[0046] In the present invention, the reagent used for dissolving the solid is preferably ethyl acetate (EA).

[0047] In the present invention, the washing is preferably: dissolving the solid and washing the resulting solution with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, respectively.

[0048] In the present invention, the number of washings is preferably independently 3 or more times.

[0049] In the present invention, the drying is preferably drying with anhydrous sodium sulfate; the filtering is preferably suction filtration; and the suction filtration is preferably suction filtration at normal pressure. The present invention removes anhydrous sodium sulfate by suction filtration at normal pressure.

[0050] In the present invention, the filtrate is preferably concentrated under reduced pressure; the pressure of the reduced pressure concentration is preferably 50-200 mbar, more preferably 70-160 mbar, further preferably 90-140 mbar, further preferably 100-120 mbar, the temperature is preferably 25-50 °C, more preferably 30-45 °C, further preferably 40 °C; the filtrate is preferably concentrated to dryness.

[0051] In the present invention, the recrystallization is preferably: the solid obtained by washing is redissolved and then recrystallized, filtered and the filter cake is recovered in sequence; the reagent used for the redissolution is preferably dichloromethane; the recrystallization is preferably PE recrystallization; the filtration is preferably normal pressure filtration.

[0052] The present invention also provides the use of the aromatic compound described in the above scheme or the aromatic compound obtained by the preparation method described in the above scheme in the preparation of anti-inflammatory and anti-tumor drugs.

[0053] The aromatic compound provided by the invention has good anti-cancer efficacy, can be used for preparing anti-inflammatory and anti-tumor drugs, and has good social benefits.

[0054] In order to further illustrate the present invention, the scheme of the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be understood as limiting the protection scope of the present invention.

[0055] In the specific embodiments and test examples of the present invention, the specifications and sources of the reagents used are: Cinnamic acid (CA, Lot: C832420, purity: 99%), ferulic acid (FA, Lot: F809522, purity: 99%), indole-3-acetic acid (IA, Lot: I6311, purity: 98%), and m-aminophenylboronic acid (Lot: 1028866, purity: 98%) were purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; aniline (Lot: 1028866, purity: 99%) and benzylamine (Lot: B108477, purity: 99%) were purchased from Aladdin Reagent (Shanghai) Co., Ltd.; Carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) were purchased from Shanghai Haohong Technology Co., Ltd.; nitrogen-methylmorpholine (NMM), tetrahydrofuran (THF), petroleum ether (PE), ethyl acetate (EA), dichloromethane (DCM), sodium bicarbonate, sodium chloride, potassium bisulfate and anhydrous sodium sulfate were purchased from Beijing Chemical Reagent Company; Fetal bovine serum (FBS), DMEM and trypsin were purchased from Gibco; dimethyl sulfoxide (DMSO) was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; CCK-8 kit was purchased from Beijing Solebow Technology Co., Ltd.

[0056] Example 1 First, 500 mg of the compound of formula CA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 456 mg of HOBT was added and completely dissolved in an ice bath, 696 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 463 mg of m-aminophenylboronic acid was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0057] Then, solution A and solution B were mixed and stirred at room temperature for 24 h, and the CA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out, and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized with PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula CA-1a.

[0058] Yield of compound CA-1a: 93.1%. ESI-MS (m / z): 266.35 [MH] - ; 1H NMR (300 MHz, DMSO): δ (ppm) = 10.17 (s, 1H), 7.91 (dd, J = 5.3, 1.7 Hz, 2H), 7.68 – 7.61 (m, 2H), 7.58 – 7.38 (m, 4H), 7.31 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 15.7 Hz,1H).

[0059] Example 2 First, 500 mg of the compound represented by formula CA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 456 mg of HOBT was added and completely dissolved in an ice bath, 696 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 315 mg of aniline was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0060] Then, solution A and solution B were mixed and stirred at room temperature for 24 h. The CA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized with PE, filtered under normal pressure, and the filter cake was recovered to obtain a compound of formula CA-1b.

[0061] Yield of compound CA-1b: 63.72%, ESI-MS (m / z): 224.21 [M+H] + ; 1 H NMR (300 MHz, DMSO) δ 10.20 (s, 1H), 7.91 – 7.54 (m, 5H), 7.54 – 7.29 (m, 5H), 7.17 – 6.96 (m, 1H), 6.85 (d, J = 15.7 Hz, 1H).

[0062] Example 3 First, 500 mg of the compound of formula CA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 456 mg of HOBT was added and completely dissolved in an ice bath, 696 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 362 mg of benzylamine was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0063] Then, solution A and solution B were mixed and stirred at room temperature for 24 h. The CA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized with PE, filtered under normal pressure, and the filter cake was recovered to obtain a compound of formula CA-1c.

[0064] The yield of the compound of formula CA-1c is 59.49%. ESI-MS (m / z): 238.12 [M+H] + ; 1 H NMR (300 MHz, DMSO) δ 8.62 (t, J = 6.0 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.52 – 7.16 (m, 9H), 6.70 (d, J = 15.8 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H).

[0065] Example 4 First, 500 mg of the compound of formula FA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 348 mg of HOBT was added and completely dissolved in an ice bath, 531 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 353 mg of m-aminophenylboronic acid was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0066] Then, solution A and solution B were mixed and stirred at room temperature for 24 h, and the FA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out, and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized by PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula FA-1a.

[0067] Yield of the compound of formula FA-1a: 37.38%. ESI-MS (m / z): 312.53 [MH] - ; 1 H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 8.14 (s, 1H), 7.94 – 7.81 (m, 2H), 7.53 – 7.42 (m,2H), 7.29 (s, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.86 –6.61 (m, 2H), 3.83 (s, 3H).

[0068] Example 5 First, 500 mg of the compound of formula FA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 348 mg of HOBT was added and completely dissolved in an ice bath, 531 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 240 mg of aniline was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0069] Then, solution A and solution B were mixed and stirred at room temperature for 24 h, and the FA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out, and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized by PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula FA-1b.

[0070] Yield of the compound of formula FA-1b: 66.55%, ESI-MS (m / z): 270.20 [M+H] + ; 1 H NMR (300 MHz, DMSO) δ 10.07 (s, 1H), 9.52 (s, 1H), 7.83 – 7.57 (m, 2H), 7.49 (d, J = 15.6Hz, 1H), 7.41 – 7.25 (m, 2H), 7.24 – 6.77 (m, 4H), 6.64 (d, J = 15.6 Hz, 1H), 3.83 (s, 3H).

[0071] Example 6 First, 500 mg of the compound of formula FA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 348 mg of HOBT was added and completely dissolved in an ice bath, 531 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 276 mg of benzylamine was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0072] Then, solution A and solution B were mixed and stirred at room temperature for 24 h, and the FA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out, and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized by PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula FA-1c.

[0073] Yield of the compound of formula FA-1c: 84.35%. ESI-MS (m / z): 284.12 [M+H] + ; 1H NMR (300 MHz, DMSO) δ 8.44 (d, J = 6.0 Hz, 1H), 7.48 – 7.07 (m, 7H), 6.99 (dd, J = 8.2, 1.9Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 4.38 (d, J =5.9 Hz, 2H), 3.80 (s, 3H).

[0074] Example 7 First, 500 mg of the compound of formula IA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 386 mg of HOBT was added and completely dissolved in an ice bath, 586 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 392 mg of m-aminophenylboronic acid was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0075] Then, solution A and solution B were mixed and stirred at room temperature for 24 h. The IA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized with PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula IA-1a.

[0076] Yield of the compound of formula IA-1a: 30.34%. ESI-MS (m / z): 293.32 [MH] - ; 1 H NMR (300 MHz, DMSO) δ 10.97 – 10.87 (m, 1H), 10.01 (s, 1H), 7.99 (s, 1H), 7.86 – 7.81 (m,1H), 7.78 – 7.69 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.45 (dt, J = 7.4, 1.2Hz, 1H), 7.38 – 7.31 (m, 1H), 7.27 – 7.20 (m, 1H), 7.09 – 6.94 (m, 2H), 3.71(s, 2H).

[0077] Example 8 First, 500 mg of the compound of formula IA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 386 mg of HOBT was added and completely dissolved in an ice bath, 586 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 266 mg of aniline was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0078] Then, solution A and solution B were mixed and stirred at room temperature for 24 h. The IA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized by PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula IA-1b.

[0079] Yield of the compound of formula IA-1b: 57.33%, ESI-MS (m / z): 251.26 [M+H] + ; 1 H NMR (300 MHz, DMSO) δ 10.91 (s, 1H), 10.09 (s, 1H), 7.67 – 7.53 (m, 3H), 7.40 – 7.21 (m,4H), 7.13 – 6.92 (m, 3H), 3.72 (d, J = 0.8 Hz, 2H).

[0080] Example 9 First, 500 mg of the compound of formula IA was added to tetrahydrofuran (10 mL) and stirred to dissolve, 386 mg of HOBT was added and completely dissolved in an ice bath, 586 mg of DCC was slowly added and stirred for 30 min, and the esterification reaction was carried out in an ice bath for 30 min to obtain solution A. 306 mg of benzylamine was added to 2 mL of NMM and stirred at room temperature for 30 min to obtain solution B.

[0081] Then, solution A and solution B were mixed and stirred at room temperature for 24 h. The IA raw material point disappeared under TLC (ethyl acetate: petroleum ether = 1:1). Dicyclohexylurea (DCU) was filtered out and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA), and the resulting solution was washed three times with saturated sodium bicarbonate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bisulfate aqueous solution, saturated sodium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered under reduced pressure to remove the desiccant, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized by PE, filtered under normal pressure, and the filter cake was recovered to obtain the compound of formula IA-1c.

[0082] Yield of the compound of formula IA-1c: 87.64%. ESI-MS (m / z): 265.13 [M+H] + ; 1 H NMR (300 MHz, DMSO) δ 8.44 (d, J = 6.0 Hz, 1H), 7.48 – 7.07 (m, 7H), 6.99 (dd, J = 8.2, 1.9Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 4.38 (d, J =5.9 Hz, 2H), 3.80 (s, 3H).

[0083] Test Example 1 The present invention is achieved by 1 The structures of the compounds prepared in Examples 1 to 9 were identified by H NMR and mass spectrometry. Figures 1 to 18 As shown. 1 H NMR results are as follows Figures 1 to 9 As shown, the results are Figures 10 to 18 shown.

[0084] according to Figures 1 to 18 It can be seen that the present invention successfully prepared the compound of formula CA-1a, the compound of formula CA-1b, the compound of formula CA-1c, the compound of formula FA-1a, the compound of formula FA-1b, the compound of formula FA-1c, the compound of formula IA-1a, the compound of formula IA-1b and the compound of formula IA-1c.

[0085] Test Example 2 The method for evaluating in vitro hepatocellular carcinoma activity is: 1. Cell lines and cell culture Human hepatoma cell line Hep G2 cells were obtained from the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Shanghai, China); all cells were cultured under sterile conditions and resuspended in DMEM containing 10% FBS and 1% penicillin / streptomycin amphotericin B mixture; cells were continuously cultured in an incubator (HERACELL VIOS 160i, ThermoFisher) at 5% CO2 and 37°C; cells were passaged every 3 days using trypsin digestion to maintain logarithmic growth.

[0086] 2. CCK-8 experiment The present invention detected the cytotoxicity of the compounds (the compounds represented by Formula CA, the compounds represented by Formula FA, the compounds represented by Formula IA, and the compounds prepared in Examples 1 to 9) to Hep G2 cells by CCK-8 assay. Hep G2 cells in the logarithmic growth cycle were used for the experiment. The cells were diluted with DMEM to 5×10 4 / mL, 100 μL of cell solution was seeded in each well of a 96-well plate, and then incubated in a 5% CO2 and 37 ℃ incubator for 12 h. Subsequently, different concentrations (0, 3.15, 6.25, 12.5, 25, 50, 100 μM) of the above test compounds were added to the 96-well plate at 25 μL per well and incubated for 48 h. 10% CCK8 reagent was added to the 96-well plate at 10 μL per well and incubated for 2 h. The control group was treated in the same way. The data on the plate were read at a wavelength of 450 nm using a full-wavelength microplate reader (Thermo Scientific™ Multiskan GO): cell viability (%) = 1-(OD control cells-OD treated cells) / OD control cells × 100%.

[0087] 3. Data Analysis GraphPad Prism software (version 8.3) was used to analyze the data of each experimental step. All experimental data are presented as mean ± SD. Paired sample t-test and one-way analysis of variance (ANOVA) were used for comparison between groups. Each experiment was performed at least three times. Results were marked as significant * when p < 0.05 and ** when p < 0.01.

[0088] The above method was used to detect the antitumor activity and cytotoxicity of cinnamic acid and its derivatives, ferulic acid and its derivatives, indole-3-acetic acid and its derivatives. The results are as follows: Figure 19~Figure 21 As shown. Figure 19~Figure 21It can be seen that the CA-1a compound and the FA-1a compound provided by the present invention can inhibit the survival rate of liver cancer cell lines, and the IA-1a compound can inhibit the survival rate of liver cancer cell lines at 50 μM; the CA-1b compound and the CA-1c compound have low toxicity to Hep G2 cells, the FA-1b compound, the FA-1c compound, the IA-1b compound and the IA-1c compound have basically no toxicity to Hep G2 cells, and the parent core compounds CA, FA, and IA have no toxicity to Hep G2 cells.

[0089] It can be seen from the above examples that the compounds provided by the present invention have anti-inflammatory and anti-tumor therapeutic effects and can be used as drugs for the treatment of liver cancer to improve the anti-cancer efficacy.

[0090] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An aromatic compound, characterized in that The structure is shown in Formula CA-1, Formula FA-1 or Formula IA-1: ； In formula CA-1, formula FA-1 or formula IA-1, R is a group of formula a, a group of formula b or a group of formula c; 。 2. The aryl compound according to claim 1, characterized in that The aromatic compound includes one of the compounds of formula CA-1a, CA-1b, CA-1c, FA-1a, FA-1b, FA-1c, IA-1a, IA-1b and IA-1c; 。 3. The method for preparing the aryl compound according to any one of claims 1 to 2, characterized in that: The following steps are involved: The raw material drug, 1-hydroxybenzotriazole, carbodiimide and a poor solvent are mixed for esterification reaction to obtain a solution A containing an intermediate compound, the structure of the intermediate compound is shown in Formula Z: ； The solution A and the solution B are mixed to perform an amidation reaction to obtain the aromatic compound; the solution B comprises a base catalyst, a benzene derivative and a good solvent; the benzene derivative is m-aminophenylboronic acid, m-aminobenzyl alcohol, m-aminobenzoic acid methyl ester, aniline or benzylamine; The bulk drug includes a compound of formula CA, a compound of formula FA or a compound of formula IA; 。 4. The preparation method according to claim 3, characterized in that: The mass ratio of the raw material drug to 1-hydroxybenzotriazole is 200-1000: 180-1200.

5. The preparation method according to claim 3 or 4, characterized in that: The mass ratio of the raw material to carbodiimide is 200-1000:210-1400.

6. The preparation method according to claim 3 or 4, characterized in that: The mass volume ratio of the raw material to the poor solvent is (200~1000) mg: (4~20) mL.

7. The preparation method according to claim 3, characterized in that: The concentration of the benzene derivative in the solution B is 9.5-465 mg / mL.

8. The preparation method according to claim 3 or 7, characterized in that: The mass ratio of the raw material drug to the benzene derivative in solution B is 50-2000:60-2400.

9. The preparation method according to claim 3, characterized in that: The reaction time of the amidation reaction is 20 to 36 hours; the amidation reaction is carried out under stirring conditions.

10. Use of the aromatic compound according to any one of claims 1 to 2 or the aromatic compound obtained by the preparation method according to any one of claims 3 to 9 in the preparation of anti-inflammatory and anti-tumor drugs.

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