An aryl compound, a preparation method thereof, and an application thereof in the preparation of anti-inflammatory and anti-tumor drugs

Abstract

The present invention belongs to the fields of medicine and synthesis technology, and specifically relates to an aryl compound, a preparation method thereof, and an application in the preparation of anti-inflammatory and anti-tumor drugs. The present invention constructs a new compound with anti-inflammatory and anti-tumor efficacy by covalently connecting a natural anti-inflammatory active compound containing phenylboronic acid, which can be used as a drug for the treatment of liver cancer. The anti-inflammatory regulator improves the anti-cancer efficacy through the additive effect with the organic boronic acid compound with tumor activity. The preparation method provided by the present invention has simple steps, convenient operation, good feasibility, and the potential for large-scale industrial application, and has a broad market prospect. The present invention also provides an application of the aryl compound described in the above solution or the aryl compound obtained by the preparation method described in the above solution 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.

Description

Technical Field

[0001] The present invention belongs to the technical field of drugs and synthesis, and particularly relates to an aryl compound, a preparation method thereof, and an 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, characterized by high incidence and high mortality. In the past decade or so, some molecular targeted drugs have been approved by the FDA for the treatment of advanced HCC patients (such as the kinase inhibitor sorafenib, and monoclonal antibody drugs of angiogenesis inhibitors). Although these drugs have been proven to be used as adjuvant therapies, their efficacy is not significant. For some patients, they can only extend the survival period by a few months. Therefore, there is an increasing need for the research and development of low-toxic and highly effective drugs for the treatment of liver cancer.

[0003] Natural compounds derived from plants have always been considered a reliable and consistent source for the research of anti-cancer lead drugs. Natural products usually have relatively high safety. Cinnamic acid (CA) and its derivative ferulic acid (FA) are bioactive chemical substances, which are phenolic acids commonly present in plants and have been proven to have activities such as anti-inflammatory and antibacterial. 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 mouse model of diet-induced non-alcoholic fatty liver disease (NAFLD), and the results showed the significant efficacy of IA in reducing steatosis and inflammation. IA has the potential to become a safe treatment option for NAFLD.

[0004] Innate immunity and adaptive immunity in the inflammatory response play important roles in tumorigenesis, progression, and metastasis. Therefore, the treatment-induced inflammatory response also affects the clinical treatment effect of tumors to varying degrees. However, the efficacy of conventional anti-inflammatory drugs in treating tumors is clearly limited and cannot completely inhibit tumor development and elimination. Summary of the Invention

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

[0006] To achieve the above purpose, the present invention provides the following technical solutions:

[0007] The present invention provides an aryl compound, whose structure is shown in Formula CA-1, Formula FA-1, or Formula IA-1:

[0008] ;

[0009] 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 pentagram is the connection site);

[0010] .

[0011] Preferably, the aryl compound includes one of a compound of Formula CA-1a, a compound of Formula CA-1b, a compound of Formula CA-1c, a compound of Formula FA-1a, a compound of Formula FA-1b, a compound of Formula FA-1c, a compound of Formula IA-1a, a compound of Formula IA-1b and a compound of Formula IA-1c;

[0012] .

[0013] The present invention also provides a preparation method of the aryl compound described in the above solution, including the following steps:

[0014] Mix the raw drug, 1-hydroxybenzotriazole, carbodiimide and poor solvent to carry out an esterification reaction to obtain a solution A containing an intermediate compound, and the structure of the intermediate compound is as shown in Formula Z:

[0015] ;

[0016] Mix the solution A and solution B to carry out an amidation reaction to obtain the aryl compound; the solution B includes a base catalyst, a benzene derivative and a good solvent; the benzene derivative is meta-aminophenylboronic acid, meta-aminobenzyl alcohol, methyl meta-aminobenzoate, aniline or benzylamine;

[0017] The raw drug includes a compound of Formula CA, a compound of Formula FA or a compound of Formula IA;

[0018] .

[0019] Preferably, the mass ratio of the raw drug to 1-hydroxybenzotriazole is 200~1000: 180~1200.

[0020] Preferably, the mass ratio of the raw drug to carbodiimide is 200~1000:210~1400.

[0021] Preferably, the mass-volume ratio of the raw drug to the poor solvent is (200~1000) mg:(4~20) mL.

[0022] Preferably, the concentration of the benzene derivative in the solution B is 9.5~465 mg / mL.

[0023] Preferably, the mass ratio of the raw drug to the benzene derivative in the solution B is 50~2000:60~2400.

[0024] Preferably, the reaction time of the amidation reaction is 20 - 36 h; the amidation reaction is carried out under stirring conditions.

[0025] The present invention also provides the use of the aryl compound described in the above solution or the aryl compound obtained by the preparation method described in the above solution in the preparation of anti-inflammatory and anti-tumor drugs.

[0026] The present invention provides an aryl compound. By covalently connecting a natural anti-inflammatory active compound containing phenylboronic acid, the present invention constructs a new compound with anti-inflammatory and anti-tumor effects, which can be used as a drug for the treatment of liver cancer. The anti-inflammatory regulator improves the anti-cancer efficacy through the additive effect with the organic boronic acid compound with tumor activity.

[0027] The present invention also provides a preparation method of the aryl compound described in the above solution. The preparation method provided by the present invention has simple steps, convenient operation, good feasibility, the potential for large-scale industrial application, and broad market prospects.

[0028] The present invention also provides the use of the aryl compound described in the above solution or the aryl compound obtained by the preparation method described in the above solution 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 for the preparation of anti-inflammatory and anti-tumor drugs, and has good social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0030] Figure 1 1H NMR spectrum of the compound of formula CA-1a prepared in Example 1 of the present invention 1 1H NMR spectrum

[0031] Figure 2 1H NMR spectrum of the compound of formula CA-1b prepared in Example 2 of the present invention 1 1H NMR spectrum

[0032] Figure 3 1H NMR spectrum of the compound of formula CA-1c prepared in Example 3 of the present invention 1 1H NMR spectrum

[0033] Figure 4 1H NMR spectrum of the compound of formula FA-1a prepared in Example 4 of the present invention 1 1H NMR spectrum

[0034] Figure 5 1H NMR spectrum of the compound of formula FA-1b prepared in Example 5 of the present invention 1 ;

[0035] Figure 6 1H NMR spectrum of the compound of formula FA-1c prepared in Example 6 of the present invention 1 ;

[0036] Figure 7 1H NMR spectrum of the compound of formula IA-1a prepared in Example 7 of the present invention 1 ;

[0037] Figure 8 1H NMR spectrum of the compound of formula IA-1b prepared in Example 8 of the present invention 1 ;

[0038] Figure 9 1H NMR spectrum of the compound of formula IA-1c prepared in Example 9 of the present invention 1 ;

[0039] Figure 10 MS spectrum of the compound of formula CA-1a prepared in Example 1 of the present invention

[0040] Figure 11 MS spectrum of the compound of formula CA-1b prepared in Example 2 of the present invention

[0041] Figure 12 MS spectrum of the compound of formula CA-1c prepared in Example 3 of the present invention

[0042] Figure 13 MS spectrum of the compound of formula FA-1a prepared in Example 4 of the present invention

[0043] Figure 14 MS spectrum of the compound of formula FA-1b prepared in Example 5 of the present invention

[0044] Figure 15 MS spectrum of the compound of formula FA-1c prepared in Example 6 of the present invention

[0045] Figure 16 MS spectrum of the compound of formula IA-1a prepared in Example 7 of the present invention

[0046] Figure 17 MS spectrum of the compound of formula IA-1b prepared in Example 8 of the present invention

[0047] Figure 18 MS spectrum of the compound of formula IA-1c prepared in Example 9 of the present invention

[0048] Figure 19Antitumor activity determination of cinnamic acid and the compounds prepared in Examples 1-3;

[0049] Figure 20 Antitumor activity determination of ferulic acid and the compounds prepared in Examples 4-6;

[0050] Figure 21 Antitumor activity determination of indole-3-acetic acid and the compounds prepared in Examples 7-9. Detailed implementation mode

[0051] The present invention provides an aryl compound, the structure of which is shown in Formula CA-1, Formula FA-1 or Formula IA-1:

[0052] ;

[0053] 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 pentagram is the connection site);

[0054] .

[0055] In the present invention, the aryl compound preferably includes one of the compounds of Formula CA-1a, the compounds of Formula CA-1b, the compounds of Formula CA-1c, the compounds of Formula FA-1a, the compounds of Formula FA-1b, the compounds of Formula FA-1c, the compounds of Formula IA-1a, the compounds of Formula IA-1b and the compounds of Formula IA-1c;

[0056] .

[0057] The present invention also provides a preparation method of the aryl compound described in the above scheme, including the following steps:

[0058] Mix the raw material drug, 1-hydroxybenzotriazole, carbodiimide and a poor solvent for an esterification reaction to obtain a solution A containing an intermediate compound, and the structure of the intermediate compound is shown in Formula Z:

[0059] ;

[0060] Mix the solution A and the solution B for an amidation reaction to obtain the aryl compound; the solution B includes a base catalyst, a benzene derivative and a good solvent; the benzene derivative is meta-aminophenylboronic acid, meta-aminobenzyl alcohol, methyl meta-aminobenzoate, aniline or benzylamine.

[0061] The present invention mixes the raw material drug, 1-hydroxybenzotriazole (HOBT), carbodiimide and a poor solvent (denoted as Mixing A) for an esterification reaction to obtain a solution A containing an intermediate compound.

[0062] In the present invention, the active pharmaceutical ingredient preferably includes a compound represented by formula CA, a compound represented by formula FA, or a compound represented by formula IA;

[0063] 。

[0064] In the present invention, the mass ratio of the active pharmaceutical ingredient 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 still further preferably 500-600:236.2-901.2. In the present invention, 1-hydroxybenzotriazole is used to increase the reaction rate of the intermediate after DCC activation.

[0065] In the present invention, the mass ratio of the active pharmaceutical ingredient to carbodiimide is preferably 200-1000:210-1400, more preferably 200-1000:212.2-1390.4, further preferably 200-1000:235.2-1175.95, and still further preferably 200-1000:278.1-1060.8. In the present invention, carbodiimide is used to activate the carboxyl group, increase the leaving property of the O-terminal, make the urea derivative easier to leave, and thus promote the formation of amide bonds or ester bonds.

[0066] In the present invention, the poor solvent preferably includes one or more of tetrahydrofuran and N,N-dimethylformamide.

[0067] In the present invention, the mass-volume ratio of the active pharmaceutical ingredient 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.

[0068] In the present invention, the mixing A is preferably as follows: the active pharmaceutical ingredient is added to tetrahydrofuran for mixing (denoted as the first mixing) to obtain a premixed solution, then 1-hydroxybenzotriazole is added to the premixed solution for mixing (denoted as the second mixing) to obtain a mixed solution, and then carbodiimide is added to the mixed solution while stirring at 500-700 rpm (denoted as the third mixing).

[0069] 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, and further preferably 600 rpm. The mixing time is preferably 20-60 s, more preferably 30-50 s, and further preferably 40 s.

[0070] In the present invention, the second mixing is preferably carried out under ice bath conditions; the second mixing is preferably stirring mixing; the rotation speed of the stirring mixing is preferably 500-700 rpm, more preferably 550-650 rpm, and further preferably 600 rpm until 1-hydroxybenzotriazole is dissolved.

[0071] In the present invention, the third mixing is preferably carried out under ice bath conditions; the third mixing is preferably stirring mixing; the rotation speed of the stirring mixing is preferably 500-700 rpm, more preferably 550-650 rpm, and further preferably 600 rpm, and the mixing time is preferably 20-60 min, more preferably 25-45 min, and further preferably 30 min.

[0072] In the present invention, the esterification reaction is preferably carried out under ice bath conditions, and the reaction time is preferably within 30 min, more preferably 20-30 min.

[0073] In the present invention, in solution B, the base catalyst is preferably N-methylmorpholine.

[0074] In the present invention, in solution B, the good solvent preferably includes one or more of dioxane, tetrahydrofuran, and N,N-dimethylformamide.

[0075] 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 still further preferably 150-200 mg / mL.

[0076] In the present invention, the preparation method of the solution B is preferably: mixing the base catalyst and the good solvent to obtain a premixed solution, and then adding the benzene derivative to the premixed solution for mixing (denoted as mixing B). In the present invention, the base catalyst is used to provide an alkaline environment, activate the amino group in the benzene derivative, interact with the substrate through proton transfer, which is beneficial to the formation of amide bonds, accelerate the rate of chemical reactions, and thus improve the efficiency of the condensation reaction.

[0077] In the present invention, the mixing B is preferably stirring mixing; the rotation speed of the stirring 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 mixing B is preferably room temperature.

[0078] After obtaining Solution A, the present invention mixes the Solution A and Solution B to conduct an amidation reaction to obtain the aryl compound. In the present invention, the mass ratio of the active pharmaceutical ingredient 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.

[0079] In the present invention, the temperature of the amidation reaction is preferably room temperature, the reaction time is preferably 20-36 h, more preferably 24-32 h, and further preferably 27-30 h; the amidation reaction is preferably carried out under stirring conditions; the rotation speed of the stirring is preferably 500-700 rpm, more preferably 550-650 rpm, and further preferably 600 rpm. The present invention detects whether the reaction is complete by TLC (ethyl acetate: petroleum ether = 1:1-2).

[0080] In the present invention, after the amidation reaction, it preferably further includes successively performing solid-liquid separation and solid purification on the obtained reaction product.

[0081] In the present invention, the solid-liquid separation is preferably filtration followed by vacuum distillation; the pressure of the vacuum distillation is preferably 50-200 mbar, more preferably 80-150 mbar, and further preferably 100-120 mbar, and the temperature is preferably 25-50 °C, more preferably 30-45 °C, and further preferably 40 °C. The present invention removes dicyclohexylurea (DCU) and tetrahydrofuran through solid-liquid separation.

[0082] In the present invention, the solid purification preferably includes successively performing washing and recrystallization.

[0083] In the present invention, the washing is preferably: dissolving the solid and then washing, recovering the ethyl acetate layer, drying it, and then successively performing filtration and concentration of the filtrate.

[0084] In the present invention, the reagent used for dissolving the solid is preferably ethyl acetate (EA).

[0085] In the present invention, the washing is preferably: washing the solution obtained by dissolving the solid successively 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.

[0086] In the present invention, the number of times of the washing is independently preferably more than 3 times.

[0087] In the present invention, the drying is preferably drying with anhydrous sodium sulfate; the filtration is preferably suction filtration; the suction filtration is preferably normal pressure suction filtration. The present invention removes anhydrous sodium sulfate through normal pressure suction filtration.

[0088] In the present invention, the concentration of the filtrate is preferably carried out under reduced pressure; the pressure for the concentration under reduced pressure is preferably 50 - 200 mbar, more preferably 70 - 160 mbar, further preferably 90 - 140 mbar, still further preferably 100 - 120 mbar, and the temperature is preferably 25 - 50 °C, more preferably 30 - 45 °C, further preferably 40 °C; the concentration of the filtrate is preferably concentrated to dryness.

[0089] In the present invention, the recrystallization is preferably as follows: the solid obtained by washing is redissolved and then recrystallized, filtered, and the filter cake is recovered in sequence; the reagent used for redissolving is preferably dichloromethane; the recrystallization is preferably PE recrystallization; the filtration is preferably carried out by suction filtration at normal pressure.

[0090] 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.

[0091] The aryl compound provided by the present invention has good anti-cancer efficacy, can be used in the preparation of anti-inflammatory and anti-tumor drugs, and has good social benefits.

[0092] In order to further illustrate the present invention, the solutions of the present invention will be described in detail below in conjunction with the drawings and examples, but they should not be construed as limiting the protection scope of the present invention.

[0093] In the specific examples and test examples of the present invention, the specifications and sources of the reagents used are as follows:

[0094] Cinnamic acid (CA, Lot: C832420, purity: 99%), ferulic acid (FA, Lot: F809522, purity: 99%), indole-3-acetic acid (IA, Lot: I6311, purity: 98%), meta-aminophenylboronic acid (Lot: 1028866, purity: 98%) were all purchased from Shanghai Macklin Biochemical Co., Ltd.; aniline (Lot: 1028866, purity: 99%), benzylamine (Lot: B108477, purity: 99%) were all purchased from Aladdin Reagent (Shanghai) Co., Ltd.;

[0095] Carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) were purchased from Shanghai Haohong Technology Co., Ltd.; N-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 Co., Ltd.;

[0096] Fetal bovine serum (FBS), DMEM, and trypsin were purchased from Gibco; dimethyl sulfoxide (DMSO) was purchased from Shanghai Macklin Biochemical Co., Ltd.; the CCK-8 kit was purchased from Beijing Solarbio Science & Technology Co., Ltd.

[0097] Example 1

[0098] First, 500 mg of the compound shown by formula CA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 456 mg of HOBT was added and completely dissolved in an ice bath. 696 mg of DCC was slowly added and stirred continuously for 30 min. An esterification reaction was carried out for 30 min under ice bath conditions 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.

[0099] After that, solution A and solution B were mixed and stirred at room temperature for 24 h. Under the TLC (ethyl acetate: petroleum ether = 1:1) display, the CA raw material spot disappeared. Dicyclohexylurea (DCU) was filtered off, and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA). The resulting solution was washed three times successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the desiccant was removed by vacuum filtration. The filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized with PE, and filtered at atmospheric pressure. The filter cake was recovered to obtain the compound of formula CA-1a.

[0100] Yield of the compound of formula CA-1a: 93.1%. ESI-MS (m / z): 266.35 [M-H] - ; 1 H 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).

[0101] Example 2

[0102] First, 500 mg of the compound shown by formula CA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 456 mg of HOBT was added and completely dissolved in an ice bath. 696 mg of DCC was slowly added and stirring was continued for 30 min. An esterification reaction was carried out for 30 min under ice bath conditions 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.

[0103] Subsequently, solution A and solution B were mixed and stirred at room temperature for 24 h. The disappearance of the starting material point of CA was shown by 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). The resulting solution was washed three times successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the desiccant was removed by vacuum filtration. The filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized from PE, and filtered under normal pressure. The filter cake was recovered to obtain the compound of formula CA-1b.

[0104] Yield of the compound of formula 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).

[0105] Example 3

[0106] First, 500 mg of the compound shown by formula CA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 456 mg of HOBT was added and completely dissolved in an ice bath. 696 mg of DCC was slowly added and stirring was continued for 30 min. An esterification reaction was carried out for 30 min under ice bath conditions 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.

[0107] Subsequently, Solution A and Solution B were mixed and stirred at room temperature for 24 h. The starting material spot of CA disappeared as shown by 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 successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, the desiccant was removed by vacuum filtration, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized from PE, filtered under atmospheric pressure, and the filter cake was recovered to obtain the compound of formula CA-1c.

[0108] Yield of the compound of formula CA-1c: 59.49%. ESI-MS (m / z): 238.12 [M+H] + ; 1 1H 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).

[0109] Example 4

[0110] First, 500 mg of the compound shown by formula FA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 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. The esterification reaction was carried out for 30 min under ice bath conditions 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.

[0111] Subsequently, Solution A and Solution B were mixed and stirred at room temperature for 24 h. The starting material spot of FA disappeared as shown by 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 successively with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, the desiccant was removed by vacuum filtration, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM, recrystallized from PE, filtered under atmospheric pressure, and the filter cake was recovered to obtain the compound of formula FA-1a.

[0112] Yield of the compound of formula FA-1a: 37.38%. ESI-MS (m / z): 312.53 [M-H] - ; 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).

[0113] Example 5

[0114] First, 500 mg of the compound shown by formula FA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 348 mg of HOBT was added and completely dissolved in an ice bath. 531 mg of DCC was slowly added and stirring was continued for 30 min. An esterification reaction was carried out for 30 min under ice bath conditions 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.

[0115] Afterwards, solution A and solution B were mixed and stirred at room temperature for 24 h. Under the TLC (ethyl acetate: petroleum ether = 1:1) display, the FA raw material spot disappeared. Dicyclohexylurea (DCU) was filtered off, and tetrahydrofuran was evaporated under reduced pressure. The solid was dissolved in 50 mL of ethyl acetate (EA). The obtained solution was washed three times with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution respectively. The ethyl acetate layer was dried with anhydrous sodium sulfate, the desiccant was removed by vacuum filtration, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized with PE, and then filtered under normal pressure. The filter cake was recovered to obtain the compound of formula FA-1b.

[0116] Yield of the compound of formula FA-1b: 66.55%, ESI-MS (m / z): 270.20 [M+H] + ; 11H NMR (300 MHz, DMSO) δ 10.07 (s, 1H), 9.52 (s, 1H), 7.83 – 7.57 (m, 2H), 7.49 (d, J = 15.6 Hz, 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).

[0117] Example 6

[0118] First, 500 mg of the compound shown by formula FA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 348 mg of HOBT was added and completely dissolved in an ice bath. 531 mg of DCC was slowly added and stirring was continued for 30 min. The esterification reaction was carried out for 30 min under ice bath conditions 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.

[0119] Then, solution A and solution B were mixed and stirred at room temperature for 24 h. The disappearance of the FA raw material spot was shown by 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). The resulting solution was washed three times with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized with PE, and suction filtration was carried out at atmospheric pressure. The filter cake was recovered to obtain the compound of formula FA-1c.

[0120] Yield of the compound of formula FA-1c: 84.35%. ESI-MS (m / z): 284.12 [M+H] + ; 1 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, 1.9 Hz, 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).

[0121] Example 7

[0122] First, 500 mg of the compound shown in Formula IA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 386 mg of HOBT was added and completely dissolved in an ice bath. 586 mg of DCC was slowly added and stirring was continued for 30 min. An esterification reaction was carried out for 30 min under ice bath conditions 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.

[0123] Subsequently, Solution A and Solution B were mixed and stirred at room temperature for 24 h. The disappearance of the starting material point of IA was shown by 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). The resulting solution was washed three times with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized from PE, and suction filtration was carried out at atmospheric pressure to recover the filter cake to obtain the compound of Formula IA-1a.

[0124] Yield of the compound of Formula IA-1a: 30.34%. ESI-MS (m / z): 293.32 [M-H] - ; 1 1H 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).

[0125] Example 8

[0126] First, 500 mg of the compound shown in Formula IA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 386 mg of HOBT was added and completely dissolved in an ice bath. 586 mg of DCC was slowly added and stirring was continued for 30 min. An esterification reaction was carried out for 30 min under ice bath conditions 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.

[0127] Subsequently, Solution A and Solution B were mixed and stirred at room temperature for 24 h. The starting material point of IA disappeared as shown by 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). The resulting solution was washed three times with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, the desiccant was removed by vacuum filtration, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized from PE, and then filtered under atmospheric pressure to recover the filter cake to obtain the compound of formula IA-1b.

[0128] Yield of the compound of formula IA-1b: 57.33%, ESI-MS (m / z): 251.26 [M+H] + ; 1 1H 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).

[0129] Example 9

[0130] First, 500 mg of the compound shown by formula IA was added to tetrahydrofuran (10 mL) and stirred until dissolved. 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. The esterification reaction was carried out for 30 min under ice bath conditions 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.

[0131] Subsequently, Solution A and Solution B were mixed and stirred at room temperature for 24 h. The starting material point of IA disappeared as shown by 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). The resulting solution was washed three times with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bisulfate solution, saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution respectively. The ethyl acetate layer was dried over anhydrous sodium sulfate, the desiccant was removed by vacuum filtration, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid was redissolved in DCM and recrystallized from PE, and then filtered under atmospheric pressure to recover the filter cake to obtain the compound of formula IA-1c.

[0132] 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).

[0133] Test Example 1

[0134] The present invention identified the structures of the compounds prepared in Examples 1-9 by 1 H NMR and mass spectrometry analysis, and the results are as Figures 1 to 18 shown. Among them 1 The H NMR results are as Figures 1 to 9 shown, and the results are as Figures 10 to 18 shown.

[0135] According to Figures 1 to 18 it can be seen that the present invention successfully prepared the compounds of formula CA-1a, formula CA-1b, formula CA-1c, formula FA-1a, formula FA-1b, formula FA-1c, formula IA-1a, formula IA-1b and formula IA-1c.

[0136] Test Example 2

[0137] The method for evaluating the in vitro anti-hepatocarcinoma activity is as follows:

[0138] 1. Cell line and cell culture

[0139] The human hepatocarcinoma 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 the cells were resuspended in DMEM containing 10% FBS and 1% penicillin / streptomycin amphotericin B mixture; the cells were continuously cultured in an incubator (HERACELL VIOS 160i, ThermoFisher) under the conditions of 5% CO2 and 37 °C; the cells were passaged once every 3 days using trypsin digestion to maintain logarithmic growth of the cells.

[0140] 2. CCK-8 assay

[0141] By CCK-8 assay, the present invention detected the cytotoxicity of compounds (compounds shown in formula CA, compounds shown in formula FA, compounds shown in formula IA, and compounds prepared in Examples 1-9) against hepatocellular carcinoma Hep G2 cells. HepG2 cells in the logarithmic growth phase were used for the experiment. The cells were diluted with DMEM to 5×10 4 cells / mL, and 100 μL of the cell suspension was seeded in each well of a 96-well plate, and then cultured in an incubator with 5% CO2 at 37 °C for 12 h. Subsequently, the above-mentioned test compounds at different concentrations (0, 3.15, 6.25, 12.5, 25, 50, 100 μM) were added to each well of the 96-well plate at 25 μL per well and incubated for 48 h. 10% CCK8 reagent was added to each well at 10 μL per well and incubated for 2 h. The control group was treated in the same manner. The data on the plate was 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%.

[0142] 3. Data analysis

[0143] The data of each experimental step were analyzed using GraphPad Prism software (version 8.3). All experimental data were expressed 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. When p < 0.05, the results were marked as significant *, and when p < 0.01, the results were marked as **.

[0144] The antitumor activity and cytotoxicity of cinnamic acid and its derivative compounds, ferulic acid and its derivative compounds, indole-3-acetic acid and its derivative compounds were detected using the above method, and the results are as Figures 19 to 21 shown. It can be seen from Figures 19 to 21 that the compounds of formula CA-1a and formula FA-1a provided by the present invention can inhibit the survival rate of hepatocellular carcinoma cell lines, and the compound of formula IA-1a can inhibit the survival rate of hepatocellular carcinoma cell lines at 50 μM; the compounds of formula CA-1b and formula CA-1c have low cytotoxicity to Hep G2 cells, and the compounds of formula FA-1b, formula FA-1c, formula IA-1b and formula IA-1c have basically no toxicity to Hep G2 cells, and the parent nucleus compounds CA, FA, and IA have no toxicity to Hep G2 cells.

[0145] As can be seen from the above examples, the compounds provided by the present invention have anti-inflammatory and antitumor effects and can be used as drugs for the treatment of liver cancer to improve the anti-cancer efficacy.

[0146] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. Other embodiments can also be obtained based on these embodiments without creative work, and these embodiments all fall within the protection scope of the present invention.

Claims

1. An aryl compound, characterized in that, One of the compounds of formula CA-1a, formula FA-1a and formula IA-1a; 。 2. The method for preparing the aryl compound according to claim 1, characterized in that, Comprising the following steps: Mixing the raw material drug, 1-hydroxybenzotriazole, carbodiimide and poor solvent for an esterification reaction to obtain solution A containing an intermediate compound, and the structure of the intermediate compound is as shown in formula Z: ； Mixing solution A and solution B for an amidation reaction to obtain the aryl compound; solution B comprises a base catalyst, a benzene derivative and a good solvent; the benzene derivative is meta-aminophenylboronic acid; The raw material drug is a compound of formula CA, a compound of formula FA or a compound of formula IA; 。 3. The preparation method according to claim 2, characterized in that The reaction time of the amidation reaction is 20-36 h; the amidation reaction is carried out under stirring conditions.

4. Use of the aryl compound according to claim 1 or the aryl compound obtained by the preparation method according to any one of claims 2-3 in the preparation of an anti-inflammatory and anti-tumor drug; the anti-inflammatory and anti-tumor drug is a human liver cancer drug.

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