2-hydroxy-2-aryl-2-(3, 4, 5-trimethoxyphenyl) acetic acid compound as well as preparation and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a 2-hydroxy-2-aryl-2-(3, 4, 5-trimethoxyphenyl) acetic acid compound as well as a preparation method and application thereof in an anti-tumor aspect. The compound is a compound as shown in a general formula M or pharmaceutically acceptable salt, racemate, solvent compound or hydrate thereof, detailed substituent groups are shown in the specification. The compound provided by the invention has the effect of inhibiting tumor proliferation, and has a good prospect in the aspect of development of antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compound, a preparation method thereof and an application thereof in anti-tumor aspects. Background Art

[0002] Malignant tumors pose a serious threat to human health and are the second leading cause of death after cardiovascular disease. Currently, commonly used chemotherapy drugs in clinical practice suffer from poor tolerance, numerous side effects, and high toxicity. Therefore, the search for more effective and safer anti-cancer drugs remains crucial.

[0003] Microtubules are widely present in the cytoplasm of eukaryotic cells and are an important component of the cytoskeleton. They play an important role in cellular activities such as maintaining cell morphology, cell proliferation, mitosis, intracellular transport, and cell migration. Given the important role of microtubules in cell growth and division, tubulin has been a popular target for the development of anti-cancer drugs.

[0004] 2-Hydroxyacetic acid is an important pharmacophore. Compounds containing this pharmacophore exhibit a wide range of biological activities, such as anti-infection and antihypertensive effects. For related reports, see: Pierre, et al. Bioorganic & Medicinal Chemistry Letters. 1995, 2611-2616; KE Kinnamon, et al. Experimental Parasitology. 1998, 251-256.

[0005] There are relatively few reports on 2-hydroxy-2-arylacetic acid compounds. For a report on the synthesis of such compounds, see GKSurya Prakash, et al. Proceedings of the National Academy of Sciences of the United States of America. 2007, 3026-3030. For research on the biological activity of such compounds, see C.Alain, et al. Preparation of 1-(biphenylylmethyl)imidazole-5-carboxylates and analogs as angiotensin II receptor antagonists: WO9523792 A1 (1995-09-08). Representative compounds described in this patent (see below) can act on angiotensin II receptors and are used to treat hypertension.

[0006]

[0007] However, the research on the anti-tumor activity of the 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compounds involved in the present invention has not been reported in the literature so far. Summary of the Invention

[0008] The purpose of the present invention is to design and synthesize a 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compound with good anti-tumor activity, a preparation method thereof and an application thereof in anti-tumor aspects.

[0009] To achieve the above purpose, the present invention adopts the following technical solutions:

[0010] A 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compound, wherein the compound is a compound represented by the general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof;

[0011]

[0012] Wherein, in the general formula M, V is S, NCH3 or CH, U is O, N or CH, W is S or CH; R 1 、R 2 、R 2 、R 4 、R 5 R may be the same or different and each independently represents hydrogen, C1-C6 alkyl, C1-C6 alkyloxy, halogen, acetyl, nitro, hydroxy, C1-C6 haloalkyl, or amino which is unsubstituted or substituted with at least one C1-C6 alkyl; 6 It is hydrogen or C1-C6 alkyl.

[0013] Preferably, the compound is a compound represented by the general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof;

[0014] In the general formula M, V is S, NCH3 or CH, U is O, N or CH, and W is S or CH;

[0015] R 1 、R 2 、R 2 、R 4 、R 5 R may be the same or different and each independently represents hydrogen, C1-C3 alkyl, C1-C3 alkyloxy, halogen, acetyl, nitro, hydroxy, C1-C3 haloalkyl, or amino which is unsubstituted or substituted with at least one C1-C6 alkyl; 6 It is hydrogen or C1-C3 alkyl.

[0016] Further preferably, the compound is a compound represented by the general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof;

[0017] In the general formula M, V is S, NCH3 or CH, U is O, N or CH, and W is S or CH;

[0018] R 1 、R 2 、R 2 、R 4 、R 5 R may be the same or different and each independently represents hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, acetyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, hydroxyl, or trifluoromethyl; 6 It is hydrogen, methyl, and ethyl.

[0019] More preferably, the compound represented by the general formula M is:

[0020] Compound 1

[0021]

[0022] 2-Hydroxy-2-(5-phenylfuran-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0023] Compound 2

[0024]

[0025] 2-Hydroxy-2-(5-(4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0026] Compound 3

[0027]

[0028] 2-Hydroxy-2-(5-(3-methoxyphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0029] Compound 4

[0030]

[0031] 2-Hydroxy-2-(5-(4-methoxyphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0032] Compound 5

[0033]

[0034] 2-Hydroxy-2-(5-(3-chlorophenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0035] Compound 6

[0036]

[0037] 2-Hydroxy-2-(5-(4-chlorophenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0038] Compound 7

[0039]

[0040] 2-Hydroxy-2-(5-(3,5-dimethylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0041] Compound 8

[0042]

[0043] 2-Hydroxy-2-(5-(3-fluoro-4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0044] Compound 9

[0045]

[0046] 2-Hydroxy-2-(4-phenylthiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0047] Compound 10

[0048]

[0049] 2-Hydroxy-2-(5-(4-methylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0050] Compound 11

[0051]

[0052] 2-Hydroxy-2-(5-(3-methoxyphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0053] Compound 12

[0054]

[0055] 2-Hydroxy-2-(5-(4-methoxyphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0056] Compound 13

[0057]

[0058] 2-Hydroxy-2-(5-(3-chlorophenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0059] Compound 14

[0060]

[0061] 2-Hydroxy-2-(5-(4-chlorophenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0062] Compound 15

[0063]

[0064] 2-Hydroxy-2-(5-(3,5-dimethylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0065] Compound 16

[0066]

[0067] 2-Hydroxy-2-(5-(3-fluoro-4-methylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0068] Compound 17

[0069]

[0070] 2-Hydroxy-2-(2-phenylthiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0071] Compound 18

[0072]

[0073] 2-Hydroxy-2-(2-(4-methylphenyl)thiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0074] Compound 19

[0075]

[0076] 2-Hydroxy-2-(2-(4-methoxyphenyl)thiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0077] Compound 20

[0078]

[0079] 2-Hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0080] Compound 21

[0081]

[0082] 2-Hydroxy-2-(2-(4-methylphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0083] Compound 22

[0084]

[0085] 2-Hydroxy-2-(2-(4-methoxyphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0086] Compound 23

[0087]

[0088] 2-Hydroxy-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0089] Compound 24

[0090]

[0091] 2-Hydroxy-2-(1-methyl-4-(4-methylphenyl)-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0092] Compound 25

[0093]

[0094] 2-Hydroxy-2-(1-methyl-4-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0095] Compound 26

[0096]

[0097] Methyl 2-hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetate

[0098] Compound 27

[0099]

[0100] ethyl 2-hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetate

[0101] The salt is a salt formed by the compound represented by general formula M and an acid or base, the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, and malic acid, and the base is selected from sodium hydroxide, sodium carbonate, and potassium hydroxide; the hydrate of the compound represented by general formula M, the number of crystal waters of the hydrate is any real number between 0 and 16.

[0102] The preparation method of 2-hydroxy-2-(3,4,5-trimethoxyphenyl)acetic acid compounds is to use 3,4,5-trimethoxybenzaldehyde I as a starting material, and to obtain 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compounds through addition, hydroxyl protection, substitution, deprotection, oxidation, rearrangement, esterification and other reactions. The reaction formula is:

[0103]

[0104] Further speaking

[0105] (1) 3,4,5-trimethoxybenzaldehyde I and dimethyl phosphite are dissolved in methanol, and sodium methoxide is added to cause an addition reaction to obtain compound II;

[0106] (2) Compound II and 3,4-dihydro-2H-pyran are dissolved in toluene, and p-toluenesulfonic acid is added to protect the hydroxyl group to obtain compound III;

[0107] (3) Compound III is dissolved in anhydrous tetrahydrofuran, n-butyl lithium is added, and then compound IV is added. After the reaction is completed, the crude product is dissolved in methanol, and hydrochloric acid is added dropwise to obtain compound V;

[0108] (4) dissolving compound V and selenium dioxide in dimethyl sulfoxide to undergo oxidation reaction to obtain compound VI;

[0109] (5) Compound VI and potassium hydroxide are dissolved in n-butanol to produce compound VII by benzyl alcohol rearrangement;

[0110] (6) Compound VII is dissolved in alcohol, concentrated sulfuric acid is added, and an esterification reaction occurs to obtain compound M.

[0111] Going further:

[0112] (1) 3,4,5-trimethoxybenzaldehyde I and dimethyl phosphite are dissolved in methanol, sodium methoxide is added, and an addition reaction occurs. After the reaction is completed, the mixture is extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Compound II is obtained by column chromatography; wherein the molar ratio of compound I, dimethyl phosphite, and sodium methoxide is 1:1-4:1-4; the reaction temperature is 30°C-65°C; and the reaction time is 1-12 hours.

[0113] (2) Compound II and 3,4-dihydro-2H-pyran are dissolved in toluene, and p-toluenesulfonic acid is added. After the reaction is completed, the mixture is extracted with dichloromethane, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Compound III is obtained by column chromatography; wherein the molar ratio of compound II, 3,4-dihydro-2H-pyran and p-toluenesulfonic acid is 1:1-4:0.05-1; the reaction temperature is 50°C-85°C; and the reaction time is 1-6 hours.

[0114] (3) Compound III is dissolved in anhydrous tetrahydrofuran, n-butyl lithium is added, and then compound IV is added. After the reaction is completed, the crude product is dissolved in methanol, and hydrochloric acid is added dropwise. After the reaction is completed, compound V is obtained by filtration; wherein the molar ratio of compound III, substituted aromatic formaldehyde IV, n-butyl lithium, and hydrochloric acid is 1:1-2:1-3:4-12; the reaction temperature is -78°C to -20°C; and the reaction time is 1 to 10 hours.

[0115] (4) Compound V and selenium dioxide are dissolved in dimethyl sulfoxide to cause an oxidation reaction. After the reaction is completed, the mixture is extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Compound VI is obtained by column chromatography; wherein the molar ratio of compound V to selenium dioxide is 1:1 to 4; the reaction temperature is 80°C to 110°C; and the reaction time is 0.1 to 2 h.

[0116] (5) Compound VI and potassium hydroxide are dissolved in n-butanol, and after the rearrangement reaction of the benzyl alcohol is completed, the mixture is extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Column chromatography is performed to obtain a 2-hydroxy-2-(3,4,5-trimethoxyphenyl)acetic acid compound having the structure of Formula M; wherein the molar ratio of compound VI to potassium hydroxide is 1:1 to 3; the reaction temperature is 65°C to 100°C; and the reaction time is 0.1 to 0.5 h.

[0117] (6) Compound VII is dissolved in the corresponding alcohol, concentrated sulfuric acid is added dropwise to cause esterification reaction. After the reaction is completed, the mixture is extracted with ethyl acetate, washed with saturated brine, dried over anhydrous Na2SO4, and the solvent is removed under reduced pressure. Compound M is obtained by column chromatography; wherein the molar ratio of compound VI to concentrated sulfuric acid is 1:0.01-0.05; the reaction temperature is 65°C-78°C; and the reaction time is 0.5-2 h.

[0118] A pharmaceutical composition comprising a compound represented by general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof; the content of the compound is 0.01-99% of the mass of the composition.

[0119] Application of the compound or the composition: application of the compound of the general formula M or its pharmaceutically acceptable salt, racemate, solvate or hydrate or the composition in the preparation of anti-tumor drugs.

[0120] The tumor is a human breast cancer, gastric cancer or lung cancer tumor strain.

[0121] The substituted aryl formaldehyde compound (Compound IV) of the present invention is preferably 5-phenyl-2-furaldehyde, 5-(4-methylphenyl)-2-furaldehyde, 5-(3-methoxyphenyl)-2-furaldehyde, 5-(4-methoxyphenyl)-2-furaldehyde, 5-(3-chlorophenyl)-2-furaldehyde, 5-(4-chlorophenyl)-2-furaldehyde, 5-(3,5-dimethylphenyl)-2-furaldehyde, 5-(3-fluoro-4-methylphenyl)-2-furaldehyde, 4-phenyl-2-thiophenecarboxaldehyde, 4-(4-methylphenyl)-2-thiophenecarboxaldehyde, 4-(3-methoxyphenyl)-2-thiophenecarboxaldehyde, 4-(4-methoxyphenyl)-2-thiophenecarboxaldehyde, 4-(3-chlorophenyl)-2-thiophenecarboxaldehyde. formaldehyde, 4-(4-chlorophenyl)-2-thiophenecarboxaldehyde, 4-(3,5-dimethylphenyl)-2-thiophenecarboxaldehyde, 4-(3-fluoro-4-methylphenyl)-2-thiophenecarboxaldehyde, 2-phenyl-4-thiazolecarboxaldehyde, 2-(4-methylphenyl)-4-thiazolecarboxaldehyde, 2-(4-methoxyphenyl)-4-thiazolecarboxaldehyde, 4-phenyl-2-thiazolecarboxaldehyde, 4-(4-methylphenyl)-2-thiazolecarboxaldehyde, 4-(4-methoxyphenyl)-2-thiazolecarboxaldehyde, 1-methyl-4-phenyl-1H-imidazole-2-carboxaldehyde, 1-methyl-4-(4-methylphenyl)-1H-imidazole-2-carboxaldehyde, 1-methyl-4-(4-methoxyphenyl)-1H-imidazole-2-carboxaldehyde (see Examples 1-27).

[0122] The preparation method of the 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compounds provided by the present invention is simple and feasible, and has a high yield.

[0123] The present invention further provides the use of the above-mentioned 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compounds, their salts and hydrates, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating tumor diseases, wherein the tumor is a human breast cancer, gastric cancer, or lung cancer tumor strain.

[0124] 2-Hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compounds have the effect of inhibiting tumor proliferation, can effectively treat tumor diseases, and have good development prospects in the development of anti-tumor drugs. DETAILED DESCRIPTION

[0125] The following examples will help to understand the present invention, but the content of the present invention is not limited to the examples.

[0126] All reagents used in the present invention are commercially available. Nuclear magnetic resonance spectra were measured using a Bruker AVANCE 600 nuclear magnetic resonance spectrometer, and high-resolution mass spectra were measured using an Agilent Accurate-Mass Q-TOF 6530 (Agilent, Santa Clara, CA, USA) mass spectrometer.

[0127] Example 1: Preparation of 2-hydroxy-2-(5-phenylfuran-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0128] Dissolve dimethyl phosphite (13.0 g, 0.12 mol) and freshly prepared sodium methoxide (0.8 g, 0.15 mol) in methanol. Slowly add 3,4,5-trimethoxybenzaldehyde (20.0 g, 0.10 mol) with stirring. Raise the reaction temperature to 50°C and allow to react for 3 hours. After completion, concentrate the reaction mixture, add ice water (100 mL), and extract with dichloromethane (30 mL x 3). Collect the organic extracts, wash once with saturated NaCl solution, collect the organic phases, dry over anhydrous Na2SO4, concentrate, and filter by column chromatography to obtain 3,4,5-trimethoxybenzylhydroxymethyl dimethyl phosphate (28.0 g) as a white solid in a 92% yield.

[0129] 3,4,5-Trimethoxyphenyl hydroxymethyl dimethyl phosphate (4.0 g, 0.01 mol) and p-toluenesulfonic acid (0.1 g, 2 mol%) were dissolved in toluene. 3,4-dihydro-2H-pyran (DHP, 2.2 g, 0.03 mol) was then added dropwise to the reaction solution. The reaction temperature was then raised to 65°C for 2 hours. After completion, the reaction was concentrated, and water (100 mL) was added to the reaction system. Extraction was performed with dichloromethane (30 mL x 3). The organic extract was collected and washed once with saturated NaCl solution. The organic phase was collected, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain dimethyl (((tetrahydro-2H-pyran-2-yl)oxy)(3,4,5-trimethoxyphenyl)methyl)phosphonate (4.5 g) as a colorless oily liquid with a yield of 89%.

[0130] Under nitrogen, dimethyl (((tetrahydro-2H-pyran-2-yl)oxy)(3,4,5-trimethoxyphenyl)methyl)phosphonate (4.5 g, 0.01 mol) was dissolved in anhydrous tetrahydrofuran, and the reaction temperature was lowered to -78°C. Next, n-BuLi (6 mL, 0.02 mol) was added dropwise to the reaction solution, and the reaction was stirred for 1 hour. 5-Phenyl-2-furaldehyde (1.72 g, 0.01 mol) was dissolved in anhydrous THF and slowly added dropwise to the reaction solution. After the reaction, the solvent was removed under reduced pressure to yield a yellow oil. 20 mL of anhydrous methanol was added dropwise to the reaction flask, and concentrated HCl (3-5 mL, 12 M) was added dropwise with stirring at room temperature. The mixture was stirred for 1 hour until a solid precipitated, yielding a crude white solid (3.2 g) that was used in the next step without purification.

[0131] Dissolve 2-(4-phenylfuran-2-yl)-1-(3,4,5-trimethoxyphenyl)-1-ethanone (3.5 g, 0.01 mol) and selenium dioxide (3.0 g, 0.02 mol) in DMSO (30 mL) and react at 100°C for 2 h. After completion, pour the reaction solution into ice water (100 mL) and extract with dichloromethane (30 mL x 3). The organic extract is collected and washed once with saturated NaCl solution. The organic phase is collected, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain 1-(4-phenylfuran-2-yl)-2-(3,4,5-trimethoxyphenyl)ethanedione (2.1 g) as a white solid in a 62% yield.

[0132] Weigh KOH (2.21 g, 0.04 mol) into a reaction flask, add n-BuOH, and heat the reaction to 85°C. After the KOH is completely dissolved, add 1-(4-phenylfuran-2-yl)-2-(3,4,5-trimethoxyphenyl)ethanedione (3.6 g, 0.01 mol) as a solid to the reaction solution and react for 0.1 h. After the reaction is complete, adjust the pH of the reaction solution to 6 with HCl (2 M), extract with ethyl acetate (30 mL x 3), collect the organic extracts, wash once with saturated NaCl solution, collect all the organic phases, dry over anhydrous Na2SO4, concentrate, and column chromatography to obtain 2-hydroxy-2-(5-phenylfuran-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid (1.6 g). White solid; yield 41%; 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.66(d,J=7.20Hz,2H),7.55(t,J=7.60Hz,1H),7.43(d,J=7. 20Hz, 2H), 6.94 (s, 2H), 6.86 (d, J = 3.20Hz, 1H), 6.31 (d, J = 3.20Hz, 1H), 3.75 (s, 6H), 3.69 (s, 3H). 13 C NMR(100MHz,DMSO-d6)δ173.18,155.73,152.85,152.68(2C),137.64,130.71,129.34(2C) ,128.65,127.96,123.81(2C),110.85,106.56,104.49(2C),76.65,60.48,56.31(2C).HRMS calcd for C 21 H 21 O7[M+H] + :385.1287,found:385.1288.

[0133] Example 2: Preparation of 2-hydroxy-2-(5-(4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0134] 2-Hydroxy-2-(5-(4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 5-(4-methylphenyl)-2-furaldehyde was used as the starting material; the yield was 23%; 1H NMR(400MHz,DMSO-d6)δ7.54(d,J=8.16Hz,2H),7.23(d,J=8.04Hz,2H),6.91(s,2H),6 .77(d,J=3.32Hz,1H),6.27(d,J=3.36Hz,1H),3.77(s,3H),3.74(s,6H),2.31(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.17,153.24,152.95,152.66(2C),144.64,136.37,134.20,129.89 (2C),128.81(2C),128.09,110.79,105.76,104.48(2C),76.63,60.48,56.30(2C),19.01.HRMS calcd for C 22 H 23 O7[M+H] + :399.1444,found:399.1444.

[0135] Example 3: Preparation of 2-hydroxy-2-(5-(3-methoxyphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0136] 2-Hydroxy-2-(5-(4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 5-(3-methoxyphenyl)-2-furaldehyde was used as the starting material; the yield was 27%; 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.63(d,J=7.64Hz,1H),7.52(s,1H),7.47(t,J=8.00Hz,1H),7 .31(s,2H),7.25(d,J=9.96Hz,1H),5.43(d,J=7.68Hz,1H),3.84(s,3H),3.78(s,6H),3.68(s,3H). 13 C NMR(100MHz,DMSO-d6)δ176.38,172.18,163.47,159.98,152.99(2C),137.99,136.79,130.48,12 6.53,121.16,120.36,113.07,104.62(2C),102.06,98.46,73.03,60.54,56.22(2C),55.86.HRMS calcd for C 22 H 23O8[M+H] + :415.1393,found:415.1389.

[0137] Example 4: Preparation of 2-hydroxy-2-(5-(4-methoxyphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0138] 2-Hydroxy-2-(5-(4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 5-(4-methoxyphenyl)-2-furaldehyde was used as the starting material; the yield was 22%; 1 H NMR(400MHz,DMSO-d6)δ7.58(d,J=8.00Hz,2H),6.99(d,J=8.00Hz,2H),6.92(s ,2H),6.68(d,J=3.20Hz,2H),6.24(d,J=3.20Hz,2H),3.78(s,3H),3.74(s,9H). 13 C NMR(100MHz,DMSO-d6)δ173.29,159.23,153.16,152.75(2C),152.63,137.59,136.51,131.02 (2C),129.88,125.36(2C),114.45(2C),110.74,104.75,74.18,60.51,56.49(2C),56.31.HRMS calcdfor C 22 H 23 O8[M+H] + :415.1393,found:415.1395.

[0139] Example 5: Preparation of 2-hydroxy-2-(5-(3-chlorophenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0140] 2-Hydroxy-2-(5-(3-chlorophenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 5-(3-chlorophenyl)-2-furaldehyde was used as the starting material; the yield was 21%; 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.66(s,1H),7.59(d,J=7.76Hz,1H),7.44( t,J=7.92Hz,1H),7.32(d,J=7.76Hz,1H),6.94(s,3H),6.28(s,1H),3.62(s,9H). 13C NMR(100MHz,DMSO-d6)δ172.73,156.98,152.58(2C),151.16,137.42,136.70,134.19,132.64,13 1.37,127.55,123.14,122.28,110.74,108.07,104.37(2C),70.20,60.50,56.26(2C).HRMScalcd for C 21 H 20 ClO7[M+H] + :419.0898,found:419.0894.

[0141] Example 6: Preparation of 2-hydroxy-2-(5-(4-chlorophenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0142] 2-Hydroxy-2-(5-(4-chlorophenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 5-(4-chlorophenyl)-2-furaldehyde was used as the starting material; the yield was 19%; 1 H NMR (400MHz, DMSO-d6) δ8.19 (s, 1H), 7.67 (d, J = 8.52Hz, 2H), 7.48 (d, J = 8.52Hz, 2H),6.92(s,1H),6.91(s,2H),6.31(d,J=3.36Hz,1H),3.77(s,6H),3.74(s,3H). 13 C NMR(100MHz,DMSO-d6)δ176.53,156.08,152.98(2C),152.70,139.15,135.28,130.63(2C) ,129.45(2C),126.62,125.50,111.02,107.38,104.58(2C),76.63,60.54,56.23(2C).HRMS calcd forC 21 H 20 ClO7[M+H] + :419.0898,found:419.0898.

[0143] Example 7: Preparation of 2-hydroxy-2-(5-(3,5-dimethylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0144] 2-Hydroxy-2-(5-(3,5-dimethylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 5-(3,5-dimethylphenyl)-2-furaldehyde was used as the raw material; the yield was 30%; 1 HNMR(400MHz,DMSO-d6)δ8.14(s,1H),7.28(s,2H),7.24(s,1H),6.93(s,2H),6.79 (d,J=3.32Hz,1H),6.27(d,J=3.32Hz,1H),3.76(s,6H),3.74(s,3H),2.29(s,6H). 13 C NMR(100MHz,DMSO-d6)δ173.17,155.39,153.30,152.68(2C),138.35(2C),137.64,136.34,130. 62,129.52,121.56(2C),110.78,106.27,104.47(2C),76.65,60.47,56.29(2C),21.38(2C).HRMS calcd for C 23 H 25 O7[M+H] + :413.1600,found:413.1598.

[0145] Example 8: Preparation of 2-hydroxy-2-(5-(3-fluoro-4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0146] Hydroxy-2-(5-(3-fluoro-4-methylphenyl)furan-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that (3-fluoro-4-methylphenyl)-2-furaldehyde was used as the starting material; the yield was 23%; 1 HNMR(400MHz,DMSO-d6)δ7.48(t,J=7.72Hz,1H),7.40(dd,J1=3.64Hz,J2=1.28Hz,1H),7.34(d,J=7.84Hz ,1H),6.91(s,2H),6.89(d,J=3.40Hz,1H),6.29(d,J=3.40Hz,1H),3.77(s,3H),3.75(s,6H),2.24(s,3H). 13C NMR(100MHz,DMSO-d6)δ173.08,162.31,155.83,152.97,152.69(2C),137.65,132.67,131.33,13 0.48,124.76,123.85,119.59,110.90,107.17,104.42(2C),76.61,60.47,56.30(2C),14.63.HRMS calcd for C 22 H 22 FO7[M+H] + :417.1350,found:417.1349.

[0147] Example 9: Preparation of 2-hydroxy-2-(4-phenylthiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0148] 2-Hydroxy-2-(4-phenylthiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-phenyl-2-thiophenecarboxaldehyde was used as the raw material; the yield was 30%; 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.76(s,1H),7.64(d,J=7.64Hz,2H),7.50(s,1H),7.39( t,J=7.48Hz,2H),7.27(t,J=7.24Hz,1H),6.93(s,1H),6.89(s,2H),3.74(s,6H),3.67(s,3H). 13 C NMR(100MHz,DMSO-d6)δ174.01,152.73(2C),149.35,140.77,139.04,137.54,135.71,1 29.39(2C),127.52,126.27(2C),124.68,121.13,104.22(2C),78.49,60.46,56.32(2C).

[0149] Example 10: Preparation of 2-hydroxy-2-(5-(4-methylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0150] 2-Hydroxy-2-(5-(4-methylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(4-methylphenyl)-2-thiophenecarboxaldehyde was used as the starting material; the yield was 31%; 1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.15(s,1H),7.68(s,1H),7.53(d,J=8.00Hz,2H),7 .47(s,1H),7.20(d,J=7.92Hz,2H),6.89(s,2H),3.73(s,6H),3.67(s,3H),2.30(s,3H). 13 CNMR(100MHz,DMSO-d6)δ174.02,152.70(2C),149.27,140.73,139.12,137.53,136.72,132.97 ,129.92(2C),126.13(2C),124.59,120.31,104.26(2C),78.47,60.43,56.52(2C),21.11.HRMS calcd for C 22 H 22 NaO6S[M+Na] + :437.1035,found:437.1030.

[0151] Example 11: Preparation of 2-hydroxy-2-(5-(3-methoxyphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0152] 2-Hydroxy-2-(5-(3-methoxyphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(3-methoxyphenyl)-2-thiophenecarboxaldehyde was used as the starting material; the yield was 32%; 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),7.79(d,J=1.24Hz,1H),7.48(d,J=1.28Hz,1H),7.31(t,J=7.88Hz,1H),7. 25(s,1H),7.20(d,J=7.80Hz,1H),7.17(d,J=1.88Hz,1H),6.87(s,2H),3.80(s,3H),3.73(s,6H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.96,160.18,152.72(2C),149.15,140.66,139.00,137.53,137.10,13 0.46,124.79,121.49,118.70,113.12,111.77,104.20(2C),78.46,60.46,56.33(2C),55.56.HRMS calcd forC23 H 21 ClNaO6[M+H] + :431.1164,found:431.1164.

[0153] Example 12: Preparation of 2-hydroxy-2-(5-(4-methoxyphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0154] 2-Hydroxy-2-(5-(4-methoxyphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(4-methoxyphenyl)-2-thiophenecarboxaldehyde was used as the starting material; the yield was 30%; 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.14(s,1H),7.61(s,1H),7.56(d,J=8.68Hz,2H),7 .42(s,1H),6.95(d,J=8.68Hz,2H),6.87(s,2H),3.77(s,3H),3.73(s,6H),3.66(s,3H). 13 CNMR(100MHz,DMSO-d6)δ173.98,158.89,152.68(2C),149.23,140.49,139.18,137.49,128.50 ,127.46(2C),124.55,119.43,114.74(2C),104.25(2C),78.45,60.45,56.33(2C),55.78.HRMS calcd for C 22 H 23 O7S[M+H] + :431.1164,found:431.1161.

[0155] Example 13: Preparation of 2-hydroxy-2-(5-(3-chlorophenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0156] 2-Hydroxy-2-(5-(3-chlorophenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(3-chlorophenyl)-2-thiophenecarboxaldehyde was used as the starting material; the yield was 27%; 1H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.90(s,1H),7.73(s,1H),7.62(d,J=7.16Hz,1H),7.53( s,1H),7.42(t,J=9.76Hz,1H),7.33(d,J=7.16Hz,1H),6.88(s,2H),3.73(s,6H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.89,152.72(2C),149.78,139.18,139.07,137.77,137.52,134.19 ,131.23,127.28,125.93,124.93,124.50,122.38,104.18(2C),78.44,60.45,56.34(2C).HRMS calcd for C 21 H 19 ClNaO6S[M+Na] + :457.0489,found:457.0488.

[0157] Example 14: Preparation of 2-hydroxy-2-(5-(4-chlorophenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0158] 2-Hydroxy-2-(5-(3-chlorophenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(4-chlorophenyl)-2-thiophenecarboxaldehyde was used as the starting material; the yield was 25%; 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.82(d,J=1.20Hz,1H),7.68(d,J=8.52Hz,2H),7 .47(d,J=1.28Hz,1H),7.44(d,J=8.52Hz,2H),6.86(s,2H),3.73(s,6H),3.66(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.90,152.73(2C),149.63,139.42,138.95,137.54,134.53,132.00 ,129.33(2C),128.03(2C),124.52,121.77,104.15(2C),78.44,60.46,56.34(2C).HRMScalcd for C 21 H 19 ClNaO6S[M+Na]+ :457.0489,found:457.0484.

[0159] Example 15: Preparation of 2-hydroxy-2-(5-(3,5-dimethylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0160] 2-Hydroxy-2-(5-(3,5-dimethylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(3,5-dimethylphenyl)-2-thiophenecarboxaldehyde was used as the raw material; the yield was 26%; 1 HNMR(400MHz,DMSO-d6)δ8.14(s,1H),8.09(s,1H),7.70(s,1H),7.47(s,1H), 7.24(s,2H),6.90(s,1H),6.86(s,2H),3.73(s,6H),3.66(s,3H),2.29(s,6H). 13 C NMR(100MHz,DMSO-d6)δ174.00,152.70(2C),149.08,140.95,138.32(2C),137.55,135.59,12 9.94,129.00,124.76,124.07(2C),120.78,104.31(2C),78.48,60.46,56.34(2C),21.41(2C).

[0161] Example 16: Preparation of 2-hydroxy-2-(5-(3-fluoro-4-methylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0162] 2-Hydroxy-2-(5-(3-fluoro-4-methylphenyl)thiophen-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1, except that 4-(3-fluoro-4-methylphenyl)-2-thiophenecarboxaldehyde was used as the starting material; the yield was 21%; 1 H NMR (400MHz, DMSO-d6) δ9.87 (s, 1H), 7.81 (d, J = 1.52Hz, 1H), 7.49 (d, J = 1.52Hz, 1H), 7.45 (dd, J1 = 11.36Hz, J2 = 1.44Hz, 1H),7.39(dd,J1=7.80Hz,J2=1.84Hz,1H),7.29(t,J=8.08Hz,1H),6.87(s,2H),3.73(s,6H),3.66(s,3H),2.23(s,3H). 13C NMR(100MHz,DMSO-d6)δ173.92,161.52,152.73(2C),149.41,139.56,138.97,137.55,135.48,13 2.44,124.53,123.21,121.99,121.52,112.56,104.19(2C),78.44,60.45,56.34(2C),14.32.HRMS calcd for C 22 H 21 FNaO6S[M+Na] + :455.0941,found:455.0942.

[0163] Example 17: Preparation of 2-hydroxy-2-(2-phenylthiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0164] 2-Hydroxy-2-(2-phenylthiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 2-phenyl-4-thiazolecarboxaldehyde was used as the raw material; the yield was 21%; 1 H NMR (400MHz, DMSO-d6) δ7.92(s,1H),7.48(s,5H),7.38(s,1H),7.07(s,2H),3.75(s,6H),3.68(s,3H). 13 C NMR(100MHz,DMSO-d6)δ172.54,166.78,160.17,152.42(2C),137.74,137.30,133.57, 130.63,129.63(2C),126.51(2C),117.71,105.08(2C),78.57,60.40,56.21(2C).HRMS calcd forC 20 H 20 NO6S[M+H] + :402.1011,found:402.1008.

[0165] Example 18: Preparation of 2-hydroxy-2-(2-(4-methylphenyl)thiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0166] 2-Hydroxy-2-(2-(4-methylphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 2-(4-methylphenyl)-4-thiazolecarboxaldehyde was used as the starting material; the yield was 37%; 1H NMR (400MHz, DMSO-d6) δ8.22(s,1H),8.14(s,1H),7.81(d,J=8.00Hz,2H),7.32(s ,1H),7.31(d,J=8.10Hz,2H),7.03(s,2H),3.75(s,6H),3.68(s,3H),2.36(s,3H). 13 C NMR(100MHz,DMSO-d6)δ173.94,166.98,159.67,152.47(2C),140.53,137.39,137.34,130 .97,130.21(2C),126.46(2C),117.28,105.00(2C),78.40,60.44,56.26(2C),21.37.HRMS calcd forC 21 H 22 NO6S[M+H] + :416.1168,found:416.1165.

[0167] Example 19: Preparation of 2-hydroxy-2-(2-(4-methoxyphenyl)thiazol-4-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0168] 2-Hydroxy-2-(2-(4-methoxyphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 2-(4-methoxyphenyl)-4-thiazolecarboxaldehyde was used as the starting material; the yield was 34%; 1 H NMR (400MHz, DMSO-d6) δ8.22(s,1H),8.14(s,1H),7.85(d,J=8.80Hz,2H),7.27(s ,1H),7.05(d,J=8.80Hz,2H),7.02(s,2H),3.82(s,3H),3.75(s,6H),3.68(s,3H). 13 C NMR(100MHz,DMSO-d6)δ174.00,166.76,161.31,159.55,152.45(2C),137.40,137.36,128 .10(2C),126.39,116.68,115.02(2C),105.00(2C),78.38,60.44,56.26(2C),55.83.HRMS calcdfor C 21 H 22 NNaO7S[M+Na] + :454.0936,found:454.0404.

[0169] Example 20: Preparation of 2-hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0170] 2-Hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-phenyl-2-thiazolecarboxaldehyde was used as the raw material; the yield was 27%; 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.92(d,J=7.84Hz,2H),7.51(s,1H),7.49(s,2H),7.37(s,1H),7.04(s,2H),3.75(s,6H),3.68(s,3H). 13 C NMR(100MHz,DMSO-d6)δ174.01,166.80,163.56,152.45(2C),137.31,133.55,130.70, 129.70(2C),128.94,126.53(2C),117.81,104.95(2C),78.41,60.44,56.25(2C).HRMS calcd for C 20 H 20 NO6S[M+H] + :402.1011,found:402.0999.

[0171] Example 21: Preparation of 2-hydroxy-2-(2-(4-methylphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0172] 2-Hydroxy-2-(2-(4-methylphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(4-methylphenyl)-2-thiazolecarboxaldehyde was used as the starting material; the yield was 27%; 1 H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.93(s,1H),7.80(d,J=8.12Hz,2H),7 .22(d,J=7.96Hz,2H),6.83(s,1H),3.76(s,6H),3.63(s,3H),2.32(s,3H). 13C NMR(100MHz,DMSO-d6)δ176.38,154.56,153.18(3C),138.73,137.69,137.33,132.07 ,129.78(2C),126.28(2C),113.54,104.13(2C),72.79,60.44,56.34(2C),21.26.HRMS calcd for C 21 H 22 NO6S[M+H] + :416.1168,found:416.1174.

[0173] Example 22: Preparation of 2-hydroxy-2-(2-(4-methoxyphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0174] 2-Hydroxy-2-(2-(4-methylphenyl)thiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 4-(4-methoxyphenyl)-2-thiazolecarboxaldehyde was used as the starting material; the yield was 21%; 1 H NMR (400MHz, DMSO-d6) δ7.86 (s, 1H), 7.85 (d, J = 8.84Hz, 2H), 6.98 (d, J = 8.44Hz, 2H), 6.85 (s, 2H), 3.77 (s, 9H), 3.64 (s, 3H). 13 C NMR(100MHz,DMSO-d6)δ176.34,159.52,154.40,153.25,153.18(2C),138.79,137.29,1 27.70(2C),127.57,114.57(2C),112.33,104.10(2C),72.79,60.43,56.32(2C),55.59.

[0175] Example 23: Preparation of 2-hydroxy-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0176] 2-Hydroxy-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1 except that 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde was used as the starting material; the yield was 26%; 1HNMR(400MHz,DMSO-d6)δ7.69(d,J=7.20Hz,2H),7.64(s,1H),7.36(t,J=7.20Hz, 2H),7.20(t,J=7.20Hz,1H),6.73(s,2H),3.70(s,6H),3.68(s,3H),3.43(s,3H). 13 C NMR(100MHz,DMSO-d6)δ163.51,153.13(2C),152.68,138.22,137.74,137.44,136.94,1 28.95(2C),126.63,124.64(2C),119.31,103.81(2C),68.73,60.44,56.27(2C),33.63.

[0177] Example 24: Preparation of 2-hydroxy-2-(1-methyl-4-(4-methylphenyl)-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0178] 2-Hydroxy-2-(1-methyl-4-(4-methylphenyl)-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1, except that 1-methyl-4-(4-methylphenyl)-1H-imidazole-2-carbaldehyde was used as the starting material; the yield was 22%; 1 H NMR (400MHz, DMSO-d6) δ7.56(s,3H),7.15(s,2H),6.75(s,2H),3.69(s,9H),3.44(s,3H),2.29(s,3H). 13 C NMR(100MHz,DMSO-d6)δ172.90,153.06(2C),149.15,138.46,137.85,136.87,135.54,132. 10,129.10(2C),124.53(2C),118.71,103.75(2C),77.06,60.43,56.24(2C),33.50,21.18.

[0179] Example 25: Preparation of 2-hydroxy-2-(1-methyl-4-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid

[0180] 2-Hydroxy-2-(1-methyl-4-(4-methoxyphenyl)-1H-imidazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid was prepared by the same method as in Example 1, except that 1-methyl-4-(4-methoxyphenyl)-1H-imidazole-2-carbaldehyde was used as the starting material; the yield was 29%; 1 H NMR (400MHz, DMSO-d6) δ8.13(s,2H),7.73(s,1H),6.99(s,2H),6.78(s,2H),3.76(s,3H),3.71(s,9H),3.38(s,3H). 13 C NMR(100MHz,DMSO-d6)δ170.79,158.76,153.15,152.59(2C),147.25,137.50,136.05,132. 19,127.45(2C),125.66,114.36(2C),104.93(2C),77.67,60.46,56.33(2C),55.54,49.04.

[0181] Example 26: Preparation of methyl 2-hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetate

[0182] 2-Hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetic acid (0.42 g, 0.01 mol) was dissolved in methanol, and concentrated sulfuric acid was added dropwise to the solution. The reaction was refluxed for 2 h. After completion of the reaction, the mixture was concentrated, and water (100 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (30 mL x 3). The organic extract was collected and washed once with saturated NaCl solution. The organic phase was collected, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to obtain a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ8.00(s,1H),7.80(d,J=8.08Hz,2H),7.23(d,J=8.00Hz,2 H),6.77(s,2H),5.65(s,1H),3.77(s,6H),3.65(s,3H),3.41(s,3H),2.31(s,3H).

[0183] Example 27: Preparation of ethyl 2-hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)carboxylate

[0184] Ethyl 2-hydroxy-2-(4-phenylthiazol-2-yl)-2-(3,4,5-trimethoxyphenyl)acetate was prepared by the same method as in Example 26 except that ethanol was used as the starting material; the yield was 86%; 1H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.79(d,J=8.12Hz,2H),7.22(d,J=7.96Hz,2H),6.79(s,2H),5 .75(s,1H),3.77(s,6H),3.64(s,3H),3.61(q,J=2.76Hz,2H),2.31(s,3H),1.22(t,J=7.00Hz,3H).

[0185] Example 28: Anti-tumor activity test of the compounds of the present invention

[0186] The in vitro activity test methods and results are as follows:

[0187] The specific operation is as follows: 1. Take cells in the logarithmic growth phase and add 3-5×10 3 2. After incubation at 37°C in a CO2 incubator for 12 hours, dilute the compound to a concentration of 10 μg / mL in serum-free medium and add it to the 96-well plate for a further 72 hours. 3. Discard the supernatant and add 20 μL of freshly prepared 5 mg / mL MTT to each well. Incubate at 37°C for 4 hours. Discard the supernatant and add 150 μL of DMSO to each well. Vortex for 15 minutes to fully dissolve the formazan. Measure the absorbance (OD) at 492 nm.

[0188] Among them, colchicine reported in the literature was the positive experimental group.

[0189] Cell lines: human breast cancer cell line (MCF-7 cell line), human gastric cancer cell line (SGC-7901 cell line), human lung cancer cell line (A549 cell line)

[0190] Effect time: 72 hours

[0191] Inhibition rate calculation formula:

[0192]

[0193] The inhibition rate of each compound on the growth of three tumor cells (10 μg / mL) is shown in Table 1.

[0194] Table-1

[0195]

[0196] As shown in Table 1, all compounds achieved inhibition rates exceeding 60% against the three tumor cell lines at a concentration of 10.0 μg / mL. Compound 21 exhibited the highest inhibition rate, exceeding that of the positive control, colchicine, against both the human gastric cancer cell line SGC-7901 and the human lung cancer cell line A549.

[0197] The compounds of the present invention were then used to conduct anti-tumor activity tests in animals, using compound 21 as an example:

[0198] Compound 21 with good in vitro activity was selected for in vivo anti-tumor activity testing in animals. The model used was the mouse S-180 sarcoma model, and the positive control drug was the clinically commonly used anti-tumor drug fluorouracil (5-Fu).

[0199] Experimental method: 18-22g female Kunming mice were selected with well-grown 7-11-day-old S-180 tumors. The tumor tissue was made into a cell suspension and inoculated subcutaneously into the right axilla of the mice, with a volume of approximately 1.0-2.0×10 6 1 cell / animal. 24 hours after inoculation, animals were randomly divided into cages and intraperitoneally injected for 7 consecutive days. 24 hours after drug withdrawal, animals were sacrificed, body and tumor weights were weighed, and the average tumor weight of each group was calculated. The tumor inhibition rate was calculated according to the following formula and a t-test was performed.

[0200] Tumor inhibition rate = [(average tumor weight of blank control group - average tumor weight of treatment group) / (average tumor weight of blank control group)] × 100%

[0201] The experimental results are shown in Table 2

[0202] Table-2

[0203]

[0204] The experimental results above demonstrate that Compound 21 achieved a tumor inhibition rate of 69.9%, comparable to that of the positive control, fluorouracil. Mouse weight data indicate that while the positive control, fluorouracil, group exhibited slow weight gain, the Compound 21 group maintained weight gain during the experiment, reaching a weight comparable to that of the blank control group at the end. This suggests that Compound 21 exhibits minimal toxicity in mice and demonstrates a favorable safety profile.

Claims

1. A 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compound, characterized in that: The compound is a compound represented by the general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof; Wherein, in the general formula M, V is S, NCH3 or CH, U is O, N or CH, W is S or CH; R 1 、R 2 、R 2 、R 4 、R 5 R may be the same or different and each independently represents hydrogen, C1-C6 alkyl, C1-C6 alkyloxy, halogen, acetyl, nitro, hydroxy, C1-C6 haloalkyl, or amino which is unsubstituted or substituted with at least one C1-C6 alkyl; 6 It is hydrogen or C1-C6 alkyl.

2. The compound according to claim 1, wherein The compound is a compound represented by the general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof; In the general formula M, V is S, NCH3 or CH, U is O, N or CH, and W is S or CH; R 1 、R 2 、R 2 、R 4 、R 5 R may be the same or different and each independently represents hydrogen, C1-C3 alkyl, C1-C3 alkyloxy, halogen, acetyl, nitro, hydroxy, C1-C3 haloalkyl, or amino which is unsubstituted or substituted with at least one C1-C6 alkyl; 6 It is hydrogen or C1-C3 alkyl.

3. The compound according to claim 2, wherein The compound is a compound represented by the general formula M or a pharmaceutically acceptable salt, racemate, solvate or hydrate thereof; In the general formula M, V is S, NCH3 or CH, U is O, N or CH, and W is S or CH; R 1 、R 2 、R 2 、R 4 、R 5 R may be the same or different and each independently represents hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, acetyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, hydroxyl, or trifluoromethyl; 6 It is hydrogen, methyl, and ethyl.

4. The compound according to any one of claims 1 to 3, characterized in that The salt is a salt formed by the compound represented by general formula M and an acid or base, the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, and malic acid, and the base is selected from sodium hydroxide, sodium carbonate, and potassium hydroxide; the hydrate of the compound represented by general formula M, the number of crystal waters of the hydrate is any real number between 0 and 16.

5. A method for preparing 2-hydroxy-2-(3,4,5-trimethoxyphenyl)acetic acid compounds according to any one of claims 1 to 4, characterized in that: Starting from 3,4,5-trimethoxybenzaldehyde I, 2-hydroxy-2-aryl-2-(3,4,5-trimethoxyphenyl)acetic acid compounds are obtained through addition, hydroxyl protection, substitution, deprotection, oxidation, rearrangement, esterification and other reactions. The reaction formula is:

6. The preparation method according to claim 5, wherein: (1) 3,4,5-trimethoxybenzaldehyde I and dimethyl phosphite are dissolved in methanol, and sodium methoxide is added to cause an addition reaction to obtain compound II; (2) Compound II and 3,4-dihydro-2H-pyran are dissolved in toluene, and p-toluenesulfonic acid is added to protect the hydroxyl group to obtain compound III; (3) Compound III is dissolved in anhydrous tetrahydrofuran, n-butyl lithium is added, and then compound IV is added. After the reaction is completed, the crude product is dissolved in methanol, and hydrochloric acid is added dropwise to obtain compound V; (4) dissolving compound V and selenium dioxide in dimethyl sulfoxide to undergo oxidation reaction to obtain compound VI; (5) Compound VI and potassium hydroxide are dissolved in n-butanol to produce compound VII by benzyl alcohol rearrangement; (6) Compound VII is dissolved in alcohol, concentrated sulfuric acid is added, and an esterification reaction occurs to obtain compound M.

7. A pharmaceutical composition, characterized in that: The composition comprises the compound represented by the general formula M according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, racemate, solvate or hydrate; the content thereof is 0.01-99% by mass of the composition.

8. The use of the compound of claim 1 or the composition of claim 7, wherein: The use of the compound of formula M shown in claim 1 or its pharmaceutically acceptable salt, racemate, solvate or hydrate or the composition according to claim 7 in the preparation of anti-tumor drugs.

9. The use according to claim 8, characterized in that The tumor is a human breast cancer, gastric cancer or lung cancer tumor strain.

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