A carboxyl-substituted quinoxalinone derivative and its preparation method and application

Abstract

The present invention discloses a carboxyl-substituted quinoxalinone derivative and a preparation method and application thereof, and belongs to the technical field of synthetic drugs. The present invention provides a novel compound having a strong specific inhibitory ability against aldose reductase. By extracting aldose reductase from rat lens and conducting an activity assay experiment on the inhibitory activity of the compound, it is proved that the compound of the present invention has significant AKR1B1 inhibitory activity; by extracting aldehyde reductase from rat kidney and conducting an activity assay experiment on the inhibitory activity of the compound, the inhibitory selectivity of aldose reductase is evaluated, and it is proved that the compound of the present invention has high safety, can reduce toxic side effects, and achieve the effect of treating diabetic complications.

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic drugs, and specifically relates to a carboxyl-substituted quinoxalinone derivative and a preparation method and application thereof. Background Art

[0002] Diabetes has become the world's third most lethal disease after cancer and cardiovascular disease. Continuous high blood sugar in diabetic patients will cause a series of damage to the body of diabetic patients, and then develop into diabetic complications, such as diabetic neuropathy, diabetic nephropathy and diabetic retinopathy, which are the main causes of death in diabetic patients. Clinical experiments have shown that the abnormal increase in the glucose polyol pathway under the stimulation of continuous high blood sugar is the main cause of diabetic complications, and aldose reductase is the key rate-limiting enzyme in this metabolic pathway. Therefore, taking aldose reductase as a drug intervention target and creating aldose reductase inhibitors is an important way to discover drugs against diabetic complications.

[0003] Aldose reductase (AKR1B1) is an oxidoreductase widely present in mammalian cells. It uses phosphoamido adenine dinucleotide (NADPH) as a coenzyme to catalyze the reduction of a series of carbonyl compounds, including glucose. Under normal blood glucose concentrations, aldose reductase has a very weak affinity for glucose, and only trace amounts of glucose react with aldose reductase. However, under high blood glucose concentrations, the polyol pathway is activated, and a large amount of glucose is reduced to sorbitol through aldose reductase, which directly leads to a large consumption of intracellular NADPH and a large amount of sorbitol production. Sorbitol is converted into sorbitol in the human body through sorbitol dehydrogenase and the coenzyme NAD + Sorbitol dehydrogenase is an enzyme that metabolizes sorbitol, but its function is limited. This causes a large amount of sorbitol to accumulate in the cells, triggering a series of stress responses, which leads to the onset of diabetic complications.

[0004] Carboxylic acid aldose reductase inhibitors are the most studied aldose reductase inhibitors. Since the carboxyl functional group has the conditions to form strong hydrogen bonds with aldose reductase, most of them show excellent aldose reductase inhibitory activity and have excellent prospects for the development of anti-diabetic complications drugs. Epalrestat is the only aldose reductase inhibitor currently on the market for the treatment of diabetic complications, but the drug has failed to pass FDA certification due to its low in vivo activity and severe side effects. It can only be sold and used in a few Asian countries. Currently, no anti-diabetic complication drug can be circulated worldwide. Therefore, the development of a safe and effective aldose reductase inhibitor is a key issue that needs to be urgently addressed in the current anti-diabetic complication discovery process. Summary of the invention

[0005] Technical problem to be solved: In response to the above technical problem, the present invention provides a carboxyl-substituted quinoxalinone derivative and a preparation method and application thereof. The compound has a strong specific inhibitory ability against aldose reductase, and has high safety and low toxic and side effects, and can be used for the prevention and treatment of diabetic complications.

[0006] Technical solution: A carboxyl-substituted quinoxalinone derivative, the structural formula of which is:

[0007]

[0008] Among them, R 1 -CH 2 COOH, R 2 It is a hydrogen atom, a halogen atom or a nitro group.

[0009] The preparation method of the carboxyl-substituted quinoxalinone derivative having the structure of formula (I) is as follows:

[0010]

[0011] Preferably, the reaction from Ia to Ib is as follows: Ia is used as a raw material and acetonitrile is used as a solvent, and methyl bromoacetate is refluxed at 60-70° C. After the reaction is completed, the reaction system temperature is cooled, filtered, and concentrated to obtain a solid, and the solid is then slurried and purified with petroleum ether to obtain Ib.

[0012] Furthermore, the reflux reaction is terminated when the raw material spot disappears as detected by thin layer chromatography.

[0013] Preferably, the reaction from Ib to Ic is as follows: Ib is used as a raw material, and a hydrogenation reaction of a carbon-nitrogen double bond is carried out under hydrogen pressure conditions, using Pd / C as a catalyst and anhydrous ethanol as a solvent. After the reaction is completed, the filtrate is filtered and concentrated to obtain a crude product, and the crude product is subjected to column chromatography to obtain Ic.

[0014] Furthermore, the pressurization condition is 1.5-3.0Mpa.

[0015] Preferably, the reaction from Ic to Id is as follows: Ic is used as a raw material, acetonitrile and potassium carbonate are added, and the mixture is heated to 60-70° C. After the reflux reaction is completed, the mixture is cooled, filtered, and the filtrate is concentrated to obtain a crude product, and the crude product is purified by column chromatography to obtain Id.

[0016] Preferably, the reaction from Id to Ie is as follows: Id is used as a raw material, tetrahydrofuran and a saturated lithium hydroxide aqueous solution are added, the reaction is stirred, after the reaction is completed, rotary evaporation is performed, the remaining aqueous phase is adjusted to acidity, and the filter cake is filtered to obtain Ie.

[0017] A pharmaceutical composition comprises a carboxyl-substituted quinoxalinone derivative of a structure shown in formula (I) and a pharmaceutically acceptable carrier.

[0018] Use of a carboxyl-substituted quinoxalinone derivative of the structure shown in formula (I) in the preparation of a drug for preventing and / or treating diabetic complications.

[0019] Beneficial effects: The present invention provides a class of novel compounds with strong specific inhibitory ability against aldose reductase and a preparation method thereof. The inhibitory activity of the compounds against aldose reductase extracted from rat lens is tested for activity, which proves that the compounds have significant AKR1B1 inhibitory activity. The inhibitory activity of the compounds against aldehyde reductase extracted from rat kidney is tested for activity, and the inhibitory selectivity of aldose reductase is evaluated, which proves that the compounds of the present invention have high safety, can reduce toxic side effects, and achieve the effect of treating diabetic complications. DETAILED DESCRIPTION

[0020] The present invention will be further described below in conjunction with specific embodiments.

[0021] Example 1

[0022] Synthesis of 2-(1-benzyl-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 1)

[0023]

[0024] 4-Hydroxyquinazoline (20.53 mmol), potassium carbonate (41.05 mmol) and solvent acetonitrile (55 mL) were added to a three-necked flask in sequence, and finally methyl bromoacetate (22.58 mmol) was added. The resulting mixture was heated and refluxed at 65° C. for 2 h. The raw material point disappeared as monitored by thin layer chromatography (TLC). The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was slurried with petroleum ether (5 vol.) to obtain methyl 2-(4-oxoquinazoline-3(4H)-yl)acetate (4.37 g, yield 97.6%) as a white solid;

[0025] Methyl 2-(4-oxoquinazolin-3(4H)-yl)acetate (9.16 mmol) and Pd / C (1.0 g, 10%) were added to a three-necked flask, and then anhydrous ethanol (60 mL) was added as a solvent. The reaction system was placed in a pressurized hydrogen environment (1.5-3.0 MPa), and stirred at room temperature for 2.5 h. After the reaction was completed, the filtrate was filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography (volume ratio of petroleum ether: ethyl acetate = 3:1) to obtain methyl 2-(4-carbonyl-1,2-trimethyl-3(4h)-yl)acetate (1.92 g, yield 95.8%);

[0026] Methyl 2-(4-carbonyl-1,2-trimethyl-3(4h)-yl)acetate (4.54mmol) and potassium carbonate (9.09mmol) were added to a three-necked flask, acetonitrile was used as the reaction solvent (30mL), and finally benzyl bromide (5.00mmol) was added, the reaction system was heated, and refluxed at 65°C for 5h. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (volume ratio of petroleum ether: ethyl acetate = 2:1) to obtain methyl 2-(4-carbonyl-1,2-trimethyl-3(4h)-yl)acetate (1.25g, yield 89.3%) as a white solid;

[0027] Into a single-necked bottle, methyl 2-(4-carbonyl-1,2-trimethyl-3(4H)-yl)acetate (1.6 mmol), tetrahydrofuran (5 mL) and saturated aqueous lithium hydroxide solution (15 mL) were added in sequence, and the mixture was stirred at room temperature until the starting material disappeared (by thin-layer chromatography). The reaction mixture was rotary evaporated to remove most of the tetrahydrofuran, and the pH of the remaining reactants was adjusted to acidic (pH = 2-3) with 1M HCl aqueous solution. The mixture was stirred, precipitated, and the suspension was filtered to obtain 2-(1-benzyl-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (0.46 g, yield: 97.3%) as a white solid.

[0028] Melting point: 210-214°C; 1 H NMR (400 MHz, [D 6 ]DMSO)δ / ppm=7.93(dd,J=8.5,1.6Hz,1H),7.40(td,J=7.7,1.6Hz,1H),7.32–7 .18(m,6H),7.03(dd,J=7.4,1.4Hz,1H),4.89(s,2H),4.75(s,2H),4.29(s,2H); 13 C NMR (100MHz, [D 6 ]DMSO)δ / ppm=171.86,163.84,146.52,137.80,134.91,128.51,128.42,127.74,127.32,123.47,120.47,115.50,65.05,56.01,47.24.MS m / z:319.1[M+Na] + .

[0029] Example 2

[0030] Synthesis of 2-(1-(3-fluorobenzyl)-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 2)

[0031]

[0032] The benzyl bromide in Example 1 was replaced by 3-fluorobenzyl bromide and the product was prepared according to the preparation method described in Example 1.

[0033] Melting point: 217-219°C; 1 H NMR (400 MHz, [D 6 ]DMSO): δ / ppm=δ7.93(dd,J=8.5,1.6Hz,3H),7.43–7.30(m,6H),7.25–7.18(m,5H),7 .18–7.16(m,1H),7.10–7.00(m,9H),4.90(s,6H),4.70(t,J=1.0Hz,6H),4.29(s,6H); 13 C NMR (100MHz, [D 6 ]DMSO)δ / ppm=171.86,163.99,163.84,162.02,146.52,139.53,139.48,134.97,130.12,130.04,127.32, 124.34,124.32,123.47,120.47,116.03,115.86,115.51,113.21,113.03,65.05,55.86,55.83,47.24.MS m / z:337.1[M+Na] + .

[0034] Example 3

[0035] Synthesis of 2-(1-(3-chlorobenzyl)-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 3)

[0036]

[0037] The benzyl bromide in Example 1 was replaced by 3-chlorobenzyl bromide and the product was prepared according to the preparation method described in Example 1.

[0038] Melting point: 223-227°C; 1 H NMR (400 MHz, [D 6]DMSO): δ / ppm=7.93(dd,J=8.5,1.6Hz,1H),7.40(td,J=7.8,1.6Hz,1H),7.34(dt,J=8.1,1.6Hz,1H),7.28(t,J=8.1Hz,1H), 7.25(tt,J=2.0,1.1Hz,1H),7.25–7.18(m,2H),7.03(dd,J=7.5,1.4Hz,1H),4.89(s,2H),4.69(t,J=1.0Hz,2H),4.29(s,2H); 13 C NMR (100MHz, [D 6 ]DMSO)δ / ppm=171.86,163.84,146.53,138.58,134.91,134.30,130.22,129. 51,128.11,127.32,127.10,123.47,120.47,115.50,65.05,55.52,47.24.MS m / z:353.1[M+Na] + .

[0039] Example 4

[0040] Synthesis of 2-(1-(3-bromobenzyl)-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 4)

[0041]

[0042] The benzyl bromide in Example 1 was replaced by 3-bromobenzyl bromide and the product was prepared according to the preparation method described in Example 1.

[0043] Melting point: 231-234°C; 1 H NMR (400 MHz, [D 6 ]DMSO): δ / ppm=7.93(dd,J=8.5,1.6Hz,1H),7.44–7.35(m,3H),7.31–7.25(m,1H),7.25–7 .18(m,2H),7.03(dd,J=7.5,1.4Hz,1H),4.89(s,2H),4.68(t,J=1.0Hz,2H),4.29(s,2H); 13 C NMR (100MHz, [D 6 ]DMSO)δ / ppm= 13CNMR(125MHz,Common NMR Solvents)δ171.86,163.84,146.54,139.66,134.91,132.02,130.82,130.56,127.5 3,127.32,123.47,122.77,120.47,115.50,65.05,55.51,47.24; MSm / z:397.0[M+Na] + .

[0044] Example 5

[0045] Synthesis of 2-(1-(4-nitrobenzyl)-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 5)

[0046]

[0047] The benzyl bromide in Example 1 was replaced by 4-nitrobenzyl bromide and the product was prepared according to the preparation method described in Example 1.

[0048] Melting point: 226-229°C; 1 H NMR (400 MHz, [D 6 ]DMSO): δ / ppm=8.16–8.10(m,2H),7.93(dd,J=8.5,1.6Hz,1H),7.54(dt,J=8.6,1.1Hz,2H),7.40(td,J=7.8,1.6H z,1H),7.21(td,J=8.1,1.3Hz,1H),7.03(dd,J=7.5,1.4Hz,1H),4.89(s,2H),4.74(t,J=1.0Hz,2H),4.29(s,2H); 13 CNMR(100MHz,[D 6 ]DMSO)δ / ppm= 13 C NMR (125MHz, Common NMR Solvents)δ171.86,163.84,147.51,146.54,141.34,134.91,129.37,127.32,123.82,123.47,120.47,115.50,65.05,55.58,47.24; MS m / z:342.1[M+H] + ,364.1[M+Na] + .

[0049] Example 6

[0050] Synthesis of 2-(1-(2-fluorobenzyl)-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 6)

[0051]

[0052] The benzyl bromide in Example 1 was replaced by 2-fluorobenzyl bromide and the product was prepared according to the preparation method described in Example 1.

[0053] Melting point: 229-233°C; 1 H NMR (400 MHz, [D 6 ]DMSO): δ / ppm=7.83(dd,J=8.5,1.6Hz,1H),7.43–7.36(m,2H),7.30(dddd,J=8.6,7.7,4.0,1.6Hz,1H),7.20(dtd,J=14.8,8.5,1 .3Hz,2H),7.12(ddd,J=10.1,7.7,1.4Hz,1H),7.03(dd,J=7.5,1.4Hz,1H),4.91(s,2H),4.69(dd,J=3.7,1.0Hz,2H),4.29(s,2H); 13 C NMR (100MHz, [D 6 ]DMSO)δ / ppm=171.86,163.84,162.22,160.26,146.19,134.97,131.48,131.43,129.24,129.18,127.32, 125.24,125.12,124.82,124.79,123.47,120.13,115.58,115.50,115.33,65.02,52.10,52.06,47.24; MS m / z:315.1[M+H] + ,337.1[M+Na] + .

[0054] Example 7

[0055] Synthesis of 2-(1-(2-fluoro-4-bromobenzyl)-4-oxo-1,2-dihydro-quinazolin-3(4H)-yl)acetic acid (Compound 7)

[0056]

[0057] The benzyl bromide in Example 1 was replaced by 2-fluoro-4-bromobenzyl bromide and the product was prepared according to the preparation method described in Example 1.

[0058] Melting point: 238-242°C; 1 H NMR (400 MHz, [D 6]DMSO): δ / ppm=7.93(dd,J=8.5,1.6Hz,1H),7.43–7.34(m,2H),7.32–7.24(m,2H),7.28–7.1 8(m,1H),7.03(dd,J=7.5,1.4Hz,1H),4.91(s,2H),4.75(dd,J=3.6,0.7Hz,2H),4.29(s,2H); 13 C NMR (100MHz, [D 6 ]DMSO)δ / ppm=171.86,163.84,163.04,161.07,146.19,134.97,132.77,132.71,128.03,128.00,127.32, 124.71,124.59,123.47,120.94,120.87,120.13,119.40,119.23,115.58,65.02,52.04,52.00,47.24;MS m / z:415.0[M+Na] + .

[0059] Example 8 In vitro inhibition of aldose reductase by compounds and inhibition selectivity experiment

[0060] The target compounds 1-7 prepared in Examples 1-7 were subjected to in vitro inhibitory activity experiments on aldose reductase and aldehyde reductase using AKR1B1 extracted from rat lens and AKR1A1 extracted from kidney, respectively.

[0061] Materials preparation before the experiment: phosphate buffer solution for AKR1B1 inhibitory activity assay, sodium phosphate buffer solution 1 for AKR1A1 inhibitory activity assay, sodium phosphate buffer solution 2, sodium D-glucuronic acid solution, reduced nicotinamide adenine dinucleotide phosphate (NADPH) solution and D,L-glyceraldehyde solution. The specific preparation process is as follows:

[0062] (1) Prepare 0.1 M, pH 6.2 phosphate buffer solution for AKR1B1 inhibitory activity assay

[0063] Solution A: Accurately weigh 6.24 g NaH 2 PO 4 ·2H 2 O was dissolved in 200 mL of deionized water to make a 0.2 M solution;

[0064] Solution B: Accurately weigh 7.16 g Na 2 HPO 4 12H 2 O was dissolved in 100 mL of water to make a 0.2 M solution.

[0065] Accurately measure 163 mL of solution A and 37 mL of solution B, dilute with water to a final volume of 400 mL, adjust the pH to 6.2, and the phosphate buffer solution for AKR1B1 determination is prepared.

[0066] (2) Prepare 10 mM sodium phosphate buffer solution, pH = 7.2, for assay of AKR1A1 inhibitory activity

[0067] Accurately weigh 0.7602 g of sodium phosphate, 0.1618 g of dipotassium ethylenediaminetetraacetic acid, 17.1026 g of sucrose, and 0.0350 mL of β-mercaptoethanol and dissolve them in 200 mL of water. Adjust the pH to 7.2, and the sodium phosphate buffer solution 1 for determination is prepared.

[0068] (3) Prepare 10 mM sodium phosphate buffer solution, pH = 7.2, for assay of AKR1A1 inhibitory activity

[0069] Accurately weigh 0.7602 g of sodium phosphate, 0.1618 g of dipotassium ethylenediaminetetraacetic acid, and 0.0280 mL of β-mercaptoethanol and dissolve them in 200 mL of water. Adjust the pH to 7.2, and the sodium phosphate buffer solution 2 for AKR1A1 determination is prepared.

[0070] (4) Prepare 0.104 mM NADPH solution

[0071] Accurately weigh 0.0086 g of NADPH and dissolve it in 100 mL of phosphate buffer solution for AKR1B1 assay.

[0072] (5) Prepare 10 mM D,L-glyceraldehyde solution

[0073] Accurately 0.180 g of D,L-glyceraldehyde was dissolved in 100 mL of phosphate buffer solution for AKR1B1 assay.

[0074] (6) Preparation of 20 mM sodium D-glucuronic acid solution

[0075] 0.4682 g of sodium D-glucuronic acid was dissolved in 100 mL of sodium phosphate buffer solution 1.

[0076] (7) Handling of dialysis bags

[0077] ① Cut the dialysis bag into three 15 cm long sections and place the three dialysis bags in 2% (W / V) NaHCO 3 The mixture was boiled in a solution of 1 mM EDTA dipotassium salt (pH=8.0) for 10 min.

[0078] ② Rinse the dialysis bag with deionized water, and continue to place the dialysis bag in 1mM EDTA dipotassium salt (pH=8.0) and boil for 10 minutes.

[0079] ③ Cool the dialysis bag to room temperature and store it in a 4℃ cold water environment. Make sure the dialysis bag is always immersed in the solution and wear gloves when handling the dialysis bag. Fill the dialysis bag with water before use, then drain and clean it.

[0080] (8) Extraction of AKR1B1: The lens was quickly removed from the eyes of rats killed normally, 3-4 volumes of cold distilled water (0-4°C) were added, and then homogenized. The homogenate was centrifuged in a refrigerated centrifuge at 12000×g and 0-4°C for 30 min. The supernatant was taken, which was the aqueous solution of AKR1B1, and stored in a -45°C refrigerator for enzyme activity testing.

[0081] (9) Extraction of AKR1A1: The rats were killed, and the kidneys were removed by rapid dissection. A volume of 3 mL / g kidney of cooled (0-4°C) 10 mM sodium phosphate buffer 1 was added and homogenized using a Glas-Potter homogenizer. The homogenate was centrifuged in a low-temperature centrifuge at 12,000 × g and 0-4°C for 30 min. The supernatant was taken, saturated ammonium sulfate solution was added, stirred at 0-4°C for 30 min, and low-temperature centrifuged at 12,000 × g for 15 min. The supernatant was taken and the above steps were repeated to make the saturation of ammonium sulfate reach 55%, and then 75% saline solution. The precipitate after centrifugation of the 75% saturated ammonium sulfate solution was dissolved with 50 volumes of 10 mM sodium phosphate buffer 2 (pH = 7.2, containing 2.0 mM EDTA dipotassium salt, 2.0 mM β-mercaptoethanol), and dialyzed with this buffer overnight. The dialysis solution was an aqueous solution of AKR1A1, which was used for enzyme activity testing.

[0082] (10) Test of aldose reductase and aldehyde reductase activity: At 30°C, 0.25 mL of 0.104 mM NADPH, 0.25 mL of 0.1 M phosphate buffer solution (pH = 6.2), 0.1 mL of the extracted enzyme solution, and 0.15 mL of deionized water were added to a 1 mL measuring cuvette. Similarly, 0.25 mL of 0.104 mM NADPH, 0.50 mL of 0.1 M phosphate buffer solution (pH = 6.2), 0.1 mL of the extracted enzyme solution, and 0.15 mL of deionized water were added to a 1 mL reference cuvette. The two cuvettes containing the above mixed solutions were then kept at 30°C for 10 min. Finally, 0.25 mL of 10 mM substrate was added to the test cuvette to start the reaction. The UV-visible spectrophotometer was used to measure the absorbance at 340 nm for 5 min. A straight line was obtained with absorbance as the vertical axis and time as the horizontal axis. The slope of this straight line was calculated and recorded as I. 0, which is the enzyme activity. The optimal value of enzyme activity is when the NADPH absorbance changes within the range of 0.01±0.0010 (AKR1B1) or 0.015±0.0010 (AKR1A1) absorbance units / min. If it is not within this range, the enzyme solution concentration can be changed to reach this range. The control cuvette is added to the test cuvette to correct the oxidation of NADPH caused by non-enzymatic factors (such as oxygen in the air that also oxidizes NADPH).

[0083] (11) Test of compound inhibition percentage: Similar to the test of enzyme activity, 5 μL of the test compound solution was added to the test cuvette and the reference cuvette without adding substrate. The slope of the resulting straight line was recorded as I x Then the inhibition percentage at this concentration can be calculated according to the following formula.

[0084] I%=(|I 0 -I x | / |I 0 |)×100%

[0085] In the formula, I% represents the inhibition percentage, I 0 The slope of the linear regression equation for enzyme activity, I x It represents the slope of the linear regression line equation for enzyme activity after adding the compound.

[0086] Repeat the above activity determination experiment, measure the inhibition percentage under different concentrations of compound solutions, and summarize to get a straight line of "inhibition percentage" versus "concentration logarithm". Then calculate the logarithm of the concentration corresponding to 50% inhibition percentage, and the antilogarithm can get IC 50 .

[0087] The ability of the compounds to inhibit the activity of AKR1B1 and AKR1A1 in vitro is shown in Table 1.

[0088] Table 1 Inhibitory activity of compounds 1-7 against AKR1B1 and AKR1A1

[0089]

[0090]

[0091] a IC50 (μM) (95% CL) is the value measured in the experimental system implemented in the present invention.

[0092] b IC 50 AKR1A1 / IC 50 AKR1B1

[0093] The results of enzyme activity experiments showed that these compounds had significant inhibitory effects on aldose reductase in vitro, especially compound 7, with an enzyme inhibition IC 50 The value is 12nM, and these compounds have no obvious inhibitory effect on aldehyde reductase. Their selectivity is better than that of the positive control drug Epalrestat, indicating that this series of compounds have better safety and are more conducive to the development of universal drugs against diabetic complications.

Claims

1. A carboxyl-substituted quinoxalinone derivative, characterized in that: Its structural formula is: , wherein R2 is a halogen atom or a nitro group.

2. The method for preparing the carboxyl-substituted quinoxalinone derivative according to claim 1, characterized in that: The route is as follows: ， Wherein, R2 is a halogen atom or a nitro group.

3. The method for preparing a carboxyl-substituted quinoxalinone derivative according to claim 2, characterized in that: The specific reaction from Ia to Ib is as follows: Ia is used as a raw material and acetonitrile is used as a solvent, and reflux reaction is carried out with potassium carbonate and methyl bromoacetate at 60-70°C. After the reaction is completed, the temperature of the reaction system is cooled, filtered, and concentrated to obtain a solid, and then the solid is slurried and purified with petroleum ether to obtain Ib.

4. The method for preparing a carboxyl-substituted quinoxalinone derivative according to claim 3, characterized in that: The reflux reaction was terminated when the starting material disappeared as detected by thin layer chromatography.

5. The method for preparing a carboxyl-substituted quinoxalinone derivative according to claim 2, characterized in that: The specific reaction from Ib to Ic is as follows: Ib is used as the raw material, and a hydrogenation reaction of the carbon-nitrogen double bond is carried out under hydrogen pressure conditions, with Pd / C as a catalyst and anhydrous ethanol as a solvent. After the reaction is completed, the filtrate is filtered and concentrated to obtain a crude product, and the crude product is purified by column chromatography to obtain Ic.

6. The method for preparing a carboxyl-substituted quinoxalinone derivative according to claim 5, characterized in that: The pressurization condition is 1.5-3.0 Mpa.

7. The method for preparing a carboxyl-substituted quinoxalinone derivative according to claim 2, characterized in that: The reaction from Ic to Id is as follows: As raw materials, acetonitrile and potassium carbonate are added, and the mixture is heated to 60-70°C. After the reflux reaction is completed, the temperature is lowered, the filtrate is filtered, and the filtrate is concentrated to obtain a crude product. The crude product is purified by column chromatography to obtain Id.

8. The method for preparing a carboxyl-substituted quinoxalinone derivative according to claim 2, characterized in that: The specific reaction from Id to Ie is as follows: Id is used as a raw material, tetrahydrofuran and a saturated lithium hydroxide aqueous solution are added, and the reaction is stirred. After the reaction is completed, rotary evaporation is performed, the remaining aqueous phase is adjusted to acidity, and the filter cake is filtered to obtain Ie.

9. A pharmaceutical composition comprising the carboxyl-substituted quinoxalinone derivative according to claim 1 and a pharmaceutically acceptable carrier.

10. Use of the carboxyl-substituted quinoxalinone derivative according to claim 1 in the preparation of a drug for preventing and / or treating diabetic complications.

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