Anti-ROS (reactive oxygen species) multifunctional aldose reductase inhibitor as well as preparation method and application thereof

Abstract

The invention discloses an anti-ROS (reactive oxygen species) multifunctional aldose reductase inhibitor as well as a preparation method and application thereof. The anti-ROS multifunctional aldose reductase inhibitor is a 1, 2, 4-oxadiazole-5 (4H)-ketone derivative, the structural formula is shown in the specification, n represents the number of R and is a natural number, the R is independently selected from a hydrogen atom, a hydroxyl group or a halogen atom, and the anti-ROS multifunctional aldose reductase inhibitor has relatively strong inhibition capability on AKR1B1, has a relatively high dissociation constant and has anti-ROS activity. According to the invention, carboxyl in a carboxylic acid AKR1B1 inhibitor is replaced by an electron isomer 1, 2, 4-oxadiazole-5 (4H)-ketone of carboxyl, the dissociation degree of inhibitor molecules is improved under the condition of maintaining enzyme inhibition activity, the inhibitor molecules existing in a molecular form under physiological conditions are obtained, and the defect of low in-vivo utilization degree of carboxylic acid AKR1B1 is fundamentally solved. Besides, an anti-ROS structural feature is introduced into a traditional aldose reductase inhibitor structure, the oxidative stress state of the downstream of a polyhydric alcohol pathway is relieved, the synergistic effect is achieved, the application effect of medicine molecules is improved, and therefore the effect of treating diabetic complications is achieved.

Description

Technical Field

[0001] This invention relates to the fields of organic chemistry, medicinal chemistry, and pharmacotherapeutic science, and to a multifunctional aldose reductase inhibitor against ROS, its preparation method, and its uses. Specifically, it relates to a 1,2,4-oxadiazole-5(4H)-one derivative, its preparation method, and its applications. Background Technology

[0002] Diabetic complications are serious chronic complications that develop from poorly controlled blood sugar in diabetic patients, and are the leading cause of death and disability among diabetic patients. The main harm of diabetes comes from the various serious complications it causes.

[0003] Under sustained hyperglycemia, abnormally enhanced aldose reductase (AKR1B1) activity leads to an abnormally enhanced glucose polyol metabolic pathway (metabolic pathway such as...). Figure 1 Aldose metabolism (AKR1B1) is an important pathogenesis of diabetic complications. In the glucose polyol metabolic pathway, AKR1B1 is a key rate-limiting enzyme. Using AKR1B1 as a drug target, designing and synthesizing AKR1B1 inhibitors to inhibit aldose reductase activity and regulate the abnormal glucose metabolism caused by enhanced AKR1B1 activity is the preferred direction and important means for the discovery of drugs to combat diabetic complications.

[0004] Carboxylic acid aldose reductase inhibitors, due to the presence of one hydrogen bond donor and two hydrogen bond acceptors in their carboxyl structure, possess the conditions for strong hydrogen bonding with AKR1B1, exhibiting excellent in vitro AKR1B1 inhibitory activity and selectivity, and showing promising drug development prospects. However, the presence of a carboxyl group in their structure often results in a low pKa of carboxylic acid AKR1B1 inhibitors, which remain ionized under normal physiological pH conditions, leading to potential risks such as poor membrane permeability, metabolic instability, and toxic side effects. The only marketed aldose reductase inhibitor is a carboxylic acid AKR1B1 inhibitor, primarily used for diabetic peripheral neuropathy. However, this type of inhibitor contains a carboxyl group, resulting in a low dissociation constant, ionization under normal physiological pH conditions, membrane permeability defects, and low in vivo biological activity. Therefore, it suffers from low in vivo activity and requires relatively high dosages. Summary of the Invention

[0005] To address the poor membrane permeability of carboxylic acid AKR1B1, this invention aims to provide a multifunctional anti-ROS aldose reductase inhibitor, its preparation method, and its applications. This anti-ROS multifunctional aldose reductase inhibitor is a 1,2,4-oxadiazole-5(4H)-one derivative, featuring a novel structure. It exhibits strong inhibitory activity against AKR1B1, a high dissociation constant, and anti-ROS activity. This invention replaces the carboxyl group in the carboxylic acid AKR1B1 inhibitor with the isosteric isomer 1,2,4-oxadiazole-5(4H)-one, increasing the degree of dissociation of the inhibitor molecule while maintaining enzyme inhibitory activity. This results in an inhibitor molecule existing in its physiological molecular form, fundamentally solving the problem of low in vivo bioavailability of carboxylic acid AKR1B1. Simultaneously, the introduction of anti-ROS structural features into the traditional aldose reductase inhibitor structure alleviates oxidative stress downstream of the polyol pathway, enhancing the therapeutic effect of the drug molecule through a multifunctional synergistic approach, thereby achieving the therapeutic effect on diabetic complications.

[0006] To address the problems in the existing technology, the technical solution adopted by this invention is as follows:

[0007] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Where n represents the number of R, which is a natural number, and R is independently selected from hydrogen atoms, hydroxyl groups or halogen atoms.

[0010] A method for preparing the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof includes the following steps:

[0011] (i) A mixture of compound 1 benzothiadiazine (5.00 g, 24.98 mmol), Et3N (9.37 mL, 67.44 mmol) and acetic anhydride (4.69 mL, 49.95 mmol) was added to a three-necked flask containing CH2Cl2 (65.00 mL). The mixture was heated to 50 °C and stirred under reflux until the starting material spot completely disappeared as monitored by TLC. After the reaction system cooled to room temperature, the reaction mixture was poured into ice water and extracted three times with CH2Cl2. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain compound 2.

[0012] (ii) Compound 2 (4.00 g, 16.44 mmol) was added to a three-necked flask containing anhydrous methanol (80.00 mL), stirred and dissolved. Sodium borohydride (1.24 g, 32.89 mmol) was added in portions under nitrogen protection. After stirring for 15 min, the mixture was heated to 40 °C and refluxed until the starting material spot was completely disappeared by TLC monitoring. The reaction system was cooled to room temperature, and excess sodium borohydride was quenched by adding 1 M HCl (10.00 mL). The reaction solution was extracted three times with CH2Cl2. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain crude compound 3. The crude product was purified by column chromatography to obtain compound 3.

[0013] (iii) Compound 3 (3.00 g, 12.28 mmol), benzyl bromide or its substituted derivative (2.52 g, 14.74 mmol) were added to a three-necked flask containing K2CO3 (3.40 g, 24.57 mmol) and acetonitrile (30.00 mL). The reaction system was stirred at room temperature for 15 min and then heated to 65 °C. The reaction was continued until the starting material spot completely disappeared on TLC monitoring. After the reaction system was cooled to room temperature, the solvent was removed by vacuum filtration and vacuum distillation to obtain the crude product. A small amount of ethyl acetate and a large amount of petroleum ether were added to the crude product for purification by slurrying. The system was separated by vacuum filtration, and the filter cake was dried under vacuum to obtain compound 4.

[0014] (iv) Compound 4 (2.00 g, 12.28 mmol) was added to a flask containing methanol (20.00 mL) and sodium methoxide solution (0.5 mol / L, 20.00 mL). The solution was briefly sonicated and stirred at room temperature until the starting material spot completely disappeared on TLC monitoring. Methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (125.00 mL) and water (150.00 mL) and extracted. The aqueous layer was extracted three times with ethyl acetate (100.00 mL). The organic layers were combined, washed with saturated brine (100.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5. This compound can be used directly in the next step without further purification.

[0015] (v) Using compound 5 (2.00 g, 6.84 mmol) and bromoacetonitrile (0.98 g, 8.21 mmol) as raw materials, under inert conditions, 40.00 ml of acetonitrile and potassium carbonate (1.89 g, 13.68 mmol) were added. After stirring at room temperature for 15 min, the reaction system was heated to 65 °C and refluxed. After the starting material spot disappeared as monitored by TLC, the reaction system was cooled, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by pulping to obtain compound 6.

[0016] (vi) Compound 6 (1.00 g, 3.02 mmol) was dissolved in ethanol (10.00 mL), and hydroxylamine aqueous solution (50%, 0.20 mL, 3.62 mmol) was added. The mixture was heated to reflux until the starting material spot was completely disappeared by TLC monitoring. After the reaction solution was cooled, the solvent was removed by concentration under reduced pressure to obtain compound 7.

[0017] (i) A tetrahydrofuran (6 mL) solution of compound 7 (1.00 g, 2.74 mmol) was treated with TEA (triethanolamine) (0.41 g, 2.74 mmol), cooled to 0 °C, and CDI (N,N'-carbonyldiimidazole) (0.67 g, 4.12 mmol) was added. The mixture was stirred at room temperature for 16 hours, and TLC was used to detect the disappearance of the starting material. After the reaction was complete, the reaction solution was quenched with distilled water (50 mL), extracted with ethyl acetate (3 × 100 mL), and the organic phases were combined. Wash with saturated brine (3 × 25 mL), dry with anhydrous Na₂SO₄, filter, concentrate the filtrate under reduced pressure to remove the solvent, and purify by column chromatography to obtain compound 8; or, treat a tetrahydrofuran (6 mL) solution of compound 7 (1.00 g, 2.74 mmol) with TEA (triethanolamine) (0.41 g, 2.74 mmol), cool to 0 °C, add CDI (N,N'-carbonyldiimidazole) (0.67 g, 4.12 mmol), stir the mixture at room temperature for 16 hours, TL C was detected until the starting material disappeared. After the reaction was complete, the reaction solution was quenched with distilled water (50 mL), extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with saturated brine (3 × 25 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The intermediate compound was purified by column chromatography. Boron tribromide (2.38 mmol, one molecule of methoxy corresponds to one molecule of boron tribromide) was dissolved in 100.00 mL of anhydrous CH₂Cl₂, and then slowly added dropwise to a container containing the intermediate compound. In a three-necked flask containing 2.38 mmol of the compound, the mixture was stirred at -20 °C for 30 min, then cooled to room temperature and stirred for 10 min, and then heated to 35 °C. The reaction was stopped when the starting material spot disappeared during TLC monitoring. The mixture was cooled to room temperature and quenched with ice water (50.00 mL). The mixture was extracted with CH2Cl2 (50.00 mL × 3), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain compound 8.

[0018] The use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicaments for the prevention or treatment of diabetic complications.

[0019] A pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof.

[0020] As an improvement, the dosage form of the pharmaceutical composition includes, but is not limited to, tablets, capsules, and granules.

[0021] An AKR1B1 inhibitor, the active ingredient of which is the above-mentioned compound or a pharmaceutically acceptable salt thereof.

[0022] Beneficial effects:

[0023] This invention provides a novel AKR1B1 inhibitor structure with both anti-ROS activity and bioactivity. The bioactivity of this AKR1B1 inhibitor was demonstrated through aldose reductase and reactive oxygen species (ROS) scavenging experiments, as well as a compound dissociation constant test. These results show that this type of compound is a highly efficient aldose reductase inhibitor with excellent membrane permeability and ROS scavenging activity, exhibiting high in vivo bioavailability, high dissociation degree, and efficient aldose reductase inhibition and ROS scavenging effects. Compared to traditional carboxylic acid inhibitors, this type of inhibitor has high membrane permeability and ROS scavenging function, enabling it to efficiently inhibit aldose reductase activity in vivo, preventing sorbitol accumulation while alleviating downstream oxidative stress reactions in the polyol pathway. Therefore, its inhibitory effect on aldose reductase (AKR1B1) and reactive oxygen species (ROS) can help prevent or inhibit diabetic complications. Attached Figure Description

[0024] Figure 1 To investigate the polyol metabolism pathway of glucose and the pathogenesis of diabetic complications;

[0025] Figure 2 The route diagram for preparing 1,2,4-oxadiazole-5(4H)-one derivatives according to the present invention. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0027] Example 1

[0028] 3-((2-benzyl-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazine-4-yl)methyl

[0029] )-1,2,4-oxadiazol-5(4H)-one (compound 8a)

[0030]

[0031] A mixture of compound 1, benzothiadiazine (5.00 g, 24.98 mmol), Et3N (9.37 mL, 67.44 mmol), and acetic anhydride (4.69 mL, 49.95 mmol), was added to a three-necked flask containing CH2Cl2 (65.00 mL). The mixture was heated to 50 °C and stirred under reflux until the starting material spot completely disappeared as monitored by TLC. After cooling the reaction system to room temperature, it was poured into ice water. The resulting mixture was extracted three times with CH2Cl2. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 2, namely 1-(7-fluoro-1,1-dioxo-4H-benzo[e][1,2,4]thiadiazine-4-yl)ethyl-1-one (white solid, yield 95.00%, purity 97.40%).

[0032] Reaction 1:

[0033]

[0034] Compound 2 (4.00 g, 16.44 mmol) was dissolved in anhydrous methanol (80.00 mL). Under nitrogen protection, sodium borohydride (1.24 g, 32.89 mmol) was added in portions. After stirring at room temperature for 15 min, the mixture was heated to 40 °C and stirred under reflux until the starting material spot completely disappeared as monitored by TLC. The mixture was cooled to room temperature, and excess sodium borohydride was quenched dropwise with 1 M HCl (10.00 mL). The reaction mixture was extracted three times with CH2Cl2. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give compound 3,1-(7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)ethyl-1-one (white solid, yield 92.00%, purity 98.40%).

[0035] Reaction 2:

[0036]

[0037] Using compound 3 (3.00 g, 12.28 mmol) and benzyl bromide (2.52 g, 14.74 mmol) as starting materials, the mixture was added to a three-necked flask containing K2CO3 (3.40 g, 24.57 mmol) and acetonitrile (30.00 mL). The mixture was heated to 65 °C and stirred under reflux until the starting material spot completely disappeared as monitored by TLC. After the reaction system was cooled to room temperature, the solvent was removed by filtration and vacuum distillation. Then, 50 mL of a mixture of ethyl acetate and petroleum ether (1:10 v / v) was added for purification by stirring and filtration. The filter cake was dried under vacuum (40 °C) to obtain compound 4,1-(2-benzyl-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)ethyl-1-one (white solid, yield 96.00%, purity 98.10%).

[0038] Reaction 3:

[0039]

[0040] Compound 4 (2.00 g, 12.28 mmol), methanol (20.00 mL), and sodium methoxide solution (0.5 mol / L, 20.00 mL) were added to a clean three-necked flask. The solution was sonicated for 10 min and then stirred at room temperature until the starting material disappeared (TLC detection). The methanol was removed from the reaction system under reduced pressure, and the residue was dissolved in ethyl acetate (125.00 mL) and water (150.00 mL). Extraction and separation were performed. The aqueous phase was extracted three times with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (100.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. No further purification was required to obtain compound 5,2-benzyl-7-fluoro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (white crystals, yield 99.00%, purity 99.20%).

[0041] Reaction 4:

[0042]

[0043] Using compound 5 (2.00 g, 6.84 mmol) and bromoacetonitrile (0.98 g, 8.21 mmol) as starting materials, 40.00 mL of acetonitrile and 1.89 g of potassium carbonate (13.68 mmol) were added to a three-necked flask under inert conditions. The mixture was heated to 65 °C and refluxed. After the starting material spot disappeared under TLC monitoring, the reaction system was cooled, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by slurrying (50 mL ethyl acetate / v / v 1:15) to obtain compound 6,2-(2-benzyl-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)acetonitrile (white solid, yield 97.20%, purity 98.00%).

[0044] Reaction 5:

[0045]

[0046] Compound 6 (1.00 g, 3.02 mmol) was dissolved in ethanol (10.00 mL), and an aqueous solution of hydroxylamine (50%, 0.20 mL, 3.62 mmol) was added. The mixture was heated under reflux and stirred until the starting material spot disappeared on the TCL detector. The reaction solution was cooled and concentrated under reduced pressure to give compound 7, (Z)-2-(2-benzyl-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)-N'-hydroxyethylimine amide (pale yellow crystals, yield 96.00%, purity 96.6%).

[0047] Reaction 6:

[0048]

[0049] Compound 7 (1.00 g, 2.74 mmol) was dissolved in tetrahydrofuran (6 mL), treated with TEA (triethanolamine) (0.41 g, 2.74 mmol), and the reaction mixture was cooled to 0 °C and stirred for 15 min. CDI (N,N'-carbonyldiimidazole) (0.67 g, 4.12 mmol) was added, and the resulting mixture was stirred at room temperature until the starting material spot disappeared (TLC detection). The reaction mixture was quenched with H2O (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (3 × 25 mL), dried over anhydrous Na₂SO₄, filtered, concentrated to remove the solvent, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) and dried to give compound 8a, 3-((2-benzyl-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one. (Yellow solid, yield 90.00%, purity 99.1%). 1 HNMR (500MHz, Chloroform-d) δ = 7.51 (dd, J = 12.2, 2.0Hz, 0H), 7.37–7.23 (m, 3H), 7.21–7.12 (m, 1H), 4.87 (s, 1H), 4.51 (t, J = 1.0Hz, 1H).

[0050] Reaction 7:

[0051]

[0052] Example 2

[0053] 3-((7-fluoro-2-(4-fluorobenzyl)-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8b)

[0054]

[0055] The benzyl bromide in Example 1 was replaced with 4-fluorobenzyl bromide, and the preparation was carried out according to the preparation method described in Example 1.

[0056] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.30(ddt,J=7.9,2.3,1.2Hz,2H),7.22(d,J=8 .5Hz,1H),7.09–7.02(m,2H),6.99(dd,J=8.6,2.2Hz,1H),4.82(s,2H),4.45–4.38(m,3H),4.33(d,J=13.4Hz,1H).

[0057] Example 3

[0058] 3-((2-(4-bromobenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8c)

[0059]

[0060] The benzyl bromide in Example 1 was replaced with 4-bromobenzyl bromide, and the preparation was carried out according to the preparation method described in Example 1.

[0061] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.53–7.46(m,2H),7.39(d,J=2.2Hz,1H),7.29–7. 23(m,2H),7.22(d,J=8.5Hz,1H),6.99(dd,J=8.6,2.2Hz,1H),4.82(s,2H),4.47–4.30(m,4H).

[0062] Example 4

[0063] 3-((2-(4-chlorobenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8d)

[0064]

[0065] The benzyl bromide in Example 1 was replaced with 4-chlorobenzyl bromide, and the preparation was carried out according to the preparation method described in Example 1.

[0066] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.35–7.25(m,4H),7.22(d,J=8.5Hz,1H),6.99(dd,J =8.6, 2.2Hz, 1H), 4.82 (s, 2H), 4.46 (dt, J = 13.3, 1.0Hz, 1H), 4.40 (ddd, J = 13.2, 1.9, 1.0Hz, 2H), 4.33 (d, J = 13.4Hz, 1H).

[0067] Example 5

[0068] 3-((2-(4-bromo-2-fluorobenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8e)

[0069]

[0070] The benzyl bromide in Example 1 was replaced with 2-fluoro,4-bromobenzyl bromide, and the preparation was carried out according to the preparation method described in Example 1.

[0071] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.33–7.20(m,5H),6.99(dd,J=8 .6,2.2Hz,1H),4.85(s,2H),4.46(d,J=0.9Hz,2H),4.41(d,J=13.4Hz,1H),4.33(d,J=13.4Hz,1H).

[0072] Example 6

[0073] 3-((7-fluoro-2-(4-methoxybenzyl)-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8f)

[0074]

[0075] The benzyl bromide was replaced with 4-methoxybenzyl bromide in Example 1, and prepared according to the preparation method described in Example 1.

[0076] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.25–7.17(m,3H),6.99(dd,J=8.6,2.2Hz,1H),6 .82–6.76(m,2H),4.82(s,2H),4.45(dt,J=13.4,0.9Hz,1H),4.44–4.36(m,2H),4.33(d,J=13.4Hz,1H),3.78(s,2H).

[0077] Example 7

[0078] 3-((2-(3,5-dimethoxybenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8g)

[0079]

[0080] The benzyl bromide in Example 1 was replaced with 3,5-dimethoxybenzyl bromide, and the preparation was carried out according to the preparation method described in Example 1.

[0081] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.22(d,J=8.5Hz,1H),6.99(dd,J=8.6,2 .2Hz,1H),6.59(dt,J=2.2,1.0Hz,2H),6.37(t,J=2.4Hz,1H),4.82(s,2H),4.44–4.27(m,4H),3.80(s,5H).

[0082] Example 8

[0083] 3-((2-(3,4-dimethoxybenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8h)

[0084]

[0085] The benzyl bromide in Example 1 was replaced with 3,4-dimethoxybenzyl bromide, and the preparation was carried out according to the preparation method described in Example 1.

[0086] 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.22(d,J=8.5Hz,1H),6.99(dd,J=8.6,2.2Hz,1H),6.85–6 .80(m,2H),6.76(ddt,J=8.8,2.0,1.0Hz,1H),4.82(s,2H),4.45–4.38(m,3H),4.33(d,J=13.4Hz,1H),3.81(d,J=4.4Hz,6H).

[0087] Example 9

[0088] 3-((7-fluoro-2-(4-hydroxybenzyl)-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8i)

[0089]

[0090] The benzyl bromide in Example 1 was replaced with 4-methoxybenzyl bromide, and reactions 1-6 were carried out according to the preparation method described in Example 1. Compound 8i was prepared according to reaction 7 by the following method.

[0091] The tetrahydrofuran (6 mL) solution of compound 7 (1.00 g, 2.74 mmol) prepared in Example 1 was treated with TEA (triethanolamine) (0.41 g, 2.74 mmol), cooled to 0 °C, and CDI (N,N'-carbonyldiimidazole) (0.67 g, 4.12 mmol) was added. The mixture was stirred at room temperature for 16 hours, and TLC was performed until the starting material spot disappeared. After the reaction was complete, the reaction solution was quenched with distilled water (50 mL), extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with saturated brine (3 × 25 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The intermediate compound was purified by column chromatography. Boron tribromide (2.38 mmol, one molecule of methoxy corresponds to one molecule of boron tribromide) was dissolved in 100.00 mL of anhydrous CH₂Cl₂, and then... The mixture was slowly added dropwise to a three-necked flask containing the intermediate compound (2.38 mmol). The mixture was stirred at -20°C for 30 min, then cooled to room temperature and stirred for 10 min. The temperature was then raised to 35°C. The reaction was stopped when the starting material spot disappeared during TLC monitoring. The mixture was cooled to room temperature and quenched with ice water (50.00 mL). The mixture was extracted with CH2Cl2 (50.00 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation of the filtrate. The crude product was purified by column chromatography to give compound 8i, 3-((7-fluoro-2-(4-hydroxybenzyl)-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (yellow solid, yield 95.00%, purity 98.00%). 1 HNMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.22(d,J=8.5Hz,1H),7.16–7.10(m,2H),7.03–6 .96(m,2H),6.77–6.71(m,2H),4.82(s,2H),4.45(dt,J=13.4,0.9Hz,1H),4.44–4.36(m,2H),4.33(d,J=13.4Hz,1H).

[0092] Reaction 7 is:

[0093]

[0094] Example 10

[0095] 3-((2-(3,5-dihydroxybenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8j)

[0096]

[0097] The benzyl bromide in Example 1 was replaced with 3,5-dimethoxybenzyl and prepared according to reaction formulas 1-7 as described in Example 9.

[0098] 1 H NMR(500MHz,Chloroform-d)δ8.82(s,1H),8.35(s,2H),7.39(d,J=2.2Hz,1H),7.22(d,J=8.5Hz,1H),6.99(dd,J=8.6,2.2Hz,1H),6.48 (dt,J=2.0,0.9Hz,2H),6.01(t,J=2.1Hz,1H),4.82(s,2H),4.41(d,J=13.4Hz,1H),4.36–4.30(m,2H),4.28(s,0H),4.30–4.24(m,1H).

[0099] Example 11

[0100] 3-((2-(3,4-dihydroxybenzyl)-7-fluoro-1,1-dioxo-2,3-dihydro-4H-benzo[e][1,2,4]thiadiazin-4-yl)methyl)-1,2,4-oxadiazol-5(4H)-one (compound 8k)

[0101]

[0102] The benzyl bromide in Example 1 was replaced with 3,4-dimethoxybenzyl and prepared according to reaction formulas 1-7 as described in Example 9.

[0103] 1 H NMR(500MHz,Chloroform-d)δ8.82(s,1H),7.39(d,J=2.2Hz,1H),7.22(d,J=8.5Hz,1H),6.99(dd,J=8.6,2.2Hz,1H),6.7 8–6.73(m,2H),6.71(d,J=9.3Hz,1H),6.62(s,1H),6.27(s,1H),4.82(s,2H),4.44–4.38(m,3H),4.33(d,J=13.4Hz,1H).

[0104] Example 12

[0105] Examples 1-11: Experiments on the in vitro inhibitory effect of the prepared compounds on AKR1B1

[0106] The examples used phosphate buffer solution, NADPH solution, D,L-glyceraldehyde solution, and D-glucuronide sodium solution for AKR1B1 determination. Their preparation methods are as follows:

[0107] (1) Prepare a 0.1M phosphate buffer solution for AKR1B1 determination at pH 6.2.

[0108] Solution A: Dissolve 3.12g NaH2PO4·2H2O in 100mL of water to prepare a 0.2M solution;

[0109] Solution B: Dissolve 3.58g Na2HPO4·12H2O in 50mL of water to prepare a 0.2M solution.

[0110] Take 81.5 mL of solution A and 18.5 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 6.2.

[0111] (2) Prepare a 10 mM phosphate buffer solution for AKR1B1 assay at pH 7.2.

[0112] Dissolve 0.3801g sodium phosphate, 8.5513g sucrose, 0.0809g dipotassium EDTA, and 0.0175mL β-mercaptoethanol in 100mL of water and adjust the pH to 7.2 to obtain the final product.

[0113] (3) Prepare a 0.104 mM NADPH solution (using buffer solution 1 as the solvent).

[0114] 0.0043 g NADPH was dissolved in 50 mL of buffer solution 1 to prepare the solution.

[0115] (4) Prepare a 10 mM D,L-glyceraldehyde solution (using buffer solution 1 as the solvent).

[0116] 0.045 g of D,L-glyceraldehyde was dissolved in 50 mL of buffer solution 1 to prepare the solution.

[0117] (5) Prepare a 20 mM sodium D-glucuronide solution (using buffer solution 2 as the solvent).

[0118] 0.2341 g of sodium D-glucuronide was dissolved in 50 mL of buffer solution 2 to prepare the solution.

[0119] (5) Processing dialysis bags:

[0120] Cut the dialysis bag into three segments of appropriate length (10-20 cm). Boil the dialysis bag in a large volume of 2% (w / v) NaHCO3 and 1 mM EDTA dipotassium salt (pH=8.0) for 10 minutes. Then thoroughly rinse the dialysis bag with distilled water and boil it again in 1 mM EDTA dipotassium salt (pH=8.0) for 10 minutes. After cooling, store at 4°C, ensuring the dialysis bag remains submerged in the solution at all times. Gloves must be worn when handling the dialysis bag from this point onwards. Before use, fill the dialysis bag with water, then drain and rinse thoroughly.

[0121] (6) Extraction of AKR1B1: Lenses were rapidly extracted from the eyeballs of normally euthanized mice, and then three times their volume (0.4 mL / lens) of cold deionized water (0-4 °C) was added. The mixture was then homogenized using a Glas-Potter homogenizer. The homogenate was centrifuged at 12000 rpm in a low-temperature centrifuge. Centrifuge at 0-4 °C for 30 min using a high rotation speed. Collect the supernatant, which is the aqueous solution of AKR1B1, for enzyme activity testing.

[0122] (7) At 30℃, add 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 to a 1 mL test cuvette. Add 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 to a reference cuvette. Then place both cuvettes containing the above mixtures at 30℃ for 10 min. Finally, add 0.25 mL of 10 mM substrate to the test cuvette to start the reaction, and monitor the reaction at 340 nm for 5 min using a UV spectrophotometer. From the obtained data, plot the absorbance on the vertical axis and time on the horizontal axis to obtain a straight line. Calculate the slope of this line, denoted as I0, representing enzyme activity. The optimal enzyme activity is achieved when the NADPH absorbance variation is within the range of 0.01 ± 0.0010 absorbance units / min. If it is not within this range, the enzyme solution should be diluted to bring it within this range. A control cuvette should be added to the test cuvette to correct for NADPH oxidation caused by non-enzymatic factors (such as oxidation of NADPH by oxygen in the air).

[0123] (8) The method for testing the percentage inhibition of a compound is similar to that for measuring enzyme activity, except that, without adding a substrate, 5 μL of the compound solution to be tested should be added to both the test cuvette and the reference cuvette. The slope of the resulting straight line is denoted as I. x Then, the inhibition percentage at that concentration can be calculated using the formula below.

[0124] I%=(|I0-I c | / |I0|×100%

[0125] By repeatedly measuring compound solutions of different concentrations and calculating the inhibition percentage at each concentration, a straight line can be obtained between the "inhibition percentage" and the "logarithm of concentration". Then, the logarithm and antilogarithm corresponding to a 50% inhibition percentage can be read from the graph to obtain the IC50. 50 .

[0126] The ability of the compounds to inhibit AKR1B1 activity in vitro is shown in Table 1.

[0127] Table 1. In vitro inhibitory activity of some compounds against AKR1B1

[0128]

[0129]

[0130] Note: a IC 50 (μM)(95% CL) is the value measured in the experimental system implemented in this invention.

[0131] Example 13

[0132] Examples 1-11: Experiments on the determination of the degree of dissociation of prepared compounds

[0133] (1) Prepare 0.1M phosphate buffer solutions for AKR1B1 assay with pH values ​​of 5.82, 6.30, 6.83, 7.32, 7.80, 8.28, and 8.82.

[0134] Solution A: Dissolve 3.12g NaH2PO4·2H2O in 100mL of water to prepare a 0.2M solution;

[0135] Solution B: Dissolve 3.58g Na2HPO4·12H2O in 50mL of water to prepare a 0.2M solution.

[0136] Take 92.0 mL of solution A and 8.0 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 5.82 to obtain the corresponding pH phosphate buffer solution;

[0137] Take 77.6 mL of solution A and 22.4 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 6.30 to obtain the corresponding pH phosphate buffer solution;

[0138] Take 50.4 mL of solution A and 49.6 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 6.83 to obtain the corresponding pH phosphate buffer solution.

[0139] Take 23.2 mL of solution A and 76.8 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 7.32 to obtain the corresponding pH phosphate buffer solution.

[0140] Take 8.5 mL of solution A and 91.5 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 7.80 to obtain the corresponding pH phosphate buffer solution.

[0141] Take 3.0 mL of solution A and 97.0 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 8.28 to obtain the corresponding pH phosphate buffer solution.

[0142] Take 1.5 mL of solution A and 98.5 mL of solution B, dilute with water to a final volume of 200 mL, and adjust the pH to 8.82 to obtain the corresponding pH phosphate buffer solution.

[0143] (2) Accurately weigh 10.00 mg of the compound and place it in a 100 mL volumetric flask. Add water to make up to the volume to prepare a stock solution. Transfer 4.00 mL to a 10 mL volumetric flask and add phosphate buffer solutions of different pH values ​​to dilute and make up to the volume. Shake well.

[0144] (3) Using the corresponding solution as a blank, scan at wavelengths of 200-400 nm. For ultraviolet absorption spectroscopy, select wavelengths of 215, 220, 225, and 230 nm to measure the absorbance of target compound A solutions at different pH values. Plot pH value on the x-axis (X) and absorbance A on the y-axis (Y). The Sigmoidal mathematical model fits the curve equation Y = A² + (A₁ - A₂) / [1 + exp(X - X₀) / d]. X ], and perform second derivative, the inflection point X0 is the dissociation constant pKa of the compound.

[0145] Table 2 Results of compound dissociation test

[0146]

[0147] Example 14

[0148] MDA method was used to determine the in vitro reactive oxygen species scavenging activity of the compounds prepared in Examples 1-11.

[0149] 1. Solution preparation

[0150] (1) Preparation of 20 μM / mL ferric chloride solution

[0151] Dissolve 0.0027g of ferric chloride (FeCl3·6H2O) in 10mL of double-distilled water. Take 1mL of this solution, add 9mL of double-distilled water, and dilute 10 times. Then take 1mL of this diluted solution, add 4mL of double-distilled water, and stir until completely dissolved.

[0152] (2) Preparation of 100 μM / mL Vitamin C solution

[0153] Dissolve 0.0088g of vitamin C in 10mL of double-distilled water. Take 1mL of this solution, add 9mL of double-distilled water, and dilute it 10 times. Then take 1mL of the diluted solution, add 4mL of double-distilled water, and stir until completely dissolved.

[0154] (3) Preparation of methanol solution of compound

[0155] Different compounds were prepared into methanol solutions with a concentration of 100 μM / mL and stirred until completely dissolved.

[0156] 2. Preparation of brain homogenate

[0157] (1) Rats were euthanized by perfusion, and brain tissue was quickly removed. After being moistened with filter paper, the wet weight was measured. 2 grams were weighed for each experiment and added to a manual homogenizer.

[0158] (2) Add a certain volume of cold physiological saline to the homogenizer and manually homogenize for 10 minutes in an ice bath atmosphere;

[0159] (3) Pour the homogenate into a centrifuge tube and centrifuge at 4℃ and 3000r / min for 10min. Take the supernatant and store it at -20℃.

[0160] 3. Co-incubation of the compound with brain homogenate

[0161] Take out the prepared homogenate and other solutions, and add 0.5 mL of brain homogenate, drug solution, ferric chloride, vitamin C, etc. into a 1.5 mL centrifuge tube according to Table 3. Mix well. For blank tubes and control tubes, methanol or double-distilled water should be added to make up the volume of the reaction system to 0.5 mL.

[0162] Place the centrifuge tube in a 37°C water bath and incubate for 30 minutes, shaking the centrifuge tube 2-3 times during the incubation period to ensure that the compound reacts fully with the brain homogenate. Remove the centrifuge tube and place it in ice water. Proceed with the next steps according to the kit instructions.

[0163] Table 3. Lipid peroxidation in brain homogenate induced by the ferric chloride-vitamin C system (unit: mL)

[0164]

[0165]

[0166] 4. Determination of MDA (lipid peroxide) content in brain homogenate

[0167] (1) Composition and solution preparation of the MDA reagent kit (purchased from Nanjing Jiancheng Bioengineering Institute):

[0168] Reagent 1: 20 mL liquid, store at room temperature for later use;

[0169] Reagent 2: This is a 12mL liquid. When using it, add a certain amount of double-distilled water to each bottle according to the kit instructions, mix thoroughly, and store in a refrigerator at 4℃.

[0170] Reagent 3: This is a powder. When using it, add the powder to hot double-distilled water at 90-100℃, dissolve it completely, and then make up the volume with double-distilled water according to the kit instructions. Then add glacial acetic acid according to the instructions, mix thoroughly, protect from light, and store in a refrigerator at 4℃.

[0171] Standard: 10 nmol / mL tetraethoxypropane, stored at 4°C.

[0172] (2) Experimental steps

[0173] 1) Take several centrifuge tubes, make three parallel tubes for each sample, and add the samples according to Table 4;

[0174] Table 4. Sample loading table for the determination of lipid peroxide (MDA) content in brain homogenate (unit: mL)

[0175]

[0176] 2) Shake the test tube rack a few times to mix well. Then add the other reagents according to Table 5;

[0177] Table 5. Sample loading table for the determination of lipid peroxide (MDA) content in brain homogenate (unit: mL)

[0178]

[0179] 3) Mix well with a vortex mixer, seal the mouth of the test tube with plastic wrap, poke a small hole with a needle, and place in a 95-degree water bath or boil for 40 minutes.

[0180] 4) Remove, cool with running water, centrifuge at 3500-4000 rpm for 10 minutes, then take the supernatant, and measure the absorbance of each tube at 532 nm with distilled water as the zero point.

[0181] 5) MDA content calculation formula:

[0182]

[0183] 5. The inhibition rate of the compound on lipid peroxides in brain homogenate was measured, and the results are shown in Table 6.

[0184] Table 6. Inhibition rate of compounds on lipid peroxides in brain homogenate.

[0185]

[0186] Experiments have demonstrated that the compounds of this invention have a significant inhibitory effect on lipid peroxides in brain homogenates, indicating that the compounds of this invention are highly efficient, highly selective, and multifunctional aldose reductase inhibitors, and are suitable for use in the preparation of drugs for the prevention and / or treatment of diabetic complications.

Claims

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, n represents the number of R atoms, which is a natural number, and R atoms are independently selected from hydrogen atoms, hydroxyl groups, or halogen atoms.

2. A method for preparing the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: (i) A mixture of compound 1 benzothiadiazine (5.00 g, 24.98 mmol), Et3N (9.37 mL, 67.44 mmol) and acetic anhydride (4.69 mL, 49.95 mmol) was added to a three-necked flask containing CH2Cl2 (65.00 mL). The mixture was heated to 50 °C and stirred under reflux until the starting material spot completely disappeared as monitored by TLC. After the reaction system cooled to room temperature, the reaction mixture was poured into ice water and extracted three times with CH2Cl2. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The crude product was purified by column chromatography to obtain compound 2. (ii) Compound 2 (4.00 g, 16.44 mmol) was added to a three-necked flask containing anhydrous methanol (80.00 mL), stirred and dissolved. Sodium borohydride (1.24 g, 32.89 mmol) was added in portions under nitrogen protection. After stirring for 15 min, the mixture was heated to 40 °C and refluxed until the starting material spot was completely disappeared by TLC monitoring. The reaction system was cooled to room temperature, and excess sodium borohydride was quenched by adding 1 M HCl (10.00 mL). The reaction solution was extracted three times with CH2Cl2. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain crude compound 3. The crude product was purified by column chromatography to obtain compound 3. (iii) Compound 3 (3.00 g, 12.28 mmol), benzyl bromide or its substituted derivative (2.52 g, 14.74 mmol) were added to a three-necked flask containing K2CO3 (3.40 g, 24.57 mmol) and acetonitrile (30.00 mL). The reaction system was stirred at room temperature for 15 min and then heated to 65 °C. The reaction was continued until the starting material spot completely disappeared on TLC monitoring. After the reaction system was cooled to room temperature, the solvent was removed by vacuum filtration and vacuum distillation to obtain the crude product. A small amount of ethyl acetate and a large amount of petroleum ether were added to the crude product for purification by slurrying. The system was separated by vacuum filtration, and the filter cake was dried under vacuum to obtain compound 4. (iv) Compound 4 (2.00 g, 12.28 mmol) was added to a flask containing methanol (20.00 mL) and sodium methoxide solution (0.5 mol / L, 20.00 mL). The solution was briefly sonicated and stirred at room temperature until the starting material spot completely disappeared on TLC monitoring. Methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (125.00 mL) and water (150.00 mL) and extracted. The aqueous layer was extracted three times with ethyl acetate (100.00 mL). The organic layers were combined, washed with saturated brine (100.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5. This compound can be used directly in the next step without further purification. (v) Using compound 5 (2.00 g, 6.84 mmol) and bromoacetonitrile (0.98 g, 8.21 mmol) as raw materials, under inert conditions, 40.00 ml of acetonitrile and potassium carbonate (1.89 g, 13.68 mmol) were added. After stirring at room temperature for 15 min, the reaction system was heated to 65 °C and refluxed. After the starting material spot disappeared as monitored by TLC, the reaction system was cooled, filtered, and rotary evaporated to obtain the crude product. The crude product was purified by pulping to obtain compound 6. (vi) Compound 6 (1.00 g, 3.02 mmol) was dissolved in ethanol (10.00 mL), and hydroxylamine aqueous solution (50%, 0.20 mL, 3.62 mmol) was added. The mixture was heated to reflux until the starting material spot was completely disappeared by TLC monitoring. After the reaction solution was cooled, the solvent was removed by concentration under reduced pressure to obtain compound 7. (vii) A tetrahydrofuran (6 mL) solution of compound 7 (1.00 g, 2.74 mmol) was treated with TEA (triethanolamine) (0.41 g, 2.74 mmol), cooled to 0 °C, and CDI (N,N'-carbonyldiimidazole) (0.67 g, 4.12 mmol) was added. The mixture was stirred at room temperature for 16 hours, and TLC was used to detect the disappearance of the starting material. After the reaction was complete, the reaction solution was quenched with distilled water (50 mL), extracted with ethyl acetate (3 × 100 mL), and the organic compounds were combined. The phase was washed with saturated brine (3 × 25 mL), dried over anhydrous Na₂SO₄, filtered, and the resulting filtrate was concentrated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain compound 8; alternatively, a tetrahydrofuran (6 mL) solution of compound 7 (1.00 g, 2.74 mmol) was treated with TEA (triethanolamine) (0.41 g, 2.74 mmol), cooled to 0 °C, and CDI (N,N'-carbonyldiimidazole) (0.67 g, 4.12 mmol) was added. The mixture was stirred at room temperature for 16 hours. LC detection continued until the starting material spot disappeared. After the reaction was complete, the reaction solution was quenched with distilled water (50 mL), extracted with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with saturated brine (3 × 25 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The intermediate compound was purified by column chromatography. Boron tribromide (2.38 mmol, one molecule of methoxy corresponds to one molecule of boron tribromide) was dissolved in 100.00 mL of anhydrous CH₂Cl₂ and then slowly added dropwise to a container containing the intermediate. In a three-necked flask containing compound (2.38 mmol), the mixture was stirred at -20 °C for 30 min, then cooled to room temperature and stirred for 10 min, and then heated to 35 °C. The reaction was stopped when the starting material spot disappeared as monitored by TLC. The mixture was cooled to room temperature and quenched with ice water (50.00 mL). The mixture was extracted with CH2Cl2 (50.00 mL × 3), and the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation of the filtrate. The crude product was purified by column chromatography to obtain compound 8.

3. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of diabetic complications.

4. A pharmaceutical composition, characterized in that, It comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, characterized in that, The dosage forms of the pharmaceutical composition include, but are not limited to, tablets, capsules, and granules.

6. An AKR1B1 inhibitor, characterized in that, The active ingredient of the AKR1B1 inhibitor is the compound described in claim 1 or a pharmaceutically acceptable salt thereof.

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