CN111499616B

CN111499616B - Aromatic heterocycle substituted quinazolinone derivative and synthesis method and application thereof

Info

Publication number: CN111499616B
Application number: CN202010377905.6A
Authority: CN
Inventors: 郝鑫; 韩忠飞; 祁刚
Original assignee: Yancheng Institute of Technology
Current assignee: YANCHENG LIMIN CHEMICAL CO Ltd
Priority date: 2020-05-07
Filing date: 2020-05-07
Publication date: 2022-07-22
Anticipated expiration: 2040-05-07
Also published as: CN111499616A

Abstract

An aromatic heterocyclic ring substituted quinazolinone derivative, a synthetic method and application thereof belong to the technical field of organic compound preparation. The structural formula is shown as the formula (I):

(I) wherein X is CH₂CH = CH or CH₂CH₂；R₁Is at least one of H, halogen, hydroxyl, C1-C4 alkoxy and C1-C4 haloalkyl; r₂Is H, a C4-C7 heterocyclic or heterocycloalkyl group containing one to four oxygens or nitrogens, a substituted or unsubstituted aryl or aralkyl group. The product of the invention can fundamentally improve the defects of low carboxyl bioavailability and poor selectivity of hydantoin to ALR2, can also improve the antioxidant activity of the compound, develop a multifunctional multi-target aldose reductase inhibitor, relieve the oxidative stress reaction caused by continuous hyperglycemia while inhibiting ALR2, and improve the drug effect on the pharmacokinetic level.

Description

Aromatic heterocycle substituted quinazolinone derivative and synthesis method and application thereof

Technical Field

The invention belongs to the technical field of organic compound preparation, and particularly relates to an aromatic heterocycle substituted quinazolinone derivative, and a synthetic method and application thereof.

Background

Diabetes Mellitus (DM) is a metabolic disorder syndrome caused by hypofunction of pancreatic islets, insulin resistance, etc., which threatens human health and is becoming more serious. The biggest harm faced by diabetics is various chronic complications induced by the diabetics, such as cataract, retinopathy, nervous system lesion, nephropathy, atherosclerosis and the like. Because of its high disability rate and high mortality rate, diabetic complications have become one of the major threats to the health and longevity of the inhabitants of most countries. However, the current drugs for treating diabetic complications worldwide are almost in the blank state. Epalrestat (Epalrestat) is the only diabetes complication treatment drug on the market, but is limited to the japanese market and has recently been introduced in china and india.

The full research evidence indicates that sorbitol accumulation in the polyol pathway and a series of oxidative stress reactions downstream of the sorbitol accumulation have extremely remarkable correlation with the occurrence and the development of diabetic complications and are important targets for preventing and treating the diabetic complications. Aldose reductase is a key rate-limiting enzyme in polyol metabolic pathways, and therefore, Aldose Reductase Inhibitors (ARIs) can inhibit abnormal accumulation of sorbitol and indirectly inhibit oxidative stress, thereby developing a preventive and therapeutic drug for diabetic complications.

Aldose reductase inhibitors developed to date are numerous and the predominant one is the carboxylic acid type structure. Numerous animal and clinical trials have demonstrated that aldose reductase inhibitors are very effective in treating diabetic complications, and 14 aldose reductase inhibitors have passed phase II clinical trials. However, most aldose reductase inhibitors have insufficient drug efficacy or significant side effects, which may be due to drug selectivity or poor drug bioavailability of carboxylic acid structures, and insufficient efficacy against oxidative stress. Antioxidants are also important candidates for diabetic complications, but are difficult to be effective drugs because of their insufficient strength of aldose reductase inhibitory activity. Therefore, it is urgent to develop a safer and more effective therapeutic agent for diabetic complications based on a multi-target concept of simultaneously inhibiting aldose reductase and its oxidative stress.

Existing aldose reductase inhibitors can be roughly classified into three classes according to their structural features: hydantoin-based ARIs, carboxylic acid-based ARIs and sulfonyl-based ARIs. Representative ARIs are as follows:

the first type is a cyclic imide type (hydantoin type ARIs), and the representative group is mainly spirocyclic hydantoin. Typical hydantoin compounds are mainly sorbini, fidarestat, minalrestat, etc., wherein sorbini is the first inhibitor developed by hydantoin for preventing cataract development. The second is the carboxylic acid class of ARIs, which is the most important class of ARIs that first appeared and are also the most structurally abundant. Such ARIs are still the mainstream of research at present, and the most representative of the ARIs is the only diabetes complication treatment drug Epalrestat on the market. The third class is sulfonyl-type ARIs, which appear later than the first two classical inhibitors. The sulfonyl ARIs can act on different drug targets in different modes to treat diabetes and complications thereof, and the main action mechanisms of the sulfonyl ARIs comprise sugar metabolism regulation, insulin secretion improvement or insulin resistance improvement and the like.

Hydantoin-like ARIs have poor selectivity for aldose Reductase and Aldehyde Reductase (ALR1), inhibit the activity of aldose Reductase as well as the activity of Aldehyde Reductase, and cause adverse anaphylactic reaction. The aldehyde reductase has 71 percent of amino acid sequence homology with aldose reductase and is mainly responsible for clearing harmful aldehyde substances in vivo, and the inhibition of the activity of the aldehyde reductase can cause the content of the harmful substances in the body to increase so as to cause serious anaphylactic reaction. The research shows that the poor selectivity of the compound on aldose reductase may be caused by the hydantoin ring structure of the compound.

The key problem to be solved in the development of carboxylic acid ARIs is low in-vivo efficacy. Carboxylic acid compounds generally exist in an ionized form under physiological conditions due to their low pKa values, and thus do not easily penetrate biological membranes, resulting in low bioavailability and further reduced in vivo activity.

Disclosure of Invention

The technical problem to be solved is as follows: aiming at the technical problems, the invention provides an aromatic heterocycle substituted quinazolinone derivative and a synthesis method and application thereof, wherein the product has stronger inhibition capability and selectivity on ALR2 and stronger antioxidation capability at the same time, and the defects of low carboxyl bioavailability and poor selectivity of hydantoin on ALR2 are fundamentally overcome by introducing a novel bioelectronic isostere hydroxypyrazole structure to replace carboxyl or hydantoin ring; on the other hand, the compound can improve the antioxidant activity of the compound, develop a multifunctional multi-target aldose reductase inhibitor, inhibit ALR2, relieve the oxidative stress reaction caused by continuous hyperglycemia and improve the drug effect on the pharmacokinetic level.

The technical scheme is as follows: an aromatic heterocyclic substituted quinazolinone derivative, which has a structural formula shown in formula (I):

wherein X is CH₂CH or CH₂CH₂；R₁Is at least one of H, halogen, hydroxy, C1-C4 alkoxy, and C1-C4 haloalkyl; r₂Is H, C4-C7 heterocycle or heterocycloalkyl containing one to four oxygens or nitrogens, substituted or unsubstituted aryl or aralkyl, wherein the substituents are selected from halogen, hydroxy, amino, nitro, C1-C4 alkoxy or C1-C4 haloalkyl.

Preferably, the structural formula is shown in formula (II):

wherein X is CH₂、CH＝CH、CH₂CH₂；R₁Is at least one of H, halogen, hydroxyl, C1-C4 alkoxy and C1-C4 halogenated alkyl.

Preferably, the aromatic heterocyclic substituted quinazolinone derivative is one of the following compounds:

another technical scheme of the present invention is a synthetic method based on the aromatic heterocycle substituted quinazolinone derivative, wherein the preparation method comprises the following steps:

step one, when X is CH₂When in the form of compounds Ia

As a raw material with R₁Benzyl bromide as substituent is first reacted in acetonitrile solution of dissolved alkali at 50-80 deg.c while stirring to react until the material disappears, and the reacted product is cooled to room temperature, filtered, decompression treated to eliminate solvent and column layerSeparating, separating and purifying to obtain a compound Ib

When X is CH ═ CH, compound Ia

As raw material, under the protection of nitrogen, reacting with a catalyst containing R₁Dissolving substituted bromostyrene, alkali and catalyst in solvent, reacting at 80-110 deg.C, cooling to room temperature, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound Ib

Dissolving a compound Ib serving as a raw material in an anhydrous tetrahydrofuran solution, sequentially adding a reducing reagent and MeOH at 0 ℃ under the protection of nitrogen, stirring at room temperature for 2 hours, concentrating a reaction solution after the reaction is finished, adding water, repeatedly extracting with ethyl acetate for 3 times, collecting an organic phase, and adding anhydrous MgSO (MgSO) into the organic phase₄Drying, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain compound Ic

Dissolving the compound Ic serving as a raw material, 1- (benzyloxy) -4-iodo-1H-pyrazole, alkali and a catalyst in a solvent under the protection of nitrogen, refluxing at 90-130 ℃ until the reaction is finished, cooling the reaction liquid to room temperature, adding water, repeatedly extracting with dichloromethane for 3 times, collecting an organic phase, adding anhydrous MgSO (MgSO) into the organic phase₄Drying, filtering and concentrating under reduced pressure, and separating and purifying by column chromatography to form the compound Id

Step four, dissolving the compound Id serving as a raw material and ammonium formate in anhydrous methanol/tetrahydrofuran in a volume ratio of 1:1, adding 10 wt.% palladium carbon under the protection of nitrogen, reacting at 0 ℃, filtering after the reaction to obtain filtrate, washing with methanol, concentrating under reduced pressure, and carrying out column chromatographySeparating and purifying to form a compound Ie

When X is CH₂CH₂Dissolving compound Ie with X being CH ═ CH in tetrahydrofuran, adding 10 wt.% palladium carbon dissolved in methanol, reacting at normal temperature in hydrogen environment, filtering to remove catalyst, vacuum concentrating, and column chromatography separating and purifying to obtain compound Ie with X being CH₂CH₂Compound Ie of (2)

Preferably, in the first step, the base is potassium carbonate, sodium carbonate or cesium carbonate, the catalyst is cuprous iodide and N, N-dimethylethylenediamine, cuprous iodide and N, N-dimethylcyclohexanediamine, cuprous iodide and ethylenediamine, cupric chloride and N, N-dimethylethylenediamine or cupric bromide and N, N-dimethylethylenediamine, and the solvent is anhydrous dioxane, toluene or N, N-dimethylformamide; the reducing reagent in the second step is sodium borohydride, potassium borohydride or lithium borohydride; the alkali in the third step is potassium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate, the catalyst is cuprous iodide and N, N-dimethylethylenediamine, cuprous iodide and ethylenediamine, cuprous iodide and N, N-dimethylcyclohexanediamine, cupric chloride and N, N-dimethylethylenediamine or cupric bromide and N, N-dimethylethylenediamine, and the solvent is dioxane, toluene, N-dimethylformamide or dimethyl sulfoxide.

Preferably, the end of the reaction of the starting compound is detected by TLC.

The application of the aromatic heterocycle substituted quinazolinone derivative in preparing medicines for preventing and/or treating diabetic complications is provided.

Preferably, the medicament for preventing and/or treating diabetic complications comprises an active ingredient and a pharmaceutically acceptable carrier, excipient or sustained-release agent, wherein the active ingredient comprises a therapeutically effective amount of the aromatic heterocycle substituted quinazolinone derivative and/or pharmaceutically acceptable salt thereof.

Preferably, the aromatic heterocyclic substituted quinazolinone derivative and/or pharmaceutically acceptable salt thereof is used as aldose reductase inhibitor.

Has the advantages that: 1. the invention designs and synthesizes a novel non-carboxylic acid non-hydantoin compound with a structural formula I by taking quinazolinone as a parent structure, and tests on the inhibiting effect, selectivity and antioxidation effect of ALR2 prove that the compound is a high-efficiency and high-selectivity multifunctional aldose reductase inhibitor, can selectively inhibit the activity of ALR2 and can effectively inhibit the generation of lipid peroxide and free radicals, so that the compound has the application of preparing medicines for preventing and/or treating diabetic complications.

2. According to the invention, the isostere 1-hydroxypyrazole of carboxyl replaces carboxyl in the existing carboxylic acid ALR2 inhibitor to obtain the molecular inhibitor under physiological conditions, so that the structural defect of low bioavailability of the carboxylic acid ALR2 inhibitor is overcome, and specific comparison results are shown in the following table 1.

Table 1 comparison of biological activity of hydroxypyrazole ALR2 inhibitors with corresponding carboxylic acid ALR2 inhibitors

^aIC₅₀(μ M) (95% c.l.) is the value measured in the experimental system in which the present invention was carried out;^bat a concentration of 10^-5The inhibition ratio of M;^cthe carboxylic acid positive control is the carboxylic acid compound corresponding to compound 7.

Detailed Description

In the present invention, the term "C1-C4 alkyl group" means a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or the like.

The term "C1-C4 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy or the like.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "C1-C4 haloalkyl" means the above-mentioned C1-C4 alkyl groups, such as trifluoromethyl, pentafluoroethyl or the like, substituted with the same or different 1 to 6 of the above-mentioned halogen atoms.

The term "heterocycle of C4-C7" refers to an aromatic or non-aromatic heterocycle having a skeletal structure consisting of 4 to 7C atoms and N or O or S, such as tetrazole, oxadiazolone, pyridazine, pyrimidine or the like.

The term "aryl" refers to a monocyclic to tricyclic aromatic hydrocarbon group such as benzene, naphthalene, or the like.

The term "aralkyl" refers to a C1-C4 hydrocarbon group substituted with the above aryl group, such as benzyl, naphthylmethyl or the like.

In the context of the present invention, a "pharmaceutically acceptable" component is a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

In the present invention, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to humans and/or animals. The carrier may be solid or liquid.

The active ingredients contained in the pharmaceutical composition of the invention account for 0.01 to 99.9 percent of the total weight of the pharmaceutical composition; and a pharmaceutically acceptable carrier, excipient or sustained release agent, wherein the total weight of the composition is 100%.

The invention will be further illustrated by the following examples. These examples are intended to illustrate the invention, but not to limit it in any way. All parameters and descriptions in the examples are based on mass unless otherwise specified. The test methods in the examples, in which the specific conditions are not specified, are generally carried out under the conventional conditions or under the conditions recommended by the manufacturers.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.

The structural formula of the aromatic heterocycle substituted quinazolinone derivative is shown as the formula (I):

wherein X is CH₂CH or CH₂CH₂；R₁Is H, halogen, hydroxy, C1-C4 alkoxy or C1-C4 haloalkyl; r₂Is H, C4-C7 heterocycle or heterocycloalkyl containing one to four oxygens or nitrogens, substituted or unsubstituted aryl or aralkyl, wherein the substituents are selected from halogen, hydroxy, amino, nitro, C1-C4 alkoxy or C1-C4 haloalkyl.

Example 1

In this example, X is CH₂，R₁Is H, R₂Is composed of

Namely compound 1

3-benzyl-1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one.

The preparation method of the 3-benzyl-1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one comprises the following steps:

step one 292mg (2mmol) of the starting quinazolin-4 (3H) -one (Compound Ia), 513mg (3mmol) of benzyl bromide and 829mg (6mmol) of K₂CO₃Dissolving in 10mL acetonitrile, stirring at 65 deg.C, reacting until the raw material point detected by TLC plate disappears, cooling to room temperature, filtering the reaction solution, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound Ib

(i.e., 3-benzylquinazolin-4 (3H) -one (white solid, 86% yield, 406 mg):¹H NMR(400MHz,CDCl₃):δ8.25(dd,1H,J＝8.0,1.6Hz),8.08(s,1H),7.73–7.64(m,2H), 7.48–7.42(m,1H),7.29–7.23(m,5H),5.14(s,2H))。

step two, dissolving 1.73g (7.3mmol) of 3-benzyl quinazoline-4 (3H) -ketone in 24mL of anhydrous tetrahydrofuran, cooling to 0 ℃, slowly adding 0.55g (14.6mmol) of sodium borohydride and 6mL of methanol, stirring for 2 hours at room temperature under the protection of nitrogen, detecting the disappearance of a raw material point on a TLC plate, concentrating the reaction solution, adding a proper amount of water, repeatedly extracting for 3 times by using ethyl acetate, collecting an organic phase, drying by using anhydrous magnesium sulfate, filtering to obtain a filtrate, removing the solvent by reduced pressure rotary evaporation, and performing column chromatography separation and purification to obtain a compound Ic

(i.e., 3-benzyl-2, 3-dihydroquinazolin-4 (1H) -one (white solid, 83% yield, 1.4 g):¹H NMR(400MHz,CDCl₃):δ7.96(dd,1H,J＝7.7,1.3Hz),7.32–7.24(m,6H),6.68(d,1H,J＝ 7.5Hz),6.64(d,1H,J＝8.0Hz),4.72(s,2H),4.51(br s,1H),4.48(s,2H))。

step three, under nitrogen protection, add 3-benzyl-2, 3-dihydroquinazolin-4 (1H) -one (286mg, 1.2mmol), cuprous iodide (19mg,0.1mmol), potassium carbonate (415mg,3mmol), 1- (benzyloxy) -4-iodo-1H-pyrazole (300mg,1mmol), N-dimethylethylenediamine (18mg,0.2mmol), and anhydrous dioxane (8mL) to the round bottom flask and keep the reaction under nitrogen atmosphere until the TLC assay starting point disappears. Cooling the reaction solution to room temperature, adding appropriate amount of water, extracting with dichloromethane repeatedly for 3 times, collecting organic phase, adding anhydrous MgSO₄Drying, filtering to obtain filtrate, concentrating under reduced pressure, and purifying by column chromatography to obtain compound Id

(i.e. 3-benzyl-1- (1-benzyloxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one (white solid, 75% yield, 369 mg):¹H NMR(400MHz,CDCl₃):δ8.11(d,1H,J＝8.2Hz),7.98 (dd,1H,J＝7.8,1.4Hz),7.92(d,1H,J＝8.0Hz),7.48–7.21(m,11H),6.72(d,1H,J＝7.7Hz), 6.68(d,1H,J＝8.0Hz),5.23(s,2H),4.75(s,2H),4.49(s,2H))。

step four, 3-benzyl-1- (1-benzyloxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazoline-4 (1H)) Adding ketone (410mg, 1mmol), ammonium formate (352mg,5.6mmol) and absolute methanol/tetrahydrofuran (18mL, volume ratio 1:1) into a round-bottom flask, adding 10 wt.% palladium carbon (352mg,3.2mmol) under the protection of nitrogen, reacting at 0 ℃ until a TLC detection raw material point disappears, filtering to obtain a filtrate, washing with methanol, concentrating under reduced pressure, and carrying out column chromatography separation and purification to obtain a target product compound Ie

(i.e., 3-benzyl-1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one (white solid, 72% yield, 230 mg): melting point: 195 ℃ C.,;¹H NMR(400MHz,CDCl₃):δ8.13(d,1H,J＝8.0Hz), 7.98(dd,1H,J＝7.7,1.5Hz),7.92(d,1H,J＝8.2Hz),7.44(d,1H,J＝7.8Hz),7.34–7.23(m,5H), 6.73(d,1H,J＝7.7Hz),6.68(d,1H,J＝8.2Hz),4.76(s,2H),4.51(s,2H))。

example 2

In this example, X is CH₂，R₁Is composed of

(substitution at position C4), R₂Is composed of

I.e. Compound 2

1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one.

The above-mentioned 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one was prepared in the same manner as in example 1, except that 4-methoxybenzyl bromide was used instead of benzyl bromide in example 1. Finally obtaining the compound 2, 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxybenzyl) -2, 3-dihydroquinazoline-4 (1H) -ketone (melting point: 213-215 ℃;¹H NMR(400MHz, CDCl₃):δ8.11(d,1H,J＝8.2Hz),7.97(dd,1H,J＝7.7,1.3Hz),7.90(d,1H,J＝8.4Hz),7.46(d, 1H,J＝8.2Hz),7.29–7.21(m,2H),7.02(d,1H,J＝8.0Hz),6.82–6.74(m,2H),6.64(d,1H,J＝ 8.0Hz),4.73(s,2H),4.48(s,2H),3.86(s,3H))。

example 3

In this example, X is CH₂，R₁Is hydroxy (substituted at the C4 position), R₂Is composed of

I.e. Compound 3

1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-hydroxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one.

The preparation method of the 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-hydroxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one comprises the following steps: 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one prepared in example 2 as a raw material (350mg,1mmol) was dissolved in an ice-bath flask containing 20mL of anhydrous dichloromethane, the flask temperature was reduced to 0 ℃ under nitrogen protection, and BBr was added dropwise₃(1mmol, dissolved in 5mL of anhydrous dichloromethane, BBr₃In addition to boron tribromide, aluminum trichloride or thiophenol) for demethylating reagent, reacting at room temperature, adding the reaction solution into 40mL of ice water after TLC monitoring reaction is finished, repeatedly extracting with dichloromethane for 3 times, and collecting organic phase anhydrous MgSO₄Drying, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain the product compound 3, 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-hydroxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one (light yellow solid, yield 72%, 242 mg; melting point: 240-;¹H NMR(400MHz, CDCl₃):δ8.20(d,1H,J＝7.2Hz),8.02(d,1H,J＝6.8Hz),7.96(dd,1H,J＝7.8,1.6Hz),7.47(d, 1H,J＝7.8Hz),7.30–7.24(m,2H),7.03(d,1H,J＝8.2Hz),6.75–6.67(m,3H),4.74(s,2H),4.58 (s,2H))。

example 4

In this example, X is CH₂，R₁Is composed of

(C3 and C5 substitution), R₂Is composed of

I.e. Compound 4

3- (3, 5-dimethoxybenzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one.

The above 3- (3, 5-dimethoxybenzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one was prepared in the same manner as in example 1, except that 3, 5-dimethoxybenzyl bromide was used instead of benzyl bromide in example 1. Finally obtaining the compound 4, 3- (3, 5-dimethoxybenzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one (melting point: 212-;¹H NMR (400MHz,CDCl₃):δ8.08(d,1H,J＝8.0Hz),7.95(dd,1H,J＝7.7,1.5Hz),7.89(d,1H,J＝8.2 Hz),7.43(d,1H,J＝7.6Hz),7.14–7.02(m,2H),6.79–6.64(m,2H),6.53(d,1H,J＝8.2Hz),4.82 (s,2H),4.53(s,2H),3.83(s,6H))。

example 5

In this example, X is CH₂，R₁Is hydroxy (C3 and C5 position substitution), R₂Is composed of

I.e. Compound 5

3- (3, 5-dihydroxybenzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one.

The preparation method of the 3- (3, 5-dihydroxy benzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one comprises the following steps: taking 3- (3, 5-dimethoxybenzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazolin-4 (1H) -one prepared in example 4 as a raw material (380mg,1mmol), dissolving the raw material in an ice bath flask containing 20mL of anhydrous dichloromethane, adding anhydrous aluminum trichloride (1.33g,10mmol) after the temperature of the flask is reduced to 0 ℃, stirring in the ice bath for 15min, reacting at 45 ℃ until the raw material on a TLC plate disappears, cooling the reaction to room temperature, pouring the reaction liquid into ice water, and repeatedly extracting with dichloromethane for 3 timesCombining the organic phases and using anhydrous MgSO₄Drying, filtering, distilling under reduced pressure to remove the solvent, and separating and purifying by column chromatography to obtain the product compound 5, 3- (3, 5-dihydroxy benzyl) -1- (1-hydroxy-1H-pyrazol-4-yl) -2, 3-dihydroquinazoline-4 (1H) -ketone (light yellow solid, yield 65%, 229mg, melting point: 233-;¹H NMR(400MHz,CDCl₃):δ8.13(d,1H,J＝8.0Hz), 7.97(dd,1H,J＝7.7,1.5Hz),7.89(d,1H,J＝7.8Hz),7.44(t,1H,J＝7.6Hz),7.05–6.96(m,2H), 6.74–6.67(m,2H),6.59(d,1H,J＝8.0Hz),4.78(s,2H),4.52(s,2H))。

example 6

In this embodiment, X is CH ═ CH, R₁Is H, R₂Is composed of

I.e. Compound 6

1- (1-hydroxy-1H-pyrazol-4-yl) -3-styryl-2, 3-dihydroquinazolin-4 (1H) -one.

The above-described process for preparing 1- (1-hydroxy-1H-pyrazol-4-yl) -3-styryl-2, 3-dihydroquinazolin-4 (1H) -one is the same as in example 1, except that 3-styryl-quinazolin-4 (3H) -one is used instead of 3-benzylquinazolin-4 (3H) -one in example 1. Wherein, the preparation process of the 3-styryl quinazoline-4 (3H) -ketone comprises the following steps: 292mg (2mmol) of quinazolin-4 (3H) -one, 549mg (3mmol) of bromostyrene, 1.95g (6mmol) of Cs under nitrogen protection₂CO₃190mg (1mmol) of cuprous iodide and 1.23g (14mmol) of N, N-dimethylethylenediamine are dissolved in 20mL of anhydrous dioxane, reacted at 100 ℃ until the TLC detection starting material point disappears, the reaction is cooled to room temperature after the completion, the solvent is removed by filtration and reduced pressure, and the 3-styrylquinazolin-4 (3H) -one (pale yellow solid, yield 82%, 407mg) is obtained by column chromatography separation and purification:¹H NMR(400MHz,CDCl₃): δ8.55(s,1H),8.32(dd,1H,J＝8.0,1.2Hz),7.73–7.86(m,3H),7.54–7.61(m,3H),7.28–7.41(m, 3H),7.25(d,1H,J＝14.8Hz)。

finally obtaining the compound 6, 1- (1-hydroxy-1H-pyrazol-4-yl) -3-styryl-2, 3-dihydroquinazolLin-4 (1H) -one (melting point: 209-211 ℃;¹H NMR(400MHz,CDCl₃):δ8.15(d,1H,J＝8.2Hz),7.96(d,1H,J＝8.0Hz), 7.88–7.67(m,4H),7.52–7.35(m,4H),7.02–6.94(m,1H),6.75(d,1H,J＝6.8Hz),6.08(d,1H,J＝ 7.8Hz),4.79(s,2H))。

example 7

In this embodiment, X is CH ═ CH, R₁Is hydroxy (substituted at the C4 position), R₂Is composed of

I.e. Compound 7

1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-hydroxystyryl) -2, 3-dihydroquinazolin-4 (1H) -one.

The preparation method of the 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-hydroxystyryl) -2, 3-dihydroquinazolin-4 (1H) -one comprises the following steps: 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxystyryl) -2, 3-dihydroquinazolin-4 (1H) -one was prepared according to the preparation method described in example 6, using 4-methoxystyryl bromide instead of bromostyrene in example 6; 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxystyryl) -2, 3-dihydroquinazolin-4 (1H) -one of example 3 was substituted for 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-methoxybenzyl) -2, 3-dihydroquinazolin-4 (1H) -one, the final product, compound 7, 1- (1-hydroxy-1H-pyrazol-4-yl) -3- (4-hydroxystyryl) -2, 3-dihydroquinazolin-4 (1H) -one, was prepared according to the preparation method described in example 3 (melting point: 245 ℃ and 247 ℃;¹H NMR(400MHz,CDCl₃):δ8.11(d,1H,J＝8.0Hz),7.92(d,1H,J＝7.8Hz), 7.74–7.63(m,2H),7.58–7.45(m,3H),7.02(d,1H,J＝7.8Hz),6.79–6.65(m,3H),6.12(d,1H,J＝ 7.2Hz),4.83(s,2H))。

example 8

In this example, X is CH₂CH₂，R₁Is H, R₂Is composed of

I.e. Compound 8

1- (1-hydroxy-1H-pyrazol-4-yl) -3-phenethyl-2, 3-dihydroquinazolin-4 (1H) -one.

The preparation method of the 1- (1-hydroxy-1H-pyrazol-4-yl) -3-phenethyl-2, 3-dihydroquinazolin-4 (1H) -one comprises the following steps: dissolving 1- (1-hydroxy-1H-pyrazol-4-yl) -3-styryl-2, 3-dihydroquinazolin-4 (1H) -one (compound 6, 332mg and 1mmol) in 10mL tetrahydrofuran, adding 10 wt.% of palladium carbon (0.36g) dissolved in 10mL methanol, reacting at normal temperature in a hydrogen environment, monitoring by TLC until a raw material point disappears, filtering to remove the catalyst, concentrating under reduced pressure, and purifying by column chromatography to obtain 1- (1-hydroxy-1H-pyrazol-4-yl) -3-phenethyl-2, 3-dihydroquinazolin-4 (1H) -one (white solid, yield 76%, 254mg, melting point: 224-;¹H NMR(400MHz,CDCl₃):δ8.08(d,1H,J＝8.0Hz),7.92(d,1H,J＝7.8Hz), 7.68(d,1H,J＝8.2Hz),7.52–7.40(m,3H),7.35–7.24(m,3H),6.95(d,1H,J＝7.8Hz),6.78(d, 1H,J＝6.8Hz),4.72(s,2H),3.53(t,J＝7.2Hz,2H),2.87(t,J＝7.6Hz,2H))。

example 9

The products prepared in examples 1-8 were tested for in vitro inhibitory activity against ALR2 and ALR 1.

The phosphate buffer solution for ALR2 measurement, the sodium phosphate buffer solution 1 for ALR1 measurement, the sodium phosphate buffer solution 2, the NADPH solution, the D, L-glyceraldehyde solution and the D-sodium glucuronate solution are prepared by the following preparation method:

(1) a phosphate buffer solution was prepared for ALR2 assay at 0.1M pH 6.2

Solution A: 3.12g NaH₂PO₄·2H₂Dissolving O in 100ml of water to prepare 0.2M solution;

solution B: 3.58g Na₂HPO₄·12H₂O was dissolved in 50ml of water to prepare a 0.2M solution.

And taking 81.5mL of A and 18.5mL of B, diluting with water until the final volume is 200mL, and adjusting the pH value to 6.2 to obtain the composition.

(2)10 mM ALR 1(pH 7.2) was prepared as phosphate buffer solution 1 for assay

0.3801g of sodium phosphate, 8.5513g of cane sugar, 0.0809g of EDTA dipotassium salt and 0.0175mL of beta-mercaptoethanol are dissolved in 100mL of water, and the pH value is adjusted to 7.2, so that the sodium glutamate-disodium salt is obtained.

(3) 10mM ALR 1(pH 7.2) was prepared and used in phosphate buffer solution 2

0.3801g of sodium phosphate, 0.0809g of EDTA dipotassium salt and 0.0140mL of beta-mercaptoethanol are dissolved in 100mL of water, and the pH is adjusted to 7.2, thus obtaining the sodium EDTA disodium salt.

(4) A0.104 mM NADPH solution (buffer solution as solvent) was prepared

0.0043g NADPH was dissolved in 50mL of buffer solution to prepare.

(5) Preparing 10mM D, L-glyceraldehyde solution (using buffer solution as solvent)

0.045g D, L-glyceraldehyde was dissolved in 50mL of a buffer solution to prepare a solution.

(6) Preparing 20mM D-sodium glucuronate solution (taking a buffer solution as a solvent)

0.2341g D-sodium glucuronate was dissolved in 50mL of buffer solution 1.

(7) Treating the dialysis bag:

firstly, cutting the dialysis bag into three small sections with proper length (10-20cm), and adding 2% (W/V) NaHCO in large volume₃And 1mM dipotassium EDTA (pH 8.0) the dialysis bag was boiled for 10 min.

② the dialysis bag was thoroughly washed with distilled water, and placed in 1mM dipotassium EDTA (pH 8.0) and boiled for 10 min.

③ after cooling, storage at 4 ℃ it is necessary to ensure that the dialysis bag is always immersed in the solution, from which time it must be taken out with gloves. Before use, the dialysis bag is filled with water, then drained and cleaned.

(8) Extraction of ALR 2: the lens was quickly extracted from a normally killed rat eyeball, 3 times (0.4mL/lens) cold deionized water (0-4 ℃) was added to its volume, and homogenized with a Glas-Potter homogenizer. The homogenate was centrifuged in a low temperature centrifuge at 12000 Xg for 30min at 0-4 ℃. And finally taking the supernatant, namely the water solution of ALR2, for enzyme activity test.

(9) Extraction of ALR 1: rats were sacrificed by cervical dislocation, the kidneys were removed rapidly, 3-fold (3mL/g kidney) cooled in volume 10mM sodium phosphate buffer 1(pH 7.2 containing 0.25M sucrose, 2.0mM dipotassium EDTA, 2.5mM β -mercaptoethanol) (0-4 ℃) was added and homogenized with a Glas-Potter homogenizer. The homogenate was centrifuged in a low temperature centrifuge at 12000 Xg for 30min at 0-4 ℃. Collecting supernatant, adding saturated ammonium sulfate solution to form 40% ammonium sulfate solution, stirring at 0-4 deg.C for 30min, and centrifuging at 12000 Xg speed for 15 min. The supernatant was taken and the above steps were repeated to achieve 55% saturation of ammonium sulfate and then 75% salt solution, respectively. The precipitate after centrifugation of a 75% saturated ammonium sulfate solution was dissolved in 50 volumes of 10mM sodium phosphate buffer 2(pH 7.2 containing 2.0mM dipotassium EDTA, 2.0mM β -mercaptoethanol) and dialyzed overnight against this buffer. The dialyzed solution was ALR1 in water for enzyme activity test.

(10) Testing of enzyme Activity: 0.25mL of 0.104mM NADPH, 0.25mL of 0.1M phosphate buffer (pH 6.2),0.1mL of the extracted enzyme solution, and 0.15mL of deionized water were added to a 1mL test cuvette at 30 ℃. To a reference cuvette, 0.25mL of 0.104mM NADPH,0.50mL of 0.1M phosphate buffer (pH 6.2),0.1mL of the extracted enzyme solution, and 0.15mL of deionized water were added. Then, the two cuvettes containing the above mixed solution were kept at 30 ℃ for 10 min. Finally, the reaction was started by adding 0.25mL of 10mM substrate to the test cuvette and monitoring with UV spectrophotometer at 340 nm for 5 min. From the obtained data, a straight line was obtained with the absorbance as the vertical axis and time as the horizontal axis, and the slope of the straight line was obtained and designated as I₀And represents enzyme activity. The optimum value of the activity of the enzyme is in the range where the variation in NADPH absorbance is 0.01. + -. 0.0010(ALR2) or 0.015. + -. 0.0010(ALR1) absorbance units/min, and if not, this range is reached by diluting the enzyme solution. The control cuvette was added to the test cuvette to correct for the oxidation of NADPH due to non-enzymatic factors (e.g., oxygen in air also oxidizes NADPH).

(11) Test of percent inhibition of compounds: similar to the method for measuring enzyme activity, except that 5. mu.L of each test compound solution was added to each of the test cuvette and the reference cuvette without adding the substrate. The slope of the resulting line is denoted as I_x. The percent inhibition at this concentration was then calculated according to the following equation.

I％＝(|I₀-I_x|/|I₀|)×100％

Wherein I% represents the percentage of inhibition, I₀Slope of linear equation expressing linear regression of enzyme activity, I_xThe slope of the linear equation representing the linear regression of enzyme activity after addition of the compound was determined.

Repeatedly measuring compound solutions with different concentrations, respectively calculating the inhibition percentage of corresponding concentration to obtain a straight line of the inhibition percentage to the concentration logarithm, then obtaining the concentration logarithm corresponding to the inhibition percentage of 50%, and obtaining IC by inverse logarithm₅₀。

The ability of compounds to inhibit ALR2 and ALR1 activity in vitro is shown in table 2.

TABLE 2 inhibitory Activity of Compounds 1-8 on ALR2 and ALR1

^aIC₅₀(. mu.M) (95% C.L.) is the value measured in the experimental system in which the invention was carried out

^bAt a concentration of 10^-5Inhibition ratio of M

The enzyme activity experiment proves that the compounds have obvious inhibiting effect on ALR2 in vitro, in particular to the compound 7, IC₅₀The value was 378nM and these compounds had no significant inhibitory effect on ALR1, indicating that these compounds are highly selective.

Example 10

In vitro antioxidant Activity of Compounds 1-8 prepared in examples 1-8 by MDA method

1. Preparation of the solution

(1) Preparation of 20 mu M/mL ferric trichloride solution

0.0027g of ferric chloride (FeCl)₃·6H₂O), dissolving in 10mL of double distilled water, taking 1mL of the solution, adding 9mL of double distilled water, diluting by 10 times, taking 1mL of the diluted solution, adding 4mL of double distilled water, and stirring to completely dissolve.

(2) Preparation of 100. mu.M/mL vitamin C solution

Dissolving 0.0088g of vitamin C in 10mL of double distilled water, taking 1mL of the solution, adding 9mL of double distilled water, diluting by 10 times, then taking 1mL of the diluent, adding 4mL of double distilled water, and stirring to completely dissolve the solution to obtain the vitamin C.

(3) Preparation of Compound methanol solution

Preparing different compounds into methanol solution with the concentration of 100 MuM/mL, and stirring for complete dissolution to obtain the final product.

2. Preparation of brain homogenate

(1) The rat is killed by perfusion, brain tissues are rapidly taken out, after the brain tissues are absorbed by filter paper, the wet weight is weighed, 2g of the wet weight is weighed in each experiment, and the wet weight is added into a manual homogenizer;

(2) adding a certain volume of cold normal saline into a homogenizer, and manually homogenizing for 10 minutes in an ice bath atmosphere;

(3) pouring the homogenate into a centrifuge tube, centrifuging for 10min at 4 ℃ and 3000r/min, taking supernatant, and storing at-20 ℃.

3. Co-incubation of Compounds with brain homogenates

Taking out the prepared homogenate and other solutions, adding 0.5mL of the brain homogenate, the liquid medicine, ferric trichloride, vitamin C and the like into a 1.5mL centrifuge tube according to the table 3 in sequence, mixing uniformly, and adding methanol or double distilled water to the blank tube and the reference tube to complement the volume of the reaction system to be 0.5 mL.

Placing the centrifuge tube in a 37 deg.C water bath, incubating for 30min, and continuously shaking the centrifuge tube for 2-3 times to make the compound and brain homogenate fully act; the centrifuge tube was taken out and placed in ice water, and the following operations were performed according to the kit.

TABLE 3 lipid peroxidation in brain homogenate induced by the iron trichloride vitamin C System (Unit: mL)

4. Determination of lipid peroxide MDA content in brain homogenate

(1) The kit comprises the following components in part by weight:

a first reagent: storing the liquid in a bottle of 20mL at room temperature for later use;

and a second reagent: the liquid is 12mL, when the liquid is used, a certain amount of double distilled water is added into each bottle according to the instruction of the kit, the double distilled water is fully and uniformly mixed, and the mixture is stored in a refrigerator at 4 ℃;

and (3) reagent III: adding the powder into hot double distilled water of 90-100 deg.C, dissolving completely, adding double distilled water to complement volume according to kit instruction, adding glacial acetic acid according to instruction, mixing completely, keeping out of the sun, and storing in 4 deg.C refrigerator;

and (3) standard substance: tetraethoxypropane of 10n mol/mL, stored in a refrigerator at 4 ℃.

(2) Experimental procedure

1) Taking a plurality of centrifuge tubes, making three parallel tubes for each sample, and adding samples according to the table 4;

TABLE 4 measurement of lipid peroxide MDA content in brain homogenate sample application Table (Unit: mL)

2) Shake the tube rack several times and mix well. Then adding other reagents according to the table 5;

TABLE 5 measurement of lipid peroxide MDA content in brain homogenate sample application Table (Unit: mL)

3) Mixing with vortex mixer, tightening test tube with preservative film, pricking a small hole with needle, and boiling in 95 deg.C water bath for 40 min;

4) taking out, cooling by running water, centrifuging for 10 minutes at the speed of 3500-4000 rpm, taking the supernatant, adjusting the position to zero by distilled water at 532nm, and measuring the absorbance value of each tube;

5) MDA content calculation formula:

5. the inhibitory rate of the compounds against lipid peroxides in brain homogenates was determined as shown in table 6.

TABLE 6 inhibition of lipid peroxides in brain homogenates by compounds

Experiments prove that part of compounds (compound 3, compound 5 and compound 7) have obvious inhibition effect on lipid peroxide in brain homogenate, which indicates that the quinazolinone derivative is a high-efficiency, high-selectivity and multifunctional aldose reductase inhibitor and has application in preparing medicines for preventing and/or treating diabetic complications.

Example 11

An aromatic heterocyclic substituted quinazolinone derivative, the structural formula of which is shown in formula (I):

wherein X is CH₂；R₁Is H; r is₂Is H.

The synthetic method of the aromatic heterocyclic ring substituted quinazolinone derivative comprises the following steps:

step one, compound Ia

As a raw material with R₁Adding benzyl bromide as substituent into acetonitrile solution with alkali dissolved, stirring at 50 deg.C for reaction, reacting until the raw material disappears, cooling to room temperature, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound Ib

Dissolving compound Ib serving as a raw material in an anhydrous tetrahydrofuran solution, and keeping the temperature at 0 ℃ under the nitrogen protection conditionAdding reducing agent and MeOH in sequence, stirring at room temperature for 2h, concentrating the reaction solution after the reaction is finished, adding water, extracting with ethyl acetate for 3 times, collecting the organic phase, and adding anhydrous MgSO₄Drying, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain compound Ic

Dissolving the compound Ic serving as a raw material with 1- (benzyloxy) -4-iodo-1H-pyrazole, alkali and a catalyst in a solvent under the protection of nitrogen, refluxing at 90 ℃ until the reaction is finished, cooling the reaction liquid to room temperature, adding water, repeatedly extracting with dichloromethane for 3 times, collecting an organic phase, and adding anhydrous MgSO (MgSO) into the organic phase₄Drying, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain compound Id

Step four, taking the compound Id as a raw material, dissolving the compound Id and ammonium formate in absolute methanol/tetrahydrofuran with the volume ratio of 1:1, adding 10 wt.% palladium carbon under the protection of nitrogen, reacting at 0 ℃, filtering after the reaction to obtain filtrate, washing with methanol, concentrating under reduced pressure, and separating and purifying by column chromatography to form the compound Ie

The application of the aromatic heterocyclic substituted quinazolinone derivative in preparing a medicament for preventing and/or treating diabetic complications comprises an active ingredient and a pharmaceutically acceptable carrier, excipient or sustained-release agent, wherein the active ingredient comprises a therapeutically effective amount of the aromatic heterocyclic substituted quinazolinone derivative and/or pharmaceutically acceptable salt thereof. The aromatic heterocyclic substituted quinazolinone derivative and/or pharmaceutically acceptable salt thereof can be used as aldose reductase inhibitor.

Example 12

wherein X is CH ═ CH; r₁Is H; r₂Is H.

The synthetic method of the aromatic heterocycle substituted quinazolinone derivative comprises the following steps:

step one, compound Ia

Is used as raw material and is reacted with a catalyst containing R under the protection of nitrogen₁Dissolving substituted bromostyrene, alkali and catalyst in solvent, reacting at 110 deg.C, cooling to room temperature, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound Ib

Dissolving the compound Ic serving as a raw material, 1- (benzyloxy) -4-iodo-1H-pyrazole, alkali and a catalyst in a solvent under the protection of nitrogen, refluxing at 130 ℃ until the reaction is finished, cooling the reaction liquid to room temperature, adding water, repeatedly extracting with dichloromethane for 3 times, collecting an organic phase, adding anhydrous MgSO (MgSO) into the organic phase₄Drying, filtering and concentrating under reduced pressure, and separating and purifying by column chromatography to obtain compound Id

Step four, dissolving the compound Id serving as a raw material and ammonium formate in anhydrous methanol/tetrahydrofuran in a volume ratio of 1:1, adding 10 wt.% palladium carbon under the protection of nitrogen, reacting at 0 ℃, filtering to obtain filtrate, washing with methanol, concentrating under reduced pressure, and separating and purifying by column chromatography to form a compound Ie

The application of the aromatic heterocyclic substituted quinazolinone derivative in preparing a medicament for preventing and/or treating diabetic complications comprises an active ingredient and a pharmaceutically acceptable carrier, excipient or sustained-release agent, wherein the active ingredient comprises a therapeutically effective amount of the aromatic heterocyclic substituted quinazolinone derivative and/or pharmaceutically acceptable salt thereof. The aromatic heterocyclic substituted quinazolinone derivative and/or pharmaceutically acceptable salt thereof are used as aldose reductase inhibitors.

Claims

1. An aromatic heterocyclic substituted quinazolinone derivative is characterized in that the structural formula is shown as a formula (I):

2. An aromatic heterocycle substituted quinazolinone derivative according to claim 1, characterized in that said aromatic heterocycle substituted quinazolinone derivative is one of the following compounds:

3. the method for synthesizing aromatic heterocycle substituted quinazolinone derivative according to claim 1, wherein the method comprises the following steps:

step one, when X is CH₂In the presence of a compound Ia

As a raw material with R₁Benzyl bromide as substituent is first reacted in acetonitrile solution with alkali dissolved at 50-80 deg.c while stirring to react until the material disappears, and the reacted product is cooled to room temperature, filtered, decompression eliminated in solvent and column chromatographic separation and purification to obtain compound Ib

When X is CH ═ CH, compound Ia

Is used as raw material and is reacted with a catalyst containing R under the protection of nitrogen₁Dissolving substituted bromostyrene, alkali and catalyst in solvent, reacting at 80-110 deg.C, cooling to room temperature, filtering, removing solvent under reduced pressure, and purifying by column chromatography to obtain compound Ib

Dissolving a compound Ib serving as a raw material in an anhydrous tetrahydrofuran solution, sequentially adding a reducing reagent and MeOH at 0 ℃ under the protection of nitrogen, stirring at room temperature for 2 hours, concentrating the reaction solution after the reaction is finished, adding water, repeatedly extracting with ethyl acetate for 3 times, collecting the organic phase, adding anhydrous MgSO (MgSO) as the organic phase, and adding water to the organic phase₄Drying, filtering, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain compound Ic

Step three, taking the compound Ic as a raw material, under the protection of nitrogen,dissolving 1- (benzyloxy) -4-iodo-1H-pyrazole, alkali and catalyst in solvent, refluxing at 90-130 deg.C until the reaction is finished, cooling the reaction solution to room temperature, adding water, repeatedly extracting with dichloromethane for 3 times, collecting organic phase, adding anhydrous MgSO, and stirring to obtain solid phase₄Drying, filtering and concentrating under reduced pressure, and separating and purifying by column chromatography to form the compound Id

When X is CH₂CH₂Dissolving a compound Ie with X being CH (CH) in tetrahydrofuran, adding 10 wt.% palladium carbon dissolved in methanol, reacting at normal temperature in a hydrogen environment, filtering to remove a catalyst after the reaction is finished, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain the compound Ie with X being CH₂CH₂Compound Ie of (1)

4. The method of claim 3, wherein the base is potassium carbonate, sodium carbonate or cesium carbonate, the catalyst is cuprous iodide and N, N-dimethylethylenediamine, cuprous iodide and N, N-dimethylcyclohexyldiamine, cuprous iodide and ethylenediamine, cupric chloride and N, N-dimethylethylenediamine or cupric bromide and N, N-dimethylethylenediamine, and the solvent is anhydrous dioxane, toluene or N, N-dimethylformamide; the reducing reagent in the second step is sodium borohydride, potassium borohydride or lithium borohydride; the alkali in the third step is potassium carbonate, cesium carbonate, potassium tert-butoxide or potassium phosphate, the catalyst is cuprous iodide and N, N-dimethylethylenediamine, cuprous iodide and ethylenediamine, cuprous iodide and N, N-dimethylcyclohexanediamine, cupric chloride and N, N-dimethylethylenediamine or cupric bromide and N, N-dimethylethylenediamine, and the solvent is dioxane, toluene, N-dimethylformamide or dimethyl sulfoxide.

5. The method for synthesizing an aromatic heterocycle substituted quinazolinone derivative according to claim 3, wherein the end of the reaction of the starting compound is detected by TLC.

6. Use of an aromatic heterocyclic substituted quinazolinone derivative according to claim 1 for the preparation of a medicament for the prevention and/or treatment of diabetic complications.

7. The use according to claim 6, wherein the medicament for preventing and/or treating diabetic complications comprises an active ingredient comprising a therapeutically effective amount of the aromatic-heterocyclic-substituted quinazolinone derivative according to claim 1 and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or sustained release agent.

8. The use according to claim 6, wherein said aryl-heterocyclic-substituted quinazolinone derivative and/or a pharmaceutically acceptable salt thereof is used as an aldose reductase inhibitor.