A 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor and its preparation method and application

Abstract

The present invention discloses a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor and its preparation method and application. The chemical structure of this type of α-glucosidase inhibitor is shown in formula (I): #imgabs0# The 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor disclosed by the present invention not only has good effects of inhibiting the activity of α-glucosidase and reducing postprandial blood sugar, but can be used as a lead compound for novel anti-diabetic research; it also has low toxicity to normal human cells and high safety; and the preparation method of the 1,2,4-triazole-phenylacetamide compound disclosed by the present invention is simple, the synthetic route is short, it is easy to prepare in large quantities, the price is low, and it is suitable for market promotion and application.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor, a preparation method thereof, and application thereof in the preparation of anti-diabetic drugs. Background Art

[0002] Diabetes mellitus (DM) is a serious endocrine and metabolic disease caused by impaired insulin secretion and insulin resistance, characterized by abnormally elevated blood glucose levels. Chronic elevated blood glucose levels can have detrimental effects on the vascular endothelium and may lead to various microvascular and macrovascular complications. The use of glucose-lowering medications can reduce the risk of various complications in patients with type 2 diabetes by controlling postprandial hyperglycemia.

[0003] α-Glucosidase is an important membrane-bound enzyme that hydrolyzes the glycosidic bonds of disaccharides or polysaccharides, releasing monosaccharides, which can lead to postprandial hyperglycemia. Therefore, α-glucosidase inhibitors can inhibit carbohydrate intake and thus suppress postprandial hyperglycemia. Currently, α-glucosidase inhibitors such as acarbose, voglibose, and miglitol are on the market and clinically used to treat type 2 diabetes. However, long-term use of these drugs may cause some gastrointestinal side effects, such as stomach pain, diarrhea, and flatulence.

[0004] Therefore, how to develop a new type of α-glucosidase inhibitor that can effectively and safely treat type 2 diabetes remains a technical problem that needs to be solved urgently by those skilled in the art. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor and a preparation method thereof to address the problems existing in the prior art.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor having a structure as shown in formula (I):

[0008]

[0009] Wherein, R1 in the general formula I is at least one of chlorine, bromine, and hydroxyl; R2 is at least one of hydrogen, 4-methyl, 4-fluoro, 4-ethoxy, 4-chloro, and 2,4-dimethyl.

[0010] Exemplarily, the structural formula of the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor includes:

[0011]

[0012] The present invention also seeks to protect a method for preparing the above-mentioned 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor, which specifically comprises the following steps:

[0013] Step 1: Chloroacetic acid is added to a stirred mixed solution of phenol and 32% NaOH, and the reaction mixture is stirred at 80-85°C for 2.5-4 hours. After the reaction is completed, the reaction mixture is diluted with cold water and the pH is adjusted to 1-2 with HCl at room temperature. The mixture is filtered and dried to obtain the product 2-phenoxyacetic acid;

[0014]

[0015] Step 2: reflux a mixture of thiocarbohydrazide and 2-phenoxyacetic acid prepared in step 1 at 150-160° C. for 0.5-1 h. After the reaction is completed, the product is crushed and diluted with an appropriate amount of water, filtered, and then dried at room temperature to prepare 4-amino-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol;

[0016]

[0017] Step 3: mixing the para-substituted benzaldehyde with the 4-amino-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol prepared in step 2 and glacial acetic acid to obtain a reaction mixture, stirring the mixture at 110-120° C. for 3.5-5 hours, cooling the mixture until a large amount of solid precipitate is produced, filtering the mixture, and drying the mixture to obtain a substituted (E)-4-(benzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol;

[0018]

[0019] Step 4: DMF and triethylamine are added to a mixture of 2-chloro-N-(substituted phenyl)acetamide and substituted (E)-4-(benzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol prepared in Step 3 to obtain a reaction mixture. The mixture is ultrasonically reacted at 25-50°C for 2-3 hours. After cooling to room temperature, an appropriate amount of ultrapure water is added. After a large amount of precipitate is precipitated, it is filtered and dried to obtain the target product I.

[0020]

[0021] Preferably, the ratio of chloroacetic acid, phenol and 32% NaOH is 90 mmol:50 mmol:16 mL.

[0022] Preferably, the molar ratio of thiocarbohydrazide to 2-phenoxyacetic acid is 1:1.

[0023] Preferably, the molar ratio of the p-substituted benzaldehyde to 4-amino-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol is 1:1; and 10 ml of glacial acetic acid is added for every 1 mmol of p-substituted benzaldehyde.

[0024] Preferably, the molar ratio of the 2-chloro-N-(substituted phenyl)acetamide and the substituted (E)-4-(benzylideneamino)-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol is 1:1; and 5 ml of DMF and 140 μL of triethylamine are added for every 0.5 mmol of substituted phenylacetamide.

[0025] In addition, the present invention also seeks to protect the use of the above-mentioned 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor in the preparation of anti-diabetic drugs.

[0026] Compared with the prior art, the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor disclosed in the present invention, as well as its preparation method and application, has the following advantages:

[0027] 1. The 1,2,4-triazole-phenylacetamide α-glucosidase inhibitors disclosed in the present invention have good effects of inhibiting α-glucosidase activity and lowering postprandial blood glucose, and can be used as a lead compound for novel anti-diabetic research;

[0028] 2. The preparation method of the 1,2,4-triazole-phenylacetamide compounds disclosed in the present invention is simple, the synthetic route is short, it is easy to prepare in large quantities, and the price is low;

[0029] 3. The 1,2,4-triazole-phenylacetamide α-glucosidase inhibitors disclosed in the present invention have low toxicity to normal human cells and high safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0031] Figure 1 The present invention is a preparation route of the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor.

[0032] Figure 2 The effect of compound 7 on postprandial blood glucose in Kunming mice; (A) The inhibitory effect of compound 7 on blood glucose in Kunming mice after administration of sucrose; (B) The AUC 0-120minThe increment of the expression level was 0.05, and the letters (ad) indicated significant differences, P < 0.05.

[0033] Figure 3 is the H NMR spectrum of compound 7.

[0034] Figure 4 is the carbon NMR spectrum of compound 7.

[0035] Figure 5 This is the high-resolution mass spectrum of compound 7. DETAILED DESCRIPTION

[0036] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0037] For a better understanding of the present invention, the present invention is further specifically described below through the following examples, but it should not be understood as limiting the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above invention content are also considered to fall within the scope of protection of the present invention.

[0038] The invention discloses a 1,2,4-triazole-phenylacetamide alpha-glucosidase inhibitor and a preparation method thereof.

[0039] In order to further illustrate the technical solution disclosed in the present invention, the inventors also conducted the following examples:

[0040] Example 1:

[0041] Preparation of (E)-2-((4-((4-chlorobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(p-tolyl)acetamide (Compound 1)

[0042] The structural formula of compound 1 is shown below:

[0043]

[0044] The specific preparation steps are as follows:

[0045] Step 1: Chloroacetic acid is added to a stirred mixed solution of phenol and 32% NaOH, and the reaction mixture is stirred at 85°C for 3 hours. After the reaction is completed, the reaction mixture is diluted with cold water and the pH is adjusted to 1-2 with HCl at room temperature. The mixture is filtered and dried to obtain the product 2-phenoxyacetic acid;

[0046] Step 2: A mixture of thiocarbohydrazide and 2-phenoxyacetic acid prepared in step 1 at a molar ratio of 1:1 was refluxed at 160° C. for 1 h. After the reaction was completed, the product was crushed and diluted with an appropriate amount of water, filtered, and dried at room temperature to prepare 4-amino-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol;

[0047] Step 3: Mixing 4-chlorobenzaldehyde with 4-amino-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol prepared in step 2 and glacial acetic acid to obtain a reaction mixture, stirring the mixture at 120° C. for 4 hours, cooling the mixture until a large amount of solid precipitate is generated, filtering the mixture, and drying the mixture to obtain (E)-4-((4-chlorobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol;

[0048] Step 4: DMF and triethylamine were added to a mixture of 2-chloro-N-(p-methylphenyl)acetamide and (E)-4-((4-chlorobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazole-3-thiol obtained in step 3 to obtain a reaction mixture. The mixture was ultrasonically reacted at room temperature for 2-3 h. After cooling to room temperature, an appropriate amount of ultrapure water was added to precipitate a large amount of precipitate, which was then filtered and dried to obtain the target compound 1.

[0049] Compound 1 is a white solid with a yield of 84.86% and a melting point of 180-183°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 1 are shown below:

[0050] 1 H NMR(400MHz, DMSO-d6)δ:10.27(s,1H),8.94(s,1H),7.84(d,J=8.8Hz,2H),7.62(d,J=8.8Hz,2H),7.43(d,J=8.4Hz,2H),7 .31-7.25(m,2H),7.10(d,J=8.4Hz,2H),7.07-7.02(m,2H),6.97(t,J=7.2Hz,1H),5.38(s,2H),4.19(s,2H),2.25(s,3H).

[0051] 13 C NMR(100MHz,DMSO-d6)δ:165.21,163.97,157.37,149.00,148.08,137.84,136.34,132.5 0,130.61,130.58,129.65,129.47,129.24,121.69,119.10,115.06,59.74,36.75,20.51.

[0052] HRMS(ESI)calcd for[MH] - C 25 H 21 ClN5O2S - :490.1099,found:490.1108.

[0053] The preparation methods of the following examples are similar to those of Example 1, and the ratios of the raw materials used are the same as those of Example 1, except that the 4-chlorobenzaldehyde in Example 1 is replaced with other corresponding substituted benzaldehydes, and the 2-chloro-N-(p-methylphenyl)acetamide is replaced with other corresponding 2-chloro-N-(substituted phenyl)acetamides.

[0054] Example 2:

[0055] Preparation of (E)-2-((4-((4-chlorobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-fluorophenyl)acetamide (Compound 2)

[0056] Compared with Example 1, the difference is that only 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-fluorophenyl)acetamide.

[0057] The structural formula of compound 2 is shown below:

[0058]

[0059] Compound 2 is a white solid with a yield of 93.87% and a melting point of 210-213°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 2 are shown below:

[0060] 1 H NMR (400MHz, DMSO-d6) δ: 10.40 (s, 1H), 8.94 (s, 1H), 7.84 (d, J = 8.4Hz, 2H), 7.64-7.53 (m, 4 H),7.32-7.24(m,2H),7.18-7.01(m,4H),6.97(t,J=7.4Hz,1H),5.39(s,2H),4.20(s,2H).

[0061] 13 C NMR (100MHz, DMSO-d6) δ: 165.37, 163.99, 157.34, 156.92 (d, 1C, J = 238.7Hz, 1 J CF ),148.82,148.07,137.80,135.18(d,1C,J=2.3Hz, 4J CF ),130.56,130.53,129.58,129.42,121.64,120.83(d,1C,J=7.6Hz, 3 J CF ),115.27(d,1C,J=22.2Hz, 2 J CF ),115.05,59.74,36.62.

[0062] HRMS(ESI)calcd for[MH] - C 24 H 18 ClFN5O2S - :494.0848,found:494.0861.

[0063] Example 3:

[0064] Preparation of (E)-2-((4-((4-chlorobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-ethoxyphenyl)acetamide (Compound 3)

[0065] Compared with Example 1, the difference is that only 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-ethoxyphenyl)acetamide.

[0066] The structural formula of compound 3 is shown below:

[0067]

[0068] Compound 3 is a white solid with a yield of 77.89% and a melting point of 180-183°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 3 are shown below:

[0069] 1 H NMR(400MHz, DMSO-d6)δ:10.18(s,1H),8.94(s,1H),7.84(d,J=8.4Hz,2H),7.62(d,J=8.4Hz,2H),7.44(d,J=8.8Hz,2H),7.28(t,J=7.8Hz,2H ),7.04(d,J=7.6Hz,2H),6.97(t,J=7.2Hz,1H),6.86(d,J=8.8Hz,2H),5.38(s,2H),4.17(s,2H),3.97(q,J=7.0Hz,2H),1.31(d,J=7.0Hz,3H).

[0070] 13C NMR(100MHz,DMSO-d6)δ:165.03,164.20,157.44,154.80,149.04,148.20,137.98,131.91,1 30.69,130.66,129.77,129.57,121.82,120.79,115.15,114.54,63.21,59.82,36.77,14.82.

[0071] HRMS(ESI)calcd for[MH] - C 26 H 23 ClN5O3S - :520.1205,found:520.1210.

[0072] Example 4:

[0073] Preparation of (E)-2-((4-((4-chlorobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide (Compound 4)

[0074] Compared with Example 1, the difference is that only 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-phenylacetamide.

[0075] The structural formula of compound 4 is shown below:

[0076]

[0077] Compound 4 is a white solid with a yield of 51.68% and a melting point of 182-185°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum of compound 4 are shown below:

[0078] 1 H NMR(400MHz, DMSO-d6)δ:10.36(s,1H),8.94(s,1H),7.84(d,J=8.6Hz,2H),7.62(d,J=8.6Hz,2H),7.55( d,J=7.6Hz,2H),7.33-7.25(m,4H),7.08-7.02(m,3H),6.97(t,J=7.2Hz,1H),5.38(s,2H),4.21(s,2H).

[0079] 13C NMR(100MHz,DMSO-d6)δ:165.48,163.98,157.37,149.01,148.08,138.84,137.85 ,130.59,129.65,129.49,128.88,123.58,121.70,119.11,115.07,59.75,36.74.

[0080] HRMS(ESI)calcd for[MH] - C 24 H 19 ClN5O2S - :476.0942,found:476.0950.

[0081] Embodiment 5:

[0082] Preparation of (E)-2-((4-((4-bromobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(p-tolyl)acetamide (Compound 5)

[0083] Compared with Example 1, the difference is that only 4-chlorobenzaldehyde is replaced by 4-bromobenzaldehyde.

[0084] The structural formula of compound 5 is shown below:

[0085]

[0086] Compound 5 is a white solid with a yield of 89.85%; its melting point is 193-197°C; and the H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 5 are shown below:

[0087] 1 H NMR(400MHz, DMSO-d6)δ:10.25(s,1H),8.93(s,1H),7.76(s,4H),7.43(d,J=8.8Hz,2H),7.28(t,J=8.2Hz,2H ),7.10(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),6.97(t,J=7.2Hz,1H),5.38(s,2H),4.18(s,2H),2.25(s,3H).

[0088] 13C NMR(100MHz,DMSO-d6)δ:165.20,164.05,157.36,149.02,148.06,136.34,132.50,132.4 0,130.93,130.68,129.65,129.23,126.94,121.69,119.10,115.06,59.75,36.75,20.51.

[0089] HRMS(ESI)calcd for[MH] - C 25 H 21 BrN5O2S - :534.0594,found:534.0605.

[0090] Example 6:

[0091] Preparation of (E)-2-((4-((4-bromobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-fluorophenyl)acetamide (Compound 6)

[0092] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-bromobenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-fluorophenyl)acetamide.

[0093] The structural formula of compound 6 is shown below:

[0094]

[0095] Compound 6 is a white solid with a yield of 82.16%; its melting point is 210-214°C; and the H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 6 are shown below:

[0096] 1 H NMR(400MHz,DMSO-d6)δ:10.32(s,1H),8.93(s,1H),7.76(s,4H),7.58-7.53(m,2H),7.32-7.25(m, 2H),7.13(t,J=8.8Hz,2H),7.04(d,J=7.6Hz,2H),6.97(t,J=7.2Hz,1H),5.37(s,2H),4.17(s,2H).

[0097] 13 C NMR (100MHz, DMSO-d6) δ: 165.43, 164.09, 157.36, 156.96 (d, 1C, J = 239.2Hz, 1J CF ),148.98,148.08,135.22(d,1C,J=2.5Hz, 4 J CF ),132.41,130.93,130.69,129.66,126.96,121.71,120.85(d,1C,J=8.0Hz, 3 J CF ),115.35(d,1C,J=22.1Hz, 2 J CF ),115.07,59.76,36.63.

[0098] HRMS (ESI) calculation for [MH]-C 24 H 18 BrFN5O2S - :538.0343,found:538.0353.

[0099] Embodiment seven:

[0100] Preparation of (E)-2-((4-((4-bromobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-ethoxyphenyl)acetamide (Compound 7)

[0101] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-bromobenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-ethoxyphenyl)acetamide.

[0102] The structural formula of compound 7 is shown below:

[0103]

[0104] Compound 7 is a white solid with a yield of 86.85%; its melting point is 185-190°C; and the H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 7 are shown below:

[0105] 1H NMR (400MHz, DMSO-d6) δ: 10.18 (s, 1H), 8.93 (s, 1H), 7.76 (s, 4H), 7.44 (d, J = 8.8Hz, 2H), 7.28 (t, J = 8.0Hz, 2H), 7.04 (d, J = 8.4 Hz,2H),6.97(t,J=7.6Hz,1H),6.86(d,J=8.8Hz,2H),5.38(s,2H),4.17(s,2H),3.97(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H).

[0106] 13 C NMR(100MHz,DMSO-d6)δ:164.91,164.08,157.37,154.68,149.01,148.07,132.41,131.87,1 30.94,130.69,129.65,126.94,121.70,120.64,115.07,114.44,63.10,59.75,36.70,14.74.

[0107] HRMS(ESI)calcd for[MH] - C 26 H 23 BrN5O3S - :564.0699,found:564.0703.

[0108] Embodiment 8:

[0109] Preparation of (E)-2-((4-((4-bromobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(4-chlorophenyl)acetamide (Compound 8)

[0110] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-bromobenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-chlorophenyl)acetamide.

[0111] The structural formula of compound 8 is shown below:

[0112]

[0113] Compound 8 is a white solid with a yield of 87.18%; its melting point is 200-205°C; and the H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 8 are shown below:

[0114] 1HNMR(400MHz,DMSO-d6)δ:10.50(s,1H),8.93(s,1H),7.76(s,4H),7.58(d,J=8.8Hz,2H),7.36(d,J=8 .8Hz,2H),7.31-7.26(m,2H),7.03(d,J=7.8Hz,2H),6.97(t,J=7.4Hz,1H),5.38(s,2H),4.20(s,2H).

[0115] 13 CNMR(100MHz,DMSO-d6)δ:165.69,164.06,157.35,148.96,148.08,137.79,132.40,13 0.92,130.68,129.65,128.79,127.11,126.95,121.70,120.64,115.06,59.74,36.68.

[0116] HRMS(ESI)calcdfor[MH] - C 24 H 18 BrClN5O2S - :554.0048,found:554.0056.

[0117] Example 9: Preparation of (E)-2-((4-((4-bromobenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide (Compound 9)

[0118] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-bromobenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-phenylacetamide.

[0119] The structural formula of compound 9 is shown below:

[0120]

[0121] Compound 9 is a white solid with a yield of 45.56% and a melting point of 182-186°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 9 are shown below:

[0122] 1HNMR(400MHz,DMSO-d6)δ:10.33(s,1H),8.93(s,1H),7.76(s,4H),7.55(d,J=7.2Hz,2H) ,7.34-7.25(m,4H),7.09-7.01(m,3H),6.97(t,J=7.2Hz,1H),5.38(s,2H),4.21(s,2H).

[0123] 13 CNMR(100MHz,DMSO-d6)δ:165.47,164.06,157.36,149.03,148.06,138.84,132.41,13 0.94,130.69,129.65,128.88,126.94,123.57,121.69,119.10,115.07,59.75,36.73.

[0124] HRMS(ESI)calcdfor[MH] - C 24 H 19 BrN5O2S - :520.0437,found:520.0450.

[0125] Embodiment 10:

[0126] Preparation of (E)-2-((4-((4-bromobenzylidene)amino)-5-(phenoxymethyl)-4H-12,4-triazol-3-yl)thio)-N-(2,4-dimethylphenyl)acetamide (Compound 10)

[0127] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-bromobenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(2,4-dimethylphenyl)acetamide.

[0128] The structural formula of compound 10 is shown below:

[0129]

[0130] Compound 10 is a white solid with a yield of 93.65%; its melting point is 151-155°C; and the H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 10 are shown below:

[0131] 1HNMR(400MHz,DMSO-d6)δ:9.61(s,1H),8.93(s,1H),7.77(s,4H),7.32-7.23( m,3H),7.06-6.93(m,5H),5.39(s,2H),4.20(s,2H),2.23(s,3H),2.12(s,3H).

[0132] 13 CNMR(100MHz,DMSO-d6)δ:165.66,164.15,157.39,149.01,148.12,134.46,133.40,132.43,131.45,1 30.95,130.90,130.70,129.66,126.97,126.52,124.65,121.70,115.08,59.76,36.26,20.54,17.74.

[0133] HRMS(ESI)calcdfor[MH] - C 26 H 23 BrN5O2S - :548.0750,found:548.0760.

[0134] Example 11:

[0135] Preparation of (E)-2-((4-((4-hydroxybenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-(p-tolyl)acetamide (Compound 11)

[0136] The difference compared with Example 1 is that only 4-chlorobenzaldehyde is replaced by 4-hydroxybenzaldehyde.

[0137] The structural formula of compound 11 is shown below:

[0138]

[0139] Compound 11 is a white solid with a yield of 77.82% and a melting point of 220-223°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum of compound 11 are shown below:

[0140] 1HNMR(400MHz,DMSO-d6)δ:10.50(s,1H),10.27(s,1H),8.75(s,1H),7.69(d,J=8.8Hz,2H),7.44(d,J=8.4Hz,2H),7.31-7.25(m,2H) ,7.11(d,J=8.0Hz,2H),7.04(d,J=7.6Hz,2H),6.96(t,J=7.4Hz,1H),6.89(d,J=8.8Hz,2H),5.28(s,2H),4.18(s,2H),2.25(s,3H).

[0141] 13 CNMR(100MHz,DMSO-d6)δ:166.38,165.29,162.32,157.45,148.43,148.12,136.37,132.5 0,131.41,129.64,129.25,122.55,121.61,119.12,116.16,115.01,59.58,36.64,20.51.

[0142] HRMS(ESI)calcdfor[MH] - C 25 H 22 N5O3S - :472.1438,found:472.1445.

[0143] Example 12:

[0144] Preparation of (E)-N-(4-fluorophenyl)-2-((4-((4-hydroxybenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (Compound 12)

[0145] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-hydroxybenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-fluorophenyl)acetamide.

[0146] The structural formula of compound 12 is shown below:

[0147]

[0148] Compound 12 is a white solid with a yield of 74.13% and a melting point of 218-221°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum of compound 12 are shown below:

[0149] 1H NMR(400MHz, DMSO-d6)δ:10.49(s,1H),10.42(s,1H),8.75(s,1H),7.69(d,J=8.8Hz,2H),7.61-7.54(m,2H),7.32-7.25(m ,2H),7.15(t,J=8.8Hz,2H),7.04(d,J=7.6Hz,2H),6.96(t,J=7.2Hz,1H),6.89(d,J=8.8Hz,2H),5.29(s,2H),4.18(s,2H).

[0150] 13 C NMR (100MHz, DMSO-d6) δ: 166.35, 165.45, 162.28, 157.42, 156.93 (d, 1C, J = 238.5Hz, 1 J CF ),148.25,148.12,135.18(d,1C,J=2.5Hz, 4 J CF ),131.34,129.57,122.51,121.56,120.86(d,1C,J=7.9Hz, 3 J CF ),116.11,115.28(d,1C,J=22.1Hz, 2 J CF ),114.99,59.59,36.52.

[0151] HRMS(ESI)calcd for[MH] - C 24 H 19 FN5O3S - :476.1187,found:476.1192.

[0152] Example 13:

[0153] Preparation of (E)-N-(4-ethoxyphenyl)-2-((4-((4-hydroxybenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (Compound 13)

[0154] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-hydroxybenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-ethoxyphenyl)acetamide.

[0155] The structural formula of compound 13 is shown below:

[0156]

[0157] Compound 13 is a white solid with a yield of 69.50%; its melting point is 203-206°C; and the H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 13 are shown below:

[0158] 1 H NMR (400MHz, DMSO-d6) δ: 10.50 (s, 1H), 10.22 (s, 1H), 8.75 (s, 1H), 7.69 (d, J = 8.8Hz, 2H), 7.45 (d, J = 8.8Hz, 2H), 7.32-7.25 (m, 2H), 7. 04(d,J=7.6Hz,2H),6.96(t,J=7.2Hz,1H),6.92-6.84(m,4H),5.28(s,2H),4.16(s,2H),3.97(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H).

[0159] 13 C NMR(100MHz,DMSO-d6)δ:166.41,165.00,162.33,157.46,154.70,148.41,148.14,131.89,1 31.42,129.65,122.57,121.62,120.68,116.17,115.02,114.46,63.11,59.59,36.60,14.74.

[0160] HRMS(ESI)calcd for[MH] - C 26 H 24 N5O4S - :502.1544,found:502.1551.

[0161] Example 14:

[0162] Preparation of (E)-N-(4-chlorophenyl)-2-((4-((4-hydroxybenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (Compound 14)

[0163] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-hydroxybenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(4-chlorophenyl)acetamide.

[0164] The structural formula of compound 14 is shown below:

[0165]

[0166] Compound 14 is a white solid with a yield of 67.51% and a melting point of 216-218°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 14 are shown below:

[0167] 1 H NMR (400MHz, DMSO-d6) δ: 10.50 (s, 2H), 8.75 (s, 1H), 7.68 (d, J = 8.8Hz, 2H), 7.59 (d, J = 9.2Hz, 2H), 7.37 (d, J = 9.2Hz, 2 H),7.31-7.26(m,2H),7.03(d,J=7.6Hz,2H),6.96(t,J=7.2Hz,1H),6.89(d,J=8.8Hz,2H),5.28(s,2H),4.19(s,2H).

[0168] 13 C NMR(100MHz,DMSO-d6)δ:166.46,165.82,162.37,157.47,148.38,148.20,137.84,13 1.46,129.69,128.85,127.17,122.58,121.67,120.73,116.21,115.04,59.62,36.60.

[0169] HRMS(ESI)calcd for[MH] - C 24 H 19 ClN5O3S - :492.0892,found:492.0900.

[0170] Embodiment 15:

[0171] Preparation of (E)-2-((4-((4-hydroxybenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)-N-phenylacetamide (Compound 15)

[0172] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-hydroxybenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-phenylacetamide.

[0173] The structural formula of compound 15 is shown below:

[0174]

[0175] Compound 15 is a white solid with a yield of 39.93% and a melting point of 213-217°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum data of compound 15 are shown below:

[0176] 1 H NMR (400MHz, DMSO-d6) δ: 10.50 (s, 1H), 10.36 (s, 1H), 8.76 (s, 1H), 7.69 (d, J = 8.4Hz, 2H), 7.56 (d, J = 7.2Hz, 2H) ,7.34-7.26(m,4H),7.09-7.02(m,3H),6.96(t,J=7.4Hz,1H),6.89(d,J=8.4Hz,2H),5.29(s,2H),4.20(s,2H).

[0177] 13 C NMR(100MHz,DMSO-d6)δ:166.38,165.56,162.32,157.45,148.42,148.13,138.87,13 1.42,129.64,128.89,123.58,122.56,121.61,119.12,116.17,115.01,59.59,36.64.

[0178] HRMS(ESI)calcd for[MH] - C 24 H 20 N5O3S - :458.1281,found:458.1286.

[0179] Example 16:

[0180] Preparation of (E)-N-(2,4-dimethylphenyl)-2-((4-((4-hydroxybenzylidene)amino)-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (Compound 16)

[0181] Compared with Example 1, the difference is that 4-chlorobenzaldehyde is replaced by 4-hydroxybenzaldehyde, and 2-chloro-N-(p-methylphenyl)acetamide is replaced by 2-chloro-N-(2,4-dimethylphenyl)acetamide.

[0182] The structural formula of compound 16 is shown below:

[0183]

[0184] Compound 16 is a white solid with a yield of 72.70% and a melting point of 205-210°C. The H-NMR spectrum, C-NMR spectrum, and high-resolution mass spectrum of compound 16 are shown below:

[0185] 1 HNMR(400MHz,DMSO-d6)δ:10.50(s,1H),9.63(s,1H),8.76(s,1H),7.69(d,J=8.8Hz,2H),7.32-7.24( m,3H),7.07-6.93(m,5H),6.89(d,J=8.8Hz,2H),5.30(s,2H),4.19(s,2H),2.23(s,3H),2.13(s,3H).

[0186] 13 CNMR(100MHz,DMSO-d6)δ:166.44,165.73,162.33,157.46,148.40,148.18,134.42,133.42,131. 41,130.89,129.64,126.52,124.62,122.55,121.60,116.17,115.01,59.59,36.15,20.52,17.73.

[0187] HRMS(ESI)calcdfor[MH] - C 26 H 24 N5O3S - :486.1594,found:486.1602.

[0188] In order to further verify the excellent effect of the present invention, the inventors also conducted the following comparative experiments:

[0189] Experiment 1

[0190] Different concentrations of compound or acarbose (10 μL) and 150 μL α-glucosidase solution (0.1 U / mL) were added to a 96-well plate, and the mixture was incubated at 37°C for 15 minutes. Then 40 μL p-nitrophenyl-α-D-pyranoglucopyranoside (1.25 mM) was added to the above mixture and incubated for another 30 minutes. The detection wavelength was 405 nm on a microplate reader, and the IC was calculated. 50 , the results are shown in Table 1.

[0191] Table 1. α-glucosidase inhibitory activity (IC) of 1,2,4-triazole-phenylacetamide compounds 50 ):

[0192]

[0193]

[0194] It can be seen from Table 1 that the compounds synthesized in the present invention have good activity in inhibiting α-glucosidase, with compounds 2, 3, 7, 9 and 16 having the best activity (IC 50 Among them, compound 7 had the best activity, with an IC of 0. 50 It was 6.69±0.18μM, which was better than the positive control drug acarbose (723.06±11.26μM).

[0195] Experiment 2

[0196] Compound 7 was used to investigate its effect on postprandial blood glucose in normal Kunming mice.

[0197] In this experiment, all experimental mice were fasted for 12 hours before the experiment (with free access to water). All Kunming mice were randomly divided into four groups, with 7 mice in each group. They were: model group (0.5% CMC-Na solution), acarbose group (20 mg / kg, dissolved in 0.5% CMC-Na solution), test compound group (compound 720 mg / kg, dissolved in 0.5% CMC-Na solution) and blank control group (0.5% CMC-Na solution). After administration, the above groups were gavaged with 2.5 g / kg of sucrose (the blank control group used a blank 0.5% CMC-Na solution), and their postprandial blood glucose was detected from the tail of the mice using Roche Accu-ChekInstant at 0 hours, 0.25 hours, 0.5 hours, 1 hour, 1.5 hours and 2 hours. Kunming mice (25-30 g) were purchased from the Experimental Animal Center of Guizhou Medical University with license number SYXK (Qian) 2018-0001. All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals, and the experiments were approved by the Animal Ethics Committee of Guizhou Medical University.

[0198] Depend on Figure 2 (A) It can be seen that the blood glucose level of the model group increased rapidly and reached a peak after oral administration of sucrose, while the blood glucose level of the acarbose group and compound 7 group after oral administration of sucrose was significantly lower than that of the model group, and the blood glucose level was steadily reduced. Figure 2 (B) describes the changes in blood glucose load levels in mice after oral administration of sucrose, which shows that compound 7 can reduce postprandial blood glucose levels.

[0199] It should be noted that the properties of other compounds of the same type were mapped out based on the structure of compound 7, and based on the results of Experiment 2, it was inferred that the homologues of compound 7 also have the corresponding performance of lowering postprandial blood glucose levels.

[0200] Experiment 3

[0201] Human normal embryonic kidney (HEK293) cells were seeded in 96-well plates and cultured at 37°C for 24 hours. Compound 7 (25, 45, 85, and 125 μM) was then added to the plates and cultured for an additional 24 hours. Following cell culture, the effects of the compounds on cell growth were determined using the MTT assay, and the inhibitory rate of the compounds on normal cells was calculated.

[0202] The experimental results showed that the inhibition rates of compound 7 on normal cells were 88.47%, 89.15%, 87.52% and 87.13%, respectively, indicating that compound 7 has low toxicity and high safety.

[0203] It should be noted that the properties of other compounds of the same type were mapped out based on the structure of compound 7, and based on the results of Experiment 3, it was inferred that the homologues of compound 7 also have low cytotoxicity.

[0204] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor, characterized in that: It has the general structural formula shown in formula (I): ； Wherein, R1 in the general formula I is one of chlorine, bromine, and hydroxyl; R2 is one of hydrogen, 4-methyl, 4-fluoro, 4-ethoxy, 4-chloro, and 2,4-dimethyl.

2. A method for preparing the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor according to claim 1, characterized in that: The method specifically comprises the following steps: Step 1: Chloroacetic acid is added to a stirred mixed solution of phenol and 32% NaOH, and the reaction mixture is stirred at 80-85°C for 2.5-4 hours. After the reaction is completed, the reaction mixture is diluted with cold water and the pH is adjusted to 1-2 with HCl at room temperature. The mixture is filtered and dried to obtain the product 2-phenoxyacetic acid. Step 2: Reflux the mixture of thiocarbohydrazide and 2-phenoxyacetic acid prepared in step 1 at 150-160°C for 0.5-1h. After the reaction is complete, crush the product and dilute it with water, filter it, and dry it at room temperature to prepare 4-amino-5-(phenoxymethyl)-4-(phenoxymethyl)- H -1,2,4-triazole-3-thiol; Step 3: Resuspend the para-substituted benzaldehyde in 4-amino-5-(phenoxymethyl)-4- H -1,2,4-triazole-3-thiol and glacial acetic acid were mixed to obtain a reaction mixture, which was stirred at 110-120 ° C for 3.5-5 h, and then cooled until a large amount of solid precipitate was generated, filtered, and dried to obtain a replacement ( E )-4-(benzylideneamino)-5-(phenoxymethyl)-4 H -1,2,4-triazole-3-thiol; Step 4: To 2-chloro- N -(substituted phenyl)acetamide and the substituted ( E )-4-(benzylideneamino)-5-(phenoxymethyl)-4 H DMF and triethylamine are added to a mixture of 1,2,4-triazole-3-thiol to obtain a reaction mixture, which is subjected to ultrasonic reaction at 25-50° C. for 2-3 h. After cooling to room temperature, ultrapure water is added. After a large amount of precipitate is precipitated, it is filtered and dried to obtain the target product I, i.e., the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor.

3. The method for preparing a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor according to claim 2, characterized in that: In step 1, the ratio of chloroacetic acid, phenol and 32% NaOH is 90 mmol:50 mmol:16 mL.

4. The method for preparing a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor according to claim 2, characterized in that: In step 2, the molar ratio of thiocarbohydrazide to 2-phenoxyacetic acid is 1:

1.

5. The method for preparing a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor according to claim 2, characterized in that: In step 3, the para-substituted benzaldehyde, 4-amino-5-(phenoxymethyl)-4 H The ratio between -1,2,4-triazole-3-thiol and glacial acetic acid was 1 mmol:1 mmol:10 mL.

6. The method for preparing a 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor according to claim 2, characterized in that: In step 4, the 2-chloro- N -(substituted phenyl)acetamides and substituted ( E )-4-(benzylideneamino)-5-(phenoxymethyl)-4 H The molar ratio of 1,2,4-triazole-3-thiol was 1:1; and the ratio of substituted phenylacetamide to DMF and triethylamine was 0.5 mmol:5 mL:140 μL.

7. Use of the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor according to claim 1 or the 1,2,4-triazole-phenylacetamide α-glucosidase inhibitor prepared by the method according to any one of claims 2 to 6 in the preparation of an antidiabetic drug.

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