Indolone derivative containing triazole structure as well as preparation method and application of indolone derivative

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses an indolone derivative containing a triazole structure as well as a preparation method and application of the indolone derivative. The indolone derivative has a structural formula as shown in a formula (I): # imgabs0 #, wherein R represents a substituted or unsubstituted phenyl group. The compound can effectively inhibit alpha-glucosidase, and can be used for preparing related products for treating / preventing diabetes mellitus to play a role in reducing blood sugar.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an indolinone derivative containing a triazole structure, a preparation method thereof, and an application thereof. Background Art

[0002] Diabetes is a chronic disease marked by hyperglycemia, caused by absolute or relative insulin deficiency and utilization disorders. This disease is mainly divided into three types: type 1, type 2, and gestational diabetes. The causes are mainly attributed to the combined effects of genetic and environmental factors, including decreased insulin secretion due to pancreatic islet cell dysfunction, or the body's insensitivity to insulin action or both, resulting in the ineffective utilization and storage of glucose in the blood. Currently, the incidence and prevalence of diabetes are on the rise globally.

[0003] Currently, there are oral hypoglycemic drugs with multiple targets on the market, including sulfonylurea drugs (glyburide, glimepiride, and tolbutamide), guanidine drugs (metformin), sodium-glucose cotransporter 2 (SGLT2) inhibitors (dapagliflozin), etc. In addition, there are common α-glucosidase inhibitors, including acarbose, voglibose, etc.

[0004] α-Glucosidase hydrolyzes the α-glucoside bond of the substrate from the non-reducing end of the polysaccharide to produce α-D-glucose. Intestinal α-glucosidase can promote the conversion of carbohydrates consumed by humans into glucose for absorption by humans, increasing postprandial blood glucose. α-Glucosidase inhibitors can competitively and reversibly inhibit this intestinal enzyme, preventing the hydrolysis of the non-reducing end of oligosaccharides and reducing the release of α-glucose. In addition, α-glucosidase inhibitors can also cause a long-term and continuous increase in endogenous GLP-1, thereby stimulating insulin secretion and reducing glucagon secretion, thus achieving the effect of controlling postprandial hyperglycemia.

[0005] Based on the advantageous characteristics of α-glucosidase inhibitors, many new studies on α-glucosidase inhibitors have been carried out in recent years, which may contribute to the discovery of new α-glucosidase inhibitors in the future. Through continuous research, the present invention has developed a novel indolinone derivative containing a triazole structure, which can effectively inhibit α-glucosidase and thus be used for the treatment and / or prevention of diabetes. Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the above prior art. For this purpose, the present invention provides an indolinone derivative containing a triazole structure, a preparation method thereof, and an application thereof. Such compounds can effectively inhibit α-glucosidase and can be used for the preparation of products for treating / preventing diabetes, exerting the hypoglycemic effect.

[0007] The present invention provides an indolinone derivative containing a triazole structure, and the indolinone derivative has a structural formula as shown in formula (I);

[0008]

[0009] In formula (I), R represents a substituted or unsubstituted phenyl group.

[0010] Based on the indolinone structure as the core, the present invention designs and synthesizes a series of indolinone derivatives containing a triazole structure, which exhibit strong α-glucosidase inhibitory activity and have outstanding potential as drugs for treating / preventing diabetes.

[0011] Preferably, the substitution is single substitution or multiple substitutions.

[0012] More preferably, R is selected from any one of the following groups:

[0013]

[0014] In the substituted phenyl group, the relevant substituents include but are not limited to halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, tert-butyl. Among the above compounds, the IC 50 value of the indolinone derivative corresponding to the substituent X15 is 3.79 ± 0.40 μM, which is 169 times that of acarbose, demonstrating good efficacy and being able to be used as an α-glucosidase inhibitor for treating or preventing diabetes.

[0015] In the present invention, the appearing in the structural formula represents the connection site of the group.

[0016] The present invention also provides a preparation method of the above indolinone derivative containing a triazole structure, including the following steps:

[0017] (1) Using compound S1 (2-indolinone) and compound S2 (5-formyl-1H-pyrrole-2-carboxylic acid) as raw materials to prepare compound S3;

[0018] (2) Using compound S4 (3-amino-5-mercapto-1,2,4-triazole compound) as a raw material and substituted benzyl bromide to prepare compound S5;

[0019] (3) Performing a condensation reaction on compound S3 and compound S5 to obtain the indolinone derivative;

[0020] Among them, the order of steps (1) and (2) can be interchanged, and the structural formulas of compound S1, compound S2, compound S3, compound S4, and compound S5 are as shown below:

[0021]

[0022] It can be seen that the route for synthesizing the indolone derivatives is relatively simple, convenient to implement and operate, with controllable production costs, and has good prospects for industrialized and large-scale production.

[0023] Preferably, in the step (1), compound S1 and compound S2 undergo a condensation reaction under the action of a base to obtain compound S3.

[0024] More preferably, the base is at least one of sodium hydroxide and potassium hydroxide.

[0025] More preferably, the molar ratio of compound S1 to the base is 1:(5 - 7). For example, it can be 1:5, 1:6, or 1:7.

[0026] More preferably, after the condensation reaction is completed, the pH value is adjusted to neutral, and after standing, suction filtration is carried out to obtain compound S3.

[0027] Preferably, in the step (1), the solvent used is ethanol (EtOH).

[0028] Preferably, in the step (1), the molar ratio of compound S1 to compound S2 is 1:(1 - 1.1). For example, it can be 1:1 or 1:1.1.

[0029] Preferably, in the step (2), compound S4 and substituted benzyl bromide undergo a substitution reaction under the action of a base to obtain compound S5.

[0030] More preferably, the base is potassium carbonate.

[0031] More preferably, the molar ratio of compound S4 to the base is 1:(1 - 1.2). For example, it can be 1:1, 1:1.1, or 1:1.2.

[0032] More preferably, after the substitution reaction is completed, water is added to generate a solid, and suction filtration is carried out to obtain compound S5.

[0033] Preferably, in the step (2), the solvent used is dimethylformamide (DMF).

[0034] Preferably, in the step (2), the molar ratio of compound S4 to substituted benzyl bromide is 1:(1 - 1.1). For example, it can be 1:1 or 1:1.1.

[0035] Preferably, in the step (3), compound S3 and compound S5 undergo a condensation reaction under the action of a base to obtain the indolone derivatives.

[0036] More preferably, the base is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).

[0037] More preferably, the molar ratio of compound S3 to the base is 1:(1 - 2.5). For example, it can be 1:1, 1:2, or 1:2.5.

[0038] Preferably, in the step (3), the solvent used is pyridine.

[0039] Preferably, in the step (3), the molar ratio of compound S3 to compound S5 is 1:(1 - 1.2). For example, it can be 1:1, 1:1.1, or 1:1.2.

[0040] More preferably, after the condensation reaction is completed, dilute hydrochloric acid is added to produce a solid, which is filtered by suction and then recrystallized to obtain the indolinone derivative.

[0041] Further preferably, the solvent used for the recrystallization is ethanol (EtOH).

[0042] The present invention also provides an α - glucosidase inhibitor, which contains the above indolinone derivative containing a triazole structure or a pharmaceutically acceptable salt thereof.

[0043] The present invention also provides the application of the above indolinone derivative containing a triazole structure in the preparation of a product for preventing / treating diabetes.

[0044] Preferably, the product is a drug or a food.

[0045] The present invention also provides a drug for preventing / treating diabetes, which contains the above indolinone derivative containing a triazole structure or a pharmaceutically acceptable salt thereof.

[0046] Preferably, the dosage form of the drug is a tablet, a capsule, an oral liquid, or an injection.

[0047] The term "pharmaceutically acceptable salt" used in the present invention refers to a substance that is acceptable for pharmaceutical applications from a toxicological perspective and does not have an adverse interaction with the active ingredient.

[0048] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0049] The indolinone derivatives containing a triazole structure proposed by the present invention all exhibit strong α - glucosidase inhibitory effects, and their IC 50 value can be as low as 3.79 ± 0.40 μM at the lowest, and can be used for the preparation of products for treating / preventing diabetes, exerting the hypoglycemic effect, and having good market application and large - scale production prospects.

[0050] Description of the Drawings

[0051] Figure 1This is the inhibition concentration graph of the indolinone derivative X15 containing a triazole structure as an α-glucosidase inhibitor against α-glucosidase in vitro in Example 2 of the present invention;

[0052] Figure 2 This is the enzyme kinetics graph of the indolinone derivative X15 containing a triazole structure as an α-glucosidase inhibitor against α-glucosidase in vitro in Example 3 of the present invention;

[0053] Figure 3 This is the substrate kinetics graph of the indolinone derivative X15 containing a triazole structure as an α-glucosidase inhibitor against α-glucosidase in vitro in Example 4 of the present invention. Detailed implementation manners

[0054] In order to make those skilled in the art more clearly understand the technical solutions described in the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the protection scope required by the present invention.

[0055] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial channels or can be obtained by existing known methods.

[0056] Reagents used in the examples of the present invention:

[0057] 2-Indolinone, CAS No.: 59-48-3;

[0058] 5-Formyl-1H-pyrrole-2-carboxylic acid, CAS No.: 7126-51-4;

[0059] 3-Amino-5-mercapto-1,2,4-triazole, CAS No.: 16691-43-3;

[0060] Sodium hydroxide, CAS No.: 1310-73-2;

[0061] Potassium carbonate, CAS No.: 584-08-7;

[0062] EDCI, CAS No.: 7084-11-9;

[0063] Pyridine, CAS No.: 110-86-1.

[0064] Example 1

[0065] In this example, a series of indolinone derivatives containing a triazole structure were prepared, and the preparation route is as follows:

[0066]

[0067] The preparation method includes the following specific steps:

[0068] Synthesis of Compound S3: Weigh 1.052 g of NaOH and dissolve it ultrasonically in 200 mL of ethanol solution to prepare a sodium hydroxide - ethanol solution. Then weigh 500 mg of 2 - indolinone (S1, 3.75 mmol) and 523 mg of 5 - formyl - 1H - pyrrole - 2 - carboxylic acid (S2, 3.75 mmol) into a 250 mL round - bottom flask. Add the sodium hydroxide - ethanol solution under ice - bath conditions, stir for 5 - 10 min, and then react at room temperature for 2 h. Monitor with a TLC plate. After the reaction is completed, adjust the pH to 7 with dilute hydrochloric acid solution, and filter out the solid to obtain Compound S3.

[0069] Synthesis of Compound S5: Weigh 1.00 g of 3 - amino - 5 - mercapto - 1,2,4 - triazole (S3, 8.6096 mmol), 1.69 g of substituted benzyl bromide (8.6096 mmol), and 1.43 g of potassium carbonate (10.331 mmol) into a reaction flask, add 10 mL of DMF, and react overnight at room temperature. Monitor with a TLC plate. After the reaction is completed, quench with water and filter out the solid to obtain Compound S5.

[0070] Synthesis of Compounds X1 - X21: Weigh 70 mg of Compound S3 (0.2755 mmol), Compound S5 (0.3306 mmol), and 80 mg of EDCI (0.4132 mmol) into a 35 mL reaction tube, then add 3 mL of pyridine and react at room temperature for 3 h. Monitor with a TLC plate. After the reaction is completed, add an excess of dilute hydrochloric acid and filter. The product obtained by filtration is purified by recrystallization with ethanol to obtain the target compounds (named X1 - X21 respectively).

[0071]

[0072] Based on the above chemical structural formula, the R groups and the corresponding target compounds are shown in Table 1 below.

[0073] Table 1 Structural formula of R group

[0074]

[0075]

[0076] Characterize the structures of Compounds X1 - X21 by NMR. The following are the properties, yields, and NMR characterization results of each compound:

[0077] (Z)-N-(5-(benzylthio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X1). Orange solid; yield 62%; m.p. 292.0 - 292.9 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ14.10 (s, 1H), 11.10 (s, 1H), 7.86 (d, J = 15.0 Hz, 3H), 7.71 (d, J = 5.0 Hz, 1H), 7.57 (dd, J = 5.0, 2.3 Hz, 1H), 7.46 (d, J = 5.0 Hz, 2H), 7.32 (t, J = 5.0 Hz, 2H), 7.28 - 7.22 (m, 2H), 7.04 (d, J = 5.0 Hz, 1H), 6.95 - 6.88 (m, 2H), 4.47 (s, 2H); 13 C NMR (125 MHz, DMSO-d 6 ) δ168.81, 161.52, 158.55, 156.87, 140.35, 137.60, 134.26, 128.91, 128.88, 128.51, 127.30, 126.02, 124.41, 124.17, 123.80, 121.70, 121.37, 119.88, 119.85, 110.03, 34.12.

[0078] (Z)-N-(5-((2-fluorobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X2). Orange solid; yield 66%; m.p. 273.6 - 274.7 °C; 1 H NMR (500MHz, DMSO-d 6)δ14.11(s,1H),11.08(s,1H),7.89(s,2H),7.85(s,1H),7.71(d,J=5.0 Hz,1H),7.57-7.54(m,2H),7.35-7.31(m,1H),7.25-7.19(m,2H),7.15(td,J=5.0,1.2 Hz,1H),7.04(td,J=10.0,5.0 Hz,1H),6.92-6.90(m,2H),4.50(s,2H); 13 C NMR(125 MHz,DMSO-d 6 )δ168.79,161.38,161.06,159.42,158.58,156.86,140.35,134.28,131.12(d,J=3.8 Hz),129.65(d,J=8.8Hz),128.90,125.98,124.54(d,J=2.5 Hz),124.42,124.37,124.15,123.82,121.68,121.32,119.84,115.41(d,J=21.3Hz),110.01,27.60(d,J=3.8 Hz).

[0079] (Z)-N-(5-((3-fluorobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide(X3).Orange solid;yield 61%;m.p.329.4 - 330.4 oC; 1 H NMR(400MHz,DMSO-d 6 )δ14.10(s,1H),11.09(s,1H),7.88(s,2H),7.86(s,1H),7.71(d,J=8.0 Hz,1H),7.55(dd,J=4.0,2.3 Hz,1H),7.35(dd,J=8.0,4.0 Hz,1H),7.32(d,J=4.0 Hz,1H),7.31–7.28(m,1H),7.25(dd,J=8.0,4.0 Hz,1H),7.11–7.03(m,2H),6.92–6.90(m,2H),4.48(s,2H); 13 C NMR(100 MHz,DMSO-d 6)δ168.81,163.23,161.23,160.81,158.56,156.85,140.76(d, J = 8.0 Hz),140.34,134.27,130.39(d, J = 8.0 Hz),128.89,125.97,124.91(d, J = 3.0 Hz),124.38,124.16,123.80,121.68,121.34,119.83,115.58(d, J = 22 Hz),114.06(d, J = 20.0 Hz),110.01,33.46.

[0080] (Z)-N-(5-((4-fluorobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X4). Orange solid; yield 64%; m.p. 316.1 - 317.2 °C; 1 H NMR (500 MHz, DMSO-d 6 )δ14.10(s, 1H),11.09(s, 1H),7.88(s, 2H),7.85(s, 1H),7.71(d, J = 10.0 Hz, 1H),7.56(dd, J = 5.0, 2.3 Hz, 1H),7.52 - 7.48(m, 2H),7.24(td, J = 10.0, 5.0 Hz, 1H),7.16 - 7.13(m, 2H),7.04(td, J = 10.0, 5.0 Hz, 1H),6.92 - 6.90(m, 2H),4.46(s, 2H); 13 C NMR (125 MHz, DMSO-d 6 )δ169.27,162.80,161.84,160.87,159.01,157.32,140.81,134.73,134.42(d, J = 3.8 Hz),131.29(d, J = 7.5 Hz),129.37,126.47,124.87,124.63,124.26,122.16,121.82,120.33(d, J = 2.5 Hz),115.73(d, J = 18.8 Hz),110.48,33.71.

[0081] (Z)-N-(5-((2-chlorobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X5). Orange solid; yield 62%; m.p. 248.2 - 349.4 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ 14.12 (s, 1H), 11.07 (s, 1H), 7.89 (s, 2H), 7.86 (s, 1H), 7.71 (d, J = 10.0 Hz, 1H), 7.62 (dd, J = 10.0, 5.0 Hz, 1H), 7.56 (dd, J = 5.0, 2.3 Hz, 1H), 7.49 (dd, J = 5.0, 1.7 Hz, 1H), 7.31 (td, J = 5.0, 1.8 Hz, 2H), 7.26 - 7.22 (m, 1H), 7.04 (td, J = 5.0, 1.0 Hz, 1H), 6.93 - 6.90 (m, 2H), 4.56 (s, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 168.78, 161.05, 158.58, 156.83, 149.60, 140.34, 134.92, 134.27, 133.27, 131.06, 129.49, 129.40, 128.89, 127.42, 125.98, 124.37, 124.14, 123.89, 123.81, 121.67, 121.30, 119.83, 110.00, 33.33.

[0082] (Z)-N-(5-((3-chlorobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X6). Orange solid; yield 67%; m.p. 281.9 - 283.0 °C; 1 H NMR (400 MHz, DMSO-d 6)δ14.09(s,1H),11.09(s,1H),7.88(s,2H),7.85(s,1H),7.70(d,J=10.0 Hz,1H),7.54 - 7.52(m,2H),7.44(dt,J=10.0,5.0 Hz,1H),7.34(t,J=10.0 Hz,1H),7.32 - 7.29(m,1H),7.24(t,J=10.0 Hz,1H),7.04(t,J=7.5Hz,1H),6.92 - 6.90(m,2H),4.47(s,2H); 13 C NMR(100MHz,DMSO - d 6 )δ168.81,161.16,158.55,156.84,140.52,140.33,134.27,132.89,130.30,128.88,128.66,127.42,127.15,125.94,124.40,124.15,123.79,121.68,121.32,119.83,110.00,33.31.

[0083] (Z)-N-(5-((4-chlorobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide(X7).Orange solid; yield 65%; m.p. 311.3 - 312.3 oC; 1 H NMR(400MHz,DMSO - d 6 )δ14.09(s,1H),11.08(s,1H),7.87(s,2H),7.84(s,1H),7.70(d,J=10.0 Hz,1H),7.53(dd,J=5.0,2.3 Hz,1H),7.50 - 7.47(m,2H),7.39 - 7.35(m,2H),7.26 - 7.22(m,1H),7.06 - 7.02(m,1H),6.92 - 6.90(m,2H),4.46(s,2H); 13¹³C NMR (101 MHz, DMSO) δ 168.79, 161.24, 158.54, 156.84, 140.33, 136.91, 134.26, 131.84, 130.65, 128.88, 128.42, 125.97, 124.38, 124.15, 123.79, 121.68, 121.35, 119.84, 110.01, 33.28.

[0084] (Z)-N-(5-((2-bromobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X8). Orange solid; yield 64%; m.p. 334.5 - 335.7 °C; 1 ¹H NMR (500 MHz, DMSO-d 6 ) δ 14.10 (s, 1H), 11.10 (s, 1H), 7.88 (s, 2H), 7.86 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 4.0 Hz, 1H), 7.53 (dd, J = 4.0, 2.3 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44 (dt, J = 8.0, 1.3 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.92 - 6.90 (m, 2H), 4.46 (s, 2H); 13 ¹³C NMR (126 MHz, DMSO-d 6 ) δ 168.82, 161.15, 158.56, 156.84, 140.82, 140.33, 134.28, 131.55, 130.60, 130.04, 128.89, 127.80, 125.95, 124.44, 124.16, 123.79, 121.69, 121.49, 121.33, 119.88, 119.84, 110.01, 33.23.

[0085] (Z)-N-(5-((3-bromobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X9). Orange solid; yield 67%; m.p. 360.1 - 361.1 °C; 1 H NMR(400MHz,DMSO-d 6 )δ14.09(s,1H),11.09(s,1H),7.88(s,2H),7.85(s,1H),7.70(d,J = 5.0 Hz,1H),7.68(t,J = 5.0 Hz,1H),7.53(dd,J = 5.0,2.3Hz,1H),7.48(dt,J = 10.0,1.3 Hz,1H),7.45 - 7.42(m,1H),7.28(d,J = 10.0 Hz,1H),7.25 - 7.22(m,1H),7.04(t,J = 10.0 Hz,1H),6.93 - 6.90(m,2H),4.46(s,2H); 13 C NMR(100 MHz,DMSO-d 6 )δ168.81,161.15,158.56,156.84,140.81,140.33,134.27,131.55,130.59,130.03,128.88,127.80,125.94,124.42,124.16,123.78,121.68,121.48,121.32,119.87,119.83,110.01,33.24.

[0086] (Z)-N-(5-((4-bromobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X10). Orange solid; yield 61%; m.p. 315.8 - 317.0 °C; 1 H NMR(400MHz,DMSO-d 6)δ14.08(s,1H),11.07(s,1H),7.85(d,J=12.0 Hz,3H),7.70(d,J=8.0 Hz,1H),7.53-7.49(m,3H),7.42(d,J=8.0 Hz,2H),7.24(t,J=8.0 Hz,1H),7.04(t,J=8.0 Hz,1H),6.92-6.90(m,2H),4.45(s,2H); 13 C NMR(100MHz,DMSO-d 6 )δ168.78,161.21,158.53,156.83,140.33,137.34,134.25,131.33,130.98,128.87,125.96,124.37,124.14,123.79,121.67,121.34,120.33,119.83,110.00,33.33.

[0087] (Z)-N-(5-((2-cyanobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide(X11).Orange solid;yield 63%;m.p.315.8 - 317.0 oC; 1 H NMR(400MHz,DMSO-d 6 )δ14.11(s,1H),11.07(s,1H),7.90(s,2H),7.87(dd,J=8.0,1.4 Hz,1H),7.84(s,1H),7.74(dd,J=8.0,1.2 Hz,1H),7.70(d,J=7.5 Hz,1H),7.66(td,J=8.0,4.0 Hz,1H),7.53(dd,J=4.0,2.3 Hz,1H),7.48(td,J=8.0,1.9 Hz,1H),7.24(td,J=8.0,4.0 Hz,1H),7.04(td,J=8.0,4.0 Hz,1H),6.92 - 6.90(m,2H),4.65(s,2H); 13 C NMR(100 MHz,DMSO-d 6)δ168.80,160.55,158.61,156.85,141.09,140.35,134.33,133.46,133.23,130.07,128.90,128.37,125.91,124.35,124.15,123.87,121.68,121.38,119.83,117.33,111.76,110.01,32.59.

[0088] (Z)-N-(5-((3-cyanobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide(X12). Orange solid; yield 61%; m.p. 336.7 - 337.7 °C; 1 H NMR(500MHz, DMSO-d 6 )δ14.10(s, 1H), 11.09(s, 1H), 7.92(t, J = 5.0 Hz, 1H), 7.88(s, 2H), 7.87(s, 1H), 7.82(d, J = 5.0 Hz, 1H), 7.72(d, J = 10.0 Hz, 2H), 7.54(d, J = 10.0 Hz, 1H), 7.52 - 7.50(m, 1H), 7.24(t, J = 10.0 Hz, 1H), 7.04(t, J = 10.0 Hz, 1H), 6.92 - 6.91(m, 2H), 4.52(s, 2H); 13 C NMR(125 MHz, DMSO-d 6 )δ168.86, 161.04, 158.61, 156.87, 140.35, 139.88, 134.32, 133.71, 132.38, 131.04, 129.77, 128.93, 125.96, 124.45, 124.18, 123.83, 121.74, 121.32, 119.89, 118.64, 111.31, 110.06, 33.12.

[0089] (Z)-N-(5-((4-cyanobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide(X13). Orange solid; yield 64%; m.p. 322.7 - 323.7 °C;1 1H NMR (400 MHz, DMSO-d 6 ) δ 14.08 (s, 1H), 11.08 (s, 1H), 7.88 (s, 2H), 7.84 (s, 1H), 7.80 - 7.77 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 - 7.65 (m, 2H), 7.48 (dd, J = 4.0, 2.3 Hz, 1H), 7.24 (td, J = 8.0, 4.0 Hz, 1H), 7.04 (td, J = 8.0, 4.0 Hz, 1H), 6.92 - 6.89 (m, 2H), 4.55 (s, 2H); 13 13C NMR (100 MHz, DMSO-d 6 ) δ 168.80, 160.96, 158.58, 156.82, 144.01, 140.34, 134.29, 132.38, 129.73, 129.71, 128.90, 125.93, 124.38, 124.15, 123.82, 121.69, 121.33, 119.84, 118.74, 110.02, 109.94, 33.58.

[0090] (Z)-N-(5-((2-nitrobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X14). Orange solid; yield 63%; m.p. 339.0 - 340.1 °C; 1 1H NMR (500 MHz, DMSO-d 6 ) δ 14.12 (s, 1H), 11.08 (s, 1H), 8.06 (d, J = 10.0 Hz, 1H), 7.89 (s, 2H), 7.85 (s, 1H), 7.77 (d, J = 10.0 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.67 (t, J = 10.0 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.24 (t, J = 10.0 Hz, 1H), 7.04 (t, J = 10.0 Hz, 1H), 6.91 (t, J = 5.0 Hz, 2H), 4.75 (s, 2H); 13 13C NMR (125 MHz, DMSO-d 6)δ168.83,160.96,158.61,156.84,148.11,140.37,134.33,133.96,133.14,132.05,129.08,128.93,125.97,125.11,124.41,124.16,123.85,121.71,121.28,119.89,119.86,110.03,31.45.

[0091] (Z)-N-(5-((3-nitrobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X15). Orange solid; yield 65%; m.p. 315.3 - 316.5 °C; 1 H NMR (400 MHz, DMSO-d 6 )δ14.09 (s, 1H), 11.09 (s, 1H), 8.36 (t, J = 4.0 Hz, 1H), 8.09 (ddd, J = 8.0, 2.4, 1.1 Hz, 1H), 7.94 (dd, J = 8.0, 4.0 Hz, 1H), 7.88 (s, 2H), 7.85 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 4.0, 2.3 Hz, 1H), 7.23 (td, J = 8.0, 4.0 Hz, 1H), 7.04 (td, J = 8.0, 4.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 4.0, 2.2 Hz, 1H), 4.62 (s, 2H); 13 C NMR (100 MHz, DMSO-d 6 )δ168.82,160.91,158.60,156.82,147.63,140.67,140.32,135.41,134.32,129.94,128.88,125.92,124.44,124.16,123.78,123.43,122.13,121.68,121.30,119.84,119.81,110.01,33.00.

[0092] (Z)-N-(5-((3-nitrobenzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X16). Orange solid; yield 62%; m.p. 307.1 - 308.0 °C; 1 1H NMR (500 MHz, DMSO-d 6 ) δ 14.08 (s, 1H), 11.09 (s, 1H), 8.17 (d, J = 8.0 Hz, 2H), 7.89 (s, 2H), 7.84 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 4.0, 2.3 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 4.0, 2.2 Hz, 1H), 4.61 (s, 2H); 13 13C NMR (126 MHz, DMSO) δ 168.81, 160.87, 158.59, 156.82, 146.58, 146.22, 140.34, 134.30, 129.98, 128.90, 125.93, 124.40, 124.15, 123.81, 123.57, 121.69, 121.33, 119.85, 119.82, 110.02, 33.29.

[0093] (Z)-5-((2-oxoindolin-3-ylidene)methyl)-N-(5-((3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)-1H-pyrrole-2-carboxamide (X17). Orange solid; yield 64%; m.p. 349.0 - 350.2 °C; 1 1H NMR (500 MHz, DMSO-d 6)δ14.10(s,1H),11.10(s,1H),7.88(s,2H),7.86(s,1H),7.84(s,1H),7.79(d,J=5.0 Hz,1H),7.71(d,J=10.0 Hz,1H),7.60(d,J=5.0 Hz,1H),7.55(d,J=5.0 Hz,1H),7.53 - 7.51(m,1H),7.23(td,J=10.0,1.2 Hz,1H),7.04(td,J=5.0,1.0 Hz,1H),6.92 - 6.89(m,2H),4.57(s,2H); 13 C NMR(125 MHz,DMSO - d 6 )δ168.83,161.06,158.59,156.83,140.33,139.65,134.30,132.83,129.53,129.15,128.89,125.93,125.41(d,J=3.8 Hz),125.19,124.44,124.16,123.89(d,J=3.8 Hz),123.78,123.02,121.69,121.28,119.82(d,J=5.0 Hz),110.01,33.25.

[0094] (Z)-5-((2-oxoindolin-3-ylidene)methyl)-N-(5-((2-(trifluoromethoxy)benzyl)thio)-4H-1,2,4-triazol-3-yl)-1H-pyrrole-2-carboxamide(X18). Orange solid; yield 61%; m.p.357.9 - 359.0 oC; 1 HNMR(400 MHz,DMSO - d 6 )δ14.11(s,1H),11.08(s,1H),7.89(s,2H),7.85(s,1H),7.71(d,J=8.0 Hz,1H),7.67(dd,J=8.0,1.8 Hz,1H),7.54(dd,J=4.0,2.3 Hz,1H),7.45–7.41(m,1H),7.40(s,1H),7.37–7.34(m,1H),7.24(t,J=8.0 Hz,1H),7.04(t,J=8.0 Hz,1H),6.92–6.89(m,2H),4.52(s,2H); 13 C NMR(100 MHz,DMSO - d 6)δ168.80, 160.95, 158.62, 156.87, 149.61, 146.73, 140.35, 134.30, 131.34, 129.91, 129.50, 128.89, 127.54, 125.93, 124.34, 124.15, 123.85, 121.67, 121.28, 120.37, 119.78 (d, J = 7.0 Hz), 110.00, 28.54.

[0095] (Z)-5-((2-oxoindolin-3-ylidene)methyl)-N-(5-((3-(trifluoromethoxy)benzyl)thio)-4H-1,2,4-triazol-3-yl)-1H-pyrrole-2-carboxamide (X19). Orange solid; yield 64%; m.p. 303.8 - 304.9 °C; 1 1H NMR (500 MHz, DMSO-d 6 )δ14.10 (s, 1H), 11.10 (s, 1H), 7.88 (s, 2H), 7.86 (s, 1H), 7.71 (d, J = 10.0 Hz, 1H), 7.53 (dd, J = 5.0, 2.3 Hz, 1H), 7.51 (d, J = 10.0 Hz, 1H), 7.46 (s, 1H), 7.44 (d, J = 10.0 Hz, 1H), 7.25 - 7.22 (m, 2H), 7.04 (t, J = 10.0 Hz, 1H), 6.92 - 6.89 (m, 2H), 4.53 (s, 2H); 13 13C NMR (126 MHz, DMSO-d 6 )δ168.83, 161.08, 158.58, 156.83, 148.23, 140.91, 140.33, 134.29, 130.39, 128.90, 127.88, 125.96, 124.44, 124.17, 123.78, 121.70, 121.31, 121.23, 121.03, 119.83 (d, J = 3.8 Hz), 119.69, 119.00, 110.01, 33.20.

[0096] (Z)-5-((2-oxoindolin-3-ylidene)methyl)-N-(5-((4-(trifluoromethoxy)benzyl)thio)-4H-1,2,4-triazol-3-yl)-1H-pyrrole-2-carboxamide (X20). Orange solid; yield 67%; m.p. 346.4 - 347.5 °C; 1 HNMR(400 MHz, DMSO-d 6 ) δ 14.09(s, 1H), 11.09(s, 1H), 7.88(s, 2H), 7.86(s, 1H), 7.71(d, J = 8.0 Hz, 1H), 7.61 - 7.58(m, 2H), 7.53(dd, J = 4.0, 2.3 Hz, 1H), 7.33(s, 1H), 7.31(s, 1H), 7.24(t, J = 8.0 Hz, 2H), 7.05(t, J = 8.0 Hz, 1H), 6.92 - 6.89(m, 2H), 4.51(s, 2H); 13 C NMR(126 MHz, DMSO-d 6 ) δ 168.81, 161.23, 158.57, 156.85, 147.43, 140.34, 137.47, 134.28, 130.68, 128.90, 125.98, 124.41, 124.16, 123.81, 121.69, 121.34, 121.07, 119.85, 119.04, 117.01, 110.02, 33.14.

[0097] (Z)-N-(5-((4-(tert-butyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrole-2-carboxamide (X21). Orange solid; yield 65%; m.p. 351.3 - 352.3 °C; 1 H NMR(500 MHz, DMSO-d 6)δ14.10(s,1H),11.09(s,1H),7.86(s,3H),7.71(d,J=8.0 Hz,1H),7.57(dd,J=4.0,2.3 Hz,1H),7.39–7.37(m,2H),7.34–7.32(m,2H),7.24(t,J=8.0 Hz,1H),7.06–7.03(m,1H),6.92–6.91(m,2H),4.43(s,2H),1.25(s,9H); 1 H NMR(500 MHz,DMSO-d 6 )δ14.10,11.09,7.86,7.72,7.70,7.57,7.57,7.56,7.56,7.39,7.38,7.37,7.37,7.34,7.34,7.33,7.32,7.26,7.24,7.23,7.06,7.06,7.04,7.04,7.03,7.03,6.92,6.91,6.91,6.91,4.43,1.25.

[0098] Example 2

[0099] This example provides a test for the α-glucosidase inhibitory activity of indolinone derivatives containing a triazole structure

[0100] 1. Preparation of reagents and standard solutions

[0101] (1) 100 mM phosphate buffer (PBS, pH = 6.8): Weigh a certain mass of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve with ultrapure water, and use it to dissolve and dilute reagents.

[0102] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100 mM PBS to the enzyme with an enzyme activity of 100 U to make a working concentration of 0.05 U / mL, and dispense and freeze.

[0103] (3) Preparation of substrate: Accurately weigh an appropriate amount of 4-nitrophenyl-D-glucopyranoside (PNPG), add it to 100 mM PBS solution to dissolve, and prepare a substrate working solution with a concentration of 0.25 mM. Vortex and mix well, and freshly prepare before each experiment.

[0104] Preparation of test drug: Accurately weigh an appropriate amount of the test drug, dissolve it with DMSO to prepare a stock solution of 10 mM, and store it in the dark at -20 °C. Dilute it to different required concentrations (0 - 200 μM) with DMSO before the experiment, and the DMSO content is equal to 5%.

[0105] 2. Experimental procedure

[0106] (1) Add 10 μL of α-glucosidase with a working concentration of 0.05 U / mL, 130 μL of phosphate buffer with a concentration of 100 mM (pH = 6.8), and 10 μL of compound solutions with different concentrations (indolinone derivatives X1 - X21 containing triazole structure prepared in Example 1) to a 96-well plate in sequence. In the blank control group, replace 10 μL of compound solutions with different concentrations with 10 μL of 5% DMSO. Use acarbose as the positive control, and set 4 parallel replicates for each group. Incubate the enzyme reaction system on a microplate reader at 37 °C for 10 min.

[0107] (2) Subsequently, add 50 μL of the substrate PNPG working solution to the enzyme reaction system to initiate the enzyme reaction. Place the microplate on a microplate reader and continue to incubate at 37 °C for 15 min, and record the absorbance value of the system at a wavelength of 405 nm.

[0108] (3) The α-glucosidase inhibitory activity of the test compound is calculated according to the following formula:

[0109] Inhibition rate (%) = [(OD 2 - OD 1 ) / OD 1 × 100%

[0110] where OD 2 is the change in absorbance value of the enzyme system after adding the compound, and OD 1 is the change in absorbance value of the enzyme system without adding the compound. Data processing: Analyze and process the data using MS Excel, and calculate the half-maximal inhibitory concentration (IC 50 ) using Origin 9.1. IC 50 represents the concentration of the test compound required to inhibit the activity of α-glucosidase by 50% under the experimental conditions.

[0111] 3. Result analysis

[0112] Evaluate the α-glucosidase inhibitory activity of the compounds synthesized in Example 1 using an in vitro enzymology experiment. The measurement results are shown in Table 2:

[0113] Table 2 In vitro inhibitory activity evaluation of α-glucosidase of compounds X1 - X21

[0114]

[0115] Among them, the IC 50 of the positive control drug acarbose is 640.85 μM. All indolinone derivatives X1 - X21 containing triazole structure have good α-glucosidase inhibitory activity, and the IC 50The values were between 3.79 ± 0.40 μM and 15.55 ± 1.37 μM, all superior to the positive control acarbose. Among them, compound X15 (IC 50 = 3.79 ± 0.40) showed the most significant inhibitory effect, and its half-inhibition concentration graph is as shown in Figure 1 . The results indicated that these compounds exhibited strong binding affinities when interacting with α-glucosidase. Therefore, compound X15 can be used as a lead compound for developing α-glucosidase inhibitors with antidiabetic activity, followed by compound X12, compound X16, compound X4, compound X7, etc.

[0116] Example 3: Enzyme kinetics experiment

[0117] The inhibitory activity kinetics of the synthesized active compounds against α-glucosidase was evaluated by in vitro enzyme kinetics experiments, and the specific process was as follows:

[0118] 1. Preparation of reagents and standard solutions

[0119] 1) 100 mM phosphate buffer (PBS, pH 6.8): Weigh a certain mass of potassium dihydrogen phosphate and disodium hydrogen phosphate, dissolve them with ultrapure water, and use it to dissolve and dilute reagents.

[0120] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100 mM PBS to the enzyme with an enzyme activity of 100 U to prepare working concentrations of 0.0375 U / mL, 0.05 U / mL, 0.0625 U / mL, and 0.075 U / mL, and dispense and freeze.

[0121] (3) Preparation of substrate: Accurately weigh 4-nitrophenyl-D-glucopyranoside (PNPG), add it to a 100 mM PBS solution to dissolve, and prepare a substrate working solution with a concentration of 0.25 mM. Vortex and mix well, and freshly prepare it before each experiment.

[0122] Preparation of test drugs: Accurately weigh an appropriate amount of the test drug, dissolve it with DMSO to prepare a 10 mM stock solution, and store it in the dark at -20 °C. Dilute it with DMSO to different required concentrations (0 - 200 μM) before the experiment.

[0123] 2. Experimental steps

[0124] (1) Add 10 μL of α-glucosidase solutions with concentrations of 0.0375 U / mL, 0.05 U / mL, 0.0625 U / mL, and 0.075 U / mL, 130 μL of 100 mM phosphate buffer (pH 6.8), and 10 μL of compound solutions with different concentrations (indolinone derivatives X15 containing a triazole structure prepared in Example 1) to a 96-well plate in sequence. For the blank control group, replace 10 μL of compound solutions with different concentrations with 10 μL of DMSO with a content equal to 5%. Use acarbose as the positive control. Set up 4 replicate wells in parallel for each group. Incubate the enzyme reaction system on an enzyme-labeling instrument at 37 °C for 10 min.

[0125] (2) Subsequently, add 50 μL of a 0.25 mM substrate PNPG working solution to the enzyme reaction system to initiate the enzyme reaction. Place the microplate on an enzyme-labeling instrument and continue to incubate at 37 °C for 15 min. During the incubation process, divide the time evenly into 3 intervals, and take a reading at a wavelength of 405 nm each time. The readings are recorded as OD 1 、OD 2 、OD 3 。

[0126] (3) Data processing: Use MS Excel to analyze and process the data. The reaction rate of the enzyme reaction system is △OD / min.

[0127] 3. Result analysis

[0128] The results of the enzyme kinetic inhibition type evaluation experiment are as Figure 2 shown. It can be seen from Figure 2 that the indolinone derivative X15 containing a triazole structure has a reversible inhibitory effect on the activity of α-glucosidase.

[0129] Example 4: Substrate kinetics experiment

[0130] An in vitro substrate kinetics experiment was used to evaluate the α-glucosidase inhibitory activity kinetics of the synthesized active compound. The specific process is as follows:

[0131] 1. Preparation of reagents and standard solutions

[0132] (1) 100 mM phosphate buffer (PBS, pH 6.8): Weigh a certain mass of potassium dihydrogen phosphate and disodium hydrogen phosphate, and dissolve them with ultrapure water for dissolving and diluting reagents.

[0133] (2) Preparation of α-glucosidase solution: Add an appropriate amount of 100 mM PBS to an enzyme with an enzyme activity of 100 U to make a working concentration of 0.05 U / mL, and dispense and freeze.

[0134] (3) Substrate preparation: Weigh an appropriate amount of 4-nitrophenyl-D-glucopyranoside (PNPG) accurately, dissolve it in 100 mM PBS solution, and prepare substrate working solutions with different concentrations (0.25 mM, 0.5 mM, 0.75 mM, 1 mM). Vortex and mix well, and freshly prepare it before each experiment.

[0135] Test drug preparation: Weigh an appropriate amount of the test drug accurately, dissolve it with DMSO to prepare a 10 mM stock solution, and store it in the dark at -20 °C. Dilute it to different required concentrations (0 - 200 μM) with DMSO before the experiment.

[0136] 2. Experimental procedures

[0137] (1) Add 10 μL of α-glucosidase solution with a concentration of 0.5 U / mL, 130 μL of phosphate buffer with a concentration of 100 mM (pH 6.8), and 10 μL of compounds with different concentrations (indolinone derivatives X15 containing a triazole structure prepared in Example 1) to the 96-well plate in sequence. For the blank control group, replace 10 μL of compounds with different concentrations with 10 μL of DMSO with a content equal to 5%. Use acarbose as the positive control, and set 4 parallel replicates for each group. Incubate the enzyme reaction system on the microplate reader at 37 °C for 10 min.

[0138] (2) Subsequently, add 50 μL of substrate PNPG working solutions with different concentrations to the enzyme reaction system to initiate the enzyme reaction. Place the microplate on the microplate reader and continue to incubate at 37 °C for 15 min. During the incubation process, divide the time evenly into 3 times, and take readings at a wavelength of 405 nm each time. The readings are recorded as OD 1 、OD 2 、OD 3 .

[0139] (3) Data processing: Use MS Excel to analyze and process the data. The reaction rate of the enzyme reaction system is △OD / min.

[0140] 3. Result analysis

[0141] The experimental determination results of the substrate kinetic inhibition type evaluation are as Figure 3 shown, Figure 3 which is the substrate kinetic graph of indolinone derivatives X15 containing a triazole structure on α-glucosidase in vitro. As Figure 3 can be seen, all the straight lines almost intersect in the third quadrant, proving that indolinone derivatives X15 containing a triazole structure have the effect of a mixed inhibitor.

[0142] The above has described the embodiments of the present invention in detail. However, this application is not limited to the above embodiments. Within the scope of knowledge possessed by those of ordinary skill in the art, various changes can be made without departing from the purpose of this application.

Claims

1. An indole ketone derivative containing a triazole structure, characterized in that: The indole derivative has a structural formula as shown in formula (I); In the formula (I), R represents a substituted or unsubstituted phenyl group.

2. The indole ketone derivative containing a triazole structure according to claim 1, characterized in that: The substitution is mono-substitution or poly-substitution.

3. The indole ketone derivative containing a triazole structure according to claim 1 or 2, characterized in that: The R is selected from any one of the following groups:

4. The method for preparing the indole ketone derivative containing a triazole structure according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) Using compound S1 and compound S2 as raw materials to prepare compound S3; (2) Compound S5 was prepared using compound S4 as a raw material and substituted benzyl bromide; (3) performing a condensation reaction with compound S3 and compound S5 to obtain the indole ketone derivative; The order of step (1) and step (2) can be reversed, and the structural formulas of compound S1, compound S2, compound S3, compound S4 and compound S5 are as follows:

5. An α-glucosidase inhibitor, characterized in that A triazole structure-containing indolone derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

6. Use of the indolone derivative containing a triazole structure according to any one of claims 1 to 3 in the preparation of a product for preventing / treating diabetes.

7. The use according to claim 6, characterized in that: The product is a medicine or a food.

8. A drug for preventing / treating diabetes, characterized in that: A triazole structure-containing indolone derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

9. The medicine according to claim 8, characterized in that The dosage form of the medicine is tablet, capsule, oral solution or injection.

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