Anti-type 2 diabetes compounds and uses thereof

Abstract

The present application provides a compound for treating type 2 diabetes and its use, the compound being compound 3 or compound 4. The compound provided by the present invention can stimulate GLP-1R to produce downstream signals and can bind to DPP4 to prevent its degradation of glucagon-like polypeptide-1 (GLP-1). The present invention further optimizes the synthesis method, shortens the time, and improves the yield, providing a theoretical basis for the development of small molecule oral drugs for type 2 diabetes.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and more particularly to compounds for resisting type 2 diabetes and uses thereof. Background Art

[0002] There are currently a large number of diabetes treatments on the market, but even the most commonly used first-line drug, metformin, has a variety of side effects ranging from mild to severe, leading to poor patient compliance. This indicates that monotherapy with diabetes drugs cannot provide satisfactory blood sugar level management and treatment of other comorbidities. Therefore, the treatment of diabetes is often achieved through combination therapy with drugs with different mechanisms of action. However, this strategy may be affected by the problems associated with polytherapy, such as some side effects, toxicity, and unnecessary drug-drug interactions. Therefore, there is still a strong demand for new drugs with better therapeutic effects and reduced adverse reactions.

[0003] Traditionally, drug design has aimed to selectively target a single receptor. However, this approach is now considered outdated, and over the past few years, most drug design efforts have focused on developing compounds that can exert multiple physiological effects, particularly for diseases with complex etiologies such as cancer, inflammation, central nervous system disorders, and diabetes. A strategy that can be considered to address these needs is to select single molecules that regulate different targets, which may have the potential to improve efficacy and balance safety compared to single-target agents. The design of such multi-target ligands must focus on selecting appropriate targets.

[0004] Glucagon-like peptide-1 (GLP-1) is a naturally occurring glucose-lowering peptide and a substrate for dipeptidyl peptidase IV (DPP4). Therefore, inhibiting DPP4 can effectively increase GLP-1 concentrations, thereby lowering blood glucose. DPP4 degrades GLP-1 by acting on the alanine-8 recognition site of GLP-1(7-37) and GLP-1(7-36)NH2. Dipeptidyl peptidase IV inhibitors (DPP4Is) act on DPP4 and are compounds optimized by mimicking the structure of peptide substrates. Therefore, it is reasonable to assume that GLP-1 and DPP4I may have similar effects. GLP-1 receptor agonists (GLP-1RAs) directly affect the incretin system by mimicking the effects of endogenous GLP-1, while DPP4i increase active incretin levels by preventing DPP4 from degrading endogenous incretins. Although the market prospects for incretin-targeted treatments for type 2 diabetes (T2DM) appear promising, certain limitations, such as the repeated injections required for GLP-1R peptide agonists and the various side effects of DPP4i treatment, may prevent drugs targeting incretin effects from fully realizing their therapeutic potential. This has prompted efforts to identify functional molecules. Developing new drugs with novel mechanisms of action to treat T2DM has become both a key and difficult task in current clinical research. Summary of the Invention

[0005] To address the significant side effects of existing diabetes medications, the present invention has designed an oral GLP-1R agonist to reduce these side effects. This oral GLP-1R agonist can simultaneously inhibit DPP4, thereby improving patient compliance, increasing medication convenience, and reducing drug side effects. The compound is a small molecule with dual efficacy as a GLP-1R agonist and a DPP4 inhibitor. Another object of the present invention is to provide the use of a compound of formula A in the preparation of a diabetes medication.

[0006] The present invention provides a compound, which is compound 3 or compound 4:

[0007]

[0008] In some embodiments, the preparation steps of compound 3 are as follows:

[0009] Step 1: 1-adamantanecarboxylic acid reacts with benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBT), and then reacts with 2-bromoethylamine hydrobromide. The resulting mixture is washed with water, alkali, acid, and salt, and the organic phases are combined and rotary evaporated to obtain compound 1;

[0010]

[0011] Step 2: (2,4-difluorophenyl)piperazine, 8-bromo-7-(2-butynyl)-3-methylxanthine, anhydrous potassium carbonate, and potassium iodide were added to N,N-dimethylformamide to react. The resulting mixture was cooled, precipitated, vacuum filtered, and dried to obtain compound 2;

[0012]

[0013] Step 3: Compound 1 reacts with compound 2, anhydrous potassium carbonate and potassium iodide in N,N-dimethylformamide. The resulting mixture is cooled, precipitated, vacuum filtered, dried and purified to obtain compound 3.

[0014] In some embodiments, the preparation steps of compound 4 are as follows:

[0015] 2-Chloromethyl-4-methylquinazoline reacts with compound 2, anhydrous potassium carbonate, and potassium iodide in N,N-dimethylformamide. The resulting mixture is cooled, precipitated, vacuum filtered, dried, and purified to obtain compound 4.

[0016] The present invention also provides use of the compound for preparing medicine for treating type 2 diabetes.

[0017] The present invention provides a small molecule framework with dual efficacy as a glucagon-like polypeptide-1 receptor (GLP-1R) agonist and a dipeptidyl hydrolase IV inhibitor, and its preparation method. This small molecule can both stimulate GLP-1R to generate downstream signals and bind to DPP4 to prevent its degradation of glucagon-like polypeptide-1 (GLP-1). The present invention further optimizes the synthesis method, shortens the synthesis time, and improves the yield, providing a theoretical basis for the development of small molecule oral drugs for type 2 diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The H NMR spectrum of compound 3 is shown.

[0019] Figure 2 The high-resolution mass spectrum of compound 3 is shown.

[0020] Figure 3 The H NMR spectrum of compound 4 is shown.

[0021] Figure 4 The high-resolution mass spectrum of compound 4 is shown.

[0022] Figure 5 The graph shows the effect concentration of compound 3 on GLP-1R, where the abscissa is the logarithm of the concentration of compound 3 and the ordinate is the relative luminescence value normalized to 0.5% dimethyl sulfoxide.

[0023] Figure 6 The graph shows the effect concentration of compound 4 on GLP-1R, where the abscissa is the logarithm of the concentration of compound 4 and the ordinate is the relative luminescence value normalized to 0.5% dimethyl sulfoxide.

[0024] Figure 7 The fluorescence intensity of compound 3 at different concentrations over time is shown.

[0025] Figure 8 The graph shows the effect concentration of compound 3 on DPP4, where the abscissa is the logarithm of the concentration of compound 3 and the ordinate is the inhibition rate.

[0026] Figure 9 Shown are the fluorescence intensities of compound 4 at different concentrations over time.

[0027] Figure 10 The graph shows the effect concentration of compound 4 on DPP4, where the abscissa is the logarithm of the concentration of compound 4 and the ordinate is the inhibition rate. DETAILED DESCRIPTION

[0028] The following examples may enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way.

[0029] The present invention provides a small molecule compound skeleton, the compound structural formula of which is A:

[0030]

[0031] In order to verify the effectiveness of the skeleton, the present invention used molecular docking technology to dock five DPP4i to the GLP-1R binding site, and after analyzing the results, small molecule compounds 3 and 4 were obtained.

[0032]

[0033]

[0034] The preparation method of small molecule compound 3 comprises the following steps:

[0035] Step 1: 1-adamantanecarboxylic acid reacts with benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBT), and then reacts with 2-bromoethylamine hydrobromide. The resulting mixture is washed with water, alkali, acid, and salt, and the organic phases are combined and rotary evaporated to obtain compound 1.

[0036]

[0037] Step 2: (2,4-Difluorophenyl)piperazine, 8-bromo-7-(2-butynyl)-3-methylxanthine, anhydrous potassium carbonate, potassium iodide, and N,N-dimethylformamide are added to react. The resulting mixture is cooled, precipitated, a poor solvent is added, vacuum filtered, and dried to obtain compound 2.

[0038]

[0039] Step 3: Compound 1 reacts with compound 2, anhydrous potassium carbonate and potassium iodide in N,N-dimethylformamide. The resulting mixture is cooled, precipitated, added with a poor solvent, vacuum filtered, dried and purified to obtain compound 3.

[0040] In the preparation method of small molecule compound 3, the specific content of step 1 is as follows: 1.11mmol 1-adamantanecarboxylic acid is added to 5mL ultra-dry grade CH2Cl2, stirred evenly, and then 1.11mmol HBTU and 0.55mmol HOBT are added. The temperature is raised to 35°C, activated for 5h, and then 1.32mmol 2-bromoethylamine hydrobromide and 2.42mmol triethylamine are added to react overnight. After the reaction is completed, the solvent is evaporated under reduced pressure to obtain a yellow oil. 5mL of water is added to dissolve the water-soluble impurities, and 10mL of ethyl acetate is added for extraction. The organic layer is taken and washed with 10mL of saturated sodium bicarbonate, 10mL of dilute hydrochloric acid, and then washed twice with 10mL of saturated sodium chloride. The mixture is dried over anhydrous sodium sulfate for 2h and concentrated under reduced pressure. A poor solvent is added to promote precipitation to obtain a crude product of compound 1.

[0041] In the preparation method of small molecule compound 3, step 2 specifically involves the following: 1.51 mmol (2,4-difluorophenyl)piperazine, 1.36 mmol 8-bromo-7-(2-butynyl)-3-methylxanthine, 3.02 mmol anhydrous potassium carbonate, and 0.15 mmol potassium iodide are added sequentially to 10 mL N,N-dimethylformamide at room temperature and reacted at 80°C for 12 hours. An additional 1.01 mmol (2,4-difluorophenyl)piperazine is added and reacted for 6 hours. A plate is used to monitor the reaction progress during the reaction. After completion, the reaction solution is cooled to room temperature. 20 mL of water is added to precipitate a pale yellow solid, which is then stirred for 2 hours, vacuum filtered, and dried to obtain compound 2 as a pale yellow powder.

[0042] In the preparation method of small molecule compound 3, step three specifically involves the following steps: 2.0 mmol of compound 1 and 1.0 mmol of intermediate compound 2 are added to 10 mL of N,N-dimethylformamide at room temperature and stirred evenly. Then, 2.0 mmol of anhydrous potassium carbonate and 0.2 mmol of potassium iodide are added and the reaction is carried out at 80°C for 6 hours. A spot plate is used to monitor the reaction progress during the reaction. After thin-layer chromatography (TCL) confirms the completion of the reaction, the mixture is filtered and the filtrate is cooled to approximately 18°C. Stirred on a magnetic stirrer for 2 hours, a yellow solid precipitates. This solid is filtered again, dried under vacuum, and purified by high-performance liquid chromatography (HPLC) to obtain compound 3 as a pale yellow powder.

[0043] The preparation method of small molecule compound 4 comprises the following steps:

[0044] Step a: 2-chloromethyl-4-methylquinazoline reacts with compound 2, anhydrous potassium carbonate, and potassium iodide in N,N-dimethylformamide. The resulting mixture is cooled, precipitated, added with a poor solvent, vacuum filtered, dried, and purified to obtain compound 4.

[0045] In the preparation method of small molecule compound 4, step a specifically involves the following steps: 2.0 mmol of 2-chloromethyl-4-methylquinazoline and 1.0 mmol of intermediate compound 2 are added to 10 mL of N,N-dimethylformamide at room temperature and stirred. Then, 2.0 mmol of anhydrous potassium carbonate and 0.2 mmol of potassium iodide are added and the reaction is carried out at 80°C for 6 h. A spot plate is used to monitor the reaction progress during the reaction. Upon completion of the reaction by TLC, the reaction is filtered, and the filtrate is cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitates, which is then filtered again, dried under vacuum, and purified by HPLC to obtain compound 4 as a pale yellow powder.

[0046] The present invention also provides the use of the small molecule compound, which is suitable for oral administration, and the diabetes is type 2 diabetes.

[0047] In some embodiments, GLP-1R and DPP4 are targeted to design dual-action small molecules that may be effective as GLP-1R agonists and DPP4 inhibitors.

[0048] In some embodiments, small molecule compounds GLP-1R, after being stimulated, have the advantages of lowering blood pressure, lowering fasting blood glucose levels, lowering HbA1c, inducing weight loss, promoting the growth and development of pancreatic β cells, and being associated with a low incidence of hypoglycemia.

[0049] In the present invention, the synthesis of compounds 3 and 4 significantly increased yield to 90% by optimizing the reaction solvent, catalyst, feed ratio, and reaction temperature. Compounds 3 and 4 exhibit agonist activity at the GLP-1R, triggering downstream biological signaling shifts. Compounds 3 and 4 also exhibit inhibitory activity against DPP4, binding to it and preventing it from degrading active GLP-1.

[0050] The small molecule compound 3 (SU01) of the present invention was synthesized according to the following synthetic steps:

[0051]

[0052] Example 1: 0.2000 g (1.11 mmol) of 1-adamantanecarboxylic acid was added to 5 mL of ultra-dry CH2Cl2, stirred, and then 0.2699 g (1.67 mmol) of CDI was added. The temperature was raised to 35°C and activated for 5 h. After that, 0.227 g (1.11 mmol) of 2-bromoethylamine hydrobromide and 0.31 mL (2.42 mmol) of triethylamine were added and allowed to react overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, 5.00 mL of water was added to dissolve water-soluble impurities, and extraction was performed with 10.00 mL of ethyl acetate. The organic layer was washed sequentially with 10.00 mL of saturated sodium bicarbonate, 10.00 mL of dilute hydrochloric acid, and then twice with 10.00 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate for 2 h and concentrated under reduced pressure. Water was added as a poor solvent to promote precipitation, yielding crude Compound 1.

[0053] At room temperature, 0.3000 g (1.51 mmol) of (2,4-difluorophenyl)piperazine, 0.4047 g (1.36 mmol) of 8-bromo-7-(2-butynyl)-3-methylxanthine, and 0.4183 g (3.02 mmol) of anhydrous potassium carbonate were added sequentially to 10.00 mL of N,N-dimethylformamide. The mixture was allowed to react at 45°C for 12 h. A spot plate was used to monitor the reaction. After completion, the reaction solution was cooled to room temperature. 20.00 mL of water was added to precipitate a pale yellow solid. The mixture was stirred for 2 h, vacuum filtered, and dried to obtain Compound 2 as a pale yellow powder.

[0054] At room temperature, 0.4144 g (1.00 mmol) of compound 2 and 0.5724 g (2.00 mmol) of compound 1 were added to 10.00 mL of N,N-dimethylformamide and stirred. Then, 0.2764 g (2.00 mmol) of anhydrous potassium carbonate was added and the mixture was allowed to react at 45°C for 6 h. A spot plate was used to monitor the reaction progress. TLC confirmed the completion of the reaction, and the mixture was filtered. The filtrate was cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitated, which was filtered again and dried under vacuum. Purification by preparative HPLC gave 0.2661 g of compound 3 as a pale yellow powder in a 43% yield. The HPLC purity was 93.4%.

[0055] Example 2: 0.2000 g (1.11 mmol) of 1-adamantanecarboxylic acid was added to 5 mL of ultra-dry CH2Cl2 and stirred thoroughly. 0.4207 g (1.11 mmol) of HBTU and 0.0844 g (0.55 mmol) of HOBT were then added. The mixture was heated to 35°C and activated for 5 h. 0.227 g (1.11 mmol) of 2-bromoethylamine hydrobromide and 0.31 mL (2.42 mmol) of triethylamine were then added and allowed to react overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, 5.00 mL of water was added to dissolve water-soluble impurities, and extraction was performed with 10.00 mL of ethyl acetate. The organic layer was washed sequentially with 10.00 mL of saturated sodium bicarbonate, 10.00 mL of dilute hydrochloric acid, and then twice with 10.00 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate for 2 h and concentrated under reduced pressure. Water was added as a poor solvent to promote precipitation, yielding crude Compound 1.

[0056] At room temperature, 0.3000 g (1.51 mmol) of (2,4-difluorophenyl)piperazine, 0.4047 g (1.36 mmol) of 8-bromo-7-(2-butynyl)-3-methylxanthine, and 0.4183 g (3.02 mmol) of anhydrous potassium carbonate were added sequentially to 10.00 mL of N,N-dimethylformamide. The mixture was allowed to react at 45°C for 12 h. A spot plate was used to monitor the reaction. After completion, the reaction solution was cooled to room temperature. 20.00 mL of water was added to precipitate a pale yellow solid. The mixture was stirred for 2 h, vacuum filtered, and dried to obtain Compound 2 as a pale yellow powder.

[0057] At room temperature, 0.4144 g (1.00 mmol) of compound 2 and 0.5724 g (2.00 mmol) of compound 1 were added to 10.00 mL of N,N-dimethylformamide and stirred. Then, 0.2764 g (2.00 mmol) of anhydrous potassium carbonate was added and the mixture was allowed to react at 45°C for 6 h. A spot plate was used to monitor the reaction progress. TLC confirmed the completion of the reaction, and the mixture was filtered. The filtrate was cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitated, which was filtered again and dried under vacuum. Purification by preparative HPLC gave 0.3219 g of compound 3 as a pale yellow powder in a 52% yield. The HPLC purity was 91.3%.

[0058] Example 3: 0.2000 g (1.11 mmol) of 1-adamantanecarboxylic acid was added to 5 mL of ultra-dry CH2Cl2 and stirred thoroughly. 0.4207 g (1.11 mmol) of HBTU and 0.0844 g (0.55 mmol) of HOBT were then added. The mixture was heated to 35°C and activated for 5 h. Afterwards, 0.227 g (1.11 mmol) of 2-bromoethylamine hydrobromide and 0.31 mL (2.42 mmol) of triethylamine were added and allowed to react overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, 5.00 mL of water was added to dissolve water-soluble impurities, and extraction was performed with 10.00 mL of ethyl acetate. The organic layer was washed sequentially with 10.00 mL of saturated sodium bicarbonate, 10.00 mL of dilute hydrochloric acid, and then twice with 10.00 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate for 2 h and concentrated under reduced pressure. Water was added as a poor solvent to promote precipitation, yielding crude Compound 1.

[0059] At room temperature, 0.3000 g (1.51 mmol) of (2,4-difluorophenyl)piperazine, 0.4047 g (1.36 mmol) of 8-bromo-7-(2-butynyl)-3-methylxanthine, 0.4183 g (3.02 mmol) of anhydrous potassium carbonate, and 0.0250 g (0.15 mmol) of potassium iodide were added sequentially to 10.00 mL of N,N-dimethylformamide. The mixture was reacted at 80°C for 12 h. A spot plate was used to monitor the reaction. After completion, the reaction solution was cooled to room temperature. 20.00 mL of water was added to precipitate a pale yellow solid. The mixture was stirred for 2 h, vacuum filtered, and dried to obtain Compound 2 as a pale yellow powder.

[0060] At room temperature, 0.4144 g (1.00 mmol) of compound 2 and 0.5724 g (2.00 mmol) of compound 1 were added to 10.00 mL of N,N-dimethylformamide and stirred. Then, 0.2764 g (2.00 mmol) of anhydrous potassium carbonate and 0.0332 g (0.20 mmol) of potassium iodide were added and the mixture was allowed to react at 80°C for 6 h. A spot plate was used to monitor the reaction progress. TLC confirmed the completion of the reaction, and the mixture was filtered. The filtrate was cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitated, which was filtered again and dried in vacuo. Purification by preparative HPLC gave 30.5076 g of the compound as a pale yellow powder in 82% yield. The HPLC purity was 94.7%.

[0061] Example 4: 0.2000 g (1.11 mmol) of 1-adamantanecarboxylic acid was added to 5 mL of ultra-dry CH2Cl2 and stirred thoroughly. 0.4207 g (1.11 mmol) of HBTU and 0.0844 g (0.55 mmol) of HOBT were then added. The mixture was heated to 35°C and activated for 5 h. 0.227 g (1.11 mmol) of 2-bromoethylamine hydrobromide and 0.31 mL (2.42 mmol) of triethylamine were then added and allowed to react overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, 5.00 mL of water was added to dissolve water-soluble impurities, and extraction was performed with 10.00 mL of ethyl acetate. The organic layer was washed sequentially with 10.00 mL of saturated sodium bicarbonate, 10.00 mL of dilute hydrochloric acid, and then twice with 10.00 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate for 2 h and concentrated under reduced pressure. Water was added as a poor solvent to promote precipitation, yielding crude Compound 1.

[0062] At room temperature, 0.3000 g (1.51 mmol) of (2,4-difluorophenyl)piperazine, 0.4047 g (1.36 mmol) of 8-bromo-7-(2-butynyl)-3-methylxanthine, 0.4183 g (3.02 mmol) of anhydrous potassium carbonate, and 0.0250 g (0.15 mmol) of potassium iodide were added sequentially to 10.00 mL of N,N-dimethylformamide. The mixture was reacted at 45°C for 12 h. A spot plate was used to monitor the reaction. After completion, the reaction solution was cooled to room temperature. 20.00 mL of water was added to precipitate a pale yellow solid. The mixture was stirred for 2 h, vacuum filtered, and dried to obtain Compound 2 as a pale yellow powder.

[0063] At room temperature, 0.4144 g (1.00 mmol) of compound 2 and 0.5724 g (2.00 mmol) of compound 1 were added to 10.00 mL of N,N-dimethylformamide and stirred. Then, 0.2764 g (2.00 mmol) of anhydrous potassium carbonate and 0.0332 g (0.20 mmol) of potassium iodide were added and the mixture was allowed to react at 45°C for 6 h. A spot plate was used to monitor the reaction progress. TLC confirmed the completion of the reaction, and the mixture was filtered. The filtrate was cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitated, which was filtered again and dried in vacuo. Purification by preparative HPLC gave 30.4147 g of the compound as a pale yellow powder in a 67% yield. The HPLC purity was 92.5%.

[0064] Example 5: 0.2000 g (1.11 mmol) of 1-adamantanecarboxylic acid was added to 5 mL of ultra-dry CH2Cl2 and stirred thoroughly. 0.4207 g (1.11 mmol) of HBTU and 0.0844 g (0.55 mmol) of HOBT were then added. The mixture was heated to 35°C and activated for 5 h. 0.227 g (1.11 mmol) of 2-bromoethylamine hydrobromide and 0.31 mL (2.42 mmol) of triethylamine were then added and allowed to react overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, 5.00 mL of water was added to dissolve water-soluble impurities, and extraction was performed with 10.00 mL of ethyl acetate. The organic layer was washed sequentially with 10.00 mL of saturated sodium bicarbonate, 10.00 mL of dilute hydrochloric acid, and then twice with 10.00 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate for 2 h and concentrated under reduced pressure. Water was added as a poor solvent to promote precipitation, yielding crude Compound 1.

[0065] At room temperature, 0.3000 g (1.51 mmol) of (2,4-difluorophenyl)piperazine, 0.4047 g (1.36 mmol) of 8-bromo-7-(2-butynyl)-3-methylxanthine, 0.4183 g (3.02 mmol) of anhydrous potassium carbonate, and 0.0250 g (0.15 mmol) of potassium iodide were added sequentially to 10.00 mL of N,N-dimethylformamide and reacted at 80°C for 12 h. An additional 0.2000 g (1.01 mmol) of (2,4-difluorophenyl)piperazine was added and the reaction continued for 6 h. A spot plate was used to monitor the reaction progress. After completion, the reaction solution was cooled to room temperature. 20.00 mL of water was added to precipitate a pale yellow solid. The mixture was stirred for 2 h, vacuum filtered, and dried to obtain Compound 2 as a pale yellow powder.

[0066] At room temperature, 0.4144 g (1.00 mmol) of compound 2 and 0.5724 g (2.00 mmol) of compound 1 were added to 10.00 mL of N,N-dimethylformamide and stirred. Then, 0.2764 g (2.00 mmol) of anhydrous potassium carbonate and 0.0332 g (0.20 mmol) of potassium iodide were added and the mixture was allowed to react at 80°C for 6 h. A spot plate was used to monitor the reaction progress. TLC confirmed the completion of the reaction, and the mixture was filtered. The filtrate was cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitated, which was filtered again and dried in vacuo. Purification by preparative HPLC gave 30.5633 g of the compound as a pale yellow powder in a 91% yield. The HPLC purity was 96.8%.

[0067] The obtained compound 3 was subjected to nuclear magnetic resonance hydrogen spectrum and high-resolution mass spectrum, such as Figure 1 and Figure 2 As shown:

[0068] N-(2-(7-(2-butynyl)-8-(4-(2,4-difluorophenyl)piperazinyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)ethyl)adamantane-1-carboxamide (SU01): 1 HNMR (400MHz, DMSO): δ8.10 (s, 1H), 7.23 (ddd, J = 12.2, 8.9, 2.9Hz, 1H), 7.10 (td, J =9.4,5.9Hz,1H),7.04-6.99(m,1H),5.44(q,J=2.4Hz,2H),3.53(dt,J=12.9,5.0H z,4H),3.30(s,3H),2.96(t,J=5.0Hz,4H),2.90(t,J=5.2Hz,4H),2.03(p,J=3.1Hz ,3H),1.81(d,J=3.0Hz,6H),1.69(t,J=2.4Hz,3H),1.57-1.48(m,6H).MS(m / z):[M] + calcd.for C33H40F2N7O3 + ,620.31494Da; found,620.31494D.

[0069] Compound 4 (SU02) of the present invention was synthesized according to the following synthetic steps:

[0070]

[0071] Example 6: At room temperature, 0.4144 g (1.00 mmol) of compound 2 and 0.3841 g (2.00 mmol) of 2-chloromethyl-4-methylquinazoline were added to 10 mL of N,N-dimethylformamide and stirred. After uniform mixing, 0.2764 g (2.00 mmol) of anhydrous potassium carbonate and 0.0332 g (0.20 mmol) of potassium iodide were added and the reaction was allowed to proceed at 80°C for 6 h. A spot plate was used to monitor the reaction progress. TLC confirmed the reaction was complete. The reaction was filtered, and the filtrate was cooled to approximately 18°C and stirred on a magnetic stirrer for 2 h. A yellow solid precipitated, which was filtered again and dried in vacuo. Purification by preparative HPLC gave 40.5075 g of the compound as a yellow powder in 89% yield. HPLC purity was 93.2%.

[0072] The obtained compound 4 was subjected to nuclear magnetic resonance hydrogen spectrum and high-resolution mass spectrum, such as Figure 3 and Figure 4 As shown:

[0073] 7-(2-Butynyl)-8-(4-(2,4-difluorophenyl)piperazinyl)-3-methyl-1-((4-methylquinazoline)-2-methyl)-3,7-dihydro-1H-purine-2,6-dione (SU02): light yellow solid powder, yield 91%, purity 95%, 1H NMR (400 MHz, Chloroform-d): δ 8.11 (ddd, J = 8.3, 1.4, 0.7 Hz, 1H), 8.03 (ddd, J = 8.5, 1.2, 0.7 Hz, 1H), 7.90 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.66 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 6.95 (td, J = 9.9, 9.4 ,5.8Hz,1H),6.90-6.80(m,2H),4.99(s,2H),4.83(s,2H),3.57(d,J=8.1Hz,3H),3.08(dd,J=5 .9,3.3Hz,4H),3.05-3.01(m,4H),2.42(s,3H),1.53(t,J=2.4Hz,3H).MS(m / z):[M]+calcd.for C30H29F2N8O2+,571.23676Da; found,571.23676D.

[0074] Verification test of GLP-1R activity of compounds 3 (SU01) and 4 (SU02);

[0075] A high-throughput screening cell model for GLP-1R agonists was performed using the luciferase reporter gene assay. Three replicate wells were set up, and compounds 3 and 4 were added to each group at final concentrations of 0 nmol / L, 100 nmol / L, 200 nmol / L, 500 nmol / L, 600 nmol / L, 800 nmol / L, 1000 nmol / L, 2000 nmol / L, 3000 nmol / L, 4000 nmol / L, and 5000 nmol / L. GLP-1 was used as a positive control, and water was used as a negative control. The results are shown in Figure 2. Figure 5 and Figure 6 The EC of compound 3 for GLP-1R is shown in Figure 2. 50 =857.1 nmol / L, EC of compound 4 for GLP-1R 50 =1650nmol / L.

[0076] Verification test of compound 3 (SU01) and compound 4 (SU02) on DPP4 activity:

[0077] The DPP4 inhibitor screening model was used to test Gly-Pro-7-amido-4-methylcoumarin hydrobromide (GP-AMC) as a control. Three replicate wells were set up, and the final concentrations of compounds 3 and 4 added were 100nmol / L, 500nmol / L, 750nmol / L, 1000nmol / L, 2000nmol / L, and 3000nmol / L. Vildagliptin was used as a positive control, and water was used as a negative control. The results are shown in Figure 2. Figures 7 to 10 As shown. IC of compound 3 for DPP4 50 =1046.0nmol / L, IC of compound 4 for DPP4 50 =612.3nmol / L.

[0078] In summary, the synthesized compounds 3 and 4 have certain biological activities and can be used as potential compounds for treating type 2 diabetes and can be further modified. The present invention optimizes the synthesis method, greatly improving the yield and facilitating subsequent synthesis.

[0079] It should be understood by those skilled in the art that the above embodiments are merely exemplary embodiments and that various changes, substitutions, and alterations may be made without departing from the spirit and scope of the present invention.

Claims

1. A compound, characterized in that The compound is compound 3 or compound 4:

2. The compound according to claim 1, characterized in that The preparation steps of compound 3 are as follows: Step 1: 1-adamantanecarboxylic acid reacts with benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBT), and then reacts with 2-bromoethylamine hydrobromide. The resulting mixture is washed with water, alkali, acid, and salt, and the organic phases are combined and rotary evaporated to obtain compound 1; Step 2: (2,4-difluorophenyl)piperazine, 8-bromo-7-(2-butynyl)-3-methylxanthine, anhydrous potassium carbonate, and potassium iodide were added to N,N-dimethylformamide to react. The resulting mixture was cooled, precipitated, vacuum filtered, and dried to obtain compound 2; Step 3: Compound 1 reacts with compound 2, anhydrous potassium carbonate and potassium iodide in N,N-dimethylformamide. The resulting mixture is cooled, precipitated, vacuum filtered, dried and purified to obtain compound 3.

3. The compound according to claim 1, characterized in that The preparation steps of compound 4 are as follows: 2-Chloromethyl-4-methylquinazoline reacts with compound 2, anhydrous potassium carbonate, and potassium iodide in N,N-dimethylformamide. The resulting mixture is cooled, precipitated, vacuum filtered, dried, and purified to obtain compound 4.

4. The use of the compound according to claim 1, characterized in that The compound is used for preparing medicine for treating type 2 diabetes.

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