A sulfonamidine compound and its application in inflammation treatment

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a sulfonamid compound and application thereof in inflammation treatment. The present application performs structure splicing of a sulfonamid skeleton and a gentiopicroside nitroxide radical derivative, realizes advantage complementation of two types of active skeletons, and is worth a series of sulfonamid compounds with good anti-inflammatory activity. The present application has the following beneficial effects: on the one hand, the sulfonamid skeleton can improve water solubility and metabolic stability of the gentiopicroside nitroxide radical derivative, and improve its drug property; on the other hand, the anti-inflammatory activity of the gentiopicroside nitroxide radical can further enhance the free radical scavenging capacity and inflammation pathway regulation effect of the sulfonamid compound, form a double anti-inflammatory mechanism, inhibit excessive activation of an inflammation signal pathway through the sulfonamid skeleton, remove excessive ROS, NO and other inflammation mediators through the gentiopicroside nitroxide radical, and synergistically improve the anti-inflammatory activity.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and specifically relates to a sulfonylamidine compound and its application in the treatment of inflammation. Background Technology

[0002] Inflammation is the body's core defense response to infection, tissue damage, or stress. Its overactivation and chronicity are closely related to the occurrence and development of major diseases such as rheumatoid arthritis, inflammatory bowel disease, neurodegenerative diseases, and tumors, and have become a core challenge that urgently needs to be addressed in the global public health field.

[0003] In recent years, the development of small molecule drugs targeting inflammatory mediators such as reactive oxygen species (ROS) and nitric oxide (NO), as well as inflammatory signaling pathways such as NF-κB and MAPK, has become a hot topic. In medicinal chemistry, the sulfonyl group, with its unique electronic effects and structural characteristics, serves as an important pharmacophore, demonstrating significant advantages in endowing molecules with diverse pharmacological activities such as anti-inflammatory, anti-tumor, and anti-diabetic effects. Particularly in anti-inflammatory drug development, compounds containing sulfonyl groups or sulfonamide structures have become an important source of classic COX-2 inhibitors. The success of representative drugs such as celecoxib, rofecoxib, etoricoxib, and nimesulide strongly confirms that this group is a key structure for achieving high COX-2 selectivity. Taking nimesulide as an example, the methanesulfonyl group in its parent structure N-(4-nitro-2-phenoxyphenyl)methanesulfonamide has been proven to be the core functional group that achieves moderately selective COX-2 inhibition and exerts potent anti-inflammatory and analgesic effects. It is evident that if sulfonyl groups can be used as functional carriers and their structural modifications endow them with the ability to simultaneously scavenge reactive oxygen species, it is hoped that they can synergistically intervene through two pathways: inhibiting inflammatory enzyme activity and blocking oxidative damage, thus opening up a new direction for the development of a new generation of anti-inflammatory drugs with both higher efficacy and safety.

[0004] Meanwhile, gentiopicroside, the core active ingredient of the traditional Chinese medicine gentian, has become an important direction for the development of anti-inflammatory natural products due to its nitroxide radical derivatives, which possess the properties of efficiently scavenging free radicals and inhibiting the release of inflammatory mediators. However, gentiopicroside nitroxide radical derivatives suffer from problems such as poor water solubility, insufficient in vivo stability, and limited anti-inflammatory activity, which restricts their clinical translation. Meanwhile, simple sulfonylamidine compounds still face technical bottlenecks such as insufficient structural diversity, narrow anti-inflammatory spectrum, and the need to improve target selectivity.

[0005] Structural splicing of sulfonylamidine skeletons with gentiopicroside nitroxide radical derivatives holds promise for achieving complementary advantages between the two active skeletons. However, there are currently no reports of structural fusion of sulfonylamidine skeletons with gentiopicroside nitroxide radical derivatives in existing technologies. Research on the anti-inflammatory activity, mechanism of action, and druggability of such hybrid compounds remains incomplete, and their application potential in the field of inflammation treatment has not been fully explored. In summary, the development of novel anti-inflammatory compounds based on the sulfonylamidine-gentiopicroside nitroxide radical hybrid skeleton has significant theoretical and practical value for overcoming the efficacy and safety limitations of existing anti-inflammatory drugs and enriching the pipeline of anti-inflammatory drugs. Summary of the Invention

[0006] To address the above-mentioned technical problems, this invention proposes a sulfonylamidine compound and its application in the treatment of inflammation.

[0007] In this invention, a series of sulfonylamidine compounds with good anti-inflammatory activity were prepared by structurally splicing a sulfonylamidine skeleton with a gentiopicroside nitric oxide radical derivative. On the one hand, the sulfonylamidine skeleton can improve the water solubility and metabolic stability of the gentiopicroside nitric oxide radical derivative, thereby enhancing its drug-likeness. On the other hand, the anti-inflammatory activity of the gentiopicroside nitric oxide radical can further enhance the free radical scavenging ability and inflammatory pathway regulation of the sulfonylamidine compounds, forming a dual anti-inflammatory mechanism. This mechanism inhibits the excessive activation of inflammatory signaling pathways through the sulfonylamidine skeleton and scavenges excessive ROS, NO and other inflammatory mediators through the gentiopicroside nitric oxide radical, thus synergistically enhancing the anti-inflammatory activity.

[0008] The technical solution of this invention is:

[0009] Use of sulfonylamidine compounds of Formula I or their pharmaceutical salts in the preparation of medicaments for treating diseases or conditions selected from those caused by aging or inflammation:

[0010] The disease or symptom described is selected from any one of the following: skin inflammation, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, thrombophlebitis, systemic juvenile idiopathic arthritis, neuroinflammation, viral hepatitis, alcoholic hepatitis, fatty liver disease, gingivitis, periodontitis, myocarditis, cystitis, prostatitis, and skin aging.

[0011] ;

[0012] Formula I;

[0013] Where n is independently selected from any natural number from 0 to 10;

[0014] R1 is independently selected from ethyl, propyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, o-bromophenyl, o-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, p-methoxyphenyl, and p-trifluoromethylphenyl.

[0015] R2 is independently selected from any one of the structures shown in A-1, A-2, A-3, and A-4. X is independently selected from ether bonds and imine bonds.

[0016] Preferably, the compound is selected from, etc. Figure 1 Compounds GPS-1 to GPS-12 with the structures shown.

[0017] Furthermore, the present invention also provides a pharmaceutical composition for treating and / or improving inflammation-related diseases, wherein, preferably, the pharmaceutical composition contains a sulfonylamidine compound with the structure described above or a pharmaceutically acceptable salt, hydrate, solvate, pharmaceutically acceptable carrier thereof, and pharmaceutical excipients.

[0018] Preferably, the pharmaceutical composition is any one of the following forms: capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, and patches.

[0019] In this invention, sulfonylamidine compounds having the structure described in Formula I are prepared by the following method:

[0020] S1: The compound shown in structural formula II and the compound shown in structural formula III react under organic solvent and alkaline conditions, with or without the addition of a condensing agent, to obtain the alkyne compound shown in structural formula IV.

[0021] ;

[0022] The base is selected from at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, 4-dimethylaminopyridine, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium hydroxide, cesium carbonate, sodium bicarbonate, potassium bicarbonate, barium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0023] The condensing agent is selected from at least one of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, and triethylamine;

[0024] The organic solvent is selected from at least one of tetrahydrofuran, acetonitrile, dichloromethane, benzene, toluene, xylene, chlorobenzene, chloroform, methanol, ethanol, petroleum ether, N,N-dimethylformamide, and dimethyl sulfoxide;

[0025] S2: The alkyne compound shown in structural formula IV reacts with the gentiopicroside amine derivative shown in structural formula V and the sulfonyl azide compound shown in structural formula VI in the presence of an organic solvent, a base and a catalyst to obtain the sulfonyl amidine compound of formula I.

[0026] ;

[0027] The base is at least one of triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydroxide, cesium carbonate, sodium bicarbonate, potassium bicarbonate, barium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

[0028] The organic solvent is selected from at least one of tetrahydrofuran, acetonitrile, dichloromethane, benzene, toluene, xylene, chlorobenzene, chloroform, methanol, ethanol, petroleum ether, N,N-dimethylformamide, and dimethyl sulfoxide;

[0029] The catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, copper sulfate, and copper acetate.

[0030] In the compounds and their structures involved in S1~S2 above, n is independently selected from any natural number from 0 to 10; R1 is independently selected from ethyl, propyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, o-bromophenyl, o-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, p-methoxyphenyl, and p-trifluoromethylphenyl.

[0031] R2 is independently selected from any one of the structures shown in A-1, A-2, A-3, and A-4:

[0032] ;

[0033] X is independently selected from ether bonds and imine bonds.

[0034] Preferably, the organic solvent in S1 is N,N-dimethylformamide; the base is sodium cyanide; and the condensing agent is at least one of N,N'-dicyclohexylcarbodiimide, triethylamine, p-dimethylaminopyridine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine.

[0035] Preferably, the organic solvent in S2 is at least one of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, chloroform, and anhydrous methanol; the catalyst is any one of cuprous iodide, cuprous bromide, cuprous chloride, and cuprous iodide; and the base is at least one of triethylamine, potassium carbonate, 4-dimethylaminopyridine, sodium carbonate, pyridine, and barium carbonate.

[0036] The present invention has the following advantages and effects compared with the prior art:

[0037] This invention provides a series of sulfonylamine compounds by adding sulfonyl groups to the gentiopicroside nitric oxide radical derivatives. These compounds exhibit a ROS scavenging rate of 35.72% to 51.45% at a concentration of 3 μM. Furthermore, each derivative can effectively inhibit the release of the inflammatory mediator nitric oxide during the inflammatory process, especially GPS-5, which has an inhibitory effect almost equivalent to that of celecoxib. Attached Figure Description

[0038] Figure 1 The chemical structure diagrams of the sulfonylamidine compounds GPS-1 to GPS-12 provided in this invention are shown below.

[0039] Figure 2 The high-resolution mass spectrum of GPS-1, a sulfonylamidine compound;

[0040] Figure 3 High-resolution mass spectrum of sulfonylamidine compound GPS-2;

[0041] Figure 4 High-resolution mass spectrum of sulfonylamidine compound GPS-3;

[0042] Figure 5 High-resolution mass spectrum of sulfonylamidine compound GPS-4;

[0043] Figure 6 High-resolution mass spectrum of GPS-5, a sulfonylamidine compound;

[0044] Figure 7 High-resolution mass spectrum of GPS-6, a sulfonylamidine compound;

[0045] Figure 8 High-resolution mass spectrum of GPS-7, a sulfonylamidine compound;

[0046] Figure 9 High-resolution mass spectrum of sulfonylamidine compound GPS-8;

[0047] Figure 10 High-resolution mass spectrum of sulfonylamidine compound GPS-9;

[0048] Figure 11High-resolution mass spectrum of sulfonylamidine compound GPS-10;

[0049] Figure 12 High-resolution mass spectrum of sulfonylamidine compound GPS-11;

[0050] Figure 13 This is a high-resolution mass spectrum of the sulfonylamidine compound GPS-12. Detailed Implementation

[0051] To enable those skilled in the art to better understand the present invention, the present invention will now be further described in conjunction with specific embodiments. Specific Implementation Example 1:

[0053] The synthetic route for the preparation of the sulfonylamidine compound GPS-1 is as follows:

[0054] .

[0055] The specific steps are as follows:

[0056] In S1, 0.50 mmol of nitroxide radical 1a and 0.60 mmol of compound 1b were added to a round-bottom flask and dissolved in N,N-dimethylformamide. The mixture was stirred until fully dissolved. Subsequently, 0.8 mmol of sodium hydride was added to the reaction system. After the reaction was completed at room temperature, the mixture was quenched with water, concentrated under reduced pressure, and separated by column chromatography to obtain alkyne compound 1c.

[0057] Gentianoside amine derivative (1 mmol), nitroxyl alkynyl 1c (1.5 mmol), and sulfonyl azide 1d (1.3 mmol) were dissolved in 15 mL of anhydrous dichloromethane. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete, then the reaction was stopped, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient elution ratio 30:1 to 15:1, v / v) to obtain the sulfonylamidine compound GPS-1. The high-resolution mass spectrum is shown below. Figure 2 As shown, high-resolution mass spectrometry data m / z: theoretical value C 30 H 46 N3O 12 S·Na: 695.2694 [M+Na] + Actual value: 695.2693 [M+Na] + . Specific Implementation Example 2:

[0059] The synthetic route for the preparation of the sulfonylamidine compound GPS-2 is as follows:

[0060] .

[0061] The specific steps are as follows:

[0062] S1 is the same as in Example 1;

[0063] S2: Gentianopiclinamine derivative (1 mmol), nitroxyl alkynyl 1c (1.5 mmol), and sulfonyl azide 2d (1.3 mmol) were dissolved in 15 mL of anhydrous dichloromethane. Subsequently, cuprous iodide catalyst (0.1 mmol) and potassium carbonate (2 mmol) were added sequentially to the reaction system. After stirring at room temperature until the reaction was complete, purification was performed according to the method of Example 1 to obtain the sulfonylamidine compound GPS-2. The high-resolution mass spectrum is shown below. Figure 3 As shown, high-resolution mass spectrometry data m / z: theoretical value C 31 H 48 N3O 12 S·Na: 709.2851 [M+Na] + Actual value: 709.2843 [M+Na] + . Specific Implementation Example 3:

[0065] The synthetic route for the preparation of the sulfonylamidine compound GPS-3 is as follows:

[0066] .

[0067] The specific steps are as follows:

[0068] S1 is the same as in Example 1;

[0069] S2: Gentianopiclinamine derivative (1 mmol), nitroxyl alkynyl 1c (1.5 mmol), and sulfonyl azide 3d (1.3 mmol) were dissolved in 15 mL of anhydrous tetrahydrofuran. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. After stirring at room temperature, the reaction was purified according to the method in Example 1 to obtain the sulfonylamidine compound GPS-3. The high-resolution mass spectrum is shown below. Figure 4 As shown, high-resolution mass spectrometry data m / z: theoretical value C 34 H 46 N3O 12 S·Na: 743.2694 [M+Na] + Actual value: 743.2704 [M+Na] + . Specific Implementation Example 4:

[0071] The synthetic route for the preparation of the sulfonylamidine compound GPS-4 is as follows:

[0072] .

[0073] The specific steps are as follows:

[0074] S1 is the same as in Example 1;

[0075] S2: A gentiopicrin amine derivative (1 mmol), a nitroxide radical yne 1c (1.5 mmol), and a sulfonyl azide 4d (1.3 mmol) were dissolved in 15 mL of anhydrous tetrahydrofuran. Subsequently, cuprous bromide (0.1 mmol) and the base 4-dimethylaminopyridine (2 mmol) were added sequentially to the reaction system. After stirring at room temperature, the reaction was completed, and the mixture was purified according to the method in Example 1 to obtain the sulfonylamidine compound GPS-4. The high-resolution mass spectrum is shown below. Figure 5 As shown, high-resolution mass spectrometry data m / z: theoretical value C 35 H 48 N3O 12 S·Na: 757.2851 [M+Na] + Actual value: 757.2832 [M+Na] + . Specific Implementation Example 5:

[0077] The synthetic route for the preparation of the sulfonylamidine compound GPS-5 is as follows:

[0078] .

[0079] The specific steps are as follows:

[0080] S1 is the same as in Example 1;

[0081] S2: A gentiopicrin derivative (1 mmol), a nitroxide radical yne 1c (1.5 mmol), and a sulfonyl azide 5d (1.3 mmol) were dissolved in 15 mL of anhydrous acetonitrile. Subsequently, cuprous chloride (0.1 mmol) and sodium carbonate (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. Purification was performed according to the method in Example 1 to obtain the sulfonylamidine compound GPS-5. The high-resolution mass spectrum is shown below. Figure 6 As shown, high-resolution mass spectrometry data m / z: theoretical value C 35 H 48 N3O 13 S·Na: 773.2800 [M+Na] + Actual value: 773.2775 [M+Na] + . Specific Implementation Example 6:

[0083] The synthetic route for the preparation of the sulfonylamidine compound GPS-6 is as follows:

[0084] .

[0085] The specific steps are as follows:

[0086] S1 is the same as in Example 1;

[0087] S2. Gentianopiclinamine derivative (1 mmol), nitroxyl alkynyl 1c (1.5 mmol), and sulfonyl azide 6d (1.3 mmol) were dissolved in 15 mL of anhydrous N,N-dimethylformamide. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. Purification was performed according to the method in Example 1 to obtain the sulfonylamidine compound GPS-6. The high-resolution mass spectrum is shown below. Figure 7 As shown, high-resolution mass spectrometry data m / z: theoretical value C 35 H 45 F3N3O 12 S·Na: 811.2568 [M+Na] + Actual value: 811.2560 [M+Na] + . Specific Implementation Example 7:

[0089] The synthetic route for the preparation of the sulfonylamidine compound GPS-7 is as follows:

[0090] .

[0091] The specific steps are as follows:

[0092] S1 is the same as in Example 1;

[0093] S2: A gentiopicroside derivative (1 mmol), a nitroxide radical yne 1c (1.5 mmol), and a sulfonyl azide 7d (1.3 mmol) were dissolved in 15 mL of anhydrous chloroform. Subsequently, cuprous chloride (0.1 mmol) and pyridine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. The mixture was then purified according to the method in Example 1 to obtain the sulfonylamidine compound GPS-7. The high-resolution mass spectrum is shown below. Figure 8 As shown, high-resolution mass spectrometry data m / z: theoretical value C 36 H 50 N3O 14 S·Na: 803.2906 [M+Na] + Actual value: 803.2897 [M+Na] + . Specific Implementation Example 8:

[0095] The synthetic route for the preparation of the sulfonylamidine compound GPS-8 is as follows:

[0096] .

[0097] The specific steps are as follows:

[0098] S1 is the same as in Example 1;

[0099] S2. Gentianopiclinamine derivative (1 mmol), nitroxide radical yne 1c (1.5 mmol), and sulfonyl azide 8d (1.3 mmol) were dissolved in 15 mL of anhydrous dichloromethane. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete, and then purified according to the method in Example 1 to obtain the sulfonylamidine compound GPS-8. The high-resolution mass spectrum is shown below. Figure 9 As shown, high-resolution mass spectrometry data m / z: theoretical value C 34 H 45 FN3O 12 S·Na: 761.2660 [M+Na] + Actual value: 761.2578 [M+Na] + . Specific Implementation Example 9:

[0101] The synthetic route for the preparation of the sulfonylamidine compound GPS-9 is as follows:

[0102] .

[0103] The specific steps are as follows:

[0104] S1 is the same as in Example 1;

[0105] S2: Gentianopiclinamine derivative (1 mmol), nitroxyl alkynyl 1c (1.5 mmol), and sulfonyl azide 9d (1.3 mmol) were dissolved in 15 mL of anhydrous methanol. Subsequently, cuprous iodide catalyst (0.1 mmol) and barium carbonate (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. The solution was purified according to the method in Example 1 to obtain the sulfonylamidine compound GPS-9. The high-resolution mass spectrum is shown below. Figure 10 As shown, high-resolution mass spectrometry data m / z: theoretical value C 34 H 45 ClN3O 12 S·Na: 777.2305 [M+Na] + Actual value: 777.2276 [M+Na] + . Specific Implementation Example 10:

[0107] The synthetic route for the preparation of the sulfonylamidine compound GPS-10 is as follows:

[0108] .

[0109] The specific steps are as follows:

[0110] In S1, nitroxide radical 2a (0.50 mmol) and compound 5b (0.60 mmol) were added to a round-bottom flask and dissolved in dichloromethane. The mixture was stirred until fully dissolved. Subsequently, condensing agents N,N'-dicyclohexylcarbodiimide (0.60 mmol) and triethylamine (0.5 mmol) were added to the reaction system. After the reaction was completed at room temperature, the mixture was quenched with water, concentrated under reduced pressure, and separated by column chromatography to obtain alkyne compound 2c.

[0111] S2. Gentianopiclinamine derivative (1 mmol), nitroxide radical alkyne 2c (1.5 mmol), and sulfonyl azide 9d (1.3 mmol) were dissolved in 15 mL of anhydrous dichloromethane. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. Purification was performed according to the method in Example 1 to obtain the sulfonylamidine compound GPS-10. The high-resolution mass spectrum is shown below. Figure 11 As shown, high-resolution mass spectrometry data m / z: theoretical value C 36 H 45 ClN3O 13 S·Na: 817.2254 [M+Na] + Actual value: 817.2215 [M+Na] + . Specific Implementation Example 11:

[0113] The synthetic route for the preparation of the sulfonylamidine compound GPS-11 is as follows:

[0114] .

[0115] The specific steps are as follows:

[0116] In S1, nitroxide radical 3a (0.50 mmol) and compound 2b (0.60 mmol) were added to a round-bottom flask and dissolved in tetrahydrofuran. The mixture was stirred until fully dissolved. Subsequently, condensing agents N,N'-dicyclohexylcarbodiimide (0.60 mmol) and p-dimethylaminopyridine (0.5 mmol) were added to the reaction system. After the reaction was completed at room temperature, the mixture was quenched with water, concentrated under reduced pressure, and separated by column chromatography to obtain alkyne compound 3c.

[0117] S2. Gentianopiclinamine derivative (1 mmol), nitroxide radical alkyne 3c (1.5 mmol), and sulfonyl azide 3d (1.3 mmol) were dissolved in 15 mL of anhydrous dichloromethane. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. Purification was performed according to the method in Example 1 to obtain the sulfonylamidine compound GPS-11. The high-resolution mass spectrum is shown below. Figure 12 As shown, high-resolution mass spectrometry data m / z: theoretical value C 35 H 46 N3O 13 S·Na: 771.2644 [M+Na] + Actual value: 771.2613 [M+Na] + . Specific Implementation Example 12:

[0119] The synthetic route for the preparation of the sulfonylamidine compound GPS-12 is as follows:

[0120] .

[0121] The specific steps are as follows:

[0122] In S1, nitroxide radical 4a (0.50 mmol) and compound 3b (0.60 mmol) were added to a round-bottom flask and dissolved in N,N-dimethylformamide. The mixture was stirred until fully dissolved. Subsequently, condensing agents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.60 mmol) and N,N-diisopropylethylamine (0.5 mmol) were added to the reaction system. After the reaction was completed at room temperature, the mixture was quenched with water, concentrated under reduced pressure, and separated by column chromatography to obtain alkyne compound 4c.

[0123] S2: Gentianopiclinamine derivative (1 mmol), nitroxyl 4c (1.5 mmol), and sulfonyl azide 4d (1.3 mmol) were dissolved in 15 mL of anhydrous dichloromethane. Subsequently, cuprous iodide catalyst (0.1 mmol) and triethylamine (2 mmol) were added sequentially to the reaction system. The mixture was stirred at room temperature until the reaction was complete. Purification was performed according to the method in Example 1 to obtain the sulfonylamidine compound GPS-12. The high-resolution mass spectrum is shown below. Figure 13 As shown. High-resolution mass spectrometry data m / z: theoretical value C 37 H 51 N4O 12 S·Na: 798.3116 [M+Na] + Actual value: 798.3103 [M+Na] + . Specific Implementation Example 13:

[0125] In vitro anti-inflammatory effects of sulfonylamidine compounds GPS-1~GPS-12.

[0126] The in vitro anti-inflammatory activity of sulfonamide compounds was investigated using mouse mononuclear macrophage leukemia cells (RAW 264.7 cells) as a model. RAW 264.7 cells were seeded in 96-well plates and cultured at 37°C with 5% CO2 for 24 hours. Celecoxib, a widely used clinical anti-inflammatory drug, was used as a positive control.

[0127] The experiment was divided into the following groups: blank control group (no LPS treatment), LPS control group (with an equal volume of PBS), positive control group (celecoxib, 20 μM), and drug-treated groups (sulfonamide compounds GPS-1~GPS-12, all at 20 μM). After pretreatment for 4 hours, cells in each group were stimulated with LPS (1 μg / mL) for 24 h (except for the blank control group), and samples were then collected for subsequent analysis. After incubation, the nitric oxide content in the culture medium was measured to assess the anti-inflammatory effect. The nitric oxide content in RAW 264.7 cells after treatment is shown in Table 1.

[0128] Table 1. NO concentration in cells after treatment with sulfonylamidine compounds of different structures. serial number Nitric oxide concentration (μM) GPS-1 6.38±0.53 GPS-2 6.02±0.89 GPS-3 4.38±0.55 GPS-4 5.13±0.53 GPS-5 2.48±0.68 GPS-6 6.45±0.56 GPS-7 3.97±0.67 GPS-8 6.63±0.43 GPS-9 6.58±0.51 GPS-10 7.29±1.33 GPS-11 5.81±1.07 GPS-12 4.23±0.35 Celecoxib 2.13±0.34 Blank group 1.05±0.27 LPS Group 8.87±0.72

[0129] As shown in Table 1, celecoxib, a COX-2 inhibitor widely used in clinical practice, exhibits strong anti-inflammatory activity. The sulfonylamidine compounds GPS-1 to GPS-12 provided in this application all exhibited certain anti-inflammatory activities at a concentration of 20 μM. Among them, after treatment with GPS-5, the nitric oxide concentration in cells was comparable to that of the celecoxib group. It can be seen that the sulfonylamidine compounds obtained by structurally splicing the sulfonylamidine skeleton with the gentiopicroside nitric oxide radical derivative in this invention have significantly enhanced anti-inflammatory activities. The possible reason is that the sulfonylamidine skeleton can improve the water solubility and metabolic stability of the gentiopicroside nitric oxide radical derivative, thereby improving its drug-likeness. At the same time, the anti-inflammatory activity of the gentiopicroside nitric oxide radical can further enhance the free radical scavenging ability and inflammatory pathway regulation of the sulfonylamidine compounds, forming a dual anti-inflammatory mechanism. It inhibits the excessive activation of inflammatory signaling pathways through the sulfonylamidine skeleton and scavenges excess ROS, NO and other inflammatory mediators through the gentiopicroside nitric oxide radical, thus synergistically enhancing anti-inflammatory activity. Therefore, the sulfonylamidine compounds provided in this invention can be used for the preparation of anti-inflammatory drugs. Specific Implementation Example 14

[0131] Validation of the in vitro ROS scavenging activity of sulfonylamidine compounds GPS-1~GPS-12.

[0132] The in vitro ROS scavenging activity was determined using the DPPH method. The test compound dissolved in DMSO was added to 200 µL of DPPH solution (final DMSO concentration 0.5%) to form the test reaction mixture, with a final compound concentration of 30 µM. In the control group, an equal volume of DMSO was added to 200 µL of DPPH solution to prepare a DPPH control mixture, and an equal volume of DMSO was added to 200 µL of methanol to prepare a blank control mixture. Celecoxib, a widely used clinical anti-inflammatory drug, was used as the positive control. All mixtures were incubated at room temperature in the dark for 30 minutes. The optical density (OD) of each well was then measured using a microplate reader to calculate the ROS scavenging activity. As shown in Table 2, the sulfonylamidine compounds GPS-1 to GPS-12 provided in this application all exhibited certain ROS scavenging activity at a concentration of 30 µM. Therefore, the sulfonylamidine compounds provided in this invention can be used to scavenge ROS to enhance their anti-inflammatory activity.

[0133] Table 2. In vitro ROS scavenging activity of sulfonylamidine compounds GPS-1~GPS-12 serial number Clearance rate (%) GPS-1 42.72±4.23 GPS-2 39.46±4.40 GPS-3 37.94±0.51 GPS-4 45.40±1.34 GPS-5 50.89±0.78 GPS-6 35.74±0.65 GPS-7 38.49±1.62 GPS-8 43.67±4.56 GPS-9 39.24±1.14 GPS-10 46.60±0.41 GPS-11 43.38±1.62 GPS-12 51.45±1.11 Celecoxib <10 Specific Implementation Example 15:

[0135] A pharmaceutical composition for treating and / or improving inflammation-related diseases, comprising a sulfonamide compound GPS-5 and pharmaceutically acceptable excipients, wherein the sulfonamide compound GPS-5 comprises 0.1 to 10% by mass in the pharmaceutical composition. Specific Implementation Example 16:

[0137] A pharmaceutical composition for treating and / or improving inflammation-related diseases is prepared by mixing sulfonylamidine compound GPS-5 and sulfonylamidine compound GPS-12 in a mass ratio of 1:1 to 2, adding at least one filler selected from microcrystalline cellulose, lactose, and mannitol, a binder selected from hydroxypropyl methylcellulose and povidone (PVP-K30), at least one disintegrant selected from cross-linked povidone and sodium carboxymethyl starch, and magnesium stearate.

[0138] The above are merely preferred embodiments of the present invention and do not limit the scope of the patent. All equivalent changes and modifications made within the scope of the present invention should still fall within the scope of the present invention.

Claims

1. Use of sulfonylamidine compounds of Formula I or their pharmaceutical salts in the preparation of medicaments for treating diseases or conditions selected from those caused by aging or inflammation: The disease or condition described is selected from any one of the following: skin inflammation, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, thrombophlebitis, systemic juvenile idiopathic arthritis, neuroinflammation, viral hepatitis, alcoholic hepatitis, fatty liver disease, gingivitis, periodontitis, myocarditis, cystitis, prostatitis, and skin aging. ； Formula I; in, n is any natural number independently selected from 0 to 10; R1 is independently selected from ethyl, propyl, phenyl, p-tolyl, p-chlorophenyl, p-fluorophenyl, o-bromophenyl, o-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, p-methoxyphenyl, and p-trifluoromethylphenyl. R2 is independently selected from any one of the structures shown in A-1, A-2, A-3, and A-4. X is independently selected from ether bonds and imine bonds.

2. The use of the sulfonylamidine compound or its pharmaceutically acceptable salt as described in claim 1, characterized in that, The compounds are selected from GPS-1 to GPS-12: 。 3. A pharmaceutical composition for treating and / or improving inflammation-related diseases, characterized in that, The compound comprises any one of the sulfonylamidine compounds of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, pharmaceutically acceptable carrier, and pharmaceutical excipients thereof.

4. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition is any one of the following forms: capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, and patches.

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