Use of a series of tri-substituted acridine derivatives in the preparation of anti-inflammatory drugs
Patent Information
- Application Number
- CN202611211587.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-08-11
- Publication Date
- 2026-09-25
AI Technical Summary
然而，传统吖啶化合物主要应用于抗肿瘤领域，且存在脂溶性过强、靶向性差、毒性较高等缺点，限制了其在疾病治疗，尤其是抗炎治疗中的广泛应用
1）本发明通过在吖啶骨架上引入不同的苯胺基团和不同的含氮杂环侧链，显著改善了化合物的理化性质与生物活性，含氮杂环侧链能够提高分子的水溶性和离子结合能力，从而增强在生理环境中的稳定性与生物利用度；而不同的苯胺基团和含氮杂环增强分子与靶蛋白（如NF-κB、MAPK信号通路相关酶）的相互作用，发挥抗炎信号调节作用；
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Figure CN122805650A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of acridine derivatives, and more particularly to the application of a trisubstituted acridine series derivative in the preparation of anti-inflammatory drugs. Background Technology
[0002] Inflammation is a defensive response of the body to external stimuli or endogenous damage. However, excessive or persistent inflammation often leads to tissue damage, which in turn induces various serious diseases, such as acute lung injury (ALI), sepsis, and ulcerative colitis (UC). These diseases not only have high morbidity but also high mortality rates. Currently, commonly used anti-inflammatory drugs in clinical practice, such as glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs), can temporarily relieve symptoms, but they suffer from problems such as strong drug resistance and significant side effects. There is an urgent need to develop novel, highly effective, and low-toxicity anti-inflammatory candidate compounds.
[0003] Acridine compounds are a class of heterocyclic compounds with diverse biological activities, particularly exhibiting significant activity in antitumor, antibacterial, and anti-inflammatory fields. Their planar conjugated tricyclic skeleton structure enables them to effectively interact with DNA, enzymes, and inflammation-related signaling molecules. However, traditional acridine compounds are mainly used in the antitumor field, and their high lipophilicity, poor targeting, and high toxicity limit their widespread application in disease treatment, especially in anti-inflammatory therapy. Therefore, introducing hydrophilic and anti-inflammatory substituents through structural modification has become a key strategy for optimizing the pharmacological properties of acridine molecules.
[0004] Therefore, it is of great significance to explore the application of trisubstituted acridine derivatives in the preparation of anti-inflammatory drugs. Summary of the Invention
[0005] The purpose of this invention is to provide an application of trisubstituted acridine derivatives in the preparation of anti-inflammatory drugs, thereby solving the above-mentioned technical problems.
[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides the application of trisubstituted acridine derivatives in the preparation of anti-inflammatory drugs, wherein the trisubstituted acridine derivatives include: N,N'-(9-((4-(dimethylamino)phenyl)amino)acridin-3,6-diyl)dibutyramide, its structural formula is: ; N 9 -(4-(dimethylamino)phenyl)acridin-3,6,9-triamine, its structural formula is: ; N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)bis(3-piperidinylpropionamide) has the following structural formula: .
[0007] Furthermore, the indications for the anti-inflammatory drug include acute lung injury, sepsis, and ulcerative colitis.
[0008] Furthermore, the dosage forms of the anti-inflammatory drugs include injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents, or nano-formulations.
[0009] The beneficial effects of this invention are: 1) This invention significantly improves the physicochemical properties and biological activity of the compound by introducing different aniline groups and different nitrogen-containing heterocyclic side chains onto the acridine skeleton. The nitrogen-containing heterocyclic side chains can improve the water solubility and ion binding capacity of the molecule, thereby enhancing its stability and bioavailability in the physiological environment; while different aniline groups and nitrogen-containing heterocycles enhance the interaction between the molecule and target proteins (such as NF-κB and MAPK signaling pathway-related enzymes), thereby playing an anti-inflammatory signaling regulatory role. 2) The trisubstituted acridine derivatives prepared in this invention can effectively inhibit the transcription and expression of pro-inflammatory factors (TNF-α, IL-6, IL-1β) mRNA in animal models of acute lung injury, sepsis and ulcerative colitis, effectively reduce their secretion, improve tissue damage and oxidative stress levels, and exhibit significant anti-inflammatory and tissue protective effects, with broad-spectrum anti-inflammatory activity. Attached Figure Description
[0010] Figure 1 The N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)dibutyramide prepared in Example 1 1 HNMR nuclear magnetic resonance spectrum; Figure 2 The N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)dibutyramide prepared in Example 1 13 C10 NMR spectrum; Figure 3 N prepared in Example 2 9 -(4-(dimethylamino)phenyl)acridin-3,6,9-triamine 1 HNMR nuclear magnetic resonance spectrum; Figure 4 N prepared in Example 2 9 -(4-(dimethylamino)phenyl)acridin-3,6,9-triamine 13 C10 NMR spectrum; Figure 5 The N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)bis(3-piperidinylpropionamide) prepared in Example 3 1 HNMR nuclear magnetic resonance spectrum; Figure 6 The N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)bis(3-piperidinylpropionamide) prepared in Example 3 13 C10 NMR spectrum. Detailed Implementation
[0011] This invention provides the application of trisubstituted acridine derivatives in the preparation of anti-inflammatory drugs, wherein the trisubstituted acridine derivatives include: N,N'-(9-((4-(dimethylamino)phenyl)amino)acridin-3,6-diyl)dibutyramide, its structural formula is: ; N 9 -(4-(dimethylamino)phenyl)acridin-3,6,9-triamine, its structural formula is: ; N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)bis(3-piperidinylpropionamide) has the following structural formula: .
[0012] In this invention, the indications for the anti-inflammatory drug include acute lung injury, sepsis, and ulcerative colitis.
[0013] In this invention, the dosage forms of the anti-inflammatory drugs include injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents, or nano-formulations.
[0014] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.
[0015] Example 1
[0016] 116.6 mmol of 2-chloro-4-aminobenzoic acid and 30 mL of acetic anhydride were mixed and stirred at 800 rpm at 100 °C for the first condensation reaction. After 30 min, the reaction was completed, and a clear solution was obtained. 90 mL of dichloromethane was added to the clear solution to precipitate the product, which was then filtered through a sintered glass funnel to obtain a solid product. The solid product was washed three times with dichloromethane to obtain the condensation intermediate: 4-(acetamido)-2-chlorobenzoic acid. The condensation intermediate was a white solid with a mass of 17.2 g and a yield of 69.1%. 2.34 mmol anhydrous potassium carbonate, 0.46 mmol copper powder, 0.43 mmol cuprous oxide, 4.68 mmol condensation intermediate, 5.15 mmol m-aminoacetanilide, and 8 mL ethylene glycol ethyl ether were mixed and subjected to a Ullmann reaction at 135 °C and 500 rpm with stirring. After 5 h, the reaction was completed, and the reaction mixture was obtained. The reaction mixture was poured into 30 mL of distilled water and filtered through a diatomaceous earth filter to obtain the filtrate. Hydrochloric acid (HCl to water volume ratio of 3:1) was added to the filtrate for acidification until the pH of the filtrate reached 2.5. The acidification was stopped, and the mixture was filtered again to obtain the crude product. The crude product was dried at 50 °C for 24 h to obtain the benzoic acid intermediate: 4-(acetamido)-2-(3-(acetamido)phenylamino)benzoic acid. The benzoic acid intermediate was a gray solid with a mass of 420 mg and a yield of 27.4%. 12 mL of 96% sulfuric acid was added dropwise to 15.3 mmol of benzoic acid intermediate at a rate of 1 drop / s. The mixture was stirred at 500 rpm at 100 °C to carry out the cyclization reaction. After 2 h, the reaction was completed and cooled to room temperature to obtain a reaction mixture. The reaction mixture was poured into 100 mL of ice water at 0 °C to obtain a crude mixture. The pH of the crude mixture was adjusted to 12.5 with saturated sodium hydroxide solution. The mixture was then filtered through a sintered glass funnel to obtain a filter residue. The filter residue was dried at 45 °C for 24 h to obtain acridinone intermediate 1: 3,6-diamino-9(10H)-acridone. Acridinone intermediate 1 was a yellow-green solid and did not require further purification. It was directly used in the next reaction step. 1.33 mmol of acridinone intermediate 1 was placed in a 100 mL round-bottom flask, and 10 mL of butyric anhydride was added. The second condensation reaction was carried out at 100 °C and stirred at 500 rpm. After 2 h, the reaction was completed, and a reaction mixture was obtained. The pH of the reaction mixture was adjusted to 12.5 using a 40% sodium hydroxide solution. The mixture was then filtered through a sintered glass funnel to obtain the filter residue. The filter residue was dried at 50 °C for 24 h to obtain acridinone intermediate 2: 3,6-bis(butyrylamino)-9(10H)-acridone. Acridinone intermediate 2 was a gray solid and did not require further purification. It was directly used in the next reaction step. Add 20 mL of phosphorus oxychloride to 13.7 mmol of acridinone intermediate 2, and carry out an electrophilic substitution reaction by stirring at 500 rpm at 70 °C. After the reaction is completed in 1.5 h, cool to room temperature to obtain a reaction mixture. Place the reaction mixture in a rotary evaporator and distill under reduced pressure at 55 °C and 0.1 MPa for 10 min. Pour the product from the reduced pressure distillation into 100 mL of ice water at 0 °C to obtain a crude product. Adjust the pH of the crude product to 12.5 with saturated sodium hydroxide solution to obtain a mixed solution. Extract the mixed solution with dichloromethane and methanol at a volume ratio of 10:1 three times to obtain an organic layer. Dry the organic layer with anhydrous magnesium sulfate and place it in a rotary evaporator for reduced pressure distillation at 55 °C and 0.1 MPa for 15 min. The product obtained from vacuum distillation was subjected to silica gel column chromatography using dichloromethane and methanol at a volume ratio of 30:1 (dropping rate of 5 drops / s) to obtain an acridine intermediate: 3,6-bis(butyrylamino)-9-chloroacridine. The acridine intermediate was a bright yellow solid with a mass of 1.6 g and a yield of 30.5%. 2.61 mmol acridine intermediate, 10.42 mmol N,N-dimethyl-p-phenylenediamine, and 12 mL phenol were mixed and stirred at 500 rpm at 100 °C for a nucleophilic substitution reaction. After 2 h, the reaction was completed, and the reaction mixture was poured into 100 mL of distilled water. The pH of the reaction mixture was adjusted to 12.5 with saturated sodium hydroxide solution. Then, the mixture was extracted three times with a 1:1 volume ratio of dichloromethane and saturated sodium chloride solution to obtain an organic layer. The organic layer was dried with anhydrous magnesium sulfate and then placed in a rotary evaporator for distillation at 55 °C and 0.1 MPa under reduced pressure for 15 min. The product obtained by vacuum distillation was subjected to silica gel column chromatography with dichloromethane and methanol in a volume ratio of 20:1 (dropping rate of the product was 5 drops / s) to obtain the trisubstituted acridine derivative C1: N,N'-(9-((4-(dimethylamino)phenyl)amino)acridin-3,6-diyl)dibutyramide, which was a reddish-brown solid with a yield of 60.46%.
[0017] Example 2
[0018] 10 mL of 96% sulfuric acid was added dropwise to 1.04 mmol of the trisubstituted acridine derivative C1 at a rate of 1 drop / s. The mixture was stirred at 500 rpm at 100 °C for 0.5 h to carry out hydrolysis. After the reaction was completed, the mixture was cooled to room temperature to obtain a reaction mixture. The reaction mixture was poured into 50 mL of ice water at 0 °C to obtain a crude product. The pH of the crude product was adjusted to 12.5 with saturated sodium hydroxide solution, and then filtered through a sintered glass funnel to obtain a filter residue. The filter residue was dried at 45 °C for 24 h to obtain the trisubstituted acridine derivative C17:N. 9-(4-(dimethylamino)phenyl)acridin-3,6,9-triamine, a reddish-brown solid, yield: 70.41%.
[0019] Example 3
[0020] 0.72 mmol of the trisubstituted acridine derivative C17 and 1 mL of triethylamine were mixed, followed by the sequential addition of 4 mL of N,N-dimethylformamide and 3.64 mmol of 3-chloropropionyl chloride. The mixture was stirred at 500 rpm at 60 °C for the first nucleophilic addition reaction, which was completed after 2 h, yielding a reaction mixture. Two drops of distilled water were added to the reaction mixture, and the mixture was placed in a rotary evaporator and distilled under reduced pressure at 65 °C and 0.1 MPa for 25 min. The product was extracted three times with a 1:1 volume ratio of dichloromethane and saturated sodium chloride solution to obtain an organic layer. The organic layer was dried with anhydrous magnesium sulfate and then distilled under reduced pressure at 55 °C and 0.1 MPa for 15 min in a rotary evaporator. The product obtained by vacuum distillation was subjected to silica gel column chromatography with dichloromethane and methanol in a volume ratio of 20:1 (dropping rate of 5 drops / s) to obtain a trisubstituted acridine intermediate 2a: N,N'-(9-(4-(dimethylamino)phenylamino)acridin-3,6-diyl)bis(3-chloropropionamide), which was a reddish-brown solid. 2a was not further purified and was directly used in the next reaction.
[0021] 0.34 mmol of trisubstituted acridine intermediate 2a, 0.17 mmol of potassium iodide, and 0.17 mmol of potassium carbonate were mixed, and then 15 mL of anhydrous ethanol and 1.72 mmol of morpholine ring were added sequentially. The mixture was stirred at 50 rpm at 90 °C for a second nucleophilic addition reaction. After 2 h, the reaction was completed, and a reaction mixture was obtained. The reaction mixture was added dropwise to 2 drops of distilled water and placed in a rotary evaporator. The mixture was distilled under reduced pressure at 50 °C and 0.1 MPa for 25 min. The product of the reduced pressure distillation was extracted three times with a 1:1 volume ratio of dichloromethane and saturated sodium chloride solution to obtain an organic layer. The organic layer was dried with anhydrous magnesium sulfate and then placed in a rotary evaporator for reduced pressure distillation at 50 °C and 0.1 MPa for 15 min. The product obtained by vacuum distillation was subjected to silica gel column chromatography with dichloromethane and methanol in a volume ratio of 20:1 (dropping rate of 5 drops / s) to obtain a trisubstituted acridine derivative C27: N,N'-(9-((4-(dimethylamino)phenyl)amino)acridin-3,6-diyl)bis(3-piperidinylpropionamide), which was a reddish-brown solid with a yield of 24.75%.
[0022] The trisubstituted acridine series derivative C1 prepared in Example 1 was characterized by nuclear magnetic resonance. Figure 1 The trisubstituted acridine derivative C1 prepared in Example 1 1 HNMR nuclear magnetic resonance spectrum1 H NMR is: 1 H NMR (400 MHz, DMSO-d6) δ10.95 (s, 1H), 10.81 (s, 2H), 8.47 (d, J = 2.1 Hz, 2H), 8.07 (d, J = 9.4 Hz,2H), 7.39 – 7.27 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H),2.97 (s, 6H), 2.42 (t, J = 7.4 Hz, 4H), 1.65 (h, J = 7.4 Hz, 4H), 0.94 (t, J= 7.4 Hz, 6H).; Figure 2 The trisubstituted acridine derivative prepared in Example 1 13 C10 NMR spectrum 13 CNMR is: 13 C NMR (101 MHz, Methanol-d4) δ 163.84, 143.04, 140.67, 136.44, 134.22, 125.08, 118.10, 115.60, 107.56, 105.29, 103.51, 99.95, 45.93, 45.59, 31.65, 25.17, 17.26. Figure 1 and Figure 2 It can be seen that the trisubstituted acridine derivative C1 prepared in Example 1 is N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)dibutyramide.
[0023] Figure 3 The trisubstituted acridine derivative C17 prepared in Example 2 1 HNMR nuclear magnetic resonance spectrum 1 H NMR (400MHz, Methanol-d4) δ 7.74 (d, J = 9.2 Hz, 2H), 7.17 – 7.10 (m, 2H), 6.85 (d, J= 8.5 Hz, 2H), 6.65 – 6.57 (m, 4H), 3.02 (s, 6H). Figure 4 The trisubstituted acridine derivative prepared in Example 2 13 C10 NMR spectrum 13C NMR (101 MHz, DMSO-d6) δ 151.45, 149.64, 146.16, 127.40, 121.07, 113.80, 111.60, 108.27, 97.77, 40.80. Figure 3 and Figure 4 It can be seen that the trisubstituted acridine derivative prepared in Example 2 has C17 as N. 9 -(4-(dimethylamino)phenyl)acridin-3,6,9-triamine.
[0024] Figure 5 The trisubstituted acridine derivative C27 prepared in Example 3 1 HNMR nuclear magnetic resonance spectrum 1 H NMR (400MHz, Methanol-d4) δ 8.38 (s, 2H), 8.00 (d, J = 9.6 Hz, 2H), 7.37 – 7.09 (m,4H), 6.85 (d, J = 8.6 Hz, 2H), 3.85 (t, J = 5.0 Hz, 8H), 3.19 (t, J = 7.2 Hz, 4H), 3.03 (s, 4H), 3.01 – 2.95 (m, 6H), 2.91 (t, J = 7.0 Hz, 4H), 2.89 – 2.79 (m, 3H). Figure 6 The trisubstituted acridine derivative prepared in Example 3 13 C10 NMR spectrum 13 C NMR (101MHz, Methanol-d4) δ 173.38, 151.66, 145.67, 143.21, 130.12, 127.83, 127.17,117.69, 114.19, 110.64, 106.38, 67.54, 55.09, 54.40, 40.65, 34.69. Depend on Figure 5 and Figure 6 It can be seen that the trisubstituted acridine derivative C27 prepared in Example 3 is N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)bis(3-piperidinylpropionamide).
[0025] The mouse macrophage line RAW264.7 (purchased from the Cell Bank of the Chinese Academy of Sciences) was cultured in DMEM medium containing 10% FBS. After seeding cells in 6-well plates, an inflammation model was established by stimulation with 1 μg / mL lipopolysaccharide (LPS, 1 mL / well) for 6 h. Simultaneously, the trisubstituted acridine derivatives (10.0 μM) prepared in Examples 1-5 were added for treatment for 24 h. The 0.01% DMSO group served as a negative control. After treatment, the effects of compounds C1, C17, and C27 on the expression and secretion of inflammatory factors IL-6 and TNF-α were detected by ELISA. The inhibitory effects of each compound on RAW264.7 cell viability under corresponding time and dosage conditions were evaluated by MTT assay. The experimental results are shown in Table 1.
[0026] Table 1. Inhibition rates of compound BRACO-19 and the trisubstituted acridine derivatives prepared in Examples 1-3 against IL-6 and TNF-α as determined by ELISA, and cytotoxicity at corresponding doses and treatment times as determined by MTT assay.
[0027] As can be seen from the above embodiments, the present invention provides an application of trisubstituted acridine derivatives in the preparation of anti-inflammatory drugs. The trisubstituted acridine derivatives of the present invention possess excellent anti-inflammatory activity, significantly reducing inflammatory responses caused by various factors; they can effectively treat acute lung injury and ulcerative colitis by alleviating the body's overall inflammatory response; and they have no obvious toxic side effects on the body.
[0028] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. The application of a trisubstituted acridine derivative in the preparation of anti-inflammatory drugs, characterized in that, The trisubstituted acridine series derivatives include: N,N'-(9-((4-(dimethylamino)phenyl)amino)acridin-3,6-diyl)dibutyramide, its structural formula is: ； N 9 -(4-(dimethylamino)phenyl)acridin-3,6,9-triamine, its structural formula is: ； N,N'-(9-((4-(dimethylamino)phenyl)amino)acrid-3,6-diyl)bis(3-piperidinylpropionamide) has the following structural formula: 。 2. The application of a trisubstituted acridine derivative according to claim 1 in the preparation of anti-inflammatory drugs, characterized in that, The indications for the anti-inflammatory drugs include acute lung injury, sepsis, and ulcerative colitis.
3. The application of a trisubstituted acridine derivative according to claim 1 or 2 in the preparation of anti-inflammatory drugs, characterized in that, The dosage forms of the anti-inflammatory drugs include injections, tablets, capsules, aerosols, suppositories, films, pellets, ointments, controlled-release agents, sustained-release agents, or nano-formulations.