Nitrogen nitidine sulfanilamide derivative as well as preparation method and application thereof

Abstract

The invention relates to a nitrogen-containing nitidine sulfanilamide derivative, and belongs to the technical field of organic synthesis. The provided nitrogen-containing nitidine sulfanilamide derivative has a structure as shown in a general formula A: # imgabs0 #, n is 4-6, and when R1 and R2 are hydrogen, R3 and R4 can be hydrogen, methyl, fluorine, chlorine, nitro and the like; when R1 and R2 are methyl, R3 is hydrogen, and R4 is methyl. According to the derivative, a sulfanilamide group and a specific substituent are introduced into a nitidine skeleton, the molecular structure is optimized, and the derivative has the preparation advantages of being wide in substrate applicability, easy and convenient to operate, few in by-product, convenient to separate and purify and the like. Experiments prove that the compound has a remarkable inhibiting effect on various tumor cells and is relatively low in toxicity to normal cells. The nitrogen-containing nitidine sulfanilamide derivative is mainly used for preparing medicines for treating tumors, particularly shows a good application prospect in treatment of tumors such as leukemia and cervical cancer, and provides a high-efficiency and low-toxicity candidate compound for research and development of novel anti-tumor medicines.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more particularly to a nitrogen-based nitidine sulfonamide derivative and a preparation method and application thereof. Background Art

[0002] Cancer, a genetic disease that poses a serious threat to human health, arises from oncogenic factors-induced changes in cellular genes, leading to uncontrolled growth regulation and abnormal proliferation. Current clinically used anticancer drugs generally suffer from bottlenecks such as insufficient target specificity, significant toxic side effects, and the development of drug resistance, which greatly limit treatment efficacy and patient quality of life. In contrast, traditional Chinese medicine (TCM) anti-tumor agents exhibit unique advantages with their multi-faceted targets, multi-effect synergistic mechanisms, and low drug resistance potential. Their multi-target nature is particularly critical in the pathological process of reversing tumor resistance.

[0003] Zanthoxylum nitidum, as a traditional medicinal plant, is rich in a variety of active ingredients such as alkaloids, flavonoids, steroids and esters, and has pharmacological effects such as anti-inflammatory, antioxidant, anti-cancer and cardiovascular protection. Among them, Nitidine Chloride (NC), a phenanthridine alkaloid isolated from this plant, has attracted much attention due to its broad-spectrum anti-tumor activity. However, natural nitidine analogues generally have pharmacokinetic defects such as poor water solubility and low oral bioavailability, which seriously restrict their practical application in drug development. Therefore, how to improve the water solubility of such compounds, enhance anti-tumor activity and reduce cytotoxicity through structural modification has become a key scientific issue that needs to be overcome urgently.

[0004] In recent years, the potential of sulfonamide groups in the development of anti-tumor drugs has gradually become prominent. Studies have shown that sulfonamide derivatives improve the water solubility of molecules by introducing polar groups, while exerting multi-target synergistic effects. Their inhibitory activity against human breast cancer, malignant melanoma, liver cancer and renal cancer cells is significantly better than that of sorafenib, and their toxicity to human breast cancer and cervical cancer cells is comparable to that of pentafluorouracil. Based on this, if we can design and synthesize nitrogen-containing nitidine sulfonamide derivatives with high water solubility, high anti-tumor activity and low cytotoxicity by reducing the strategy of reducing fat-soluble groups and introducing polar structures (such as sulfonamide groups) combined with the principle of active fragment splicing, it will not only enrich the molecular diversity of nitidine derivatives and provide candidate molecules for the discovery of new anti-tumor drugs, but also promote the in-depth development and clinical transformation of nitidine resources, which has important scientific significance and application value. Summary of the Invention

[0005] An object of the present invention is to solve at least the above problems and to provide at least the advantages which will be described hereinafter.

[0006] Another object of the present invention is to provide a nitrogen-based nitidine sulfonamide derivative, which has a novel structure, wide substrate applicability, simple operation, few by-products, is easy to separate and purify, can be applied to large-scale preparation, and has anti-tumor activity.

[0007] In order to achieve these objects and other advantages according to the present invention, a nitrogen-containing nitidine sulfonamide derivative is provided, wherein the derivative has a structure as shown in the general formula A:

[0008]

[0009] In formula A, n=4-6; when R1 and R2 are hydrogen, R3 and R4 are both hydrogen, or R3 is hydrogen and R4 is methyl, or R3 is fluorine and R4 is hydrogen, or R3 and R4 are both chlorine, or R3 is hydrogen and R4 is nitro;

[0010] When R1 and R2 are methyl, R3 is hydrogen and R4 is methyl.

[0011] Preferably, intermediate 7 or intermediate 10 is dissolved in dichloromethane, triethylamine is added at a temperature of 0°C-5°C, and after stirring, benzenesulfonyl chloride derivatives 11a-11f are added, wherein the molar ratio of intermediate 7:triethylamine:benzenesulfonyl chloride derivatives 11a-11f is 1:5-10:0.1-5, and the target compound: a nitrogen-containing nitidine sulfonamide derivative is synthesized by reaction;

[0012] The structural formula of intermediate 7 is shown below:

[0013]

[0014] The structural formula of intermediate 10 is shown below:

[0015]

[0016] The structural formulas of benzenesulfonyl chloride derivatives 11a-11f are shown below:

[0017]

[0018] wherein, when R1 and R2 are hydrogen, R3 and R4 are both hydrogen, or R3 is hydrogen and R4 is methyl, or R3 is fluorine and R4 is hydrogen, or R3 and R4 are both chlorine, or R3 is hydrogen and R4 is nitro;

[0019] When R1 and R2 are methyl, R3 is hydrogen and R4 is methyl.

[0020] Preferably, the preparation method of intermediate 7 is to dissolve 1 mmol of intermediate 6 in 5-20 mL of 20%-40% methylamine aqueous solution, stir to react, add NaOH solution, stir, then add sodium chloride, stir to react, and the synthesis product contains intermediate 7;

[0021] The structural formula of intermediate 6 is shown below:

[0022]

[0023] Preferably, the preparation method of intermediate 6 is to dissolve intermediate 5, phthalimide, potassium carbonate, and potassium iodide in acetonitrile at a molar ratio of 1:0.5-5:1-5:0.05-0.5, and heat and stir to react, and the reaction product contains intermediate 6;

[0024] The structural formula of intermediate 5 is shown below:

[0025]

[0026] Preferably, the preparation method of intermediate 5 is to dissolve intermediate 4 in DMF, add sodium hydride at a temperature of 0°C-5°C, stir, and then add 1,4-dibromobutane to react, and the reaction product contains intermediate 5; the molar ratio of intermediate 4: sodium hydride: 1,4-dibromobutane is 1:1-10:1-10;

[0027] The structural formula of intermediate 4 is shown below:

[0028]

[0029] Preferably, the intermediate 3 is dissolved in 1,4-dioxane, the volume of 1,4-dioxane being 1-10 times the mass of the intermediate 3, and a hydrochloric acid solution having an equal volume to that of the 1,4-dioxane is added, and the mixture is heated to react, and the product contains the intermediate 4;

[0030] The structural formula of intermediate 3 is shown below:

[0031]

[0032] Preferably, intermediate 2, palladium acetate, silver carbonate, and formylmethyltriphenylphosphine are dissolved in DMF, with the molar ratio of palladium acetate: silver carbonate: formylmethyltriphenylphosphine: intermediate 2 being 1:20-40:5-15:10-50, and the reaction is heated under reflux under N2 protection, and the reaction product contains intermediate 3;

[0033] The structural formula of intermediate 2 is shown below:

[0034]

[0035] Preferably, the intermediate 1 is dissolved in DMF, NaH is added at 0°C-5°C under nitrogen protection, chloromethyl ether is added, and the reaction is carried out at room temperature. The molar ratio of the intermediate 1, NaH, and chloromethyl ether is 1:5-10:1-5, and the reaction product contains the intermediate 2.

[0036] The structural formula of intermediate 1 is shown below:

[0037]

[0038] Preferably, 2-bromonicotinoic acid is dissolved in dichloromethane, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine are added at a temperature of 0°C-5°C. After stirring, 1-naphthylamine is added for reaction. The molar ratio of 4-dimethylaminopyridine:1-naphthylamine:2-bromonicotinoic acid:1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1:1-10:1-10:1-10, and the reaction product contains intermediate 1.

[0039] The invention relates to the use of nitrogen-containing nitidine sulfonamide derivatives in the preparation of anti-tumor drugs, wherein the tumors are leukemia, colon cancer, cervical cancer, liver cancer and lung cancer.

[0040] The present invention has at least the following beneficial effects:

[0041] First, the present invention designs and synthesizes nitrogen-containing nitrile sulfonamide derivatives, and forms a novel compound skeleton (general formula A) by introducing sulfonamide groups and specific substituents (such as fluorine, chlorine, nitro, etc.), providing a new structural template for the development of anti-tumor drugs.

[0042] Second, the present synthetic route uses 2-bromonicotinic acid and 1-naphthylamine as starting materials and proceeds through eight steps to produce the target compound. Each step operates under mild reaction conditions (e.g., room temperature or moderate temperature), requiring no complex equipment. The substrates offer broad applicability, allowing for the flexible synthesis of a variety of derivatives (e.g., 8a-8f) by adjusting the substituents (R1-R4) of the benzenesulfonyl chloride derivatives (11a-11f). Separation and purification are simple (column chromatography or filtration), making it suitable for large-scale production.

[0043] Third, the target compound prepared in this invention exhibited inhibitory effects against various tumor cell lines (leukemia HL-60, colon cancer SW480, cervical cancer Hela, liver cancer HepG2, and lung cancer H460), with particularly strong effects against leukemia cells. At a concentration of 40 μmol / L, compound 8d achieved an inhibition rate of 93.43±0.88% against leukemia cells (HL-60), significantly outperforming the positive control drug nitidine chloride (NC, 87.27±1.12%).

[0044] Fourth, by introducing a polar sulfonamide group, this invention improves the poor water solubility of traditional nitidine analogs, reduces the presence of lipid-soluble groups, and mitigates potential damage to normal cells. The synergistic effect of nitidine and the sulfonamide group expands the application of natural product derivatives in the anti-tumor field and promotes the in-depth development and innovative utilization of nitidine resources.

[0045] Other advantages, objectives and features of the present invention will be reflected in part from the following description and will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 The reaction mechanism of the nitrogen-containing nitidine analog skeleton;

[0047] Figure 2 To construct the skeleton of nitrogen-containing nitidine analogs;

[0048] Figure 3 This is the reaction formula for cyclization without a protecting group;

[0049] Figure 4 The reaction formula for the introduction of long-chain alkanes;

[0050] Figure 5 The possible reaction mechanism of intermediate 5 is shown in FIG. DETAILED DESCRIPTION

[0051] The present invention is described in further detail below so that those skilled in the art can implement the invention with reference to the description.

[0052] It should be understood that terms such as “having”, “including” and “comprising” used herein do not preclude the existence or addition of one or more other elements or combinations thereof.

[0053] It should be noted that the experimental methods described in the following embodiments are conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0054] A nitrogen-containing nitidine sulfonamide derivative having a structure as shown in general formula A:

[0055]

[0056] In formula A, n may be 4, 5 or 6; when R1 and R2 are hydrogen, R3 and R4 are both hydrogen, or R3 is hydrogen and R4 is methyl, or R3 is fluorine and R4 is hydrogen, or R3 and R4 are both chlorine, or R3 is hydrogen and R4 is nitro;

[0057] When R1 and R2 are methyl, R3 is hydrogen and R4 is methyl.

[0058] A method for preparing a nitrogen-containing nitidine sulfonamide derivative comprises the following steps:

[0059] Step 1: Using 2-bromonicotinoic acid and 1-naphthylamine as raw materials and dichloromethane as solvent, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP), synthesize the intermediate 1 shown in Formula 1; wherein the molar ratio of 4-dimethylaminopyridine (DMAP), 1-naphthylamine, 2-bromonicotinoic acid, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) is 1:5:5.5:6.5;

[0060]

[0061] Step 2: Dissolve the intermediate 1 in DMF, add NaH, and under nitrogen protection, add chloromethyl ether to react and synthesize the intermediate 2 shown in Formula 2; wherein the molar ratio of the intermediate 1, NaH, and chloromethyl ether is 1:4:3;

[0062]

[0063] Step 3: Dissolve intermediate 2, palladium acetate, silver carbonate, and formylmethyltriphenylphosphine in DMF, and react under N2 protection to synthesize intermediate 3 as shown in Formula 3; wherein the molar ratio of palladium acetate, silver carbonate, formylmethyltriphenylphosphine, and intermediate 2 is 1:30:12:20;

[0064]

[0065] Step 4: Dissolve intermediate 3 in 1,4-dioxane, add 1N hydrochloric acid solution, and react to synthesize intermediate 4 as shown in formula 4;

[0066]

[0067] Step 5: Dissolve the intermediate 4 in DMF, add sodium hydride and 1,4-dibromobutane, and react to synthesize the intermediate 5 shown in Formula 5; wherein the molar ratio of the intermediate 4, sodium hydride, and 1,4-dibromobutane is 1:4:4;

[0068]

[0069] Step 6: Dissolve intermediate 5, phthalimide, potassium carbonate, and potassium iodide in acetonitrile and react to synthesize intermediate 6 as shown in Formula 6; wherein the molar ratio of intermediate 5, phthalimide, potassium carbonate, and potassium iodide is 1:2:3:0.1;

[0070]

[0071] Step 7: Dissolve the intermediate 6 in a methylamine aqueous solution, add 20% NaOH, and then add sodium chloride to react to synthesize the intermediate 7 shown in Formula 7; wherein 1 mmol of the intermediate 6 is reacted with a 20%-40% methylamine aqueous solution;

[0072]

[0073] Step 8. Dissolve intermediate 7 or intermediate 10 in dichloromethane, add triethylamine and benzenesulfonyl chloride derivatives 11a-11f, and react to synthesize target compounds 8a-8f as shown in Formulas 8a-8f; wherein the molar ratio of intermediate 7 or intermediate 10, triethylamine, and benzenesulfonyl chloride derivatives 11a-11f is 1:7.2:1.

[0074]

[0075] wherein, when R1 and R2 are hydrogen, R3 and R4 are both hydrogen, or R3 is hydrogen and R4 is methyl, or R3 is fluorine and R4 is hydrogen, or R3 and R4 are both chlorine, or R3 is hydrogen and R4 is nitro;

[0076] When R1 and R2 are methyl, R3 is hydrogen and R4 is methyl.

[0077] <Example 1>

[0078] A method for preparing a nitrogen-containing nitidine sulfonamide derivative comprises the following steps:

[0079] Step 1: Take a 50 mL round-bottom flask, add 2-bromonicotinic acid (4.444 g, 22 mol) and dissolve it in 10 mL of dichloromethane. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (4.984 g, 26 mmol) and 4-dimethylaminopyridine (DMAP) (0.491 g, 4 mmol) at 0°C, stir for 5 min, then add 1-naphthylamine (2.864 g, 20 mmol), slowly return to room temperature, react overnight, and detect by TLC. After the reaction is completed, concentrate under reduced pressure to remove dichloromethane, add 200 mL of water for washing, add a small amount of ethyl acetate, and filter to obtain intermediate 1.

[0080] Step 2: Take a 50 mL round-bottom flask, add intermediate 1 (0.326 g, 1 mmol), dissolve it with 10 mL DMF, add NaH (60%, 0.160 g, 4 mmol) at 0 ° C, stir under N2 protection for 30 min, add chloromethyl ether (0.278 mL, 3 mmol) and slowly warm to room temperature, stir for 30 min, and monitor the reaction by TLC. After the reaction is completed, add 100 mL of water, extract three times with ethyl acetate (20 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, and separate and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain intermediate 2.

[0081] Step 3: Take a 50 mL round-bottom flask and add intermediate 2 (0.384 g, 1 mmol), palladium acetate (0.112 g, 0.05 mmol), silver carbonate (0.411 g, 1.5 mmol), and formylmethyltriphenylphosphine (0.183 g, 0.6 mmol) in sequence, dissolve with 15 mL DMF, and reflux at 140 ° C under N2 protection for 5 h. After the reaction is completed, cool to room temperature, filter out the insoluble matter, add a large amount of water to the filtrate, extract with ethyl acetate (30 mL × 3), and separate and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain intermediate 3.

[0082] Step 4: Take a 50 mL round-bottom flask, add intermediate 3 (0.304 g, 1 mmol), dissolve it with 5 mL of 1,4-dioxane, and then add 1N hydrochloric acid solution (5 mL). React at 80°C for 2 h. After the reaction is completed, filter and obtain intermediate 4.

[0083] Step 5. Take a 50 mL round-bottom flask, add intermediate 4 (0.246 g, 1 mmol) and dissolve it with 5 mL DMF. Add sodium hydride (60%, 0.160 g, 4 mmol) at 0°C and stir for 30 min. Then add 1,4-dibromobutane (0.484 mL, 4 mmol) and slowly warm to room temperature. Continue the reaction for 6 h and monitor by TLC. After the reaction is completed, add 50 mL of water and extract with ethyl acetate (20 mL × 3). Combine the organic layers, dry over anhydrous sodium sulfate, and separate and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain intermediate 5.

[0084] Step 6: Take a 50 mL round-bottom flask, add intermediate 5 (0.380 g, 1 mmol), phthalimide (0.294 g, 2 mmol), potassium carbonate (0.414 g, 3 mmol), potassium iodide (0.017 g, 0.1 mmol), dissolve with 10 mL of acetonitrile, stir and react at 80 ° C overnight, monitor by TLC, add 50 mL of water after the reaction, extract with ethyl acetate (20 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, and separate and purify by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain intermediate 6.

[0085] Step 7: Take a 50 mL round-bottom flask, add intermediate 6 (0.446 g, 1 mmol), dissolve it in methylamine aqueous solution (40%, 10 mmL), stir at room temperature and react overnight, monitor by TLC, add 20% NaOH (20 mL) after the reaction is completed, stir for 1.5 h, add sodium chloride (4 g), continue stirring for 5 min, extract with dichloromethane (20 mL × 3), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain intermediate 7, which is directly used in the next step without purification, with a yield of 50%-60%.

[0086] Step 8. Take a 50 mL round-bottom flask, add intermediate 7 (0.159 g, 0.5 mmol), dissolve it in 10 mL of dichloromethane, add triethylamine (0.500 mL, 3.6 mmol) at 0°C, stir for 10 min, then add benzenesulfonyl chloride derivative 11a (0.5 mmol), stir and react for 3 h, monitor by TLC, and concentrate under reduced pressure after completion of the reaction. Purify by column chromatography (petroleum ether:ethyl acetate = 4:1, 2:1) to obtain the target compound 8a.

[0087] The structural formula of benzenesulfonyl chloride derivative 11a is as follows:

[0088] Wherein, R1=H, R2=H, R3=H, R4=H;

[0089] The specific structural formula and characteristic characterization of compound 8a are shown below:

[0090]

[0091] 8a: white solid, yield: 49%, mp 177.4-178.2 °C; HRMS (ESI), m / z: calculated for C 26 H 23 N3O3S[M+H] + :458.158, FOUND: 458.1544. 1 H NMR (500 MHz, DMSO-d 6): δ9.23(dd,J=4.4,1.8Hz,1H,ArH),9.09–9.05(m,1H,ArH),8.87(d,J=8.7Hz,1H,ArH),8.59(dd,J=8. 1,1.8Hz,1H,ArH),8.09–8.05(m,1H,ArH),7.99(d,J=8.7Hz,1H,ArH),7.84–7.81(m,2H,ArH),7.78(d d,J=8.2,4.4Hz,1H,ArH),7.74(m,J=5.4,4.4Hz,3H,ArH),7.64–7.55(m,3H,-NH,ArH),4.69(t,J=6.3 Hz,2H,-CH2),2.91(t,J=7.1Hz,2H,-CH2),1.92(m,J=8.6,6.4Hz,2H,-CH2),1.73–1.64(m,2H,-CH2). 13 C NMR (126 MHz, DMSO-d 6 ): δ158.25,154.53,150.11,141.57,141.03,134.55,133.18,132.76,130.44,129.64,128.33,128 .26,126.94,126.90,125.44,124.73,123.42,121.06,119.50,114.52,66.34,42.88,26.44,26.05.

[0092] <Example 2>

[0093] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 1>, except that a benzenesulfonyl chloride derivative 11b (0.5 mmol) is added in step eight.

[0094] The structural formula of benzenesulfonyl chloride derivative 11a is as follows:

[0095] Wherein, R1=H, R2=H, R3=H, R4=CH3;

[0096] The target compound 8b was obtained, and its specific structural formula and characteristic characteristics are shown below:

[0097]

[0098] 8b: white solid, yield: 57%, mp 165.0-165.8 °C; HRMS (ESI), m / z: calculated for C 27 H 25 N3O3S[M+H]+ :472.1695, FOUND: 472.1702. 1 H NMR (500MHz, Chloroform-d): δ9.13 (mt, J=6.5, 3.2Hz, 2H, ArH), 8.92 (d, J=8.8Hz, 1H, ArH), 8.57 (dd, J=8.1, 1.8Hz,1H,ArH),7.98–7.94(m,1H,ArH),7.90(d,J=8.8Hz,1H,ArH),7.76–7.72(m,2H,ArH),7.67(m,J=7.0,5. 1Hz,2H,ArH),7.53(dd,J=8.1,4.4Hz,1H,ArH),7.23(d,J=8.0Hz,2H,ArH),4.74(dt,J=12.7,6.3Hz,3H,-NH, -CH2),3.10(q,J=6.9Hz,2H,-CH2),2.34(s,3H,-CH3),2.03–1.96(m,2H,-CH2),1.79(m,J=7.2Hz,2H,-CH2-). 13 C NMR (126MHz, CDCl3): δ157.90,153.32,150.64,143.47,141.94,136.83,134.62,132.94,130.72,129.73,127.8 2,127.57,127.08,126.19,125.16,124.68,121.99,120.98,119.65,114.73,65.85,43.09,26.76,26.07,21.49.

[0099] <Example 3>

[0100] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 1>, except that a benzenesulfonyl chloride derivative 11c (0.5 mmol) is added in step eight.

[0101] The structural formula of benzenesulfonyl chloride derivative 11c is as follows:

[0102] Among them, R1=CH3, R2=CH3, R3=H, R4=CH3;

[0103] The target compound 8c was obtained, and its specific structural formula and characteristic characteristics are shown below:

[0104]

[0105] 8c: white solid, yield: 61%, mp 162.1-162.5 °C; HRMS (ESI), m / z: calculated for C 29 H 29 N3O3S[M+H] + :500.2008,FOUND:500.2011. 1 H NMR (500MHz, Chloroform-d): δ9.14 (m, J=8.2, 5.5, 2.3Hz, 2H, ArH), 8.94 (d, J=8.8Hz, 1H, ArH), 8.58 (dd, J=8.1, 1.8Hz,1H,ArH),7.98–7.94(m,1H,ArH),7.92(d,J=8.8Hz,1H,ArH),7.70–7.64(m,2H,ArH),7.55(dd,J=8.2,4.4 Hz,1H,ArH),6.88(s,2H,ArH),4.73(t,J=6.3Hz,2H,-CH2),4.66(t,J=6.3Hz,1H,-NH),3.06(q,J=6.8Hz,2H,-CH 2),2.62(s,6H,-CH3-×2),2.21(s,3H,-CH3),1.98(m,J=8.7,6.2Hz,2H,-CH2),1.78(m,J=8.6,6.2Hz,2H,-CH2). 13 C NMR (126MHz, CDCl3): δ157.91,153.33,153.31,150.67,142.21,141.96,139.03,134.63,133.56,132.93,131.96,130.7 3,127.83,127.58,126.18,125.18,124.68,121.97,121.00,119.67,114.74,65.85,42.48,26.82,26.14,23.00,20.88.

[0106] <Example 4>

[0107] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 1>, except that a benzenesulfonyl chloride derivative 11d (0.5 mmol) is added in step eight.

[0108] The structural formula of benzenesulfonyl chloride derivative 11d is as follows:

[0109] Wherein, R1=H, R2=H, R3=F, R4=H;

[0110] The target compound 8d was obtained, and its specific structural formula and characteristic characteristics are shown below:

[0111]

[0112] 8d: white solid, yield: 65%, mp 162.7-163.3 °C; HRMS (ESI), m / z: calculated for C 26 H 22 FN3O3S[M+H] + :476.1444, FOUND: 476.1469. 1 H NMR (500MHz, DMSO-d6): δ9.23(dd,J=4.4,1.7Hz,1H,ArH),9.10–9.04(m,1H,ArH),8.87(d,J=8.8Hz,1H,ArH),8.5 9(dd,J=8.2,1.7Hz,1H,ArH),8.10–8.05(m,1H,ArH),7.99(d,J=8.8Hz,1H,ArH),7.88(t,J=5.7Hz,1H,ArH),7.77 (dd,J=8.2,4.4Hz,1H,ArH),7.75–7.72(m,2H,ArH),7.70–7.60(m,3H,NH,ArH),7.49(m,J=8.2,2.0Hz,1H,ArH),4 .69(t,J=6.3Hz,2H,-CH2),2.95(q,J=6.7Hz,2H,-CH2),1.93(m,J=6.4Hz,2H,-CH2),1.70(m,J=7.1Hz,2H,-CH2). 13 C NMR (126MHz, DMSO-d6): δ161.24,158.23,154.51,150.10,143.17,141.56,134.54,133.13,132.11,132.05,130.43,1 28.31,128.24,126.91,125.43,124.72,123.38,123.18,123.16,121.05,119.49,114.50,66.31,42.90,26.45,26.03.

[0113] <Example 5>

[0114] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 1>, except that a benzenesulfonyl chloride derivative 11e (0.5 mmol) is added in step eight.

[0115] The structural formula of benzenesulfonyl chloride derivative 11e is as follows:

[0116] Wherein, R1=H, R2=H, R3=Cl, R4=Cl;

[0117] The target compound 8e was obtained, and its specific structural formula and characteristic characteristics are shown below:

[0118]

[0119] 8e: white solid, yield: 63%, mp 159.7-160.5 °C; HRMS (ESI), m / z: calculated for C 26 H 21 C l2 N3O3S[M+H] + :526.0759,FOUND:526.0754. 1 H NMR (500MHz, DMSO-d6): δ9.24(dd,J=4.4,1.8Hz,1H,ArH),9.10–9.06(m,1H,ArH),8.88(d,J=8.8Hz,1H ,ArH),8.61(dd,J=8.2,1.8Hz,1H,ArH),8.10–8.05(m,1H,ArH),8.00(dd,J=5.5,3.4Hz,2H,ArH),7.96( m,J=5.4Hz,1H,ArH),7.85(d,J=8.4Hz,1H,ArH),7.80–7.76(m,2H,NH,ArH),7.75–7.72(m,2H,ArH),4.7 1(t,J=6.4Hz,2H,-CH2),2.96(m,J=6.7Hz,2H,-CH2),1.98–1.91(m,2H,-CH2),1.75–1.67(m,2H,-CH2). 13 C NMR (126MHz, DMSO): δ158.25,154.53,150.12,141.58,141.39,135.85,134.56,133.13,132.56,132.11,130.44,128 .73,128.32,128.25,127.11,126.92,125.45,124.74,123.41,121.07,119.52,114.51,66.33,42.88,26.44,26.01.

[0120] <Example 6>

[0121] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 1>, except that a benzenesulfonyl chloride derivative 11f (0.5 mmol) is added in step eight.

[0122] The structural formula of benzenesulfonyl chloride derivative 11f is as follows:

[0123] Wherein, R1=H, R2=H, R3=H, R4=NO2;

[0124] The target compound 8f was obtained, and its specific structural formula and characteristic characteristics are shown below:

[0125]

[0126] 8f: white solid, yield: 45%, mp 153.4-154.3 °C; HRMS (ESI), m / z: calculated for C 26 H 22 N4O5S[M+H] + :503.1389,FOUND:503.1389. 1 H NMR (500MHz, DMSO-d6): δ9.24(dd,J=4.4,1.8Hz,1H,ArH),9.09–9.05(m,1H,ArH),8.87(d,J=8 .8Hz,1H,ArH),8.61(dd,J=8.1,1.8Hz,1H,ArH),8.40–8.36(m,2H,ArH),8.14–8.10(m,1H,NH), 8.09–8.04(m,3H,ArH),8.00(d,J=8.8Hz,1H,ArH),7.77(dd,J=8.2,4.4Hz,1H,ArH),7.76–7.72 (m,2H,ArH),4.71(t,J=6.3Hz,2H,-CH2),2.98(m,J=6.5Hz,2H,-CH2),1.98–1.90(m,2H,-CH2),

[0127] 1.76–1.67 (m, 2H, -CH2). 13 C NMR (126MHz, DMSO): δ158.25,154.55,150.11,149.90,146.64,141.56,134.56,133.14,130.43,128.49,128 .34,128.26,126.93,125.46,125.04,124.71,123.41,121.07,119.51,114.50,66.29,42.90,26.48,26.01.

[0128] <Example 7>

[0129] A method for preparing a nitrogen-containing nitrile sulfonamide derivative adopts the preparation method of <Example 1>, except that intermediate 7 in step eight is replaced by intermediate 10 (0.173 g, 0.5 mmol) to obtain the target compound 13a.

[0130] The structural formula of the target compound 13a is shown below:

[0131]

[0132] 13a: white solid, yield: 51%, mp 133.8-134.2 °C; HRMS (ESI) m / z: calculated for C 28 H 27 N3O3S[M+H] + :486.1851,FOUND:486.1856. 1 H NMR (500MHz, CDCl3) δ9.21–9.14(m,2H,ArH),8.94(d,J=8.8Hz,1H,ArH),8.64(dd,J=8.1,1.8Hz,1H,ArH),7.98–7.9 5(m,1H,ArH),7.91(d,J=8.8Hz,1H,ArH),7.86(dd,J=7.8,1.7Hz,2H,ArH),7.67(pd,J=6.9,1.6Hz,2H,ArH),7.57(d d,J=8.1,4.4Hz,1H,ArH),7.55–7.51(m,1H,ArH),7.51–7.47(m,2H,ArH),4.75(t,J=6.5Hz,2H,CH2),4.63(t,J=6.2 Hz,1H,NH),2.99(q,J=6.8Hz,2H,CH2),1.94(p,J=6.8Hz,2H,CH2),1.58–1.51(m,4H,CH2×2),1.47–1.40(m,2H,CH2). 13 C NMR (126MHz, CDCl3) δ158.17,153.29,150.68,142.08,139.95,134.64,133.07,132.63,130.79,129.15,129.13,127.8 3,127.55,127.03,126.14,125.06,124.72,121.99,121.02,119.60,114.91,66.41,43.21,29.65,28.79,26.39,25.88.

[0133] <Example 8>

[0134] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 7>, except that 11a in step eight is replaced by 11b to obtain the target compound 13b.

[0135] The structural formula of target compound 13b is shown below:

[0136]

[0137] 13b: white solid, yield: 60%, mp 100.5-101.4 °C; HRMS (ESI) m / z: calculated for C 29 H 29 N3O3S[M+H] + :500.2008,FOUND:500.2010. 1 H NMR (500MHz, CDCl3) δ9.17(dd,J=7.7,1.9Hz,1H,ArH),9.15(dd,J=4.3,1.8Hz,1H,ArH),8.94(d,J=8.8Hz,1H,ArH),8.64( dd,J=8.1,1.8Hz,1H,ArH),7.99–7.94(m,1H,ArH),7.91(d,J=8.8Hz,1H,ArH),7.76–7.72(m,3H,ArH),7.67(pd,J=6.9,1. 6Hz,2H,ArH),7.56(dd,J=8.1,4.4Hz,1H,ArH),7.30(d,J=8.1Hz,1H,ArH),4.74(t,J=6.5Hz,2H,CH2),4.63(t,J=6.2Hz,1 H,NH),2.99–2.94(m,2H,CH2),2.38(s,3H,CH3),1.98–1.90(m,2H,CH2),1.59–1.50(m,4H,CH2×2),1.47–1.40(m,2H,CH2). 13C NMR (126MHz, CDCl3) δ158.17,153.28,150.67,143.39,142.08,136.93,134.63,133.08,130.78,129.75,129.72,127.82,127.5 5,127.29,127.10,126.14,125.05,124.73,122.00,121.01,119.60,114.91,66.43,43.17,29.62,28.80,26.41,25.89,21.52.

[0138] <Example 9>

[0139] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 7>, except that 11a in step eight is replaced by 11c to obtain the target compound 13c.

[0140] The structural formula of the target compound 13c is shown below:

[0141]

[0142] 13c: white solid, yield: 47%, mp 135.1-136.0 °C; HRMS (ESI) m / z: calculated for C 31 H 33 N3O3S[M+H] + :528.2321,FOUND:528.2329. 1 H NMR (500MHz, CDCl3) δ9.22–9.15(m,2H,ArH),8.96(d,J=8.8Hz,1H,ArH),8.66(dd,J=8.2,1.9Hz,1H,ArH),7.97( dd,J=7.6,1.7Hz,1H,ArH),7.92(d,J=8.8Hz,1H,ArH),7.71–7.65(m,2H,ArH),7.58(dd,J=8.1,4.4Hz,1H,ArH), 6.94(d,J=8.9Hz,3H,ArH),4.76(t,J=6.5Hz,2H,CH2),4.49(t,J=6.4Hz,1H,NH),2.93(q,J=6.8Hz,2H,CH2),2.6 3(s,6H,CH3×2),2.26(s,3H,CH3),1.98–1.91(m,2H,CH2),1.53(q,J=7.3Hz,4H,CH2×2),1.45–1.40(m,2H,CH2). 13C NMR (126MHz, CDCl3) δ158.18,153.30,150.71,142.17,142.09,139.06,134.65,133.62,133.06,131.97,130.79,127.84,1 27.55,126.14,125.08,124.72,121.99,121.03,119.63,114.92,66.42,42.53,29.63,28.80,26.48,25.88,23.00,20.92.

[0143] <Example 10>

[0144] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 7>, except that 11a in step eight is replaced by 11d to obtain the target compound 13d.

[0145] The structural formula of the target compound 13d is shown below:

[0146]

[0147] 13d: white solid, yield: 68%, mp 112.4-113.3 °C; HRMS (ESI) m / z: calculated for C 28 H 26 FN3O3S[M+H] + :504.1757,FOUND:504.1755. 1 H NMR (500MHz, CDCl3) δ9.17 (dd, J=7.6, 2.0Hz, 1H, ArH), 9.15 (dd, J=4.3, 1.8Hz, 1H, ArH), 8.94 (d, J=8.8Hz, 1H, ArH), 8.6 4(dd,J=8.1,1.9Hz,1H,ArH),7.96(dd,J=7.2,1.9Hz,1H,ArH),7.91(d,J=8.8Hz,1H,ArH),7.71–7.63(m,3H,ArH),7.59– 7.55(m,2H,ArH),7.47(td,J=8.1,5.3Hz,1H,ArH),7.23(dd,J=8.3,2.6Hz,1H,ArH),4.75(t,J=6.5Hz,2H,CH2),4.69(t ,J=6.2Hz,1H,NH),3.01(q,J=6.8Hz,2H,CH2),1.99–1.91(m,2H,CH2),1.59–1.52(m,4H,CH2×2),1.47–1.41(m,2H,CH2). 13C NMR (126MHz, CDCl3) δ161.46,158.16,153.29,150.68,142.12,142.07,134.64,133.06,130.99,130.93,130.78,127.83,12 7.55,126.14,125.06,124.71,122.78,122.75,121.99,121.01,119.61,114.90,66.38,43.28,29.67,28.79,26.37,25.88.

[0148] <Example 11>

[0149] A method for preparing a nitrogen-containing nitidine sulfonamide derivative adopts the preparation method of <Example 7>, except that 11a in step eight is replaced by 11e to obtain the target compound 13e.

[0150] The structural formula of the target compound 13e is shown below:

[0151]

[0152] 13e: white solid, yield: 58%, mp 108.5-109.1 °C; HRMS (ESI) m / z: calculated for C 28 H 25 C l2 N3O3S[M+H] + :554.1072,FOUND:554.1078. 1 H NMR (500MHz, CDCl3) δ9.20–9.14(m,2H,ArH),8.95(d,J=8.8Hz,1H,ArH),8.65(dd,J=8.2, 1.9Hz,1H,ArH),7.99–7.94(m,2H,ArH),7.91(d,J=8.9Hz,1H,ArH),7.71–7.64(m,3H,ArH) ,7.60–7.54(m,2H,ArH),4.77(t,J=6.5Hz,2H,CH2),4.66(t,J=6.2Hz,1H,NH),3.00(q,J= 6.8Hz,2H,CH2),2.02–1.93(m,2H,CH2),1.61–1.52(m,4H,CH2×2),1.48–1.42(m,2H,CH2). 13C NMR (126MHz, CDCl3) δ158.16,153.31,150.70,142.07,139.89,137.46,134.65,133.77,133.05,131.19,130.78,129.03,12 7.84,127.56,126.15,126.10,125.08,124.71,121.99,121.02,119.62,114.90,66.35,43.29,29.71,28.81,26.37,25.88.

[0153] <Example 12>

[0154] A method for preparing a nitrogen-containing nitrile sulfonamide derivative adopts the preparation method of <Example 7>, except that 11a in step eight is replaced by 11f to obtain the target compound 13f.

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

[0156]

[0157] 13f: white solid, yield 55, m.p. 129.5-130.4.°C; HRMS (ESI) m / z: calculated for C 28 H 26 N4O5S[M+H] + :531.1702,FOUND:531.1708. 1 H NMR(500MHz, CDCl3δ9.18–9.14(m,2H,ArH),8.94(d,J=8.8Hz,1H,ArH),8.64(dd,J=8.1,1.8Hz,1H, ArH),8.34–8.29(m,2H,ArH),8.03–7.98(m,2H,ArH),7.98–7.95(m,1H,ArH),7.91(d,J=8.8Hz,1H,A rH),7.67(tt,J=7.0,5.1Hz,2H,ArH),7.57(dd,J=8.2,4.4Hz,1H,ArH),4.79–4.74(m,3H,NH,CH2),3 .02(q,J=6.8Hz,2H,CH2),2.00–1.93(m,2H,CH2),1.60–1.52(m,4H,CH2×2),1.48–1.40(m,2H,CH2). 13C NMR (126MHz, CDCl3) δ158.14,153.34,153.32,150.69,150.00,145.98,142.04,134.65,133.02,130.75,128.23,127.8 7,127.58,126.15,125.11,124.67,124.39,122.00,121.02,119.62,114.88,66.29,43.36,29.79,28.78,26.33,25.83.

[0158] <Synthetic Comparative Test>

[0159] Experiment 1: In the synthesis of intermediate 1, the catalytic effects of various condensation reagents (BOP, TBTU, HATU, EDCI) were compared. That is, four common condensation reagents, namely, uronium cation condensation agent O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 2-(1H-benzo[d][1,2,3]triazo-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), phosphonium cation condensation agent Carter condensation agent (BOP), and carbodiimide condensation agent N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI), were used to explore the condensation reaction conditions. The results are shown in Table 3.

[0160] Table 3 Condensation results of different condensation reagents

[0161]

[0162]

[0163] Experiments show that combining EDCI with DMAP significantly increases yields to 65% (Table 3). The high water solubility of its byproducts simplifies purification steps. In contrast, other condensation agents yield yields below 50% due to difficulties in separating their byproducts or insufficient reactivity. Therefore, the EDCI / DMAP system is preferred for efficient and scalable amide condensation reactions.

[0164] In Experiment 2, in the synthesis of Intermediate 2, when the ratio of amide intermediate: chloromethyl ether: sodium hydride was 1:1:2, the raw material spots of the amide intermediate could not be completely eliminated, and increasing the amount of sodium hydride to four times still did not result in complete reaction. At a sodium hydride to amide intermediate feed ratio of 1:4, increasing the amount of chloromethyl ether to three times the amount completely eliminated the raw material spots. Furthermore, the reaction time should not be too long; the reaction is complete within 30 minutes. Excessive reaction time or the lack of N2 protection can lead to an increase in byproducts and a decrease in yield. This invention successfully suppresses byproduct formation by optimizing the feed ratio of chloromethyl ether (EOM) to sodium hydride (1:3:4) and reaction conditions (N2 protection, stepwise addition at 0°C), ensuring the high efficiency of amide N-protection. The reaction time is controlled within 30 minutes to avoid impurity accumulation caused by excessive reaction.

[0165] Experiment 3: Intermediate 2 was subjected to cyclization reaction at 100°C using palladium acetate as catalyst, silver carbonate as oxidant, and formylmethyltriphenylphosphine as ligand. The cyclization product 3 was successfully obtained through Heck reaction. The possible reaction mechanism is shown in Figure 1 The protecting group of the cyclization product 3 was removed under acidic conditions. The cyclization product 3 was dissolved in 1,4-dioxane and then added with 1N hydrochloric acid solution. The deprotection reaction was carried out at 80°C to successfully obtain the nitrogen-containing nitidine analog skeleton 4 ( Figure 2 ), and its structure was confirmed by X-ray single crystal diffraction. After successfully obtaining analog skeleton 4, attempts to reduce the lactam ring using a borane-tetrahydrofuran complex at room temperature failed. The synthesized skeleton may be relatively stable, and the mild reaction conditions may have prevented the reagents used from destroying the lactam ring of the analog skeleton, leading to the inability to proceed with the reaction.

[0166] Experiment 4: Using phenylacetyl chloride as the starting material, it reacted with methoxyamine hydrochloride to generate N-methoxyphenylacetamide, and then the amide was cyclized with 2-iodonaphthalene under the catalysis of palladium acetate, but failed to successfully obtain the ring-expanded nitidine skeleton; replacing 2-iodonaphthalene with the highly active 2-naphthaleneboronic acid was also unsuccessful, and increasing the temperature and changing the oxidant did not yield the desired product.

[0167] Experiment 5: Using 2-iodophenylacetic acid as the starting material, the amide intermediate 26 was successfully obtained under the action of a condensing agent. Then, the cyclization was directly carried out at 120°C using palladium acetate as a catalyst, silver acetate as an oxidant, sodium acetate as an additive, and N,N-dimethylacetamide as a solvent. The uncyclized structure 27 and the cyclized structure 28 after the removal of the iodine atom were obtained in the experiment, of which the uncyclized structure 27 was the main product ( Figure 3 ).

[0168] Experiment 6: Using long-chain alkanes as bridge chains and sodium hydride as an activating agent, intermediates 5 and 6 were obtained ( Figure 4), it was found that the long-chain alkane was connected to the O-terminal of the analogue skeleton, which was inconsistent with the results of the N-terminal product reported in the literature and the inventor's previous research. We speculate that its possible reaction mechanism is similar to the reaction pathway proposed by Nguyen et al., and intermediate 29 undergoes bromine atom elimination and intramolecular cyclization to obtain intermediate 30, and then under the attack of bromide anion, a mixture of intermediate 5 connected to the O-terminal and compound 29 connected to the N-terminal is obtained, with intermediate 5 as the main product ( Figure 5 ).

[0169] Experiment 7: Dibromoalkanes of varying lengths (1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, and 1,6-dibromohexane) were introduced into analogue skeleton 4. The experiments revealed that carbon chain length affected the yield of the compound to a certain extent, but excessively long carbon chains could generate more byproducts, reducing the yield. Bromoalkanes with carbon chains greater than four (1,4-dibromobutane and 1,6-dibromohexane) produced higher yields, ranging from 69% to 75%, with no significant difference in yield between the two. However, bridging with 1,6-dibromohexane produced more byproducts and was more difficult to purify. Conversely, shorter-chain alkanes, such as 1,2-dibromoethane and 1,3-dibromopropane, produced lower yields, less than 20%, making subsequent reactions difficult.

[0170] <Effect Test>

[0171] The MTS method was used to study the inhibitory rate of nitrogen-containing nitidine sulfonamide derivatives on leukemia cells (HL-60), human colon cancer cells (SW480), human cervical cancer cells (Hela), human liver cancer cells (HepG2), human lung cancer cells (H460) and human normal liver cells (LO2) at a concentration of 40 μmol / L.

[0172] (1) Cell recovery: Remove the frozen cells from the -80°C freezer, completely thaw in a 37°C water bath, disinfect with alcohol, and place in a clean bench. Transfer the cell suspension to a centrifuge tube containing 10% DMEM medium and centrifuge at 800 rpm for 5 minutes. After centrifugation, discard the supernatant and add 1 mL of 10% DMEM medium. Resuspend the cells in a suspension and transfer to a culture flask containing 10% DMEM medium. Mix well and culture in a 37°C, 5% CO2 incubator. Observe the cell status after 12 hours.

[0173] (2) Seeding: When the cells grow densely at the bottom of the flask (about 80%), remove the culture medium and wash 1-2 times with PBS buffer. Digest with 1 mL of 0.25% trypsin for 1-2 minutes, add 3 mL of culture medium to terminate the digestion, transfer to a centrifuge tube and centrifuge, discard the supernatant, and add 1 mL of culture medium to make a cell suspension. Pipette 10 μL of cell solution into a cell counting plate and count the cells under a microscope. The cells are seeded in a 96-well plate at a density of 4,000 to 15,000 cells per well, with 100 μL of cell solution per well.

[0174] (3) Administration: The target compound and the positive control drug NC were fully dissolved in DMSO and prepared into a sample concentration of 40 μmol / L. Three replicate wells were set up for each concentration, with 100 μL of the sample solution per well. The blank control group was treated with 100 μL of 1% DMEM medium. The cells were cultured for an additional 24 h.

[0175] (4) Detection: Prepare MTS solution (MTS:1% DMEM = 1:5) according to the number of wells. Remove the 96-well plate from the incubator after 24 hours of drug administration and incubation. Discard the old solution and add 120 μL of MTS solution to each well. Incubate at 37°C in the dark for 4 hours. Measure the absorbance at a wavelength of 492 nm.

[0176] (5) The formula for calculating the tumor cell growth inhibition rate is: cell growth inhibition rate = [1-(A1 / A0)] × 100%, where A1 is the absorbance value of the drug-treated group and A0 is the absorbance value of the blank control group.

[0177] After calculation, the inhibition rates of tetracyclic nitrogen-containing nitidine analogs on cells are shown in Table 1:

[0178] Table 1 Cell inhibition rate of tetracyclic nitrogen-containing nitidine analogs

[0179]

[0180] Results showed that nitidine-like sulfonamide derivatives 12d, 13a, and 13d exhibited potent inhibitory effects against HL-60, with inhibition rates ranging from 66.32%±4.46% to 93.43%±0.88%. 12d not only exhibited the highest inhibition rate against HL-60, at 93.43%±0.88%, but also exhibited an inhibition rate of 58.03%±1.92% against human cervical cancer cells, HeLa. Sulfonamides showed no significant toxicity against normal human hepatocytes, with inhibition rates below 50%.

[0181] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the description and implementation methods. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A nitrogen-containing nitidine sulfonamide derivative, characterized in that: The derivative has the structure of general formula A: In formula A, n is 4-6; when R1 and R2 are hydrogen, R3 and R4 are both hydrogen, or R3 is hydrogen and R4 is methyl, or R3 is fluorine and R4 is hydrogen, or R3 and R4 are both chlorine, or R3 is hydrogen and R4 is nitro; When R1 and R2 are methyl, R3 is hydrogen and R4 is methyl.

2. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 1, wherein: Dissolve intermediate 7 or intermediate 10 in dichloromethane, add triethylamine at 0°C-5°C, stir, and add benzenesulfonyl chloride derivatives 11a-11f. The molar ratio of intermediate 7:triethylamine:benzenesulfonyl chloride derivatives 11a-11f is 1:5-10:0.1-5. The target compound: nitrogen-containing nitidine sulfonamide derivative is synthesized by reaction. The structural formula of intermediate 7 is shown below: The structural formula of intermediate 10 is shown below: The structural formulas of benzenesulfonyl chloride derivatives 11a-11f are shown below: wherein, when R1 and R2 are hydrogen, R3 and R4 are both hydrogen, or R3 is hydrogen and R4 is methyl, or R3 is fluorine and R4 is hydrogen, or R3 and R4 are both chlorine, or R3 is hydrogen and R4 is nitro; When R1 and R2 are methyl, R3 is hydrogen and R4 is methyl.

3. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 2, wherein: The preparation method of intermediate 7 is as follows: 1 mmol of intermediate 6 is dissolved in 5-20 mL of 20%-40% methylamine aqueous solution, stirred for reaction, NaOH solution is added, stirred, and then sodium chloride is added, stirred for reaction, and the resultant product contains intermediate 7; The structural formula of intermediate 6 is shown below:

4. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 3, wherein: The preparation method of intermediate 6 is as follows: intermediate 5, phthalimide, potassium carbonate, and potassium iodide at a molar ratio of 1:0.5-5:1-5:0.05-0.5 are dissolved in acetonitrile, and the mixture is heated and stirred for reaction. The reaction product contains intermediate 6; The structural formula of intermediate 5 is shown below:

5. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 4, wherein: The preparation method of intermediate 5 is as follows: dissolving intermediate 4 in DMF, adding sodium hydride at a temperature of 0°C-5°C, stirring, and then adding 1,4-dibromobutane to react. The reaction product contains intermediate 5; the molar ratio of intermediate 4: sodium hydride: 1,4-dibromobutane is 1:1-10:1-10; The structural formula of intermediate 4 is shown below:

6. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 5, wherein: Dissolve intermediate 3 in 1,4-dioxane, the volume of 1,4-dioxane is 1-10 times the mass of intermediate 3, add hydrochloric acid solution with the same volume as 1,4-dioxane, and heat to react. The product contains intermediate 4; The structural formula of intermediate 3 is shown below:

7. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 6, wherein: Dissolve intermediate 2, palladium acetate, silver carbonate, and formylmethyltriphenylphosphine in DMF, with the molar ratio of palladium acetate: silver carbonate: formylmethyltriphenylphosphine: intermediate 2 being 1:20-40:5-15:10-50, and heat under reflux under N2 protection to react, to obtain a reaction product containing intermediate 3; The structural formula of intermediate 2 is shown below:

8. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 7, wherein: Dissolve intermediate 1 in DMF, add NaH at 0°C-5°C, add chloromethyl ether under nitrogen protection, and react at room temperature. The molar ratio of intermediate 1, NaH, and chloromethyl ether is 1:5-10:1-5. The reaction product contains intermediate 2. The structural formula of intermediate 1 is shown below:

9. The method for preparing the nitrogen-containing nitidine sulfonamide derivative according to claim 8, wherein: 2-Bromonicotinic acid is dissolved in dichloromethane, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine are added at 0°C-5°C. After stirring, 1-naphthylamine is added for reaction. The molar ratio of 4-dimethylaminopyridine:1-naphthylamine:2-bromonicotinic acid:1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1:1-10:1-10:1-10. The reaction product contains intermediate 1.

10. Use of the nitrogen-containing nitidine sulfonamide derivative according to claim 1 in the preparation of anti-tumor drugs, wherein the tumor is leukemia, colon cancer, cervical cancer, liver cancer, or lung cancer.

Images