Synthesis of 10-arylamino evodiamine derivative and anti-tumor application of 10-arylamino evodiamine derivative

Abstract

The invention belongs to the field of new drug design and synthesis, and relates to a synthesis method of a 10-arylamino evodiamine derivative, the 10-arylamino evodiamine derivative is shown as a formula 4, and R is selected from H, alkyl, alkoxy or fused aryl. The synthetic route comprises the following steps: (1) taking 10-hydroxyevodiamine (1) as a raw material, and reacting with trifluoromethanesulfonic anhydride (Tf2O) under proper conditions to obtain 10-trifluoromethanesulfonyloxy evodiamine 2; (2) reacting the compound 2 with an arylamine reagent 3 under proper conditions to obtain a 10-arylamine evodiamine derivative 4; wherein R of the arylamine reagent 3 in the step (2) is selected from H, alkyl, alkoxy or fused aryl. The 10-arylamino evodiamine derivative 4 synthesized by the invention shows good anti-cancer activity on liver cancer cells and neuroblastoma cells, and can be applied to preparation of corresponding anti-tumor drugs.

Description

Technical Field

[0001] This invention belongs to the field of new drug design and synthesis, specifically relating to the synthesis of a 10-arylaminoevodiamine derivative and its antitumor application. Background Technology

[0002] Quinazolinones are a class of nitrogen-containing heterocyclic compounds whose core structure consists of a fused benzene ring and a pyrimidinone ring. They possess a wide range of biological activities, including antitumor, antibacterial, and anti-inflammatory effects. In natural products, quinazolinones are mainly produced by microorganisms such as Streptomyces and Aspergillus, or through plant metabolism. Some natural product structures have been shown to possess good antitumor activity, including camptothecin and evodiamine. Given the excellent biological activity of quinazolinones, structural modification to further enhance their performance is of significant research value. Aromatic amines are an extremely important class of drug groups, and several aromatic amine drugs are currently used clinically, including classic drugs such as procaine hydrochloride and acetaminophen. Although transition metal catalysis plays an important role in organic synthesis and other fields, it also has some significant drawbacks, including high cost, difficulties in catalyst recovery and reuse, and limited substrate applicability. Therefore, developing other methods to introduce aryl coupling into the structure of quinazolinones is expected to yield novel derivatives with better activity and pharmacokinetic properties, opening new pathways for the development of antitumor and other drugs. Summary of the Invention

[0003] This invention addresses the shortcomings of existing technologies by researching and designing a series of novel 10-arylaminoevodiamine derivatives. Using the Buchwald-Hartwig reaction, an aromatic amino group was introduced at the C-10 position of the 10-trifluoromethanesulfonylevodiamine parent structure, resulting in the synthesis of a series of novel 10-arylaminoevodiamine derivatives. Activity studies have shown that these new derivatives exhibit good inhibitory effects on liver cancer and neuroblastoma cells.

[0004] One objective of this invention is to provide 10-arylaminoevodiamine derivatives, the structural formula of which is shown in Formula 4.

[0005]

[0006] Preferably, R is selected from H, alkyl, alkoxy, or fused aromatic groups.

[0007] Most preferably, R is selected from H, methyl, ethyl, methoxy, ethoxy, or fused phenyl.

[0008] The synthetic route for the above-mentioned 10-arylaminoevodiamine derivative series 4 is as follows:

[0009]

[0010] The steps include: (1) using 10-hydroxyevodiamine 1 as a raw material, reacting it with trifluoromethanesulfonic anhydride (Tf2O) under appropriate conditions to obtain 10-trifluoromethanesulfonyloxyevodiamine 2; (2) reacting compound 2 with aromatic amination reagent 3 under appropriate conditions to obtain 10-aromatic aminoevodiamine derivative 4; wherein, the R of the aromatic amination reagent 3 in step (2) is selected from H, alkyl, alkoxy or fused aromatic group.

[0011] Preferably, the appropriate conditions in step (1) are to use dichloromethane as the reaction solvent, add trifluoromethanesulfonic anhydride (Tf2O) dropwise under nitrogen protection at 0°C, and after the addition is complete, the reaction temperature is from 0°C to room temperature, and the reaction time is 1 to 2 hours.

[0012] Preferably, the appropriate conditions in step (2) are to use 1,4-dioxane as the reaction solvent, add carbonate as the base catalyst, add palladium catalyst, and organophosphorus ligand.

[0013] Preferably, the carbonate is selected from sodium carbonate, potassium carbonate, or cesium carbonate; the palladium catalyst is selected from Pd(dppf)Cl2 or Pd2(dba)3; and the organophosphorus ligand is selected from Xphos. More preferably, the carbonate is selected from potassium carbonate.

[0014] Preferably, the synthesis method according to claim 3 is characterized in that the reaction temperature of step (2) is 80℃~100℃ and the reaction time is 2~6 hours.

[0015] Furthermore, the present invention also provides the use of 10-arylaminoevodiamine derivatives in the preparation of antitumor drugs.

[0016] Preferably, the above-mentioned quinazolinone derivatives are used in the preparation of two anti-tumor drugs for liver cancer and neuroblastoma.

[0017] The beneficial effects of this invention are: the raw materials, reagents, and solvents used in the synthesis method are inexpensive and readily available; the synthesis method is mild and easy to implement. Studies have shown that the 10-arylaminoevodiamine derivative 4 synthesized in this invention has a good inhibitory effect on HepG2 liver cancer and SK-N-SH neuroblastoma tumor cells. Attached Figure Description

[0018] Figure 1 For compound 2 1 H NMR spectrum;

[0019] Figure 2 For compound 2 13 C10 NMR spectrum;

[0020] Figure 3 For compound 4a 1 H NMR spectrum;

[0021] Figure 4 For compound 4a 13 C10 NMR spectrum;

[0022] Figure 5 For compound 4b 1 H NMR spectrum;

[0023] Figure 6 For compound 4b 13 C10 NMR spectrum;

[0024] Figure 7 For compound 4c 1 H NMR spectrum;

[0025] Figure 8 For compound 4c 13 C10 NMR spectrum;

[0026] Figure 9 For compound 4d 1 H NMR spectrum;

[0027] Figure 10 For compound 4d 13 C10 NMR spectrum;

[0028] Figure 11 For compound 4e 1 H NMR spectrum;

[0029] Figure 12 For compound 4e 13 C10 NMR spectrum;

[0030] Figure 13 For compound 4f 1 H NMR spectrum;

[0031] Figure 14 For compound 4f 13 C10 NMR spectrum;

[0032] Figure 15 4g of compound 1 H NMR spectrum;

[0033] Figure 16 4g of compound 13 C10 NMR spectrum;

[0034] Figure 17 For compound 4h 1H NMR spectrum;

[0035] Figure 18 For compound 4h 13 C10 NMR spectrum;

[0036] Figure 19 For compound 4i 1 H NMR spectrum;

[0037] Figure 20 For compound 4i 13 C10 NMR spectrum;

[0038] Figure 21 For compound 4j 1 H NMR spectrum;

[0039] Figure 22 For compound 4j 13 C10 NMR spectrum. Detailed Implementation

[0040] The following detailed description illustrates the specific implementation method:

[0041] In the following examples, unless otherwise stated, the test methods are generally carried out under conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown are all commercially available.

[0042] Example 1. Preparation of 10-Aromatic amino evodiamine derivative 4

[0043] The preparation method of 10-arylaminoevodiamine derivative 4 includes the following steps: (1) using 10-hydroxyevodiamine (1) as a raw material, reacting it with trifluoromethanesulfonic anhydride (Tf2O) under appropriate conditions to obtain 10-trifluoromethanesulfonyloxyevodiamine 2; (2) reacting compound 2 with arylamine reagent 3 under appropriate conditions to obtain 10-arylaminoevodiamine derivative 4; the synthetic route is as follows:

[0044]

[0045] In step (2), the R of the aromatic amination reagent 3 is selected from H, alkyl, alkoxy or fused aromatic groups.

[0046] Step (1). Preparation of intermediate 2

[0047] 10-Hydroxyevodiamine 1 (319.00 mg, 1.00 mmol, 1.0 equivalent) was dissolved in 25 mL of dichloromethane under nitrogen protection, with the reaction solvent maintained at 0 °C. Pyridine (0.33 mL, 3.91 mmol, 4.0 equivalent) was then added dropwise to the reaction solution. After stirring for 10 minutes, trifluoromethanesulfonic anhydride (Tf₂O) (0.20 mL, 1.21 mmol, 1.2 equivalent) was slowly added, and the reaction was continued with stirring for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was directly purified by silica gel column chromatography (eluting solvent: petroleum ether:ethyl acetate = 4:1, v / v) to finally give a pale yellow solid product 2 (392.72 mg, 0.87 mmol, yield 87%).

[0048] Step (2). Preparation of 10-arylaminoevodiamine derivative 4

[0049] In the experiment of preparing 10-arylaminoevodiamine derivative 4, taking the preparation of derivative 4a as an example, we reacted 10-trifluoromethanesulfonate evodiamine intermediate 2 with unsubstituted aniline 3a to obtain compound 4a, and optimized the reaction conditions of this step. The results are shown in Table 1.

[0050]

[0051] Table 1. Optimization of conditions for the 10-position aromatic amination of evodiamine

[0052]

[0053]

[0054] Note: 1,4-dioxane is 1,4-dioxane, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, and Toluene is toluene; *: In this reaction, the amount of palladium catalyst is 10%-20% of the mass of starting compound 2 and the amount of ligand is 10%-20% of the mass of starting compound 2.

[0055] After obtaining intermediate 2, an aromatic amine was introduced to the 10-position of evodiamine via the Buchwald-Hartwig reaction. Inorganic bases such as K₂CO₃ or Cs₂CO₃ were chosen because organic bases would hydrolyze the trifluoromethanesulfonate group of the intermediate during the reaction. Using K₂CO₃ as the base, several catalysts, including Pd(PPh₃)₄, Pd(dppf)Cl₂, and Pd₂(dba)₃, were tried but none reacted, requiring the addition of a phosphine ligand to promote the reaction. The combination of catalyst and ligand is not fixed; when Pd(dppf)Cl₂ was combined with Xphos, the reaction was incomplete under K₂CO₃ or Cs₂CO₃ conditions. Using Pd₂(dba)₃ as the catalyst, the target product was obtained in 83% yield under K₂CO₃ conditions at 100°C for 4 hours. Under the same experimental conditions, the solvents were changed to DMF, DMSO, and toluene. When DMSO is used as a solvent, it destroys the starting material, resulting in no product formation. When DMF is used as a solvent, some of the starting material is lost, and the product formation is relatively small. When toluene is used as a solvent, the reaction is incomplete, leaving some starting material. Therefore, the optimal reaction conditions are: using aniline (1.5 equivalents) and K2CO3 (2 equivalents), under 10% Pd2(dba)3 and 20% Xphos catalysis, with 1,4-dioxane as the solvent, and reacting at 100°C for 4 hours.

[0056] Taking compound 4a as an example, the synthesis method is as follows:

[0057] Compound 2 (50 mg, 0.11 mmol), K2CO3 (31 mg, 0.22 mmol), Pd2(dba)3 (10 mg, 20% of the mass of compound 2) and Xphos (10 mg, 20% of the mass of compound 2) were weighed into a dry double-necked flask, purged with nitrogen, and dissolved in 5 mL of anhydrous 1,4-dioxane. Then, aniline (15 μL, 0.17 mmol) was added, and the reaction was carried out at 100 °C for 4 hours. The reaction was monitored by TLC. When the reaction was complete and no starting material was found, the reaction was stopped. 10 mL of aqueous solution was added to quench the reaction, and the mixture was extracted with CH2Cl2 (20 mL × 3). The CH2Cl2 extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed by vacuum distillation to obtain a crude black oily solid. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain pure product 4a (36 mg, 0.091 mmol, 83%), which was a brown solid.

[0058] When reacting with other anilines under optimal conditions, it was found that these reaction conditions only apply to aromatic amines substituted with electron-donating groups; aliphatic amines, heterocyclic aromatic amines, and aromatic amines substituted with electron-withdrawing groups do not react.

[0059]

[0060] Table 2. Preparation of 10-Aromatic Amine Evodiamine Series Derivatives 4

[0061]

[0062]

[0063] Following the synthetic method and process conditions of compound 4a above, compound 4a (brown solid, yield 83%) was prepared. TLC thin-layer chromatography was performed. f =0.27 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 167.7-168.9℃. 1 HNMR(400MHz,DMSO-d6)δ10.89(s,1H),7.76(d,J=8.4Hz,2H),7.44(t,J=7.9Hz,1H), 7.27(d,J=8.6Hz,1H),7.16(s,1H),7.10(t,J=7.8Hz,2H),6.99(d,J=8.4Hz,1H),6.9 0(t,J=8.1Hz,4H),6.63(t,J=7.4Hz,1H),6.08(s,1H),4.58(dd,J=12.8,5.4Hz,1H), 3.16(t,J=11.4Hz,1H),2.90(s,3H),2.83(d,J=11.7Hz,1H),2.67(d,J=15.1Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ164.87,149.02,146.68,135.40,134.06,133.04,131.83,129.51,128.44,127.02,120.48 ,119.24,118.14,117.68,117.46,114.74,112.69,111.51,109.13,70.46,41.59,36.91,19.90.HRMS-ESI(m / z):C 25 H 23 N4O[M+H] + The calculated value is 395.1867, and the measured value is 395.1863.

[0064]

[0065] Following the synthetic method and process conditions of compound 4a above, compound 4b (brown solid, yield 85%) was prepared. TLC thin-layer chromatography was performed. f =0.30 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 208.8-210.1℃. 1HNMR (400MHz, CDCl3) δ8.56 (s, 1H), 8.11 (d, J = 7.9Hz, 1H), 7.47 (t, J = 7.8Hz, 1H ),7.34(d,J=8.6Hz,1H),7.27(s,1H),7.17(d,J=7.7Hz,2H),7.15–7.08(m,2H) ,7.04(d,J=9.4Hz,3H),6.86–6.77(m,1H),5.86(s,1H),4.84(d,J=13.1Hz,1H) ,3.25(dt,J=13.9,7.8Hz,1H),2.86(d,J=7.1Hz,2H),2.53(s,3H),2.30(s,3H). 13 C NMR (100MHz, CDCl3) δ164.89,150.56,144.11,135.99,133.34,133.19,130.74,129.13,128.97,127.02,126.84,124.94,123 .80,123.34,121.96,119.67,118.90,114.83,113.14,112.10,110.83,68.95,39.74,37.16,20.16,17.90.HRMS-ESI(m / z):C 26 H 25 N4O[M+H] + The calculated value is 409.2023, and the measured value is 409.2022.

[0066]

[0067] Following the synthetic method and process conditions of compound 4a above, compound 4c (brown solid, yield 82%) was prepared. TLC thin-layer chromatography was performed. f =0.32 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 212.3-213.7℃. 1 HNMR(400MHz,DMSO-d6)δ10.90(s,1H),7.76(s,1H),7.44(s,1H),7.26(s,1H),7.18(s,1H),6.90(d,J=22.8Hz ,6H),6.68(s,2H),6.08(s,1H),4.58(s,1H),3.80(s,3H),3.28(s,1H),3.16(s,1H),2.89(s,3H),2.68(s,1H). 13C NMR(100MHz,DMSO-d6)δ164.78,149.10,147.95,135.95,135.14,133.97,133.19,131.72,128.45,126.98,121.13,120.54,11 9.44,118.42,118.28,117.60,112.79,112.52,111.54,111.22,110.00,70.38,55.87,41.49,36.90,19.94.HRMS-ESI(m / z):C 26 H 25 N4O2[M+H] + The calculated value is 425.1973, and the measured value is 425.1970.

[0068]

[0069] Following the synthetic method and process conditions of compound 4a above, compound 4d (brown solid, yield 86%) was prepared. TLC thin-layer chromatography was performed. f =0.33 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 206.1-207.8℃. 1 HNMR(400MHz,DMSO-d6)δ10.88(s,1H),7.76(dd,J=7.7,1.7Hz,1H),7.67(s,1H),7.44(t,J=7.7Hz, 1H),7.27(d,J=8.6Hz,1H),7.15(d,J=2.1Hz,1H),6.98(dd,J=12.1,8.0Hz,2H),6.94–6.87(m,2H),6 .72–6.67(m,2H),6.45(d,J=7.4Hz,1H),6.08(s,1H),4.59(dd,J=12.7,5.3Hz,1H),3.17(td,J=12. 3,4.7Hz,1H),2.90(s,3H),2.84(dt,J=11.2,4.7Hz,1H),2.67(dd,J=15.4,4.5Hz,1H),2.15(s,3H). 13C NMR(100MHz,DMSO-d6)δ164.83,149.04,146.75,138.52,135.49,134.02,133.04,131.81,129.34,128.45,127.03,120.48,11 9.29,119.01,117.84,117.47,115.42,112.64,111.98,111.49,109.32,70.46,41.56,36.93,21.78,19.91.HRMS-ESI(m / z):C 26 H 25 N4O[M+H] + The calculated value is 409.2023, and the measured value is 409.2020.

[0070]

[0071] Following the synthetic method and process conditions of compound 4a above, compound 4e (brown solid, yield 84%) was prepared. TLC thin-layer chromatography was performed. f =0.24 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 211.1-213.6℃). 1 HNMR (400MHz, CDCl3) δ8.48(s,1H),8.11(d,J=7.8Hz,1H),7.47(t,J=7.5Hz,1H),7.32( d,J=9.6Hz,2H),7.16(dd,J=14.3,6.7Hz,2H),7.13–7.09(m,2H),7.06(d,J=8.6Hz,1H) ,6.57–6.48(m,2H),6.38(d,J=8.2Hz,1H),5.86(s,1H),4.84(d,J=12.9Hz,1H),3.75(d ,J=1.3Hz,3H),3.24(dt,J=13.9,7.9Hz,1H),2.87(d,J=5.9Hz,2H),2.54–2.49(m,3H). 13 CNMR(100MHz, CDCl3)δ164.77,160.78,147.42,135.17,133.52,133.17,130.08,129.00,126.97,124.05,123.52,12 2.19,119.29,113.36,112.03,111.55,108.21,104.35,101.19,68.95,55.19,39.64,37.29,20.13.HRMS-ESI(m / z):C 26 H 25N4O2[M+H] + The calculated value is 425.1973, and the measured value is 425.1971.

[0072]

[0073] Following the synthetic method and process conditions of compound 4a above, compound 4f (brown solid, yield 88%) was prepared. TLC thin-layer chromatography was performed. f =0.33 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 159.7-160.3℃. 1 HNMR(400MHz, CDCl3)δ8.29(s,1H),8.11(dd,J=7.8,1.6Hz,1H),7.47(td,J=7.6, 1.6Hz,1H),7.34–7.27(m,2H),7.23–7.15(m,1H),7.12(d,J=8.0Hz,1H),7.08–6.9 9(m,3H),6.94–6.87(m,2H),5.87(d,J=1.5Hz,1H),5.59–5.55(m,1H),4.84(dt,J= 12.9,3.7Hz,1H),3.31–3.19(m,1H),2.91–2.83(m,2H),2.52(s,3H),2.28(s,3H). 13 C NMR (100MHz, CDCl3) δ164.79,150.59,143.07,136.43,133.14,133.03,129.87,129.77,129.08,129.00,128.93,126.96 ,124.05,123.60,122.28,118.19,116.37,113.21,112.05,109.63,68.78,39.64,37.23,20.59,20.12.HRMS-ESI(m / z):C 26 H 25 N4O[M+H] + The calculated value is 409.2023, and the measured value is 409.2021.

[0074]

[0075] Following the synthetic method and process conditions of compound 4a above, compound 4g (brown solid, yield 85%) was prepared. TLC thin-layer chromatography was performed. f =0.22 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 155.5-157.2℃. 1HNMR(400MHz,DMSO-d6)δ10.98–10.70(m,1H),7.76(s,1H),7.55–7.34(m,3H),7.21(s,2H),7.01(s,2H),6.85 (d,J=44.0Hz,4H),6.07(s,1H),4.58(s,1H),3.63(s,3H),3.14(s,1H),2.87(s,3H),2.65(s,1H),2.49(s,1H). 13 C NMR(100MHz,DMSO-d6)δ164.78,152.84,149.08,139.69,137.34,133.97,132.34,131.54,128.44,127.03,120.50,11 9.39,117.74,117.54,116.14,114.98,112.66,111.29,106.25,70.41,55.67,41.51,36.87,19.94.HRMS-ESI(m / z):C 26 H 25 N4O2[M+H] + The calculated value is 425.1973, and the measured value is 425.1972.

[0076]

[0077] Following the synthetic method and process conditions of compound 4a above, compound 4h (brown solid, yield 80%) was prepared. TLC thin-layer chromatography was performed. f =0.35 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 216.0-217.1℃. 1 HNMR (400MHz, CDCl3) δ8.41 (s, 1H), 8.11 (d, J = 7.8Hz, 1H), 7.47 (t, J = 7.7Hz, 1H), 7.33 (d, J = 10.3Hz, 2H), 7.17 (dd, J = 17.2, 9.8Hz, 2H), 7.12–7. 03(m,2H),6.59(s,2H),6.50(s,1H),5.87(s,1H),4.85(d,J=13.1Hz,1H ),3.25(dt,J=14.2,7.9Hz,1H),2.88(s,2H),2.52(s,3H),2.24(s,6H). 13C NMR (100MHz, CDCl3) δ164.83,150.59,145.93,139.05,135.72,133.35,133.15,129.09,128.99,126.98,123.98,123 .55,122.19,121.32,119.14,113.33,113.29,111.99,111.09,68.92,39.65,37.25,21.49,20.15.HRMS-ESI(m / z):C 27 H 26 N4ONa[M+Na] + The calculated value is 445.1999, and the measured value is 445.1995.

[0078]

[0079] Following the synthetic method and process conditions of compound 4a above, compound 4i (brown solid, yield 82%) was prepared. TLC thin-layer chromatography was performed. f =0.34 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 151.3-152.7℃. 1 HNMR (400MHz, CDCl3) δ8.35 (s, 1H), 8.11 (d, J = 8.0Hz, 1H), 7.47 (t, J = 7.7Hz, 1H), 7.31 (d, J = 9 .1Hz,2H),7.18(t,J=7.6Hz,1H),7.15–7.10(m,2H),7.09(s,1H),7.03(d,J=8.9Hz,1H),6.95 –6.90(m,2H),5.87(s,1H),5.63(s,1H),4.84(d,J=13.0Hz,1H),3.25(dt,J=13.7,7.8Hz,1H) ,2.87(d,J=7.6Hz,2H),2.85–2.79(m,1H),2.52(d,J=1.4Hz,3H),1.23(dd,J=7.0,1.3Hz,6H). 13 C NMR (100MHz, CDCl3) δ164.81,150.61,143.44,140.27,136.28,133.13,133.07,129.05,128.99,127.19,127.00,123.99 ,123.59,122.22,118.30,116.07,113.25,112.00,109.81,68.91,39.63,37.24,33.33,24.24,20.15.HRMS-ESI(m / z):C 28H 29 N4O[M+H] + The calculated value is 437.2336, and the measured value is 437.2335.

[0080]

[0081] Following the synthetic method and process conditions of compound 4a above, compound 4j (brown solid, yield 85%) was prepared. TLC thin-layer chromatography was performed. f =0.32 (eluent: petroleum ether: ethyl acetate = 2:1); Mp 229.5-230.8℃. 1 HNMR (400MHz, CDCl3) δ8.36(s,1H),8.11(d,J=7.8Hz,1H),8.06(d,J=7.4Hz,1H),7.85( d,J=7.3Hz,1H),7.48(dd,J=10.3,5.7Hz,3H),7.43(d,J=8.2Hz,1H),7.38–7.33(m,1H) ,7.30(d,J=6.7Hz,2H),7.19(t,J=7.5Hz,1H),7.11(t,J=9.2Hz,3H),6.06(s,1H),5.88 (s,1H),4.84(d,J=13.3Hz,1H),3.25(dt,J=13.9,7.7Hz,1H),2.86(s,2H),2.53(s,3H). 13 C NMR (100MHz, CDCl3) δ163.76,149.54,140.62,135.58,133.59,132.22,132.09,128.11,127.94,127.58,126.07,125.21,124.97,124.70, 124.28,122.95,122.53,121.17,119.95,119.48,117.60,112.24,111.07,110.12,109.57,67.87,38.57,36.22,19.09.HRMS-ESI(m / z):C 29 H 24 N4ONa[M+Na] + The calculated value is 467.1843, and the measured value is 467.1841.

[0082] Example 4.10 Solubility test of 4-arylaminoevodiamine series derivatives

[0083] The solubility of evodiamine, 10-hydroxyevodiamine, and 10-arylaminoevodiamine derivatives 4 were tested. The results showed that evodiamine and its derivatives are almost insoluble or insoluble in water (meaning that 1 g of solute cannot be completely dissolved in 10,000 ml of solvent); the solubility in chloroform is shown in Table 3.

[0084] Table 3. Solubility of Evodiaein and its derivatives

[0085]

[0086] Table 3 shows that the solubility of compounds with an aromatic amine introduced at the 10 position in chloroform is significantly improved compared to erythritol and 10-OH erythritol. Furthermore, the type of substituent on the aryl group also affects solubility: compounds with a methyl group exhibit the best solubility, while those with -OCH3,4-isopropyl,1-naphthyl substituents show lower solubility than those with methyl substituents.

[0087] Example 5.10 Antitumor Activity Test of 10-Aromatic Amine Evodiamine Series Derivative 4

[0088] Experimental Methods: Human hepatocellular carcinoma HepG2 cells and human neuroblastoma cells SK-N-SH were used. Tumor cells were cultured in DMEM medium containing 10% fetal bovine serum; dimethyl sulfoxide (DMSO) was used as the solvent. CCK-8 staining method for detecting antitumor activity: Cells in logarithmic growth phase were used for the experiment. Cells were digested, counted, and prepared into a cell suspension, seeded in 96-well plates (100 μL / well), and cultured at 37°C in a 5% CO2 incubator for 24 hours. Positive control groups (camptothecin and evodiamine), blank solvent control groups, and test drug groups were established. For the positive control group and test drug groups, each well was treated with a concentration of 50 μmol / L. Each sample was tested in 5 replicates. After culturing the plates in an incubator for 72 hours, cell morphology was observed under a microscope. 10 μL of CCK-8 solution was added to each well, and the cells were incubated for another 4 hours. The absorbance was measured at 450 nm, and the cell inhibition rate was calculated. Statistical analysis: Data analysis was performed using SPSS 22.0 software. The t-test was used for comparisons between groups, and p < 0.05 was considered statistically significant. All experiments were repeated three times. Detailed experimental results are shown in Table 4.

[0089] Table 4. Inhibition rate (%) of 10-arylaminoevodiamine derivatives on tumor cells

[0090]

[0091] Note* * Compared with the blank solvent control, p < 0.01.

[0092] As shown in Table 4, the 10-arylaminoevodiamine quinazolinone designed and synthesized in this invention exhibits excellent antitumor effects against both hepatocellular carcinoma and neuroblastoma cells. Furthermore, compounds 4a and 4d show good inhibitory effects on the proliferation of SK-N-SH tumor cells, while compounds 4a–4h show good activity against HepG2 tumor cells. The compounds obtained by substituting aniline show reduced activity against SK-N-SH, with only compounds 4a and 4d showing higher proliferation inhibition rates than the two positive controls. Compounds 4a–4h showed higher proliferation inhibition rates against HepG2 tumor cells than the positive controls. The relationship between structure and activity is: meta-substituent > para-substituent > ortho-substituent. Therefore, these novel derivatives can be used to prepare antitumor drugs, especially for the preparation of drugs against hepatocellular carcinoma and neuroblastoma cells.

[0093] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. 10-Aromatic amino evodiamine derivatives, characterized in that, The structural formula is shown in Equation 4. R is selected from H, alkyl, alkoxy or fused aromatic groups.

2. The 10-arylaminoevodiamine derivative according to claim 1, characterized in that, R is selected from H, methyl, ethyl, methoxy, ethoxy, and fused phenyl.

3. The method for synthesizing the 10-arylaminoevodiamine derivative according to claim 1 or 2, characterized in that, The synthetic route is as follows: The steps include: (1) using 10-hydroxyevodiamine 1 as a raw material, reacting it with trifluoromethanesulfonic anhydride under appropriate conditions to obtain 10-trifluoromethanesulfonyloxyevodiamine 2; (2) reacting compound 2 with aromatic amination reagent 3 under appropriate conditions to obtain 10-aromatic aminoevodiamine derivative 4.

4. The synthesis method according to claim 3, characterized in that: The appropriate conditions in step (1) are to use dichloromethane as the reaction solvent, add trifluoromethanesulfonic anhydride dropwise under nitrogen protection at 0°C, and after the addition is complete, the reaction temperature is reduced from 0°C to room temperature, and the reaction time is 1 to 2 hours.

5. The synthesis method according to claim 4, characterized in that: The appropriate conditions in step (2) are to use 1,4-dioxane as the reaction solvent, add carbonate as the base catalyst, add palladium catalyst, and add organophosphorus ligand.

6. The synthesis method according to claim 5, characterized in that: The carbonate is selected from sodium carbonate, potassium carbonate or cesium carbonate, the palladium catalyst is selected from Pd(dppf)Cl2 or Pd2(dba)3, and the organophosphine ligand is selected from Xphos.

7. The synthesis method according to claim 6, characterized in that: The carbonate mentioned is selected from potassium carbonate.

8. The synthesis method according to claim 7, characterized in that: The reaction temperature in step (2) is 80℃~100℃, and the reaction time is 2~6 hours.

9. The use of the 10-arylaminoevodiamine derivatives according to claim 1 or 2 in the preparation of antitumor drugs.

10. The application according to claim 9, characterized in that: The tumor is either liver cancer or neuroblastoma.

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