Furoquinoline dictamnine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a furo-quinoline dictamnine derivative as well as a preparation method and application thereof. The compound is novel and stable in structure, has a remarkable anti-cancer effect, particularly has a relatively high inhibition rate on NCI-H460 and 786-O tumor cells, has relatively low IC50, has a remarkable anti-tumor cell effect, and has a relatively good application prospect in the aspect of anti-cancer treatment. Besides, the preparation method of the furo-quinoline dictamnine derivative has the advantages of wide substrate application range, good functional group compatibility, mild reaction conditions, simplicity and convenience in operation and the like, can be used for large-scale industrial production, and has wide application value in the aspect of developing anti-cancer drugs.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology. More specifically, it relates to a furanoquinoline-based dictamnus derivative, its preparation method, and its applications. Background Technology

[0002] Cancer, as one of the world's major public health issues, has always presented a core challenge in medical research. Lung cancer and renal cell carcinoma, common and deadly malignant tumors, have seen significant progress in treatment, but still face many limitations. Treatment options for lung cancer include surgical resection, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Among these, targeted drugs against specific driver gene mutations (such as EGFR and ALK) and immunotherapies such as PD-1 / PD-L1 inhibitors have significantly improved the prognosis of some patients. Renal cell carcinoma, however, is not sensitive to traditional chemotherapy, and treatment primarily involves surgery, targeted drugs (such as VEGFR inhibitors), and immunotherapy. However, both types of cancer are prone to recurrence and drug resistance, especially for advanced or metastatic patients, where the efficacy of existing therapies remains limited. Therefore, developing novel and highly effective anticancer drugs to enrich clinical treatment options and improve patients' quality of life has become an urgent need in the field of oncology pharmacology.

[0003] Against this backdrop, natural products, due to their structural diversity and favorable biological activity, have become an important source for anticancer drug development. Modern pharmacological studies have shown that dictamnus alkaloids and their analogues, as a class of furanoquinoline alkaloids, exhibit broad anticancer potential. For example, current technology indicates that dictamnus alkaloids can inhibit the proliferation of non-small cell lung cancer cells (such as A549 and H1299) and c-Met-dependent cells (such as EBC-1) by directly inhibiting c-Met receptors, thereby downregulating the PI3K / AKT / mTOR and MAPK signaling pathways. However, although dictamnus alkaloids show activity against lung adenocarcinoma cells such as A549, its activity against more aggressive lung cancer subtypes with limited treatment options, such as large cell lung cancer, remains unknown. Large cell lung cancer (represented by the NCI-H460 cell line) accounts for approximately 10% of non-small cell lung cancers, characterized by rapid progression, easy metastasis, and poor response to conventional treatment regimens, representing a clear unmet clinical need. Therefore, developing novel compounds effective against this type of refractory lung cancer subtype is of great significance. In addition, the number of chemotherapy drugs that can be successfully applied in clinical practice is relatively limited, and more anti-cancer drugs are still needed to provide more diverse and effective drug options for the treatment of malignant tumors such as lung cancer and renal cell carcinoma. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the shortcomings and deficiencies of existing anticancer drugs and to provide a furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof.

[0005] The purpose of this invention is to provide a method for preparing the furanoquinoline derivative of dictamnus alkaloid.

[0006] Another object of the present invention is to provide the use of the furanoquinoline derivatives of dictamnus alkaloid or pharmaceutically acceptable salts thereof.

[0007] Another object of the present invention is to protect a pharmaceutical composition.

[0008] The above-mentioned objective of this invention is achieved through the following technical solution: This invention protects a furanoquinoline dictamnus derivative or a pharmaceutically acceptable salt thereof, said furanoquinoline dictamnus derivative having the following structure:

[0009] Among them, R 1 Selected from hydrogen, C 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, halogen, amino, nitro, ester, carbonyl, or aryl group; R 2 Selected from hydrogen, C 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, halogen, ester, or nitro groups; R 3 Selected from hydrogen, halogen, amino, nitro, ester, C 2~6 alkenyl, C 2~6 acetylenic, silicon-based, C 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, phenyl, naphthyl, phenanthrene, organometallic groups, substituted benzo[a]heterocyclic, substituted aryl, heteroaryl or substituted heteroaryl; The heterocyclic group of the substituted benzo[a]heterocyclic group is a 5-6 membered saturated ring, and the heterocyclic group has 1-2 heteroatoms, which are selected from N or S; The substituted benzo[a]heterocyclic group may have one or more substituents, each of which is independently selected from C[a]. 1~6 alkyl; The heteroaryl group is a 5-6 member aromatic monocyclic ring or an 8-10 member aromatic bicyclic ring, and the heteroaryl group has 1-4 heteroatoms, which are selected from N, S or O; The substituted heteroaryl group may have one or more substituents, each of which is independently selected from C10. 1~6 alkyl; The aryl group in the substituted aryl group is a benzene ring; The substituted aryl group is one or more, and each substituent is independently selected from halogen, amino, nitro, ester, C... 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 alkoxy, phenyl, or -NR 4 R 5 ; The R 4 R 5 Each is independently selected from C 1~6 Alkyl or phenyl.

[0010] Furthermore, the R 1 Selected from hydrogen, C 1~4 Alkyl, Halogenated C 1~3 alkoxy, halogen or (i.e., benzoyl group); R 2 Selected from hydrogen, C 1~4 Alkyl, Halogenated C 1~3 Alkyl, halogen, ester, or nitro groups; R 3 Selected from hydrogen, naphthyl, phenanthryl, organometallic groups, substituted benzo[a]heterocyclic groups, substituted aryl, heteroaryl or substituted heteroaryl; The metal-containing organic group is selected from ferrocene-based groups; The heterocyclic group of the substituted benzo[a]heterocyclic group is a 5-6 membered saturated ring, and the heterocyclic group has 1-2 heteroatoms, which are selected from S; The substituents of the substituted benzo[a]heterocyclic group are located on the heterocyclic group, and there may be one or more substituents, each of which is independently selected from C[a]. 1~3 alkyl; The heteroaryl group is a 5-6 membered aromatic monocyclic ring, and the heteroaryl group has 1-2 heteroatoms, which are selected from N or S; The substituted heteroaryl group may have one or more substituents, each of which is independently selected from C10. 1~3 alkyl; The substituents of the substituted aryl group are selected from halogens, amino groups, ester groups, and C. 1~4 Alkyl, Halogenated C 1~3 Alkyl, C 1~3 Alkoxy, halogenated C 1~3 alkoxy, phenyl, or -NR 4 R 5 ; The R 4 R 5 Each is independently selected from C 1~3 Alkyl or phenyl; The substituents of the substituted heteroaryl group are selected from C. 1~3 alkyl.

[0011] Furthermore, the R 1 Selected from hydrogen, isopropyl, tert-butyl, fluorine, chlorine, bromine, trifluoromethoxy or ; R 2 Selected from hydrogen, tert-butyl, trifluoromethyl, fluorine, chlorine, bromine, methyl ester, or nitro; R 3 Selected from hydrogen, naphthyl, phenanthryl, ferrocene, substituted benzo[a]heterocyclic, substituted aryl or heteroaryl; The heteroaryl group is a 5-6 membered aromatic monocyclic ring, and the heteroaryl group has one heteroatom, which is selected from N; The heterocyclic group is a 6-membered saturated ring, and the heterocyclic group has one heteroatom, which is selected from S; The substituents of the substituted benzo[a]heterocyclic group are on the heterocyclic group, and there are one or more substituents, each of which is independently selected from methyl; The substituents of the substituted aryl group are selected from fluorine, chlorine, bromine, amino, methyl ester, methyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, phenyl, or -NR. 4 R 5 ; The R 4 R 5 Each is independently selected from methyl or phenyl.

[0012] Preferably, the R 1 Selected from hydrogen, 10-isopropyl, 8-tert-butyl, 10-fluoro, 10-chloro, 10-bromo, 10-trifluoromethoxy, or 10-benzoyl; R 2 Selected from hydrogen, 3-tert-butyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-bromo, 3-methyl ester, or 2-nitro; R 3 Selected from hydrogen, , , , , , , , , , , , , , , , , , or .

[0013] This invention protects a method for preparing the furanoquinoline dictamnus derivative or a pharmaceutically acceptable salt thereof, wherein the furanoquinoline dictamnus derivative is prepared by the following steps: Under an inert atmosphere, using the quinolinone-fused cyclic diaryliodonium salt of Formula 1 and the alkyne of Formula 2 as raw materials, in the presence of a palladium catalyst, copper salt, organic ligand, and base, the reaction is carried out in an organic solvent, first at room temperature, and then heated to obtain the furanoquinoline benzoic acid derivative of Formula 3. ; Wherein, the R 1 R 2 R 3 Same as the definition described above.

[0014] Furthermore, the preparation method includes one or more of the following (1) to (9): (1) The organic ligand is selected from halogenated arylphosphine ligands; (2) The organic solvent includes at least one of N,N-dimethylformamide (DMF), dimethyl sulfoxide, and n-butanol, preferably DMF.

[0015] (3) The palladium catalyst is selected from at least one of palladium acetate, tetra(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium, preferably palladium acetate; the target product can be synthesized using these palladium catalysts.

[0016] (4) The copper salt is selected from cuprous iodide; (5) The alkali is at least one of sodium carbonate, potassium carbonate, and sodium hydroxide, preferably sodium carbonate.

[0017] (6) The molar ratio of the quinolinone-fused cyclic diaryliodonium salt, alkyne, palladium catalyst, copper salt, organic ligand and base is 1:(1~2):(0.05~0.15):(0.1~0.3):(0.2~0.4):(2~4), preferably 1:(1~1.5):(0.08~0.12):(0.15~0.25):(0.25~0.35):(2.5~3.5); (7) The reaction time at room temperature is 1 to 3 hours, preferably 1 to 2 hours; (8) The reaction temperature for the heating process is 80~120 ℃, preferably 90~110 ℃; (9) The reaction time for heating is 2 to 12 hours, preferably 4 to 12 hours.

[0018] Preferably, the molar volume ratio of the quinolinone fused cyclic diaryliodonium salt to the organic solvent is 1 mol: (15~25) mL, more preferably 1 mol: (18~22) mL.

[0019] Furthermore, the halogen-containing arylphosphine ligand is selected from any of the following structures: .

[0020] Preferably, the halogenated arylphosphine ligand is selected from tris[3,5-bis(trifluoromethyl)phenyl]phosphine.

[0021] Furthermore, the gas in the inert atmosphere is selected from at least one of argon, nitrogen, neon, and helium.

[0022] Furthermore, after the reaction is completed by heating, a post-treatment process is included, which comprises cooling, extraction, washing, drying, concentration under reduced pressure, and silica gel column purification. Specifically, the process includes the following steps: cooling the reaction solution to room temperature, extracting with ethyl acetate, combining the organic layers, washing successively with water and saturated brine, drying with anhydrous sodium sulfate, and concentrating under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1).

[0023] Furthermore, when R 2 When hydrogen is selected, the quinolinone-fused cyclic diaryliodonium salt is prepared by the following steps: S1. Mix (diacetoxyiodine)benzene, sodium carbonate, water and the compound shown in Formula 1-1, react at room temperature, and then treat to obtain a solid. Dissolve the obtained solid in N,N-dimethylformamide and react under oil bath conditions to obtain the compound shown in Formula 1-2. S2. Dissolve the compound shown in Formula 1-2 obtained in step S1 in dichloromethane, add m-chloroperoxybenzoic acid and trifluoromethanesulfonic acid, and react at room temperature to obtain the quinolinone-fused cyclic diaryliodonium salt shown in Formula 1: ; When R 2 When the hydrogen content is not hydrogen, the quinolinone-fused cyclic diaryliodonium salt is prepared by the following steps: sI. The compounds shown in Formula 1-3 and 2,4-dichloroquinoline were dissolved in N,N-dimethylformamide and reacted in the presence of cesium carbonate to obtain the compounds shown in Formula 1-4; sII. Mix the compounds shown in formula 1-4 obtained in step sI with an aqueous solution of acetic acid and reflux to obtain the compounds shown in formula 1-5; sIII. The compounds of formulas 1-5 obtained in step sII are dissolved in dichloromethane, and m-chloroperoxybenzoic acid and trifluoromethanesulfonic acid are added. The mixture is reacted at room temperature to obtain the quinolinone-fused cyclic diaryliodonium salt of formula 1: ; Wherein, the R 1 R 2 Same as the definition stated above.

[0024] Further, in step S1, R in the compound represented by formula 1-1 1 When the hydrogen content is not hydrogen, the compound represented by Formula 1-1 is prepared by the following steps: reacting the compound represented by Formula 1-6 with 2,2-dimethyl-1,3-dioxane-4,6-dione under reflux conditions, adding Eaton reagent, and continuing the reaction to obtain the compound represented by Formula 1-1. .

[0025] Furthermore, the reaction temperature under the reflux conditions is 70~90 ℃, preferably 75~85 ℃.

[0026] Furthermore, the reaction time under the reflux condition is 1 to 3 hours, preferably 1 to 2 hours.

[0027] Furthermore, the temperature for the continued reaction is 70~90 ℃, preferably 75~85 ℃.

[0028] Furthermore, the duration of the continued reaction is 8 to 12 hours, preferably 9 to 11 hours.

[0029] Furthermore, the reaction under reflux conditions includes a post-treatment process, which involves solvent removal. More specifically, the solvent is removed by using a rotary evaporator to evaporate the solvent, yielding a solid residue. The resulting solid residue is then reacted with Eaton reagents.

[0030] Furthermore, after the continued reaction is completed, a post-processing procedure is also included, which includes cooling, filtration, and washing. Specifically, the procedure includes the following steps: cooling the solution after the reaction is complete and treating it with ice water, filtering to collect the solid, and washing with water to obtain the target product.

[0031] Furthermore, in step S1, the reaction time at room temperature is 3-6 h, preferably 4-5 h.

[0032] Furthermore, in step S1, the completion of the reaction at room temperature also includes post-processing, which includes filtration and drying, specifically including the following steps: filtering and vacuum drying the reaction mixture after the reaction at room temperature to obtain a solid.

[0033] Furthermore, in step S1, the reaction temperature under the oil bath conditions is 140~160 ℃, preferably 145~155 ℃.

[0034] Furthermore, in step S1, the reaction time under the oil bath condition is 10-14 h, preferably 11-13 h.

[0035] Furthermore, in step S1, after the reaction under the oil bath conditions is completed, a post-processing is also included, which includes the following steps: cooling the solution after the reaction is complete and treating it with ice water, filtering and collecting the solid, and washing it with water to obtain the target product.

[0036] Furthermore, in step S2, the reaction time at room temperature is 1-3 h, preferably 1-2 h.

[0037] Further, in step S2, after the reaction at room temperature is completed, a post-treatment is also included. The post-treatment includes solvent removal, washing, filtration, and drying, specifically including the following steps: the solvent is removed from the solution after the reaction is completed by a rotary evaporator, diethyl ether is added to the remaining solid and the mixture is stirred thoroughly and then filtered. The obtained solid is washed three times with diethyl ether and dried under vacuum to obtain the target product.

[0038] Furthermore, in step sI, the reaction temperature is 70~90 ℃, preferably 75~85 ℃.

[0039] Furthermore, in step sI, the reaction time is 10-14 h, preferably 11-13 h.

[0040] Further, in step sI, after the reaction is completed, a post-processing step is included, which includes extraction, washing, drying, concentration, and purification. Specifically, it includes the following steps: After the reaction is completed, the mixture is extracted with ethyl acetate, the combined organic phases are washed successively with water and saturated brine, dried with anhydrous sodium sulfate, and then concentrated under vacuum. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1 to 20 / 1) to obtain the target product.

[0041] Furthermore, in step sII, the reflux reaction time is 10-14 h, preferably 11-13 h.

[0042] Furthermore, in step sII, after the reflux reaction is completed, a post-processing is also included, which includes cooling, filtration and washing, specifically including the following steps: after the reaction is complete, the solution is cooled and treated with ice water, the solid is collected by filtration and washed with water to obtain the target product.

[0043] Furthermore, in step sIII, the reaction time at room temperature is 1-3 h, preferably 1-2 h.

[0044] Furthermore, in step sIII, the reaction under room temperature conditions also includes post-treatment, which includes solvent removal, pulping, filtration, washing and drying. Specifically, it includes the following steps: removing the solvent from the solution after the reaction is completed by rotary evaporator, adding diethyl ether to the remaining solid, stirring the mixture thoroughly and filtering, washing the obtained solid three times with diethyl ether, and drying under vacuum to obtain the target product.

[0045] This invention protects the use of the furanoquinoline derivatives of dictamnus alkaloid or their pharmaceutically acceptable salts in the preparation of anticancer drugs.

[0046] Furthermore, the cancers in the said anticancer drugs include lung cancer and / or renal cell carcinoma.

[0047] Furthermore, the lung cancer in question is human large cell lung cancer.

[0048] Furthermore, the tumor cells corresponding to the human large cell lung cancer are NCI-H460.

[0049] Furthermore, the tumor cells corresponding to the renal cell carcinoma are 786-O.

[0050] The present invention also protects a pharmaceutical composition comprising one or more of the furanoquinoline dictamnus derivatives or pharmaceutically acceptable salts thereof.

[0051] Compared with the prior art, the present invention has the following beneficial effects: The present invention discloses a furanoquinoline derivative of dictamnus alkaloid. This type of compound has a novel and stable structure and exhibits significant anticancer effects, especially with high inhibition rates against NCI-H460 and 786-O tumor cells and low IC50. 50 The drug exhibits significant anti-tumor cell effects and shows promising application prospects in anti-cancer treatment. Furthermore, the preparation method of the furanoquinoline dictamnus derivative has advantages such as a wide range of applicable substrates, good functional group compatibility, mild reaction conditions, and simple operation, enabling large-scale industrial production and possessing broad application value in the development of anti-cancer drugs. Attached Figure Description

[0052] Figure 1 IC50 of different furanoquinoline compounds against large cell lung cancer NCI-H460 50 The data statistics chart.

[0053] Figure 2 IC50 of different furanoquinoline compounds against clear cell renal cell carcinoma 786-O 50The data statistics chart. Detailed Implementation

[0054] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0055] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0056] The general synthetic routes for compounds 3a-3ai obtained in Examples 1-2 of this application are as follows: .

[0057] Example 1: Preparation of compound 3a The synthetic route for compound 3a is as follows:

[0058] Specifically, the steps include the following: In a reaction tube, cyclic diaryliodonium salt 1a (102.2 mg, 0.2 mmol), sodium carbonate (63.6 mg, 0.6 mmol), palladium acetate (7.6 mg, 0.02 mmol, 10 mol%), cuprous iodide (4.5 mg, 0.04 mmol, 20 mol%), and tris[3,5-bis(trifluoromethyl)phenyl]phosphine (L5, 40.2 mg, 0.06 mmol, 30 mol%) were added. The reaction tube was evacuated and purged three times with argon. Then, p-methylphenylacetylene (2a, 28.1 mg, 0.24 mmol) and DMF (4 mL) were added using a syringe. The reaction mixture was stirred at room temperature for 2 hours, and then heated at 100 °C for 4 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give a white solid product 3a (51 mg, 73% yield).

[0059] Example 2: Preparation of compounds 3b-3t and 3u-3ai The synthetic routes for compounds 3b-3t and 3u-3ai are as follows:

[0060] Following the preparation steps of Example 1, a series of compounds 3b-3t, 3u-3ai were synthesized using the corresponding iodonium salts of Formula 1 and terminal alkynes of Formula 2 from the general pathway. The structures of all products were confirmed by nuclear magnetic resonance and high-resolution mass spectrometry.

[0061] The structural formulas, nuclear magnetic resonance (NMR) data, and high-resolution mass spectrometry (HMS) data of the compounds 3a-3ai are shown in Table 1.

[0062] Table 1. Structural formulas, NMR and high-resolution mass spectrometry data of compounds 3a-3ai

[0063] Example 3: Synthesis of compound 3a using different ligands The synthetic route for compound 3a is as follows:

[0064] Following the conditions of Example 1, but replacing ligand L5 with PPh3, SPhos, dppf, and L1-L4 respectively, the reaction conditions were as follows: 1a (0.1 mmol), 2a (1.2 equiv.), Pd(OAc)2 (10 mol%), CuI (20 mol%), ligand ligand (30 mol%), Na2CO3 (3 equiv.), and DMF (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then heated at 100°C for 12 hours.

[0065] The other steps and conditions are the same as in Example 1.

[0066] The structures of L1 to L5 are as follows:

[0067] Table 2 Yield results for different ligands

[0068] The yields of product 3a obtained by using different ligands are shown in Table 2, proving that the target product can be synthesized by using different ligands. Among them, the yield of the product obtained by using tris[3,5-bis(trifluoromethyl)phenyl]phosphine (L5) as the ligand is the best.

[0069] Example 4: Synthesis of compound 3a using different solvents The synthetic route for compound 3a is as follows:

[0070] The conditions were the same as in Example 1, but the solvent DMF was replaced with dimethyl sulfoxide (DMSO) and n-butanol, respectively. n BuOH), reaction conditions are as follows: 1a (0.1 mmol), 2a (1.2 equiv.), Pd(OAc)2 (10 mol%), CuI (20 mol%), L5 (30 mol%), Na2CO3 (3 equiv.), solvent (2 mL). The reaction mixture was stirred at room temperature for 1 hour, and then heated at 100 °C for 12 hours.

[0071] The other steps and conditions are the same as in Example 1.

[0072] Table 3 Yield results for different solvents

[0073] The yields of product 3a obtained by reacting with different solvents are shown in Table 3, proving that the target product can be synthesized using different solvents. Among them, the yield of the product obtained by using DMF as solvent is the best.

[0074] Example 5 Preparation of different cyclic diaryl iodonium salts 1a-1p The structures of different cyclic diaryl iodonium salts are as follows:

[0075]

[0076] (1) Preparation of compound 1a The synthetic route for compound 1a is as follows:

[0077] The specific preparation steps are as follows: S1. Sodium carbonate (3.95 g, 37.23 mmol) and water (80 mL) were added to a flask containing (diacetoxyiodine)benzene (6.00 g, 18.62 mmol). The reaction mixture was stirred at room temperature for 0.5 h, followed by the addition of 4-hydroxyquinoline-2(1H)-one (3.00 g, 18.62 mmol), and the reaction was continued for 4 h. The reaction mixture was then filtered and dried under vacuum to give a white solid. This solid was dissolved in N,N-dimethylformamide (40 mL) and stirred in an oil bath at 150 °C for 12 h. The reaction progress was monitored by TLC. After the reaction was complete, the solution was cooled and treated with ice water. The solid was collected by filtration and washed with water to give product 1a-1 (6.69 g, 99% yield) as a white solid.

[0078] S2. At 0 °C, to a solution of 1a-1 (3.26 g, 8.97 mmol) in 40 mL of dichloromethane, while stirring, m-chloroperoxybenzoic acid (75%, 4.13 g, 17.94 mmol) and trifluoromethanesulfonic acid (2.38 mL, 26.91 mmol) were added. After 30 minutes of addition, the solution was stirred at room temperature for 1 hour, followed by removal of dichloromethane by rotary evaporation. Diethyl ether (20 mL) was added to the remaining solid, the mixture was stirred for 30 minutes, and then filtered. The resulting solid was washed three times with diethyl ether and dried under vacuum to give a white solid product 1a (4.35 g, 95% yield).

[0079] (2) Preparation of compound 1b The synthetic route for compound 1b is as follows:

[0080] The specific preparation steps are as follows: S1. To a flask containing 2 g (14.79 mmol) of 4-isopropylaniline, add 2.56 g (17.75 mmol) of 2,2-dimethyl-1,3-dioxane-4,6-dione. The reaction mixture was refluxed at 80 °C for 1.5 h. The solvent was then removed by rotary evaporation to obtain a solid residue. This solid residue was mixed with Eaton reagent (20 mL) and heated at 80 °C for 10 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the solution was cooled and treated with ice water. The solid was collected by filtration and washed with water to give a white solid product 1b-2 (2.06 g, 69% yield).

[0081] S2. Sodium carbonate (2.09 g, 19.68 mmol) and water (45 mL) were added to a flask containing (diacetoxyiodine)benzene (3.17 g, 9.84 mmol). The reaction mixture was stirred at room temperature for 0.5 h, followed by the addition of 4-hydroxy-6-isopropylquinoline-2(1H)-one (i.e., 1b-2 obtained in step S1, 2.00 g, 9.84 mmol), and the reaction was continued for 4 h. The reaction mixture was then filtered and dried under vacuum to give a white solid. This solid was dissolved in N,N-dimethylformamide (40 mL) and stirred in an oil bath at 150 °C for 12 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the solution was cooled and treated with ice water. The solid was collected by filtration and washed with water to give a white solid product 1b-1 (2.17 g, 54% yield).

[0082] S3. At 0 °C, to a solution of 1b-1 (2.17 g, 5.35 mmol) of dichloromethane (25 mL) under stirring, m-chloroperoxybenzoic acid (75%, 2.46 g, 10.71 mmol) and trifluoromethanesulfonic acid (1.42 mL, 16.06 mmol) were added. After 30 minutes of addition, the solution was stirred at room temperature for 1 hour, and then the dichloromethane was removed by rotary evaporation. Diethyl ether (15 mL) was added to the remaining solid, the mixture was stirred for 30 minutes, and then filtered. The resulting solid was washed three times with diethyl ether and dried under high vacuum to give a white solid product 1a (1.19 g, 40% yield).

[0083] (3) Preparation of compound 1c~1h Compounds 1c to 1h were prepared using the same synthetic method as compound 1b.

[0084] (4) Preparation of compound 1i The synthetic route for compound 1i is as follows:

[0085] The specific preparation steps are as follows: S1. To a stirred solution of 2,4-dichloroquinoline (2.15 g, 10.86 mmol) in 20 mL of N,N-dimethylformamide, 4-(tert-butyl)-2-iodophenol (2 g, 7.24 mmol) and cesium carbonate (4.72 g, 14.49 mmol) were added. The reaction was carried out at 80 °C for 12 h. After the reaction was complete, the mixture was extracted with ethyl acetate, the combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under vacuum. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1 to 20 / 1) to give a gray solid product 1i-2 (3.14 g, 99% yield).

[0086] S2. The compound 1i-2 obtained in step S1 (3.14 g, 7.17 mmol) was placed in 30 mL of a mixed solution of acetic acid and water (volume ratio 2:1) and refluxed for 12 hours. After the reaction was complete, the solution was cooled and treated with ice water. The solid was collected by filtration and washed with water to give the pale yellow solid product 1i-1 (2.32 g, 77% yield).

[0087] S3. At 0 °C, to a solution of 1i-1 (2.32 g, 5.53 mmol) in 25 mL of dichloromethane under stirring, m-chloroperoxybenzoic acid (85%, 1.69 g, 8.30 mmol) and trifluoromethanesulfonic acid (1.47 mL, 16.60 mmol) were added. After 30 minutes of addition, the solution was stirred at room temperature for 1 hour, and then the dichloromethane was removed by rotary evaporation. Diethyl ether (15 mL) was added to the remaining solid, the mixture was stirred for 30 minutes, and then filtered. The resulting solid was washed three times with diethyl ether and dried under vacuum to give a white solid product 1i (1.52 g, 48% yield).

[0088] (5) Preparation of compounds 1j~1p Compounds 1j to 1p were prepared using the same synthetic method as compound 1i.

[0089] The nuclear magnetic resonance and high-resolution mass spectrometry data of the above compounds 1a~1p are shown in Table 4.

[0090] Table 4. NMR and high-resolution mass spectrometry data of compounds 1a-1p

[0091] Experimental Case Anti-cancer Effect Test I. Test of anti-cancer inhibition rate in lung cancer (1) Experimental principle: MTS reagent is reduced by cell biology to a colored formazan product that can be directly dissolved in tissue culture medium. Dehydrogenases in living cells can convert MTS into a liquid colored formazan compound. The absorbance of this compound at 490 nm can be directly measured in a 96-well plate. This reaction is completed under the action of NADPH or NADH produced by dehydrogenases in living cells.

[0092] (2) Experimental Procedure: Prepare cell suspension. Select human lung cancer cells NCI-H460 and seed them into 96-well plates at an appropriate density (3000 cells per well). Set up control and treatment groups, ensuring that each group has 3 accessory wells to improve the reliability of the experiment. After incubating at 37 ℃ and 5% CO2 for 24 hours, add 20 mM of the corresponding drug to each well. Add an equal volume of DMSO solvent to the control group. Place the 96-well plate back into the incubator and incubate at 37 ℃ and 5% CO2 for 48 hours. Add 20 mL of MTS reagent and gently shake the culture plate to mix the MTS reagent with the culture medium thoroughly. Place the 96-well plate back into the incubator and incubate at 37 ℃ and 5% CO2 for 3 hours to terminate the reaction. Use a microplate reader to measure the optical density (OD) value of each well at a wavelength of 490 nm. Subtract the OD value of the blank control well from the OD value of each test well to calculate cell viability. The OD values ​​of each parallel well were averaged for subsequent statistical analysis. The DMSO solvent group was used as a control, with 100% cell viability. The cell viability (%) and inhibition rate (%) of the drug-treated group were calculated by dividing the net OD value of the drug-treated group by the net OD value of the control group. The net OD value of the drug-treated group was calculated as: OD value of drug wells - OD value of blank wells; the net OD value of the control group was: OD value of the DMSO solvent group - OD value of blank wells.

[0093] II. Half-inhibition concentration test Cell seeding: NCI-H460 (human lung cancer cells), 786-O (human clear cell adenocarcinoma cells), and other cells in logarithmic growth phase were digested with trypsin, resuspended, and counted. 3000 cells were evenly seeded into each well of a 96-well plate, with at least 3 replicates per experimental group. The plates were incubated at 37°C with 5% CO2 for 24–48 hours until the cells were fully adhered and entered logarithmic growth phase.

[0094] Drug dilution: The test compound was serially diluted with culture medium (starting from 30 µM, serial dilutions were performed to obtain 6 concentrations). The original culture medium was aspirated, and fresh culture medium containing different concentrations of drug was added. The mixture was then incubated at 37°C with 5% CO2 for 48 hours.

[0095] MTS assay: To determine the effect of different drug concentrations on cell proliferation, the optical density (OD) value was measured at a wavelength of 490 nm using a microplate reader. Cell viability was calculated by subtracting the OD value of the blank control well from the OD value of each test well. The OD values ​​of all parallel wells were averaged for subsequent statistical analysis. The DMSO solvent group was used as a control, set at 100% viability. The net OD value of the drug-treated group was divided by the net OD value of the control group to obtain the cell viability percentage (%). Wherein, net OD value of the drug-treated group: OD value of drug wells - OD value of blank wells; net OD value of the control group: OD value of DMSO solvent group - OD value of blank wells.

[0096] Dose-response curve plotting and IC50 50 Calculate: IC 50 (Half-inhibitory concentration) refers to the concentration of the compound required to inhibit 50% cell viability. The measured OD values ​​were converted into relative survival rates using the method described above, and a dose-response curve was plotted in GraphPad Prism (Version 8.0) software, with the X-axis representing drug concentration and the Y-axis representing survival rate (Survival%). A mathematical model was used to fit the dose-response curve, performing nonlinear regression (curve fitting). The model was a four-parameter logistic model, which characterizes the bottom, top, slope, and midpoint (IC50) of the dose-response curve. 50 The software automatically calculates the half-inhibition concentration (IC50) based on the fitted curve. 50 value (or logIC) 50 The midpoint of the curve corresponds to the drug concentration at which cell survival rate decreased by 50% compared to the control group.

[0097] 2. Experimental Results Table 5. IC50 of furanoquinoline derivatives of dictamnusin on cancer cells 50

[0098] Note: "nd" means "untested".

[0099] The results are as follows Figures 1-2 As shown in Table 5, the compounds tested above all exhibited an inhibition rate of ≥35% or IC50 against human lung cancer cells at 20 μM. 50 ≤3 μM, IC50 for clear cell renal cell carcinoma 50 ≤4 μM indicates that the furanoquinoline derivative of the present invention has significant tumor cell inhibitory effects on both large cell lung cancer (NCI-H460) and clear cell renal cell carcinoma (786-O), and has good anti-lung cancer and anti-renal cell carcinoma activity.

[0100] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof, characterized in that, The furanoquinoline-based dictamnus derivative has the following structure: Among them, R 1 Selected from hydrogen, C 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, halogen, amino, nitro, ester, carbonyl, or aryl group; R 2 Selected from hydrogen, C 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, halogen, ester, or nitro groups; R 3 Selected from hydrogen, halogen, amino, nitro, ester, C 2~6 alkenyl, C 2~6 acetylenic, silicon-based, C 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 Alkoxy, phenyl, naphthyl, phenanthrene, organometallic groups, substituted benzo[a]heterocyclic, substituted aryl, heteroaryl or substituted heteroaryl; The heterocyclic group of the substituted benzo[a]heterocyclic group is a 5-6 membered saturated ring, and the heterocyclic group has 1-2 heteroatoms, which are selected from N or S; The substituted benzo[a]heterocyclic group may have one or more substituents, each of which is independently selected from C[a]. 1~6 alkyl; The heteroaryl group is a 5-6 member aromatic monocyclic ring or an 8-10 member aromatic bicyclic ring, and the heteroaryl group has 1-4 heteroatoms, which are selected from N, S or O; The substituted heteroaryl group may have one or more substituents, each of which is independently selected from C10. 1~6 alkyl; The substituted aryl group is one or more, and each substituent is independently selected from halogen, amino, nitro, ester, C... 1~6 Alkyl, Halogenated C 1~6 Alkyl, C 1~6 Alkoxy, halogenated C 1~6 alkoxy, phenyl, or -NR 4 R 5 ; The R 4 R 5 Each was independently selected from C 1~6 Alkyl or phenyl.

2. The furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The R 1 Selected from hydrogen, C 1~4 Alkyl, Halogenated C 1~3 Alkoxy, halogen or ; R 2 Selected from hydrogen, C 1~4 Alkyl, Halogenated C 1~3 Alkyl, halogen, ester, or nitro groups; R 3 Selected from hydrogen, naphthyl, phenanthryl, organometallic groups, substituted benzo[a]heterocyclic groups, substituted aryl, heteroaryl or substituted heteroaryl; The metal-containing organic group is selected from ferrocene-based groups; The heterocyclic group of the substituted benzo[a]heterocyclic group is a 5-6 membered saturated ring, and the heterocyclic group has 1-2 heteroatoms, which are selected from S; The substituents of the substituted benzo[a]heterocyclic group are located on the heterocyclic group, and there may be one or more substituents, each of which is independently selected from C[a]. 1~3 alkyl; The heteroaryl group is a 5-6 membered aromatic monocyclic ring, and the heteroaryl group has 1-2 heteroatoms, which are selected from N or S; The substituted heteroaryl group may have one or more substituents, each of which is independently selected from C10. 1~3 alkyl; The substituents of the substituted aryl group are selected from halogens, amino groups, ester groups, and C. 1~4 Alkyl, Halogenated C 1~3 Alkyl, C 1~3 Alkoxy, halogenated C 1~3 alkoxy, phenyl, or -NR 4 R 5 ; The R 4 R 5 Each was independently selected from C 1~3 Alkyl or phenyl; The substituents of the substituted heteroaryl group are selected from C. 1~3 alkyl.

3. The furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The R 1 Selected from hydrogen, isopropyl, tert-butyl, fluorine, chlorine, bromine, trifluoromethoxy or ； R 2 Selected from hydrogen, tert-butyl, trifluoromethyl, fluorine, chlorine, bromine, methyl ester, or nitro; R 3 Selected from hydrogen, naphthyl, phenanthryl, ferrocene, substituted benzo[a]heterocyclic, substituted aryl or heteroaryl; The heterocyclic group of the substituted benzo[a]heterocyclic group is a 6-membered saturated ring, and the heterocyclic group has one heteroatom, which is selected from S; The substituents of the substituted benzo[a]heterocyclic group are on the heterocyclic group, and there are one or more substituents, each of which is independently selected from methyl; The heteroaryl group is a 5-6 membered aromatic monocyclic ring, and the heteroaryl group has one heteroatom, which is selected from N; The substituents of the substituted aryl group are selected from fluorine, chlorine, bromine, amino, methyl ester, methyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, phenyl, or -NR. 4 R 5 ; The R 4 R 5 Each is independently selected from methyl or phenyl.

4. The furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The R 1 Selected from hydrogen, 10-isopropyl, 8-tert-butyl, 10-fluoro, 10-chloro, 10-bromo, 10-trifluoromethoxy, or 10-benzoyl; R 2 Selected from hydrogen, 3-tert-butyl, 3-trifluoromethyl, 3-fluoro, 3-chloro, 3-bromo, 2-bromo, 3-methyl ester, or 2-nitro; R 3 Selected from hydrogen, , , , , , , , , , , , , , , , , , or .

5. A method for preparing the furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, characterized in that, The furanoquinoline-based dictamnus derivative is prepared by the following steps: Under an inert atmosphere, using the quinolinone-fused cyclic diaryliodonium salt of Formula 1 and the alkyne of Formula 2 as raw materials, in the presence of a palladium catalyst, copper salt, organic ligand, and base, the reaction is carried out in an organic solvent, first at room temperature, and then heated to obtain the furanoquinoline benzoic acid derivative of Formula 3. ； Wherein, the R 1 R 2 R 3 Same as the definition described in any one of claims 1 to 4.

6. The preparation method according to claim 5, characterized in that, The preparation method includes one or more of the following (1) to (9): (1) The organic ligand is selected from halogenated arylphosphine ligands; (2) The organic solvent includes one or more of N,N-dimethylformamide, dimethyl sulfoxide, and n-butanol; (3) The palladium catalyst is selected from at least one of palladium acetate, tetra(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium; (4) The copper salt is selected from cuprous iodide; (5) The alkali is at least one of sodium carbonate, potassium carbonate, and sodium hydroxide; (6) The molar ratio of the quinolinone-fused cyclic diaryliodonium salt, alkyne, palladium catalyst, copper salt, organic ligand and base is 1:(1~2):(0.05~0.15):(0.1~0.3):(0.2~0.4):(2~4); (7) The reaction time at room temperature is 1~3 h; (8) The reaction temperature for the heating process is 80~120 ℃; (9) The reaction time for the heating reaction is 2 to 12 h.

7. The preparation method according to claim 5, characterized in that, When R 2 When hydrogen is selected, the quinolinone-fused cyclic diaryliodonium salt is prepared by the following steps: S1. Mix (diacetoxyiodine)benzene, sodium carbonate, water and the compound shown in Formula 1-1, react at room temperature, and then treat to obtain a solid. Dissolve the obtained solid in N,N-dimethylformamide and react under oil bath conditions to obtain the compound shown in Formula 1-2. S2. Dissolve the compound shown in Formula 1-2 obtained in step S1 in dichloromethane, add m-chloroperoxybenzoic acid and trifluoromethanesulfonic acid, and react at room temperature to obtain the quinolinone-fused cyclic diaryliodonium salt shown in Formula 1: ； When R 2 When the hydrogen content is not hydrogen, the quinolinone-fused cyclic diaryliodonium salt is prepared by the following steps: sI. The compounds shown in Formula 1-3 and 2,4-dichloroquinoline were dissolved in N,N-dimethylformamide and reacted in the presence of cesium carbonate to obtain the compounds shown in Formula 1-4; sII. Mix the compounds shown in formula 1-4 obtained in step sI with an aqueous solution of acetic acid and reflux to obtain the compounds shown in formula 1-5; sIII. The compounds of formulas 1-5 obtained in step sII are dissolved in dichloromethane, and m-chloroperoxybenzoic acid and trifluoromethanesulfonic acid are added. The mixture is reacted at room temperature to obtain the quinolinone-fused cyclic diaryliodonium salt of formula 1: ； Wherein, the R 1 R 2 Same as the definition described in any one of claims 1 to 4.

8. The use of the furanoquinoline derivative of dictamnus alkaloid or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4 in the preparation of an anticancer drug.

9. The application according to claim 8, characterized in that, The cancers mentioned in the anticancer drugs include lung cancer and / or renal cell carcinoma.

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises one or more of the furanoquinoline derivatives of dictamnus alkaloids according to any one of claims 1 to 4 or their pharmaceutically acceptable salts.

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