Tryptanthrin derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of preparation of anti-inflammatory drugs, and particularly discloses a tryptanthrin derivative and a preparation method and application thereof.The structural formula of the tryptanthrin derivative is # imgabs0, R is one of R1, R2 and R3, and when R is R1, # imgabs1 # reacts with H-R1, Pd (PPh3) 2Cl, copper iodide, triethylamine and an organic solvent to prepare the tryptanthrin derivative; when R is R2, the catalyst is prepared by reacting # imgabs2 # with H-R2, Pd2 (dppf) Cl2, potassium acetate and methylbenzene; when R is R3, the PdCl (PPh3) 4 is prepared by reacting with H-R3, silver carbonate, PdCl (PPh3) 4 and acetonitrile. The tryptanthrin derivative disclosed by the invention has high biological activity and solubility and low toxicity, and has the potential of being developed into a medicine for treating ulcerative colitis.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of anti-inflammatory drugs, and particularly relates to a tryptanthrin derivative, a preparation method thereof and an application thereof. Background Art

[0002] Ulcerative colitis (UC) is a complex chronic colon disease, characterized by mucosal inflammation starting distally and extending proximally to the entire colon. Clinically, drugs used for the treatment of UC include 5-aminosalicylic acid, glucocorticoids, immunomodulators, biological agents, etc. Long-term or high-dose use of these drugs can cause some adverse reactions such as allergic reactions and upper gastrointestinal bleeding.

[0003] Traditional Chinese medicine has no clear name record for UC. According to its different symptoms, characteristics, course of disease, etc., it is divided into different disease types. According to symptoms, it can be classified into the categories of "dysentery, diarrhea, hematochezia, abdominal pain", etc. According to the characteristics of syndromes, it can be classified into the categories of "damp-heat dysentery, intestinal wind, phlegm diarrhea", etc. According to the length of the course of disease and the severity and urgency of the condition, it can be classified into the categories of "sudden diarrhea, intermittent dysentery, chronic dysentery", etc. It can be seen from this that the internal accumulation of damp-heat is the main pathogenesis of UC, and clearing heat and removing dampness is the main treatment method. Compound Qingdai Granule is a classic prescription used by the First Clinical Hospital of China Medical University for the treatment of UC, with the effects of clearing heat and drying dampness, promoting granulation and stopping diarrhea, and is clinically safe and effective. Indigo Naturalis in the formula is the monarch drug, which is cold in nature and non-toxic, and belongs to the liver, lung and stomach meridians, with the functions of clearing heat and detoxifying, cooling blood and removing macules, and clearing liver fire, which conforms to the medication strategy of traditional Chinese medicine that especially emphasizes damp-heat in the active stage of UC and advocates clearing heat and promoting diuresis, and cooling blood and stopping bleeding.

[0004] Inflammation is a defensive response of organisms under harmful stimuli such as trauma and infection, which is beneficial for the body to recognize and remove pro-inflammatory factors. However, when the immune balance is disordered and the body's response to pro-inflammatory factors decreases or increases, various diseases will be caused. In this process, inflammatory mediators are mainly secreted by neutrophils, mononuclear macrophages and mast cells, and are important chemical factors leading to inflammatory reactions. The significant anti-inflammatory activity of tryptanthrin has attracted the attention of scholars.

[0005] Tryptanthrin is an active ingredient of traditional Chinese medicines such as Isatis indigotica Fort., Folium Isatidis and Indigo Naturalis. Tryptanthrin has good anti-inflammatory, antibacterial, anti-cancer and other activities. However, the content of tryptanthrin in nature is low and its solubility is poor. Taking tryptanthrin as a lead compound, structural modification is carried out to improve its solubility, safety and drug-likeness.

[0006] Therefore, how to provide a tryptanthrin derivative, a preparation method thereof and an application thereof, so as to develop a preparation method of tryptanthrin derivatives with high efficiency, low toxicity, high drug-likeness and suitable for industrial production is a difficult problem to be solved in this field. Summary of the Invention

[0007] In view of this, the present invention provides a tryptanthrin derivative, a preparation method thereof and an application thereof, so as to solve the problems of low content of tryptanthrin in nature and poor solubility.

[0008] In order to achieve the above object, the present invention adopts the following technical scheme:

[0009] A tryptanthrin derivative, the structural formula of the tryptanthrin derivative is:

[0010]

[0011] Wherein, R is one of R1, R2 and R3;

[0012] The R1 is

[0013] One of;

[0014] The R2 is One of;

[0015] The R3 is One of.

[0016] The present invention also provides a preparation method of a tryptanthrin derivative. When R is R1, the preparation method of the tryptanthrin derivative includes the following steps:

[0017] Mix With H-R1, Pd(PPh3)2Cl, copper iodide, triethylamine and an organic solvent, and react to obtain a tryptanthrin derivative.

[0018] Preferably, the molar ratio of H-R1, Pd(PPh3)2Cl, copper iodide and triethylamine is 0.9-1:0.9-1:0.09-0.1:0.2-0.3:7-7.2;

[0019] The organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylformamide, toluene and dichloromethane.

[0020] Preferably, the reaction temperature is 50-80 °C and the reaction time is 10-12 h.

[0021] The present invention also provides a preparation method of a tryptanthrin derivative. When R is R2, the preparation method of the tryptanthrin derivative includes the following steps:

[0022] Mix With H-R2, Pd2(dppf)Cl2, potassium acetate and an organic solvent, and react to obtain a tryptanthrin derivative.

[0023] Preferably, the The molar ratio of H-R2, Pd2(dppf)Cl2 and potassium acetate is 0.9-1:0.9-1:0.2-0.3:3-4;

[0024] The organic solvent includes one or more of toluene, N,N-dimethylformamide, dichloroethane, dichloromethane and tetrahydrofuran;

[0025] The temperature of the reaction is 100-110 °C, and the time of the reaction is 10-12 h.

[0026] The present invention also provides a preparation method of a tryptanthrin derivative. When R is R3, the preparation method of the tryptanthrin derivative includes the following steps:

[0027] Mix with H-R3, silver carbonate, PdCl(PPh3)4 and an organic solvent, and carry out a reaction to obtain a tryptanthrin derivative.

[0028] Preferably, the molar ratio of H-R3, silver carbonate and PdCl(PPh3)4 is 0.9-1:1-3:0.09-0.1:0.2-0.3;

[0029] The organic solvent includes one or more of acetonitrile, toluene, chloroform, dimethyl sulfoxide and tetrahydrofuran.

[0030] Preferably, the temperature of the reaction is 60-80 °C, and the time of the reaction is 10-12 h.

[0031] The present invention also provides an application of a tryptanthrin derivative in the preparation of drugs for ulcerative colitis.

[0032] Through the above technical solutions, compared with the prior art, the present invention has the following beneficial effects:

[0033] Tryptanthrin, with the chemical name of indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin, TRYP), its structure is composed of an indole ring and a quinazolinone ring, belonging to indoloquinazoline alkaloids. The content of tryptanthrin in plants is low, and batch production can be achieved through artificial synthesis. Through in-depth research on the structure-activity relationship and pharmacological effects of tryptanthrin, it is found that tryptanthrin has anti-inflammatory, antioxidant and anti-tumor effects, and its effective groups are mainly substituted on the D ring. The present invention further modifies the structure of the D ring of tryptanthrin and introduces polar groups to optimize and synthesize a large number of tryptanthrin derivatives with good activity and high solubility. The solubility of the tryptanthrin derivatives is enhanced, the anti-inflammatory activity is improved, and it has a therapeutic effect on ulcerative colitis mice.

[0034] The synthesized tryptanthrin derivatives of the present invention have improved activity and solubility, reduced toxicity, and have a therapeutic effect on DSS-induced UC mice, showing the potential to be developed into drugs for treating ulcerative colitis. Description of the Drawings

[0035] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required in the description of the embodiments or the prior art. Obviously, the drawings in the following description are only the embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on the provided drawings without creative efforts.

[0036] Figure 1 It is the detection result of the NO secretion amount of the tryptanthrin derivatives prepared in Examples 1-45 of the present invention;

[0037] Figure 2 It is the detection result of the cell viability of the embodiments of the present invention;

[0038] Figure 3 It is the influence of the present invention on the DAI score and colon length of DSS-induced UC mice, where Figure 3 a in it is the disease activity index score, Figure 3 b in it is the final colon length of each group of mice in the experiment;

[0039] Figure 4 It is the influence of the present invention on the pathological changes of the colon tissue of UC mice and the control results of each experimental group;

[0040] Figure 5 It is the influence of the present invention on the histological score of the colon tissue of UC mice;

[0041] Figure 6 It is the influence of the present invention on the NF-κB protein in the colon tissue of UC mice;

[0042] Figure 7 It is the influence of the present invention on the STAT3 protein in the colon tissue of UC mice. Detailed Embodiments

[0043] The present invention provides a tryptanthrin derivative, and the structural formula of the tryptanthrin derivative is:

[0044]

[0045] Among them, R is one of R1, R2, and R3.

[0046] The present invention also provides a preparation method of the tryptanthrin derivative. When R is R1, the preparation method of the tryptanthrin derivative includes the following steps:

[0047] Mix with H-R1, Pd(PPh3)2Cl, copper iodide, triethylamine, and an organic solvent, and carry out a reaction to obtain a tryptanthrin derivative.

[0048] In the present invention, the molar ratio of H-R1, Pd(PPh3)2Cl, copper iodide, and triethylamine is 0.9-1:0.9-1:0.09-0.1:0.2-0.3:7-7.2, preferably 0.95-1:0.95-1:0.095-0.1:0.22-0.28:7.05-7.15, and more preferably 1:1:0.1:0.25:7.1.

[0049] In the present invention, the organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylformamide, toluene, and dichloromethane.

[0050] In the present invention, the temperature of the reaction is 50-80°C, specifically it can be 55°C, 60°C, 65°C, 70°C, 75°C; the time of the reaction is 10-12 h, specifically it can be 10.5 h, 11 h, 11.5 h.

[0051] The present invention also provides a preparation method of a tryptanthrin derivative. When R is R2, the preparation method of the tryptanthrin derivative includes the following steps:

[0052] Mix with H-R2, Pd2(dppf)Cl2, potassium acetate, and an organic solvent, and carry out a reaction to obtain a tryptanthrin derivative.

[0053] In the present invention, the molar ratio of H-R2, Pd2(dppf)Cl2, and potassium acetate is 0.9-1:0.9-1:0.2-0.3:3-4, preferably 0.95-1:0.95-1:0.22-0.28:3.2-3.8, and more preferably 1:1:0.25:3.5.

[0054] In the present invention, the organic solvent includes one or more of toluene, N,N-dimethylformamide, dichloroethane, dichloromethane, and tetrahydrofuran.

[0055] In the present invention, the temperature of the reaction is 100-110°C, specifically it can be 102°C, 104°C, 105°C, 106°C, 108°C; the time of the reaction is 10-12 h, specifically it can be 10.5 h, 11 h, 11.5 h.

[0056] The present invention also provides a method for preparing a tryptanthrin derivative. When R is R3, the method for preparing the tryptanthrin derivative comprises the following steps:

[0057] Mix with H-R3, silver carbonate, PdCl(PPh3)4, and an organic solvent, and carry out a reaction to obtain a tryptanthrin derivative.

[0058] In the present invention, the molar ratio of H-R3, silver carbonate, and PdCl(PPh3)4 is 0.9 - 1:1 - 3:0.09 - 0.1:0.2 - 0.3, preferably 0.95 - 1:1.5 - 2.5:0.095 - 0.1:0.22 - 0.28, and more preferably 1:2:0.1:0.25.

[0059] In the present invention, the organic solvent includes one or more of acetonitrile, toluene, chloroform, dimethyl sulfoxide, and tetrahydrofuran.

[0060] In the present invention, the temperature of the reaction is 60 - 80 °C, specifically it can be 62 °C, 65 °C, 68 °C, 70 °C, 72 °C, 75 °C, 78 °C; the time of the reaction is 10 - 12 h, specifically it can be 10.5 h, 11 h, 11.5 h.

[0061] The present invention also provides an application of a tryptanthrin derivative in the preparation of a drug for ulcerative colitis.

[0062] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the protection scope of the present invention.

[0063] The structural formula of the tryptanthrin derivative raw material in all embodiments of the present invention is:

[0064]

[0065] Examples 1 - 30

[0066] 0.325 g (1.0 mmol, 1.0 eq.) of the tryptanthrin derivative raw material, 1.0 mmol (1.0 eq.) of H-R1, 0.1 mmol (0.1 eq.) of Pd(PPh3)2Cl and 0.2 mmol (0.2 eq.) of cuprous iodide were added to a flask. 4 mL of the solvent N,N'-dimethylformamide (DMF) was added, and then 1 mL of triethylamine (7.2 eq.) was added. The mixture was heated in an oil bath at 50 °C for 12 h. After standing and cooling, water was added and the mixture was extracted with dichloromethane. The organic layer was collected, rotary evaporated to obtain a solid, and then the product was passed through a silica gel column with gradient elution and recrystallized with absolute ethanol. Finally, the target product (R1 was in-situ substituted for Br, and different target products with different substitution positions were obtained due to different positions of Br) was obtained. The target product and the yield are shown in Table 1.

[0067] Table 1 Target products and yields of Examples 1 to 30

[0068]

[0069]

[0070]

[0071]

[0072] The 1H NMR data of the target products prepared in Examples 1 to 30 (correspondingly denoted as 1 to 30 in sequence) are shown in Table 2.

[0073] Table 2 1H NMR data of the target products of Examples 1 to 30

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] Examples 31 to 38

[0081] 0.325 g (1.0 mmol, 1.0 eq.) of the tryptanthrin derivative raw material, 1.0 mmol (1.0 eq.) of H-R2, 0.2 mmol (0.2 eq.) of Pd2(dppf)Cl2 and 3.0 mmol (3.0 eq.) of potassium acetate were added to a flask. The solvent toluene (5 mL) was added and the reaction was heated in an oil bath at 100 °C for 12 h. After standing and cooling, water was added and the mixture was extracted with dichloromethane. The organic layer was collected, rotary evaporated to obtain a solid, and the product was then passed through a silica gel column and eluted with a gradient to obtain the target product solid. Recrystallization from absolute ethanol gave the final target product. The target product and the yield are shown in Table 3.

[0082] Table 3 Target products and yields of Examples 31 - 38

[0083]

[0084]

[0085] The 1H NMR data of the target products prepared in Examples 31 - 38 (correspondingly denoted as 31 - 38 in sequence) are shown in Table 4.

[0086] Table 4 1H NMR data of the target products of Examples 31 - 38

[0087]

[0088]

[0089] Examples 39 - 45

[0090] 0.325 g (1.0 mmol, 1.0 eq.) of the tryptanthrin derivative raw material, 3.0 mmol (3.0 eq.) of H-R3, 0.2 mmol of PdCl(PPh3)4 and 0.1 mmol (0.1 eq.) of silver carbonate were added to a flask. Acetonitrile was added as the solvent (5 mL), and the reaction was heated in an oil bath at 70 °C for 12 h. After the reaction was completed, the reaction mixture was allowed to stand and cool, then water was added and the mixture was extracted with dichloromethane. The organic layer was collected. The solvent was removed by rotary evaporation to obtain a solid product, which was then subjected to silica gel column chromatography and gradient elution, and recrystallized from absolute ethanol to finally obtain the target product. The target product and the yield are shown in Table 5.

[0091] Table 5 Target products and yields of Examples 39 - 45

[0092]

[0093]

[0094] The 1H NMR data of the target products prepared in Examples 39 - 45 (correspondingly denoted as 39 - 45 in sequence) are shown in Table 6.

[0095] Table 6 NMR data of target products of Examples 39 to 45

[0096]

[0097]

[0098] Experimental Example 1

[0099] NO secretion detection: RAW264.7 cells were diluted with complete culture medium to 2.0×10 per well. 5 cells, seeded in a 96-well plate. After the cells adhere to the wall, gently aspirate the supernatant, and add 90 μL (at a concentration of 10 μM) of complete culture medium solution of the compounds of Examples 1 to 45 to each well. After 2 hours, add 10 μL of LPS at a concentration of 1 μg / mL to each well, and collect the supernatant after continuing to culture for 20 hours. The NO content was determined using the Griess method: 50 μL of cell supernatant was taken from each sample well, 50 μL of SUL solution was added, and the reaction was protected from light for 10 minutes; then 50 μL of NED solution was added, and the reaction was continued for 10 minutes in the dark. Finally, the absorbance value of each well at a wavelength of 562 nm was measured on a microplate reader.

[0100] Test results such as Figure 1 As shown (Examples 1 to 45 are denoted as 1 to 45 in sequence), by Figure 1 It can be seen that all compounds showed different degrees of nitric oxide inhibition (relative to the inflammatory model group, i.e., the LPS group in the figure), proving that these compounds all have anti-inflammatory activity and have the potential to become anti-inflammatory drugs. In particular, 2, 8, 14, 15, 19, 28, 31, 35 and 38 showed the most significant ability to inhibit NO secretion at the same molar concentration, showing significant anti-inflammatory activity.

[0101] MTT cell viability assay: This experiment used the MTT method to detect the proliferation activity of macrophages. The specific steps were as follows: RAW264.7 cells were prepared with complete culture medium to a density of 1.25×10 5A single-cell suspension of [[[number]]] cells / mL was inoculated at 100 μL per well in a 96-well plate. After the cells were cultured under suitable conditions for 24 hours, the original culture medium was discarded, and 100 μL of a complete culture medium solution of compounds 2, 8, 14, 15, 19, 28, 31, 35, and 38 at different concentrations was added. The test drugs were set at six concentration gradients: 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, and 3.125 μM (the drug stock solution was prepared as 1 mmol / L using biological-grade DMSO and further diluted in gradients with the culture medium when in use). At the same time, a blank group and a control group were established. After continuing to culture for 20 hours, 10 μL of MTT solution was added to each well, and after incubation for 4 hours, DMSO was added, and the mixture was shaken for 1 minute. Finally, the absorbance value (A) of each well at a wavelength of 490 nm was measured using a microplate reader, and the calculation was performed based on this.

[0102] Cell viability (%) = (A of the drug-administered group - A of the control group) / (A of the control group - A of the blank group) * 100%.

[0103] The detection results are as Figure 2 shown. Through Figure 2 it can be seen that among the 9 compounds with the best activity screened above, for 2, 14, 15, 19, 28, 31, 35, and 38 at 5 μM, the cell survival rate was higher than 50%; among them, 15 and 19 did not show cytotoxicity at 20 μM.

[0104] Experimental Example 2

[0105] Animal grouping and drug administration: According to the MTT and NO secretion detection results, experiments were carried out using tryptanthrin and the tryptanthrin derivatives prepared in the present invention. The experimental animals were divided into the following groups: control group (CON), model group (DSS), positive control group (sulfasalazine, SASP) with a drug administration dose of 125 mg / kg; tryptanthrin group (TRYP) with a drug administration dose of 78 mg / kg; and experimental group (compound 15, Example 15) with a drug administration dose of 108 mg / kg, ensuring the same molar amount of drug administration.

[0106] Sixty SPF-grade C57BL / 6 male mice aged 6 - 8 weeks and weighing (20 ± 2 g) were used in the experiment. After one week of adaptive feeding, the experiment started. The control group mice drank pure water, and the other group mice drank 2.5% DSS to induce the UC model. At the same time of model establishment, intragastric administration was carried out. The CON group and DSS group mice were intragastrically administered distilled water, and the SASP, TRYP, and experimental groups were intragastrically administered the corresponding doses of drugs. The intragastric administration volume was 10 mL / kg for 12 consecutive days.

[0107] Disease activity index score: From the first day of animal modeling, according to the DAI scoring table, record the body weight, stool texture, and blood in the stool of the mice, and perform the disease activity index (DAI) score.

[0108] H&E staining: Embed the colon tissue stored in 4% paraformaldehyde. Deparaffinize the paraffin sections to water, then place the sections in hematoxylin solution to stain the cell nuclei. After rinsing, stain the cytoplasm with eosin staining solution. After terminating the staining, dehydrate the sections in ethanol, clear them with xylene, air dry, drop neutral gum to seal the sections for fixation, and examine them under a microscope. Compare the pathological changes of colon tissue injury in each group.

[0109] Immunohistochemical observation of the changes of STAT3 and NF-κB proteins in colon tissue: Embed the colon tissue stored in 4% paraformaldehyde, and then perform STAT3 and NF-κB immunohistochemical analysis.

[0110] The effects of each treatment group on the DAI score and colon length of DSS-induced UC mice are as Figure 3 shown. By Figure 3 it can be seen that the DAI score of the mice in the model group increased significantly, showing a significant difference compared with the control group (P<0.01), indicating that the UC model was successfully constructed. Compared with the model group, although the DAI scores of each drug administration group showed an upward trend, the increase was relatively gentle (P<0.05), indicating that tryptanthrin and the compound prepared by the present invention have a certain protective effect on UC mice. The present invention shows an anti-ulcerative colitis effect, and its curative effect is better than that of the positive drug SASP and tryptanthrin.

[0111] The effects of each treatment group on the pathological changes of colon tissue in UC mice are as Figure 4 shown. By Figure 4 it can be seen that the colon length of the mice in the DSS group was the shortest, showing a significant difference compared with the CON group (P<0.01). Compared with the DSS group, the degree of colon shortening in each drug administration group became smaller, showing a significant difference (P<0.05), indicating that TRYP and the experimental group can relieve the colon shortening in UC mice.

[0112] The effects of each treatment group on the pathological score of colon tissue in UC mice are as Figure 5 shown. By Figure 5It can be seen that the colon tissue structure of the mice in the blank control group (CON group in the figure) is intact, the crypt morphology is normal, and no inflammatory cell infiltration is observed. The colon of the DSS group mice showed a significant increase in inflammatory cell infiltration, with atrophy and upward shift of the crypts, irregular morphology, and a significant reduction in goblet cells. After treatment with tryptanthrin (TRYP) and the experimental group, the colon structure and crypt morphology were restored to some extent, and the inflammatory cell infiltration was significantly reduced, indicating that TRYP and the experimental group can effectively improve the colon inflammation in DSS-induced UC mice and reduce the damage to their colon tissue.

[0113] The effects of each treatment group on the NF-κB protein in the colon tissue of UC mice (X200) are as Figure 6 shown. Through Figure 6 it can be seen that both TRYP and the experimental group have an impact on the expression of NF-κB and STAT3 proteins in the colon tissue, and both reduce the expression of NF-κB and STAT3.

[0114] The effects of each treatment group on the STAT3 protein in the colon tissue of UC mice (X200) are as Figure 7 shown. Through Figure 7 it can be seen that the positive expression of NF-κB is the highest in the DSS group, and the positive expression of NF-κB in the colon tissues of the SASP, TRYP, and experimental groups all decreased to varying degrees. There was no significant difference in the positive expression between tryptanthrin and the experimental group, and both were lower than the positive drug SASP group.

[0115] In this specification, each embodiment is described in a progressive manner. The key point of each embodiment is to illustrate the differences from other embodiments. For the same or similar parts among the embodiments, reference can be made to each other.

[0116] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments shown herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A tryptanthrin derivative, characterized in that, The structural formula of the tryptanthrin derivative is as follows: Wherein, R is one of R1, R2 and R3; Said R1 is one of; The R2 is one of; The R3 is one of the following.

2. The preparation method of a tryptanthrin derivative according to claim 1, characterized in that, When R is R1, the preparation method of the tryptanthrin derivative comprises the following steps: Mix with H-R1, Pd(PPh3)2Cl, copper iodide, triethylamine, and an organic solvent, and carry out a reaction to obtain a tryptanthrin derivative.

3. The preparation method of a tryptanthrin derivative according to claim 2, characterized in that, The The molar ratio of H-R1, Pd(PPh3)2Cl, copper iodide and triethylamine is 0.9-1:0.9-1:0.09-0.1:0.2-0.3:7-7.2; The organic solvent includes one or more of N,N-dimethylformamide, toluene and dichloromethane.

4. The preparation method of a tryptanthrin derivative according to claim 3, characterized in that, The temperature of the reaction is 50-80°C, and the time of the reaction is 10-12 h.

5. The preparation method of a tryptanthrin derivative according to claim 1, characterized in that, When R is R2, the preparation method of the tryptanthrin derivative comprises the following steps: Mix with H-R2, Pd2(dppf)Cl2, potassium acetate, and an organic solvent, and react to obtain a tryptanthrin derivative.

6. The preparation method of a tryptamine ketone derivative according to claim 5, wherein, The The molar ratio of H-R2, Pd2(dppf)Cl2 and potassium acetate is 0.9-1:0.9-1:0.2-0.3:3-4; The organic solvent includes one or more of toluene, N,N-dimethylformamide, dichloroethane, dichloromethane and tetrahydrofuran; The temperature of the reaction is 100-110°C, and the time of the reaction is 10-12 h.

7. The preparation method of a tryptanthrin derivative according to claim 1, characterized in that, When R is R3, the preparation method of the tryptanthrin derivative comprises the following steps: Mix with H-R3, silver carbonate, PdCl(PPh3)4 and an organic solvent, and react to obtain a tryptanthrin derivative.

8. A method for preparing a tryptanthrin derivative according to claim 7, characterized in that, The The molar ratio of H-R3, silver carbonate, and PdCl(PPh3)4 is 0.9-1:1-3:0.09-0.1:0.2-0.3; The organic solvent includes one or more of acetonitrile, toluene, chloroform, dimethyl sulfoxide and tetrahydrofuran.

9. The preparation method of a tryptanthrin derivative according to claim 8, characterized in that, The temperature of the reaction is 60-80°C, and the time of the reaction is 10-12 h.

10. Use of a tryptanthrin derivative according to claim 1 in the preparation of a drug for ulcerative colitis.

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