(S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine and its application

Abstract

The present invention belongs to the technical field of anticancer drug preparations, and specifically relates to a (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine and applications thereof. The compound of the present invention has higher inhibitory activity against tumors insensitive to EGFR inhibitors than EGFR inhibitors, has significant therapeutic effects when used alone, can increase the sensitivity of traditional chemotherapy drugs, has low toxicity, and can be used in the preparation of anticancer drug preparations.

Description

Technical Field

[0001] The present invention belongs to the technical field of anticancer drug preparations, and particularly relates to (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine and applications thereof. Background Art

[0002] The occurrence of many human tumors is driven by the activation of the epidermal growth factor receptor (EGFR) and subsequent signaling pathways. EGFR is one of the most common targets in cancer treatment, and EGFR-targeted drugs can be used to treat cancers with EGFR gene mutations or overexpression. Currently, EGFR-targeted drugs play an important role in the treatment of various cancers, including lung cancer, colorectal cancer, and gastric cancer. However, due to secondary drug resistance and mutations in downstream target genes of the primary EGFR pathway, EGFR inhibitors are ineffective and cannot inhibit tumor growth. In colorectal cancer, mutations in genes encoding EGFR-mediated downstream signaling pathway proteins, such as RAS, RAF, MEK, and ERK, make tumors insensitive to EGFR inhibitors.

[0003] As a result, a large number of inhibitors targeting the EGFR downstream signaling pathway have emerged. The main RAS inhibitors that have entered the clinical stage include Salirasib and PRLX-93936; the RAF inhibitors on the market include sorafenib, regorafenib, dabrafenib, etc., but most of them are multi-target and multi-kinase inhibitors, which have the disadvantage of high toxicity. There are also several MEK inhibitors on the market, and their clinical indications are mainly melanoma, such as trametinib and selumetinib; as for ERK inhibitors, no inhibitors have been officially approved for marketing, but some ERK small molecule inhibitors are already in the clinical research stage. Controlling the activation of the EGFR downstream signaling pathway is crucial to controlling the development of malignant tumors. Judging from the domestic research and development layout of products for this signaling pathway and the current momentum of related protein activity inhibitors under development, EGFR downstream signaling pathway inhibitors have a large room for development. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound and its application. The anti-tumor activity of the compound is higher than that of the EGFR inhibitor gefitinib, and the monotherapy efficacy is significant, and the compound can be used in the preparation of anticancer drug preparations.

[0005] The present invention is specifically achieved through the following technical solutions.

[0006] Currently, RAS, RAF, and MAPK inhibitors that overcome EGFR inhibitor resistance have poor single-drug efficacy and high toxicity of multi-target multi-kinase inhibitors. To this end, the first object of the present invention is to provide a (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound having the structural formula:

[0007]

[0008] The present invention also includes pharmaceutically acceptable salts of the above-mentioned (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound.

[0009] A second object of the present invention is to provide a method for preparing the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound, comprising the following steps:

[0010] Compound c was prepared by nucleophilic substitution reaction using compound a and compound b as raw materials in DCM as solvent under the action of N,N-diisopropylethylamine (DIPEA);

[0011] Compound e was prepared by a nucleophilic substitution reaction using compound c and compound d as raw materials and ethanol as solvent under alkaline conditions of sodium carbonate;

[0012] The compound e is dissolved in methanol, and a reduction reaction occurs under the catalysis of Pd / C in a hydrogen atmosphere to prepare compound f;

[0013] Compound f and compound g are used as raw materials, 1,2-dichloroethane is used as solvent, EDC is used as condensation agent, and N,N-diisopropylethylamine is used to cause a condensation reaction to prepare compound h;

[0014] The protecting group of compound h was removed under acidic conditions to prepare the target product, compound 719.

[0015] The synthetic route is as follows:

[0016]

[0017] In a preferred embodiment of the present invention, the molar ratio of compound a to compound b is 1:1.5-3, and the molar ratio of DIPEA to compound b is 2-4:1;

[0018] When preparing compound c, the reaction temperature is 0°C to 4°C.

[0019] In a preferred embodiment of the present invention, the molar ratio of compound c to compound d is 1:1-1.5, and the molar ratio of sodium carbonate to compound c is 1.5:1;

[0020] When preparing compound e, the reaction was carried out under stirring at room temperature for 3-6 hours.

[0021] In a preferred embodiment of the present invention, the mass fraction of Pd in ​​Pd / C is 5%; the mass ratio of Pd / C to compound e is 1:20; and when preparing compound f, the reaction is stirred at room temperature.

[0022] In a preferred embodiment of the present invention, the molar ratio of compound f to compound g is 1:1-1.5, the molar ratio of EDC, DIPEA and compound g is 1:1:1, and when preparing compound h, the reaction temperature is 50°C-70°C.

[0023] In a preferred embodiment of the present invention, the protecting group of compound h is removed in a hydrochloric acid-ethanol solution, the concentration of the hydrochloric acid-ethanol solution is 10 mol / L, and the ratio of the hydrochloric acid-ethanol solution to compound h is 10 mL:2 mmol. When preparing compound 719, the reaction temperature is room temperature.

[0024] The third object of the present invention is to provide the use of the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound in the preparation of anticancer drugs, which can be used to treat solid tumors such as colorectal cancer.

[0025] The fourth object of the present invention is to provide an anticancer drug comprising the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound or a pharmaceutically acceptable salt of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine.

[0026] The compound of the present invention has higher inhibitory activity on tumors insensitive to EGFR inhibitors than EGFR inhibitors, can be used as an inhibitor of EGFR downstream signaling pathway, and expands the development scope of EGFR downstream signaling pathway inhibitors.

[0027] In a preferred embodiment of the present invention, other anticancer drugs are also included, and the other anticancer drugs are cytotoxic anticancer drugs, antimetabolite anticancer drugs, EGFR inhibitors, RAS inhibitors or immunotherapy drugs.

[0028] In a preferred embodiment of the present invention, the composition further comprises an excipient, which comprises one or more of a stabilizer, a solubilizer, a lubricant, and a disintegrant. Further preferably, the excipient comprises one or more of starch, dextrin, glucose, lactose, cellulose, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, pectin, cyclodextrin, Tween-80, polyvinyl alcohol, magnesium stearate, and talc.

[0029] In a preferred embodiment of the present invention, the anticancer drug preparation is a tablet, capsule or injection, wherein each tablet, capsule or injection contains 10 to 100 mg of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound.

[0030] In a preferred embodiment of the present invention, the anticancer drug preparation is a tablet or capsule, each tablet or capsule containing 10 to 50 mg of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The present invention provides a compound with a novel structure, namely (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine. The compound has a higher inhibitory activity against tumors insensitive to EGFR inhibitors than EGFR inhibitors, has a significant therapeutic effect when used alone, can increase the sensitivity of traditional chemotherapy drugs, has low toxicity, and can be used in the preparation of anticancer drug preparations.

[0033] The compound provided by the present invention has low toxicity. When the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound is intraperitoneally administered to mice (once every two days, a single dose of 50 mg / kg), the growth of subcutaneous tumors in the mice is significantly inhibited, and no significant change in body weight is observed.

[0034] Therefore, the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound provided by the present invention can be used to prepare anticancer drug preparations, which can provide more options for the clinical treatment of cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the MS spectrum of compound 719 prepared in Example 1.

[0036] Figure 2 Compound 719 prepared in Example 1 1 H NMR spectrum.

[0037] Figure 3 Compound 719 prepared in Example 1 13 C NMR spectrum.

[0038] Figure 4 The effect of compound 719 of the present invention on subcutaneous tumors in C57 mice; wherein A is the change in tumor volume of each group of mice during the administration period; B is the change in body weight of each group of mice during the administration period; n=7, compared with the solvent group, *P<0.05; **P<0.01.

[0039] Figure 5 In the figure, A is a schematic diagram of the establishment process of the AOM / DSS colorectal cancer tumor model; B is a schematic diagram of the tumors in each group in A; C is the tumor burden of each group of mice after drug administration; D is the number of tumors in each group of mice after drug administration; n=6, compared with the solvent group, *P<0.05; **P<0.01. DETAILED DESCRIPTION

[0040] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below with reference to specific embodiments and drawings, but the embodiments are not intended to limit the present invention.

[0041] The experimental methods and detection methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0042] The present invention provides a (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound having the structural formula:

[0043]

[0044] Example 1

[0045] The preparation method of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound is synthesized through five steps, including the following steps:

[0046]

[0047] (1) Under ice-bath conditions, 2,4-dichloro-5-nitropyrimidine (compound a, 15.8 mmol) and N,N-diisopropylethylamine (DIPEA) (77.4 mmol) were mixed in a DCM solution (50 mL), and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (compound b, 31.0 mmol) was slowly added dropwise to the system. TLC monitoring indicated that the reaction was complete. The organic phase was washed with saturated brine, dried, filtered, and spin-dried to obtain a brown oily liquid with a yield of 91%, namely compound c.

[0048] (2) Compound c (19.8 mmol) was dissolved in ethanol (30 mL), and 4-(4-methyl-1-piperazinyl)aniline (compound d, 19.8 mmol) and sodium carbonate (29.7 mmol) were added. The mixture was stirred at room temperature for 3 to 6 h until the reaction was complete. The mixture was diluted with water (20 to 40 mL) and filtered to obtain a yellow powder with a yield of 88%, namely compound e.

[0049] (3) Compound e (5.0 g, 9.8 mmol) was dissolved in methanol (50 mL), and Pd / C (0.25 g, 5 wt% Pd in ​​Pd / C) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. TLC monitoring indicated that the starting material was essentially consumed. The mixture was filtered and dried to obtain compound f, which was directly used for the next step.

[0050] (4) Compound f (9.8 mmol) was dissolved in 1,2-dichloroethane (30 mL), and phenyl isothiocyanate (compound g, 11.8 mmol), EDC (11.8 mmol), and DIPEA (11.8 mmol) were added. The mixture was heated to 65°C in an oil bath and stirred overnight. Silica gel column chromatography gave a pale yellow solid powder in a 73% yield, namely compound h.

[0051] (5) Compound h (2.0 mmol) was dissolved in 10 mL of 10 mol / L hydrochloric acid ethanol solution. The mixture was stirred at room temperature overnight and the solvent was evaporated to dryness to obtain an off-white powdery solid with a yield of 93%, namely compound 719. The structural characteristics are shown in FIG. Figure 1-Figure 3 shown.

[0052] 1H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.33(s,1H),7.83(d,J=7.8Hz,2H),7.72–7.61(m,2H),7.3 9–7.31(m,2H),6.97(t,J=7.3Hz,1H),6.92–6.82(m,2H),4.79(s,1H),3.58–3.49(m,1H),3.18( dd,J=12.7,4.3Hz,1H),3.06(t,J=5.0Hz,4H),2.99(s,1H),2.95–2.85(m,1H),2.47(t,J=5.0Hz ,4H),2.38–2.26(m,1H),2.24(s,3H),2.00–1.90(m,1H),1.82–1.74(m,1H),1.66–1.57(m,1H). 13 C NMR (150 MHz, DMSO-d6) δ 155.0, 153.5, 150.0, 145.8, 142.4, 141.3, 134.5, 129.2, 127.5, 121.6, 119.6, 118.4, 116.5, 55.2, 50.8, 49.6, 47.3, 46.2, 45.4, 29.4. MS (ESI): calculated (C 27 H 33 N9): 484.29[M+H] + ; Measurement value: 484.39.

[0053] Example 2

[0054] (1) Under ice-bath conditions, 2,4-dichloro-5-nitropyrimidine (compound a, 15 mmol) and DIPEA (77.4 mmol) were mixed in a DCM solution (50 mL), and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (compound b, 22.5 mmol) was slowly added dropwise to the system. The reaction was completed by TLC monitoring. The organic phase was washed with saturated brine, dried, filtered, and spin-dried to obtain a brown oily liquid with a yield of 85%, namely compound c.

[0055] (2) Compound c (19.8 mmol) was dissolved in ethanol (30 mL), and 4-(4-methyl-1-piperazinyl)aniline (compound d, 19.8 mmol) and sodium carbonate (29.7 mmol) were added. The mixture was stirred at room temperature for 3 to 6 h until the reaction was complete. The mixture was diluted with water (20 to 40 mL) and filtered to obtain a yellow powdery product with a yield of 88%, namely compound e.

[0056] (3) Compound e (5.0 g, 9.8 mmol) was dissolved in methanol (50 mL), and Pd / C (0.25 g, 5 wt% Pd in ​​Pd / C) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. TLC monitoring indicated that the starting material was essentially consumed. The mixture was filtered and dried to obtain compound f, which was directly used for the next step.

[0057] (4) Compound f (9.8 mmol) was dissolved in 1,2-dichloroethane (30 mL). Phenyl isothiocyanate (compound g, 9.8 mmol), EDC (9.8 mmol), and DIPEA (9.8 mmol) were added. The mixture was heated to 65°C in an oil bath and stirred overnight. The mixture was separated by silica gel column chromatography to obtain a pale yellow solid powder in a 57% yield, yielding compound h.

[0058] (5) Compound h (2.0 mmol) was dissolved in 10 mL of 10 mol / L hydrochloric acid ethanol solution. The mixture was stirred at room temperature overnight and the solvent was evaporated to dryness to obtain an off-white powdery solid with a yield of 93%, namely compound 719. The structural characterization was similar to that of Example 1.

[0059] Example 3

[0060] (1) Under ice-bath conditions, 2,4-dichloro-5-nitropyrimidine (compound a, 15 mmol) and DIPEA (90 mmol) were mixed in a DCM solution (100 mL), and (S)-tert-butyl 3-aminopiperidine-1-carboxylate (compound b, 45 mmol) was slowly added dropwise to the system. The reaction was completed by TLC monitoring. The organic phase was washed with saturated brine, dried, filtered, and spin-dried to obtain a brown oily liquid with a yield of 85%, namely compound c.

[0061] (2) Compound c (19.8 mmol) was dissolved in ethanol (30 mL), and 4-(4-methyl-1-piperazinyl)aniline (compound d, 27 mmol) and sodium carbonate (29.7 mmol) were added. The mixture was stirred at room temperature for 3 to 6 h until the reaction was complete. The mixture was diluted with water (20 mL) and filtered to obtain a yellow powder with a yield of 78%, namely compound e.

[0062] (3) Compound e (5.0 g, 9.8 mmol) was dissolved in methanol (50 mL), and Pd / C (0.25 g, 5 wt% Pd in ​​Pd / C) was added. The mixture was stirred at room temperature overnight under a hydrogen atmosphere. TLC monitoring indicated that the starting material was essentially consumed. The mixture was filtered and dried to obtain compound f, which was directly used for the next step.

[0063] (4) Compound f (9.8 mmol) was dissolved in 1,2-dichloroethane (30 mL). Phenyl isothiocyanate (compound g, 14.7 mmol), EDC (14.7 mmol), and DIPEA (14.7 mmol) were added. The mixture was heated to 65°C in an oil bath and stirred overnight. Silica gel column chromatography gave a pale yellow solid powder in a 68% yield, compound h.

[0064] (5) Compound h (2.0 mmol) was dissolved in ethanolic hydrochloric acid solution (20 mL, 10 mol / L). The mixture was stirred at room temperature overnight, and the solvent was evaporated to dryness to obtain an off-white powdery solid with a yield of 90%, namely compound 719. The structural characterization was similar to that of Example 1.

[0065] The (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound prepared in Example 1 is described below. Examples 2 and 3 are similar to Example 1 and are not described in detail.

[0066] 1. Verification of in vitro antitumor activity

[0067] To verify the anticancer activity of the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound synthesized in the present invention, the MTT colorimetric assay was used to determine the growth inhibitory effect of the compound on colorectal cancer cells, using the classic EGFR inhibitor gefitinib as a positive control drug.

[0068] Verification method: Tumor cells were cultured in DMEM medium containing 10% calf serum and 100 U·mL penicillin. -1 , streptomycin 100 μg·mL -1 , and subcultured in a 37°C, 5% CO2 incubator. Adherent tumor cells were digested with 0.25% trypsin, and a cell suspension was prepared in culture medium containing 10% calf serum. 200 μL (approximately 3,000 tumor cells) was added to each well of a 96-well culture plate and cultured at 37°C for 24 hours. Different drugs were added to the drug-treated groups, and the concentrations of each drug were set at 0.01, 0.05, 0.1, 0.5, 1.0, 2, 5, 10, 20, and 40 μmol·L -1 The control group was added with a solvent of equal volume to the drug and cultured in a 37°C, 5% CO2 incubator for 72 h. After that, the culture medium was discarded and 20 μL of 5 mg·mL was added to each well. -1 After incubation for 4 h, the supernatant was discarded and 150 μL of DMSO was added to each well. After slight shaking, the optical density (OD) was measured at 490 nm using a microplate reader.

[0069] Result calculation: The tumor cells treated with solvent control were used as the control group, and the inhibition rate of drug on tumor cell proliferation was calculated according to the following formula:

[0070]

[0071] According to the inhibition rate, the IC50 values ​​of different compounds for inhibiting the proliferation of A549 and HCT116 were calculated by linear regression method. The results are shown in Table 1.

[0072] Table 1 Inhibitory effect of compounds on the growth of colorectal cancer cells (IC 50 ,μmol / L)

[0073]

[0074] Compound 719 of the present invention has good anti-tumor activity against various colorectal cancer cells, and its activity is significantly better than that of the EGFR inhibitor gefitinib. It is particularly effective against human colorectal cells HT29 (BRAF mutation) and HCT116 (KRAS mutation), with IC 50 The values ​​reached 0.56 and 1 μmol / L respectively.

[0075] 2. Verification of in vivo antitumor activity

[0076] In order to verify the in vivo anti-cancer activity of the compound provided by the present invention, the subcutaneous tumor model of C57 mice and the AOM / DSS chemically induced colorectal cancer model were used, and the compound 719 was intraperitoneally injected to preliminarily explore the in vivo anti-tumor activity of the compound.

[0077] 1) C57 mouse subcutaneous tumor model

[0078] Verification method: C57 mice, male, 4-6 weeks old. MC38 cells were cultured in vitro. After the cells grew to a sufficient number, they were digested with 0.25% trypsin, collected, centrifuged, and the supernatant was discarded. The cells were resuspended in PBS to a cell suspension density of 5×10 cells per 0.1 mL. 5 Each nude mouse was inoculated with 0.1 mL of cell suspension subcutaneously in the left anterior armpit. 3 The nude mice were randomly divided into 5 groups, 7 in each group, and intraperitoneally administered with the following drugs:

[0079] Solvent group (DMSO:Tween-80:PBS=1:2:7, ip)

[0080] Positive control group (gefitinib, 50 mg kg -1 , ip)

[0081] 719 low-dose group (5 mg·kg -1 , ip)

[0082] 719 medium dose group (20 mg·kg -1 , ip)

[0083] 719 high-dose group (50 mg·kg -1 , ip)

[0084] The day of group administration was recorded as day 1 (d1), and the administration volume was 5 mL·kg -1 The drug was administered once every two days. The weight and tumor volume of the nude mice were recorded every two days. Tumor volume = tumor length × width 2 ÷2, calculate the volume.

[0085] See the results Figure 4 The experimental results showed that when the dosage was 20 mg / kg, compound 719 could significantly inhibit tumor growth; when the dosage was 50 mg / kg, the tumor growth was extremely slow, and the weight changes of mice in each group were not obvious during the administration period.

[0086] Conclusion: Compound 719, administered intraperitoneally, has a significant inhibitory effect on the growth of subcutaneous tumors in C57 mice.

[0087] 2) AOM / DSS chemically induced colorectal cancer tumor model in C57 mice

[0088] Verification method: C57 mice, male, 9 weeks old. Modeling began with intraperitoneal injection of AOM, 10mg / kg, 100uL / 20g, followed by one week of recovery. Oral administration of DSS for three cycles, with a certain proportion of DSS administered orally for one week each cycle, followed by two weeks of recovery. For specific modeling methods, see Figure 5 Middle A. After the three-cycle modeling, intraperitoneal administration was started once every three days. The mice were randomly divided into 6 groups, with 6 mice in each group, namely:

[0089] Solvent group (DMSO:Tween-80:PBS=1:2:7, ip)

[0090] 719 high-dose group (50 mg·kg -1 , ip)

[0091] 719 low-dose group (10 mg·kg -1 , ip)

[0092] Cisplatin-treated group (2 mg·kg -1 , ip)

[0093] Cisplatin combined with 719 low-dose group (DDP 2 mg·kg -1 , ip; 71910mg·kg -1 ,ip)

[0094] Cisplatin combined with 719 medium dose group (DDP 2mg·kg -1 , ip; 71920mg·kg -1 ,ip)

[0095] See the results Figure 5 Results from experiments B, C, and D in Figure 1 demonstrate that compound 719 significantly inhibited tumor growth at a dose of 10 mg / kg, with even more pronounced inhibition at a dose of 50 mg / kg. Combining low-dose 719 with low-dose cisplatin resulted in minimal weight changes during dosing, demonstrating superior tumor suppression with reduced toxicity.

[0096] Conclusion: Compound 719, administered intraperitoneally, has a significant inhibitory effect on the growth of AOM / DSS chemically induced colorectal cancer in C57 mice.

[0097] In summary, the compound (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine disclosed herein is easy to synthesize, highly active, low in toxicity, and effective upon intraperitoneal injection. It can be used to prepare anticancer pharmaceutical preparations. These preparations can be in the form of tablets, capsules, oral liquids, granules, or injections. These preparations can be prepared according to conventional preparation processes for various preparations, and the active ingredient content is 10-100 mg, preferably 10-50 mg.

[0098] The preparations involved in the present invention may contain pharmaceutical excipients, including stabilizers, solubilizers, lubricants, etc., such as glucose, lactose, cellulose, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, starch, pectin, cyclodextrin, Tween-80, polyvinyl alcohol, magnesium stearate, talc, etc.

[0099] The drug complex composed of the (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound of the present invention and other types of anticancer drugs, such as cytotoxic anticancer drugs, antimetabolite anticancer drugs, EGFR inhibitors, RAS inhibitors, immunotherapy drugs, etc., achieves better anticancer effects.

[0100] The preparation of the present invention is a tablet, capsule or injection, wherein each tablet, capsule or injection contains 10 to 100 mg of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound.

[0101] The preparation of the present invention is a tablet or capsule, each tablet or capsule containing 10 to 50 mg of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine compound.

[0102] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications of the present invention fall within the scope of the claims and their equivalents, such changes and modifications are intended to be included.

Claims

1. A use of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine or a pharmaceutically acceptable salt thereof in the preparation of an anti-colorectal cancer drug, characterized in that: The structural formula of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine is: 。 2. A pharmaceutical composition, characterized in that The invention comprises (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine or a pharmaceutically acceptable salt thereof and an excipient, wherein the excipient is one or more of a stabilizer, a solubilizer, a lubricant, and a disintegrant; The structural formula of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine is: 。 3. The pharmaceutical composition according to claim 2, characterized in that The dosage form is tablet, capsule or injection, wherein each tablet, capsule or injection contains 10 to 100 mg of (S)-2-(4-(4-methyl-1-piperazinyl)anilino)-8-anilino-9-(3-piperidinyl)-9H-purine or a pharmaceutically acceptable salt thereof.

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