Diimide derivatives, their preparation and use

Abstract

The present invention provides a diimide derivative, its preparation method and use, which has excellent antitumor activity and antiproliferative activity against multiple types of cancer cells that is far superior to similar compounds. TIFF2025502475000028.tif40170

Description

[Technical field]

[0001] The present invention relates to diimide derivatives, their preparation methods and uses, which belong to the field of medicinal chemistry. [Background technology]

[0002] Diimides are important compounds in the field of medicinal chemistry and possess many interesting pharmacological activities.

[0003] When diimide is further condensed with several condensed rings, a unique planar structure is formed, the molecular volume is greatly reduced, and it can be embedded between the base pairs of the DNA double strand and cause the denaturation of the DNA double helix, which has unique application value against cell proliferation diseases such as cancer. The most common condensed rings condensed with diimide are naphthalene and anthracene. Many compounds with these structures have been reported to have antitumor activity, but few compounds have entered the clinical stage.

[0004] Amonafide is one of the representative compounds, and has been reported to have strong cytotoxic activity against various cancer cells, including colon cancer, lung cancer, gastric cancer, esophageal cancer, and leukemia. Antisoma advanced amonafide into Phase III clinical trials for the treatment of acute myeloid leukemia, but ultimately discontinued development due to low efficacy. TIFF2025502475000002.tif37170

[0005] Currently, the industry continues to research other diimide-based compounds to obtain better potential compounds, but it remains difficult to find compounds with stronger activity than amonafide. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a fused ring diimide compound having excellent properties. [Means for solving the problem]

[0007] In a first aspect, the present invention provides a compound having a diimide structure according to formula I: TIFF2025502475000003.tif39170 (in formula I, A is a naphthalene or anthracene ring, which is condensed to the diimide through three carbon atoms; R1 is selected from a hydrogen atom, alkyloxy or nitro; m or n is 1, 2 or 3, and m+n≦4; R2 is alkyl; R3 is selected from a hydrogen atom or an alkyl; R4 or R5 is selected from alkyl, haloalkyl, or nitroso.

[0008] Also in formula I, R3 optionally forms a ring with R2.

[0009] In some examples, in formula I, the alkyl is a C1-C4 alkyl.

[0010] In some examples, in formula I, the alkyloxy is a C1-C4 alkyloxy.

[0011] In some examples, in formula I, the haloalkyl is haloC1-C4 alkyl.

[0012] In some examples, A is preferably a naphthalene ring in formula I. Some preferred compounds of formula I have better properties, such as higher activity.

[0013] In some examples, in the formula I, R1 is preferably nitro or C1-C4 alkyloxy, more preferably nitro. Some preferred compounds of formula I have better properties, for example higher activity.

[0014] In some examples, R3 is preferably a hydrogen atom in formula I. Some preferred compounds of formula I have better properties, such as higher activity.

[0015] In some examples, in formula I, R3 and R2 together form a 5-membered ring, a 6-membered ring, etc. For example, R3 and R2 together with the nitrogen atom to which they are each attached form a saturated nitrogen heterocycle.

[0016] In some examples, R4 is preferably halo C1-C4 alkyl and R5 is preferably nitroso in formula I. Some preferred compounds of formula I have better properties, e.g., higher activity.

[0017] In some examples, in formula I, m and n are preferably m=1 and n=3, m=1 and n=2, or m=2 and n=2, more preferably m=2 and n=2. Some preferred compounds of formula I have better properties, e.g., higher activity.

[0018] In some examples, in said formula I, said C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like; and said halogen includes fluorine, chlorine, and bromine.

[0019] In a second aspect, the present invention provides a method for preparing a compound of formula I, comprising reacting a compound of formula M7 with a compound of formula M8 in the presence of an alkali to produce a compound of formula I, as shown in the reaction scheme. TIFF2025502475000004.tif26170 (wherein A, m, n, R1, R2, R3, R4 and R5 in the reaction formula are as defined above.)

[0020] In some examples, the alkali is selected from sodium hydroxide, potassium carbonate, cesium carbonate, or sodium phosphate.

[0021] The compounds represented by formula M7 and M8 may be commercially available or may be obtained by chemical synthesis.

[0022] In some examples, the compound of formula M7 may be prepared by first reacting a compound of formula M4 with a compound of formula M5 to produce a compound of formula M6, and then treating the compound of formula M6 in the presence of an acid to obtain a compound of formula M7, as shown in the reaction scheme. TIFF2025502475000005.tif64170 (A, m, n, R1, R2, and R3 in the reaction formula are as defined above.)

[0023] In some instances, the acid is a common acid, such as hydrochloric acid.

[0024] Compounds of formula M4 may be commercially available or may be obtained by chemical synthesis.

[0025] In some examples, the compound of formula M4 may be prepared by first reacting a compound of formula M1 with a compound of formula M2 to produce a compound of formula M3, and then hydrogenating the compound of formula M3 to obtain a compound of formula M4, as shown in the reaction scheme. TIFF2025502475000006.tif49170 (In the reaction formula, X is a halogen, Cbz is benzyloxycarbonyl, Boc is tert-butoxycarbonyl, and m, n, R2, and R3 are as defined above.)

[0026] In a third aspect, the present invention provides the use of a compound of formula I in the preparation of a medicament for treating a cell proliferative disorder.

[0027] In some instances, the cell proliferative disorder is cancer.

[0028] In some instances, the cancer is a gastrointestinal tumor, a respiratory tumor, and / or a hematopoietic tumor, such as a colon tumor, a lung tumor, and a blood tumor.

[0029] In a fourth aspect, the present invention provides a method for treating a cell proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I above.

[0030] In some instances, the cell proliferative disorder is cancer.

[0031] In some instances, the cancer is a gastrointestinal tumor, a respiratory tumor, and / or a hematopoietic tumor, such as a colon tumor, a lung tumor, and a blood tumor. Effect of the Invention

[0032] The diimide derivative according to the present invention is a novel compound. Research results have shown that the diimide derivative has excellent in vivo and in vitro antitumor activity, and has significant inhibitory effects on various tumors such as colon tumors, lung tumors, and blood tumors. Moreover, its antitumor activity is far superior to that of similar compounds, and it has promising future applications. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The present invention will be further described below with reference to examples, and some preferred compounds are illustrated, but the examples are not intended to limit the technical solutions and technical effects of the present invention. Example 1: Compound I-01

[0034] Reaction scheme: According to the reaction scheme TIFF2025502475000007.tif83170, specifically, compound I-01 was prepared as follows. 1.1 Preparation of intermediate I-01-M3: Compound I-01-M2 (3.48 g, 20 mmol) was dissolved in 30 mL of DMF, and then K2CO3 (4.16 g, 30 mmol), NaI (3.00 g, 20 mmol), and compound I-01-M1 (5.14 g, 20 mmol) were added to the mixture in sequence, and the mixture was reacted at 30° C. overnight. After the reaction was completed, purified water (120 ml) was added to the reaction solution, which was then extracted three times with ethyl acetate (180 ml), dried over anhydrous MgSO4, filtered, and the mother liquor was concentrated and purified by column chromatography to obtain intermediate I-01-M3 (4.07 g, 11.6 mmol) in a yield of 58%. 1.2 Preparation of intermediate I-01-M4: Intermediate I-01-M3 (4.07 g, 11.6 mmol) was dissolved in methanol (25 mL), 10% Pd / C (0.3 g) was added, hydrogen gas was replaced three times, and the mixture was reacted overnight at normal pressure. The mixture was filtered through diatomaceous earth, and the mother liquor was concentrated to obtain intermediate I-01-M4 (2.50 g, 11.5 mmol) as a colorless oil in a yield of 99.1%. 1.3 Preparation of intermediate I-01-M6: intermediate I-01-M4 (2.50 g, 11.5 mmol), ethanol (60 ml), and compound I-01-M5 (2.79 g, 11.5 mmol) were sequentially added to a reaction flask, heated to 80°C and reacted for 2 hours, cooled, and the reaction liquid was concentrated and purified by column chromatography to obtain intermediate I-01-M6 (3.63 g, 8.2 mmol) in a yield of 71.3%. 1.4 Preparation of intermediate I-01-M7: intermediate I-01-M6 (3.63 g, 8.2 mmol) was dissolved in 4% hydrogen chloride in ethyl acetate (50 ml), reacted at room temperature overnight, filtered and dried to obtain intermediate I-01-M7 (2.67 g, 7.8 mmol) in a yield of 95.1%. 1.5 Synthesis of compound I-01: Compound I-01-M8 (2.46 g, 9 mmol), dichloromethane (30 ml), triethylamine (2.02 g, 20 mmol) were added to a reaction flask in sequence, cooled to 0°C, intermediate I-01-M7 (2.67 g, 7.8 mmol) was added in batches, reacted at 0°C overnight, washed with water (20 ml), dried over anhydrous MgSO4, filtered, concentrated the mother liquor, and purified by column chromatography to obtain compound I-01 (2.14 g, 4.5 mmol) in a yield of 57.7%. Product identification: 1 H-NMR(400MHz,d6-DMSO)δ:2.97(s,3H),3.34-3.40(m,2H),3.46-3.51(m,2H),3 .58(t,J=6.5Hz,2H),3.72-3.77(m,2H),3.98-4.11(m,2H),4.46(t,J=6.2Hz,2H) ,8.06(dd,J=8.2,7.4Hz,1H),8.67-8.62(dd,J=7.3,1.1Hz,1H),8.78(dd,J=8.5 ,1.1Hz,1H),8.89(d,J=2.3Hz,1H),9.00(t,J=5.5Hz,1H),9.48(d,J=2.3Hz,1H). Example 2: Compound I-02

[0035] Compound I-02 was prepared by referring to the method of Example 1. Product Identification: 1 H-NMR(400MHz,d6-DMSO)δ:1.04(t,J=7.6Hz,3H),2.81-2.84(m,4H),2.92(s,3H),3.45 -3.50(m,2H),3.52-3.55(m,2H),3.70(t,J=2.9Hz,2H),3.82(t,J=2.9Hz,2H),4.46(t, J=4.6Hz,2H),8.06(dd,J=8.2,7.4Hz,1H),8.67-8.62(dd,J=7.3,1.1Hz,1H),8.78(dd, J=8.5,1.1Hz,1H),8.89(d,J=2.3Hz,1H),9.00(t,J=5.5Hz,1H),9.48(d,J=2.3Hz,1H). Example 3: Compound I-03

[0036] Compound I-03 was prepared by referring to the method of Example 1. Product Identification: 1 H-NMR(400MHz,d6-DMSO)δ:1.73-1.79(m,2H),2.94(s,3H),3.25(t,J=5.1Hz,2H), 2.47-2.53(m,2H),3.55(t,J=2.9Hz,2H),3.78(t,J=2.9Hz,2H),4.76(d,J=2.9Hz, 2H),8.06(dd,J=8.2,7.4Hz,1H),8.67-8.62(dd,J=7.3,1.1Hz,1H),8.78(dd,J=8. 5,1.1Hz,1H),8.90(d,J=2.3Hz,1H),9.00(t,J=5.5Hz,1H),9.48(d,J=2.3Hz,1H). Example 4: Compound I-04

[0037] Compound I-04 was prepared by referring to the method of Example 1. Product Identification: 1 H-NMR(400MHz,d6-DMSO)δ:1.04(t,J=7.6Hz,3H),1.18(t,J=7.6Hz,3H),2.64-2.68(m, 4H),2.96(s,3H),3.28(q,J=5.8Hz,2H),3.44(t,J=4.5Hz2H),3.78-3.82(m,2H),4.44( t,J=4.4Hz2H),8.06(dd,J=8.2,7.4Hz,1H),8.67-8.62(dd,J=7.3,1.1Hz,1H),8.81(dd ,J=8.5,1.1Hz,1H),8.89(d,J=2.3Hz,1H),9.07(t,J=5.5Hz,1H),9.48(d,J=2.3Hz,1H). Example 5: Compound I-05

[0038] Compound I-05 was prepared according to the method of Example 1. Product Identification: 1H-NMR(400MHz,d6-DMSO)δ:2.98(s,3H),3.16(s,3H),3.44-3.47(m,2H),3.56-3.63(m,4H),4.33(t,J=4.6Hz,2H),8.06(dd,J=8.2,7.4Hz ,1H),8.67-8.62(dd,J=7.3,1.1Hz,1H),8.81(dd,J=8.5,1.1Hz,1H),8.89(d,J=2.3Hz,1H),9.02(t,J=5.5Hz,1H),9.51(d,J=2.3Hz,1H). Example 6: Compound 1-06

[0039] TIFF2025502475000012.tif30170 refers to the method of Example 1 and the preparation of compound I-06. The identity of the product: 1 H-NMR(400MHz,d6-DMSO)δ:1.17(t,J=5.8Hz,6H),2.87(s,3H),3.15(q,J=5.8Hz,4H),3.22-3.25(m,2H),3.38(t,J=4.5Hz,2H),3.89 (s,3H),4.86(s,2H),7.65(t,J=7.8Hz,1H),8.06(dd,J=8.2,7.4Hz,1H),8.13(d,J=8.4Hz,1H),8.32-8.42(m,2H),8.62-8.68(m,1H). Example 7: Compound 1-07

[0040] TIFF2025502475000013.tif34170 refers to the method of Example 1 and the preparation of compound I-07. The identity of the product: 1 H-NMR(400MHz,d6-DMSO)δ:1.77-1.83(m,2H),2.91(s,3H),2.94(s,6H),3.25(t,J=5.1Hz,2H),3.5 4-3.58(m,2H),4.84(d,J=3.5Hz,2H),7.65(d,J=7.4Hz,1H),7.83-7.86(m,2H),8.43-8.52(m,4H). Example 8: Compound 1-08

[0041] According to the reaction scheme TIFF2025502475000014.tif81170, compound I-08 was prepared. The specific method is as follows: 8.1 Synthesis of intermediate I-08-M3: Compound I-08-M2 (3.72 g, 20 mmol) was dissolved in 30 mL of DMF, and then K2CO3 (4.16 g, 30 mmol), NaI (3.00 g, 20 mmol), and compound I-08-M1 (5.14 g, 20 mmol) were added to the mixture in sequence, and the mixture was reacted at 30° C. overnight. After the reaction was completed, purified water (120 ml) was added to the reaction solution, which was then extracted three times with ethyl acetate (180 ml), dried over anhydrous MgSO4, filtered, and the mother liquor was concentrated and purified by column chromatography to obtain intermediate I-08-M3 (4.39 g, 12.1 mmol) in a yield of 60.5%. 8.2 Synthesis of intermediate I-08-M4: Intermediate I-08-M3 (4.39 g, 12.1 mmol) was dissolved in methanol (20 mL), 10% Pd / C (0.3 g) was added, hydrogen gas was replaced three times, and the mixture was reacted overnight at normal pressure. The mixture was filtered through diatomaceous earth, and the mother liquor was concentrated to obtain intermediate I-08-M4 (2.75 g, 12.0 mmol) as a colorless oil in a yield of 99.2%. 8.3 Synthesis of intermediate I-08-M6: intermediate I-08-M4 (2.75 g, 12.0 mmol), ethanol (50 ml), and compound I-08-M5 (2.92 g, 12.0 mmol) were sequentially added to a reaction flask, heated to 80°C and reacted for 2 hours, cooled, and the reaction liquid was concentrated and purified by column chromatography to obtain intermediate I-08-M6 (4.22 g, 9.3 mmol) in a yield of 77.5%. 8.4 Synthesis of intermediate I-08-M7: Intermediate I-08-M6 (4.22 g, 9.3 mmol) was dissolved in 4% hydrogen chloride in ethyl acetate (60 ml), reacted at room temperature overnight, filtered and dried to give intermediate I-08-M7 (3.12 g, 8.8 mmol) in a yield of 94.6%. 8.5 Synthesis of compound I-08: Compound I-08-M8 (2.62 g, 9.6 mmol), dichloromethane (35 ml), triethylamine (2.02 g, 20 mmol) were added to a reaction flask in sequence, cooled to 0°C, intermediate I-08-M7 (3.12 g, 8.8 mmol) was added in batches, reacted at 0°C overnight, washed with water (25 ml), dried over anhydrous MgSO4, filtered, concentrated the mother liquor, and purified by column chromatography to obtain compound I-08 (2.54 g, 5.2 mmol) in a yield of 59.1%. Product identification: 1 H-NMR(400MHz,d6-DMSO)δ:2.61-2.73(m,4H),2.94-2.98(m,2H),3.19-3.34(m,4H),3.57(t,J=2.9Hz,2H),3.78(t,J=2.9Hz,2H),4.45(t,J=4 .6Hz,2H), 8.67-8.62(dd,J=7.3,1.1Hz,1H),8.78(dd,J=8.5,1.1Hz,1H),8.89(d,J=2.3Hz,1H),9.00(t,J=5.5Hz,1H),9.48(d,J=2.3Hz,1H). Example 9: Compound I-09

[0042] Compound I-09 was prepared by referring to the method of Example 1 of TIFF2025502475000015.tif34170. Product Identification: 1 H-NMR(400MHz,d6-DMSO)δ:2.61-2.73(m,4H),2.94-2.98(m,2H),3.19-3.34( m,4H),3.57(t,J=2.9Hz,2H),3.78(t,J=2.9Hz,2H),4.47(t,J=4.6Hz,2H),7.5 3(t,J=6.1Hz,1H),7.58-7.65(m,1H),7.79(t,J=7.8Hz,1H),8.04-8.10(m,1H) ,8.33-8.35(m,1H),8.49(d,J=6.3Hz,1H),8.84(s,1H),9.38(d,J=7.8Hz,1H). Example 10: Compound I-10

[0043] Compound I-10 was prepared by referring to the method of Example 1. Product Identification: 1 H-NMR(400MHz,d6-DMSO)δ:1.72-177(m,2H),2.95(s,3H),3.35-3.38(m,2H),3.54(t,J=2.9Hz,2H),3.68(t,J=5.1Hz,2H),3.82(t,J=2.9Hz,2H ),4.65(s,2H),7.73-7.81(m,2H),8.27(d,J=6.2Hz,1H),8.39-8.50(m, 2H), 8.87(d,J=6.2Hz,1H),9.28(d,J=2.6Hz,1H),9.52(d,J=7.9Hz,1H). Example 11: Compound I-11

[0044] Compound I-11 was prepared by referring to the method of Example 1. Product Identification: 1 H-NMR(400MHz,d6-DMSO)δ:2.94(s,3H),2.95-3.05(m,2H),3.40(t,J=4.5Hz,2H), 3.56(t,J=2.9Hz,2H),3.80-3.82(m,2H),3.84(t,J=2.9Hz,2H),4.49(t,J=4.5Hz, 2H),7.53(t,J=6.1Hz,1H),7.59-7.66(m,1H),7.78(t,J=6.2Hz,1H),8.04-8.10(m ,2H),8.33-8.35(m,1H),8.49(d,J=6.2Hz,1H),8.73(s,1H),9.38(d,J=7.8Hz,1H). Example 12: Compound I-12

[0045] Compound I-12 was prepared by referring to the method of Example 1. Product Identification: 1H-NMR(400MHz,d6-DMSO)δ:1.04(t,J=7.2Hz,3H),2.56(q,J=5.8Hz,2H),2.94(t,J=4.4Hz, 2H),3.27-3.31(m,2H),3.45(t,J=4.4Hz,2H),3.54(t,J=2.9Hz,2H),3.77(t,J=2.9Hz,2H), 4.14(t,J=4.6Hz,2H),7.53(t,J=6.2Hz,1H),7.59-7.66(m,1H),7.78(t,J=6.2Hz,1H),8.04 -8.10(m,2H),8.33-8.35(m,1H),8.49(d,J=6.2Hz,1H),8.73(s,1H),9.38(d,J=7.8Hz,1H). Example 13: Study on the in vitro antitumor activity of compounds of formula I

[0046] Study objective: To test the antiproliferative activity of the compounds of the present invention against various tumor cells.

[0047] Test compounds: compounds of the present invention I-01, I-02, I-03, I-04, I-05, I-06, I-07, I-08, I-09, I-10, I-11, I-12, amonafide and lomustine as positive compounds, and comparison compounds 1, 1d, Cob280, and Cob281. Among them, compound 1 is "component 1" described in the literature Journal of Experimental Therapeutics and Oncology, 2005, 5: p 15-22, compound 1d is "1d" described in the literature Journal of Cancer Molecules, 2010, 5(2): p 41-47, compound Cob280 is "Cob280" described in Example 17a of the literature WO2012104788, and compound Cob281 is "Cob281" described in Example 17b of the literature WO2012104788, which are prepared by the methods described in the literature, and the positive compounds amonafide and lomustine are commercially available products. TIFF2025502475000019.tif80170

[0048] Test cells: human colon cancer cells (HT-29, COLO 205), human lung cancer cells (NCI-H460, A549), human leukemia cells (HL-60, U-937).

[0049] Test method: Each tumor cell was manipulated individually. The cells were cultured in culture medium at 37°C for 24 hours to prepare for use. Cells in the exponential growth phase were harvested and treated with trypsin to prepare a cell suspension, the cell suspension was centrifuged, and then the cell pellet was resuspended in a small amount of fresh medium as a stock cell solution. This stock solution was diluted to the desired cell concentration. The concentration of each cell is shown in Table 1.

[0050] [Table 1]

[0051] A 96-well plate was prepared and a blank control group, a cell control group, and a compound group were set up. For the blank control group, only 10% PBS was added to each well. For the cell control group and the compound group, 100 μL of cells at the above concentrations were added to each well. The remaining wells were filled with 200 μL of 10% PBS. The plate was placed in an incubator and left overnight. For the compound group, 100 μL of each test compound at different dilutions was added. The compound dilution concentrations are shown in Table 2.

[0052] [Table 2]

[0053] After adding the drugs, the plates were placed in an incubator and incubated for 96 hours, 22 μL of resazurin sodium solution (Alarm blue, SIGMA R7017) was added to each well, and the plates were returned to the incubator and incubated for another 4 hours. After removal, the plates were shaken for 10 seconds, and the fluorescence value of each well was recorded at 530 / 590 nm.

[0054] The above procedure was repeated three times.

[0055] Using Prism7 software, the IC of each test compound was calculated. 50 The IC values ​​were calculated. 50 are divided into various levels according to the magnitude of the values, i.e., SSS: <0.5 μM; SS: 0.5-1 μM; S: 1-5 μM; A: 5-10 μM; B: 11-20 μM; C: 21-50 μM; D: 51-100 μM; E: >100 μM. The main results are shown in Table 3.

[0056] [Table 3]

[0057] The results of the test suggest that lomustine has low activity against various tumor cells, whereas amonafide has high activity.The activity of compounds 1d, 1, Cob280 and Cob281 is not superior to that of amonafide, and even has reduced activity.However, surprisingly, the antitumor activity of the compounds of the present invention is significantly superior to that of amonafide, lomustine and similar compounds 1d, 1, Cob280 and Cob281.The specific preferred compounds of the present invention have 100 times or more activity than similar compounds. Example 22: Study on the in vivo antitumor activity of the compound of formula I

[0058] Study objective: To further test the in vivo antitumor effects of the compounds of the present invention.

[0059] Test compounds: I-01, I-08.

[0060] Test animals: 5-week-old female BALB / c nude mice. After 7 days of regular feeding, mice in good health were selected for testing.

[0061] Tumor cells: human colon cancer cells COLO 205 cultured in RPMI-1640 medium containing 10% fetal bovine serum. Passage was performed once or twice a week, with a passage ratio of 1:3 to 1:6.

[0062] Modeling and grouping: COLO 205 cells in logarithmic growth phase were harvested and injected into the right front mammary fat pad of nude mice to establish the COLO 205 tumor transplant model, with the injection volume being 5 × 10 per animal. 6 The condition of the animals was observed periodically, the tumor diameter was measured, and the tumor volume was calculated. 3 After reaching 100 mg / kg, tumor-bearing mice in good health and with similar tumor volumes were selected and randomly divided into a solvent control group, an I-01 group, and an I-08 group.

[0063] Administration: Each test compound was dissolved in a solvent, and the corresponding compound or blank solvent was administered to each animal group. The administration method was intragastric administration, and the dosage was 10 mg / kg, once a day, for a total of 21 times.

[0064] Results: On the final day of the experiment, tumor diameter and tumor weight were measured, and tumor volume inhibition rate (GI) and tumor weight inhibition rate (IR) were calculated. The main results are shown in Table 4.

[0065] Tumor volume inhibition rate = 100% x [1 - (Tvt - Tvini) ÷ (Cvt - Cvini)], where Tvt represents the tumor volume at the end of the study in the treatment group, Tvini represents the tumor volume at the time of grouping in the treatment group, Cvt represents the tumor volume at the end of the study in the solvent control group, and Cvini represents the tumor volume at the time of grouping in the solvent control group.

[0066] Tumor weight inhibition rate=100%×(Cw−Tw)÷Cw, where Cw represents the tumor weight at the end of the study in the vehicle control group, and Tw represents the tumor weight at the end of the study in the treatment group.

[0067] [Table 4]

[0068] The test results show that the compounds of the present invention have a strong antitumor effect in vivo.

[0069] The present invention has been described in detail above by using general descriptions and specific embodiments. Those skilled in the art may make some modifications or improvements based on the present invention without departing from the spirit of the present invention, all of which fall within the scope of protection claimed by the present invention.

Claims

1. A diimide derivative represented by formula I: 【Chemistry 1】 (In formula I, A is a naphthalene or anthracene ring, condensed to the diimide through three carbon atoms; R １ is selected from a hydrogen atom, alkyloxy or nitro; m or n is 1, 2 or 3, and m+n≦4; R ２ is alkyl, R ３ is selected from a hydrogen atom or alkyl; R ４ Or R ５ is selected from alkyl, haloalkyl, or nitroso.

2. 2. The diimide derivative according to claim 1, wherein said alkyl is a C1-C4 alkyl, said alkyloxy is a C1-C4 alkyloxy, and said haloalkyl is a haloC1-C4 alkyl.

3. The diimide derivative according to claim 1 , wherein A is a naphthalene ring.

4. The R １ The diimide derivative according to claim 1, wherein is nitro or C1-C4 alkyloxy.

5. The R ３ The diimide derivative according to claim 1 , wherein is a hydrogen atom.

6. The R ３ and R ２ The diimide derivative according to claim 1 , wherein together form a ring.

7. The R ４ is haloC1-C4 alkyl, and R ５ The diimide derivative according to claim 1 , wherein is nitroso.

8. 2. The diimide derivative according to claim 1, wherein m and n are selected from m=1 and n=3, m=1 and n=2, or m=2 and n=2.

9. A method for preparing a diimide derivative of formula I, comprising reacting a compound of formula M7 with a compound of formula M8 in the presence of an alkali to produce a compound of formula I according to the reaction scheme: 【Chemistry 2】 (Here, A, m, n, and R in the reaction formula １ , R ２ , R ３ , R ４ , and R ５ is as described in claim 1.)

10. The preparation method of claim 9, wherein the compound of formula M7 is prepared by first reacting a compound of formula M4 with a compound of formula M5 to produce a compound of formula M6 according to the reaction scheme, and then treating the compound of formula M6 in the presence of an acid to obtain the compound of formula M7. 【Chemistry 3】 (A, m, n, R in the reaction formula １ , R ２ , and R ３ is as described in claim 1.

11. The preparation method according to claim 10, wherein the compound of formula M4 is prepared by first reacting a compound of formula M1 with a compound of formula M2 to produce a compound of formula M3 according to the reaction scheme, and then hydrogenating the compound of formula M3 to obtain the compound of formula M4. 【Chemistry 4】 (In the reaction formula, X is a halogen, Cbz is benzyloxycarbonyl, Boc is tert-butoxycarbonyl, and m, n, R ２ , and R ３ is as described in claim 1.)

12. Use of the diimide derivative according to any one of claims 1 to 8 in the preparation of a medicament for treating a cell proliferative disorder.

13. The use according to claim 12, wherein the cell proliferative disorder is cancer.

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