TWI235750B - Anti-cancer pharmaceutical composition containing xanthone derivative - Google Patents

Abstract

The present invention discloses an anti-cancer use of garcinone E in xanthone derivative extracted from shell of mature Garcinia mangostana Linn, which has a significantly cytotoxic effect on cancer cells in stomach, lung and liver, indicating its potential as an anti-cancer medicine along or in conjunction with other drugs.

Description

1235750 A7 --- B7 V. Description of the invention (1) Background of the invention

Clij ketones (Xanthone) are natural or synthetic chemicals that are similar in structure to anthraquinones. Among the compounds of the anthracene series, mitoxanUone is a drug that has been proven to have a strong anticancer effect. Nil ketones are commonly found in the shells of gutiferaeous plants such as mangosteen and dried gums (Govindachari, T.R., Kalyanaraman, P. S. and

Muthukumaraswamy, N. 1971 Xanthones of Garcinia mangostana Linn. Tetrahedron 27, 3919-3926 .; Printed by the Consumer Cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs -------- • Installation ------ (Please read the back first (Notes to fill out this page)

Goncalves DE Oliverira, W., Gottlieb, OR and Lins Mesquita, AA 1972 Xanthones from Tovomita macrophylla. Phytochemistry 11, 3323-3325), immunosuppressants were found in the extracts of the outer skin of mature fruits (Chanarat, P., Chanarat, N., Fujihara, M. and Nagumo, T. 1997 Immunopharmacological activity of polysaccharide from the pericarb of mangosteen garcinia: phagocytic intracellular killing activities. J Med Asso Thail 80, S 1 49-S 1 54; Gopalakrishnan, C. ,, Shankaranarayanan, D., Kameswaran, L. and Nazimudeen, SK 1980 Effect of mangostin, a xanthone from Garcinia mangostana Linn. In immunopathological & Inflammatory reactions. Indian J Exper Biol 18, 843-846), antibacterial (Iinuma, M. , Tosa, H., Tanaka, T., Asai, F., Kobsyashi, Y., Shimano, R. and Miyauchi, KI. 1996 Antibacterial activity of xanthones from Guttiferaeous plants against methic ill in · 4 This paper standard applies to China National Standard (CNS) A4 Specification (210 X 297 mm) Published 1235750 A7 ___B7 V. Description of the invention (2) resistant Staphylococcus aureus. J Pharm Pharmacol 48, 861 -865), anti-mutation (Shankaranarayan, D., Gopalakrishnan, C. and Kameswaran, L. 1 979 Pharmacological profile of mangostin and its derivatives. Arch Internat Pharmaco Therapie 239, 257-269 .; Edenharder, R. and Tang, X. 1 997 Inhibition of the mutagenicity of 2-Nitrofluorene, 3-Nitrofluranthene and 1-Nitropyrene by Flavonoids, Coumarians, Quinones and other Phenolic compounds.

Food and Chem Toxicol 35, 357-3 72), anti-cancer and other medicinal active ingredients (Liou, SS ·, Sheih, WL ·, Cheng, T · Η., Won, SJ · and Lin, CN 1 993 γ -Pyrone compounds as potential anti-cancer drugs. J Pharm Pharmacol 45, 791-794; Lin, CN, Liou, SJ, Lee, TH, Chuang, YC and Won, SJ 1 996 Xanthone derivatives as potential anti-cancer drugs. J Pharm Pharmacol 48, 539-544) o Summary of the invention The present invention discloses that an oil ketone derivative, garcinone E, has a powerful cytotoxic effect on different cancer cell lines. The efficacy of garcinone is compared with chemotherapy drugs commonly used in cancer treatment. E's toxicity to four target cell lines HEp 3B, HEp G2, TONG and SK-HEp-1 is lower than that of taxol but better than five chemotherapeutics such as mitoxantrone, cisplatin, methrothrexate, vincristine, and 5-flurouracil. In addition, garcinone E has also been found to effectively kill different gastric and lung cancer cell lines. Explanation of the above results 5 The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) I. ——..---------- (Please read the precautions on the back before filling in this Page) Order. 丨

V. Explanation of the invention (3)! 235750 garcinoneE has the potential to develop into new anticancer drugs, especially for the treatment of gastric cancer, lung cancer and liver cancer. Detailed description of the invention Materials and methods Cell culture The different cell lines tested in the present invention include those derived from the liver: TONG (Lin et al., 1984), HA22T (Zhang et al., 1 983), and HEp3B, HEpG2, and SK-B from ATCC. ΗΕρ-1; lungs: NCI-Hut-125, CH2 7LC-:!, H29 81 and Calu-1 (all purchased from ATCC); stomach: AZ521 (Taki et al., 1985), NUGC-3 (Baba et al. (1,995), KATO-III and AGS (purchased from ATCC). All the above cell lines are stored in the cell bank of Rongmin General Hospital for long-term use. The culture medium of each cell is shown in Table 1. Cells were colonized twice a week using the trypsin / versese method. ▼ Packing -------- Order ---- (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6 This paper size applies to China National Standard (CNS) A4 Specifications (210 X 297 public love) 1235750 A7 —______ B7__ 5. Description of the invention (4) Table 1. List of human cell strains used for screening anti-cancer compounds in this study, their tissue sources and culture media used

Cell line tissue source medium HEp3B Liver DMEM + 1% NE AA + 10% FBS HCC36 Liver DMEM + 1% NEAA + 10% FBS TONG Liver DMEM + 1% NEAA + 10% FBS HA22T Liver DMEM + 1% NEAA + 10% FBS HEpG2 Liver DMEM + 1% NEAA + 10% FBS Sk-HEp-1 Liver MEM + 10% FBS NCI-Hut 125 Lung DMEM + 5% FBS CH27 LC-1 Lung DMEM + 5% FBS H298 1 Lung DMEM + 5% FBS Calu-1 Lung DMEM + 5% FBS AZ5 21 Stomach RPMI-1 640 hh 10% FBS NUGC-3 Stomach RPMI-1640-h 10% FBS KATO-III Stomach RPMI-1640-f 10% FBS AGS Stomach F12 + 10% FBS IJHJ ------ # pack (please read the notes on the back before filling this page) -ISO, · Printed gi | ketone (Xanthones) and purified mountain from the Intellectual Property Bureau of the Ministry of Economic Affairs' Consumer Cooperatives The bamboo is provided by a local fruit supplier. The shell is first washed and dried with hydrocarbons and then extracted with ethanol. The extract is first concentrated in a vacuum and then dissolved in ethyl acetate (EtoAc). It is divided into soluble and insoluble In two parts, the ethyl acetate soluble part is refilled into the silicon gel column and the following Solvent mixtures with the same ingredients dissolve in sequence, including n-hexane-ethyl acetate 7 This paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1235750 A7 B7 V. Description of the invention (5) Ester (20: 1 To 10: 1), dichloromethane-acetone (10: 1 to 0: 1), dichloromethane-acetone (10: 1 to 0: 1), and co-dissolved to obtain 22 components, of which components 4 and 5 8-desoxygartanin (1) and gartanin (2); component 7 (n-hexane-EtoAc 1 0: 1 solvent) were re-crystallized from ethyl acetate of Zhengjiyuan and re-injected into the column layer Sephadex LH-20. (Methanol-water = 3: 1) After purification, garcinone E (3) and tovophyllin A (4) can be obtained; component 13 (dichloromethane-acetone, 10: 1 solvent) is further purified using a silica gel column layer, and A-mangostin (5) was dissolved by dissociation of acetone (4: 1) in dichloromethane; finally, the crystal of r-mangostin (6) can be obtained by using Sephadex LH-20 (methanol-water = 3 ·· 1). .

Identification of Garcinone E

Garcinone E crystals are identified using traditional infrared spectrum (IR), mass spectrum (MS), and nuclear magnetic resonance (NMR). The obtained physical and chemical properties are simultaneously with Sakai et al. (Sakai, SI, Katsura, M., Takayama, H., Aimi, N., Chokethaworn, N. and Surttajit, M. 1993 The structure of garcinone. Chem Pharm Bull 41,958 -960). Cell killing test Cells (1 X 105 / ml) were placed in a 24-well (1 ml / well) petri dish (Falcon, Lincoln Park 'NJ) and cultured at 37C. Garcinone E (0-10 / i M) was then added to the medium in duplicates. Cells will follow the Chinese paper standard (CNS) A4 specifications (210 X 297 mm) following 8 paper sizes (please read the precautions on the back before filling out this page) ----) alr Printed by the cooperative A7 B7 1235750 V. Description of the invention (6 After 3 to 6 days of continuous culture, the survival rate of the cells is determined by the MTT method (Mosmann, 1 983). The killing is based on the 50% killing dose (LD5Q), and Calculated based on the dose extension above and below 50% cytotoxicity. Cell cycle analysis: Cells were seeded in a p60 culture dish (1 X 105 / ml), and Garcinone E (0-10 # M) was added at different concentrations. The cell harvest is used for cycle analysis 12 or 48 hours after treatment. The method is to do as recommended by the CycleTest assay Kit (Becton-Dickinson) manufacturer, and the processed cells are processed by the FACScan flow cytometer ) To determine the area ratio of the Go / Gl, S and G2 / M phases in the cell cycle under the cell histogram, respectively, and express it as a percentage. This measurement is repeated at least three times.

Purification of Garcinone E A total of six different xantrone derivatives were purified from the extract of the mangosteen shell. After identification, they were: 8-desoxygartanin (1): yellow needle-like crystals from acetone / n-hexane component; gartanin (2): yellow needle-like crystals from acetone / n-hexane component; garcinone E (3) : Yellow needle-like crystals from the methanol / water component; tovophyllin A (4): yellow needle-like crystals from the acetone / n-hexane component; a -Mangostin (5): yellow needle-like crystals from the methanol / water component and T- MangoStin (6): yellow powdery crystals from acetone / water component. 9 Qiaozhi scale applies Chinese National Standard (CNS) A4 specification (21Gx 297 public love) I-(Please read the precautions on the back before filling this page) ----- Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Cooperatives, Printing Economy Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau 1235750 A7 --- B7 V. Description of Invention (7) Identification of parcinone E

The physical and chemical properties of Garcinone E were identified by infrared spectrometer (IR), tritium and 13C nuclear magnetic resonance spectrometer (NMR) and mass spectrometer (MS). The results are as follows: (EIMS) (20eV) m / z 464 [M ] + (C28H3206, 1 00);] H NMR (Me2CO- ^ 6, 500 MHz) δ 1.62, 1.63, 1.64, 1.77, 1.81 and 1.87 (each 3H, s, 6xCH3), 3.35, 3.61 and 4.20 (each 2H , D, J = 7.5 Hz, Hl 1, 16, 21), 5.25 (3H, m, H-1 2, 1 7, 22), 6.47 (1H, s, H-4), 13.90 (1H, s, OH-1); 13C NMR (Me2CO-d6, 125 MHz) δ 17.86, 18.10, and 18.28 (3 > < CH3), 21.95 and 23.16 (2xCH2), 25.84, 25.85 and 25.92 (3 xCH3), 26.35 (CH2) , 93.03 (C-4), 1 03.57 (C-9a), 110.77 (C-2), 111.88 (C-8), 114.23 (C-5), 122.54 (C-17), 123.57 (C-22) , 124.43 (C-12), 128.22 (C-8a), 131.26 (C-23) '131.49 (C-13), 132.35 (C-18), 151.72 and 152.21 (C-6, 10a), 155.69 (C -4a), 161.55 (Cl), 162.80 (C-3), 1 83.42 (C-9). The molecular formula of Garcinone E is C28H3206, and its structural formula is shown in Figure 1. The above results are consistent with the characteristics found by Sakai et al (1 993).

Toxicity effect of Garcinone E In preliminary experiments, I have tested all six xanthone derivatives from mangosteen, and found that the cytocidal effect of garcinone E is much better than other compounds, so in future experiments we will focus on It is mainly garcinone E. From Figure 2, we can know that six types of hepatocellular carcinoma cell lines include Hep 3B, HCC36, TONG, HA22T and SK-HEp-1. 10 paper sizes for garcinone E are applicable to Chinese National Standard (CNS) A4 specifications ( 210 X 297 public love) I " --- .17II ----------- (Please read the precautions on the back before filling this page) ΊβΊτ · 1235750 A7 B7 V. Description of the invention (8) All have anti-cell effects. This toxic effect is directly proportional to the treatment time and dose. It can produce a complete cytotoxic effect on various cell lines at a dose of S 100 Μ, and garcinoneE can also kill cells from lung cancer tissues. (Figure 3) Garcinone E is also effective when tested against gastric cancer cells and shown in Figure 4. All the treated cells died after six days. A summary of the above results can be found in Table 2. If LD5. The relative effect of garcinone E against hepatocellular carcinoma cell lines was calculated as SK-HEp-1> HA22T > HEp G2 > HEp 3B > HCC36. At the same time, all cell lines could achieve complete cytotoxicity. In terms of anti-lung cancer cell lines, the relative effect is NCI-Hut-125 > Calu-1 > H289 1 > CH27LC-1. Except for the CH27LC-1 cell line, all other cell lines can have a complete poisoning effect. Furthermore, it can be seen from Table 2 that the effective sequence of g a r c i η ο n e E poisoning gastric cancer cells is N U C C-3 > AZ521> KATO III = AGS, and the same complete poisoning can be seen in experiments of such cells. ---------------- (Please read the notes on the back before filling this page)

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1235750 V. Description of the invention C) Table 2. Effect of the compound garcinone E on cytotoxicity of different cancer cell lines Cell line cytotoxicity 50% * Completely toxic * _ (LD5〇, // M) _

Hep3B 3.2 + HCC36 4.1 + TONG 5.4 + HA22T 1.6 + HepG2 2.5 + SK-Hep-1 0.5 + NCI-Hut 125 0.1 + CH27 LC-1 > 10-H2891 2.7 + Calu-1 2.3 + AZ521 0.5 + NUGC-3 0.4 + KATO-III 2.5 + AGS 2.5 + * Poisoning effect after six days of treatment with garcinone E ** +: 100% poisoning; less than 100% poisoning (at 10 μM or more of garcinone E) Relative poisoning effect To evaluate garcinone Effectiveness of E as an anticancer drug, we apply Chinese National Standard (CNS) A4 specifications (210 X 297 mm) on 12 paper sizes -IH ί —wnn H »Yi t · an I n ϋ (Please read the back first Note to note? Please write this page again) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1235750 A / B7 V. Description of the Invention (1G) Four types of liver cancer cell lines are targeted cells to compare garcinone E with six other commonly used The relative toxicity of cancer drugs is identified by two criteria: ld50 and complete toxicity. From Table 3, it can be seen that the LD50gar of gar cinone E is distributed in a narrow range from 0.5 to 5.4 #M, and can achieve complete cytotoxicity against all four cell lines. Relative taxol has the smallest LD5.値 From 0.06 to 0.76 #M, and can also complete complete poison killing (Table 3). Take LD5. As a standard, mitoxantrone and metherotherxate have strong cytotoxic effects on all liver cancer cell lines. But in terms of complete poisoning, the effect of these two drugs is worse, which are 50 to 75% (2/4 to 3/4) and 11 ^ 1; 111 * 〇111 [6 \ 316 of 25 ° / . (1/4). Table 3 also shows that the toxicity of vincristine, 5-Fu, and cisplatin to liver cancer cell lines is not good. The above results indicate that taxol has the best effect on killing liver cancer cells' garcinoneE, followed by mitoxantrone and methodothrexate, and the remaining vincristine, 5-Fu, and cisplatin have limited effects (Table 2) ° (Please read the precautions on the back before filling in this page)

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i— 一 ： —— · ---------- (Please read the notes on the back before filling in this page) 丨 Order · The standard of private paper is applicable to China National Standard (CNS) A4 (210 χ 297 public) 1235750 A7 --- B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs i. Invention Description (12) Cell cycle analysis In many experiments, we did not measure HEp G2, HEp 3B, Calu-1 and What are the changes in cell cycle distribution of AGS and other cells in the 12 to 48 hours after treatment with high doses of garcinone E? Therefore, the cytotoxic effect may not be related to the blocking of the cell cycle, and the mechanism of garcinone E needs to be further explored. Discussion The structure of Oil ketone compounds is similar to anthraquinone and has been found to be antibacterial (Iinuma et al., 1996), antimutagenic (Shankaranarayan et al., 1979), and anti-cell (Lin et al., 1996). Biological activity. However, unlike anthraquinone derivatives, Oil ketones are not documented as having a chemotherapeutic agent with a prominent effect like mitoxantrone for cancer treatment. The present invention unexpectedly found an aU ketone derivative, garcinone E, which can effectively kill different liver cancer (Figure 2), lung cancer (Figure 3) and gastric cancer (Figure 4) cell lines, and has the potential to develop an effective Cancer treatment drugs. Garcinone E has a wide range of cytotoxicity. For each target cell line tested, in addition to the O-71 71-1 lung cancer cell line, its 1 ^ 5. Rhenium is 0.1 to 5.4 / M. Of particular note is that garcinone E has a powerful cytotoxic effect on liver cancer cell lines (Figure 2 and Table 2). Because clinical treatment of liver cancer with chemotherapy is usually ineffective. Unlike other anticancer drugs such as methotrexate and vincristine, the present invention finds that the toxicity of garcinone E on cancer cell lines is not significantly different (Table 3), and almost all cell lines can achieve complete toxicity (Table 2) And 3), in line with the currently used anticancer drugs 15 (Please read the precautions on the back before filling this page) -------- Order --------- I · — This paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 1235750 ___B7____ V. Description of the invention (13) By comparison, we estimate that the effect of garcinone E on liver cancer cell lines is equal to or higher than 111 丨 1: 1: 0 \ & 1111 * 01 ^ but not as good as 13 \ 〇1 (Table 3). At the same time, 8 & 1 '(: 丨 11011 € E should be more effective than methrothrexate, vincristine, 5-Fu, and cisplatin (Table 2). When assessing the feasibility of anticancer drugs, complete poisoning is an important criterion because As long as there are very few cancer cells that can survive, 'they may produce drug-resistant cells and eventually lead to the recurrence of cancer. From this point of view, garcinone E should be a powerful anti-cancer drug. Although garcinone E is used The possible side effects are not covered in the present invention, but it is not expected to be too high, because ketone compounds are not well-known toxins, and some ketone compounds are now being considered as antibiotics. In addition, the development of anticancer drugs One of the difficulties is the lack of an appropriate comparison model. The results obtained by using the mouse as a model are often inconsistent with the actual situation of humans. For example, compounds that are very effective in mice are ineffective in human experiments. The converse is also possible Occurs. In other words, the in vitro model is not necessarily worse than the animal model. The ultimate test is still in human experiments. Chemotherapy makes Treating liver cancer with a killer drug will make the disease worse, and a milder drug may be a more suitable treatment for a longer period of time. Therefore, Garcinone E may not be more effective in treating certain cancers than others. Drugs such as Taxol, which have a strong toxic effect, are inferior. In short, the present invention discloses the use of garcinone E as a chemotherapeutic drug composition for treating liver, lung, and gastric cancer. Brief description of the figure 16 This paper standard is applicable to Chinese national standards (CNS) A4 specifications (21G X 297 public love) " "-• I 1 I —ai m I n an n I nnn —a · an a— n one 0, ni ϋ I (Please read the note on the back first Please fill in this page again) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1235750 A7 B7 V. Description of the invention (14) Figure 1 shows a q_L | ketone (Xanthone) extracted from the shell of Garcinia mangostana Linn according to the present invention The basic chemical structural formula of the derivative garcinone E. Figure 2 shows three different cell lines derived from liver cancer tissues treated with different concentrations of garcinone E (0-1 0 # Μ) according to the present invention three days (a) and The toxic effect of day (-1), the bar (bar) represents the average standard deviation (SEM) of the four experiments. Figure 2 shows that according to the present invention, different concentrations of garcinone E (0-1 0 // M) were used for four Three days (-) and six days (---) of the cytotoxic effects of different lung cancer-derived cell lines were treated. Bars represent the mean standard deviation (SEM) of four experiments. Figure 4 shows three days (a) and six days of toxic effect of garcinone E (O-10 / z Μ) on four different cell lines derived from gastric cancer tissues in accordance with the present invention, straight (bar) Represents the mean standard deviation (SEM) of four experiments. (Please read the precautions on the back before filling out this page) ----- n mmamm nl «· n i_l ϋ ϋ i_i I i ^ i · # 1 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Consumption Cooperative Paper Size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

1235750 AS B8 C8 D8 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 6. Application for patents 1. An anti-cancer pharmaceutical composition containing aU ketone derivatives, which contains an effective amount for treating cancer and has the following formula as an active ingredient ( I) Compounds and their pharmaceutically acceptable salts ... hmm. 2. An anti-liver cancer pharmaceutical composition containing a ketone derivative, comprising an effective amount for treating liver cancer as an active ingredient, such as the compound of formula (I) in the first patent application scope and a pharmaceutically acceptable salt thereof. 3. An anti-lung cancer pharmaceutical composition containing a ketone derivative, comprising an effective amount for treating lung cancer as an active ingredient, such as the compound of formula (I) in the first patent application scope and a pharmaceutically acceptable salt thereof. 18 This paper size applies the Chinese National Standard (CNS) Λ4 is present (210X297 public trend ’(Please read the precautions on the back before filling this page) 1235750 VI. Patent application scope ABCD 4. An anti-gastric cancer pharmaceutical composition containing an oil ketone derivative, comprising an effective amount for treating gastric cancer as an active ingredient, such as the compound of formula (I) in item 1 of the patent application scope and its medicine Allow salt. 5. · An anti-liver cancer, gastric cancer and lung cancer pharmaceutical composition containing a qij ketone derivative, comprising an effective amount of simultaneously treating liver cancer, gastric cancer and lung cancer as an active ingredient, such as the compound of formula (I) in item 1 of the scope of patent application And its medicine allows salt. 6. · An antihepatic and gastric cancer pharmaceutical composition containing an oil ketone derivative, comprising an effective amount for simultaneous treatment of liver and gastric cancer as an active ingredient, such as a compound of formula (I) and a pharmaceutically acceptable salt thereof in item 1 of the scope of patent application. (Please read the notes on the back before filling this page) Ordered by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China 7-a kind of anti-liver cancer and lung cancer pharmaceutical composition containing aU ketone derivative, including an effective amount for simultaneous treatment of liver cancer and lung cancer The compound of formula (I) and its pharmaceutically acceptable salts. 8 · A pharmaceutical composition for anti-gastric cancer and lung cancer containing a qU ketone derivative, comprising an effective amount for simultaneous treatment of gastric cancer and lung cancer as an active ingredient, such as the compound of formula (I) in item 1 of the patent application scope, and its medical allowance salt. 19 This paper size applies to Chinese National Standard (CNS) Λ4 size (210 X 297 cm)