JP2554447B2 - New xanthone compound - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel xanthone compound and an anticancer agent containing the compound as an active ingredient.

[0002]

2. Description of the Related Art Cancer is a disease that affects various organs of the body and often leads to death. Therefore, methods such as relieving pain of cancer patients and removing cancer cells are used. Has become a priority issue in recent research.

Conventionally, for example, acute leukemia, which is common in children, Burkitt's lymphoma, retinoblastoma, testicular cancer, or choroidal epithelioma, Ewing tumor, which is common in women, malignant granuloma, lymphosarcoma, mycosis fungoides, rhabdomy. Although chemotherapeutic agents are clinically used for myomas, etc., there is no effective chemotherapeutic agent for liver cancer or nasopharynageal carcinoma. Many chemotherapeutic agents only temporarily suppress the growth of cancer cells.

Compounds having cytotoxicity against cells of liver cancer or nasopharyngeal cancer are known, and some results have been obtained by long-term research and development of drugs for treating cancer. However, these compounds have an insufficient suppressive effect on cancer cells or have extremely great side effects. For example, we have found that some anthraquinone compounds, steroidal alkaloid compounds isolated from Solanum plants,
Polyhydroxysteroids and lanosteroids found in monkey strains and mushroom plants show extremely strong cytotoxicity against human PLC / PRF / 5 and KB cells in vitro. However, there are many issues to consider, such as the balance between efficacy and side effects, so it is necessary to evaluate whether it is worth continuing development. Further, even if a natural compound having an anticancer activity is obtained, it is difficult to produce it by chemical synthesis because the natural product has a complicated chemical structure and a low yield. Therefore, although there are many kinds of natural products having these anticancer activities,
Often, the sources are not sufficient to continue research to determine their clinical applicability. The development of chemotherapeutic agents for liver cancer and nasopharyngeal cancer is currently the mainstream of research.
The present inventor discovered a compound having an effective anticancer property from xanthone compounds.

It has already been described in the literature that natural compounds having a γ-pyrone structure or xanthone compounds have strong cytotoxicity. For example, Habib, AM et al., 1987, Journal of Organic Chemistry (J.Org.Chem.), 52, 412-418.
In Figure 1 on page 3 ', 4'-deoxysolospermine,
3 ', 4'- Deoxysorospermine 3', 4'-geo-
Le, 3 ′, 4′-deoxy-4′-chlorosolespermine-
Solospermine compounds (1) such as 3′-diol, O ⁵ -methyl 3 ′, 4′-deoxystrospermine-3′-diol have potent leukemia cytotoxicity, and recently Cushman and M. (Cushman, M.) et al. (1991, Journal of
Natural Products (J. Nal. Prod.), Volume 54, 16
56 to 1660) report that γ-pyrone flavonoid compounds have strong cytotoxicity.

The inventor of the present invention has published a 1991 phytochemical magazine, Vol. 30, 16
69-1671; 31; 364-367; 2563-2564; 2922-2.
On page 924, Taiwanese Alto Calpas Comunis (Arto
carpus communis) plant as shown in Fig. 1 of the present application, cyclomorusin (2), cycloaltomnin (cyc
loarutomunin (3), dihydrocycloaltomine (dih
ydrocycloaruto-munin (4), dihydroisocycloarutomunin (5), arthomnoxanthone (6), arthomoxanthotrione epoxide (artomunoxanthotrione ep)
oxide) (7), cyclocommunol
(8), cyclomulberrin (9), cyclocommunin (cyclocommunin) (10) and other γ-pyrone-based flavonoid compounds, as a result of experimenting them in a test tube, human PLC / PRF / 5 and It was announced that they all showed very strong cytotoxicity against KB cells. PLC / PR
F / 5 is a human liver cancer cell and KB cell is a human nasopharyngeal cancer cell. In 1982, Nakajima et al., Microbiological Immunological (Micro-biol. Immunol.) Vol. 26, 705.
And Ito et al. In Journal of Interferon Research (J. Interferom. Res.) Vol. 4, 603,
Since it was announced that these cells would be used in vitro for the evaluation of drug anticancer activity, the method using these cells has been regarded as an official anticancer activity evaluation method.

[0007]

The present invention provides (1) general formula (I):

[0008]

Embedded image

(Wherein R ¹ is a hydroxyl group, R ² , R ⁴ and R ⁶
And R ⁷ is a hydrogen atom, R ³ and R ⁵ are 2,3-epoxypropoxy groups, or R ¹ , R ³ , R ⁴ , R ⁵
And R ⁷ is a hydrogen atom, R ² and R ⁶ are 2,3-epoxypropoxy groups, or R ¹ , R ² , R ⁴ , R ⁵
And R ⁷ is a hydrogen atom, and R ³ and R ⁶ are 2,3-epoxypropoxy groups) or a salt thereof.

Further, the present invention relates to (2) an anticancer agent comprising the compound according to the above item (1) as an active ingredient.

[0011]

EXAMPLE A xanthone compound which is a compound of the present invention is
General formula (I):

[0012]

Embedded image

(Wherein R ¹ is a hydroxyl group, R ² , R ⁴ and R ⁶
And R ⁷ is a hydrogen atom, R ³ and R ⁵ are 2,3-epoxypropoxy groups, or R ¹ , R ³ , R ⁴ , R ⁵
And R ⁷ is a hydrogen atom, R ² and R ⁶ are 2,3-epoxypropoxy groups, or R ¹ , R ² , R ⁴ , R ⁵
And R ⁷ is a hydrogen atom, and R ³ and R ⁶ are 2,3-epoxypropoxy groups).

The present invention includes these flavonoid compounds and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salt is a commonly used organic acid or inorganic acid addition salt,
For example, it refers to hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate and the like.

One of the compounds of the present invention, 3,5-di (2,3-
Epoxypropoxy) -1-hydroxyxanthone can be obtained by the reaction shown in FIG. In FIG. 2, 2,3-dimethoxybenzoyl chloride is first synthesized by reacting 2,3-dimethoxybenzoic acid and oxalyl chloride. Then, 2,3-dimethoxybenzoyl chloride and 1,
From 3,5-trimethoxybenzene, a benzophenone intermediate containing a hydroxyl group and a methoxy group was synthesized by the Friedel-Crafts reaction, and further subjected to a ring closure reaction and treatment with hydrogen halide to synthesize 1,3,5-trihydroxyxanthone. To do. Subsequent introduction of an epoxypropoxy group gives 3,5-di (2,3-epoxypropoxy) -1-hydroxyxanthone. Further, the other compounds of the present invention can be obtained by selecting a raw material and an intermediate suitable for the intended product and carrying out the same reaction as described above.

The obtained compound is purified by column chromatography, crystallized by a usual method, and then UV and I, respectively.
It can be identified by measuring physical data such as R, NMR and mass spectrometry.

Experimental Example PLC / PRF / 5 liver cancer cells containing hepatitis B virus antigen and KB cells of nasopharyngeal carcinoma containing Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum, L-glutamine and antibiotics. And cultivated for 4 days and then ED50
Is calculated and the activity of the compound is evaluated. The ED50 was determined by semilogarithmic plotting the percent viable cells on day 4 against compound concentration (which can be said to have significant cytotoxicity at ED50 <40 μg / ml).

[0018]

[Table 1]

The anticancer activity of the compounds of the present invention is shown in Table 1.
The compounds of the present invention have marked cytotoxicity against human PLC / PRF / 5 liver cancer cells and nasopharyngeal carcinoma KB cells. In particular, the cytotoxicity of 2,6-di (2,3-epoxypropoxy) xanthone against nasopharyngeal carcinoma KB cells is 40 times stronger than that of clinically used drug cisplatin and ED50. 3,5-di (2,3-epoxypropoxy) -1-hydroxyxanthone, which is an epoxy compound of a xanthone compound in which the 1, 3, and 5 positions are substituted with a methoxy group, is human PLC / PRF /
5 It has strong cytotoxicity against both liver cancer cells and nasopharyngeal carcinoma KB cells. From the above results, the compound of the present invention is recognized to have an anticancer action, and is expected as a particularly potent anticancer drug.

The compound of the present invention can be made into a pharmaceutical composition by adding various excipients, carriers, diluents and pharmaceutically acceptable addition salts of acid, if necessary. These preparations can be solid or liquid preparations for oral or rectal administration, injection preparations for parenteral administration, or ointment preparations for direct application to the affected area. These solid preparations are added with a disintegrant such as starch, sodium carboxymethylcellulose, an adhesive such as ethanol and glycerin, or magnesium stearate, lactose, etc., into tablets or filled into suppositories by a well-known preparation method. Etc. to prepare a solid preparation. An injection or other liquid preparation can be prepared by adjusting the pH of an aqueous solution or salt solution of the compound of the present invention with a phosphate buffer and adding an auxiliary agent or an emulsifier. A drug containing the compound (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof as an active ingredient has an anticancer effect in mammals, and the general dose varies depending on the symptom, but it is usually 50 to 300 mg once per person. , Can be administered 3 times a day.

Reference Example 1 2-Hydroxy-4,6-dimethoxy-2 ′, 3′-dimethoxybenzophenone 2,4,6-trimethoxy-2′-hydroxy-3′-methoxybenzophenone 1.8 g (9.89 mmol) of 2 3.5 ml of 1,3-dimethoxybenzoic acid and 25 ml of dry benzene were stirred at room temperature under argon atmosphere.
After reacting with oxazol chloride, the solvent and excess reagent were removed under reduced pressure, the remaining 2,3-dimethoxybenzochloride was dissolved in 40 ml anhydrous ether, and 1.6 g (9.52 mmol) of 1,3,5-
Add trimethoxybenzene and 4.0g aluminum chloride,
After stirring at room temperature for 15 hours, ice water containing 35 ml of concentrated hydrochloric acid
It was hydrolyzed with 300 ml, extracted with dichloromethane, and subjected to column chromatography (silica gel, dichloromethane) to obtain 2.9 g (9.15 mmol, 92%) of a pale yellow oily target product.

¹ H-NMR (CDCl ₃ , δ): 3.70 (12H, s, 4OMe), 3.86 (6H, s, 2OMe), 3.91 (6H, s, 2OMe), 6.16 (4H, s, 18a and 18b H-3 and H-5), 6.72 (2H, t, J = 8.0Hz, 18a and 18b H-4 ′), 6.91 ~ 7.06 (4H, m, 18a and 18b H-5 ′ and H- 6 '), 12.51 (exchanged with 2H, s, 18a and 18b for 2OH and D ₂ O) Reference Example 2 1,3,5-trimethoxyxanthone 2,4,6-trimethoxy-2'-hydroxy-3'- Methoxybenzophenone and 2-hydroxy-4,6-dimethoxy-2 ', 3'
-Mixture of dimethoxybenzophenone 2.9 g (9.15 mmol)
Pyridine (52.8 ml), water (26.4 ml) and 10% tetramethylammonium hydroxide aqueous solution (18 ml) were mixed and refluxed for several hours, added to ice water, extracted with ether, and subjected to column chromatography (silica gel, chloroform).
Crystallization from methanol gave 2.03 g (7.10 mmol, 78%) of colorless powder of 1,3,5-trimethoxyxanthone.

MP: 233-235 ° C .; ¹ H-NMR (CDCl ₃ , δ): 3.89,3.96,4.00 (9H, 3s, 3OMe), 6.34 (1H, d, J = 2.5Hz, H-2), 6.62 (1H, d, J = 2.5Hz, H-4), 7.13 ~ 7.28 (2H, m, H-6 and H-7), 7.86 (1H, dd, J = 9.0,2.5Hz, H-8) Reference Example 3 1,3,5-trihydroxyxanthone 1.9 g (6.64 mmol) of 1,3,5-trimethoxyxanthone, 42 ml
A mixture of phenol and hydrogen iodide (35 ml) was refluxed at 160 ° C. for 8 hours and then added to an aqueous sodium hydrogen sulfite solution to give a yellow precipitate. This precipitate was collected by filtration and subjected to column chromatography (silica gel, chloroform-methanol 4:
1) and crystallized from methanol to give 1.410 g (5.78 mmol, 87) of yellow needle crystals of 1,3,5-trihydroxyxanthone.
%).

MP: 211-213 ° C .; ¹ H-NMR (CDCl ₃ , δ): 6.91 (1H, d, J = 2.0Hz, H-2), 6.39 (1H, d, J = 2.0Hz, H- 4), 7.07 to 7.19 (2H, m, H-6 and H-7), 7.62 (1H, dd, J = 9.0,2.5Hz, H-8) Example 1 3,5-di (2,3- Epoxypropoxy) -1-hydroxyxanthone 0.28 g (5.0 mmol) caustic soda was dissolved in 3 ml of water, and 25 ml of 2-
Propanol and 1.3 g (5.33 mmol) 1,3,5-trihydroxyxanthone were added in this order, 7.5 ml (93.47 mmol) epichlorohydrin was added, and then treated in the same manner as in Comparative Example 3 below, the methano- When crystallized from
3-epoxypropoxy) -1-hydroxy-xanthone 0.
Obtained 45 g (1.26 mmol, 35%).

MS (m / z)%: 356 (100) (M ⁺ ); IR (KBr): 3500, 1670, 1620cm ^-1 ; ¹ H-NMR (CDCl ₃ , δ): 1.61 to 2.78 (2H, m, epoxy ring CH ₂ ), 2.94 to 3.01 (2H, m, epoxy ring CH ₂ ), 3.41 (1H, m, epoxy ring CH), 3.50 (1H, m, epoxy ring CH), 4.03 ( 1H, dd, J = 111,6.0Hz, OCHH), 4.11 (1H, dd, J = 111,6.0Hz, OCHH), 4.35 (1H, dd, J = 111,3.0Hz, OCHH), 4.48 (1H, dd, J = 11,3.0Hz, OCHH), 6.38 (1H, d, J = 2.5Hz, H-2), 6.57 (1H, d, J = 2.5Hz, H-4), 7.30 (2H, m, H-6 and H-7), 7.85 (1H, dd, J = 9.0,2.5Hz, H-8) ¹³ C-NMR (CDCl ₃ , δ) 44.6 (2CH _{2 of} epoxy ring), 49.7 and 50.1 (epoxy Ring 2CH), 69.2 and 70.6 (2 OCH ₂ ), 93.5 (C-4), 97.9 (C-2), 104.2 (C-8b), 117.7 (C-8), 118.0 (C-6), 122.0 (C-8a), 123.6 (C-7), 147.2 (C-4b, C-5), 157.5 (C-4a), 163.4 (C-1), 165.4 (C-3), 180.8 (CO) Anal : (C ₁₉ H ₁₆ O ₇ ) C, H. Example 2 2,6-di (2,3-epoxypropoxy) xanthone 0.42 g (10.5 mmol) caustic soda was dissolved in 3 ml of water, and 50 ml2-
Propanol and 1.2 g (5.26 mmol) 2,6-dihydroxyxanthone were added in this order, and 10 ml (124.63 mmol) epichlorohydrin was added, followed by the same treatment as in Comparative Example 2 below to give 2,6-colorless powder. Di (2,3-epoxypropoxy) xanthone 1.2g
(3.85mmol, 73%) was obtained.

MS (m / z)%: 340 (100) (M ⁺ ); IR (KBr): 1655, 1620 cm ^-1 ; ¹ H-NMR (CDCl ₃ , δ): 2.81 (2H, m, epoxy ring CH ₂ ), 2.96 (2H, dd, J = 10,4.5Hz, CH _{2 of} epoxy ring), 3.42 (2H, M, 2CH of epoxy ring), 4.01 (1H, dd, J = 111,6.0Hz, OCHH), 4.05 (1H, dd, J = 111,6.0Hz, OCHH), 4.38 (1H, t, J = 3.0Hz, OCHH), 4.43 (1H, t, J = 3.0Hz, OCHH), 6.91 (1H , d, J = 2.5Hz, H-5), 6.97 (1H, dd, J = 9.0,2.5Hz, H-
3), 7.35 (1H, dd, J = 9.0,2.5Hz, H-7), 7.41 (1H, d, J = 9.0Hz, H-
4), 7.68 (1H, d, J = 2.5Hz, H-1), 8.26 (1H, dd, J = 9.0Hz, H-8) ¹³ C-NMR (CDCl ₃ , δ) 44.5,44.6 (epoxy ring CH ₂ ), 49.8,50.0 (epoxy ring
CH), 69.3, 69.4 (OCH ₂ ), 100.9 (C-5), 106.19 (C-1), 113.5 (C-
7), 115.6 (C-8a), 119.3 (C-4), 122.2 (C-8b), 124.6 (C-3), 128.
3 (C-8), 151.2 (C-4a), 154.8 (C-2), 157.8 (C-4b), 163.7 (C-5), 176.
0 (CO) Anal: (C ₁₉ H ₁₆ O ₆ ) C, H. Comparative Example 1 3-hydroxyxanthone 1.6 g (7.08 mmol) of 3-methoxyxanthone was added to hydrogen iodide 35.
The mixture was refluxed for 8 hours at 160 ° C. in a mixed solution of 42 ml of phenol and 42 ml of phenol and then poured into an aqueous solution of sodium bisulfite to give a yellow precipitate.

The precipitate was collected by filtration, subjected to column chromatography (silica gel, chloroform-methanol 4: 1) and crystallized from methanol to obtain 1.40 g (6.60 mmol, 93%) of yellow needle crystals of 3-hydroxyxanthone.

MP: 241-242 ° C .; MS (m / z)%: 212 (100) (M ⁺ ); UV: λmax (MeOH) nm (log ε): 235 (4.06), 265 (3.39), 330 (3.
59); λmax (MeOH + NaOAc): 230,265 (sh), 335; IR (KBr): 3115, 1615cm ^-1 ; ¹ H-NMR (DMSO): 8.04 (1H, d, H-1), 6.91 (1H , dd, H-2), 6.87 (1H, d, H-4), 7.43 (1H, m, H-6), 7.59 (1H, m, H-7), 8.16 (1H, dd, H-8 ) Anal: (C ₁₃ H ₈ O ₃ ) C, H. Comparative Example 2 3- (2,3-epoxypropoxy) xanthone 0.19 g (4.71 mmol) of caustic soda was dissolved in 6.18 ml isopropanol and 1.3 ml water, and 1.00 g After adding (4.72 mmol) 3-hydroxyxanthone and 3.76 ml (46.86 mmol) epichlorohydrin and reacting at 70 ° C. for 2 hours under stirring, the by-product (dipolymer) was filtered off, and the filtrate was separated by 50-60. Concentrate under reduced pressure at ℃, add 10 ml of isopropanol, reflux and filter the dipolymer, cool the clear filtrate, collect the solid formed, wash with 1.4 ml isopropanol and dry in air. Then, 945 mg (4.46 mmol, 74%) of a brown product was obtained. It was subjected to column chromatography (silica gel) and crystallized from dichloromethane to obtain 3- (2,3-epoxypropoxy) xanthone as a colorless powder.

MP: 157-158 ° C; MS (m / z)%: 268 (100) (M ⁺ ); IR (KBr): 1645, 1265cm ^-1 ; ¹ H-NMR (CDCl ₃ , δ): 2.79 ~ 2.99 (m, CH _{2 of} epoxy ring), 3.42 (m, 1H, CH of epoxy ring), 4.05 (dd, J = 111,6.0Hz, 1H), 4.39 (dd, J = 11,3.0Hz, 1H ), 6.91 (d, J = 2.4Hz, 1H, H-4), 6.95 (dd, J = 9.0,2.4Hz, 1H, H-
2), 7.27 ~ 7.47 (m, 2H, H-6 and H-7), 7.65 ~ 7.70 (m, 1H, H-
5), 8.26 (d, J = 9.0Hz, 1H, 1-H), 8.32 (dd, J = 9.0,1.5Hz, 1H, H-
8); ¹³ C-NMR (CDCl ₃ , δ) 44.5 (CH _{2 of} epoxy ring), 69.2 (OCH ₂ ), 49.7 (CH of epoxy ring), 101.1 (C-4), 113.4 (C-2), 116.2 (C-8b), 117.7 (C-5), 121.9 (C-8a), 123.9 (C-7), 126.6 (C-8), 128.4 (C-1), 134.3 (C-6), 156.2 (C-4b), 157.9 (C-4a), 163.7 (C-3), 176.2 (CO); Anal: (C ₁₆ H ₁₂ O ₄ ) C, H. Comparative Example 3 6- (2,3-epoxy Propoxy) -1-hydroxyxanthone 0.42 g (10.5 mmol) caustic soda was dissolved in 3 ml of water, and 50 ml 2
-Propanol and 1.2 g (5.26 mmol) 1,6-dihydroxyxanthone were added in this order, 10 ml (124.63 mmol) epichlorohydrin was added, and after reacting at 70 ° C for 3 hours with stirring, the by-product (dipolymer) was filtered off. Separately, the filtrate was concentrated under reduced pressure at 50-60 ° C., 20 ml of 2-propanol was added to the semi-solid residue, and after refluxing, the dipolymer was filtered off, and the clear filtrate was cooled, and the solid produced was collected. Collected, washed with 3 ml of 2-propanol and dried in air to give a brown product. This was subjected to column chromatography (silica gel, dichloromethane), crystallized from dichloromethane, and yellow powder of 6- (2,3-epoxypropoxy) -1-hydroxyxanthone 1.4 g (4.93 mmo)
l, 94%).

MS (m / z)%: 284 (100) (M ⁺ ); IR (KBr): 3450, 1650, 1630cm ^-1 ; ¹ H-NMR (CDCl ₃ , δ): 2.81 (1H, dd, J = 11,6.0Hz, epoxy ring CH ₂ ), 2.91 (1H, t, J = 5.0Hz, epoxy ring CH ₂ ), 3.42 (1H, m, epoxy ring CH), 4.04 (1H, dd, J = 11,6.0Hz, OCHH), 4.43 (1H, dd, J = 111,3.0Hz, OCHH), 6.78 (1H, dd, J = 9.0,1.0Hz, H-2), 6.88 (2H, m, H-4 and H-
5), 6.97 (1H, dd, J = 9.0,2.5Hz, H-7), 7.55 (1H, t, J = 9.0Hz, H-
3), 8.16 (1H, d, J = 9.0Hz, H-8), 12.75 (1H, s, 1-OH, exchanged with D ₂ O) ¹³ C-NMR (CDCl ₃ , δ) 44.5 (of epoxy ring CH ₂ ), 49.7 (CH of epoxy ring), 69.4 (OCH ₂ ), 100.9 (C-5), 106.8 (C-4), 108.4 (C-8b), 110.2 (C-2), 113.7 (C- 7), 114.7 (C-8a), 127.6 (C-8), 136.2
(C-3), 156.3 (C-4a), 158.0 (C-4b), 161.9 (C-1), 164.4 (C-6), 181.
3 (CO); Anal: (C ₁₆ H ₁₂ O ₅ ) C, H. Based on the above Reference Examples, Examples and Comparative Examples, the following compounds were produced.

Example 3 3,6-di (2,3-epoxypropoxy) xanthone Comparative Example 4 1,3,6,7-Tetrahydroxyxanthone Comparative Example 5 3,4,6,7-Tetrahydroxyxanthone Example The melting points of the compounds described in Comparative Examples are shown in Table 2.

[0032]

[Table 2]

[0033]

INDUSTRIAL APPLICABILITY The present invention provides a novel and useful xanthone compound and an anticancer agent containing the same as an active ingredient.

[Brief description of drawings]

FIG. 1 Known γ-pyrone flavonoid compounds (1) to (1
It is a figure which shows the structure of (0).

FIG. 2 shows an example of a method for producing the compound of the present invention.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References J. PHARM. PHARMACO L. , 45-9! (1993.9) P. 791-794

Claims (2)

(57) [Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a hydroxyl group, R ² , R ⁴ , R ⁶ and R ⁷ are
Hydrogen atom, R ³ and R ⁵ are 2,3-epoxypropoxy groups
Or R ¹ , R ³ , R ⁴ , R ⁵ and R ⁷ are
Hydrogen atom, R ² and R ⁶ are 2,3-epoxypropoxy groups
Or R ¹ , R ² , R ⁴ , R ⁵ and R ⁷ are
Hydrogen atom, R ³ and R ⁶ are 2,3-epoxypropoxy groups
Or a salt thereof represented by the a). 2. An anticancer agent comprising the compound according to claim 1 as an active ingredient.