WO2012036180A1 - Xanthone derivative and use thereof - Google Patents

Abstract

Provided is a novel compound having excellent anticancer activity and metastasis inhibition activity. An α-mangosteen diester represented by general formula (1): (in the formula, R¹ represents the residue after a hydroxyl group is removed from a C8-14 medium chain triglyceride), and an anticancer agent or metastasis inhibiting agent including said compound as the active component thereof.

Description

Xanthone derivatives and uses thereof

The present invention relates to xanthone derivatives and uses thereof, and more particularly to α-mangostin C _8-14 medium chain fatty acid diesters having excellent pharmaceutical action and uses thereof.

Mangosteen (scientific name: Garcinia mangostana L) is an evergreen small Takagi of Guttiferae native to Southeast Asia. The fruit is one of the three largest fruits in the world, called the fruit queen, and is a high-class tropical fruit that represents Southeast Asia. The size of the fruit is about 5cm in size and has a thick skin. The pulp is white and is divided like a mandarin orange bag. The pericarp contains yellow pigments (xanthones) and has long been used as an astringent such as hemostatic, analgesic, antiseptic and anti-inflammatory, and is an important natural resource as a folklore drug.

The main components of xanthone derivatives contained in mangosteen peel are α-mangostin and γ-mangostin.

Recently, α- and γ-mangosteen has been reported to have antibacterial, anti-inflammatory, antiallergic and anticancer effects. Specifically, anti-MRSA (mesitillin-resistant Staphylococcus aureus) activity (Non-patent document 1), histamine and serotonin receptor inhibitory activity (Non-patent document 2), antioxidant activity (Non-patent document 3), antiallergic activity ( Non-patent document 4), various physiological activities such as apoptosis-inducing ability against cancer cells (non-patent document 5), cell cycle arrest (non-patent document 6), and various effects of mangosteen are explained by them. It has also been confirmed that NK activity is increased in mice and humans administered with α-mangostin or γ-mangostin (Non-patent Documents 7 and 8). Furthermore, panaxanthone (a mixture of α-mangostin 75 to 85% and γ-mangostin 5 to 15%, and the total content of both is 90% or more) is an antitumor effect on mouse breast cancer. (Non-patent document 9), and when α-mangostin was administered to mouse breast cancer using an osmotic pump at a dose of 20 mg / kg, prolonged survival and suppression of lymph node metastasis were observed. (Non-Patent Documents 10 and 11) have been reported.

The terminal image of cancer is death due to metastasis. Even in breast cancer, most of the causes of death are due to metastasis to lymph nodes, lungs, etc., and suppressing metastasis is the biggest problem in cancer treatment.

On the other hand, as a derivative of α-mangostin, for example, α-mangosteen triacetate is known, and this compound is said to have an action of improving the aesthetic appearance of the skin and a therapeutic action against telangiectasia (patent). Reference 1).

JP 2005-518399 Gazette

Α-Mangosteen has an anticancer effect and a cancer metastasis inhibitory effect as described above, but its effect is not always sufficient. An object of the present invention is to provide an α-mangostin derivative having a more excellent anticancer activity and cancer metastasis suppressing activity.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that _C8-14 medium chain fatty acid diester of α-mangostin has significantly superior anticancer activity and cancer metastasis inhibitory activity compared to α-mangostin. As a result, the present invention has been completed.

That is, the present invention
(1) General formula (1):

(In the formula, R ¹ represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
Α-mangosteen diester represented by
(2) The α-mangosteen diester as described in 1 above, wherein R ¹ is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid having 8 to 14 carbon atoms,
(3) The α-mangosteen diester as described in 1 above, wherein R ¹ is a residue obtained by removing a hydroxyl group from an unsaturated medium chain fatty acid having 8 to 14 carbon atoms,
(4) α-Mangosteen according to the above item 1, wherein R ¹ is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid selected from octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid and tetradecanoic acid. Diester,
(5) The α-mangosteen diester according to claim 1, wherein R ¹ is a residue obtained by removing a hydroxyl group from 10-undecenoic acid,
(6) Formula (1-a)

Α-mangosteen dodecanoic acid diester represented by
(7) An anticancer agent containing the α-mangosteen diester according to any one of items 1 to 6 as an active ingredient, and (8) Suppression of cancer metastasis containing the α-mangostin diester according to any one of items 1 to 6 as an active ingredient Agent,
It is.

The α-mangostin diester (1) according to the present invention is useful as an anticancer agent or cancer metastasis inhibitor since it has an excellent anticancer activity and cancer metastasis inhibitory activity.

FIG. 3 is a diagram showing the survival rate of mice treated with α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester or α-mangosteen dilaurate) mixed feed. The diagram which shows the time-dependent change (per animal) of the body weight of the mouse | mouth treated with the alpha-mangosteen dodecanoic acid diester mixing | blending feed. FIG. 3 is a diagram showing changes in tumor volume over time (per mouse) of mice treated with α-mangosteen dodecanoic acid diester-containing diet. The photograph which shows the bioluminescence imaging of 6-week progress of the mouse | mouth treated with the alpha-mangosteen dodecanoic acid diester mixing | blending feed. A bar graph showing the number of lymph node metastases (a) and the number of lung metastases (b) (both per mouse) in mice treated with a diet containing α-mangosteen dodecanoic acid diester. A bar graph showing the total number of organs transferred (a) and the total number per mouse (b) in mice treated with α-mangosteen dodecanoic acid diester-containing diet. The diagram which shows the time-dependent change (per animal) of the body weight of the mouse | mouth treated with the alpha-mangosteen combination feed. The diagram which shows the time-dependent change (per mouse) of the tumor volume of the mouse | mouth treated with the alpha-mangostin combination feed. A bar graph showing the number of lymph node metastases (a) and the number of lung metastases (b) (both per mouse) in mice treated with α-mangosteen-containing diet.

The compound of the present invention has the general formula (1):

(In the formula, R ¹ represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
An α-mangosteen diester represented by the formula:

R ¹ is a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms. Here, “medium chain fatty acid having 8 to 14 carbon atoms” means octanoic acid (C ₈ ) (= caprylic acid). Nonanoic acid (C ₉ ) (= pelargonic acid), decanoic acid (C ₁₀ ) (= capric acid), undecanoic acid (C ₁₁ ), dodecanoic acid (C ₁₂ ) (= lauric acid), tridecanoic acid (C ₁₃ ) , Saturated medium chain fatty acids having 8 to 14 carbon atoms such as tetradecanoic acid (C ₁₄ ) (= myristic acid), and unsaturated medium chain fatty acids having 8 to 14 carbon atoms such as 10-undecenoic acid (C ₁₁ ). Of these, saturated or unsaturated medium chain fatty acids having 8 to 12 carbon atoms are more preferable, and saturated medium chain fatty acids having 10 to 12 carbon atoms are particularly preferable.
In the α-mangosteen diester (1) of the present invention, these two ester bonds are formed by combining C _8-14 medium chain fatty acids with hydroxyl groups at the 3rd and 6th positions of the xanthone skeleton.

Specific examples of the α-mangosteen diester (1) of the present invention include, for example, α-mangosteen octanoic acid diester (= α-mangosteen caprylic acid diester), α-mangosteen nonanoic acid diester (= α-mangosteen pelargonic acid diester), α Mangosteen decanoic acid diester (= α-mangosteen capric acid diester), α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester), α-mangosteen tetradecanoic acid diester (= α-mangosteen myristic acid diester), α-mangosteen And 10-undecenoic acid diester. Of these, α-mangosteen octanoic acid diester, α-mangosteen decanoic acid diester, α-mangosteen dodecanoic acid diester and α-mangostin 10-undecenoic acid diester are preferable, and α-mangosteen dodecanoic acid diester is particularly preferable. Incidentally, α-mangosteen dodecanoic acid diester is also represented by the chemical name of 1,3,6-trihydroxy-7-methoxy-2,8-di (3-methyl-2-butenyl) xanthone and 3,6-O-didodecanoate. The structural formula is as follows.

The α-mangosteen diester (1) of the present invention has the following formula:

Α-mangosteen represented by the general formula (2):

(However, R ¹ represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
Can be produced by subjecting the C _8-14 medium chain fatty acid represented by the above _formula or a reactive derivative in the carboxyl group thereof to an esterification reaction.

Examples of the reactive derivative at the carboxyl group of the compound represented by the general formula (2) include acid halides, acid anhydrides, activated amides, activated esters and the like obtained according to a conventional method. Suitable examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl Phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids such as methanesulfonic acid, for example acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid and other aliphatic carboxylic acids, or Mixed anhydrides with acids such as aromatic carboxylic acids such as benzoic acid; symmetrical anhydrides; active amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, or eg cyanomethyl esters, methoxy Methyl ester, dimethyliminomethyl ester, vinyl ester Ter, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl ester, p-cresylthioester, carboxymethylthioester, pyranyl ester, Activated esters such as pyridyl esters, piperidyl esters, 8-quinolyl thioesters, etc., or, for example, N, N-dimethylhydroxyamine, N-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, And esters of N-hydroxy compounds such as 1-hydroxy-1H-benzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide . These reactive derivatives can be arbitrarily selected depending on the type of the compound of the general formula (2) to be used.

The esterification reaction is usually water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and pyridine. The reaction can be performed in any other organic solvent as long as it is performed in a solvent but does not adversely affect the reaction. These common solvents may be used as a mixture with water.

When the compound of the general formula (2) is used in the form of a free acid or a salt thereof, for example, N, N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N ′ -(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2 -Methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; Oxychloride Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5 -(M-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N ' It is desirable to carry out the reaction in the presence of a conventional condensing agent such as a so-called Vilsmeier reagent prepared by reaction of dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate or phosphorus oxychloride. A method using a condensing agent such as N, N′-dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole or N-hydroxy-5-norbornene-endo-2,3-dicarboximide is also desirable.

The reaction can also be carried out in the presence of an inorganic or organic base such as alkali metal bicarbonates tri (lower) alkylamine, pyridine, N- (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. You may go. The use ratio of α-mangostin as a raw material to the compound of the general formula (2) or a reactive derivative thereof in the carboxyl group is usually 2 mol or more, preferably 5 to 50 mol, with respect to 1 mol of the former. . The reaction temperature is not critical, but the reaction is usually carried out under cooling to warming (-10 to 120 ° C.). The reaction time is usually about 0.5 hour to about 10 hours, preferably about 1 hour to about 5 hours.

The α-mangosteen diester (1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent distillation, crystallization, transfer dissolution, chromatography and the like.

Raw material compound (2) can be produced, for example, by the method described in Phytochemistry 1995, 39, 943-944.

The α-mangosteen diester (1) thus obtained (hereinafter appropriately referred to as compound (1)) has excellent anticancer activity and cancer metastasis inhibitory activity, and is therefore used as an anticancer agent or cancer metastasis inhibitor. be able to. The target cancer is not particularly limited, and various cancers (for example, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma) Non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, vascular tumor, malignant lymphoma, malignant melanoma, thyroid cancer , Bone tumor, adrenal tumor, retinal tumor).
When the compound (1) of the present invention is used as an anticancer agent or a cancer metastasis inhibitor, it is used not only for humans but also for mammals other than humans (for example, horses, cows, dogs, cats, pigs, monkeys, etc.). can do.

When the compound (1) of the present invention is used as an anticancer agent or cancer metastasis inhibitor, it is mixed with itself or appropriate pharmacologically acceptable excipients, diluents, etc., and tablets, capsules, It can be formulated into granules, powders, syrups, etc. and administered orally, or can be formulated into intravenous injections, intramuscular injections, etc. and administered parenterally.

These preparations are made of excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose -Cellulose derivatives such as low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic Dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfates such as calcium sulfate Conductors, etc.), binders (for example, the aforementioned excipients; gelatin; polyvinylpyrrolidone; maglogol, etc.), disintegrants (for example, the aforementioned excipients; croscarmellose sodium, sodium carboxymethyl starch, Chemically modified starch such as cross-linked polyvinyl pyrrolidone, cellulose derivatives, etc.), lubricant (eg talc; stearic acid; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica; beer Luxes such as gums and gallows; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfate Sodium, lauryl sulfate such as magnesium lauryl sulfate; silicic anhydride Silicic acids such as silicic acid hydrate; starch derivatives in the above-mentioned excipients, etc., stabilizers (for example, para-oxybenzoic acid esters such as methylparaben and propylbaraben; chlorobutanol, benzyl alcohol, phenyl) Alcohols such as ethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.], flavoring agents (for example, Commonly used sweeteners, acidulants, fragrances, etc.), suspending agents (eg, polysorbate 80, carboxymethyl cellulose sodium, etc.), diluents, formulation solvents (eg, water, ethanol) , Glycerin and the like) and other additives.

The dose of the compound (1) of the present invention varies depending on the age, body weight, symptoms, etc., and the administration form and the number of administrations, but is usually 1 to 2000 mg per day for an adult (body weight 50 kg), particularly About 10 to 500 mg is preferably administered once or divided into several times.

The compound (1) of the present invention can be used in combination with other anticancer agents or cancer metastasis inhibitors. Examples of the concomitant agent include adriamycin, mitomycin, 5-fluorouracil, irinotecan, taxol and the like. In the case of combined use, the administration timing of each drug is not limited, and may be administered simultaneously or with a time difference. The compounding ratio of the compound (1) of the present invention to the drug used in combination can be appropriately selected according to the administration subject, administration route, target disease, symptom, combination and the like.

Hereinafter, the present invention will be described in more detail with reference to test examples, comparative examples, and examples, but these are merely examples and do not limit the present invention in any way.

[Test Example 1]
(Test substance and feed preparation)
A predetermined amount of α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester) is weighed and dissolved with corn oil (Nacalai Tesque) at 50 ° C., and then powdered feed CE-2 (Nippon Claire Co., Ltd.). ).

(Breast cancer cell line)
The breast cancer cell line BJMC3879Luc2 used in this experiment is one in which a luciferase gene is stably integrated into a BJMC3879 cell line established from breast cancer induced by inoculating BALB / c mice with MMTV (mouse breast cancer virus). Yes (see Anticancer Res 29: 4389-4396, 2009). Transplanting the BJMC3879 cell line into syngeneic mice causes a high rate of metastasis to lymph nodes and lungs (Cancer Gene Ther 9: 16-27, 2002; Carcinogenesis 25: 1887-1898, 2004; Cancer Gene ther 14: 268-278, 2007).

(In vivo breast cancer model experiment)
BJMC3879Luc2 cells (2.5 × 10 ⁶ cells / 0.3 ml) were transplanted subcutaneously into the groin area of 6-week-old BALB / c female mice (Japan SLC), resulting in a tumor diameter of 0.3 to 0.4 cm. At that time, α-mangosteen dodecanoic acid diester-containing diet (0 ppm [control group], 2000 ppm and 4000 ppm) was freely given to 10 mice in each group (30 mice in total) for 6 weeks. Ten mice in each group were housed in two cages in groups of five. Weekly, food intake was measured for each cage, and body weight and mammary tumor size were measured for each individual. Breast tumors were measured for short diameter and long diameter with a digital caliper, and the volume was determined by the formula of long diameter x (short diameter) ² x 0.4 (see EMBO J. 18: 2692-2701, 1999). At 7 weeks after the start of the experiment, all surviving animals were sacrificed and necropsied, and mammary tumors were removed and fixed with 10% buffered formalin solution. Lungs and lymph nodes (axillary region, inguinal region) were collected, and lymph nodes and various organs and tissues in which gross abnormalities were observed were also collected and histopathologically searched.

(In vivo imaging of cancer metastasis)
Six weeks after the start of the experiment, one cage was randomly selected from each group, and 5 mice housed therein were administered intraperitoneally with 3 mg of luciferin potassium salt per mouse, under isoflurane inhalation anesthesia. Then, bioluminescence imaging was performed using a photon imaging device (Photon Imager) (Biospace), and the spread of metastasis was compared between groups. However, in the control group, since death cases and drowning cases were observed, instead of these, mice were supplemented from the remaining cages, and measurement was performed.

(Statistical analysis)
The statistical analysis of the survival rate between the control group and the treatment group was performed by the Holm-Sidak method, and the quantitative data was the Student's t-test. Fisher's exact test was used to analyze the frequency of occurrence.

(result)
1. Survival rate The survival rate is as shown in FIG. As is apparent from this figure, 5 death cases (5/10) were observed at the 6th and 7th week in the control group, whereas one case at 7th week in the feed administration group containing the specimen 2000 ppm. Only death cases (1/10) were observed, and no death cases were observed in the 4000 ppm feed administration group (0/10). That is, the survival rate at the end of the experiment is 50% in the control group, 90% in the feed administration group containing 2000 ppm, 100% in the feed administration group containing 4000 ppm, and statistically between the control group and the feed administration group containing 4000 ppm. Differences were observed.

2. General symptoms, test substance intake, and body weight The general condition was very good in each group, and no symptoms that could be attributed to administration were observed. The daily intake of α-mangosteen dodecanoic acid diester per kg body weight was 359 mg in the feed administration group containing 2000 ppm and 735 mg in the feed administration group containing 4000 ppm. The change in body weight over time is as shown in FIG. 2, and no difference was observed between the control group and the administration group.

3. Tumor Volume The change in tumor volume over time is as shown in FIG. As can be seen from this figure, in the 4000 ppm-containing feed administration group, the tumor volume was significantly lower than the control group from 1 week to 6 weeks from the start of the experiment. In the feed administration group containing 2000 ppm, the tumor volume showed a significantly low value from 2 weeks to 6 weeks except at 5 weeks from the start of the experiment. At the end of the experiment, compared to the control group, the tumor volume was 26% in the feed administration group containing 2000 ppm and 38% in the feed administration group containing 4000 ppm, and the tumor volume was small.

4). In vivo imaging of cancer metastasis The results of in vivo imaging of cancer metastasis are as shown in FIG. In each figure, the tumor region appearing in an island shape in the mouse body is displayed in different colors step by step according to the intensity of the in-vivo luminescence that becomes stronger toward the center. As can be seen from these figures, metastasis to axillary lymph nodes and inguinal lymph nodes was observed in any group, but the extent of the spread was evident in both the 2000 and 4000 ppm diet-containing groups compared to the control group. It was mild.

5. Lymph node metastasis and lung metastasis The number of lymph node metastases per mouse (the number of metastasized lymph nodes) was significantly decreased in both the 2000 ppm-containing diet group and the 4000 ppm-containing diet group compared to the control group. The decrease was also statistically significant (FIG. 5a). For lung metastases, when the number of metastases was 1 mm or more and the number per mouse was calculated, both the 2000 ppm-containing feed group and the 4000 ppm-containing feed group showed a very marked decrease compared to the control group. Was also statistically significant (FIG. 5b). In FIGS. 5a and 5b, the numerical value represents the average value in each group, and the error bar represents the standard deviation (hereinafter the same in the same kind of figures).

6). Total number of organs that metastasized In addition to lymph nodes and lungs, metastasis to the ovary, adrenal gland, kidney, liver, and bone was observed histopathologically. The total number of organs that had metastasized was 125 in the control group, 48 in the feed administration group containing 2000 ppm and 37 in the feed administration group containing 4000 ppm, which was remarkably suppressed (FIG. 6a). When the number of metastatic organs per mouse was calculated, the 2000 ppm-containing feed administration group and the 4000 ppm-containing feed administration group both showed a significant decrease compared to the control group (FIG. 6b). The total number of metastasized organs is counted as above for lymph nodes and lungs, and for other organs, the left and right ovaries, adrenal glands, and kidneys are “1” if they are metastasizing only on one side, and both sides are metastasized. “2” if it was, and “1” if the liver and bone had metastasis.

[Comparative Example 1]
Using a mouse breast cancer model transplanted with BJMC cells not incorporating luciferase, a breast cancer experiment for α-mangosteen was conducted (experiment period was 8 weeks). In the same manner as in Test Example 1, 10 mice in each group (total of 30 mice) were fed at a concentration of 0 ppm (control group), 250 ppm and 2500 ppm.
As a result, one death case due to tumor was observed in each of the control group and the feed administration group containing 250 ppm. In the feed administration group containing 2500 ppm, one death was observed by being caught in the cage lid on the third week after the start of the experiment, and this animal was excluded from the analysis. There was no difference between the groups in the change in body weight (FIG. 7), and in the tumor volume, a significant suppression was observed from 4 weeks in the feed administration group containing 2500 ppm to 8 weeks after the end of the experiment (FIG. 8). When looking at the number of lymph node metastases per mouse (FIG. 9a), although a suppression tendency was observed in the 2500 ppm-containing feed group, no statistically significant difference was shown. Moreover, when the number of metastatic foci per mouse was analyzed for lung metastases of 1 mm or more, conversely, an increasing trend was shown in the feed administration group containing 2500 ppm (FIG. 9b).

[Discussion]
From the results of Test Example 1 and Comparative Example 1, it can be seen that the compound (1) of the present invention containing α-mangosteen dodecanoic acid diester has a markedly superior cancer metastasis inhibitory action compared to α-mangostin. I understand.

[Example 1]
(Synthesis of α-mangosteen dodecanoic acid diester)

Dodecanoic acid (C ₁₂ ) (5 g, 0.25 mol, Wako Pure Chemical Industries) was refluxed with thionyl chloride (7 ml, Wako Pure Chemical Industries) on a water bath for 2 hours, after which excess thionyl chloride was removed under reduced pressure. Distilled off to prepare dodecanoic acid chloride. α-Mangosteen (4.1 g, 0.01 mol) was dissolved in pyridine (3 ml) and tetrohydrofuran (30 ml), and this solution was added dropwise into dodecanoic acid chloride. The reaction solution was heated on a water bath (3 hours), cooled, added to 1N hydrochloric acid (50 ml), and extracted with ethyl acetate. The extract was concentrated, purified by silica gel column chromatography (eluent: chloroform), and α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester) (6.5 g) as a pale yellow oil. Obtained.
(Physical constant of this product)
Melting point: 39-40 ° C (solidifies as light yellow amorphous at room temperature)
Molecular formula: C ₄₈ H ₇₀ O ₈
Molecular weight: 774
EIMS m / z (%): 774 (M ⁺ , 100), 718 (6), 592 (70), 536 (28), 409 (34), 367 (36), 354 (64), 339 (99) , 323 (24), 311 (20), 183 (19), 71 (26), 57 (60).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.87, 0.89 (3H each, d, J = 6.9 Hz, dodecanoate-H-12'and H-12 ”), 1.26 (36H, m, dodecanoate-H- 3'-H-11'and H-3 ”-H-11”), 1.43 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20 ), 2.59, 2.63 (2H each, t, J = 7.5 Hz, dodecanoate-H-2'and H-2 ”), 3.30 (2H, s, J = 5.5 Hz, H-11), 3.76 (3H, s , OMe-C-7), 4.13 (2H, d, J = 5.0 Hz, H-16), 5.14, 5.19 (1H each, m, H-12 and H-17), 6.62 (1H, s, H- 4), 7.11 (1H, s, H-5).

[Example 2]
(Synthesis of α-mangosteen decanoic acid diester)

Except for using decanoic acid (C ₁₀ ) in place of dodecanoic acid, the same treatment as in Example 1 was carried out to obtain α-mangosteen decanoic acid diester (= α-mangosteen capric acid diester) as a brown oil.
(Physical constant of this product)
Molecular formula: C ₄₄ H ₆₂ O ₈
Molecular weight: 718
EIMS m / z (%): 718 (M ⁺ , 100), 662 (7), 564 (16), 508 (22), 409 (12), 355 (18), 339 (29), 325 (8) .
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.88, 0.89 (3H each, d, J = 6.9 Hz, decanoate-H-10'and H-10 ”), 1.29-1.31 (28H, m, decanoate- H-3'-H-9'and H-3 ”-H-9”), 1.68 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H -20), 2.59, 2.63 (2H each, t, J = 7.5 Hz, decanoate-H-2'and H-2 ”), 3.30 (2H, d, J = 6.9 Hz, H-11), 3.75 (3H , s, OMe-C-7), 4.13 (2H, d, J = 6.3 Hz, H-16), 5.14, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).

[Example 3]
(Synthesis of α-Mangosteen 10-Undecenoic Acid Diester)

The same treatment as in Example 1 was carried out except that 10-undecenoic acid (C ₁₁ ) was used instead of dodecanoic acid to obtain α-mangostin 10-undecenoic acid diester as a pale yellow brown oily substance.
(Physical constant of this product)
Molecular formula: C ₄₆ H ₆₂ O ₈
Molecular weight: 742
EIMS m / z (%): 742 (M ⁺ , 100), 730 (18), 576 (56), 533 (12), 520 (35), 409 (23), 355 (55), 339 (72) , 325 (15).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32-1.40 (24H, m, undecenoate-H-3'-H-8'and H-3 ”-H-8”), 1.67 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.04, 2.06 (2H each, m, undecenoate-H-9'and H-9 ”), 2.60 , 2.64 (2H each, t, J = 7.5 Hz, undecenoate-H-2'and H-2 ”), 3.30 (1H, d, J = 6.8 Hz, H-11), 3.75 (3H, s, OMe- C-7), 4.13 (1H, d, J = 6.3 Hz, H-16), 4.93 (2H, d, J = 10.3 Hz, undecenoate-H-11'a and H-11 ”a), 5.00 (2H , d, J = 17.2 Hz, undecenoate-H-11'b and H-11 ”b), 5.14, 5.19 (1H each, m, H-12 and H-17), 5.82 (2H, m, undecenoate-H -10'and H-10 "), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).

[Example 4]
(Synthesis of α-mangosteen octanoic acid diester)

Except for using octanoic acid (C ₈ ) in place of dodecanoic acid, the same treatment as in Example 1 was carried out to obtain α-mangosteen octanoic acid diester (= α-mangosteen caprylic acid diester) as a brown oil.
(Physical constant of this product)
Molecular formula: C ₄₀ H ₅₄ O ₈
Molecular weight: 662
negative HR ESI-TOFMS m / z: 661.3726 [MH] ^- , calcd. 661.3746.
negative ESI-TOFMS m / z (%): 661 (21), 535 (100), 395 (10), 281 (49), 265 (82), 255 (37), 182 (25).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 0.90 (6H each, d, J = 7.1 Hz, octanoate-H-8'and H-8 ”), 1.27-1.45 (16H, m, octanoate-H- 4'-H-7'and H-4 ”-H-7”), 1.43, 1.69, 1.77, 1.89 (3H each s, CH ₃ -C-14,15,19,20), 1.78, 1.80 (2H each, m, octanoate-H-3'and H-3 ”), 2.59, 2.64 (2H each, t, J = 7.5 Hz, octanoate-H-2'and H-2”), 3.30 (2H, d, J = 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J = 6.5 Hz, H-16), 5.15, 5.20 (1H each, m, H- 12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
¹³ C-NMR (125 MHz, CDCl ₃ ) δ: 12.6 (C-8 ', C-8 ”), 16.4, 16.7 (C-15, C-19), 20.8 (C-11), 21.1 (C- 5 ', C-5 "), 23.31, 23.34 (C-3', C-3"), 24.4, 24.3 (C-6 ', C-6 "), 25.0 (C-16), 27.42, 27.44, 27.5, 27.6 (C-4 ', C-5', C-4 ", C-5"), 30.1 (C-6 ', C-6 "), 32.7, 32.8 (C-2', C-2 ''), 60.2 (OMe -C-7), 98.8 (C-4), 105.5 (C-9a), 109.1 (C-5), 114.7, 115.2 (C-2, C-8a), 119.9, 121.2 ( C12, C-17), 130.7 (C-8, C-13), 137.5 (C-18), 145.3 (C-7), 148.0 (C-6), 152.2, 152.6, 153.5 (C-1, C -3, C-4a), 159.5 (C-10a), 169.4, 169.8 (C-1 ', C-1''), 181.6 (C-9).

[Example 5]
(Synthesis of α-mangosteen tetradecanoic acid diester)
An α-mangosteen tetradecanoic acid diester (= α-mangosteen myristic acid diester) is obtained in the same manner as in Example 1 except that tetradecanoic acid (C ₁₄ ) is used instead of dodecanoic acid.

Since the compound (1) of the present invention has an excellent anticancer activity and cancer metastasis inhibiting activity, it can be used in the fields of medicine and cancer treatment.

Claims (8)

1. General formula (1):
   

   

   (In the formula, R ¹ represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
   Α-Mangosteen diester represented by
2. The α-mangosteen diester according to claim 1, wherein R ¹ is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid having 8 to 14 carbon atoms.
3. The α-mangosteen diester according to claim 1, wherein R ¹ is a residue obtained by removing a hydroxyl group from an unsaturated medium chain fatty acid having 8 to 14 carbon atoms.
4. 2. The α-mangosteen diester according to claim 1, wherein R ¹ is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid selected from octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid and tetradecanoic acid.
5. The α-mangosteen diester according to claim 1, wherein R ¹ is a residue obtained by removing a hydroxyl group from 10-undecenoic acid.
6. Formula (1-a)
   

   

   Α-Mangosteen diester represented by
7. An anticancer agent comprising the α-mangosteen diester according to any one of claims 1 to 6 as an active ingredient.
8. A cancer metastasis inhibitor comprising the α-mangosteen diester according to any one of claims 1 to 6 as an active ingredient.

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