JPH11217353A - New cryptoporic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new cryptoporic acid derivative showing antimicrobial actions, derived from a compound prepared from a fruit body of Cryptoporus volvatus being a mushroom of the family Polyporaceae. SOLUTION: This compound is shown by formula I (R1 , R2 and R3 are each H, an alkyl or an alkali metal; R4 is an alkyl, a hydroxyalkyl or an acetoxyalkyl; R5 is an oxygen atom, hydroxy, methyl or an epoxy ring) or its dimer such as a compound of formula II. The compound is obtained, for example, by finely cutting a fruit body of Cryptoporus volvatus (e.g. collected at Mito forest park in Ibaragi Prefecture), immersing the finely cut fruit body in a solvent such as ethyl acetate or the like at a room temperature for 1-3 days, extracting an active ingredient, separating, purifying and oxidizing or epoxidizing the prepared compound by a routine procedure.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cryptopollic acid derivative, and the derivative of the present invention is a basidiomycete carrier, such as a fungus mushroom, amanita mushroom, a maggot or an eschiloamitake mushroom. These compounds are derived from sesquiterpene compounds of the type, and are effective as antifungal agents like these compounds, and the present invention belongs to the pharmaceutical production technology.

[0002]

2. Description of the Related Art With the remarkable development of antimicrobial drugs, mainly antibiotics, antifungal agents are not always in a satisfactory state, judging from their type and effectiveness. Things. Fungal infections to humans include candidiasis, aspergillosis, cryptococcosis, mucormycosis, and other imported mycosis, including actinomycosis, nocardiosis, chromoblast mycosis, histoplasmosis, coccidioidomycosis,
Geotrichum disease, penicillium disease and the like are known.
There are also superficial mycosis such as athlete's foot and bugs. Especially,
In recent years, general use of anticancer drugs, immunosuppressants, steroid hormones, etc.
Opportunistic infections caused by fungal infections such as Candida, Aspergillus, and Cryptococcus have become one medical problem, and the development of therapeutic agents for them has been desired. At present, chemotherapeutic agents such as amphoterin B, fluconazole, itraconazole, miconazole, and 5-fluorocytosine are used as therapeutic agents for these fungal infections. However, these chemotherapeutic agents are not always satisfactory in terms of toxicity and therapeutic effect, and the emergence of resistant bacteria is also a problem. In order to solve this problem, a clinically useful antifungal drug excellent in selectivity is desired. On the other hand, various physiologically active ingredients contained in mushrooms have been studied for a long time. Have been. In particular, β-D-glucan protein complex (PS-K) extracted from cultured mycelium of C. versicolor has been widely used as an anticancer agent as a pharmaceutical, and from human agaric mushroom, Lee et al., Kor. . Mycol. Vol.9, No.
3, 153-155, 1981), Kim et al., Kor. J. Myco
l. Vol. 10, No. 3, 111-117, 1982) reported that ergosterol was obtained from protein-polysaccharide or chloroform-methanol extract which showed anticancer activity from water extract (Asakawa). Et al., Trans. M
ycol. Soc. Japan 29, 281-296, 1988). Furthermore, Asakawa et al. Have also revealed that various cryptopolonic acid derivatives have been obtained as a bitter component from the human black mushroom, and that it has been reported that a different cryptopoloic acid derivative was obtained from the culture extract thereof. (M. Hirotani et a
1, Phytochemistry 30 (5), 1555-1559 (1991)). Also,
It is also reported that cryptopoloic acid derivatives can be obtained from cultured maggots. Separately, another cryptopoloic acid derivative and a similar compound to a cryptopoloic acid derivative have been reported from Escherichia coli (Y. Morita et al, Biosci. Biotech.
9) 2008-2009 (1995)). The present inventors have found that these cryptoporic acid derivatives are excellent as antifungal agents, and have previously made one proposal (International Publication WO96 / 25385).
Cryptopollic acid derivatives, some of whose properties are also known, are a group of compounds represented by the following structural formula 2.

[0003]

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In the formula, R ¹ , R ² and R ³ may be the same or different from each other, and may be a hydrogen atom, an alkyl group,
In particular, it is a lower alkyl group and more specifically a methyl group, and is an alkali metal such as sodium or kallium,
R ⁴ is a methyl group, a hydroxymethyl group or an acetoxymethyl group. Further, as the cryptoporic acid derivative, a cyclic dimer of the compound represented by the above structural formula 2 or the like can also be mentioned.

[0005]

SUMMARY OF THE INVENTION The present inventors have noted that the above cryptoporic acid derivatives are excellent as antifungal agents, prepared various novel cryptoporic acid derivatives by chemical synthesis, and prepared them. The present inventors have further studied to find a potential antifungal agent therein, and the present invention intends to provide a novel compound obtained thereby.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and have found that sesquiterpene-based compounds isolated from an extract extracted from the fruiting body of human mushroom (Cryptoporus volvatus), which is a mushroom belonging to the genus Takokinidae More specifically, they have found that there are novel compounds which exhibit antifungal activity from various cryptopoloic acid derivatives composed of sesquiterpene having a dolmen skeleton and isocitrate as raw materials, thereby completing the present invention.

That is, the present invention relates to a novel cryptoporic acid derivative, which is a compound represented by the following structural formula 1 or a dimer thereof.

[0008]

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Wherein R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group or an alkali metal which may be the same or different, and R ⁴ is an alkyl group, a hydroxyalkyl group or an acetoxy group. an alkyl group, R ⁵
Represents an oxygen atom (oxo), a hydroxy group, a methyl group or an epoxy ring. In addition, a dimer is a compound in which two cryptopolonic acid derivatives represented by the above structural formulas have a carbon (methyl group) added to the 4-position of the hydronaphthalene ring of one cryptopoloic acid derivative and another cryptopoloic acid derivative. It has a structure bonded to a carboxyl group. Further, the alkyl group includes lower alkyl, particularly a methyl group, and the alkali metal includes sodium and potassium.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
Cryptoporic acid derivatives can be extracted and obtained using a solvent from the fruiting body of Aedes agaricus, which is a mushroom belonging to the octopus family in dead red pine, as shown by Asakawa et al. Described above. Things. Furthermore, from the cultivated maggot (M.Hi
rotani et al., Phytochemistry, 30 (5): 1555-1559 (199
1)), E. white mushroom (Y. Morita et al., Biosci. Bio
tech. Biochem., 59 (19): 2008-2009, (1995)). It can also be derived from a compound named Roseolide A (Tetrahedron Letters, 34 (15) 2497-2500 (1993)) obtained from Hounentake, and the like. More specifically, an example of the obtaining method is as follows. First, the fruit body of Aedes agaricus is finely cut, and the active ingredient is extracted by immersing it in a solvent such as ethyl acetate at room temperature for 1 to 3 days. By extracting the extracted extract using silica gel column chromatography or preparative thin-layer chromatography, which is usually used for separating compounds, and further combining with high performance liquid chromatography, etc., the desired cryptoporic acid derivative is separated and collected. You. The compound of the present invention is obtained from the thus obtained cryptoporic acid derivative
It can be easily obtained by oxidizing or epoxidizing the unsaturated bond added to the position by a conventional method.

The antifungal agent containing the compound of the present invention as an active ingredient is useful as a remedy for mycosis involving fungi such as mold and yeast contained in humans. In the case of oral administration, tablets, capsules and powders In the case of parenteral administration, solutions, suspensions,
It can be used as an ointment or the like. As the dose,
Although it varies depending on the severity of the disease, the weight of the patient, and the like, it is generally preferred to be about 1 to 500 mg, and it is good to administer it once a day to several times a day. In the case of an injection solution, it can be administered by putting it in a drip. Upon formulation, commonly used vehicles, carriers, leavening agents,
Excipients, binders, lubricants, buffers, antioxidants, preservatives, stabilizers, flavoring agents, etc. are mixed and formulated into unit doses required for the formulation. Hereinafter, examples of the present invention will be described, but the examples do not limit the present invention.

[0012]

Example 1 Example 1 Aidum mushroom (1.11 kg) collected at Mito Forest Park, Ibaraki Prefecture, April 1997 was cut into small pieces and extracted with acetone (3 L) at room temperature for 3 days. After separating the acetone extract, it was further extracted with methanol (3 L) for 3 days. After distilling off the solvent, the extract was dried under reduced pressure, and the extract was 68.7 g and 26.5 g respectively.
In the yield. After analyzing the contained components by thin layer chromatography, the two extracts were combined, dissolved in methanol, and passed through an activated carbon column [50 g: 4.5 cm ID × 17.5]. Methanol (800 ml) and methanol-chloroform [3: 1
(250 ml), a 2: 1 (500 ml)] mixture, and eluted the fraction containing the cryptoporic acid derivative (Fr.
4), 65.9 g were obtained. 10.1 g of the fraction containing the cryptoporic acid derivative was hydrolyzed in ethanol (50 ml) -2N aqueous sodium hydroxide solution (50 ml) at 95-100 ° C. for 6 hours. After the ethanol was distilled off, the reaction solution was diluted with water, washed with ethyl acetate, concentrated hydrochloric acid was added dropwise to adjust the pH to around 3.5, and the mixture was extracted twice with ethyl acetate (50 ml). The combined extracts were thoroughly washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to reverse phase column chromatography (Cosmosil 140C18-OP).
N, 75C18-OPN, elution solvent: methanol-water =
(50/50 → 100/0), thereby obtaining 0.36 g of cryptoporic acid H represented by the following structural formula. These structures were determined by thin-layer chromatography, ¹ H-NMR, IR, and mass spectra, and compared with measured data described in the literature of Asakawa et al. The ¹ H-NMR chart and the IR chart of cryptoporic acid H are shown in FIG. 1 and FIG. 2, respectively.

[0013]

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Cryptopollic acid H (600 mg: 1.52 mm
ol) was dissolved in a mixture of ether (2 ml) -methanol (2 ml), and a 10% hexane solution of trimethylsilyldiazomethane was added dropwise with stirring at room temperature until the reaction solution became slightly yellow. After stirring until no gas is generated, the solvent is distilled off, and the residue is subjected to silica gel column chromatography.
Purification was performed using [6 g: 1.5 cm ID × 9, elution solvent: chloroform-ethyl acetate = 100/0 → 70/30] to obtain 566 mg of trimethyl ester of cryptoporic acid H represented by the following structural formula as a white powder. The structure decision
Performed as above. The ¹ H-NMR chart of the trimethyl ester of cryptoporic acid H is shown in FIG.

[0015]

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Trimethyl ester of cryptoporic acid H
M-chloroperbenzoic acid (250m2) in a dichloromethane (20ml) solution of (300mg: 0.68mmol) at room temperature with stirring.
g: 1.45 mmol). After stirring at the same temperature for 2 hours, the reaction solution was diluted with dichloromethane (10 ml) and diluted with 5%
The extract was washed successively with sodium thiosulfate, a saturated aqueous solution of sodium bicarbonate and saturated saline. After drying with anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [12 g: 1.5 cm ID × 15, elution solvent: chloroform-ethyl acetate = 100/0 → 90/1].
0 (40 ml)] of an 8,12-epoxy derivative of a trimethyl ester of cryptoporic acid H represented by the following structural formula:
7 mg were obtained as a colorless crystalline solid. Cryptopollic acid H
¹ H-NMR of 8,12 epoxy of trimethyl ester
Chart 4 and IR chart are shown in FIG.

[0017]

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Example 2 Next, the trimethyl ester of this cryptoporic acid H was
8,12-Epoxy (230 mg: 0.51 mmol) was added to ethanol
(2 ml)-After dissolving in tetrahydrofuran (2 ml), 1N aqueous sodium hydroxide solution (4 ml) was added, and the mixture was stirred at room temperature for 14 hours. After confirming the completion of the reaction, the reaction solution was diluted with water (5 ml) and washed with ethyl acetate. After adjusting the pH of the aqueous layer to about 3.5 with 1N hydrochloric acid, the product was extracted with ethyl acetate (15 ml), and the extract was thoroughly washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by reverse phase column chromatography to obtain 175 mg of the 8,12-epoxy derivative of cryptoporic acid H represented by the following structural formula as a white powder.

[0019]

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Example 3 Cryptopollic acid H was added to an aqueous solution (10 ml) of sodium periodate (977 mg: 4.57 mmol) while stirring at room temperature.
Of trimethyl ester (500 mg: 1.14 mmol) in t-butanol (10 ml) and a 2% aqueous solution of osmic acid (2
00 μl) were added sequentially. After the reaction solution was stirred at 50 ° C. for 5 hours, a 10% aqueous sodium thiosulfate solution (40 ml) was added.
The product was extracted twice with ethyl acetate (40ml). The extract was washed with a 10% aqueous sodium thiosulfate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained 8-oxo compound (460 mg) was dissolved in methanol (5 ml) without purification, and sodium borohydride (50 mg) was added with stirring under ice cooling. After stirring for 1 hour at the same temperature, water
(30 ml) was added and the product was extracted twice with ethyl acetate (25 ml). The extract was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography [12 g: 1.5 cm ID × 15.
5. Elution solvent: chloroform-ethyl acetate = 100/0
→ 70/30 (40 ml)] to obtain 348 mg of the 8-hydroxy form of trimethyl ester of cryptoporic acid H represented by the following structural formula as a colorless candy substance. 8-hydroxy body of trimethyl ester Crypto pole acid H ¹
The H-NMR chart is shown in FIG. 6 and the IR chart is shown in FIG.

[0021]

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Example 4 Next, the 8-hydroxy form (140 mg: 0.32 mmol) of trimethyl ester of cryptoporic acid H was added to ethanol (1 m 2).
l) After dissolving in a mixture of tetrahydrofuran (1 ml), a 1N aqueous sodium hydroxide solution (2 ml) was added with stirring under ice cooling. After stirring at room temperature for 15 hours, water (10 ml) was added to the reaction solution, and the mixture was washed with ethyl acetate. Then, the aqueous layer is p-p with 1N hydrochloric acid.
After adjusting to around H3.5, the mixture was extracted twice with ethyl acetate (15 ml), and the extract was sufficiently washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to reverse phase column chromatography [Cosmosil 75C18-OP].
N, 20 cc: 1.5 cm ID × 11 cm, eluting solvent: methanol-water = 50/50 → 100/0 (20 ml)] to obtain 117 mg of 8-hydroxy form of cryptoporic acid H represented by the following structural formula as a white powder. Was. FIG. 8 shows the ¹ H-NMR chart of the 8-hydroxy form of cryptoporic acid H.

[0023]

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Example 5 Trimethyl ester of cryptoporic acid H (99 mg: 0.1
Platinum dioxide (5 mg) in a solution of 23 mmol) in ethanol (5 ml)
Was added, and hydrogenation was performed under normal temperature and normal pressure. After confirming the completion of the reaction by thin layer chromatography, the catalyst was removed by filtration. After evaporating the solvent, the residue is purified by silica gel column chromatography.
Purification was performed using [5 g: 1.0 cm ID × 12 cm, elution solvent: n-hexane-ethyl acetate = 100/0 → 40/60 (20 ml)] to obtain 95 mg of a dihydro compound. Next, this dihydro compound (76 mg: 0.17 mmol) was dissolved in a mixed solution of ethanol (1 ml) and tetrahydrofuran (1 ml), a 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 80 ° C. for 4 hours. After confirming the completion of the reaction, water (10 ml) was added to the reaction solution, and ethyl acetate (20 ml) was added.
Washed in l). After adjusting the pH of the aqueous layer to about 3.5 with 1N hydrochloric acid, the product was extracted twice with ethyl acetate (15 ml), and the extract was thoroughly washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by reversed-phase column chromatography in the same manner as in Example 4 to obtain 68 mg of the 8-methyl form of cryptoporic acid H represented by the following structural formula as white Obtained as a powder. Cryptopollic acid H 8-
The ¹ H-NMR chart of the methyl form is shown in FIG.

[0025]

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Example 6 Trimethyl ester of cryptoporic acid H (380 mg: in an aqueous solution of sodium periodate (930 mg: 4.30 mmol))
Then, 10 ml of a t-butanol solution (0.87 mmol) and a 2% aqueous solution of osmic acid (0.5 ml) were sequentially added, followed by heating to 50 ° C. and stirring for 2 hours. After the reaction, 40 ml of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 ml). The extract is
After coalescence, the mixture was washed with a 5% aqueous solution of sodium thiosulfate, water and saturated saline. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (1 × 13 cm, n-hexane / ethyl acetate) to obtain a cryptoporic acid represented by the following structural formula. H
313 mg of the 8-oxo form of trimethyl ester of was obtained as a white solid. The ¹ H-NMR chart of the 8-oxo form of the trimethyl ester of cryptoporic acid H is shown in FIG.
The chart is shown in FIG.

[0027]

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Example 7 8-oxo compound prepared in Example 6 (200 mg: 0.45 mmo)
sodium borohydride with stirring under ice-cooling to a methanol solution (2 ml) of _{l) (NaBH 4 34mg: 0.90mmol} ) was added portionwise. After the addition, the mixture was stirred for 30 minutes on ice, and water and 1N hydrochloric acid were added.
ml) twice. After the extracts were combined, the extracts were washed with an aqueous solution of sodium hydrogen carbonate and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (1 × 18 cm, chloroform / chloroform).
Purification with ethyl acetate) gave 168 mg of the 8-hydroxy form of the trimethyl ester of cryptoporic acid H as a colorless candy.

Example 8 Trimethyl ester of cryptoporic acid H (200 mg:
M-chloroperbenzoic acid (200 mg: 1.15 mm) in a dichloromethane (20 ml) solution of 0.46 mmol) at room temperature with stirring.
ol) was added in small portions. After the addition, the mixture was further stirred at room temperature for 2 hours, dichloromethane (10 ml) was added to the reaction solution, and the mixture was washed successively with a 5% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. After the dichloromethane was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (1 × 16.5).
(chloroform / ethyl acetate) to give 186 mg of the 8,12-epoxy derivative of the trimethyl ester of cryptoporic acid H as a white solid.

○ Anti-Candida albicans (Candida a
lbicans) activity assay method Candida albicans for 8,12-epoxy form, 8-hydroxy form and 8-methyl form of cryptoporic acid H
(Candida albicans) was used as a test bacterium to test its susceptibility to the fungus in vitro to confirm its activity. The antifungal susceptibility test is described in Journal of the Japanese Society for Medical Mycology, Vol. 36 (1), 62-64.
(1995). The strains used in the experiments used were strains TIMM1776 and TIMM3318, which were provided by Teikyo University Medical Mycology Research Center. Among them, the TIMM3318 strain has resistance to an azole antifungal agent. The culture medium for sensitivity measurement was RPMI1640 (Irvine Scientific Cat. # 951).
2) was dissolved in 900 ml of sterile distilled water by dissolving 10.4 g of sodium hydrogencarbonate and 2.0 g of sodium bicarbonate, and then dissolved in MOPS buffer (0.165 M) 3.
After adding 4.53 g, the mixture was stirred well until dissolved, and then adjusted to pH 7.0 with sodium hydroxide, sterilized distilled water was added to make up to 1 liter, and sterilized by filtration and stored at 4 ° C. The test bacterium used was YM agar medium (Difco) at 35 ° C, 2
After subculture by culturing for 4 to 48 hours twice or more, 5 ml
Obtained by suspending in sterile physiological saline. The absorbance of this suspension was measured at 600 nm, the bacterial amount was determined from a previously prepared calibration curve, and diluted with a culture medium for sensitivity measurement to a bacterial count of 2 × 10 ³ cells / ml to obtain a test bacterial solution. . Test sample is 2
Dissolve the sample using a 0% methanol solution of DMSO.
A test assay solution was prepared by two-fold serial dilution. The test for antifungal susceptibility was performed in a 96-well flat-bottom microplate with 90 μl.
l of the culture medium for sensitivity measurement was dispensed, and 10 µl of the test assay solution and 100 µl of the test bacterial solution were added to each well to prepare a predetermined concentration. Incubate at 35 ° C for up to 72 hours,
Observed every 24 hours, the turbidity of the growth control is 0.2
When reached, the turbidity of each well is measured. Determination of 80% inhibitory concentration (IC ₈₀₎ after stirring the microplate mixer, 40 [mu] l up the culture growth control, which in the sensitivity measuring medium 160μl addition, IC ₈₀
Substantial wells were made. The wells exhibiting a turbidity equal to or less than the turbidity of this well were defined as the end points.
Table 1 shows the results. Cryptopollic acid E is a compound in which R ⁴ in the above structural formula 1 is a hydroxymethyl group.

[0031]

[Table 1]

○ Anti-Aspergillus fumigatus (Asp
ergillus fumigatus) activity measurement method Drug solution preparation method The test drug was weighed, and a drug dilution step was prepared with methanol containing 20% DMSO. 2. Sensitivity measurement medium and preparation method RPM11640 (Irvine Scientific Cat. # 9512) 10.4
g, 2.0 g of NaHCO _{3 in} 900 ml of sterile distilled water
Add 34.53 g of MOPS buffer (0.165 M) and stir,
After adjusting the pH to 7.0 with NaOH, the volume was increased to 1 L, and sterilized by filtration before use. 3. Preparation of Inoculated Bacterial Solution Test bacteria were cultured on a potato dextrose agar medium (Difco) at 30 ° C. for 1 week, and then 0.05% Tween80 was added.
A sterile physiological saline solution was added to obtain a conidia suspension. The number of conidia was counted under a microscope using a hemocytometer and adjusted to 2.5 × 10 ⁵ cells / ml in a measurement medium. 4. Culture 90 μl of medium was dispensed into a 96-well flat bottom microplate, 10 μl of the drug solution prepared in 1 and 80 μl of the inoculum were added.
20 μl of alamar blue solution was added to each well (final 1% DMSO, 4% methanol, alamar blue
Is 10%, and the growth control is the same medium without drug). Incubate at 30 ° C in a wet container to prevent drying, 2
Observed every 4 hours, OD _{570 of} the growth control was 0.6.
The end point was judged when reaching. 5. Judgment of results 80% growth inhibitory concentration (IC ₈₀ ) relative to growth control
This was defined as the minimum inhibitory concentration with the endpoint as the endpoint. More specifically, the drug concentration was determined to be equal to or less than 20% of the measured value of the growth control, but the drug concentration was calculated as I
C ₈₀ (MIC). Table 2 shows the results.

[0033]

[Table 2]

Infection treatment experiments Healthy growing mice (ICR, 4 weeks old, female, 19-2)
2g, CLEA Japan), Aspergillus fumigatus (2.0 × 10 ⁶ CFU / mouse) suspended in physiological saline.
The bacterial solution _0. Inoculated from 2ml tail vein, was established infection. For treatment, a sample was dissolved or suspended in a 5% gum arabic aqueous solution, and 0.2 ml each time was orally administered using a gastric probe (50 mg / kg and 10 mg / kg or 10 mg / kg and 2 mg / k).
g). The first time is 1 hour after inoculation, and once a day thereafter 24 hours
Six doses were administered every hour (once / day, for a total of 7 days). The control group received 0.2 ml of the vehicle alone. The efficacy was determined as follows from the number of surviving mice in the sample administration group at the time when all the control animal groups died. Effective 60% or more survival rate Slightly effective 40% survival rate Ineffective 20% or less survival rate

[0035]

[Table 3]

[0036]

From the above results, it can be seen that the novel compounds of the present invention exhibit excellent antifungal activity against Candida albicans and Aspergillus fumigatus, which are pathogenic fungi that infect humans. It has been shown that cryptopol acids and their derivatives are effective as chemotherapeutic agents for fungal infections such as candidiasis and aspergillosis.

[Brief description of the drawings]

FIG. 1 is a ¹ H-NMR chart of cryptoporic acid H.

FIG. 2 is an IR chart of cryptoporic acid H.

FIG. 3. Trimethyl ester of cryptoporic acid H
It is a < ¹ > H-NMR chart.

FIG. 4. Trimethyl ester of cryptoporic acid H
It is a ¹ H-NMR chart of an 8,12-epoxy compound.

FIG. 5: Trimethyl ester of cryptoporic acid H
It is an IR chart of an 8,12-epoxy compound.

FIG. 6: Trimethyl ester of cryptoporic acid H
¹ is a ¹ H-NMR chart of an 8-hydroxy form.

FIG. 7. Trimethyl ester of cryptoporic acid H
It is an IR chart of an 8-hydroxy form.

FIG. 8 ¹ H of the 8-hydroxy form of cryptoporic acid H
-It is an NMR chart.

FIG. 9 ¹ HN of the 8-methyl form of cryptoporic acid H
It is an MR chart.

FIG. 10 is a ¹ H-NMR chart of an 8-oxo form of trimethyl ester of cryptoporic acid H.

FIG. 11 is an IR chart of an 8-oxo form of trimethyl ester of cryptoporic acid H.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // A61K 31/19 ADZ A61K 31/19 ADZ 31/235 31/235 (72) Inventor Toshiaki Segawa 2nd Okubo, Tsukuba, Ibaraki, Japan Toagosei Co., Ltd. Tsukuba Research Laboratories

Claims (1)

[Claims] 1. A novel cryptoporic acid derivative which is a compound represented by the following structural formula 1 or a dimer thereof. Embedded image However, in the formula, R ¹ , R ² and R ³ are a hydrogen atom, an alkyl group or an alkali metal which may be the same or different, and R ⁴ is an alkyl group, a hydroxyalkyl group or an acetoxyalkyl group. R ⁵ is an oxygen atom (oxo), a hydroxy group, a methyl group or an epoxy ring.