JP2001097907A - Polyfunctional carboxylic acid, its ester or alcohol reduction body - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having a hydronaphthalene ring structure effective as an antifungal agent, a raw material for various antifungal agents, another medicine, its raw material such as an anticancer agent or a raw material for various anticancer agents. SOLUTION: This polyfunctional carboxylic acid is represented by the structural formula (R1 is a hydrogen atom or a protective group at the hydroxy position; R2 is an alkylene group), its ester or an alcohol reduction body.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel polycarboxylic acid having a hydronaphthalene ring structure, an ester or an alcohol reduced form thereof, and a compound of the present invention as an antifungal agent or various antifungal agents. The present invention is effective as a raw material for production, or as other pharmaceuticals or raw materials thereof, for example, as an anticancer agent or as a raw material for various anticancer agents. 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 the point of kind, effectiveness and toxicity. Mycosis to be treated with antifungal agents includes deep fungal infections and superficial fungal infections, and deep fungal infections include candidiasis, aspergillosis, cryptococcosis, and mucormycosis. Actinomycosis, Nocardiosis, Chromoblast Mycosis, Histoplasmosis, Coccidioidomycosis, Geotrichum disease, Penicillium disease, etc., including other imported mycosis. In addition, superficial mycosis includes athlete's foot, onychomycosis, and bugs. In particular, in recent years, aging, after surgery, Candida (Candida), Aspergillus (Aspergillus), Cryptococcus (Cryptoco
Opportunistic infections caused by fungal infections such as ccus) have become a medical problem, and the development of therapeutic agents has been desired. Therapeutic agents for these fungal infections currently include amphotericin B, fluconazole, itraconazole,
Chemotherapeutic agents such as miconazole, 5-fluorocytosine have been used. 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.

[0003]

SUMMARY OF THE INVENTION The present inventors have a strong antibacterial activity against the above-mentioned fungi which cause opportunistic infections, that is, as an antifungal agent or as a raw material for producing an antifungal agent. They continued their intensive studies to find effective new compounds. That is, an object of the present invention is to provide a novel compound effective as an antifungal agent, an anticancer agent or the like, or as a raw material thereof.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to achieve the above-mentioned object, and have found that the hydronaphthalene ring structure has a great influence on the antifungal action, that is, the hydronaphthalene ring structure has New compounds in which various substituents are added to arbicanol and sclareolide having a structure similar thereto and compounds having a hydronaphthalene ring structure synthesized from geraniyl, linalool, etc. as antifungal agents or production of antifungal agents The present inventors have found that the present invention is effective as a raw material for the present invention, and have completed the present invention.

That is, the present invention relates to a polycarboxylic acid represented by the following structural formula, an ester thereof, or a reduced form thereof.

[0006]

Embedded image

In the formula, R ₁ is a protecting group for a hydrogen atom or a hydroxyl group, and R ₂ is an alkylene group.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
In the compound of the present invention, the center of the structure is a hydronaphthalene ring, and more specifically, as shown by the structural formula, a hydroxyl group and a methyl group which may have a protecting group at the 8-position, and a 9-position Has an alkyl group having three carboxyl groups as substituents, wherein R ₂ is an alkylene group, a lower group, particularly an ethylene group, and the protecting group for the hydroxyl group is a methoxymethyl group (MOM) , Methylthiomethyl (MTM), tetrahydropyranyl (THP), t-butyl (tB
u), trityl (Trt), benzyl (Bzl or Bn), ether-type protecting groups such as p-methoxybenzyl (MP), acyl-type protecting groups such as acetyl groups, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS ) And the like, and the protecting groups include those having a cyclic structure. Examples of the ester of the polycarboxylic acid include alkyl esters, particularly lower esters such as methyl and ethyl, and examples of the reduced form of alcohol include reduced forms of methanol. All three carboxyl groups are esterified or reduced by alcohol. Although it is not necessary that all carboxyl groups are esterified or alcohol reduced, it is preferable from the viewpoint of easiness of production and reproducibility.
The compound of the present invention is derived from known compounds such as sclareolide by known means.

[0009]

EXAMPLES Examples of the present invention will be described below, but these examples do not limit the present invention in any way. In addition, the antifungal activity measurement method and the infection treatment test method in each Example are as follows. ○ Anti-Candida albicans (Candida albicans) activity measurement method Candida albicans (Candid albicans)
a albicans) as a test bacterium, i.
Tested in vitro to confirm its activity. Antifungal susceptibility test, Journal of the Japanese Society for Medical Mycology, Vol. 36 (1), 62-64 (1995)
Performed in accordance with the method proposed in The strains used in the experiments used were strains TIMM1768 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 is RP
MI1640 (Irvine Scientific Cat. # 9512) for 10.
4 g and 2.0 g of sodium bicarbonate in 900 m of sterile distilled water
After dissolving in l, 34.53 g of MOPS was added as a buffer,
Stir well until dissolved, then p with sodium hydroxide
After adjusting to H7.0, the volume was adjusted to 1 liter by adding sterile distilled water, and the solution was sterilized by filtration and stored at 4 ° C. Test bacteria are YM
Using an agar medium (Difco), the cells were subcultured by culturing at 35 ° C. for 24 to 48 hours twice or more, and then suspended in 5 ml of sterile physiological saline. The absorbance of this suspension was measured at 600 nm, the amount of bacteria was determined from a calibration curve created in advance, and 2 × 1
It was diluted with a culture medium for sensitivity measurement so as to have a cell count of 0 ³ cells / ml to prepare a test bacterial solution. The test sample was dissolved using a methanol solution containing 20% DMSO, and a test assay solution was prepared by 2-fold serial dilution. The test for antifungal susceptibility was 9
Dispense 90 μl of sensitivity measurement medium into a 6-well flat bottom microplate, add 10 μl of test assay solution and 100 μl
Was added to each well to prepare a predetermined concentration.
The microplate was placed in a container keeping humidity and cultured at 35 ° C. for a maximum of 72 hours. Observation was made every 24 hours, and when the turbidity of the growth control reached 0.2, the turbidity of each well was determined. It was measured. To determine the 80% growth inhibitory concentration (IC ₈₀ ), a microplate was stirred with a mixer, 40 μl of a growth control culture was taken, and 160 μl of a culture medium for sensitivity measurement was added thereto to prepare a well equivalent to IC ₈₀ . The wells exhibiting a turbidity equal to or less than the turbidity of this well were defined as the end points.

○ Anti-Aspergillus fumigatus (Aspe
rgillus 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
34.53 g of MOPS was added as a buffer solution, and the mixture was stirred.
After adjusting the pH to 7.0 with H, the volume was adjusted to 1 liter 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).

[0011] Infection treatment test Healthy growing mouse (ICR, 4 weeks old, female, 19-2)
2g, Charles River Japan) 0.1% Tween8
0.2 ml of a bacterial solution of Aspergillus fumigatus (1.0 × 10 ⁶ CFU / mouse) suspended in physiological saline to which 0 was added.
Inoculation was performed through the tail vein to establish infection. Treatment is performed by dissolving or suspending the specimen in a 5% gum arabic aqueous solution, 0.2 m each time.
l was orally administered using a gastric probe (50 mg / kg and 10 m
g / kg or 10 mg / kg and 2 mg / kg). The first administration was performed 1 hour after inoculation of the bacteria, and thereafter, 6 administrations were performed once a day every 24 hours (administered once a 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

Example 1 A commercially available sclareolide (1.25 g: 5.00 mmol, Aldrich reagent) was dissolved in a mixture of tetrahydrofuran (hereinafter referred to as THF) (10 ml) and ether (10 ml), and the mixture was stirred under ice-cooling while stirring. Lithium aluminum hydride (190 mg:
5.00 mmol) was added in small portions. After stirring at the same temperature for 1 hour, ethyl acetate was added little by little to decompose excess reagent.
After adding 1N hydrochloric acid (40 ml), the mixture was extracted twice with ethyl acetate (40 ml), and the extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the precipitated crystals were collected by filtration.
Two methyl groups at the 8 position, a methyl group and a hydroxy group at the 8 position,
1.20 g of hydronaphthalene having a 2-hydroxyethyl group at the 9-position and a methyl group at the 10-position (hereinafter referred to as AT-1) was obtained as colorless needles (unless otherwise noted in the description of the structural formula, The description of the methyl groups at the 4- and 10-positions is omitted. Its ¹ H-NMR spectrum (400 MHz) was as follows. (CDCl ₃ , ppm): 0.79 (3H, s, Me-C10), 0.79 (3H, s, Meβ-C
4), 0.88 (3H, s, Meα-C4), 1.20 (3H, s, Me-C8), 1.90 (1H,
ddd, J = 12.2,3.4,2.9, H7), 3.46 (1H, ddd, J = 10.3,8.3,5.
9, H12), 3.75 (1H, ddd, J = 10.3,4.4,4.4, H12 ')

Acetic anhydride (1 ml) was added to a solution of the above AT-1 (1.20 g: 4.72 mmol) in pyridine (1.5 ml) under ice-cooling, and the mixture was allowed to stand at room temperature overnight. Ice water (40 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 ml). The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. After drying the extract over anhydrous magnesium sulfate,
The residue obtained by evaporating the solvent was subjected to silica gel column chromatography [13 g: 1.5 cm ID × 16.5, elution solvent:
Chloroform-ethyl acetate = 100/0 → 70/30], and methyl and hydroxy groups at the 8th position and 9th position
1.35 g of hydronaphthalene having a 2-acetoxyethyl group (hereinafter referred to as AT-2) was obtained as a colorless candy substance. Its ¹ H-NMR spectrum (400 MHz) was as follows. (CDCl ₃ , ppm): 0.79 (3H, s, Me-C10), 0.79 (3H, s, Meβ-C
4), 0.87 (3H, s, Meα-C4), 1.16 (3H, s, Me-C8), 1.89 (1H, d
dd, J = 12.2,2.9,2.9, H7), 4.12 (2H, m, H12 and H12 ')

In a dichloromethane (20 ml) solution of the above AT-2 (1.85 g: 6.25 mmol), chloromethyl methyl ether (715 μl: 9.38 mmol) and diisopropylethylamine (1.74 ml: 9) were stirred with ice cooling. .99 mmol)
Were sequentially added. After stirring the reaction solution at room temperature for 8 hours, chloroform (30 ml) and water (30 ml) were added to extract the product, and the extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography [30 g: 2.0 cm ID × 20.5, elution solvent: n-hexane-ethyl acetate = 100/0 → 60/40] to give the following structure: Compound represented by the formula (hereinafter referred to as AT-6) 6
21 mg were obtained as a colorless candy. Its ¹ H-NMR spectrum (400 MHz) was as follows. (CDCl ₃ , ppm): 0.79 (3H, s, Me-C10), 0.83 (3H, s, Meβ-C
4), 0.87 (3H, s, Meα-C4), 1.23 (3H, s, Me-C8), 2.06 (1H, d
dd, J = 12.2,3.4,2.9, H7), 3.37 (3H, s, OCH ₂ OCH ₃ ), 3.45 (1
H, ddd, J = 9.8,9.8,4.4, H12), 3.72 (1H, ddd, J = 9.8,5.4,4.
4, H12 '), 4.75 (2H, s, OCH ₂ OCH ₃ )

[0015]

Embedded image

7.71 m cooled to -70 ° C. under a stream of nitrogen
To a solution of 1 ml of DMSO in 40 ml of methylene chloride was added 30 ml of a solution of 8.52 ml of trifluoroacetic anhydride in 40 ml of methylene chloride.
It was dripped slowly over a minute. After stirring for another 30 minutes,
A solution of 12 g of AT-6 in 40 ml of methylene chloride was slowly added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. After slowly adding 16.8 ml of triethylamine dropwise over 30 minutes,
Except for the dry ice bath, the mixture was further stirred for 2 hours. Chloroform was added to the reaction solution to dilute it, and the organic layer was washed twice with saturated saline, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5).
To 9: 1) to give 7.06 g (59%) of a hydronaphthalene having a methyl group, a methoxymethyloxy group at the 8-position and a formylmethyl group at the 9-position (hereinafter referred to as ALB203).
Its ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf is 0.50 (silica gel thin layer column chromatography, n-hexane: ethyl acetate = 8: 2). (CDCl ₃ , ppm): 9.61 (1H, br dd, J = 1.0,1.5Hz, CHO), 4.63
(2H, s, O-CH ₂ -O-), 3.30 (3H, s, O-Me), 2.45 (1H, m, CH-CH
O), 2.29 (1H, m, CH-CHO), 2.02 (2H, m, cyclic CH), 1.75-
1.1 (7H, m, cyclic CH), 1.21 (3H, s, Me), 1.0-0.8 (2H, m, c
yclic CH), 0.89 (3H, s, Me), 0.84 (3H, s, Me), 0.80 (3H,
s, Me)

To a solution of 20 g of (ethoxycarbonylmethyl) triphenylphosphonium bromide in 100 ml of DMSO was added 1.68 g (60 wt% in oil) of sodium hydride.
The mixture was heated to 80 ° C. and stirred for 1 hour. 6.9 g of ALB203 was dissolved in 30 ml of DMSO, added to the reaction solution, and stirred for 15 hours while heating to 80 ° C. Ethyl acetate and water were added to the reaction solution to carry out liquid separation. The organic layer was sequentially washed with water and saturated saline, and dried by adding anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration, the filtrates were combined, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
9: 1) (hereinafter referred to as ALB)
7.22 g (85%) were obtained. Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (CDCl ₃ , ppm): 7.06 (1H, m, vinyl), 5.74 (1H, m, vinyl),
4.71 (1H, d, J = 7.3Hz, O-CH-O), 4.63 (1H, d, J = 7.3Hz, O-CH-
O), 4.15 (2H, m, CH ₂ ), 3.33 (3H, s, O-Me), 2.41 (1H, m, all
ylic CH), 2.18 (1H, m, allylic CH), 1.94 (1H, m, cyclic
CH), 1.69-1.10 (15H, m, Me * 2 and cyclicCH), 0.92 (2H,
m, cyclic CH), 0.86 (6H, s, Me * 2), 0.79 (3H, s, Me)

[0018]

Embedded image

6.5 g of ALB204 was added to 100 ml of ethyl acetate
, And about 200 mg of 5% Pd / C was added. The reaction vessel was placed under a hydrogen gas atmosphere and stirred vigorously at room temperature for 5 days.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give a compound represented by the following structural formula (hereinafter referred to as ALB205) 6.11.
g (94%) was obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.75 (1H, d, J = 7.3Hz, O-CH-O), 4.63 (1H, d,
J = 7.3Hz, O-CH-O), 4.11 (2H, m, COOCH ₂ ), 3.34 (3H, s, OM
e), 2.29 (2H, m, CH ₂ -COO), 1.92 (1H, m, cyclic CH), 1.72
-1.09 (16H, m, cyclic CH, CH ₂ chain and COOCH ₂ -CH ₃ ),
0.95 (2H, m, cyclicCH), 0.86 (3H, s, Me), 0.80 (3H, s, Me),
0.78 (3H, s, Me)

[0020]

Embedded image

Under a nitrogen stream, 1.1 g of ALB205 dehydrated T
A 15 ml HF solution was cooled to -78 ° C and 1.7 ml 2M lithium diisopropylamide was slowly added dropwise. 30
After stirring at that temperature for 800 minutes, diethyl malonate 800
A solution of 5 mg of dehydrated THF was added dropwise, and the mixture was further stirred for 2 hours. The reaction solution was partitioned between ethyl acetate and an aqueous ammonium chloride solution, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate,
The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, silica gel column chromatography (n-hexane: ethyl acetate = 9: 1).
To 7: 3) (hereinafter referred to as AL)
860 mg (referred to as B207) were obtained. Part ¹ H-NMR (400
MHz) spectral data are as follows, Rf is
3-0.5 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 85: 15). (CDCl ₃ , ppm): 4.65 (2H, m, O-CH ₂ -O), 4.15 (6H, m, (CH ₂ ) *
3), 3.32 (3H, s, O-Me), 3.12 (1H, m, CH-COO), 2.75 (2H, m,
CH-COO), 2.39 (1H, m, CH-COO), 1.93 (1H, m, cyclicCH),
1.8-1.1 (26H, m, Me * 4 and cyclic CH), 0.9-0.8 (2H, m, cy
clic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me
Me)

[0022]

Embedded image

Example 2 351 mg of lithium aluminum hydride was dehydrated in THF2
The suspension was suspended in 0 ml, cooled on ice, and a solution of 2.5 g of ALB207 in 20 ml of dehydrated THF was added dropwise, and then the ice bath was removed and the mixture was stirred for 2 hours. Add 2N hydrochloric acid and ethyl acetate to the reaction solution,
After vigorous stirring, liquid separation was performed. The organic layer was washed twice with saturated saline, dried over anhydrous sodium sulfate. The aqueous layer was re-extracted twice with ethyl acetate, and the combined organic layers were washed with saturated saline and then dried over anhydrous sodium sulfate. After drying and filtration, the filtrates were combined, and the solvent was distilled off under reduced pressure.
The resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 9: 1 to 8: 2) to give 8
Compounds having a methyl group, a methoxymethyloxy group at the 9-position, and a 3,4-bishydroxymethyl-6-hydroxyhexyl group at the 9-position (hereinafter referred to as ALB208) (Fr. A = 540 mg, Fr. B = 310 mg). The ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf of Fr. A (hereinafter referred to as ALB208-A) is 0.1.
25 (silica gel thin layer chromatography, chloroform: methanol = 9: 1) and Fr. B (hereinafter ALB20)
8-B) is 0.13 to 0.18 (same as above). ALB208-A (DMSO-d6 + D ₂ O, ppm): 4.68 (1H, m, O-CH-O), 4.54 (1H, m, O-
CH-O), 3.5-3.3 (6H , m, CH 2 -O), 3.23 (3H, s, O-Me), 1.85
(1H, m, cyclic CH), 1.65-1.1 (17H, m, cyclic CH and CH-
chain), 1.11 (3H, s, Me), 0.84 (3H, s, me), 0.78 (3H, s, M
e), 0.76 (3H, s , Me) ALB208-B (DMSO-d6 + D 2 O, ppm): 4.68 (1H, m, O-CH-O), 4.54 (1H, m, O-
CH-O), 3.5-3.3 (6H , m, CH 2 -O), 3.23 (3H, s, O-Me), 1.85
(1H, m, cyclic CH), 1.65-1.1 (17H, m, cyclic CH and CH-
chain), 1.11 (3H, s, Me), 0.84 (3H, s, me), 0.78 (3H, s, M
e), 0.76 (3H, s, Me)

Example 3 To a solution of 2 g of ALB207 in ethanol was added 10 ml of a 6N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 15 hours.
The reaction solution was diluted by adding water, and neutralized by adding DOWEX 1 × 8 H-form. The filtrate was concentrated, and silica gel column chromatography (chloroform: methanol = 95: 5-
8: 2), two kinds of compounds (Fr. A =) having a methyl group, a methoxymethyloxy group at the 8-position and a 3,4,5-tricarboxypentyl group at the 9-position (hereinafter referred to as ALB215). 318 mg, Fr. B = 462 mg). The ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf of Fr. A (hereinafter referred to as ALB215-A) is 0.1.
4 (silica gel thin layer chromatography, chloroform:
Methanol = 8: 2) and Fr. B (hereinafter ALB215-B)
Is 0.3 (same as above). ALB215-A (DMSO-d6, ppm): 4.65 (1H, m, O-CH-O), 4.55 (1H, m, O-CH-
O), 3.32 (3H, m, O-Me), 3.2 (1H, m, CH-COO), 2.75 (2H, m, CH
-COO), 2.4-2.3 (1H, m, CH-COO), 1.93 (1H, m, cyclic CH),
1.8-1.1 (16H, m, cyclic CH and Me), 0.9-0.8 (2H, m, cy
clic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me
Me) ALB215-B (DMSO-d6, ppm): 4.65 (1H, m, O-CH-O), 4.55 (1H, m, O-CH-
O), 3.32 (3H, m, O-Me), 3.2 (1H, m, CH-COO), 2.75 (2H, m, CH
-COO), 2.4-2.3 (1H, m, CH-COO), 1.93 (1H, m, cyclic CH),
1.8-1.1 (16H, m, cyclic CH and Me), 0.9-0.8 (2H, m, cyc
lic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, M
e)

Example 4 An aqueous 80% acetic acid solution and 400 μl of 2N hydrochloric acid were added to a solution of 3.6 g of ALB207 in 20 ml of THF, followed by stirring at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 20 ml of ethanol. 30 ml of 6N aqueous sodium hydroxide solution is added,
Stirred at room temperature for 2 days. Dilute the reaction solution by adding water,
After adding DOWEX 1 × 8 H-form and neutralizing, the solution was concentrated and subjected to silica gel column chromatography (chloroform: methanol = 9: 1 to 6: 4) to obtain a methyl group at the 8-position.
Three kinds of compounds related to hydronaphthalene having a hydroxy group and a 3,4,5-tricarboxypentyl group at the 9-position (hereinafter referred to as ALB216) (Fr. A = 500 mg, Fr.B = 50)
0 mg, Fr. C = 645 mg). Part ¹ H-NMR (400MHz)
The spectrum data is as follows, and Rf is Fr.A
(Hereinafter referred to as ALB216-A) was 0.38 (silica gel thin layer chromatography, chloroform: methanol = 8: 2,
Acetic acid (1% added), Fr. B (hereinafter referred to as ALB216-B) was 0.28 (same as above), Fr. C (hereinafter referred to as ALB216-C)
Is 0.25 (same as above). ALB216-A and ALB216-
B contains a small amount of a compound from which the 8-position hydroxyl group has been eliminated. ALB216-A (DMSO-d6, ppm): 3.2 (1H, m, CH-COO), 2.75 (2H, m, CH-CO
O), 2.4-2.3 (1H, m, CH-COO), 1.93 (1H, m, cyclic CH), 1.
8-1.1 (16H, m, cyclic CH and Me), 0.9-0.8 (2H, m, cyclic CH
CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me) ALB216-B (DMSO-d6, ppm): 3.2 (1H, m, CH-COO) , 2.75 (2H, m, CH-CO
O), 2.4-2.3 (1H, m, CH-COO), 1.93 (1H, m, cyclic CH), 1.
8-1.1 (16H, m, cyclic CH and Me), 0.9-0.8 (2H, m, cyclic CH
CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me) ALB216-C (DMSO-d6, ppm): 3.2 (1H, m, CH-COO) , 2.75 (2H, m, CH-CO
O), 2.4-2.3 (1H, m, CH-COO), 1.93 (1H, m, cyclic CH), 1.
8-1.1 (16H, m, cyclic CH and Me), 0.9-0.8 (2H, m, cyclic CH
CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me)

測定 Measurement of compound properties Tables 1 and 2 show the results of the antifungal activity and infection treatment test of each compound prepared in each example.

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

The above results show that the compound of the present invention is a novel compound effective as an antifungal agent or as a raw material for producing an antifungal agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 43/196 C07C 43/196 59/29 59/29 69/675 69/675 (72) Inventor Toshiaki Segawa No. 2 Okubo, Tsukuba, Ibaraki Pref. Toagosei Co., Ltd. Tsukuba Research Laboratories (72) Inventor Shigeo Nozoe 1-10-4 Yagiyama Honcho, Taishiro-ku, Sendai, Miyagi 4F term (reference) 4C206 AA02 AA03 DA34 DB27 KA04 MA86 ZB26 ZB35 4H006 AA01 AB03 AB28 AB29 AB84 BJ30 BN10 BN20 BP10 BP20 BS10 FC32 FE11 FE12

Claims (1)

[Claims] 1. A polycarboxylic acid represented by the following structural formula:
Its ester or alcohol reduced form. Embedded image However, in the formula, R ₁ is a protecting group for a hydrogen atom or a hydroxyl group, and R ₂ is an alkylene group.