JP2001097925A - Hydronaphthalene derivative and its amide compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound having hydronaphthalene ring structure and effective as an antimycotic agent, its raw material, other pharmaceuticals and their raw material, e.g. as an antitumor agent and its raw material. SOLUTION: The objective compound is expressed by general formula I or its amide compound (X and Y are each a lower alkyl, hydroxy group which may have substituent or protecting group or together form methylene group; R1 and R2 are each a lower alkylene or an arylene; the bond between the 8-position and the 9-position may be double bond; when the bond is double bond, the substituent at the 8-position is only X or Y).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel compound having a hydronaphthalene ring structure, and the compound of the present invention is used as an antifungal agent, as a raw material for producing various antifungal agents, and as another pharmaceutical agent. Alternatively, it is also effective as a raw material thereof, for example, as an anticancer agent or as a raw material of various anticancer agents, and the present invention belongs to the pharmaceutical manufacturing 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 hydronaphthalene derivative represented by the following structural formula and an amide compound thereof.

[0006]

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In the formula, X and Y each represent a lower alkyl group, a hydroxyl group which may have a substituent or a protecting group or a methylene group in which both are bonded, and R ₁ and R _{2 each} represent a lower alkylene group Or, it is an arylene group, and a double bond may be provided between the 8-position and the 9-position. In the case of a double bond, the substituent at the 8-position is only one X or Y.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The compound of the present invention has a hydronaphthalene ring at the center of its structure, and may have a lower alkyl group, a substituent or a protecting group at the 8-position as shown in the above structural formula. There is a hydroxyl group or a methylene group in which both are bonded, as a substituent, a lower alkyl group or a lower alkylyl group as an ether or ester structure, and as a protecting group, a methoxymethyl group (MOM) or a methylthiomethyl (MTM) in a hydroxyl group. , Tetrahydropyranyl (THP), t-
Butyl (t-Bu), Trityl (Trt), Benzyl (Bzl or B
n), ether-type protecting groups such as p-methoxybenzyl (MP), acyl-type protecting groups such as acetyl groups, and silyl-type protecting groups such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBDMS). The protecting group may have a cyclic structure, and a carboxyl group is bonded at the 9-position to two lower alkylene groups R ₁ and R ₂ , particularly a methylene or ethylene group or an arylene group, particularly a phenylene group. The terminal of the terminal carboxyl group is a hydrogen atom, a lower alkyl group or a protecting group, and examples of the protecting group include ester-type protecting groups such as benzyl group and silyl ester-type protecting groups such as trimethylsilyl group. Can be. Also,
Amide compounds of the above derivatives include lower alkylamines such as propylamine and diethylamine, hydroxy lower alkylamines such as ethanolamine, 4- (3-aminopropyl) morpholine and 1- (3-aminopropyl) imidazole. And a reaction product with an amine having a heterocyclic ring. The compound of the present invention is derived from known compounds such as sclareolide, geraniyl, linalool and the like 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, dd
d, J = 12.2,3.4,2.9, H7), 3.46 (1H, ddd, J = 10.3,8.3,5.9, H1
2), 3.75 (1H, ddd, J = 10.3,4.4,4.4, H12 ')

2.5 g of AT-1 and 73 mg of DMAP were added to 40 ml of pyridine and stirred at room temperature for 30 minutes. To this was added 1.1 g of succinic anhydride, and the mixture was stirred for 24 hours. After the reaction solution was concentrated to about half the volume, ethyl acetate was added to dilute the mixture, and the mixture was diluted once with 2N hydrochloric acid, and further diluted with saturated saline.
It was washed twice and dried by adding anhydrous sodium sulfate. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography.
(Chloroform: methanol = 80: 20) to give 3.3 g (95%) of a compound represented by the following structural formula (hereinafter referred to as ALB206). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.10-4.19 (2H, m), 2.62-2.69 (4H, m), 1.
11-1.91 (17H, m), 0.87 (3H, s), 0.79 (6H, s)

[0014]

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Example 2 In a nitrogen stream, 354 mg of ALB206 was added to 10 ml of dehydrated DMF.
And stirred in an ice bath. Further, 200 μg of aminopropylmorpholine, 101 mg of triethylamine, and 270 mg of HOBt were added, and the mixture was stirred for 1 hour. DCC
After adding 220 mg and stirring for 1 hour in an ice bath, the mixture was further stirred at room temperature for 4 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and the organic layer was washed twice with a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography.
(Chloroform: methanol = 80: 20), 375 mg of a compound represented by the following structural formula (hereinafter referred to as ALB078)
(78%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 7.8 (1H, br, NH), 3.9-4.1 (2H, m), 3.55
(4H, t), 3.05 (2H, td), 2.24-2.47 (10H, m), 0.72-1.8 (16
H, m), 1.01 (3H, s), 0.84 (3H, s), 0.76 (3H, s), 0.73 (3H,
s)

[0016]

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Example 3 In a nitrogen stream, 354 mg of ALB206 was added to 10 ml of dehydrated DMF.
And stirred in an ice bath. Further, 150 mg of aminopropylimidazole, 101 mg of triethylamine, and 270 mg of HOBt were added, and the mixture was stirred for 1 hour. DCC
After adding 220 mg and stirring for 1 hour in an ice bath, the mixture was further stirred at room temperature for 4 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and the organic layer was washed twice with a saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography.
(Chloroform: methanol = 80: 20) 360 mg of a compound represented by the following structural formula (hereinafter referred to as ALB079)
(80%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 7.9 (1H, t, NH), 7.59 (1H, s), 7.14 (1H,
s), 6.87 (1H, s), 3.93-4.05 (4H, m), 3.00-3.01 (2H, td),
2.49 (2H, m), 2.35-2.37 (2H, t), 1.05-1.85 (16H, m), 1.
00 (3H, s), 0.84 (3H, s), 0.76 (3H, s), 0.71 (3H, s)

[0018]

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Example 4 Under nitrogen atmosphere, 354 mg of ALB206 was dehydrated in 10 ml of dehydrated DMF.
and stirred in an ice bath. Further, 150 μl of trishydroxymethylaminomethane and triethylamine 1
01 mg and HOBt 270 mg were added and stirred for 1 hour. After adding 220 mg of DCC and stirring for 1 hour in an ice bath, the mixture was further stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was diluted with saturated saline solution.
It was washed twice, dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated, and the residue is subjected to silica gel column chromatography (chloroform: methanol = 80: 20) to give a compound represented by the following structural formula (hereinafter referred to as ALB080).
420 mg (85%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 7.19 (1H, s), 4.66 (t, OH), 3.90-4.10 (2
H, m), 3.51 (6H, d), 2.43-2.51 (4H, m), 0.95-1.80 (17H,
m), 0.84 (3H, s), 0.76 (3H, s), 0.73 (3H, s)

[0020]

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Example 5 Acetic anhydride (1 ml) was added to a solution of AT-1 (1.20 g: 4.72 mmol) obtained in Example 1 in pyridine (1.5 ml) under ice-cooling. Left 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 hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography [13 g: 1.5 cm ID × 16.5, elution solvent: chloroform-ethyl acetate = 100/0 → 70/3].
0], a methyl group and a hydroxy group at the 8-position,
Hydronaphthalene having 2-acetoxyethyl group at 9-position
1.35 g (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 ')

17.0 mmol of the above AT-2: 5.1 g was added to 20
The mixture was placed in a 0 ml eggplant-shaped flask and dissolved with 50 ml of dichloromethane. While stirring under ice cooling, 2,4-dihydro-2H-pyran (manufactured by Wako Pure Chemical Industries, Ltd.) (25.5 mmol, 2.3 ml) was added dropwise, and pyridinium p-toluenesulfonate (manufactured by Wako Pure Chemical Industries, Ltd.) 1 0.7 mmol (425 mg) was added. After the temperature of the reaction solution was returned to room temperature, stirring was performed for 18 hours. After 18 hours, the reaction solution was extracted by adding 20 ml of distilled water and 10 ml of chloroform, and the chloroform layer was successively washed with 20 ml of 1N hydrochloric acid, 20 ml of a saturated aqueous solution of sodium hydrogen carbonate and 20 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate. I let it. This was distilled off under reduced pressure by filtration, and the residue was fractionated by silica gel column chromatography (3.0 cm ID × 13.0 cm, eluent: hexane / ethyl acetate = 100/0 to 50/50) to obtain hexane. 5.5 g of the fraction eluted with 90/10 to 80/20 / ethyl acetate was transferred to a 200 ml eggplant-shaped flask and dissolved in 50 ml of ethanol. After adding 1N-sodium hydroxide aqueous solution (50 ml) with stirring under ice cooling, the reaction solution was returned to room temperature and stirred for 2 hours. After 2 hours, the reaction solution was concentrated under reduced pressure to remove ethanol, and then 50 ml of ethyl acetate was added.
The extraction was performed twice. The extract was washed successively with 20 ml of distilled water and 20 ml of saturated saline and dried over anhydrous magnesium sulfate. This was distilled off under reduced pressure by filtration, and the residue was fractionated by silica gel column chromatography (3.0 cm ID × 14.0 cm, eluent: hexane / ethyl acetate = 100/0 to 50/50) to give hexane / hexane. Ethyl acetate = 70/3
As a fraction eluted with 0 to 50/50, 4.6 g of colorless columnar crystals of a compound represented by the following structural formula (hereinafter referred to as HAL-1) were obtained.
Its properties are as follows, ¹ H-NMR spectrum (400
MHz: CDCl ₃ ) chart as shown in FIG. 1, ¹³ C-NMR spectrum (400 MHz
The z: CDCl3) chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.75
[Silica gel 60F254 (Merck), developing solvent: chloroform / methanol = 20/1], 0.24 [RP-18F254s
(Merck), developing solvent: 90% methanol] Color reaction: Positive for Ehrlich reagent (brown), positive for anisaldehyde reagent (greenish brown), positive for 50% sulfuric acid reagent (black)

[0023]

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Sodium hydride (manufactured by Wako Pure Chemical Industries, Ltd.)
5.8 mmol (232 mg) was weighed into a dried 100 ml two-necked flask, and the inside of the flask was replaced with nitrogen.
4 ml of MF was injected, and 2.9 mmol of HAL-1 (100 mmol) was added.
0 mg) was dissolved in 4 ml of dehydrated DMF and injected. After the reaction solution was stirred at room temperature for 30 minutes, 5.8 mmol (1473m2) of N- (2bromoethyl) phthalimide (manufactured by Wako Pure Chemical Industries, Ltd.) was again cooled with ice.
g) was dissolved in 2 ml of DMF and injected, followed by stirring at room temperature for 20 hours. After 20 hours, 10 ml of distilled water was added to the reaction solution, and the mixture was extracted twice with 20 ml of ethyl acetate. The extract was washed successively with distilled water and saturated saline and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (3.0 cm ID × 2).
0.0 cm, eluent: hexane / ethyl acetate = 90/10
50/50) to give a colorless oil 6 of a compound represented by the following structural formula (hereinafter referred to as HAL-2) as a fraction eluted with hexane / ethyl acetate = 50/50 to 40/60.
90 mg were obtained. The characteristics are as follows. A ¹ H-NMR spectrum (400 MHz: CDCl ₃ ) chart is shown in FIG. 3, and a ¹³ C-NMR spectrum (400 MHz: CDCl ₃ ) chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.73
[Silica gel 60F254 (Merck), developing solvent: chloroform / methanol = 20/1], 0.20 [silica gel 60F2
54 (Merck), developing solvent: hexane / ethyl acetate = 2 /
1], 0.14 [RP-18F254s (Merck), developing solvent:
90% methanol] Color reaction: Positive Ehrlich reagent (brown), positive anisaldehyde reagent (yellow green), positive 50% sulfuric acid reagent (black)

[0025]

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Example 6 The method of Maria Lapis et al. (J. Chem. Soc. Perkin Tran)
s1, 815-817 (1985)), a compound represented by the following structural formula (hereinafter referred to as ALB003) was synthesized from linalool as a raw material. Its structure is the following ¹ H-NMR (400 MHz, CDCl ₃ , ppm)
It was confirmed from the spectrum data. 4.83 (1H, d, J = 1.5Hz, vinylic CH), 4.66 (1H, dJ = 1.5Hz, v
inylic CH), 3.65 (3H, s, COOMe), 2.80 (1H, s, CH-COO),
2.42 (1H, ddd, J = 2.0,4.0,13.7Hz, allylic CH), 2.06 (1H,
m, allylic CH), 1.73-1.35 (7H, m), 1.19 (2H, m), 1.06 (3
H, s, Me), 0.88 (3H, s, Me), 0.81 (3H, s, Me)

[0027]

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Similarly, the method of Maria Lapis et al. (J. Ch.
em. Soc. Perkin Trans 1, 815-817 (1985))
Using LB003 as a raw material, a compound represented by the following structural formula (hereinafter, referred to as ALB005) was synthesized. Its structure is ¹ H
-Confirmed from NMR (400 MHz) spectrum data. (CDCl ₃ , ppm): 4.94 (1H, d, J = 1.0Hz, vinyl), 4.64 (1H, d, J
= 1.0Hz, vinyl), 3.82 (2H, m, CH ₂ -O), 2.44 (1H, m, allylic
CH), 1.99 (1H, m, cyclic CH), 1.96 (1H, m, cyclic CH),
1.77-1.11 (9H, m, cyclic CH), 0.88 (3H, s, Me), 0.81 (3H,
(s, Me), 0.72 (3H, s, Me)

[0029]

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2.3 g of ALB005 and 1.69 of phthalic anhydride
g was dissolved in 20 ml of pyridine and stirred at room temperature for 15 hours. After 5 ml of water was added to the reaction solution, pyridine was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and 2N hydrochloric acid. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After drying, filtration is performed, and the filtrate is distilled off under reduced pressure. The obtained white solid is washed with a small amount of ethyl acetate, and the solid is dried to obtain a compound represented by the following structural formula (hereinafter referred to as ALB013) 3.1.
g (82% yield). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 13.1 (1H, br, COOH), 7.76-7.54 (4H, m, ar
omatic CH), 4.84 (1H, s, vinylic CH), 4.60 (1H, s, vinylic CH)
ic CH), 4.50 (1H, dd, J = 3.9,11.2Hz, CH-O), 4.31 (1H, dd,
J = 8.3,11.2Hz, CH-O), 2.4-1.1 (12H, m, cyclic CH), 0.87
(3H, s, Me), 0.80 (3H, s, Me), 0.75 (3H, s, Me)

[0031]

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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.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

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.

[Brief description of the drawings]

FIG. 1 is a ¹ H-NMR chart of HAL-1.

FIG. 2 is a ¹³ C-NMR chart of HAL-1.

FIG. 3 is a ¹ H-NMR chart of HAL-2.

FIG. 4 is a ¹³ C-NMR chart of HAL-2.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) C07C 69/80 C07C 69/80 A 233/18 233/18 C07D 233/61 103 C07D 233/61 103 295 / 12 295/12 Z (72) Inventor Takayoshi Uchida No. 2 Okubo Tsukuba, Ibaraki Pref. Inventor Shigeo Nozoe 1-10-4, Yagiyamahoncho, Taihaku-ku, Sendai-shi, Miyagi F-term (reference) 4H006 AA01 BJ30 BN20 BS10 BT20 BV22

Claims (1)

[Claims] 1. A hydronaphthalene derivative represented by the following structural formula and an amide compound thereof. Embedded image Wherein X and Y are respectively a lower alkyl group, a hydroxyl group which may have a substituent or a protecting group, or a methylene group in which both are bonded, and R ₁ and R ₂ are a lower alkylene group or an arylene group. And a double bond may be provided between the 8-position and the 9-position. In the case of a double bond, the substituent at the 8-position is only one of X or Y.