JP2001048841A - Hydronaphthalene derivative and its amide compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a hydronaphthalene structure and useful as a fungicide or a raw material of various fungicidal agents. SOLUTION: This hydronaphthalene derivative is a compound of formula I [X, Y are each a lower alkyl or a (substituted) hydroxyl group; R1 is an (unsaturated bond-containing) lower alkylene; R2 is H, a lower alkyl or a blocking group, and a bond between 8th and 9th positions may be double bond, and in the case of the double bond, the substituting group at the 8th position is one of X, Y] or its amide compound (e.g.; a reaction product with a lower alkylamine such as propylamine and a hydroxy lower alkylamine such as ethanolamine). For example, a compound of formula II. The compound of formula I is obtained e.g. by a publicly known method by using sclareolide, gelanyl, linalool, etc., and ethyl acetate as starting materials.

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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Wherein X and Y are a lower alkyl group and a hydroxyl group which may have a substituent or a protecting group;
₁ is a lower alkylene group which may have an unsaturated bond, R ₂ is a hydrogen atom, a lower alkyl group or a protecting group, and a double bond may be formed between the 8-position and the 9-position; In such a case, the substituent at the 8-position is only one of X or Y.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
The compound in the present invention has a hydronaphthalene ring at the center of its structure, and more specifically, may have a lower alkyl group and a substituent or a protecting group at the 8-position, as shown in the structural formula. There is a hydroxyl group, as a substituent, a lower alkyl group as an ether or ester structure, a lower alkyloyl group, and as a protecting group, a hydroxyl group is methoxymethyl group (MOM), methylthiomethyl (MTM), tetrahydropyranyl (THP). , T-butyl (t-Bu), trityl (Trt), benzyl (Bzl or Bn), ether-type protecting group such as p-methoxybenzyl (MP), acyl-type protecting group such as acetyl group,
Trimethylsilyl (TMS), t-butyldimethylsilyl (TBDM
S) and the like, which may have a cyclic structure and may have a carboxyl group at the 9-position via a lower alkylene group which may have an unsaturated bond. The terminal of the 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. . Examples of the amide compounds of the above derivatives include lower alkylamines such as propylamine and diethylamine, hydroxy lower alkylamines such as ethanolamine, and 4- (3
A reaction product with an amine having a hetero ring such as -aminopropyl) morpholine or 1- (3-aminopropyl) imidazole is exemplified. 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. ○ Assay for anti-Candida albicans activity Candida albicans (Candida albicans)
albicans) as a test bacterium, and
Tested in vitro to confirm its activity. The antifungal susceptibility test was performed according to the method proposed in the Journal of the Japanese Society for Medical Mycology, Vol. 36 (1), 62-64 (1995). The strain used for the experiment was strain T, which was distributed by Teikyo University Medical Mycology Research Center.
IMM1768 and TIMM3318 were used. 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 (Asper
gillus 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 Synthesis of ALB-204 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) -ether (10 ml), and ice was added. 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]

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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]

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Example 2 Synthesis of ALB-205 6.5 g of ALB204 was dissolved in 100 ml of ethyl acetate, and
About 200 mg of% 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-
6.11 g (94%) of a compound represented by the following structural formula (hereinafter referred to as ALB205) by applying hexane: ethyl acetate = 9: 1).
I got 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]

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Example 3 Synthesis of ALB-211 0.6 g of ALB204 was dissolved in 30 ml of a mixture of 2N aqueous sodium hydroxide / ethanol = 1/2 and stirred at room temperature for 15 hours. Dilute the reaction solution by adding chloroform.
After adding 2N-hydrochloric acid aqueous solution to make it acidic, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3) to give a methyl group at the 8-position.
A hydronaphthalene Fr. A (Chem. 56, hereinafter referred to as ALB211-A) having a methoxymethyloxy group and a 3-carboxy-2-propenyl group at the 9-position and represented by the following structural formula:
7, ALB211-B). Part ¹ H-NMR (400MH
z) The spectrum data is as follows, and Rf is AL
B211-A is 0.20 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2), and ALB211-B is 0.19 (same as above). ALB211-A (DMSO-d6, ppm): 6.25 (1H, m, vinyl), 5.55 (1H, d, J = 11.7H
z, vinyl), 4.63 (1H, d, J = 7.3Hz, O-CH-O), 4.58 (1H, d, J =
7.3Hz, O-CH-O), 3.20 (3H, s, O-Me), 2.97 (1H, m, allylic
CH), 2.50 (1H, m, allylic CH), 1.88 (1H, m, cyclic CH),
1.57-1.13 (9H, m, cyclic CH), 1.13 (3H, s, Me), 0.94 (2H,
m, cyclic CH), 0.85 (3H, s, Me), 0.83 (3H, s, Me), 0.77 (3
(H, s, Me) ALB211-B (DMSO-d6, ppm): 6.85 (1H, m, vinyl), 5.68 (1H, d, J = 15.6H
z, vinyl), 4.65 (1H, d, J = 7.3Hz, O-CH-O), 4.57 (1H, d, J =
7.3Hz, O-CH-O), 3.22 (3H, s, O-Me), 2.32 (1H, m, allylic
CH), 2.16 (1H, m, allylic CH), 1.88 (1H, m, cyclic CH),
1.57-1.13 (9H, m, cyclic CH), 1.13 (3H, s, Me), 0.94 (2H,
m, cyclic CH), 0.85 (3H, s, Me), 0.82 (3H, s, Me), 0.77 (3
(H, s, Me)

[0022]

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[0023]

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Example 4 Synthesis of ALB-212 ALB211 obtained by hydrolyzing ALB204 (mixture of A and B)
Was dissolved in 5 ml of THF, 20 ml of an 80% aqueous acetic acid solution and 2N
400 μl of hydrochloric acid was added, and the mixture was stirred at room temperature for 5 days. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8: 2 to 6: 4) to give a methyl group and a hydroxy group at the 8-position and 3-carboxy-2-propenyl at the 9-position. Hydronaphthalene having a group (hereinafter referred to as AL
192 mg were obtained as white crystals. Its ¹ H-NMR (4
(00 MHz) The spectral data are as follows, and Rf is 0.50 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 6: 4). (DMSO-d6): 6.91 (1H, m, vinyl), 5.68 (1H, d, J = 15.1Hz, vi
nyl), 4.08 (1H, br, OH), 2.38 (1H, m, allylic CH), 2.11 (1
H, m, allylic CH), 1.72 (1H, m, cyclic CH), 1.6-1.05 (9
H, m, cyclic CH), 1.0 (3H, s, Me), 0.85 (2H, m, cyclic C
H), 0.84 (3H, s, Me), 0.78 (3H, s, Me), 0.76 (3H, s, Me)

Example 5 Synthesis of ALB-213 1.2 g of ALB205 was dissolved in 30 ml of a mixture of 2N aqueous sodium hydroxide / ethanol = 1/2 and stirred at room temperature for 15 hours. Dilute the reaction solution by adding chloroform.
After acidification with 2N hydrochloric acid, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate were performed, and silica gel column chromatography (n-hexane:
Ethyl acetate = 7: 3), 970 mg of hydronaphthalene (hereinafter ALB213) having a methyl group, a methoxymethyloxy group at the 8-position and a 3-carboxypropyl group at the 9-position
(88%). Its ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf was 0.21 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8:
2). (DMSO-d6): 4.68 (1H, d, J = 7.3Hz, O-CH-O), 4.54 (1H, d, J =
7.3Hz, O-CH-O) , 3.22 (3H, s, O-Me), 2.15 (2H, m, CH 2 COO),
1.88 (1H, m, cyclic CH), 1.65-1.1 (13H, m, cyclic CH),
1.10 (3H, s, Me), 0.9 (2H, m, cyclic CH), 0.84 (3H, s, Me),
0.77 (3H, s, Me), 0.76 (3H, s, Me)

Example 6 Synthesis of ALB-214 779 mg of ALB213 was dissolved in 5 ml of THF, 20 ml of an 80% acetic acid aqueous solution and 400 μl of 2N hydrochloric acid were added, and the mixture was stirred at room temperature for 5 days. After evaporating the solvent under reduced pressure, silica gel column chromatography (n-hexane: ethyl acetate =
8: 2 to 6: 4) to give hydronaphthalene (hereinafter ALB214) having a methyl group, a hydroxy group at the 8-position and a 3-carboxypropyl group at the 9-position as white crystals. Part ¹
H-NMR (400 MHz) spectrum data is as follows, and Rf was 0.50 (silica gel thin layer chromatography, n
-Hexane: ethyl acetate = 6: 4). (DMSO, ppm): 2.24-2.06 ( 2H, m, CH 2 -COO), 1.74-1.52 (6
H, m, CH), 1.39-1.07 (7H, m, CH), 0.97 (3H, s, Me), 0.95-
0.7 (3H, m, cyclic CH), 0.84 (3H, s, Me), 0.75 (3H, s, Me)
0.72 (3H, s, Me)

Example 7 Synthesis of ALB-344, 345 ALB344 250 mg (0.739 mmol) of ALB211 was added under nitrogen atmosphere in 5 ml.
Was dissolved in tetrahydrofuran and cooled to -20 ° C. To this were added 0.11 ml (0.789 mmol) of triethylamine and 0.1 ml (0.812 mmol) of pivaloyl chloride, and the mixture was added at -20 ° C.
For 1 hour. Thereafter, 0.1 ml (0.838 mmol) of 1- (3-aminopropyl) imidazole was added, and the mixture was stirred overnight while warming to room temperature. Chloroform was added to the reaction solution,
3 times with a saturated aqueous solution of sodium bicarbonate and 1 with a saturated saline solution
After washing twice, the chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue 174
mg was dissolved in 5 ml of methanol, a catalytic amount of 5% palladium / activated carbon was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered using celite, and the filtrate was evaporated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (50 ml, eluted with 2% to 4% methanol / chloroform) to obtain a compound represented by the following structural formula (hereinafter referred to as ALB344) as an oil (14).
9 mg, yield 52%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 7.49 (1 H, s), 7.06 (1 H, s), 6.94 (1 H, s), 5.60 (1
H, brs), 4.00 (2H, t, J = 6.8Hz), 3.28 (2H, q, J = 6.8Hz), 2.
18-0.73 (19H, m), 1.56 (3H, s), 0.92 (3H, s), 0.88 (3H,
s), 0.82 (3H, s).

[0028]

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ALB 345 250 mg (0.739 mmol) of ALB 211 and 0.12 ml
(0.821 mmol) of 4- (3-aminopropyl) morpholine was used to carry out the same operation as ALB344, and the obtained residue was subjected to silica gel column chromatography (50 ml, 2% to 4%).
Purification by elution with methanol / chloroform) gave a compound represented by the following structural formula (hereinafter referred to as ALB345) as an oil (164 mg, 55% yield). ¹ H-NMR (400 MHz, CDCl ₃ ) δ ppm: 6.77 (1H, brs), 3.72 (4H, t, J = 4.4 Hz), 3.35 (2H,
q, J = 6.4Hz), 2.47-2.44 (6H, m), 2.18-0.73 (19H, m), 1.56
(3H, s), 0.93 (3H, s), 0.88 (3H, s), 0.82 (3H, s).

[0030]

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

[0032]

[Table 1]

[0033]

[Table 2]

[0034]

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.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Nobuaki Koike, No. 2 Okubo, Tsukuba, Ibaraki Prefecture, Toagosei Co., Ltd. (72) Inventor Toshiaki Segawa No. 2, Okubo, Tsukuba, Ibaraki Prefecture, Tokusei Co., Ltd. 72) Inventor Shigeo Nozoe 1-10-4 Yagiyama Honcho, Taihaku-ku, Sendai City, Miyagi Prefecture F-term (reference) 4H006 AA01 AB03 AB84 BJ30 BV42 FC32 FC74

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 a lower alkyl group and a hydroxyl group which may have a substituent or a protecting group, R ₁ is a lower alkylene group which may have an unsaturated bond, and R ₂ is a hydrogen atom , A lower alkyl group or a protecting 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.