JP2002179564A - Antifungal agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new antifungal agent having a strong antimicrobial activity against fungi causing opportunistic infectious diseases, etc. SOLUTION: This antifungal agent comprises a hydronaphthalene derivative as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an antifungal agent containing a compound having a hydronaphthalene ring structure as an active ingredient, and belongs to a pharmaceutical production technique.

[0002]

2. Description of the Related Art With the remarkable development of antimicrobial drugs centering on antibiotics, antifungal agents are not always in a satisfactory state, judging from their types 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. In particular,
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 is 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. The present inventors have conducted intensive studies in order to respond to this request, and have previously found that cryptoporic acid derivatives are excellent as antifungal agents, and have made one proposal (International Publication WO96 / 25385). Cryptopol acid derivatives are a group of compounds represented by the following structural formula 2, and the like.

[0003]

Embedded image

However, in the formula, R ¹ , R ² and R ³ may be the same or different from each other, and include a hydrogen atom, an alkyl group,
Particularly, it is a lower alkyl group or the like, more specifically, a methyl group, an alkali metal such as sodium or potassium, and 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 paid attention to the fact that cryptoporic acid derivatives are excellent as antifungal agents, and studied the mechanism of action, function and structure of cryptoporic acid derivatives, From these results, intensive studies are underway to find compounds other than cryptopolonic acid derivatives that have strong antibacterial activity against the above-mentioned fungi that cause opportunistic infections, that is, compounds that can be effectively used as antifungal agents. They continued. That is, the present invention seeks to provide a novel antifungal agent.

[0006]

Means for Solving the Problems The present inventors have made intensive studies in order to achieve the above-mentioned object, and found that, among the structures of cryptoporic acid derivatives, the hydronaphthalene ring structure has a great influence on the antifungal activity. That is, any of sclareol, sclareolide, manol, labdanolic acid having the structure thereof, those obtained by adding various substituents thereto, and derivatives thereof, and bicyclic diterpenes obtained from a copearl resin are all anti-oxidants. The inventors have found that they have a fungal action and completed the present invention.

That is, the present invention has a hydronaphthalene ring structure which may have an unsaturated bond represented by the following structural formula 1, wherein a structure derived from isocitrate is formed through an ether bond to form a hydronaphthalene ring. The present invention relates to an antifungal agent comprising, as an active ingredient, a compound not bonded to the methyloxy group at the 9-position.

[0008]

Embedded image

In the formula, R ¹ , R ² and R ³ are alkyl groups which may have the same or different substituents.

[0010]

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 in the structural formula 1, the compound may have two substituents at the 4-position and one substituent at the 10-position. This is a hydronaphthalene ring to which a certain alkyl group, particularly a methyl group is added, and the hydronaphthalene ring may have a partly unsaturated bond. The hydronaphthalene ring may have a substituent other than the 4-position and the 10-position, and particularly those having a substituent at the 8-position and the 9-position may be synthesized from commercially available chemicals. It is preferable for the present invention because it can be made. Examples of the substituent include various substituents, which can be applied in consideration of the antifungal action and side effects, and specific examples thereof include a hydroxy group and those protected by a protecting group, a carbonyl group and Is a group protected with a protecting group, for example, a group protected with ethylene glycol or the like, an alkylidene group having up to 6 carbon atoms, preferably up to 4 carbon atoms, preferably methylidene, etc. Branched alkyl group or alkenyl group or cycloalkyl group and the like, preferably methyl group, ethyl group, butyl group, 3-methylpentyl group, 3-methyl-4-pentaenyl group, 3-methyl-2,4- Alkyl groups having an aldehyde group, such as a pentadienyl group and a cyclohexyl group, having up to 6 carbon atoms, preferably up to 4 carbon atoms, such as formyl group and methylformyl group are preferred. An alkyl or alkenyl group having up to 10 and preferably up to 8 carbon atoms having a silicon group or a hydroxy group and an epoxy group, and preferably a hydroxy group such as a 3-hydroxy-3-methyl-4,5-epoxypentyl group; One or more carbon atoms having 12
Preferably up to 10 alkyl groups or alkenyl groups, preferably hydroxymethyl group, 2-hydroxyethyl group, 4-hydroxybutyl group, 3-hydroxy-3-methylpentyl group, 3-hydroxy-3-methyl-4 -Pentaenyl group, 3,4,5-trihydroxy-3-methylpentyl group, 3,4
-Bishydroxymethyl-6-hydroxyhexyl group and the like, and these hydroxy groups may be protected by a hydroxyl-protecting group such as a methoxymethyl group, a methylthiomethyl group or a tetrahydropyranyl group. In addition, the heterocyclic compound may be an alkyl group or an alkenyl group having no hydroxy group or having one or up to 3 hydroxy groups and having up to 10 and preferably up to 8 carbon atoms. Or a 5-membered heteroaromatic monocyclic ring containing 3 or a 6-membered heteroaromatic monocyclic ring containing one oxygen or sulfur and nitrogen, and preferably a 1-triazolylmethyl group or 3,4-dihydroxy-3-methyl- 5- (1-triazolyl) pentyl group,
A morpholinomethyl group and the like, which may form a non-toxic salt. Further, an alkyl group or an alkenyl group having one or more carboxyl groups and having up to 12, preferably up to 10 carbon atoms, preferably a carboxymethyl group, a 3-carboxypropyl group, a 3-carboxy-2-propeniel group, , 3,4,5-tricarboxypentyl groups and the like, and these carboxyl groups may form salts with non-toxic salts such as alkali metals, alkaline earth metals and amines. Further, it is an alkylamino group or an alkenylamino group having up to 8 carbon atoms, preferably up to 4 carbon atoms, and preferably an aminomethyl group and the like, and these are non-toxic salts such as hydrochloride, hydrobromide and iodo. Hydride, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, benzoate, citrate, glucuronate, methanesulfonate, A non-toxic salt such as p-toluenesulfonate may be formed. One or more of the following substituents may be further bonded to these substituents by ester, amide, ether, thioether, carbamoyl, or the like. Examples of the substituent include an alkyl group having one or more hydroxy groups, having up to 18 carbon atoms, preferably up to 14 carbon atoms, an alkenyl group having 10 carbon atoms, preferably up to 6 carbon atoms, or an allyl group.
And a cycloalkyl group having up to 10 and preferably up to 8 carbon atoms, such as a substituent derived from a compound such as methanol, ethanol, hexanol, dodecanol, cyclohexanol, allyl alcohol, benzyl alcohol, ethylene glycol or glycerin. Is preferred. Further, an alkyl group having one or more carboxyl groups or a group having up to 18 carbon atoms, preferably up to 14 carbon atoms, an alkenyl group or an aryl group, and the like, acetic acid, trifluoroacetic acid,
Substituents derived from compounds such as caproic acid, dodecanoic acid, succinic acid, and benzoic acid are preferred, and when a free carboxyl group that does not participate in binding is present, this carboxyl group forms a nontoxic salt. May be. Further, it is a hydroxy acid containing up to 10 and preferably up to 8 carbon atoms, each containing one or more hydroxy groups and carboxyl groups, for example, a compound such as glycolic acid or isocitric acid may be used as a substituent, provided that Excluding those that have an ether bond to methyloxy. When there is a free carboxyl group which does not participate in the binding, this carboxyl group may form a non-toxic salt. Further, an epoxy group and an alkyl group or a alkenyl group having a carbon number of up to 8 and preferably up to 6 having a hydroxy group, preferably, for example, a 2,3-epoxypropyloxy group and the like, and one or more hydroxy groups and A heterocyclic compound having an alkyl group or an alkenyl group having up to 8 carbon atoms, preferably up to 6 carbon atoms, such as a 5- or 6-membered saturated monocyclic ring containing 1 nitrogen, 2 or 3 nitrogens A 5-membered or 6-membered heterocyclic monocyclic ring containing oxygen or sulfur and one nitrogen, a 5- or 6-membered heterocyclic monocyclic ring containing two nitrogen atoms, and a 5- or 6-membered monocyclic ring containing one nitrogen atom Preferred examples of the membered saturated monocyclic ring include piperidine and the like, preferred substituents include a 3- (1-piperidinyl) -2-hydroxypropyloxy group and the like, and a 5-membered heteroaromatic monocyclic ring containing 2 or 3 nitrogen atoms. Preferred example As a preferred substituent, such as 2-hydroxy-3- (1-triazolyl) propyloxy group, and morpholine as a preferred example of a 6-membered saturated monocyclic ring containing oxygen or sulfur and one nitrogen. A preferred substituent is 3-
Preferred examples of a 5- or 6-membered saturated monocyclic ring containing two nitrogen atoms such as a morpholino-2-hydroxypropyloxy group are piperazine and the like, and a preferred substituent is 3- (1- (4-methyl) piperazinyl)- 2-hydroxypropyloxy group or 3
-(1- (4-hydroxyethyl) piperazinyl) -2-hydroxypropyloxy group and 3- (1-piperazinyl) -2-hydroxypropyloxy group, etc., even when these form non-toxic salts. good. Further, an aliphatic amine having one or more hydroxy groups and having up to 10, preferably up to 8 carbon atoms, preferably a 3- (tris (hydroxymethyl) methyl) amino-2-hydroxypropyloxy group, (Bishydroxyethyl) amino-2-hydroxypropyloxy group, 3-glucosamyl-2-hydroxypropyloxy group and the like, and these amino groups may form a non-toxic salt and have up to 10 carbon atoms. Preferably up to 8 aliphatic amines, preferably cyclohexylamino groups,
These amino groups may form a non-toxic salt,
An aliphatic amine having a heterocyclic compound, an alkyl group having up to 8 carbon atoms, preferably up to 4 carbon atoms. Preferred as the heterocyclic compound are 5-membered heteroaromatic rings containing 2 or 3 nitrogen atoms, oxygen or sulfur and nitrogen. A 6-membered saturated monocyclic ring containing at least one, preferably a 3- (1-imidazolyl) propylamino group or a 3-morpholinopropylamino group, and these amino groups form a non-toxic salt. Also, aromatic amines may be mentioned, and as a preferable example, a compound such as aniline may be used as a substituent, and these may form a non-toxic salt, and furthermore, an aliphatic azide is preferable. There is an azidomethyl group and the like, and an amino acid or an amino acid with a protecting group, and preferred examples thereof include lysine, aspartic acid, proline and β-alanine. May form a non-toxic salt, and these substituents may be further bonded to these substituents by ester, amide, ether, carbamoyl or the like. Preferred substituents for the present invention include
At the 8-position, a carbonyl group, a carbonyl group protected with a protecting group, an alkylidene group, an alkyl group, a hydroxy group or a group with a protecting group attached thereto, an alkyloxy group, an alkyl group or an aryl group attached via a carbamoyl ,
An alkyl group having a hydroxy group or a protecting group attached thereto, an alkyl azide group, an alkyl group containing a 5-membered heteroaromatic ring containing 2 or 3 nitrogen atoms and a non-toxic salt thereof, one oxygen atom and one nitrogen atom A non-toxic salt may be formed by an alkyl group having a 6-membered saturated monocyclic ring including a non-toxic salt, and an amino acid or a protected amino acid having an ester bond or a non-toxic salt. And an epoxy group, an alkyl group having an epoxy group, or the like is preferable. These may be used alone or in combination with a hydroxy group or a hydroxy group-protected hydroxy group such as methoxymethyloxy group, and an alkyl group, hydroxymethyl Group and hydroxy group, alkyl group and hydroxy group having a 6-membered saturated monocyclic ring containing one oxygen and nitrogen, two or three nitrogens
Combinations of an alkyl group containing a membered heteroaromatic ring and a hydroxy group are also preferred. Examples of the substituent at the 9-position include a hydroxy group, a hydroxy group protected with a protecting group,
Alkyl groups having an aldehyde group, such as alkyl groups, cycloalkyl groups and alkenyl groups having up to 10 carbon atoms, preferably up to 8 carbon atoms, up to 6 carbon atoms having preferably up to 4 carbon atoms, epoxy groups, and hydroxy- and epoxy-containing carbon groups. Number one
An alkyl group or alkenyl group having one or more hydroxy groups, such as an alkyl group or alkenyl group having up to 0, preferably up to 8, having up to 10, preferably up to 8 carbon atoms, such as a methoxymethyl group or methylthio group. An alkyl group which may be protected by a protecting group such as a methyl group or a tetrahydropyranyl group and which has no hydroxy group or which has one or more and one heterocyclic compound and has up to 10 and preferably up to 8 carbon atoms Or an alkenyl group, which may form a non-toxic salt, having one or more carboxyl groups and having 1 carbon atom.
It is an alkyl group or an alkenyl group having up to 0, preferably up to 8, and these carboxyl groups may form a non-toxic salt. The aliphatic amine having an alkyl group having up to 10 carbon atoms, preferably up to 8 carbon atoms, or Alkenyl group and the like,
The amine may form a non-toxic salt, and these substituents are further substituted with one or more of the following substituents such as esters, amides, ethers, thioethers and carbamoyl.
One or more may be combined. Examples of the substituent attached to the ester, amide, ether, thioether, carbamoyl, or the like include an alkyl group having up to 18 carbon atoms or a group having 18 or more hydroxy groups having 18 or more carbon atoms.
And preferably up to 14 alkyl groups, alkenyl groups,
An alkyl group or an alkenyl group having one or more carboxyl groups, such as an aryl group or a cycloalkyl group, having up to 10 carbon atoms, and when a free carboxyl group is present, this carboxyl group is a non-toxic salt May be a hydroxy acid having up to 10 carbon atoms containing at least one hydroxy group and at least one carboxyl group. When a free carboxyl group is present, the carboxyl group forms a non-toxic salt. The number of carbon atoms having an epoxy and a hydroxy group is preferably up to 10 and preferably 6
An alkyl or alkenyl group such as an alkyl or alkenyl group having one or more hydroxy groups and one heterocyclic compound and having up to 8 carbon atoms, preferably up to 6 carbon atoms. A 5- or 6-membered saturated monocyclic ring containing one, a 5-membered heteroaromatic ring containing 2 or 3 nitrogens, a 6-membered saturated monocyclic ring containing 1 oxygen or sulfur and nitrogen, a 5-membered nitrogen containing 2 nitrogens or It is a 6-membered saturated monocyclic ring or the like, which may form a non-toxic salt. Further, there is no hydroxy group or an aliphatic amine having one or more carbon atoms having up to 10 and preferably up to 8, and may form a non-toxic salt on these amino groups and the like,
Aliphatic amine containing heterocyclic compound and having 8 carbon atoms
Preferred examples of the heterocyclic compound are a 5-membered heteroaromatic ring containing 2 or 3 nitrogen, a 6-membered saturated monocyclic ring containing oxygen or sulfur and 1 nitrogen, and the like. These amino groups may form non-toxic salts, and further include aromatic amines and the like, which may form non-toxic salts, and may have aliphatic azides, amino acids or protective groups. These amino acids may form non-toxic salts with them, or these substituents may be further bonded to these substituents by esters, amides, ethers, carbamoyl, or the like. In fourth place,
One or two alkyl groups, hydroxyalkyl groups, substituted hydroxyalkyl groups and the like may be bonded. As a combination of the substituents at the 8- and 9-positions, an alkylidene group or an alkyl group and a hydroxy group or a hydroxy group with a protecting group at the 8-position, and a hydroxy group with a hydroxy group or a protecting group at the 9-position are bonded. Having an alkyl group or alkenyl group, etc., a hydroxyalkyl group and an alkyl group bonded at the 4-position, an alkyl group and a hydroxy group at the 8-position, or a hydroxy group with an alkyl-protecting group, and a hydroxy group at the 9-position An alkyl or alkenyl group to which a hydroxy group with a protecting group or a protecting group is bonded, an alkyl or alkenyl group containing up to 10 and preferably up to 8 carbon atoms containing a hydroxy group and an epoxy group, and a carboxyl group as an alkyloxy group Having an alkyl group having a carboxyl group or an alkyl or alkenyl group having a carboxyl group An alkyl group containing up to 10 and preferably up to 8 carbon atoms containing a hydroxy group or a hydroxy group with a protecting group and a 5-membered heteroaromatic monocycle containing one or more and two or three nitrogen atoms Or a compound in which a nitrogen-containing compound is bonded to a alkenyl group or a hydroxy group-containing alkyl group by an ether bond via a hydroxyalkyl group, such as a compound in which an alkyl group is bonded to the 4-position, and A carbonyl group or a compound protected by a protecting group, an alkyl group or alkenyl group having a carbonyl group or a carbonyl group at the 9-position, an alkyl group or an alkenyl group having a hydroxy group, an amino acid ester-bonded to a hydroxy group, etc. Preferred examples include combinations in which an alkyl group is bonded to the 4-position, and these substituents form a non-toxic salt. And it may be. The protecting group is a methoxymethyl group (MOM), methylthiomethyl (MTM), tetrahydropyranyl (THP), t-butyl (t-Bu), trityl (Trt), benzyl (Bzl), p- Ether-type protecting groups such as methoxybenzyl (MP), acyl-type protecting groups such as acetyl groups, trimethylsilyl (TMS), silyl-type protecting groups such as t-butyldimethylsilyl (TBDMS), etc. Ester-type protecting groups such as benzoyl groups and silyl ester-type protecting groups such as trimethylsilyl groups, carbonyl groups, dimethyl ketals and ketal-type such as ethylene acetal, acetal-type protecting groups and the like, amino groups are t-butyl groups, Protecting groups for amino acids, such as carbamate-type protecting groups such as benzyl groups and amide-type protecting groups such as acetyl groups, can be those used for peptide synthesis. Etc., generally the protecting groups used in organic synthesis and the like can be used. As the compound in the present invention, for example, commercially available products such as sclareol, sclareolide, manol, labdanolic acid, and the like, and furthermore, derivatives thereof obtained by employing a conventional method to these commercially available products are applied. Is done. In addition, those obtained by cyclizing naturally occurring chain-like linalool and the like, bicyclic diterpenes obtained from copearl resin, and the like are also applicable without any problem.

The antifungal agent containing the compound of the present invention as an active ingredient is particularly useful as a remedy for mycosis involving fungi such as molds and yeasts which are included in humans, and tablets for oral administration. In the case of parenteral administration, it can be used as a solution, suspension, ointment and the like. The dose varies depending on the severity of the disease, the weight of the patient, etc., but it is generally preferable to be about 1 to 500 mg, and it is better to administer the dose once to several times a day. . In the case of an injection solution, it can be administered by putting it in a drip. In the case of formulation, commonly used vehicles, carriers, swelling agents, excipients, binders, lubricants, buffers, antioxidants, preservatives, stabilizers, flavoring agents, etc. are required units for formulation. The dose is mixed and formulated.

[0012]

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 performed every 24 hours. 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, 160 μl of a culture medium for sensitivity measurement was added thereto, and a well equivalent to IC ₈₀ was prepared. The wells exhibiting a turbidity equal to or less than the turbidity of this well were defined as the end points. ○ Anti-Aspergillus fumigatus
igatus) Activity measurement method 1. 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 as a buffer solution, stir and add NaO
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 one 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 the measurement medium. 4. Culture 90 μl of the 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 prepared.
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).治療 Infection treatment test Healthy growing mice (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,
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 Preparation of Compound Preparation of AT-1 Commercially available sclareolide (1.25 g: 5.00 mmol, Aldrich reagent) was added to a mixture of tetrahydrofuran (hereinafter referred to as THF) (10 ml) -ether (10 ml). Dissolve and add lithium aluminum hydride (190 mg:
5.00 mmol) was added in small portions. After stirring for 1 hour at the same temperature, 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. 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-C ₁₀ ), 0.79 (3H, s, Meβ-
_{C 4), 0.88 (3H,} s, Meα-C 4), 1.20 (3H, s, Me-C 8), 1.90 (1H,
ddd, J = 12.2,3.4,2.9, H ₇ ), 3.46 (1H, ddd, J = 10.3,8.3,5.
_{9, H 12), 3.75 (} 1H, ddd, J = 10.3,4.4,4.4, H 12 ')

Preparation of AT-2 AT-1 (1.20 g: 4.72 mmol) of pyridine (1.5 m) was prepared.
l) Acetic anhydride (1 ml) was added to the solution 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 ethyl acetate (3
0 mL), and the extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated saline solution. The extract is dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent is subjected to silica gel column chromatography.
[13 g: 1.5 cm ID × 16.5, elution solvent: chloroform-ethyl acetate = 100/0 → 70/30], hydronaphthalene having a methyl group and a hydroxy group at the 8-position and a 2-acetoxyethyl group at the 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 , pp
m): 0.79 (3H, s, Me-C ₁₀ ), 0.79 (3H, s, Meβ-C ₄ ), 0.87 (3
_{H, s, Meα-C 4} ), 1.16 (3H, s, Me-C 8), 1.89 (1H, ddd, J = 12.2,
2.9,2.9, H ₇ ), 4.12 (2H, m, H ₁₂ and H _{1 2 '} )

Preparation of AT-3 The above AT-2 (1.35 g: 4.56 mmol) in pyridine (9 ml).
The phosphoryl chloride (860) was added to the solution while stirring under ice cooling.
μl: 9.2 mmol). After the reaction solution was stirred overnight, it was added to ice water (30 ml), and the product was extracted with ethyl acetate (30 ml).
Extracted times. The extract was washed successively with water, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Then, a part (250 mg) of the residue was dissolved in ethanol (2.5 ml), and a 1N aqueous sodium hydroxide solution (2.5 ml) was added, followed by stirring at room temperature overnight. The reaction solution was diluted with water (10 ml), and then ethyl acetate (15 m
Extracted in l), and the extract was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is repeatedly subjected to silica gel column chromatography to obtain a compound represented by the following structural formula (hereinafter referred to as AT-3) 1
14 mg were obtained as a white wax. Its ¹ H-NMR spectrum (400 MHz) was as follows. (CDCl ₃ , ppm): 0.69 (3H, s, Me-C ₁₀ ), 0.80 (3H, s, Meβ-
C ₄ ), 0.87 (3H, s, Meα-C ₄ ), 2.00 (1H, ddd, J = 12.7,12.7,4.
9, H ₇ ), 2.39 (1H, ddd, J = 12.7,4.4,2.4, H _{7 '} ), 3.49-3.58
_{(1H, m, H 12)} , 3.60-3.76 (1H, m, H 12 '), 4.54 (1H, d, J = 1.5,
H ₁₇ ), 4.83 (1H, d, J = 1.5, H _{17 '} )

[0016]

Embedded image

Preparation of AT-4 Sclareolide (1.50 g: 6.00 mmol) in THF (4
1N sodium hydroxide aqueous solution (12 ml) was added to a solution of (8 ml) -ethanol (8 ml) with stirring. After stirring for 1 hour, 1N hydrochloric acid (15 ml) was added to the reaction solution, and the product was treated with ethyl acetate (30 ml).
Extracted twice in l). The extract was thoroughly washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crystal was recrystallized from ethyl acetate. 1.25 g of hydronaphthalene having a carboxymethyl group (hereinafter referred to as AT-4) was obtained as colorless crystals. Its ¹ H-NMR spectrum (400 MHz), IR
The spectrum was as follows. (CDCl ₃ , ppm): 0.79 (3H, s, Me-C ₁₀ ), 0.79 (3H, s, Meβ-
C ₄ ), 0.88 (3H, s, Meα-C ₄ ), 1.17 (3H, s, Me-C ₈ ), 1.83 (1H,
dd, J = 5.9,4.4, H ₉ ), 1.95 (1H, ddd, J = 12.2,3.4,2.9, H ₇ ),
2.34 (1H, dd, J = 16.1,4.4, H 12), 2.50 (1H, dd, J = 16.1,6.4,
H _{12 '} ) (KBr, cm ^-1 ): 3700-2200 (br), 3491, 3340, 3119, 2927,
1720,1685, 1460, 1432, 1414, 1389, 1201, 938

Preparation of AT-6 AT-2 (1.85 g: 6.25 mmol) in dichloromethane (20
Chloromethyl methyl ether (715 μl: 9.38 mmol) and diisopropylethylamine (1.74 ml: 9.99 mmol) were sequentially added to the solution while stirring under ice-cooling. After stirring the reaction solution at room temperature for 8 hours, chloroform (30 ml) and water (30 ml) were added to extract the product.
The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent is distilled off,
The residue was subjected to silica gel column chromatography [30 g:
2.0 cmID × 20.5, elution solvent: n-hexane-ethyl acetate = 100/0 → 60/40] to obtain 621 mg of a compound represented by the following structural formula (hereinafter referred to as AT-6) as a colorless candy substance. . Its ¹ H-NMR spectrum (400 MHz) was as follows. (CDCl ₃ , ppm): 0.79 (3H, s, Me-C ₁₀ ), 0.83 (3H, s, Meβ-
C ₄ ), 0.87 (3H, s, Meα-C ₄ ), 1.23 (3H, s, Me-C ₈ ), 2.06 (1H,
ddd, J = 12.2,3.4,2.9, H ₇ ), 3.37 (3H, s, OCH ₂ OC H ₃ ), 3.45 (1
H, ddd, J = 9.8,9.8,4.4, H 12), 3.72 (1H, ddd, J = 9.8,5.4,4.
4, H _{12 '} ), 4.75 (2H, s, OC H ₂ OCH ₃ )

[0019]

Embedded image

Preparation of AT-7 Sclareolide (1.50 g: 6.00 mmol) was dissolved in a mixture of ethanol (8 ml) and THF (4 ml), and a 1N aqueous sodium hydroxide solution (12 ml) was added with stirring at room temperature. Was. After stirring the reaction solution at the same temperature for 4 hours, the precipitated crystals were collected by filtration. The crystals are sufficiently washed with water and dried under reduced pressure to give 1.51 g of hydronaphthalene (hereinafter referred to as AT-7) having a methyl group and a hydroxy group at the 8-position and a sodium carboxylate methyl group at the 9-position.
Was obtained as colorless crystals. Its ¹ H-NMR spectrum (400 MH
z) The IR spectrum was as follows. (CDCl ₃ -CD ₃ OD = 9: 1, ppm): 0.78 (3H, s, Me-C ₁₀ ), 0.79 (3H,
s, Meβ-C ₄ ), 0.87 (3H, s, Meα-C ₄ ), 1.15 (3H, s, Me-C ₈ ),
1.90 (1H, ddd, J = 12.7,3.4,2.9, H 7), 2.24 (1H, dd, J = 16.
1,3.9, H ₁₂ ), 2.31 (1H, dd, J = 16.1,6.8, H _{12 '} ) (KBr, cm ^-1 ): 3700-2600 (br), 3484, 3321, 2925, 1637,
1546, 1406, 1384

Preparation of AT-8 AT-4 (1.20 g: 4.50 mmol) was added to ether (2.5 ml)-
It was dissolved in a mixture of methanol (2.5 ml), and a 10% n-hexane solution of trimethylsilyldiazomethane was added dropwise with stirring at room temperature until the solution turned slightly yellow. After stirring for 10 minutes, the solvent was distilled off. The obtained methyl ester (1.4 g) was dissolved in pyridine (10 ml) without purification, and phosphoryl chloride (1 ml) was added with stirring under ice cooling. After stirring overnight at room temperature, the reaction solution was added to ice water (50 ml), and the product was extracted twice with ethyl acetate (50 ml). The combined extracts were washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate 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 [30 g (10% water-containing silica gel): 2.0 c.
mID × 20.5 cm, elution solvent: n-hexane-ethyl acetate =
100/0 → 97/3] to obtain 340 mg of a methyl ester of 8-methylene together with a 7,8- and 8,9-ene compound as a colorless candy substance. Next, the methyl ester of 8-methylene (250 mg: 0.94 mmol) was dissolved in ethanol (2.5 ml), and 1N sodium hydroxide solution (2.5 ml) was added.
Stirred at 0 ° C. for 6 hours. The mixture was acidified with 1N hydrochloric acid, diluted with water (5 ml) and diluted with ethyl acetate (15 ml).
Extracted times. After the combined extracts were washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography [7.5 g: 1.
0cmID × 20.5, elution solvent: chloroform-ethyl acetate = 100/0 → 90/10], and crystallized from n-hexane to obtain 197 mg of a compound represented by the following structural formula (hereinafter referred to as AT-8) as a colorless needle. Obtained as crystalline crystals. Part ¹
H-NMR spectrum (400 MHz) and IR spectrum were as follows. (CDCl ₃ , ppm): 0.70 (3H, s, Me-C ₁₀ ), 0.81 (3H, s, Meβ-
C ₄ ), 0.89 (3H, s, Meα-C ₄ ), 2.09 (br, ddd, J = 12.7,12.7,4.
9, H ₇ ), 2.39 (1H, ddd, J = 12.7,3.4,2.9, H _{7 '} ), 2.39 (1H, d
_{d, J = 15.6,2.9, H 12} ), 2.53 (1H, dd, J = 15.6,3.4, H 12 '), 4.
_{53 (1H, s, H 17} ), 4.78 (1H, s, H 17 ') (KBr, cm -1): 3600-2300 (br), 2937, 2843, 1702, 1649,
1457,1423, 1385, 1329, 1264, 1192, 896

[0022]

Embedded image

測定 Measurement of the properties of the compounds Tables 1 and 2 show the results of the antifungal activity and the infection treatment test of the prepared compounds.

[0024]

[Table 1]

[0025]

[Table 2]

Example 2 Preparation of Compound Preparation of AT-5 Water (10 ml) was added to a solution of sclareol (1.5 g: 4.86 mmol, Aldrich reagent) in acetone (10 ml), and 50% N- Methylmorpholine N-oxide
(2.37 ml: 10.1 mmol) and a 2% aqueous solution of osmic acid (250 μl) were added sequentially. After stirring the reaction solution at room temperature for 6 hours, a 20% aqueous solution of sodium thiosulfate (25 ml) was added, and the product was extracted twice with ethyl acetate (30 ml). The extract was washed sequentially with a 20% aqueous sodium thiosulfate solution, water and saturated saline, and then dried over anhydrous magnesium sulfate.
After evaporating the solvent, the residue was subjected to silica gel column chromatography [30 g: 2.0 cm IDx21, elution solvent: chloroform-methanol = 100/0 → 80/20], and crystallized from ethyl acetate. 1.55 g of a hydronaphthalene (hereinafter referred to as AT-5) having a hydroxyl group and a hydroxy group, and a 3,4,5-trihydroxy-3-methylpentyl group at the 9-position.
Was obtained as colorless needles. Its ¹ H-NMR spectrum (400 MH
z: CDCl ₃ -CD ₃ OD = 9: 1) The chart is shown in FIG.

Preparation of AT-14 and AT-15 Sclareol (2.0 g, 6.5 mmol) was added to dichloromethane.
(25 ml) and 3,4-dihydro-2H-pyran under ice-cooling and stirring
(600 μl, 6.5 mmol) and pyridinium p-toluenesulfonate (163 mg, 0.65 mmol) were added successively.
Stir for 4 hours. The reaction solution was extracted with chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (50 g, 3 cm ID × 17 c
m, developing solvent: hexane / ethyl acetate = 95/5 to 70 /
30), and 1.04 g of each of three compounds represented by the following structural formulas (hereinafter referred to as T-14 (Chemical Formula 7), AT-15 (Chemical Formula 8) and AT-16-1 (Chemical Formula 9)). (Yield 40.9%), 350 mg (13.8% yield) and 1.25 g (40.5% yield). OTHP in the structural formula represents a tetrahydropyranyloxy group.
Their properties were as follows: (AT-14) Rf value: silica gel thin layer chromatography: 0.37 [silica gel 60F ₂₅₄ (Merck), developing solvent: hexane / ethyl acetate = 4/1], 0.49 [RP-1]
8F _254s (Merck), developing solvent: methanol] Coloring reagent: anisaldehyde reagent positive (purple) ¹ H-NMR spectrum (400 MHz, CDCl ₃ , ppm): 0.79 (6H, s, 20,1)
8-CH ₃ ), 0.87 (3H, s, 19-CH ₃ ), 1,18 (3H, s, 17-CH ₃ ), 1.24
(3H, s, 16-CH ₃ ), 3.45 (1H, m, 5'-CH ₂ ), 3.97 (1H, m, 5'-C
H ₂ ), 4,59 (1H, m, 1'-CH), 5.12 (1H, d J = 0.97,15-CH ₂ ),
5.16 (1H, d J = 3.42,15-CH ₂ ), 5.80 (1H, dd J = 10.74,18.0
7,14-CH) (AT-15) Rf value: silica gel thin layer chromatography: 0.25 [silica gel 60F ₂₅₄ (Merck), developing solvent: hexane / ethyl acetate = 4/1], 0.51 [RP- 1
8F _254s (Merck), developing solvent: methanol] Coloring reagent: anisaldehyde reagent positive (purple) IR spectrum (KBr, νcm ^-1 ): 3447, 2940, 2868, 1637,
1459, 1388 ¹ H-NMR spectrum (400 MHz, CDCl ₃ , ppm): 0.78 (6H, s, 20,1
_{8-CH 3), 0.86 (} 3H, s, 19-CH 3), 1.17 (3H, s, 17-CH 3), 1.34
(3H, s, 16-CH ₃ ), 3.45 (1H, m, 5'-CH ₂ ), 3.95 (1H, m, 5'-C
H ₂ ), 4.66 (1H, m, 1'-CH ₂ ), 5.12 (1H, d, J = 1.0,15-CH ₂ ),
5.16 (1H, d, J = 3.4,15-CH ₂ ), 5.79 (1H, dd, J = 10.7,18.1,14
-CH) ¹³ C-NMR spectrum (100 MHz, CDCl ₃ , ppm): 15.5, 18.5, 1
8.9, 20.5, 20.6, 21.5, 22.4, 24.2, 25.5, 32.2, 33.
3, 33.4, 39.2, 39.7, 42.1, 44.0, 45.1, 56.2, 62.4,
63.1, 74.5, 94.6, 114.4, 143.5

[0028]

Embedded image

[0029]

Embedded image

[0030]

Embedded image

Preparation of AT-16 AT-16-1 obtained in Example 2 (900 mg, 1.89 mmol)
Was dissolved in dichloromethane (15 ml) and stirred with ice cooling.
m-perbenzoic acid (hereinafter referred to as m-CPBA) (932 mg, 5.4 mg)
(0 mmol) was added, and the mixture was stirred at room temperature for 5 hours and then left for 15 hours.
After the reaction solution was extracted with chloroform, it was washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (20
g, 1.5 cm ID × 26 cm, developing solvent: hexane / ethyl acetate = 95/5 to 80/20), and 408 mg of a compound represented by the following structural formula (hereinafter referred to as AT-16-2 (Chem. 10)) ( Yield 43.8%). Then, sodium hydride (NaH8
1 mg, 2.0 mmol) in dimethylformamide under a nitrogen atmosphere
(Hereinafter referred to as DMF) to 0.5 ml, and stirred under ice-cooling for 1H-1,2,
4-Triazole (140 mg, 0.81 mmol) in DMF
(0.5 ml) and stirred at room temperature for 1 hour. Then AT-
A solution of 16-2 (400 mg, 0.81 mmol) in DMF (1.0 ml) was added, and the mixture was stirred at 60 ° C. for 6 hours. The reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (15 g, 2 cm ID × 11 cm, developing solvent: hexane / ethyl acetate = 8/2, chloroform / methanol = 9 /
1), a compound represented by the following structural formula (hereinafter referred to as AT-16-
195 mg (yield: 42.8%) was obtained. Then, AT-16-3 (195 mg, 0.35 mmol) was added to methanol.
(15 ml) and pyridinium p-toluenesulfonate
(68 mg, 0.28 mmol) was added and left at room temperature for 15 hours. The solvent of the reaction solution was distilled off, and the residue was subjected to silica gel column chromatography (7.5 g, 1 cm ID × 24 cm, developing solvent: chloroform / methanol = 10/0 to 9/1), and a methyl group and a hydroxy Thus, 108 mg (yield: 79.4%) of hydronaphthalene (hereinafter referred to as AT-16) having a 3,4-dihydroxy-3-methyl-5- (1-triazolyl) pentyl group at the 9-position was obtained. Its properties were as follows: Rf value: silica gel thin layer chromatography: 0.30
[Silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform / methanol = 9/1], 0.64 [ RP-18F 25 4s ( Merck), developing solvent: methanol] color reagent: anisaldehyde reagent positive (purple) ¹ H-NMR spectrum (400 MHz, CDCl ₃ , ppm): 0.77 (6H, s, 18,2
0-CH ₃ ), 0.85 (3H, s, 19-CH ₃ ), 1.12 (3H, s, 17-CH ₃ ), 1.19
(3H, s, 16-CH ₃ ), 3.71 (1H, m, 14-CH), 4.07 (1H, m, 15-C
H ₂ ), 4.22 (1H, OH), 4.37 (1H, d J = 13.7,15-CH ₂ ), 7.83 (1
H, s, triasol), 8.22 (1H, s, triasol)

[0032]

Embedded image

[0033]

Embedded image

Preparation of AT-24 m-CPBA (350 mg: 2.00 mmol) was added to a solution of sclareol (250 mg: 0.81 mmol) in dichloromethane (20 ml).
l) was added little by little, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane (10 ml), washed successively with a 10% aqueous sodium thiosulfate solution (20 ml), a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified using a silica gel column [10 g: 1.5 cm ID × 14, elution solvent: chloroform-methanol = 100/0 → 97/3 (50 ml)], and crystallized from n-hexane-ethyl acetate. As a result, 152 mg of hydronaphthalene having a methyl group and a hydroxy group at the 8-position and a 3,4-dihydroxy-3-methyl-4,5-epoxypentyl group at the 9-position (hereinafter referred to as AT-24) were obtained as colorless crystals. . The ¹ H-NMR spectrum (400 MHz: CDCl ₃ ) chart is shown in FIG.

Preparation of AT-25 Chloromethyl methyl ether (1.08 ml: 15.6 mmol) and diisopropylethylamine (2.94 ml: 16) were added to a dichloromethane solution of sclareol (2.00 g: 6.49 mmol) while stirring under ice-cooling. .8 mmol) were added sequentially. After the reaction solution was stirred at room temperature for 15 hours, chloroform (30 ml) was added, and the mixture was washed with water, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography [30 g: 2.0 cmIDx21, elution solvent: n-hexane-ethyl acetate = 100/0 → 70/30] to obtain 2.21 g of a methoxymethyl ether compound as colorless Obtained as a candy. Next, the obtained methoxymethyl ether compound
(2.2 g: 5.56 mmol) in acetone (10 ml) -water (10 m
l) Add 2% osmic acid aqueous solution (200 μl) and 5%
0% N-methylmorpholine N-oxide (3.14 ml) was added sequentially, and the mixture was stirred at 54 ° C for 17 hours. After adding an aqueous 20% sodium thiosulfate solution to the reaction solution to decompose excess reagents,
The product was extracted twice with ethyl acetate (30ml). The extract was thoroughly washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography [22 g: 2.0 cm ID × 15.5 cm, elution solvent: chloroform-ethyl acetate = 95/5 → 50/50]
And a methyl and methoxymethyloxy group at the 8-position and 4,5-dihydroxy-3- (methoxymethoxy)-at the 9-position.
Hydronaphthalene having a 3-methylpentyl group (hereinafter referred to as A
T-25) was obtained as a colorless candy. That
^{The 1} H-NMR spectrum (400 MHz: CDCl ₃ ) chart is shown in FIG.

測定 Measurement of compound properties Tables 3 and 4 show the antifungal activity and the results of infection treatment tests of the prepared compounds.

[0037]

[Table 3]

[0038]

[Table 4]

Example 3 Preparation of Compound Preparation of HAL-1 17.0 mmol of AT-2 obtained in Example 1: 5.1 g
The mixture was placed in a 00 ml eggplant-shaped flask and dissolved in 50 ml of dichloromethane. While stirring under ice cooling, 25.5 mmol (2.3 ml) of 3,4-dihydro-2H-pyran (manufactured by Wako Pure Chemical Industries, Ltd.) 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, the mixture was stirred for 18 hours. Eighteen hours later, 20 ml of distilled water and 10 ml of chloroform were added to the reaction solution for extraction. The chloroform layer was successively washed with 20 ml of 1N hydrochloric acid, 20 ml of a saturated aqueous sodium hydrogen carbonate solution and 20 ml of a saturated saline solution, and dried over anhydrous magnesium sulfate. Was. 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 is shown in FIG. 4, ¹³ C-NMR spectrum (400 MHz
z: CDCl ₃ ) chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.75
[Silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform / methanol = 20/1], 0.24 [ RP-18F
_254s (Merck), developing solvent: 90% methanol] Color reaction: Positive for Ehrlich reagent (brown), positive for anisaldehyde reagent (green-brown), positive for 50% sulfuric acid reagent (black)

[0040]

Embedded image

Preparation of HAL-2 Sodium hydride (manufactured by Wako Pure Chemical Industries, Ltd.) 5.8 mmol (23
2 mg) was weighed into a dried 100 ml two-necked flask,
After the atmosphere in the flask was replaced with nitrogen, 4 ml of dehydrated DMF was injected under ice cooling, and 2.9 mmol (1000 mg) of HAL-1 was further dehydrated.
It was dissolved in 4 ml of MF and injected. After the reaction solution was stirred at room temperature for 30 minutes, 5.8 mmol (1473 mg) of N- (2-bromoethyl) phthalimide (manufactured by Wako Pure Chemical Industries, Ltd.) was added again in DMF (2 ml) under ice-cooling.
And then stirred 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 fractionated by silica gel column chromatography (3.0 cm ID × 20.0 cm, eluent: hexane / ethyl acetate = 90/10 to 50/50), Hexane / ethyl acetate = 50/5
As a fraction eluted with 0 to 40/60, 690 mg of a colorless oily product of a compound represented by the following structural formula (hereinafter referred to as HAL-2) was obtained.
Its properties are as follows: ¹ H-NMR spectrum (400
MHz: CDCl ₃ ) chart is shown in FIG. 6, ¹³ C-NMR spectrum (400 MHz
The z: CDCl ₃ ) chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.73
[Silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform / methanol = 20/1], 0.20 [silica gel 60F
₂₅₄ (Merck), developing solvent: hexane / ethyl acetate = 2 /
1], 0.14 [RP-18F _254s (Merck), developing solvent:
90% methanol] Color reaction: Positive Ehrlich reagent (brown), positive anisaldehyde reagent (yellow green), positive 50% sulfuric acid reagent (black)

[0042]

Embedded image

Preparation of HAL-3 8.8 mmol (352 mg) of sodium hydride was dried 1
Weigh into a 00 ml two-necked flask and replace the inside of the flask with nitrogen
Thereafter, 6.0 ml of dehydrated DMF was injected under ice-cooling, and HAL-
Dissolve 4.4 mmol (1500 mg) of 1 in 6.0 ml of dehydrated DMF
And injected. The reaction solution was stirred at room temperature for 30 minutes and then cooled on ice.
Allyl bromide (manufactured by Wako Pure Chemical Industries, Ltd.) 8.8 mmol (750 μl)
Was injected. Thereafter, the mixture was stirred at room temperature for 20 hours. 20
After an hour, 20 ml of distilled water is added to the reaction solution, and then ethyl acetate 30
The extract was extracted twice with distilled water and saturated saline 5 times.
wash with anhydrous magnesium sulfate
Was. After drying, the solvent is distilled off under reduced pressure and the residue is silica gel.
Column chromatography (2.0 cm ID x 18.0 cm,
Discharge: hexane / ethyl acetate = 100/0 to 20/80)
Hexane / ethyl acetate = 90/1
A compound represented by the following structural formula (hereinafter referred to as H
1300 mg of a colorless oil (hereinafter referred to as AL-3). Its characteristics
Is as follows, ¹ H-NMR spectrum (400 MHz: CDCl
_Three FIG. 8 shows the chart. ¹³ C-NMR spectrum (400 MHz: CDCl _Three )
The chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.85
[Silica gel 60F ₂₅₄ (Color reaction: Ehrlich reagent positive
(Brown), positive for anisaldehyde reagent (purple), 50% sulfuric acid
Acid reagent positive (black)

[0044]

Embedded image

Preparation of HAL-4 1.8 mmol (700 mg) of HAL-3 was weighed into a 30 ml eggplant-shaped flask, and 5 ml of acetone and 2 ml of distilled water were added thereto. (Tokyo Kasei Co., Ltd .: 50% aqueous solution) 3.3 mmol (780 μl) and 50 μl of a 2% osmic acid solution were added. Thereafter, the mixture was stirred at room temperature for 20 hours. After 20 hours, 5 ml of a 10% aqueous sodium bisulfite solution was added to the reaction solution, and the mixture was further stirred for 20 minutes. After adding 5 ml of distilled water thereto, extraction was performed twice with 10 ml of ethyl acetate. The extract was washed with distilled water and saturated saline in this order, and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure under filtration, and the residue was fractionated by silica gel column chromatography (2.0 cm ID × 15.0 cm, eluent: chloroform / methanol = 100/1 to 100/10) to give chloroform. / Methanol = 100/3
756 mg of a colorless oil of a compound represented by the following structural formula (hereinafter referred to as HAL-4) was obtained as a fraction eluted with 溶出 100/5. Its properties are as follows: ¹ H-NMR spectrum (400 MHz
z: CDCl ₃ ) chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.60
[Silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform / methanol = 10/1], 0.36 [silica gel 60F
₂₅₄ (Merck), developing solvent: hexane / ethyl acetate = 1 /
4], 0.23 [RP-18F _254s (Merck), developing solvent:
90% methanol] Color reaction: Positive for Ehrlich's reagent (purple), positive for anisaldehyde reagent (yellowish green), positive for 50% sulfuric acid reagent (purple)

[0046]

Embedded image

Preparation of HAL-5 1.6 mmol (340 mg) of sodium periodate was weighed into a 50 ml eggplant type flask, and 3.5 ml of distilled water and 1.1 mmol (435 mg) of HAL-4 were added at room temperature. In acetone, and the mixture was stirred at room temperature for 5 hours. After 5 hours, the reaction solution was concentrated under reduced pressure to remove acetone, 3 ml of distilled water was added, and the mixture was extracted twice with 8 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 under filtration to obtain 327 mg of a compound represented by the following structural formula (hereinafter referred to as HAL-4A). This was placed in a 50 ml flask, and 4 ml of acetone and Jones reagent (2.67 mmol / ml) were added under ice cooling.
1.7 mmol (636 μl) was added, and the mixture was stirred for 1 hour. One hour later, isopropyl alcohol was added until the reaction solution turned green, then an appropriate amount of celite was added, 30 ml of diethyl ether was further added, and the celite was collected by filtration. And dried. After drying, the solvent was removed by filtration under reduced pressure and the residue was subjected to silica gel column chromatography (1.5 cm ID × 15.0 c).
m, eluent: chloroform / methanol = 100/1 to 0 /
Chloroform / methanol = 100/10 to 100/50 as a fraction eluted with hydronaphthalene having a methyl group and a hydroxy group at the 8-position and a (2-carboxymethoxy) ethyl group at the 9-position (Hereinafter HAL-5
176 mg of a colorless oil. Its characteristics are as follows, and a ¹ H-NMR spectrum (400 MHz: CDCl ₃ ) chart is shown in FIG. Rf value: silica gel thin layer chromatography: 0.20
[Silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform / methanol = 5/1], 0.36 [ RP-18F 25 4s ( Merck), developing solvent: 90% methanol] Color reaction: Ehrlich's reagent positive (purple) / Anisaldehyde reagent positive (purple) / 50% sulfuric acid reagent positive (purple)

[0048]

Embedded image

測定 Measurement of compound properties Tables 5 and 6 show the antifungal activity and the results of infection treatment tests of the prepared compounds.

[0050]

[Table 5]

[0051]

[Table 6]

Example 4 Preparation of Compound Preparation of Manol 2.5 g of manol oil was subjected to silica gel column chromatography (50 g, 3 cm ID × 17 cm, developing solvent: hexane /
Ethyl acetate = 10/0 to 7/3), and the manol-containing fraction (1.28 g) was crystallized from hexane to obtain 800 mg of manol crystals represented by the following structural formula. The characteristics are as follows. Rf value: silica gel thin layer chromatography: 0.66
[Silica gel 60F ₂₅₄ (Merck), developing solvent: hexane /
Ethyl acetate = _4/1 ], 0.53 [RP-18F _254s (Merck), developing solvent: methanol] Color reaction: anisaldehyde reagent positive (purple) Melting point: 53 ° C (measured value) IR spectrum (νmax, cm) ^-1 ): 3391, 2923, 2846, 1714,
1643, 1458 ¹ H-NMR spectrum (400 MHz, CDCl ₃ , ppm): 0.67 (3H, s, 20-C
H ₃ ), 0.80 (3H, s, 18-CH ₃ ), 0.87 (3H, s, 19-CH ₃ ), 1.27 (3
H, s, 16-CH ₃ ), 4.48 (1H, d J = 1.0,17-CH ₂ ), 4.80 (1H, d J =
1.0,17-CH ₂ ), 5.06 (1H, dd J = 10.7,1.0,15-CH ₂ ), 5.21 (1
H, dd J = 17.1,1.0,15-CH ₂ ), 5.91 (1H, dd J = 17.1,10.7,14
-CH) ¹³ C-NMR spectrum (100 MHz, CDCl ₃ , ppm): 14.4, 17.7, 1
9.4, 21.7, 24.4, 28.0, 33.6, 38.4, 39.1, 39.9, 41.
4, 42.2, 55.6, 57.2, 73.7, 106.3, 111.6, 145.1, 14
8.8

[0053]

Embedded image

Preparation of Manol E 2.0 g (6.9 mmol) of manol was dissolved in 15 ml of dichloromethane, and 3.57 g (20.7 mmol) of m-CPBA was stirred under ice-cooling.
Was added and stirred at room temperature for 2 hours. The reaction solution was extracted with chloroform, washed with a 10% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (50 g, 3 cm ID × 16 cm, developing solvent: hexane / ethyl acetate = 95 / 5-60 / 40), and 1.79 g of hydronaphthalene (hereinafter referred to as manol E) represented by the following structural formula. (80.6% yield). The characteristics are as follows. Rf value: silica gel thin layer chromatography: 0.15
[Silica gel 60F ₂₅₄ (Merck), developing solvent: hexane /
Ethyl acetate = _4/1 ], 0.62 [RP-18F _254s (Merck), developing solvent: methanol] Coloring reagent: Anisaldehyde reagent positive (purple) ¹ H-NMR spectrum (400 MHz) δppm (CDCl ₃ ): 0.80 (3H, s, 20
-CH ₃ ), 0.83 (3H, s, 18-CH ₃ ), 0.90 (3H, s, 19-CH ₃ ), 1.26
(3H, s, 16-CH ₃ ), 2.50 (1H, dd J = 2.4,3.9,17-CH ₂ ), 2.65 (1
H, m, 15-CH ₂ ), 2.72 (1H, m, 17-CH ₂ ), 2.82 (1H, m, 15-CH ₂ ),
2.88, 2.92 (1H, m, 14-CH)

[0055]

Embedded image

Preparation of Manol F 2.0 g (6.9 mmol) of manol was dissolved in 20 ml of dichloromethane, and 1.79 g (10.4 mmol) of m-CPBA was stirred under ice cooling.
Was added and stirred at room temperature for 2 hours. The reaction solution was extracted with chloroform, washed with a 10% aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (50 g, 2 cm ID × 35 cm, developing solvent: hexane / ethyl acetate = 9/1 to 8/2),
1.49 g (yield: 70.6%) of hydronaphthalene (hereinafter referred to as manol F) represented by the following structural formula was obtained. The characteristics are as follows. Rf value: silica gel thin layer chromatography: 0.33
[Silica gel 60F ₂₅₄ (Merck), developing solvent: hexane /
Ethyl acetate = 4/1], 0.58 [RP-18F _254s (Merck), developing solvent: methanol] Color reaction: anisaldehyde reagent positive (purple) IR spectrum (νmax, cm ^-1 ): 3447, 2932, 2866, 1640,
1460, 1389, 1367 ¹ H-NMR spectrum (400 MHz) δ ppm (CDCl ₃ ): 0.79 (3H, s, 20
-CH ₃ ), 0.82 (3H, s, 18-CH ₃ ), 0.89 (3H, s, 19-CH ₃ ), 1.22
(3H, s, 16-CH ₃ ), 2.49 (1H, d J = 4.4,17-CH ₂ ), 2.77 (1H, dd
J = 3.90,1.5,17-CH ₂ ), 5.01 (1H, dd J = 10.7,1.5,15-C
H ₂ ), 5.19 (1H, dd J = 17.1,1.5,15-CH ₂ ), 5.88 (1H, dd J = 1
(7.1,10.5,14-CH)

[0057]

Embedded image

Preparation of Manol G 400 mg (1.25 mmol) of Manol E was added to THF / water = 13 /
3 (16 ml), and stirred with ice-cooled 70% perchloric acid 100
μl was added and stirred at room temperature for 24 hours. The reaction solution was
After extraction with chill, saturated aqueous sodium hydrogen carbonate solution, saturated diet
After washing with brine, dry over anhydrous magnesium sulfate and evaporate the solvent.
I left. Silica gel column chromatography of the residue
(10 g, 1.5 cm ID × 14 cm, developing solvent: chloroform /
Methanol = 10/0 to 8/2), reversed-phase column chromatography
Raffy (Cosmo Seal 75C18-OPN 50cc, 2cm ID x 1
6 cm, developing solvent: 20-100% methanol), silica
Gel column chromatography (9 g, 1.5 cm ID × 12 c
m, developing solvent: chloroform / methanol = 10 / 0-8 /
2), the hydroxymethyl group and hydroxy at the 8-position
Group, 3,4,5-trihydroxy-3-methylpentyl group at 9-position
(Hereinafter referred to as "manol G")
5.1 mg (19% yield) were obtained. Its characteristics are as follows
And¹H-NMR spectrum (400 MHz: CDCl_Three) Chart
Shown as 12. Rf value: silica gel thin layer chromatography: 0.24
[Silica gel 60F₂₅₄(Merck), developing solvent: chloroform
Methanol / methanol = 9/1], 0.70 [RP-18F_{twenty five 4s}(Me
Color developing reaction: anisaldehyde reagent positive (purple) IR spectrum (νmax, cm^-1): 3386, 2926, 2866, 1647,
1459, 1388

Preparation of Manol H 1.23 g (3.8 mmol) of Manol E was added to 15 ml of dichloromethane.
3,4-dihydro-2H-pyran 690 under ice-cooling and stirring.
μl (7.6 mmol), pyridinium p-toluenesulfonate 9
5 mg (0.38 mmol) were sequentially added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with chloroform, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (35 g, 2 cm ID × 25 cm, developing solvent: hexane / ethyl acetate = 100/0 to 75/25) to give a tetrahydropyranyl ether compound (manol H-1) represented by the following structural formula. 517 mg (33% yield) were obtained.

[0060]

Embedded image

Next, 154 mg of sodium hydride (6.4 mg)
mmol) was added to 1 ml of DMF under a nitrogen atmosphere, and 1H-
DMF solution of 442 mg (6.4 mmol) of 1,2,4-triazole
(1.5 ml) and stirred at room temperature for 1 hour. Thereafter, a solution of 517 mg (1.28 mmol) of manol H-1 in DMF (2 ml).
Was added and stirred at 60 ° C. for 4 hours. The reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (15 g, 1.5 cm ID × 21 cm, developing solvent: hexane / ethyl acetate = 8/2), and 250 mg of a triazole derivative (manol H-2) represented by the following structural formula (yield). 41.3
%)Obtained.

[0062]

Embedded image

Then, 250 mg (0.53) of Manol H-2 was prepared.
was dissolved in 2 ml of methanol, and 58 mg (0.23 mmol) of pyridinium p-toluenesulfonate was added.
Stirred for hours. The reaction solution was extracted with ethyl acetate, washed with saturated sodium bicarbonate and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (10 g, 1.5 cm ID x 13 cm, developing solvent: chloroform / methanol = 100/0 to 94/6) and reverse phase column chromatography (Cosmo Seal 75C18-O)
PN 50cc, 2cmID × 17cm, developing solvent: 60-85%
Methanol) to give 62.5 mg (yield 30.5%) of a compound represented by the following structural formula (hereinafter referred to as "manol H").
The characteristics are as follows. Rf value: silica gel thin layer chromatography: 0.58
[Silica gel 60F ₂₅₄ (Merck), developing solvent: chloroform / methanol = 9/1], 0.65 [ RP-18F 25 4s ( Merck), developing solvent: methanol] Color reaction: anisaldehyde reagent positive (purple) mp : 53 ° C IR spectrum (νmax, cm ^-1 ): 3421, 2936, 2366, 1717,
1647, 1513, 1460, 1388, 1367, 1276, 1205, 1139, 10
80 ¹ H-NMR spectrum (400 MHz, CDCl ₃ , ppm): 0.80 (3H, s, 20-C
H ₃ ), 0.83 (3H, s, 18-CH ₃ ), 0.90 (3H, s, 19-CH ₃ ), 1.16 (3
H, s, 16-CH ₃ ), 2.53 (1H, t, J = 4.88,17-CH ₂ ), 2.84 (1H, d J
= 3.42,1.17-CH ₂ ), 3.09 (1H, OH), 3.73 (1H, m, 14-CH), 4.
10 (1H, m, 15- CH 2), 4.24 (1H, OH), 4.41, 4.46 (1H, d J = 14.
16,15-CH ₂ ), 7.86 (1H, triazole), 8.14 (1H, triazole)

[0064]

Embedded image

測定 Measurement of compound properties Tables 7 and 8 show the results of the antifungal activity and infection treatment tests of the prepared compounds.

[0066]

[Table 7]

[0067]

[Table 8]

Example 5 Preparation of Compound Preparation of ALB003, 007, 008 Method of Maria Lapis et al. (J. Chem. Soc. Perkin Tran)
s1, 815-817 (1985)), and using linalool as a raw material, three kinds of compounds represented by the following structural formulas (hereinafter referred to as ALB003 (chemical formula 23), ALB007 (chemical formula 24), and ALB008 (chemical formula 25))
Was synthesized. Its structure is the following ¹ H-NMR (400 MHz, CDCl ₃ , pp
m) Confirmed from spectrum data. ALB003 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) ALB007 7.96 (1H, d, J = 1.0Hz, -O-CO-H), 5.27 (1H, dt, J = 5.4,11.2H
z, CH-O-CO), 3.66 (3H, s, -COOMe), 2.33 (1H, d, J = 11.2, CH
(COO), 2.29 (1H, m), 1.74 (1H, m), 1.56-1.15 (7H, m), 0.9
8 (2H, m), 1.03 (3H, s, Me), 0.89 (3H, s, Me), 0.83 (3H, s, M
e) ALB008 4.05 (1H, m, CH-O-CO), 3.69 (3H, s, -COOMe), 2.15 (1H, m, c
yclic CH), 2.08 (1H, d, J = 10.8Hz, CHCOO), 1.84 (1H, m, cy
clic CH), 1.74 (1H, m, cyclic CH), 1.56-1.15 (6H, m),
0.97 (3H, s, Me), 0.95 (2H, m), 0.89 (3H, s, Me), 0.82 (3H,
s, Me)

[0069]

Embedded image

[0070]

Embedded image

[0071]

Embedded image

Preparation of ALB004, 005, 015 The method of Maria Lapis et al. (J. Chem. Soc. Perkin Tran)
s1, 815-817 (1985)) and using ALB003 as a raw material, three kinds of compounds represented by the following structural formula (hereinafter ALB004)
6), ALB005 (Formula 27) and ALB015 (28) were synthesized. Its structure was confirmed by the following ¹ H-NMR (400 MHz) spectrum data. ALB004 (DMSO-d ₆ , ppm): 4.80 (1H, s, vinylic CH), 4.66 (1H, s, vi
nylic CH), 2.67 (1H, s, CH-COO), 2.35 (1H, m, cyclic C
H), 2.02 (1H, m, cyclic CH), 1.7-1.05 (9H, m, cyclic C
H), 0.97 (3H, s, Me), 0.86 (3H, s, Me), 0.80 (3H, s, Me) ALB005 (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) ALB015 (CDCl ₃ , ppm) _: 4.90 (1H, brs, vinyl), 4.75 (1H, brs, viny
l), 3.93-3.50 (2H, m, CH ₂ -O), 2.37-1.20 (12H, m, cyclic
CH), 0.97 (3H, s, Me), 0.89 (3H, s, Me), 0.83 (3H, s, Me)

[0073]

Embedded image

[0074]

Embedded image

[0075]

Embedded image

Preparation of ALB009, 010 Anhydrous DM was added to 15 g of ALB003 and 48.1 g of lithium iodide.
The suspension solution to which 120 ml of F was added was heated to reflux for 4 hours under a nitrogen stream. The reaction solution was transferred to chloroform and a dilute aqueous hydrochloric acid solution, and separated. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: chloroform = 6: 4 to 0:10) to have a methyl group at the 8-position and a carboxyl group at the 9-position. 3.4g of hydronaphthalene (hereinafter referred to as ALB009)
As a result, 6.2 g of hydronaphthalene (hereinafter referred to as ALB010) in which the 8-position and the 9-position are linked by a double bond was obtained. ALB009 of ¹ H-NMR and (400MHz) ALB009, ALB01
The spectrum data of ¹³ C-NMR (100 MHz) of 0 is as follows. ALB009 (CDCl ₃ , DMSO-d ₆ , ppm): 11.8 (1H, br, COOH), 5.49 (1H, br
s, vinylic CH), 2.78 (1H, brs, CH-COO), 2.03-1.16 (9H,
m, cyclic CH), 1.62 (3H, s, allylic Me), 0.94 (3H, s, M
e), 0.91 (3H, s , Me), 0.87 (3H, s, Me) (CDCl 3, DMSO-d 6, ppm): 172.3, 127.9, 121.7, 60.1, 4
7.4, 40.2, 37.8, 33.9, 31.5, 31.1, 21.7, 20.2, 19.
7, 16.8, 13.0 ALB010 (CDCl ₃ , ppm): 178.7, 138.0, 128.9, 77.3, 49.4, 41.
7, 36.1, 33.2, 31.7, 22.0, 21.3, 21.0, 18.8, 18.7,
18.5

Preparation of ALB011 1 g of ALB009 was dissolved in anhydrous THF, and red-Al (65 wt.
% In toluene) was added dropwise and stirred at room temperature for 15 hours. The reaction solution was partitioned between ethyl acetate and 2N hydrochloric acid, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8).
5:15 to 80:20), a hydronaphthalene having a methyl group at the 8-position and a hydroxymethyl group at the 9-position and having a double bond at the 7- and 8-positions (hereinafter referred to as ALB011)
590 mg (63%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm) _: 5.54 (1H, t, J = 1.95Hz, vinyl CH), 3.86 (1
H, dd, J = 2.9,11.2Hz, CH-O), 3.74 (1H, dd, J = 4.9,11.2Hz, C
HO), 1.98-1.03 (10H, m, cyclic CH), 1.79 (3H, s, allyli
c Me), 0.89 (3H, s, Me), 0.87 (6H, s, 2Me)

Preparation of ALB013 2.3 g of ALB005 and 1.69 g of phthalic anhydride were 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 saturated saline and dried over anhydrous sodium sulfate. After drying, filtration was performed, and the filtrate was distilled off under reduced pressure. The obtained white solid was washed with a small amount of ethyl acetate, and the solid was dried. (Yield 82%)
I got The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d ₆ , 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)

[0079]

Embedded image

Preparation of ALB014 10 g of ALB007 (40 ml of THF solution) was mixed with 1.75 g of lithium aluminum hydride cooled in an ice bath and TH.
F was dropped into a suspension of 20 ml. After the addition, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction solution was transferred to a mixed solution of 2N hydrochloric acid and ethyl acetate, vigorously stirred, and then separated. The organic layer was washed twice with saturated saline, dried over anhydrous sodium sulfate. The previous aqueous layer was further extracted twice with ethyl acetate, and the combined organic layers were washed with saturated saline and then dried over anhydrous sodium sulfate. After drying, the mixture was filtered, the filtrates were combined, and the solvent was distilled off under reduced pressure to obtain 7.8 g of a reaction mixture. Recrystallization and purification from ethyl acetate gave 6.4 g (80%) of hydronaphthalene having a hydroxy group at the 8-position and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB014). The structure of the compound was measured by ¹ H-NMR (400 MHz) spectral data.
Org. Chem. 59 , 5492-5495 (1994)). (CDCl ₃ , ppm) _: 4.03 (1H, d, J = 3.91Hz, OH), 4.00 (1H, m, CH-
O), 3.53 (2H, m, CH2-O), 1.83 (1H, m, cyclic CH), 1.69 (1
H, m, cyclic CH), 1.6-0.85 (10H, m, cyclic CH), 0.93 (3H,
(s, Me), 0.84 (3H, s, Me), 0.81 (3H, s, Me)

Preparation of ALB018 600 mg of ALB008, 590 mg of benzoic anhydride, and N, N
-Dimethylaminopyridine (hereinafter abbreviated as DMAP) 29mg
Was dissolved in 12 ml of pyridine and stirred at room temperature for 4 days. After a small amount of water was added to the reaction solution, pyridine was distilled off under reduced pressure, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and then dried by adding anhydrous sodium sulfate. After drying, filtration was performed, and the filtrate was concentrated under reduced pressure to obtain 900 mg of a residue. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 to 90:10) to give 700 mg of hydronaphthalene (hereinafter referred to as ALB018) having a benzoyloxy group at the 8-position and a methoxycarbonyl group at the 9-position.
%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm) _: 7.95 (2H, m, aromatic CH), 7.51 (1H, m, aromatic CH)
matic CH), 7.40 (2H, m, aromatic CH), 5.40 (1H, m, CH-O-
CO), 3.59 (3H, s, COOMe), 2.48 (1H, d, J = 11.2Hz, CH-COO),
2.42 (1H, m, cyclic CH), 1.8-1.0 (10H, m, cyclic CH),
1.10 (3H, s, Me), 0.91 (3H, s, Me), 0.86 (3H, s, Me)

Preparation of ALB019 Under nitrogen atmosphere, 4.06 g of ALB008 was dried in 50 ml of dehydrated THF.
And stirred in an ice bath. 60% NaH712m
g was added and the mixture was stirred for 20 minutes, then returned to room temperature and stirred for 1 hour. Thereafter, 1.25 ml of methyl iodide was added, and the mixture was further stirred for 14 hours. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was washed once with 2N hydrochloric acid, twice with saturated brine, and dried over anhydrous sodium sulfate. After drying, filtering and concentrating, silica gel column chromatography (n-hexane: ethyl acetate = 90:
By subjecting to 10), 4.07 g (95%) of hydronaphthalene having a methoxy group at the 8-position and a methoxycarbonyl group at the 9-position (hereinafter referred to as ALB019) was obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm) _: 3.66 (3H, s), 3.51-3.58 (1H, td), 3.30 (3H
H, s), 2.27-2.31 (1H, m), 2.09 (1H, d), 1.10-1.73 (10H,
m), 1.02 (3H, s), 0.88 (3H, s), 0.82 (3H, s)

Preparation of ALB020 When ALB008 was subjected to Swern oxidation, hydronaphthalene having a methylthiomethyloxy group at the 8-position and a methoxycarbonyl group at the 9-position (hereinafter referred to as ALB020) was also obtained. Part ¹ H-NMR
The (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm) _: 4.63 (1H, d, J = 11.2Hz, O-CH-S), 4.59 (1H,
d, J = 11.2Hz, O-CH-S), 3.99 (1H, dt, J = 5.4,11.2Hz, CH-O),
3.65 (3H, s, COOMe), 2.30 (1H, m, cyclic CH), 2.18 (1H,
d, J = 11.2Hz, CH-COO), 2.10 (3H, s, S-Me), 1.72 (1H, m, cyc
lic CH), 1.69-1.13 (10H, m, cyclic CH), 1.03 (3H, s, M
e), 0.93 (1H, m, cyclic CH), 0.88 (3H, s, Me), 0.82 (3H, s,
Me)

Preparation of ALB021 700 mg of ALB011 was dissolved in 15 ml of ethyl acetate, and
20 mg of palladium on carbon (Pd / C) was added. The inside of the reaction vessel was set to a hydrogen atmosphere, and vigorously stirred at room temperature for 7 days.
The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 85: 15) to give 8
Hydronaphthalene having a methyl group at the 9-position and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB021) 507 mg (72%)
I got The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d ₆ , ppm): 4.08 (1H, dd, J = 2.0,3.9Hz, OH), 3.59 (1
H, m, CH-O), 3.32 (1H, m, CH-O), 2.11 (1H, m, cyclic CH),
1.66-1.12 (10H, m, cyclicCH), 0.92 (2H, m, cyclicCH),
0.89 (3H, d, J = 7.3Hz, Me), 0.83 (3H, s, Me), 0.80 (3H, s, M
e), 0.79 (3H, s, Me)

Preparation of ALB023 260 mg of ALB019 was dissolved in 10 ml of THF under a nitrogen atmosphere and stirred in an ice bath. To it was added 45 mg of LiAlH ₄ and stirred for 15 minutes. After further stirring at room temperature for 1 hour, the reaction solution was diluted by adding ethyl acetate, and this was diluted with 2N
The extract was washed once with hydrochloric acid, further twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration, the residue was subjected to silica gel column chromatography (N-hexane: ethyl acetate = 80: 20) to obtain 101 mg of hydronaphthalene having a methoxy group at the 8-position and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB023). . Part ¹ H-NMR
The (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm) _: 3.78-3.81 (2H, d), 3.60-3.63 (1H, m), 3.4
0 (3H, s), 2.26-231 (1H, m), 0.95-1.79 (11H, m), 0.88 (3
H, s), 0.79 (3H, s), 0.78 (3H, s)

Preparation of ALB024 Under a nitrogen atmosphere, 400 mg of ALB019 was dissolved in 20 ml of DMF and stirred, to which 1200 mg of LiI and 200 μl of formic acid were added, followed by stirring at 145 ° C. for 4 days. Thereafter, the reaction solution was diluted by adding ethyl acetate, washed with 2N hydrochloric acid once, further washed with saturated saline twice, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 70: 30) to give hydronaphthalene having a methoxy group at the 8-position and a carboxyl group at the 9-position (hereinafter ALB0).
150 mg (40%) was obtained. Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (CDCl ₃ , ppm) _: 3.50-3.57 (1H, td), 3.33 (3H, s), 2.28-23
3 (1H, m), 2.11-2.14 (1H, d), 1.12-1.74 (11H, m), 1.04 (3
H, s), 0.89 (3H, s), 0.83 (3H, s)

Preparation of ALB082 230 mg of ALB014 was dissolved in 10 ml of DMF, and dissolved in 150 ml of DMF.
μl of pyridine was added, 700 μl of phenyl isocyanate was added thereto, and the mixture was stirred at room temperature for 1 hour. After further stirring at 40 ° C. for 2 hours, the reaction solution was diluted by adding ethyl acetate, washed with saturated saline twice, and dried by adding anhydrous sodium sulfate. After drying and filtration, the filtrate is concentrated, hexane is added to the residue to remove insolubles, and then subjected to silica gel column chromatography (n-hexane: ethyl acetate = 80: 20), and represented by the following structural formula. 280 mg (60%) of compound (hereinafter referred to as ALB082)
I got The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO, ppm): 9.45 (1H, s), 9.34 (1H, s), 7.42 (4H, d), 7.
21 (4H, t), 6.93 (2H, t), 4.80-4.90 (1H, m), 4.10-4.30 (2
H, m), 2.22 (1H, m), 1.05-1.85 (11H, m), 0.96 (3H, s), 0.
89 (3H, s), 0.83 (3H, s)

[0088]

Embedded image

測定 Measurement of Compound Properties Tables 9 and 10 show the results of the antifungal activity and the infection treatment test of each prepared compound.

[0090]

[Table 9]

[0091]

[Table 10]

Example 6 Preparation of Compound Preparation of ALB030 9 g of sclareolide was suspended in 300 ml of p-dioxane, and 200 ml of a 28% aqueous ammonia solution was added.
Stirred for days. The solvent was distilled off under reduced pressure and dried to give a hydronaphthalene having a methyl group, a hydroxy group at the 8-position and a carbamoylmethyl group at the 9-position (hereinafter referred to as ALB030) 10.69.
g obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d ₆ , ppm): 7.18 (1H, brs, NH), 6.63 (1H, brs, NH),
4.22 (1H, s, OH), 2.25 (1H, dd, J = 3.41,15.6Hz, CH-CO), 2.
00 (1H, dd, J = 6.8,15.6Hz, CH-CO), 1.72 (2H, m, cyclic C
H), 1.57-1.08 (8H, m, cyclic CH), 0.95 (3H, s, Me), 0.92
(2H, m, cyclic CH), 0.84 (3H, s, Me), 0.76 (3H, s, Me), 0.7
5 (3H, s, Me)

Preparation of ALB031 5 g of ALB030 was dissolved in a mixed solvent of 80 ml of acetonitrile and 20 ml of water, 8.8 g of bis (trifluoroacetoxy) iodobenzene was added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 98: 98).
Hydronaphthalene having a methyl group, a hydroxy group at the 8-position and an aminomethyl group at the 9-position
1.72 g (hereinafter referred to as ALB031) were obtained. Its ¹ H-NMR (40
0 MHz) The spectral data were as follows, and ninhydrin coloration was positive. (CDCl ₃ , ppm) _: 3.26 (2H, m, CH2-N), 2.03 (1H, m, cyclic C
H), 1.79-1.18 (9H, m, cyclic CH), 1.40 (3H, s, Me), 1.04
(2H, m, cyclic CH), 0.90 (3H, s, Me), 0.87 (3H, s, Me), 0.
82 (3H, s, Me)

Preparation of ALB073 254 mg of AT-1 and 100 μl of pyridine were added to 10 ml of THF.
And stirred with phenyl isocyanate 250
μl was added and stirred at room temperature for 4 hours. Thereafter, the reaction solution was diluted by adding chloroform, washed twice with a saturated saline solution, and dried by adding anhydrous sodium sulfate. After drying, filtration, the filtrate was concentrated, dissolved in n-hexane, insolubles were removed, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30). (Hereinafter referred to as ALB073) 29
5 mg (80%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d ₆ , ppm): 9.48 (1H, s, NH), 7.43-7.46 (2H, d), 7.2
3-7.29 (2H, t), 6.96-6.98 (1H, d), 3.99-4.19 (2H, m), 1.
04-1.80 (14H, m), 1.03 (3H, s), 0.85 (3H, s), 0.77 (3H,
s), 0.75 (3H, s)

[0095]

Embedded image

Preparation of ALB074 254 mg of AT-1 and 100 μl of pyridine were added to 10 ml of THF.
And 800 μl of phenyl isocyanate was added thereto, followed by stirring at 50 ° C. for 14 hours. Thereafter, chloroform was added to the reaction solution to dilute the solution, which was diluted with saturated saline solution.
It was washed twice and dried by adding anhydrous sodium sulfate. After drying, filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10).
And purified by a compound represented by the following structural formula (hereinafter ALB074).
400 mg (85%). Part ¹ H-NMR (400MHz)
The spectrum data is as follows. _{(DMSO-d 6, ppm)} : 9.54 (1H, s, NH), 9.04 (1H, s, NH), 7.45
(4H, d), 7.25 (4H, t), 6.96 (2H, m), 4.05-4.25 (2H, m),
0.95-1.95 (17H, m), 0.87 (3H, s), 0.83 (3H, s), 0.79 (3H,
s)

[0097]

Embedded image

Preparation of ALB075 256 mg of AT-1 was dissolved in 5 ml of DMF and pyridine 10
0 μl was added, and 250 μl of cyclohexyl isocyanate was added thereto, followed by stirring at room temperature for 15 hours. Thereafter, chloroform was added to the reaction solution to dilute it.
The extract was washed once with N hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 90: 10 to 70:30) to obtain 245 mg (65%) of a compound represented by the following structural formula (hereinafter referred to as ALB075). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d ₆ , ppm): 6.83 (2H, d, NH), 3.80-4.10 (3H, m), 1.0
2-1.80 (20H, m), 1.01 (3H, s), 0.84 (6H, s), 0.76 (3H, s),
0.72 (3H, s)

[0099]

Embedded image

Preparation of ALB076 256 mg of AT-1 and 100 μl of pyridine were added to 5 ml of DMF and stirred, and 200 μl of α, α, α-trifluorotolyl isocyanate was added thereto, followed by stirring at room temperature for 14 hours. Thereafter, chloroform was added to the reaction solution to dilute it, which was washed once with 2N hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-7).
0:30) to give 210 mg (48%) of a compound represented by the following structural formula (hereinafter referred to as ALB076). Part ¹ H-NMR
The (400 MHz) spectrum data is as follows. (DMSO-d ₆ , ppm): 7.55-7.70 (4H, q), 3.00-4.25 (2H, m),
1.05-1.80 (15H, m), 1.04 (3H, s), 0.84 (3H, s), 0.77 (3H,
s), 0.75 (3H, s)

[0101]

Embedded image

Preparation of ALB084 A suspension of 6.28 g of NaH (60% in oil) in 40 ml of THF was cooled on ice and 100 ml of dehydrated THF containing 20 g of AT-1.
The solution was added dropwise and stirred at room temperature for 1 hour. Thereafter, 18.7 ml of benzyl bromide was added all at once, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was partitioned between ethyl acetate and 2N hydrochloric acid, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate.
After drying, filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1).
８8: 2) to give the reaction product (28.3 g, Rf = 0.5 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2).
After dissolving in ice-cold solution and adding 6.74 ml of mesyl chloride, the ice bath was removed and the mixture was stirred at room temperature for 15 hours. After adding a small amount of water, pyridine was distilled off, and the residue was mixed with ethyl acetate.
After liquid separation with N hydrochloric acid, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5) to give a compound represented by the following structural formula
6.12 g (43%) (hereinafter referred to as ALB084) were obtained. Rf was 0.68 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 9: 1).

[0103]

Embedded image

Preparation of ALB085 4 g of ALB084 was added to 40 ml of carbon tetrachloride and 4 parts of acetonitrile
The suspension was suspended in a mixture of 0 ml and 60 ml of water, 21 g of sodium periodate and 150 mg of ruthenium trichloride were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was separated between ethyl acetate and water, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was extracted again with ethyl acetate, and the organic layer was washed with saturated saline and 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 = 9: 1) to give 1.38 g (39%) of a compound represented by the following structural formula (hereinafter referred to as ALB085). ) Was obtained. Its ¹ H-NMR (400 MHz) spectrum data was as follows, and Rf was 0.27 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 9: 1). (CDCl ₃ , ppm) _: 7.31 (5H, m, Ph), 4.49 (1H, d, J = 12.21Hz, CH
-Ph), 4.41 (1H, d, J = 12.21Hz, CH-Ph), 3.52 (1H, m, CH-O),
3.28 (1H, m, CH-O), 2.40 (1H, m, 7-CH), 2.26 (2H, m, 7-CH)
and 9-CH), 2.0 (2H, m, cyclic CH and CH-CH2-O), 1.8-
1.4 (7H, m, cyclicCH and CH-CH2-O), 1.3-1.1 (2H, m, cycl
ic CH), 0.96 (3H, s, Me), 0.85 (3H, s, Me), 0.72 (3H, s, Me)

[0105]

Embedded image

Preparation of ALB086 6 g of ALB084 was dissolved in 70 ml of dehydrated chloroform, 5.4 g of m-chloroperbenzoic acid was added in three portions, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with chloroform, washed three times with an aqueous sodium hydrogen carbonate solution and once with a saturated saline solution, and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5-9).
0:10), a compound represented by the following structural formula (hereinafter A)
3.37 g (70%) of LB086). Rf is 0.5
(Silica gel thin layer chromatography, n-hexane: ethyl acetate = 9: 1).

[0107]

Embedded image

Preparation of ALB067 2 g of ALB086 was dissolved in 10 ml of THF, 2 ml of a 70% sodium perchlorate aqueous solution was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After drying, the mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 to 7: 3). As a result, 341 mg (22%) of hydronaphthalene having an ethyl group (hereinafter referred to as ALB067) and 227 mg (11%) of its benzyl ether compound were obtained. ALB067 of ¹ H-NMR (40
(0 MHz) The spectral data was as follows, and Rf was 0.15 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2). (DMSO-d6): 4.60 (1H, t, J = 5.9Hz, -OH), 4.44 (1H, s, -OH),
3.65 (1H, m, CH-O), 3.56 (1H, dd, J = 8.3,16.1Hz, CH-O),
3.10 (1H, dd, J = 5.9,10.7Hz, CH-O), 2.87 (1H, dd, J = 5.9,1
0.7Hz, CH-O), 1.93 (1H, m, CH-CH2-O), 1.79-1.05 (11H, m,
cyclic CH and CH-CH2-O), 0.89-0.75 (2H, m, cyclic C
H), 0.87 (3H, s, Me), 0.85 (3H, s, Me), 0.84 (3H, s, Me)

Preparation of ALB068 326 mg of ALB086 was dissolved in 4 ml of THF, 0.4 ml of a 70% aqueous sodium perchlorate solution was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 to 8: 2).
Hydronaphthalene having a methyl group and a hydroxy group at the 8-position, a hydroxyethyl group and a hydroxy group at the 9-position
179 mg (hereinafter referred to as ALB068) were obtained. Its ¹ H-NMR (40
(0 MHz) The spectral data was as follows, and Rf was 0.3 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2). (DMSO-d6): 4.47 (1H, s, -OH), 3.73 (1H, m, CH-O), 3.45 (1
H, m, CH-O) , 2.01 (1H, m, CH-CH 2 -O), 1.81-1.05 (12H, m, cy
clic CH and CH-CH ₂ -O), 1.02 (6H, s, Me * 2), 0.85 (3H, s,
Me), 0.82 (3H, s, Me)

Preparation of ALB071 500 mg of ALB086, 503 mg of 1,2,4-triazole and 817 mg of potassium t-butoxide were suspended in 15 ml of dehydrated DMF, and heated under reflux for 15 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 then dried over anhydrous sodium sulfate. The aqueous layer was further extracted twice with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3 to 5: 5,
Chloroform: methanol = 7: 3) to obtain 606 mg of a reaction product. Rf was 0.23 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 6: 4). 600 mg of the above reaction product dehydrated chloroform 2
The 0 ml solution was cooled to -70 ° C, 1.6 ml of 1M boron trichloride / dichloromethane was added, and the mixture was stirred at 0 ° C for 2 hours. The reaction solution was partitioned between chloroform and an aqueous sodium hydrogen carbonate solution, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was extracted again with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After drying, filtration, the filtrate is concentrated and subjected to silica gel column chromatography (chloroform: methanol = 98: 2 to 9: 1) to give a 1-triazolylmethyl group and a hydroxy group at the 8-position, and a hydroxyethyl group at the 9-position. Hydronaphthalene (hereinafter ALB0)
212 mg (45%) was obtained. Part ¹ H-NMR (400MH
z) The spectrum data is as follows, and Rf is 0.3
8 (silica gel thin layer chromatography, chloroform: methanol = 9: 1). (DMSO-d6): 8.32 (1H, s, CH of triazole), 7.88 (1H, s, CH
of triazole), 4.29 (1H, d, J = 14.2Hz, CH-N), 4.15 (1H,
d, J = 14.2Hz, CH- N), 3.44 (2H, m, CH 2 -O), 1.76-1.3 (9H, m,
cyclic CH and 9-CH ₂ ), 1.15-0.8 (5H, m, cyclic CH), 0.
86 (3H, s, Me), 0.85 (3H, s, Me), 0.80 (3H, s, Me)

Preparation of ALB087 Literature (Helvetica Chimica Acta, Vol. 73, 1935-1947 (19
4,4-dimethyl-8-epoxy-9 obtained by the method of 90))
294 mg of a decahydronaphthalene compound having a -hydroxyethyl group introduced therein was dissolved in 5 ml of morpholine, 212 mg of lithium perchlorate was added, and the mixture was stirred at 140 ° C. for 8 hours.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 90: 10) to obtain 250 mg of a compound represented by the following structural formula (hereinafter referred to as ALB087). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 3.58 (4H, t), 3.54 (2H, t), 2.40-2.60 (4
H, m), 2.00-2.28 (2H, m), 1.00-1.8 (14H, m), 0.84 (3H, s)
, 0.77 (3H, s), 0.73 (3H, s)

[0112]

Embedded image

測定 Measurement of Compound Properties Tables 11 and 12 show the results of the antifungal activity and infection treatment test of each prepared compound.

[0114]

[Table 11]

[0115]

[Table 12]

Example 7 Preparation of compound Preparation of ALB035 A solution of 5 g of ALB014 and 3.31 g of imidazole in 150 ml of dehydrated chloroform was cooled in an ice bath, and 3.5 g of t-butyldimethylsilyl chloride was added. Stir for 15 hours. The reaction solution was partitioned between chloroform and 2N hydrochloric acid, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
95: 5 to 90:10) to give a reaction product.
Swern oxidation was performed using the above reaction product as a raw material, and the resulting reaction mixture was subjected to silica gel column chromatography.
(n-hexane: ethyl acetate = 98: 2 to 95: 5) to obtain 4.2 g (75%) of a compound represented by the following structural formula (hereinafter referred to as ALB035). Rf is 0.41 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 9)
5: 5).

[0117]

Embedded image

Preparation of ALB044 2 g of ALB035 was dehydrated in a stream of nitrogen under a stream of nitrogen.
and cooled to -20 ° C. 5.6 ml of 1.6M n-butyllithium was slowly added dropwise thereto, followed by stirring at 0 ° C. for 2 hours. The reaction solution was partitioned between ethyl acetate and 2N hydrochloric acid,
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)
8: 2) to obtain 2.1 g of a reaction product. A solution of the reaction product in 15 ml of dehydrated THF was cooled in an ice bath, 8 ml of a 1 M tetrabutylammonium fluoride / THF solution was added, and the mixture was stirred at room temperature for 15 hours. The solvent is distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 80: 20-75: 25) to give 8
Hydronaphthalene having an n-butyl group, a hydroxy group and a hydroxymethyl group at the ninth position (hereinafter referred to as ALB044)
900 mg (54%) were obtained. Its ¹ H-NMR (400 MHz) and ¹³ C-
NMR (100 MHz) spectrum data is as follows. (DMSO-d6, ppm): 4.99 (1H, t, J = 4.4Hz, OH), 3.98 (1H, s, O
H), 3.74 (1H, m, CH-O), 3.60 (1H, m, CH-O), 1.80 (1H, m, cy
clic CH), 1.6-1.05 (14H, m, cyclic CH), 1.02 (3H, s, M
e), 0.90-0.72 (6H, m, Me and cyclic CH), 0.84 (3H, s, M
e), 0.80 (3H, s, Me) (DMSO-d6, ppm): 79.15, 73.64, 57.
66, 57.09, 55.17, 42.46, 41.64, 38.07, 37.73, 33.4
8, 32.95, 25.95, 23.08, 21.65, 18.01, 17.90, 16.3
4, 14.12

Preparation of ALB045 7 g of ALB035 was placed in a 40 ml solution of dehydrated THF under a nitrogen stream, cooled in an ice bath, and 31 ml of a 1 M tetrabutylammonium fluoride / THF solution was added thereto, followed by stirring at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8:
2-7: 3) to give hydronaphthalene having a carbonyl group at the 8-position and a hydroxymethyl group at the 9-position (hereinafter ALB0).
3.45 g (74%) were obtained. Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (CDCl ₃ , ppm) _: 3.96 (1H, dd, J = 9.3,11.2Hz, CH-O), 3.60 (1
H, br, CH-O), 2.46 (1H, ddd, J = 2.0,4.9,14.2Hz, CH-CO),
2.31 (2H, m, CH-CO and CH-CO), 2.03 (1H, m, cyclicCH),
1.73-1.23 (8H, m, cyclic CH), 0.97 (3H, s, Me), 0.86 (3H,
(s, Me), 0.80 (3H, s, Me)

Preparation of ALB042 Under nitrogen atmosphere, 380 mg of ALB008 was dehydrated in 20 ml of THF.
And stirred in an ice bath, to which was added 66 mg of NaH.
Stirred for 20 minutes. After further stirring at room temperature for 1 hour, 300 mg of benzyl bromide was added and stirred. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was washed once with 2N hydrochloric acid and twice with saturated brine, and dried over anhydrous sodium sulfate. After drying, filtration, the filtrate was concentrated and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10) to give a benzyloxy group at the 8-position.
Hydronaphthalene having a methoxycarbonyl group at the 9-position
500 mg (97%) of ALB042 was obtained.

Preparation of ALB046 To a solution of 4.9 g of ALB008 and 7.54 g of DMAP in 50 ml of dehydrated acetonitrile, a solution of 4 ml of phenylchlorothionoformate in 30 ml of dehydrated acetonitrile was slowly dropped, followed by stirring for 15 hours while heating to 40 ° C. . 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. After drying, filtration and concentration of the filtrate, silica gel column chromatography (n-hexane: ethyl acetate = 85: 1)
5), a compound represented by the following structural formula (hereinafter ALB04)
6). Its ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf was 0.57 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8:
2). (CDCl ₃ , ppm) _: 7.39 (2H, m, aromatic CH), 7.26 (1H, m, aromatic CH)
matic CH), 7.05 (2H, m, aromatic CH), 5.62 (1H, dt, J = 5.
4,11.2Hz, CH-O), 3.70 (3H, s, COOMe), 2.58 (1H, m, cyclic
CH), 2.47 (1H, d, J = 11.2Hz, CH-COO), 1.78 (1H, m, cyclic
CH), 1.60-1.20 (8H, m, cyclic CH), 1.07 (3H, s, Me), 1.
02 (1H, m, cyclic CH), 0.91 (3H, s, Me), 0.84 (3H, s, Me)

[0122]

Embedded image

Preparation of ALB049 Under a nitrogen atmosphere, 2 g of ALB008 was dissolved in 40 ml of dehydrated THF, cooled in an ice bath, and 355 mg of NaH was added thereto.
Stirred for minutes. After further stirring at room temperature for 30 minutes, 1.1 g of ant iodide was added and stirred for 2 hours. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was washed once with 2N hydrochloric acid, twice with saturated brine, and dried over anhydrous sodium sulfate. After drying and filtration, the filtrate is concentrated and then subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10). Hydronaphthalene (hereinafter referred to as ALB049)
2.0 g (97%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm) _: 5.8-5.9 (1H, m), 5.08-5.22 (2H, dd), 3.88
-4.08 (2H, m), 3.69-3.73 (1H, m), 3.66 (3H, s), 2.21-2.2
6 (1H, m), 2.15 (1H, d), 1.14-1.72 (10H, m), 1.02 (3H, s),
0.88 (3H, s), 0.82 (3H, s)

[0124]

Embedded image

Preparation of ALB050 300 mg of ALB049 was dissolved in 10 ml of dehydrated chloroform and stirred. Thereto was added 50 mg of palladium carbon, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. Chloroform was added to this reaction solution to dilute it, and the organic layer was washed twice 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 = 90: 1)
By subjecting to 0), 235 mg (78%) of hydronaphthalene (hereinafter referred to as ALB050) having a propyloxy group at the 8-position and a methoxycarbonyl group at the 9-position represented by the following structural formula was obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 3.65 (3H, s), 3.54-3.63 (1H, m), 3.20-3.5
4 (2H, m), 2.1-2.26 (2H, m), 1.12-1.71 (12H, m), 1.02 (3
H, s), 0.87 (3H, t), 0.85 (3H, s), 0.82 (3H, s)

[0126]

Embedded image

Preparation of ALB051 1.25 g of ALB008 and 73 mg of DMAP were added to pyridine 2
0 ml and stirred at room temperature. 780 mg of succinic anhydride
Was added and stirred for 2 hours. After concentrating the reaction solution to about half the volume, ethyl acetate was added to dilute the solution.
The mixture was washed once with hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue was subjected to silica gel column chromatography (chloroform: methanol = 80: 20), and 1.05 g of a compound represented by the following structural formula (hereinafter referred to as ALB051) was obtained.
(60%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 4.95-5.05 (1H, td), 3.57 (3H, s), 2.39
(4H, s), 2.25-2.30 (1H, d), 0.98-1.70 (10H, m), 2.00-2.
15 (1H, m), 0.95 (3H, s), 0.86 (3H, s), 0.79 (3H, s)

[0128]

Embedded image

Preparation of ALB054 2.00 g (8.99 mmol) of ALB005 was added to methylene chloride 20.
Dissolved in 0 ml, and sodium hydrogen carbonate (1.21 g, 14.4 mm)
ol) and cooled to -78 ° C under a nitrogen atmosphere. 3.32 g (13.5 mmol) of 70% mCPBA was added to the reaction solution, and the mixture was stirred overnight while warming to room temperature. 200 ml of 0.5M ferric sulfate was added to the reaction solution, and the mixture was extracted twice with ether. The obtained organic layers were combined, and saturated aqueous sodium hydrogen carbonate solution was added for 1 hour.
It was washed once with saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (16% ethyl acetate / hexane) to give an oily compound represented by the following structural formula (hereinafter referred to as an oily compound). 1.44 g (referred to as ALB054) (yield: 67%)
Obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 3.64 (1H, ddd, J = 11.2,10.8,2.9Hz), 3.41
(1H, dd, J = 11.2,10.8Hz), 3.22 (1H, dd, J = 3.4,2.0Hz), 3.1
2 (1H, d, J = 10.8Hz), 2.72 (1H, d, J = 3.4Hz), 2.01-1.82 (3
H, m), 1.70-1.39 (6H, m), 1.21 (2H, dt, J = 12.7,4.4Hz),
1.08 (1H, dd, J = 12.7,2.9Hz), 0.91 (3H, s), 0.85 (3H, s),
0.84 (3H, s)

[0130]

Embedded image

Preparation of ALB 055 477 mg (12.6 mmol) of lithium aluminum hydride was suspended in 30 ml of THF under a nitrogen atmosphere.
A solution of 0 mg (2.10 mmol) in THF (15 ml) was added under ice cooling.
Stirred at room temperature for 2 hours. The reaction mixture was ice-cooled, 2N hydrochloric acid was added, ethyl acetate was added, and the mixture was washed three times with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give a colorless needle compound represented by the following structural formula.
415 mg (yield: 84%) were obtained (hereinafter referred to as ALB055). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 3.92 (2H, d, J = 6.8Hz), 3.33 (1H, brs), 2.8
6 (1H, brs), 1.89 (1H, dt, J = 3.4,12.2Hz), 1.76-1.07 (10
H, m), 1.35 (3H, s), 0.97 (1H, dd, J = 12.2,2.0Hz), 0.88 (3
H, s), 0.79 (6H, s)

[0132]

Embedded image

Preparation of ALB056 500 mg of ALB008 and isopropyl isocyanate 1
90 mg was added to 10 ml of dehydrated THF and stirred. Further, 500 μl of triethylamine was added and the mixture was stirred at room temperature for 1 hour, and then at 40 ° C. for 4 hours. The reaction solution was diluted by adding chloroform, and the organic layer was diluted with 2N hydrochloric acid for 1 hour.
The mixture was washed twice with saturated saline, and 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 = 80: 20) to give 250 mg (38%) of a compound represented by the following structural formula (hereinafter referred to as ALB056).
I got The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.98-5.07 (1H, m), 3.73-3.79 (1H, m), 3.6
5 (3H, s), 3.49 (1H, d), 2.19-2.33 (2H, m), 1.13-1.71 (13
H, m), 1.12 (3H, s), 1.10 (3H, s), 0.88 (3H, s), 0.83 (3H,
s)

[0134]

Embedded image

Preparation of ALB058 750 mg of ALB049 was dissolved in 50 ml of dehydrated chloroform, 1.2 g of 85% mCPBA was added little by little with stirring, and the mixture was stirred for 3 days. The reaction solution is concentrated and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8
0:20) to give 386 mg (49%) of a hydronaphthalene having a 2,3-epoxypropyloxy group at the 8-position and a methoxycarbonyl group at the 9-position (hereinafter referred to as ALB058).

Preparation of ALB059 ALB054 (480 mg, 2.01 mmol) was dissolved in DMF (10 ml), sodium azide (653 mg, 10.0 mmol) was added, and the mixture was stirred at 120 ° C. for 20 hours. After the reaction solution was cooled to room temperature, ether was added thereto, and the mixture was washed three times with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (16% ethyl acetate / hexane).
254 mg (yield: 45%) of hydronaphthalene having an azidomethyl group and a hydroxy group at the 8-position and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB059) was obtained as a yellow solid.
The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 3.94 (2H, d, J = 7.8Hz), 3.68 (1H, dd, J = 12.
2,2.0Hz), 3.54 (1H, d, J = 12.2), 3.45 (1H, brs), 305 (1H,
brs), 2.20 (1H, dt, J = 12.7,2.9Hz), 1.78-0.99 (11H, m),
0.89 (3H, s), 0.79 (6H, s)

Preparation of ALB060 Under a nitrogen atmosphere, 105 mg of Nt-Boc-phenylalanine was dissolved in toluene, and 50 μl of triethylamine was added while stirring in an ice bath. To this reaction solution, 50 μl of pivaloyl chloride was added and stirred for 15 minutes. After returning to room temperature and stirring for another 1 hour, the solvent was removed under reduced pressure. To 50 mg of ALB008, 2 ml of pyridine was added and stirred, and the residue was dissolved in 3 ml of pyridine and added. Further, 10 mg of DMAP was added and the mixture was stirred at 40 ° C. for 2 hours.
Pyridine was reduced to half volume under reduced pressure, and ethyl acetate was added. The organic layer was washed once with 2N hydrochloric acid and twice with saturated brine,
Anhydrous sodium sulfate was added and dried. After drying, filtration,
The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10).
Compound represented by the following structural formula (hereinafter referred to as ALB060) 9
8 mg (98%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 7.12-7.31 (5H, m), 5.17-5.24 (1H, td), 4.
43-4.46 (1H, m), 3.62 (3H, s), 2.79-3.09 (2H, m), 2.1-2.
4 (2H, m), 1.15-1.80 (19H, m), 1.08 (3H, s), 0.89 (3H, s),
0.83 (3H, s)

[0138]

Embedded image

Preparation of ALB061 To 98 mg of ALB060 was added 1 ml of trifluoroacetic acid.
Stir in an ice bath and after 5 minutes the trifluoroacetic acid was removed under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: methanol = 70: 30), 78 mg of a compound represented by the following structural formula (hereinafter referred to as ALB061)
(100%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 7.15-7.30 (5H, m), 5.18-5.30 (1H, m), 3.6
5-4.00 (1H, m), 3.62 (3H, s), 2.82-3.20 (2H, m), 2.2-2.4
(2H, m), 1.12-1.80 (10H, m), 0.98 (3H, s), 0.86 (3H, s),
0.81 (3H, s)

[0140]

Embedded image

Preparation of ALB062 Under nitrogen atmosphere, 215 mg of Nt-butoxycarbonyl-L-
Dissolve proline in toluene and, with stirring in an ice bath,
140 μl of triethylamine was added and stirred. After adding 125 μl of pivaloyl chloride to the reaction solution, the temperature was returned to room temperature, and the mixture was further stirred for 2 hours. Then, insolubles were removed, and the solvent was removed under reduced pressure. 125 mg of ALB008 was added to 2 ml of pyridine and stirred, and the residue obtained above was dissolved in 3 ml of pyridine and added. Further, 10 mg of DMAP was added and the mixture was stirred at 40 ° C. for 1 hour. Pyridine was reduced to half the volume under reduced pressure, and ethyl acetate was added.
The mixture was washed twice with saturated saline, and dried over anhydrous sodium sulfate. After drying, filtration and concentration, the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10) to give a compound represented by the following structural formula
220 mg (97%) of ALB062 was obtained. Part ¹
H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 5.1-5.25 (1H, m), 4.1-4.3 (1H, m), 3.62 (3
H, s), 3.3-3.5 (2H, m), 2.28-2.32 (2H, m), 1.1-2.0 (23H,
m), 1.01 (3H, s), 0.88 (3H, s), 0.83 (3H, s)

[0142]

Embedded image

Preparation of ALB063 100 mg of ALB062 was added to 1 ml of trifluoroacetic acid, cooled in an ice bath and stirred. After 5 minutes, trifluoroacetic acid was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 90: 10).
Compound represented by the following structural formula (hereinafter referred to as ALB063) 7
7 mg (100%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 5.21-5.28 (1H, m), 3.99-4.13 (1H, m), 3.6
5 (3H, s), 3.16-3.25 (2H, m), 2.3-2.38 (2H, m), 1.1-2.0
(15H, m), 1.01 (3H, s), 0.89 (3H, s), 0.82 (3H, s)

[0144]

Embedded image

Preparation of ALB064 Under a nitrogen stream, 800 mg of ALB035 was dehydrated into 10 ml of dehydrated THF.
And cooled to -20 ° C. 3.6 ml of 2M cyclohexylmagnesium chloride were slowly added dropwise thereto and then stirred at room temperature for 2 hours. Further, the mixture was heated to 60 ° C. and stirred for 7 hours. The reaction solution was partitioned between ethyl acetate and 2N hydrochloric acid, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying and filtration and concentration, dehydration T
It was dissolved in 10 ml of HF, and 3.6 ml of a 1 M tetrabutylammonium fluoride / THF solution was added in an ice bath, followed by stirring at room temperature for 3 days. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 to 8: 2) to have a cyclohexyl group and a hydroxy group at the 8-position, and a hydroxymethyl group at the 9-position. Hydronaphthalene (hereinafter referred to as ALB064) 200 mg (2
7%). Its ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf is 0.48 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2).
It is. (DMSO-d6, ppm): 4.65 (1H, m, OH), 3.99 (1H, s, OH), 1.9-
0.68 (32H, m, cyclic CH and Me * 3)

Preparation of ALB065 254 mg of ALB008 and 100 μl of pyridine were dehydrated in THF.
10 ml and stirred.
50 mg was added and the mixture was stirred at room temperature for 4 hours. Thereafter, chloroform was added to this reaction solution to dilute it, and the organic layer was washed once with 2N hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration, the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-70: 30), 210 mg (57%) of a compound represented by the following structural formula (hereinafter referred to as ALB065) I got The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 7.06-7.37 (5H, m), 5.17-5.18 (1H, td), 3.
67 (3H, s), 2.32-2.45 (1H, m), 2.30 (1H, d), 1.07-1.80 (1
0H, m), 1.00 (3H, s), 0.90 (3H, s), 0.86 (3H, s)

[0147]

Embedded image

Preparation of ALB066 In a nitrogen atmosphere, 290 mg of potassium t-butoxide was dehydrated by T
Stir in 5 ml of HF, 200 mg of 1,2,4-triazole
Was dissolved in 2 ml of DMF and added and stirred for 15 minutes. Further, 100 mg of ALB058 was added, and the mixture was stirred at 80 ° C. for 4 hours. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was washed twice with a saturated saline solution, dried over anhydrous sodium sulfate. After drying, filtration and concentration, the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 95: 5), and a 2-hydroxy-3- (1-triazolyl) propyloxy group was placed at the 8th position, and a 9th position. Having a methoxycarbonyl group (hereinafter AL)
360 mg (referred to as B066) were obtained.

測定 Measurement of Compound Properties Tables 13 and 14 show the antifungal activity and the results of infection treatment tests of the prepared compounds.

[0150]

[Table 13]

[0151]

[Table 14]

Example 8 Preparation of Compound Preparation of ALB203 7.71 ml of DMSO cooled to -70 ° C. under a nitrogen stream.
Was slowly added dropwise to a solution of 8.52 ml of trifluoroacetic anhydride in 40 ml of methylene chloride over 30 minutes. After stirring for another 30 minutes, AT-6
A solution of 2 g of methylene chloride in 40 ml was slowly added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. Triethylamine 1
After slowly adding 6.8 ml dropwise over 30 minutes, the mixture was stirred for another 2 hours except for the dry ice bath. 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).
, A methyl group, a methoxymethyloxy group at the 8-position, 9
Thus, 7.06 g (59%) of hydronaphthalene having a formylmethyl group at the 1-position (hereinafter referred to as ALB203) was obtained. Part ¹ H-NMR
(400 MHz) The spectrum data is as follows:
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)

Preparation of ALB204 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, heated to 80 ° C. and stirred for 1 hour. 6.9 g of ALB203 in DMSO 30m
l, add to the reaction solution, and heat to 80 ° C while heating.
Stir for 5 hours. 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 are 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) to obtain a compound represented by the following structural formula (hereinafter referred to as ALB204) 7.2.
2 g (85%) were obtained. The ¹ H-NMR (400 MHz) 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)

[0154]

Embedded image

Preparation of ALB205 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)

[0156]

Embedded image

Preparation of ALB206 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. After adding 1.1 g of succinic anhydride thereto, 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 solution, which was washed once with 2N hydrochloric acid and twice with a saturated saline solution.
Anhydrous sodium sulfate was added and dried. Concentrate the filtrate,
The residue was subjected to silica gel column chromatography (chloroform: methanol = 80: 20) to obtain 3.3 g of a compound represented by the following structural formula (hereinafter referred to as ALB206) (95).
%). 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)

[0158]

Embedded image

Preparation of ALB207 Under a nitrogen stream, a solution of 1.1 g of ALB205 in 15 ml of dehydrated THF was cooled to -78 ° C., and 1.7 ml of 2M lithium diisopropylamide was slowly added dropwise. After stirring at that temperature for 30 minutes, 800 mg of diethyl malonate dehydrated TH
A 5 ml solution of F 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 extracted again with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying and filtration, the filtrate is concentrated and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 to 7: 3) to give a compound represented by the following structural formula (hereinafter referred to as ALB207).
860 mg (53%) were obtained. Its ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf is from 0.3 to 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)

[0160]

Embedded image

Preparation of ALB208 351 mg of lithium aluminum hydride was dehydrated in THF 2
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 thereto. Thereafter, 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
Related to hydronaphthalene (hereinafter referred to as ALB208) having a methyl group and a methoxymethyloxy group at the 9-position, and a 3,4-bishydroxymethyl-6-6-hydroxyhexyl group at the 9-position.
A compound (Fr. A = 540 mg, Fr. B = 310 mg) was obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf is 0.25 (silica gel thin layer chromatography, chloroform: methanol = 9: 1) for Fr. A (hereinafter referred to as ALB208-A), 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)

Preparation of ALB 211 0.6 g of ALB 204 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)

[0163]

Embedded image

[0164]

Embedded image

Preparation of ALB212 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)

Preparation of ALB213 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)

Preparation of ALB214 779 mg of ALB213 was dissolved in 5 ml of THF, 20 ml of an 80% aqueous acetic acid 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)

Preparation of ALB215 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)

Preparation of ALB216 To a solution of 3.6 g of ALB207 in 20 ml of THF were added an 80% aqueous acetic acid solution and 400 μl of 2N hydrochloric acid, and the mixture was stirred 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)

Preparation of ALB222 To a solution of 7.71 ml of DMSO and 40 ml of methylene chloride cooled to -70 ° C. under a stream of nitrogen, trifluoroacetic anhydride was added in an amount of 8.
A solution of 52 ml of 40 ml of methylene chloride was slowly added dropwise over 30 minutes. After stirring for another 30 minutes, 12 g of AT-6
Was slowly added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. Triethylamine 16.8m
After slowly adding dropwise over 30 minutes, the dry ice bath was removed and 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 a saturated saline solution, dried over anhydrous sodium sulfate. After drying, the mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5-9:
1) In addition to the above-mentioned ALB203, a methyl group at the 8-position,
A methoxymethyloxy group, a methylthiomethyloxyethyl group at the 9-position, a methyl group, a methoxymethyloxy group at the 8-position, and a trifluoroacetoxyethyl group at the 9-position
Hydronaphthalene Fr. A (hereinafter referred to as ALB222)
1.17 g and 1.17 g of Fr.B (hereinafter referred to as ALB223) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf is 0.61 for ALB222 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2), and Rf is 0.68 for ALB223. Id.). ALB222 (CDCl ₃ , ppm): 4.75 (1H, d, J = 7.3Hz, O-CH-O), 4.63 (1H, d,
J = 7.3Hz, O-CH- O), 4.62 (2H, s, O-CH 2 -S), 3.61 (1H, m, CH-
O), 3.48 (1H, m, CH-O), 3.35 (3H, s, O-Me), 2.15 (3H, s, S-
Me), 1.95 (1H, m, cyclic CH), 1.8-1.1 (13H, m, cyclic C
H), 1.21 (3H, s, Me), 0.86 (3H, s, Me), 0.83 (3H, s, Me),
0.79 (3H, s, Me) ALB223 (CDCl ₃ , ppm): 4.69 (2H, m, O-CH ₂ -O), 4.47 (1H, m, CH-O),
4.33 (1H, m, CH-O), 3.33 (3H, s, O-Me), 2.0-1.0 (12H, m, cy
clic CH), 1.22 (3H, s, Me), 0.9-0.7 (2H, m, cyclic CH),
0.87 (3H, s, Me), 0.83 (3H, s, Me), 0.79 (3H, s, Me)

Preparation of ALB232 1.02 g of AT-1 and 2.02 g of Nt-Boc-γ-benzyl-L-glutamic acid p-nitrophenyl ester, DMAP980
A solution of 20 mg of dehydrated chloroform in 20 ml was stirred at 50 ° C. for 15 hours. The reaction solution was separated with ethyl acetate and water, and the organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated saline,
Dry over anhydrous sodium sulfate. The aqueous layer is ethyl acetate 2
It was re-extracted twice, and the combined organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration, the filtrates were combined, and the residue obtained by concentration was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8: 2) to obtain 1.55 g (67%) of a condensation product. 0.7 g of the obtained product was dissolved in 10 ml of methanol, and 50 mg of 5% palladium-carbon (Pd / C) was added. The reaction vessel was placed under a hydrogen atmosphere and stirred vigorously at room temperature for 15 hours. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol = 95: 5, 9: 1).
Then, 345 mg of a compound represented by the following structural formula (hereinafter referred to as ALB232) was obtained. Its Rf is 0.35 (silica gel thin layer chromatography, chloroform: methanol =
9: 1), and the ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO d6, ppm): 7.42 (1H, br, NH), 4.03 (2H, m, CH 2 -OC
O), 3.93 (1H, m , CO-CH-N), 2.21 (2H, m, CH 2 -COO), 1.91-1.
05 (14H, m, cyclic CH), 1.38 (9H, s, t-Bu), 0.9-0.7 (2H,
m, cyclic CH), 1.00 (3H, s, Me), 0.84 (3H, s, Me), 0.76 (3
H, s, Me), 0.72 (3H, s, Me)

[0172]

Embedded image

Preparation of ALB234 N, Nε-di-t-butoxycarbonyl-L-lysine 3.11 g of dicyclohexylammonium salt and 1.57 g of pentachlorophenol were dissolved in 12 ml of dehydrated DMF, and adjusted to 2M with N, N′-dicyclohexyl. Carbodiimide (hereinafter, DC
C) (abbreviated as C) was added and stirred at room temperature for 4 hours. Add 1g of AT-1 and 480mg of DMAP,
The mixture was further stirred for 2 hours. The reaction solution was separated with ethyl acetate and water, and the organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated saline in this order, and 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 dried over anhydrous sodium sulfate. After drying, filtration, the filtrates were combined, and the residue obtained by concentration was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3) to obtain 1.85 g (81%) of a condensation product. To 1.8 g of the obtained product, 10 ml of ice-cooled trifluoroacetic acid was added, and the mixture was stirred in an ice bath for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 8: 2 to 7: 3) to give a compound represented by the following structural formula (hereinafter referred to as ALB234) 1,
58 g were obtained quantitatively. Its ¹ H-NMR (400 MHz) spectrum data is as follows, and Rf is 0.29 (silica gel thin layer chromatography, chloroform: methanol = 8: 2). (DMSO-d6 + D ₂ O, ppm): 4.0 (2H, m, CH ₂ -O), 3.58 (1H, m, CO-C
HN), 2.8 (2H, t, CH ₂ -N), 2.36 (1H, m, allylic CH), 2.22
(1H, m, allylic CH), 1.98 (2H, m, cyclic CH), 1.86-1.0
(11H, m, cyclic CH), 1.58 (3H, s, Me), 0.98-0.8 (2H, m, cy
clic CH), 0.9 (3H, s, Me), 0.86 (3H, s, Me), 0.82 (3H, s, M
e)

[0174]

Embedded image

Preparation of ALB083 ALB234 is hydrolyzed in a 2N aqueous sodium hydroxide solution to have a methyl group at the 8-position and a hydroxyethyl group at the 9-position, and a double bond between the 8-position and the 9-position. Hydronaphthalene
(Hereinafter referred to as ALB083). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 4.45 (1H, m, OH), 3.35 (2H, m, CH 2 -O), 2.
20 (1H, m, allylic CH), 2.08 (1H, m, allylic CH), 2.03-1.
2 (9H, m, cyclic CH and allylic Me), 1.15-0.85 (5H, m, c
yclic CH), 0.90 (3H, s, Me), 0.86 (3H, s, Me), 0.80 (3H,
s, Me)

Preparation of ALB344 250 mg (0.739 mmol) of ALB211 was added to a T atmosphere under a nitrogen atmosphere.
It was dissolved in 5 ml of HF and cooled to -20 ° C. To the reaction mixture, 0.11 ml (0.789 mmol) of triethylamine and 0.1 ml (0.812 mmol) of pivaloyl chloride were added, and the mixture was stirred at -20 ° C for 1 hour, and then 0.1- (3-aminopropyl) imidazole was added.
1 ml (0.838 mmol) was added, and the mixture was stirred overnight while warming to room temperature. Chloroform was added to the reaction solution, and the organic layer was washed three times with a saturated aqueous solution of sodium hydrogen carbonate and once with a saturated saline solution. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. 174 mg of the obtained residue was dissolved in 5 ml of methanol, a catalytic amount of 5% Pd / C 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. The obtained residue was purified by silica gel column chromatography (methanol / chloroform = 2 / 98-4 / 96), and 149 mg (yield: 52%) of a compound represented by the following structural formula (hereinafter referred to as ALB344) as an oily substance. Obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 7.49 (1H, s), 7.06 (1H, s), 6.94 (1H, s),
5.60 (1H, brs), 4.00 (2H, t, J = 6.8Hz), 3.28 (2H, q, J = 6.8H
z), 2.18-0.73 (19H, m), 1.56 (3H, s), 0.92 (3H, s), 0.88
(3H, s), 0.82 (3H, s).

[0177]

[Of 60]

Preparation of ALB345 Using 250 mg (0.739 mmol) of ALB211 and 0.12 ml (0.821 mmol) of 4- (3-aminopropyl) morpholine, the same operation as ALB344 was carried out. The obtained residue is subjected to silica gel column chromatography (methanol /
Purification with chloroform = 2 / 98-4 / 96) gave 164 mg (yield: 55%) of a compound represented by the following structural formula (hereinafter referred to as ALB345) as an oil. Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (CDCl ₃ , ppm): 6.77 (1H, brs), 3.72 (4H, t, J = 4.4Hz), 3.3
5 (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
s).

[0179]

Embedded image

Preparation of ALB 237,238 480 mg of AT-1 and 0.99 g of N-benzyloxycarbonyl-L-aspartic acid p-nitrophenyl ester, DM
A solution of 520 mg of AP in 20 ml of dehydrated chloroform was stirred at 50 ° C. for 6 hours. The reaction solution was partitioned between ethyl acetate and water,
The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution and saturated saline, and 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 dried over anhydrous sodium sulfate. After drying, filtration, the filtrates were combined, and the residue obtained by concentration was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
8: 2 to 7: 3) to obtain 1.03 g (92%) of a condensation product (hereinafter referred to as ALB237). Its Rf is 0.55 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 6: 4), and the ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 7.79 (1H, d, J = 8.8Hz, NH), 7.35 (10H, m, P
h * 2), 5.10 (2H, s, benzylic CH), 5.05 (2H, s, benzylic C
H), 4.48 (1H, m, CO-CH-N), 4.10 (1H, m, CH-O-CO), 4.03 (1
H, m, CH-O-CO), 2.90 (1H, dd, CH-COO), 2.76 (1H, dd, CH-CO
O), 1.73-1.05 (12H, m, cyclic CH and 9-CH2), 1.01 (3H,
s, Me), 0.9-0.7 (2H, m, cyclic CH), 0.83 (3H, s, Me), 0.7
1 g of 5 (3H, s, Me), 0.71 (3H, s, Me) ALB237 was dissolved in 30 ml of methanol, and 5% Pd /
50 mg of C were added. The reaction vessel was placed under a hydrogen atmosphere and stirred vigorously at room temperature for 15 hours. After distilling off the solvent under reduced pressure,
The residue was subjected to column chromatography (Cosmo Seal 140-C18).
OPN, 70% methanol) to give 0.4 g of a compound represented by the following structural formula (hereinafter referred to as ALB238). Part ¹ H-NM
The R (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 4.15 (3H, m, CO-CH-N and CH ₂ -O), 2.50
(2H, m, CH ₂ -COO), 1.73-1.05 (14H, m, cyclic CH and CH _2-
chain), 1.01 (3H, s, Me), 0.85 (3H, s, Me), 0.76 (3H, s, M
e), 0.73 (3H, s, Me)

[0181]

Embedded image

Preparation of ALB240 2.97 g of Nt-butoxycarbonyl-β-alanine and 4.18 g of pentachlorophenol were dissolved in 30 ml of dehydrated DMF, 9.8 ml of a 2M solution of DCC in DMF was added, and the mixture was added at room temperature for 15 hours. Stirred. The reaction solution was filtered, the filtrate from which insolubles had been removed was concentrated, and 2 g of AT-1 and 30 ml of dehydrated DMF were added to the residue. Add 940 mg of DMAP and add 8
The mixture was heated to 0 ° C and stirred for 30 minutes. The solvent is distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3-6: 4) to obtain 3.5 g of a condensation product. To 3.25 g of the obtained product, 1 ml of ice-cooled trifluoroacetic acid was added, and the mixture was stirred in an ice bath for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 8: 2-
7: 3), and 1.63 g (50%) of a hydronaphthalene (hereinafter referred to as ALB240) having a methyl group and a hydroxy group at the 8-position and a (3-aminopropanoyl) oxyethyl group at the 9-position.
I got The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 7.85 (2H, broad, NH ₂ ), 3.9-4.1 (2H, m),
3.02-3.04 (2H, t), 2.64-2.68 (2H, t), 0.98-2.10 (14H, t
m), 0.91 (3H, t), 0.86 (3H, t), 0.81 (3H, s), 0.72 (3H, s)

Preparation of ALB241 480 mg of AT-1 and 1.11 g of Nα, Nε-di-benzyloxycarbonyl-L-lysine p-nitrophenyl ester, D
A solution of 508 mg of MAP in 20 ml of dehydrated chloroform at 50 ° C.
For 15 hours. The reaction solution was separated with ethyl acetate and water, and the organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated saline in this order, and 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, dried over anhydrous sodium sulfate, and filtered. The filtrates were combined and concentrated, and the residue obtained was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
7: 3 to 6: 4) to give 1.15 g of a condensation product.
0.7 g of the product obtained is dissolved in 10 ml of methanol and
50 mg of% Pd / C were added. The reaction vessel was placed under a hydrogen atmosphere and stirred vigorously at room temperature for 15 hours. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography (Cosmo Seal 140-C18OPN, 80% methanol) to obtain 0.4 g of a compound represented by the following structural formula (hereinafter referred to as ALB241). The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6 + D2O, ppm ): 4.0 (2H, m, CH 2 -O-CO), 3.4-3.2 (3H,
m, CO-CH-N and CH ₂ -N), 1.75-0.92 (17H, m, cyclic CH, 9-C
H ₂ and CH ₂ x3 of Lysine), 1.02 (3H, s, Me), 0.85-0.75
(3H, m, cyclic CH), 0.85 (3H, s, Me), 0.77 (3H, s, Me), 0.
74 (3H, s, Me)

[0184]

Embedded image

Preparation of ALB072 160 mg of ALB240 and 100 μl of pyridine were added to dehydrated DMF.
5 ml, and cyclohexyl isocyanate 1
20 μl was added and stirred at room temperature for 6 hours. Chloroform was added to this reaction solution to dilute it, and the organic layer was washed twice with saturated saline and dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 70:
30) and purified by a compound represented by the following structural formula (hereinafter ALB)
200 mg (88%). Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (DMSO-d6, ppm): 3.9-4.2 (3H, m), 3.2 (2H, q), 2.40 (2H,
t), 1.00-2.1 (22H, m), 0.91 (3H, s), 0.85 (3H, s), 0.81
(3H, s), 0.71 (3H, s)

[0186]

Embedded image

Preparation of ALB077 170 mg of ALB240 and 100 μl of pyridine were added to dehydrated DMF.
5 ml and stirred, and phenyl isocyanate 120
μl was added and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution to dilute it, and the organic layer was washed twice with saturated saline, and dried over anhydrous sodium sulfate. After drying, the mixture was filtered and the filtrate was concentrated. After n-hexane was added thereto to remove insolubles, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 70: 30) to give a compound represented by the following structural formula (hereinafter referred to as ALB077) 20.
5 mg (88%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (DMSO-d6, ppm): 8.50 (1H, s, NH), 7.36-7.38 (2H, d), 7.1
8-7.20 (2H, t), 6.88 (1H, t), 6.25 (1H, t), 3.88-4.20 (4
H, m), 2.47-2.50ppm (2H, t), 0.95-2.05 (14H, m), 0.89 (3
H, s), 0.86 (3H, t), 0.80 (3H, t) 0.69 (3H, s)

[0188]

Embedded image

Preparation of ALB078 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)

[0190]

Embedded image

Preparation of ALB079 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)

[0192]

Embedded image

Preparation of ALB080 Under a 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)

[0194]

Embedded image

測定 Measurement of compound properties Tables 15 and 16 show the results of the antifungal activity and infection treatment tests of the prepared compounds.

[0196]

[Table 15]

[0197]

[Table 16]

Example 9 Preparation of Compound Preparation of ALB104 330 mg of ALB005 was dissolved in 10 ml of pyridine, 250 μl of hexanoyl chloride was added, and the mixture was stirred at room temperature for 14 hours. After the reaction solution was concentrated to about half the volume, ethyl acetate was added to dilute the mixture, which was washed once with 2N hydrochloric acid and twice with saturated brine, and dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate =
95: 5) to give 450 mg (95%) of hydronaphthalene (hereinafter referred to as ALB104) having a methylidene group at the 8-position and a hexanoyloxymethyl group at the 9-position. Part ¹ H-NMR
The (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.74 (1H, d), 4.51 (1H, d), 4.1-4.4 (2H,
m), 2.38-2.41 (1H, m), 2.27 (2H, t), 1.93-2.15 (2H, m),
1.11-1.75 (15H, m), 0.90 (3H, t), 0.88 (3H, t), 0.82 (3H,
s), 0.75 (3H, s)

Preparation of ALB105 Under a nitrogen atmosphere, 720 mg of 60% NaH was dehydrated into 20 ml of dehydrated THF.
l in an ice bath. 660 mg of ALB005 was dissolved in 10 ml of dehydrated THF and added dropwise. After stirring for 10 minutes,
950 μl of bromohexane was added dropwise, and the mixture was stirred at 40 ° C. for 3 days. After that, the mixture was diluted by adding ethyl acetate,
The extract was washed once with N hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue was subjected to silica gel column chromatography (n-
Purification with hexane: ethyl acetate = 95: 5) yielded 860 mg of hydronaphthalene (hereinafter referred to as ALB105) having a methylidene group at the 8-position and a hexyloxymethyl group at the 9-position.
%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.86 (1H, d), 4.60 (1H, d), 3.61 (2H, dd),
3.45 (2H, m), 2.37-2.41 (1H, m), 1.10-1.75 (12H, m), 0.9
0 (3H, t), 0.87 (3H, t), 0.81 (3H, s), 0.73 (3H, s)

Preparation of ALB106 700 mg of ALB005 and 40 mg of DMAP were added to pyridine 3
0 ml, stirred for 30 minutes in an ice bath, 500 μl of acetic anhydride.
After the addition of l, the mixture was returned to room temperature and stirred for 3 hours. After the reaction solution was concentrated to about half the volume, ethyl acetate was added to dilute the mixture, which was washed once with 2N hydrochloric acid and twice with saturated brine, and 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 = 95: 5),
Hydronaphthalene (hereinafter referred to as ALB106) having a methylidene group at the 8-position and an acetoxymethyl group at the 9-position
4%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.85 (1H, d), 4.51 (1H, d), 4.16-4.36 (2H,
m), 2.38-2.43 (1H, m), 2.00-2.07 (5H, m), 1.11-1.75 (9H,
m), 0.88 (3H, s), 0.82 (3H, s), 0.76 (3H, s)

Preparation of ALB107 Under a nitrogen atmosphere, 380 mg of NaH was suspended in 20 ml of dehydrated THF in an ice bath, and 700 mg of ALB005 was added. 10
After stirring for 1 minute, 1.1 ml of bromoethane was added dropwise, and the mixture was heated at room temperature for 3 hours and at 40 ° C. for 24 hours. Then N
380 mg of aH and 1.1 ml of bromohexane were further added,
Stirred at 30 ° C. for 2 days. Thereafter, the mixture was diluted with ethyl acetate, 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 was concentrated after drying, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5). (Called ALB107) 53
0 mg (67%) was obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.86 (1H, d), 4.60 (1H, d), 3.62 (2H, dd),
3.40-3.60 (2H, m), 2.36-2.40 (1H, m), 1.93-2.09 (2H, m),
1.10-1.75 (12H, m), 0.87 (3H, t), 0.81 (3H, s), 0.73 (3H,
s)

Preparation of ALB108 350 mg of ALB005 and 20 mg of DMAP were added to pyridine 2
0 ml and stirred for 30 minutes in an ice bath. After adding 730 mg of lauric anhydride, the mixture was stirred at 40 ° C for 3 days.
After the reaction solution was concentrated to about half the volume, ethyl acetate was added to dilute the mixture, which was washed once with 2N hydrochloric acid and twice with saturated brine, and 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 = 95: 5) to give hydronaphthalene having a methylidene group at the 8-position and a lauroyloxymethyl group at the 9-position (hereinafter ALB108) 350 mg (54%). The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.84 (1H, d), 4.51 (1H, d), 4.15-4.36 (2H,
m), 2.38-2.42 (1H, m), 2.24-2.28 (2H, t), 2.03-2.07 (2H,
m), 1.11-1.75 (27H, m), 0.90 (3H, t), 0.88 (3H, s), 0.81
(3H, s), 0.76 (3H, s)

Preparation of ALB109 Under a nitrogen atmosphere, 380 mg of NaH was suspended in 20 ml of dehydrated THF in an ice bath, 350 mg of ALB005 was added, and the mixture was stirred. After 10 minutes, 2.4 ml of lauryl iodide was added dropwise,
Stirred at 7 ° C. for 7 days. Thereafter, the reaction mixture was diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with saturated brine, and 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 = 95: 5) to give hydronaphthalene having a methylidene group at the 8-position and a lauryloxymethyl group at the 9-position (hereinafter ALB109 2)
80 mg (45%) were obtained. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.85 (1H, d), 4.59 (1H, d), 3.48-3.52 (2H,
t), 3.33-3.61 (2H, d), 2.36-2.41 (1H, m), 1.96-2.07 (2
H, m), 1.09-1.74 (29H, m), 0.88 (6H, m), 0.81 (3H, s), 0.
73 (3H, s)

測定 Measurement of compound properties Tables 17 and 18 show the antifungal activity and the results of the infection treatment tests of the prepared compounds.

[0205]

[Table 17]

[0206]

[Table 18]

Example 10 Preparation of Compound Preparation of ALB 301, 302 According to the description of tetrahedron (Tetrahedron, 1995, 51, 8333-8338), Methyl (±)-(1′α, 4′aα, 8′aβ) -octahy
dro-5 ', 5', 8'a-trimethyl-spiro- [1,3-dioxolane-2,2 '
(1H) -naphthalene] -1′-carboxylate (hereinafter referred to as ALB301) and (±)-(1′α, 4′aα, 8′aβ) -Octahydro-5 ′, 5 ′, 8 ′
a-trimethyl-spiro- [1,3-dioxolane-2,2 '(1H) -naphthal
ene] -1'-methanol (hereinafter referred to as ALB302) was prepared.
Each ¹ H-NMR (400 MHz) spectrum data is as follows. ALB301 (CDCl ₃ , ppm): 4.11-4.06 (1H, m), 3.96-3.91 (1H, m), 3.8
7-3.82 (1H, m), 3.76-3.71 (1H, m), 3.63 (3H, s), 2.51 (1
H, s), 1.85 (1H, dt, J = 2.9,12.7Hz), 1.68-1.34 (7H, m),
1.23 (3H, s), 1.21-1.14 (2H, m), 0.92 (1H, dd, J = 11.7,2.4
Hz), 0.89 (3H, s), 0.85 (3H, s) .ALB302 (CDCl ₃ , ppm): 4.09-4.02 (2H, m), 3.96-3.84 (2H, m), 3.8
4 (1H, dd, J = 7.8,3.3Hz), 3.61 (1H, d, J = 11.2Hz), 1.96-1.1
1 (11H, m), 0.97 (1H, dd, J = 11.7,3.3Hz), 0.88 (3H, s), 0.
86 (3H, s), 0.82 (3H, s).

Preparation of ALB303 4.00 g (14.9 mmol) of ALB302 was added to TH under a nitrogen atmosphere.
After dissolving in 80 ml of F and adding 1.49 g (37.3 mmol) of 60% sodium hydride / liquid paraffin under ice-cooling, the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, 3.41 ml (37.3 mmol) of allyl iodide was added to the reaction solution, and the mixture was stirred at room temperature overnight.
80 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and ethyl acetate was further added. The organic layer was washed three times with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (ethyl acetate / hexane = 2 / 98-4 / 96), and hydronaphthalene having an ethylene acetal group at the 8-position and an allyloxymethyl group at the 9-position (hereinafter referred to as ALB303) 2.28 g (yield: 50%) were obtained as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 5.90 (1H, dddd, J = 17.1,10.3,4.4,2.9Hz),
5.50 (1H, dd, J = 17.1,1.5Hz), 5.14 (1H, dd, J = 10.3,1.5H
z), 4.00-3.80 (6H, m), 3.46 (1H, dd, J = 10.3,2.9Hz), 3.4
0 (1H, dd, J = 10.3,4.4Hz), 1.91-1.37 (9H, m), 1.20-1.09
(2H, m), 0.96 (1H, dd, J = 11.7,2.4Hz), 0.92 (3H, s), 0.88
(3H, s), 0.83 (3H, s).

Preparation of ALB 304 8.88 g (28.8 mmol) of ALB 303 was added to chloroform 25.
Dissolved in 0 ml and 10.7 g of 70% 3-chloroperbenzoic acid (4
(3.4 mmol) and stirred for 20 hours. The reaction solution was washed three times with a saturated aqueous solution of sodium hydrogen carbonate and once with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (SiO ₂ : 500 ml, ethyl acetate / hexane = 1).
6/84), and 7.22 g of hydronaphthalene (hereinafter referred to as ALB304) having an ethylene acetal group at the 8-position and a (2,3-epoxypropyl) oxymethyl group at the 9-position (yield: 7
7%) as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.02-3.81 (4H, m), 3.70-3.31 (4H, m), 3.1
5-3.11 (1H, m), 2.78-2.76 (1H, m), 2.61-2.58 (1H, m), 1.
92-1.37 (8H, m), 1.21-0.91 (7H, m), 0.88 (3H, s), 0.83 (3
H, s).

Preparation of ALB 305 6.72 g (20.7 mmol) of ALB 304 was added to dioxane 160
dissolved in 2 ml of sodium hydroxide and added 160 ml of 2N sodium hydroxide.
Reflux with heating for hours. After cooling the reaction solution on ice, 2N hydrochloric acid 160 ml
And extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (SiO ₂ : 500 ml, ethyl acetate / hexane = 67/2).
3 to 0/100), and hydronaphthalene having an ethylene acetal group at the 8-position and a (2,3-dihydroxypropyl) oxymethyl group at the 9-position (hereinafter referred to as ALB305) 5.6.
0 g (yield: 79%) was obtained as an oil. Part ¹ H-NMR
The (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.03-3.78 (5H, m), 3.72-3.44 (6H, m), 1.9
3-1.91 (1H, m), 1.78-1.75 (1H, m), 1.67-0.95 (10H, m),
0.88 (6H, s), 0.82 (3H, s)

Preparation of ALB307 4.18 g (12.2 mmol) of ALB305 was added to methanol 165.
of sodium periodate (6.61 g, 30.9 mm).
ol) and stirred at room temperature for 12 hours. The solvent was distilled off from the reaction solution under reduced pressure, ether was added to the residue, the insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure. The obtained residue was dissolved in a mixed solvent of 120 ml of t-butanol and 30 ml of water, and 3.23 g (20.7 mmol) of sodium dihydrogen phosphate dihydrate and 8.29 g (72.4 mmol) of sodium chlorite were added. Plus 15 at room temperature
Stirred for hours. Under ice-cooling, 200 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 150 ml of methanol, 4.54 g (22.0 mmol) of dicyclohexylcarbodiimide was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off from the reaction solution under reduced pressure, n-hexane was added to the residue, the insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (SiO ₂ : 400 ml, ethyl acetate / hexane = 1).
6/84) and purified by a compound represented by the following structural formula (hereinafter A).
1.25 g (yield: 35%) of LB307 were obtained as a white solid. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.16 (1H, d, J = 16.1Hz), 4.05 (1H, d, J = 16.1
Hz), 3.85 (1H, dd, J = 9.3,7.3Hz), 3.74 (3H, s), 3.66 (1H,
(dd, J = 9.3,3.4Hz), 2.50-2.36 (3H, m), 2.09-1.23 (8H, m),
0.97 (3H, s), 0.91-0.88 (1H, m), 0.85 (3H, s), 0.72 (3H,
s).

[0212]

Embedded image

Preparation of ALB308 0.88 g (2.57 mmol) of ALB305 was added to 35 ml of methanol.
And dissolved in 1.39 g of sodium periodate (6.50 mmo).
l) was added and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off from the reaction solution under reduced pressure, the residue was added to ether, and the insoluble matter was removed by filtration. 30 ml of the obtained residue in methanol
And 494 mg of sodium borohydride (1
3.1 mmol) and stirred at room temperature for 15 hours. below freezing,
After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (SiO ₂ : 100 m _2).
l, ethyl acetate / hexane = 32/68) to obtain 760 mg (yield: 95%) of a compound represented by the following structural formula (hereinafter referred to as ALB308) as an oily substance. Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (CDCl ₃ , ppm): 4.04-3.82 (4H, m), 3.72-3.59 (2H, m), 3.5
6-3.46 (4H, m), 2.65 (1H, brs), 1.94-1.54 (5H, m), 1.47-
1.33 (4H, m), 1.26-1.08 (2H, m), 0.98-0.95 (1H, m), 0.90
(3H, s), 0.88 (3H, s), 0.83 (3H, s).

[0214]

Embedded image

測定 Measurement of Compound Properties Tables 19 and 20 show the results of the antifungal activity and the infection treatment test of each prepared compound.

[0216]

[Table 19]

[0219]

[Table 20]

Example 11 Preparation of Compound Preparation of ALB320 10.0 g (33.5 mmol) of AT-6 was dissolved in 200 ml of THF, and 2.68 g (67 mmol) of 60% sodium hydride / liquid paraffin was added under ice-cooling and nitrogen atmosphere. ) And stirred at room temperature for 1 hour. Under ice-cooling, 6.2 ml of allyl iodide (68 ml) was added to the reaction mixture.
mmol) and stirred at room temperature for 7 hours. Under ice-cooling, 1.34 g (3%) of 60% sodium hydride / liquid paraffin was added to the reaction mixture.
4 mmol) and 3.1 ml (34 mmol) of allyl iodide,
Stir at room temperature for 13 hours. After cooling the reaction solution on ice, 200 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with a saturated saline solution, and the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
(SiO ₂ : 600 ml, ethyl acetate / hexane = 4/96), and a methyl group, methoxymethyloxy group,
As a result, 11.0 g (yield: 97%) of hydronaphthalene (hereinafter referred to as ALB320) having an allyloxyethyl group at the 1-position was obtained as an oily substance. Part ¹ H-NMR (400MH
z) The spectrum data is as follows. (CDCl ₃ , ppm): 5.91 (1H, ddt, J = 17.6,10.3,5.9Hz), 5.26
(1H, dt, J = 17.6,1.5Hz), 5.15 (1H, dt, J = 10.3,1.5Hz), 4.7
2 (1H, d, J = 7.3Hz), 4.63 (1H, d, J = 7.3Hz), 3.96 (2H, dt, J =
5.9,1.5Hz), 3.51 (1H, ddd, J = 10.7,8.8,5.9Hz), 3.37 (1
H, ddd, J = 10.7,8.8,5.9Hz), 3.33 (3H, s), 1.94 (1H, dt, J =
12.2,2.9Hz), 1.77-1.09 (11H, m), 1.20 (3H, s), 0.92-0.
88 (2H, m), 0.85 (3H, s), 0.82 (3H, s), 0.78 (3H, s).

[0219]

Embedded image

Preparation of ALB321 5.56 g (16.4 mmol) of ALB320 was used to prepare ALB304.
Almost the same operation was performed. The resulting residue was purified by silica gel column chromatography (SiO ₂ : 500 ml, ethyl acetate / hexane = 16/84), and 4.79 g (yield: 83) of a compound represented by the following structural formula (hereinafter referred to as ALB321) was obtained.
%) As an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.70-3.66 (1H, m), 3.60-3.53 (1H, m), 3.48-3.38 (2
H, m), 3.34 (3H, s), 3.16-3.13 (1H, m), 2.80 (1H, t, J = 4.9
Hz), 2.62-2.60 (1H, m), 1.95 (1H, dt, J = 12.2,3.4Hz), 1.
77-1.10 (11H, m), 1.21 (3H, s), 0.92-0.87 (2H, m), 0.86
(3H, s), 0.83 (3H, s), 0.78 (3H, s).

[0221]

Embedded image

Preparation of ALB322 Using 4.22 g (11.9 mmol) of ALB321, ALB305 was used.
Almost the same operation was performed. The resulting residue by silica gel column chromatography (SiO _2: 500 ml, ethyl acetate / hexane = 67/23 to 0/100) to give methyl group at the 8-position, methoxymethyl group, the 9-position (2,3 3.84 g of hydronaphthalene (hereinafter referred to as ALB322) having -dihydroxypropyl) oxyethyl group (yield: 87
%) As an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.73 (1H, d, J = 7.3Hz), 4.65 (1H, d, J = 7.3H
z), 3.86-3.84 (1H, m), 3.74-3.64 (2H, m), 3.57-3.45 (4
H, m), 3.34 (3H, s), 1.97 (1H, dt, J = 12.2,3.4Hz), 1.74-
1.15 (11H, m), 1.21 (3H, s), 0.93-0.90 (2H, m), 0.86 (3H,
s), 0.83 (3H, s), 0.79 (3H, s).

Preparation of ALB325 Using 5.17 g (7.17 mmol) of ALB322, ALB307 was used.
Almost the same operation was performed. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 400 ml, ethyl acetate / hexane = 16/84), and 1.33 g (yield: 50) of a compound represented by the following structural formula (hereinafter referred to as ALB325) was obtained.
%) As a white solid. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.8Hz), 4.64 (1H, d, J = 7.8H
z), 4.09 (2H, s), 3.75 (3H, s), 3.65-3.58 (1H, m), 3.50-
3.44 (1H, m), 3.34 (3H, s), 1.96 (1H, dt, J = 12.2,3.4Hz),
1.82-1.10 (11H, m), 1.21 (3H, s), 0.90 (2H, dd, J = 12.2,2.
0Hz), 0.86 (3H, s), 0.83 (3H, s), 0.78 (3H, s).

[0224]

Embedded image

Preparation of ALB 327 1.00 g (2.70 mmol) of ALB 325 was added to TH under a nitrogen atmosphere.
After dissolving in 20 ml of F and cooling to −78 ° C., 1.49 ml (2.98 mmol) of a 2M lithium diisopropylamidoheptane / THF / ethylbenzene solution was added over 5 minutes, and −78 ° C.
Stirred at C for 1 hour. Diethyl maleate was added to the reaction mixture at 0.
53 ml (3.28 mmol) was added over 5 minutes, and the temperature was raised from -78 ° C to 0 ° C over 6 hours. 20 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed three times with saturated saline. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 100 ml, ethyl acetate / n-hexane = 16/84 to 32/68) to obtain 803 m of a yellow oily substance.
g (yield: 55%) was obtained. 700 mg of the yellow oil (1.
29 mmol) was dissolved in 7 ml of ethanol, 7 ml of a 6N aqueous sodium hydroxide solution was added, and the mixture was stirred for 48 hours. After adding 30 ml of 2N hydrochloric acid to the reaction mixture under ice cooling, the mixture was extracted three times with chloroform. After the obtained organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 16/84 to 24/76). 253 mg (yield: 42%) of a hydronaphthalene represented by the following structural formula having a methyl group, a methoxymethyloxy group at the 8-position, and a (1,2,3-tricarboxypropyl) oxyethyl group at the 9-position ) Was obtained as a white powder. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.74 (1H, d, J = 7.8Hz), 4.66 (1H, d, J = 7.8H
z), 3.67-3.48 (3H, m), 3.34 (3H, s), 2.00 (1H, dt, J = 12.
2,3.4Hz), 1.82-1.11 (14H, m), 1.22 (3H, s), 0.91 (2H, d
d, J = 12.2,2.0Hz), 0.87 (3H, s), 0.84 (3H, s), 0.79 (3H,
s).

[0226]

Embedded image

Preparation of ALB328 Using 644 mg (1.73 mmol) of ALB322, ALB308 was used.
Almost the same operation was performed. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 100 ml, ethyl acetate / hexane = 32/68), and a methyl group and a methoxymethyloxy group were placed at the 8-position, and a (2-hydroxyethyl) oxyethyl group was placed at the 9-position. (Hereinafter A)
426 mg (Yield: 72%) of LB328) were obtained as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.73 (1H, d, J = 7.3Hz), 4.65 (1H, d, J = 7.3H
z), 3.72-3.71 (2H, m), 3.58-3.42 (4H, m), 3.34 (3H, s),
2.21 (1H, brs), 1.96 (1H, dt, J = 12.2,3.4Hz), 1.78-1.11
(11H, m), 1.21 (3H, s), 0.93-0.89 (2H, m), 0.86 (3H, s),
0.83 (3H, s), 0.79 (3H, s).

Preparation of ALB329 250 mg (0.705 mmol) of ALB321 and 73 mg (1.06 mmol) of 1,2,4-triazole were dissolved in 5 ml of N, N-dimethylformamide, and 95 mg of potassium t-butoxide (0.84 mmol) was dissolved.
7 mmol) and stirred at 60 ° C. for 6 hours. After cooling the reaction solution with ice, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with a saturated saline solution, and the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 1).
/ 99-2/98) and purified by the following structural formula
205 mg (yield: 69%) (hereinafter referred to as ALB329) was obtained as a white powder. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 8.16 (1H, s), 7.95 (1H, s), 4.71 (1H, d, J =
7.3Hz), 4.64 (1H, d, J = 7.3Hz), 4.35 (1H, dd, J = 13.7,3.9H
z), 4.25 (1H, dd, J = 13.7,6.8Hz), 4.19-4.09 (1H, m), 3.5
3-3.34 (4H, m), 3.33 (3H, s), 3.21 (1H, d, J = 4.9Hz), 1.97
(1H, dt, J = 12.2,3.4Hz), 1.78-1.11 (11H, m), 1.21 (3H,
s), 0.92-0.88 (2H, m), 0.86 (3H, s), 0.83 (3H, s), 0.79
(3H, s).

[0229]

[Of 75]

Preparation of ALB330 250 mg (0.705 mmol) of ALB321, 0.1 ml (0.838 mmol) of 1- (3-aminopropyl) imidazole and 150 mg (1.41 mmol) of lithium perchlorate were suspended in 5 ml of acetonitrile. Stirred at 50 ° C. for 4 hours. After the reaction solution was cooled to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed twice with a saturated aqueous solution of sodium hydrogen carbonate and once with a saturated saline solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform =
8/92 to 16/84) to give 216 mg (yield: 64%) of a compound represented by the following structural formula (hereinafter referred to as ALB330) as an oily substance. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 7.51 (1H, s), 7.02 (1H, s), 6.94 (1H, s),
4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.92-3.81
(1H, m), 3.52-3.39 (4H, m), 3.34 (3H, s), 2.70-2.61 (4H, m
m), 2.18 (3H, s), 2.00-1.94 (3H, m), 1.76-1.11 (11H, m),
1.21 (3H, s), 0.91-0.89 (2H, m), 0.86 (3H, s), 0.83 (3H,
s), 0.78 (3H, s).

[0231]

Embedded image

Preparation of ALB331 Using 250 mg (0.705 mmol) of ALB321 and 0.12 ml (0.821 mmol) of 4- (3-aminopropyl) morpholine, almost the same operation as ALB330 was performed. The obtained residue is subjected to silica gel column chromatography (SiO ₂ : 5).
0 ml, methanol / chloroform = 4/96 to 16/84)
And 283 mg (yield: 80%) of a compound represented by the following structural formula (hereinafter referred to as ALB331) was obtained as a pale yellow powder. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 4.28-4.18 (1H, m), 3.78-3.75 (4H, m), 3.55-3.42 (4
H, m), 3.34 (3H, s), 3.10-2.93 (4H, m), 2.70-2.47 (8H,
m), 1.97-1.11 (12H, m), 1.20 (3H, s), 0.92-0.89 (2H, m),
0.87 (3H, s), 0.83 (3H, s), 0.79 (3H, s).

[0233]

Embedded image

Preparation of ALB332 Using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (1.141 mmol) of morpholine, the same operation as in ALB330 was performed. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 1/99 to 2/98), and 278 mg of a compound represented by the following structural formula (hereinafter referred to as ALB332) (yield: 89)
%) As an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.92-3.87 (1H, m), 3.75-3.67 (4H, m), 3.56-3.38 (4
H, m), 3.34 (3H, s), 2.65-2.60 (2H, m), 2.49-2.37 (4H,
m), 1.95 (1H, dt, J = 12.2,3.4Hz), 1.78-1.09 (11H, m), 1.
21 (3H, s), 0.90 (2H, dd, J = 12.2,2.4Hz), 0.86 (3H, s), 0.
82 (3H, s), 0.78 (3H, s).

[0235]

Embedded image

Preparation of ALB333 Using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (1.01 mmol) of piperidine, the same operation as in ALB330 was carried out. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 2/98 to 4/96) and 273 mg (yield: 88%) of a compound represented by the following structural formula (hereinafter referred to as ALB333).
Was obtained as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.91-3.87 (1H, m), 3.56-3.52 (1H, m), 3.50-3.37 (3
H, m), 3.34 (3H, s), 2.63-2.60 (2H, m), 2.41-2.38 (4H,
m), 1.95 (1H, dt, J = 12.2,3.4Hz), 1.78-1.08 (17H, m), 1.
20 (3H, s), 0.90 (2H, dd, J = 12.2,2.4Hz), 0.86 (3H, s), 0.
82 (3H, s), 0.78 (3H, s)

[0237]

Embedded image

Preparation of ALB334 The same operation as ALB330 was carried out using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (0.90 mmol) of N-methylpiperazine. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 60 ml, methanol / chloroform = 4/96 to 16/84), and 248 mg of a compound represented by the following structural formula (hereinafter referred to as ALB334) (yield:
77%) as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.89-3.86 (1H, m), 3.56-3.38 (4H, m), 3.33 (3H, s),
2.67-2.36 (10H, m), 2.29 (3H, s), 1.95 (1H, dt, J = 12.2,3.
4Hz), 1.78-1.09 (11H, m), 1.20 (3H, s), 0.90 (2H, dd, J = 1
2.2,2.4Hz), 0.86 (3H, s), 0.82 (3H, s), 0.78 (3H, s)

[0239]

Embedded image

Preparation of ALB335 Using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (0.82 mmol) of 1- (2-hydroxyethyl) piperazine,
Almost the same operation as in ALB330 was performed. The obtained residue is subjected to silica gel column chromatography (SiO ₂ : 60 m2).
l, methanol / chloroform = 4/96 to 16/84) to obtain 262 mg (yield: 77%) of a compound represented by the following structural formula (hereinafter referred to as ALB335) as an oily substance. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.90-3.85 (1H, m), 3.61 (2H, t, J = 5.4Hz), 3.56-3.38
(4H, m), 3.34 (3H, s), 2.66-2.36 (10H, m), 2.55 (2H, t, J =
5.4Hz), 1.95 (1H, dt, J = 12.2,3.4Hz), 1.78-1.09 (11H,
m), 1.21 (3H, s), 0.90 (2H, dd, J = 12.2,2.4Hz), 0.86 (3H,
s), 0.82 (3H, s), 0.78 (3H, s)

[0241]

Embedded image

Preparation of ALB336 177 mg (0.418 mmol) of ALB329 was added to 0.5 ml of THF.
Was dissolved in a mixed solvent of 3 ml of an 80% aqueous acetic acid solution, 0.2 ml of 2N hydrochloric acid was added, and the mixture was stirred at 80 ° C for 5 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the obtained residue was dissolved in chloroform, and washed three times with a saturated aqueous solution of sodium hydrogen carbonate and once with a saturated saline solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (SiO ₂ : 30 ml, methanol / chloroform = 1/99 to 2/98) to give the following structural formula (Hereinafter referred to as ALB336) was obtained as an oily substance to obtain 116 mg (yield: 73%) as an oily substance. That
^{The 1} H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 8.14 (1H, s), 7.94 (1H, s), 4.36 (1H, dd, J =
13.7,3.9Hz), 4.26 (1H, dd, J = 13.7,6.8Hz), 4.19-4.13 (1
H, m), 3.47-3.34 (4H, m), 3.19 (1H, brs), 2.40-2.33 (1H,
m), 2.26-2.19 (1H, m), 2.03-0.90 (11H, m), 1.59 (3H, s),
0.94 (6H, s), 0.88 (3H, s)

[0243]

Embedded image

Preparation of ALB337 and ALB338 500 mg (1.41 mmol) of ALB321 and piperazine 73
The same operation as in ALB330 was performed using mg (0.847 mmol). The obtained residue was purified by silica gel column chromatography (SiO ₂ : 100 ml, methanol / chloroform = 2 / 98-4 / 96, 16 / 84-24 / 76) to give a compound represented by the following structural formula (Chemical Formula 83, hereinafter). 330 mg (yield: 59%) of ALB337, 330 mg (yield: ALB338) of a compound represented by the following structural formula
29%) were each obtained as an oil. Its ¹ H-NMR (40
0 MHz) spectrum data is as follows. ALB337 (CDCl ₃ , ppm): 4.72 (2H, d, J = 7.3Hz), 4.64 (2H, d, J = 7.3H
z), 3.89-3.85 (2H, m), 3.56-3.35 (8H, m), 3.33 (6H, s),
2.66-2.36 (14H, m), 1.95 (2H, dt, J = 12.2,3.4Hz), 1.78-1.
10 (22H, m), 1.20 (6H, s), 0.90 (4H, dd, J = 12.2,2.4Hz),
0.86 (6H, s), 0.82 (6H, s), 0.78 (6H, s) .ALB338 (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3 H
z), 3.92-3.87 (1H, m), 3.58-3.37 (4H, m), 3.33 (3H, s),
3.00-2.96 (4H, m), 2.71-2.68 (2H, m), 2.63-2.39 (6H, m),
1.95 (1H, dt, J = 12.2,2.9Hz), 1.78-1.09 (11H, m), 1.20
(3H, s), 0.90 (2H, dd, J = 12.2,1.5Hz), 0.86 (3H, s), 0.82
(3H, s), 0.78 (3H, s).

[0245]

Embedded image

[0246]

Embedded image

Preparation of ALB339 The same operation as ALB330 was carried out using 250 mg (0.705 mmol) of ALB321 and 69 mg (1.06 mmol) of sodium azide. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, ethyl acetate / n-hexane; = 16/84), and a methyl group and a methoxymethyloxy group were placed at the 8-position, and 3-azido-2 was placed at the 9-position. -Hydroxynaphthalene having a hydroxypropyloxyethyl group (hereinafter referred to as AL
209 mg (yield: 75%) of B339 were obtained as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.65 (1H, d, J = 7.3H
z), 3.95-3.91 (1H, m), 3.57-3.32 (6H, m), 3.34 (3H, s),
2.69 (1H, d, J = 4.4Hz), 1.97 (1H, dt, J = 12.7,2.9Hz), 1.78
-1.10 (11H, m), 1.21 (3H, s), 0.91 (2H, d, J = 11.7Hz), 0.8
6 (3H, s), 0.83 (3H, s), 0.79 (3H, s).

Preparation of ALB340 The same operation as ALB330 was carried out using 250 mg (0.705 mmol) of ALB321 and 128 mg (1.06 mmol) of tris (hydroxymethyl) aminomethane. The obtained residue is subjected to silica gel column chromatography (SiO ₂ : 50).
ml, methanol / chloroform = 16 / 84-28 / 72)
And a methyl group, a methoxymethyloxy group at the 8-position,
3- (tris (hydroxymethyl) methyl) amino-2-position at position 9
189 mg of hydronaphthalene having a hydroxypropyloxyethyl group (hereinafter referred to as ALB340) (yield: 56%)
Was obtained as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.95-3.91 (1H, m), 3.64-3.12 (9H, m), 3.60 (6H, s),
3.34 (3H, s), 2.86-2.83 (1H, m), 2.72-2.63 (1H, m), 1.95
(1H, d, J = 12.7Hz), 1.78-1.12 (11H, m), 1.20 (3H, s), 0.9
0 (2H, d, J = 12.2Hz), 0.86 (3H, s), 0.83 (3H, s), 0.79 (3H,
s).

Preparation of ALB341 The same operation as ALB330 was carried out using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (1.04 mmol) of diethanolamine. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 4/96 to 24/76), and 247 mg of a compound represented by the following structural formula (hereinafter referred to as ALB341) (yield:
76%) as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.93-3.92 (1H, m), 3.79-3.37 (11H, m), 3.34 (3H, s),
2.82-2.47 (6H, m), 1.95 (1H, dt, J = 12.2,2.9Hz), 1.78-1.
11 (11H, m), 1.21 (3H, s), 0.90 (2H, dd, J = 12.2,2.0Hz),
0.86 (3H, s), 0.83 (3H, s), 0.78 (3H, s).

[0250]

Embedded image

Preparation of ALB342 250 mg of ALB321 and 228 m of D-glucosamine hydrochloride
Using g, the same operation as in ALB330 was performed. The obtained residue is subjected to silica gel column chromatography (SiO ₂ :
50 ml, methanol / chloroform = 4/96 to 16/8
4) and purified by a compound represented by the following structural formula (hereinafter referred to as ALB34).
284 mg (Yield: 76%) was obtained as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows. (CDCl ₃ , ppm): 5.99 (1H, dd, J = 6.8,4.9Hz), 4.70 (1H, d, J =
7.3Hz), 4.64 (1H, d, J = 7.3Hz), 4.53-4.41 (1H, m), 3.64-
3.28 (13H, m), 3.33 (3H, s), 1.95 (1H, dt, J = 12.2,3.4Hz),
1.78-1.07 (11H, m), 1.19 (3H, s), 0.90 (2H, d, J = 12.2H
z), 0.86 (3H, s), 0.81 (3H, s), 0.78 (3H, s).

[0252]

Embedded image

Preparation of ALB343 Using 250 mg (0.705 mmol) of ALB321 and 0.11 ml (0.89 mmol) of cis-2,6-dimethylmorpholine,
Almost the same operation as in B330 was performed. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 1/99 to 2/98), and 274 mg (yield) of a compound represented by the following structural formula (hereinafter referred to as ALB343) as an oily substance. : 83%). Its ¹ H-NMR (4
(00 MHz) The spectrum data is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3H
z), 3.92-3.87 (1H, m), 3.72-3.63 (2H, m), 3.57-3.50 (1
H, m), 3.48-3.37 (3H, m), 3.34 (3H, s), 2.82-2.63 (2H,
m), 2.47-2.32 (2H, m), 2.01-1.93 (2H, m), 1.78-1.09 (12
H, m), 1.20 (3H, s), 1.16 (3H, s), 1.15 (3H, s), 0.90 (2H,
dd, J = 12.2,2.0Hz), 0.86 (3H, s), 0.82 (3H, s), 0.78 (3H,
s).

[0254]

Embedded image

測定 Measurement of Compound Properties Tables 21 and 22 show the antifungal activity and the results of infection treatment tests of the prepared compounds.

[0256]

[Table 21]

[0257]

[Table 22]

Example 12 Preparation of compound Preparation of labdanolic acid Cistus ladan purchased from Liberty Natural Products
15.0 g of LABDUNUML (oil), a solvent extraction extract of iferus, was weighed. Thereto were added 75 ml of ethyl acetate and 75 ml of a 0.5N aqueous sodium hydroxide solution to make the mixture basic (pH = 8.6), and extraction was performed. After removing the ethyl acetate layer, 100 ml of ethyl acetate and 15 ml of 1.0N hydrochloric acid were added to the aqueous layer to make it acidic (pH = about 5.8) and extracted. The ethyl acetate layer obtained under acidic conditions was passed through an activated carbon column (2.0 cm ID × 2.5 cm),
Adsorbed substances were removed. The solvent is distilled off from the passing part under reduced pressure.
45 g of extracted oil was obtained. This extract 8.4
5 g of silica gel column chromatography (4.0 cm ID
× 12.0 cm, elution solvent: hexane / ethyl acetate = 9/1
２ /)) and hexane / ethyl acetate = 5/5
1.2 g of an eluted fraction of .about.2 / 8 was obtained. This is Sephadex L
H-20 column chromatography (2.0cmID × 70.0c)
(elution solvent: methanol) at 15 ml / tube to obtain 0.96 g of Fr. (9-13). This was dissolved in 10 ml of methanol, and then activated carbon column (1.5 cm ID × 20.
0 cm), and the activated carbon column was washed with 100 ml of methanol, and the passing portion and the washing portion were united. The solvent was distilled off from the combined fractions under reduced pressure to obtain 926 mg. Next, this was subjected to reverse phase column chromatography (2.0 cm ID × 1).
5.0 cm, elution solvent: 70 to 100% methanol), and a fraction eluted with 80 to 85% methanol, 445 mg
I got This fraction was fractionated by silica gel column chromatography (2.0 cm ID × 17.0 cm, elution solvent: chloroform / methanol = 100/1 to 100/100), whereby chloroform / methanol = 100/10 to 100/100.
As a 100/20 elution fraction, 128 mg of labudanolic acid was obtained as a colorless oil. Its ^{1 H-NMR (400MHz, CDCl} 3) spectrum chart of is as in FIG. ^{13, 13 C-NMR (400MHz} , C
The spectrum data of DCl ₃ ) is as follows. 15.5, 18.5, 19.9, 20.4, 21.5, 23.0, 23.9, 31.2, 3
3.2, 33.4, 39.1, 39.6, 40.5, 41.5, 42.0, 43.9, 56.
0, 62.0, 74.9, 178.0 ppm The Rf value was 0.47 (silica gel thin layer chromatography / silica gel 60 F254 (Merck) / chloroform / methanol = 10/1), 0.51 (silica gel thin layer chromatography / silica gel 60). F254 (Merck) / hexane / ethyl acetate = 1/4) and 0.38 (reverse phase silica gel thin layer chromatography / RP-18 F254 (Merck) / 90% methanol), and the color reaction was positive for Ehrlich's reagent ( (Purple), positive for anisaldehyde reagent (purplish red) and positive for 50% sulfuric acid reagent (brown).

測定 Measurement of the properties of the compounds Table 23 and Table 24 show the results of the antifungal activity of rabudanolic acid and the results of the infection treatment test.

[0260]

[Table 23]

[0261]

[Table 24]

Example 13 Preparation of Compounds Preparation of COP-a-OH and COP-e-OH Copal resin (Copal C2) obtained from Hiratsuka Sangyo Co., Ltd.
Was dissolved in a mixed solution of chloroform / methanol, and insolubles were removed by filtration with a cotton plug. The solution is concentrated under reduced pressure and
4.0 g of extract was obtained. Next, this extract was fractionated by silica gel column chromatography (6.0 cm ID × 30 cm, elution solvent: hexane / ethyl acetate = 10/1 to 1/1), and hexane / ethyl acetate = 5/1 to 3/1. Fraction 2.1g
And hexane / ethyl acetate = 2/1 to 1/1 fraction 3.1 g
Obtained. Next, hexane / ethyl acetate = 5 / 1-3 / 1 fraction 2.
1 g was subjected to reverse phase column chromatography (3.0 cm ID x 1).
Fractionation was performed with 2.0 cm, eluting solvent: 70-100% methanol) to obtain 1.2 g of an 80% methanol eluting fraction. This fraction was further subjected to reverse phase column chromatography (3.0 cm ID
× 12.0 cm, elution solvent: 70 to 100% methanol), 584 mg of a 77.5% to 80% methanol eluted fraction and 675 of an 80 to 85% methanol eluted fraction.
mg was obtained. These were subjected to column chromatography using 10% water-containing silica gel several times (hexane / ethyl acetate = 7/1 to 3/1 or chloroform / methanol = 200/1 eluted fraction) to obtain a colorless oily compound (hereinafter, referred to as "eluate"). CO
434 mg were obtained. ¹ H-NMR of COP-e (400
MHz, CDCl ₃ ) spectrum chart is as shown in FIG. 14, ¹³ C-NMR (400 MHz, CDCl ₃ ) spectrum data is 12.
7, 18.8, 19.8, 21.6, 26.0, 28.9, 37.8, 38.6, 39.0,
39.7, 40.4, 44.1, 50.7, 55.3, 56.2, 106.5, 114.9,
147.6, 160.9, 167.3, 184.1 (ppm). The Rf value of silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.75 (chloroform / methanol = 20).
/ 1) and 0.59 (hexane / ethyl acetate = 5/2), and the Rf value of reverse phase silica gel thin layer chromatography (RP-18 F254 (Merck)) was 0.33 (90% methanol). The color reaction was positive for Ehrlich's reagent (brown), positive for anisaldehyde reagent (purplish red), and positive for 50% sulfuric acid reagent (brown). Hexane / ethyl acetate as described above = 2/1 to 1/1
Fractionation of 3.1 g of the fraction was repeated several times by reverse phase column chromatography, silica gel column chromatography, and 10% water-containing silica gel column chromatography to obtain a colorless oi.
199 mg of an l-form compound (hereinafter referred to as COP-a) was obtained. C
The spectrum chart of ¹ H-NMR (400 MHz, CDCl ₃ ) of OP-a is as shown in FIG. 15, and ¹³ C-NMR (400 MHz, CDCl ₃ )
Spectrum data is 12.7, 17.9, 19.9, 26.0, 27.5, 2
9.0, 38.0, 38.7, 39.1, 40.7, 41.4, 44.2, 56.4, 56.
6, 73.8, 106.7, 111.7, 145.1, 148.0, 183.7 (ppm). The Rf values of silica gel thin layer chromatography (silica gel 60 F254 (Merck)) were 0.52 (chloroform / methanol = 20/1) and 0.39 (hexane / ethyl acetate = 5/2). Layer chromatography
The Rf value of (RP-18 F254 (Merck)) was 0.51 (90% methanol), and the color reaction was positive for Ehrlich reagent (brown), positive for anisaldehyde reagent (purple), and positive for 50% sulfuric acid reagent (brown). )Met. 100 mg of the above COP-a (0.3
1 mmol) was dissolved in 5 ml of diethyl ether, and diazomethane was added little by little to obtain a methyl ester (102 mg). This methyl ester was dissolved in 5 ml of diethyl ether, 12 mg of lithium aluminum hydride was added little by little under ice cooling and stirring, and the mixture was stirred at room temperature for 6 hours. The reaction solution was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Silica gel column chromatography of the residue
(5.0 g, 1 cm ID × 16 cm, elution solvent: hexane / ethyl acetate = 9/1 to 1/1), and 67.4 mg of a compound represented by the following structural formula (Chemical Formula 88, hereinafter referred to as COP-a-OH). (75% yield). Its ^{1 H-NMR (400MHz, CDCl} 3) spectrum chart of is as in FIG. 16, ¹³ C-NMR (400
MHz, CDCl ₃ ) Spectral data 15.2, 17.8, 19.0, 24.
4, 27.1, 27.6, 35.4, 38.6, 38.8, 39.0, 39.7, 41.3,
56.3, 57.3, 65.0, 73.5, 106.8, 111.6, 145.2, 148.
Is one. The Rf value of silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.20 (hexane
/ Ethyl acetate = 4/1), and the color reaction was positive for anisaldehyde reagent (purple). 200mg of the above COP-e
(0.60 mmol) was dissolved in 5 ml of diethyl ether, and diazomethane was added little by little to obtain 204 mg of a methyl ester. This methyl ester was dissolved in 5 ml of diethyl ether, and 40 mg of lithium aluminum hydride was stirred under ice cooling.
Was added little by little, and the mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Silica gel column chromatography of the residue
(5.0 g, 1 cm ID × 16 cm, developing solvent: chloroform / ethyl acetate = 10/0 to 92/8), and a compound represented by the following structural formula (Chemical Formula 89, hereinafter referred to as COP-e-OH): 111 m
g (yield 64%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ )
FIG. 17 shows the spectrum chart of ¹³ C-NMR
(400 MHz, CDCl ₃ ) Spectrum data is 15.3, 16.3, 1
9.0, 21.9, 24.4, 27.1, 35.4, 38.3, 38.6, 38.7, 38.
9, 39.0, 39.5, 56.3, 59.4, 65.0, 106.5, 123.0, 14
0.5 and 148.0. The Rf value of silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.16.
(Chloroform / ethyl acetate = 9/1), and the color reaction was positive for anisaldehyde reagent (purple).

[0263]

Embedded image

[0264]

Embedded image

Preparation of COP-f-OH Ethyl acetate (300 ml) was added to 50 g of sokuhyouyou and extracted at room temperature for 24 hours. After filtration, 300 ml of ethyl acetate was added to the residue.
And extracted again at room temperature for 24 hours. Both extracts were combined and the solvent was distilled off to obtain 2.14 g of extract. This extract was subjected to activated carbon chromatography (5.0 g, 2.5
cmID × 8cm, developing solvent: methanol / chloroform = 1
0/0 to 4/1) and silica gel column chromatography (30 g, 2 cm ID × 22 cm, developing solvent: hexane / ethyl acetate = 9/1 to 7/3) to give a compound represented by the following structural formula (Chemical Formula 90, 343 mg (hereinafter referred to as COP-f) (cis,
Trans mixing). ¹ H-NMR (400 MHz, CDCl ₃ )
18 is as shown in FIG. 18. The Rf value of silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.43 (hexane / ethyl acetate = 4/1).
The color reaction is positive for anisaldehyde reagent (purple). 300 mg (0.99 mmol) of the above COP-f was dissolved in 5 ml of diethyl ether, and diazomethane was added little by little to obtain 272 mg of a methyl ester. The methyl ester was dissolved in 5 ml of diethyl ether, and 36 mg of lithium aluminum hydride was added little by little under ice-cooling and stirring, followed by stirring at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (5.0 g, 1 cm ID × 16 cm, developing solvent: hexane / ethyl acetate = 9/1 to 7/3) to give a compound represented by the following structural formula (Chemical Formula 91, hereinafter referred to as COP-f-). OH) (114 mg, cis / trans mixture, yield 40%). Its ¹ H-NMR (400 MHz, CDCl ₃ ) spectrum chart is as shown in FIG. 19, and the Rf value of silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.32.
(Hexane / ethyl acetate = 4/1), the color reaction is positive for anisaldehyde reagent (purple).

[0266]

Embedded image

[0267]

Embedded image

測定 Measurement of Compound Properties Tables 25 and 26 show the results of the antifungal activity and the infection treatment test of the prepared compounds.

[0269]

[Table 25]

[0270]

[Table 26]

Example 14 Preparation of Compound Preparation of BC-1 to BC A medium having the composition shown in the following table (100 ml was dispensed into a 500 ml Erlenmeyer flask, and 1 ml at 121 ° C.)
Bacillus cereus IFO31)
32 strains were inoculated, and 1.2 liters of a culture solution cultured at 27 ° C. for 4 days was heated at 65 ° C. for 20 minutes. went. 24 hours later, after confirming that Bacillus cereus was sufficiently grown, 8 g of sclareol (1
(0% ethanol solution), and the cells were further cultured for 14 days.

[0272]

[Table 27]

The resulting culture was centrifuged at 3000 rpm for 20 minutes to separate the cells from the culture. The culture was extracted with 40 liters of ethyl acetate, and the cells were extracted with 4 liters of ethyl acetate to obtain 8.64 g of an extract. The ethyl acetate extract was then subjected to silica gel column chromatography (200 g: 4 cm ID × 30 cm, elution solvent: ethyl acetate /
Hexane = 5.5 / 4.5-10 / 0), and ethyl acetate / hexane = 7/3 depending on the components of those fractions.
(Fraction 1: 0.15 g), ethyl acetate / hexane =
8/2 (fraction 2: 0.46 g) and ethyl acetate / hexane = 10/0 (fraction 3: 0.10 g) were divided into three fractions. Next, fraction 1 was subjected to reverse layer chromatography.
(2 cm ID × 16 cm, elution solvent: 40 to 100% methanol), and the compound (hereinafter referred to as B)
C-1) was obtained in an amount of 31.6 mg. The Rf value of the silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.38 (ethyl acetate / hexane = 9/1), and the color reaction was positive for anisaldehyde reagent (blue to red). Next, fraction 2 was recrystallized from hexane to give 69.5 mg of a white powdery compound represented by the following structural formula (Chemical Formula 9).
2, hereinafter referred to as BC-2). Rf of the silica gel thin layer chromatography (silica gel 60 F254 (Merck))
The value was 0.45 (ethyl acetate / hexane = 9/1), the color reaction was positive for anisaldehyde reagent (blue to red), and ¹ HN
FIG. 20 shows a spectrum chart of MR (400 MHz, CD ₃ OD). Next, fraction 3 was fractionated by reverse layer chromatography (2 cm ID × 16 cm, elution solvent: 50 to 100% methanol), and a compound represented by the following structural formula (hereinafter referred to as BC-3) was obtained from the 70 to 80% elution fraction. 19).
8 mg were obtained. The Rf value of the silica gel thin layer chromatography (silica gel 60 F254 (Merck)) was 0.28 (ethyl acetate / hexane = 9/1), the color reaction was positive for anisaldehyde reagent (blue to red), and ¹ H -NMR (400MHz, CD ₃ OD)
FIG. 21 shows a spectrum chart of ¹³ C-NMR.
(100 MHz: CDCl ₃ + CD ₃ OD) The spectrum chart is as shown in FIG.

[0274]

Embedded image

[0275]

Embedded image

測定 Measurement of Compound Properties Tables 28 and 29 show the antifungal activity of the prepared compounds and the results of treatment tests for infection.

[0277]

[Table 28]

[0278]

[Table 29]

[0279]

From the above results, it can be seen that the compound of the present invention is a pathogenic fungus infecting humans, Candida albicans (Candida albicans).
dida albicans) and Aspergillus fumigatus (Asper
gillus fumigatus), indicating that these compounds are effective as chemotherapeutic agents against fungal infections such as candidiasis and aspergillosis.

[Brief description of the drawings]

FIG. 1 is a ¹ H-NMR chart of AT-5.

FIG. 2 is a ¹ H-NMR chart of AT-24.

FIG. 3 is a ¹ H-NMR chart of AT-25.

FIG. 4 is a ¹ H-NMR chart of HAL-1.

FIG. 5 is a ¹³ C-NMR chart of HAL-1.

FIG. 6 is a ¹ H-NMR chart of HAL-2.

FIG. 7 is a ¹³ C-NMR chart of HAL-1.

FIG. 8 is a ¹ H-NMR chart of HAL-3.

FIG. 9 is a ¹³ C-NMR chart of HAL-3.

FIG. 10 is a ¹ H-NMR chart of HAL-4.

FIG. 11 is a ¹ H-NMR chart of HAL-5.

FIG. 12 is a ¹ H-NMR chart of Manol G.

FIG. 13 is a ¹ H-NMR chart of labdanolic acid.

FIG. 14 is a ¹ H-NMR chart of COP-a.

FIG. 15 is a ¹ H-NMR chart of COP-e.

FIG. 16 is a ¹ H-NMR chart of COP-a-OH.

FIG. 17 is a ¹ H-NMR chart of COP-a-OH.

FIG. 18 is a ¹ H-NMR chart of COP-f.

FIG. 19 is a ¹ H-NMR chart of COP-f-OH.

FIG. 20 is a ¹ H-NMR chart of BC-2.

FIG. 21 is a ¹ H-NMR chart of BC-3.

FIG. 22 is a ¹³ C-NMR chart of BC-3.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/27 A61K 31/27 4C086 31/335 31/335 4C206 31/35 31/35 31/40 31 / 40 31/41 31/41 31/415 31/415 31/445 31/445 31/495 31/495 31/535 31/535 31/60 31/60 C07D 207/16 C07D 207/16 265/30 265 / 30 295/08 295/08 Z A 295/12 295/12 Z 405/10 249 405/10 249 // C07D 233/61 102 233/61 102 249/08 519 249/08 519 522 522 303/14 303 / 14 C07H 15/18 C07H 15/18 (72) Inventor Muneaki Kano No. 2 Okubo Tsukuba, Ibaraki Prefecture Toagosei Co., Ltd. Inside Tsukuba Research Laboratories (72) Inventor Kenichi Tanaka No. 2 Okubo Tsukuba City, Ibaraki Pref. (72) Inventor Toshiyuki Wakayama, Tsukuba, Ibaraki No. 2 Okubo Toagosei Co., Ltd. in Tsukuba Research Laboratories (72) Inventor Nobuaki Koike No. 2 Okubo Tsukuba, Ibaraki Pref. In Tsukuba Research Laboratories Co., Ltd. (72) Inventor Takayoshi Uchida No. 2 Okubo Tsukuba, Ibaraki Pref. In the laboratory (72) Inventor Toshiyuki Nagata 2nd Okubo Tsukuba, Ibaraki Pref. Toagosei Co., Ltd. Tsukuba Research Co., Ltd. (72) Inventor Toshiaki Segawa 2nd Okubo Tsukuba, Ibaraki Pref. Toagosei Co., Ltd. F-term (reference) 4C048 AA01 BB08 CC01 4C056 AA02 AB01 AC03 AD01 AE01 EA01 EA03 EB01 EC08 EC12 4C057 BB02 BB05 CC03 DD01 JJ19 4C063 AA01 BB04 BB05 CC71 DD41 EE01 4C069 AA05 AA15 AA17 4C007 BC02 AA07 BC02 AA01 BC ZB35 4C206 AA01 AA02 CA09 CA14 CA25 CA32 CB02 CB16 DA11 DA13 DA36 DA37 DB04 DB11 DB15 DB27 DB29 DB56 FA03 GA08 GA22 GA23 GA25 GA26 GA31 JA01 JA79 MA01 MA04 NA14 ZB35

Claims (2)

[Claims] 1. A compound having a hydronaphthalene ring structure which may have an unsaturated bond represented by the following structural formula 1, wherein a structure derived from isocitrate is linked to the 9-position of the hydronaphthalene ring through an ether bond. An antifungal agent comprising, as an active ingredient, a compound not bound to a methyloxy group. Embedded image However, in the formula, R ¹ , R ² and R ³ are alkyl groups which may have the same or different substituents. 2. An antifungal agent comprising sclareol, sclareolide, manol or labdanolic acid or a compound derived therefrom as an active ingredient.