WO1999053911A1

WO1999053911A1 - Antifungal agents

Info

Publication number: WO1999053911A1
Application number: PCT/JP1999/001998
Authority: WO
Inventors: Shigeo Nozoe; Jun-Ichi Masuda; Akira Takahashi; Muneaki Kanou; Ken-Ichi Tanaka; Toshiyuki Wakayama; Nobuaki Koike; Takayoshi Uchida; Toshiyuki Nagata; Toshiaki Segawa; Sanae Tanaka
Original assignee: Toa Gosei Co., Ltd.
Priority date: 1998-04-14
Filing date: 1999-04-14
Publication date: 1999-10-28
Also published as: JP2002179564A

Abstract

Antifungal agents containing as the active ingredient compounds having a hydronaphthalene ring structure, in particular, albicanol in the hydronaphthalene ring structure moiety and sclareol, sclareolide, manool, labdanolic acid etc. being similar in structure thereto each optionally having various substituents. These antifungal agents are efficacious against fungi inducing opportunistic infection.

Description

Description Antifungal Technical Field

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

With the remarkable development of antimicrobial drugs, mainly antibiotics, antifungal drugs are not always in a satisfactory state, judging from their type and effectiveness.

Deep fungal infections to humans include candidiasis, aspergillosis, cryptococcosis, and mucormycosis, and include other imported mycosis, including actinomycosis, nocardiosis, chromoblast mycolysis, and hiss Toplasosis, coccidioidomycosis, geotrichum disease, penicillium disease, etc. are known. There are also superficial mycosis such as athlete's foot and bugs.

In particular, in recent years, aging and postoperative surgery have led to a decline in biodefence due to general-purpose use of anticancer drugs, immunosuppressants, steroid hormones, etc., and AIDS infection.

Opportunistic infections caused by fungal infections such as Candida, Aspergillus, and Cryptoococcus have become one medical problem, and the development of therapeutics for them is desired.

Currently, chemotherapeutic agents such as amphotericin B, fluconazole, itraconazole, miconazole, and 5-fluorocytosine are used as therapeutic agents for these fungal infections.

However, these chemotherapeutics are not always satisfactory in terms of toxicity and therapeutic effect. However, the emergence of resistant bacteria is also a problem. In order to solve this problem, clinically useful antifungal drugs with excellent selectivity are desired. The present inventors have conducted intensive studies in order to respond to this request, and have previously found that a cribtoporic acid derivative is excellent as an antifungal agent, and have made one proposal (International Publication W096 / 25385).

Cryptopollic acid derivatives are a group of compounds represented by the following structural formula and the like.

(Wherein R 11, R 12, and R 13 are the same or different and may be a hydrogen atom, an alkyl group, particularly a lower alkyl group, and more specifically, a methyl group R 14 is a methyl group, a hydroxymethyl group or an acetyloxymethyl group, and R 15 is an alkylidene group such as a methylidene.

In addition, examples of the cryptoporic acid derivative also include a dimer including a ring of the compound represented by Structural Formula 2 or the like. Disclosure of the invention

The present inventors have paid attention to the fact that cryptoporic acid derivatives are excellent as antifungal agents, studied the mechanism of action of the cryptoporic acid derivatives, and further studied the function and structure. of Accordingly, the present inventors have conducted intensive studies to find compounds that have a strong antibacterial activity against the above-mentioned fungi that cause opportunistic infections, that is, can be effectively used as antifungal agents. That is, the present invention seeks to provide a novel antifungal agent.

The present inventors have conducted intensive studies to achieve the above object, and found that among the structures of the cryptopoloic acid derivatives, the hydronaphthylene ring structure has a great effect on the antifungal activity, that is, the hydronaphthalene Albicanol having a ring structure and sclareol, sclareolide, manol, labdanolic acid, etc. having a similar structure, and those obtained by adding various substituents thereto, as well as derivatives thereof and two rings obtained from copearl resin The inventors have found that all of the sex diterpenes and their derivatives have antifungal activity, and have completed the present invention.

That is, the present invention may have an unsaturated bond represented by the following structural formula: ぃ a hydronaphthene ring structure, and the structure derived from isosquenic acid may be formed through an ether bond. The present invention relates to an antifungal agent comprising, as an active ingredient, a compound that is not bonded to the methyloxy group at the 9-position of a ren ring.

(In the formula, R 1, R 2, and R 3 may be the same or different from each other, and may be an alkyl group which may have a substituent, and R 4 may have a carbon atom which may have a substituent. The hydroxy group and the hydroxy group A carboxyl group at the head of a straight-chain hydrocarbon having 0 to 3 carbon atoms, which may have an organic group or a substituent group having an ether, ester or urethane bond derived from a droxy group, and an ester derived from the carboxyl group; Alternatively, it is an organic group having an amide bond. )

The carboxyl group at the head of a straight-chain hydrocarbon having 0 carbon atoms means that the carboxyl group is directly added to the hydronaphthalene ring.

Hereinafter, the present invention will be described in detail.

In the compound of the present invention, the center of the structure is a hydronaphthylene ring, and more specifically, as shown in the structural formula, R 4 and R 3 are substituted at the 4-position, and R 1 is substituted at the 10-position. Alkyl groups which may have a group, especially hydronaphthylene to which a methyl group is added, or R 1 and R 2 are alkyl groups, especially a methyl group, and R 3 is a hydroxyalkyl group or a substituent or a protecting group. Or a carboxyl group having a carboxyl group or a carboxyl group having a substituent or a protecting group, and the hydronaphthylene ring may partially have an unsaturated bond.

R 4 is a straight-chain hydrocarbon having 1 to 4 carbon atoms, which may have a substituent, and a hydroxy group and an organic group having an ether, ester or urethane bond originating from the hydroxy group. Or an organic group having a carboxyl group and an ester or amide bond derived from the carboxyl group at the tip of a linear hydrocarbon having 0 to 3 carbon atoms which may have a substituent.

Further, the present invention is also characterized in that an organic group defined by R 4 is further added to the 8-position to the hydronaphthylene ring, which can be actively synthesized from a commercially available drug. Is preferred.

Examples of the substituent of R 4 include the following, which have an antifungal effect and side effects. It can be appropriately selected in consideration of the specific examples. Specific examples thereof include a hydroxy group and a group having a substituent or a protecting group attached thereto, a carbonyl group and a group having the group protected by a protecting group, for example, ethylene glycol or the like. Protected, straight-chain or branched alkyl, alkenyl or cycloalkyl groups having up to 10 and preferably up to 8 carbon atoms, such as alkylidene groups having up to 6 and preferably up to 4 carbon atoms, preferably methylidene, etc. Preferably an alkyl group having an aldehyde group having up to 6 carbon atoms, preferably up to 4 carbon atoms, such as a methyl group, an ethyl group, a butyl group, or a cyclohexyl group, and a preferred example is an epoxy group such as a formyl group. Or an alkyl or alkenyl group having a hydroxy group and an epoxy group and having up to 10 carbon atoms, preferably up to 8 carbon atoms, and preferably 3- An alkyl or alkenyl group having one or more hydroxy groups, such as a hydroxy-3-methyl-4,5-epoxypentyl group and having up to 12 and preferably up to 10 carbon atoms, preferably a hydroxymethyl group , 2-hydroxyl, 4-hydroxyl, 3-hydroxy-3-methylpentyl, 3-hydroxy-3-methyl-4-pentenyl, 3,4,5-trihydroxy -3-methylpentyl group, 3,4-bishydroxymethyl-6-hydroxyhexyl group, etc., in which these hydroxy groups have a substituent {methoxymethyl group {methylthiomethyl group} It is protected by a hydroxyl-protecting group such as a tetrahydroviranyl group. Further, an alkyl group or alkenyl group having up to 10 and preferably up to 8 carbon atoms having a heterocyclic compound and up to 3 hydroxy groups, and having 2 or 3 nitrogen atoms as the heterocyclic compound. A 5-membered heteroaromatic monocyclic ring, or a 6-membered saturated monocyclic ring containing one oxygen or iodide and nitrogen, and preferably 3,4-dihydroxy-3-methyl-5- (1-triazolyl) pentyl And morpholinomethyl groups, 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 carbon atoms, preferably up to 10 carbon atoms. And preferably a carboxymethyl group, a 3-carboxypropyl group, a 3-carboxy-2-proveniel group, or a 3,4,5-tricarboxypentyl group. A salt may be formed with a salt, for example, an alkali metal, an earth metal, an amine, or the like.

Further, it is an alkylamino group or an alkenylamino group having up to 8 carbon atoms, preferably up to 4 carbon atoms, preferably an aminomethyl group and the like, which are non-toxic salts such as hydrochloride, hydrobromide, Hydroiodide, sulfate, bisulfate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, benzoate, citrate, glucuronate, methanesulfone Non-toxic salts such as acid salts, p-toluenesulfonic acid salts and the like may be formed. Then, one or more of the following substituents are further bonded to these hydroxy groups, carboxyl groups, amino groups, etc. by esterno, amidoether, tether, urethane, etc. May be. Examples of the substituent include an alkyl group having one or more hydroxy groups and having up to 18 carbon atoms, preferably up to 14 carbon atoms, an alkenyl group having 10 or preferably up to 6 carbon atoms, or an aryl group. And cycloalkyl groups having up to 10 and preferably up to 8 carbon atoms, such as methanol, ethanol, hexanol, dodecanol, cyclohexanol, aryl alcohol, benzyl alcohol, ethylene glycol and the like. And substituents derived from compounds such as glycerin are preferred. Further, it is an alkyl group, an alkenyl group or an aryl group having up to 18 and preferably up to 14 carbon atoms having one or more hydroxyl groups, such as acetic acid, trifluoroacetic acid, caproic acid, dodecanoic acid, and succinic acid. When a substituent derived from a compound such as an acid or benzoic acid is preferred, and a free carboxyl group which does not participate in the binding is present, the carboxyl group may form a non-toxic salt. Further, it is a hydroxy acid having up to 10 and preferably up to 8 carbon atoms containing one or more hydroxy groups and carboxyl groups, for example. For example, a compound such as glycolic acid disodecanoic acid may be used as a substituent, except that isoquinic acid is ether-bonded to methyloxy at the 9-position. When there is a free carboxyl group that does not participate in the binding, the carboxyl group may form a non-toxic salt. Further, it is an alkyl group or an alkenyl group having an epoxy and a hydroxy group and having up to 8 carbon atoms, preferably up to 6 carbon atoms, preferably, for example, a 2,3-epoxypropyloxy group and the like. An alkyl group or an alkenyl group having up to 8 and preferably up to 6 carbon atoms having a hydroxy group and a heterocyclic compound, and the heterocyclic compound is a 5- or 6-membered saturated monocyclic ring containing one nitrogen atom, 5-membered heteroaromatic monocyclic ring containing 2 or 3 nitrogens, 6-membered saturated monocyclic ring containing oxygen or iodine and 1 nitrogen, 5- or 6-membered saturated monocyclic ring containing 2 nitrogens, etc. A preferred example of a 5- or 6-membered saturated monocyclic ring containing one is piperidine and the like, a preferred substituent is a 3- (1-piperidinyl) -2-hydroxypropyloxy group and the like, and two or more nitrogens are used. 5 members including 3 Preferred examples of the aromatic monocyclic ring include triazoledimidazole and the like. Preferred substituents include 2-hydroxy-3- (1-triazolyl) propyloxy group and the like, and oxygen or nitrogen and nitrogen. A preferred example of a 6-membered saturated monocyclic ring containing 6 is morpholine or the like, and a preferred substituent is a 5- or 6-membered saturated monocyclic ring containing 2 nitrogen atoms, such as a 3-morpholino-2-hydroxypropyloxy group. Preferred examples of the compound include piperazine and the like. Preferred examples of the substituent include a 3- (1- (4-methyl) piperazinyl) -2-hydroxypropyloxy group and a 3- (1- (4-hydridyl) group. Xyethyl) piperazinyl) -2-hydroxypropyloxy group, 3- (topiperazinyl) -2-hydroxypropyloxy group, etc., which may form a non-toxic salt . Aliphatic amines having one or more hydroxy groups and having up to 10, preferably up to 8 carbon atoms are preferably 3- (tris (hydroxymethyl) methyl) amino-2-hydroxypropyl. Oxy group, 3-(bishydroxylethyl) amino-2-hydroxypropyloxy group, 3-glucosamyl-2-hydroxypropyloxy group, etc., and these amino groups may form non-toxic salts. Aliphatic amines having up to 10 and preferably up to 8 carbon atoms, preferably cyclohexylamino groups and the like; these amino groups may form non-toxic salts and may be heterocyclic A 5-membered heteroaromatic ring containing 2 or 3 nitrogens, such as an aliphatic amine having a compound and an alkyl group having up to 8 carbon atoms, preferably up to 4 carbon atoms; And a 3- (1-imidazolyl) propylamino group or a 3-morpholinopropylamino group. These amino groups form a non-toxic salt. I And aromatic amines. Preferred examples thereof include compounds such as aniline as a substituent, which may form a non-toxic salt, and further include an aliphatic azide. Preferred examples include an azidomethyl group, etc., and amino acids or amino acids with a protective group, and preferred examples include lysine, aspartic acid, proline, and alanine, which are non-toxic salts. May be further formed, and these substituents may be further bonded to these substituents by ester amide ether, urethane or the like.

Preferred substituents for the present invention include, as examples of the substituent R 4 at the 9-position, a hydroxy group, a hydroxy group protected or substituted with a protecting group, an epoxy group, a hydroxy group and an epoxy group. Alkyl groups or alkenyl groups having up to 10 and preferably up to 8 carbon atoms, such as alkyl groups or alkenyl groups having one or more hydroxy groups and having up to 10 and preferably up to 8 carbon atoms, This hydroxy group may have a substituent or may be protected by a protecting group such as a methoxymethyl group, a methylthiomethyl group, or a tetrahydrobiranyl group, and one or more hydroxy groups and one hetero group. A cyclic compound having an alkyl group or alkenyl group having up to 10 and preferably up to 8 carbon atoms, which may form a non-toxic salt, and having one or more carboxyl groups; Is an alkyl group or an alkenyl group of up to 10, preferably up to 8, and these carboxyl groups may form a non-toxic salt, and are aliphatic amines having up to 10 carbon atoms, preferably up to 8 carbon atoms. The amine may form a non-toxic salt, and these substituents may be further substituted with esters, amides, ethers, ethers, urethanes and the like as follows. One or more substituents may be bonded.

Examples of the substituent attached to the ester, amide-ether-thioether, urethane, or the like include an alkyl group having up to 18 carbon atoms, and a group having up to 18 carbon atoms having one or more hydroxy groups, and preferably having up to 18 carbon atoms. Alkyl group, alkenyl group, aryl group, cycloalkyl group, etc., which has one or more carboxyl groups and has up to 10 carbon atoms or alkenyl groups, etc. This carboxyl group may form a non-toxic salt, and is a hydroxy acid having up to 10 carbon atoms containing one or more hydroxyl groups and one or more carboxyl groups. In this case, the carboxyl group may form a non-toxic salt, and preferably has up to 10 carbon atoms having an epoxy and a hydroxy group. One or more hydroxy groups and one heterocyclic compound such as an alkyl group or alkenyl group having up to 6 and an alkyl group or alkenyl group having up to 8 and preferably up to 6 carbon atoms. Cyclic compounds are 5- or 6-membered saturated monocyclic rings containing one nitrogen, 5-membered heteroaromatic rings containing 2 or 3 nitrogens, 6-membered saturated monocyclic rings containing oxygen or iodine and one nitrogen, nitrogen It is a 5- or 6-membered saturated monocyclic ring containing two or more, which may form a non-toxic salt. In addition, the absence of one or more hydroxy groups Aliphatic amines having several carbon atoms of up to 10 and preferably up to 8, which may form non-toxic salts at these amino groups and the like, and containing a heterocyclic compound. A 5-membered heteroaromatic ring containing 2 or 3 nitrogens, a 6-membered heterosaturation containing oxygen or iodine and 1 nitrogen as a preferable example of the heterocyclic compound. These amino groups may be in the form of a non-toxic salt, may be a non-toxic salt, may be an aromatic amine, may be in the form of a non-toxic salt, and may be an aliphatic group. Azides, amino acids or amino acids with protecting groups, which may form non-toxic salts, or which are further substituted with ester substituents or urea. They may be combined in the evening or the like.

Examples of the substituent at the 8-position include a carbonyl group, a carbonyl group protected with a protecting group, an alkylidene group, an alkyl group, a hydroxy group or a group having a protecting group attached thereto, an alkyloxy group, or an alkyl group attached via a urethane. And aryl groups, alkyl groups having a hydroxy group or a group with a protective group attached thereto, alkylazide groups, alkyl groups containing a 5-membered heteroaromatic ring containing two or three nitrogen atoms, and their non-toxic groups. Salt, a 6-membered heterocyclic monocyclic alkyl group containing one oxygen and nitrogen, which may form a non-toxic salt, in which an amino acid or a protected amino acid is ester-bonded. It may form a non-toxic salt, and is preferably an epoxy group or an alkyl group having an epoxy group. These may be used alone or in a hydroxy group. Or a hydroxy group such as a methoxymethyloxy group with a protecting group and a 6-membered saturated monocyclic ring containing an alkyl group, a hydroxymethyl group and a hydroxy group, and one oxygen atom and one nitrogen atom. Combinations of an alkyl group and a hydroxy group having a 5-membered heteroaromatic ring containing two or three nitrogen atoms and a hydroxy group are also preferable.

R 2 at position 4 is an alkyl group, and R 3 is an alkyl group, Preferred are a hydroxyalkyl group, a hydroxyalkyl group having a substituent or a protecting group, an aldehyde group, a carboxyl group, and a carboxyl group having a protecting group.

Preferred as a combination of the substituent at the 8-position and R 4 are an alkyl group or an alkenyl group to which an alkylidene group at the 8-position and a hydroxy group which may have a substituent at R 4 are bonded, or a substituent. An alkyl or alkenyl group to which a carboxyl group is bonded, which may also have a bond, and a hydroxyalkyl group, an aldehyde group, a carboxyl group, or the like bonded to R 3. Are preferred, and these hydroxy groups and carboxyl groups may have a substituent or a protecting group.

Further, the number of carbon atoms containing an alkyl group and a hydroxy group at the 8-position, an alkyl group or an alkenyl group in which the hydroxy group is bonded to R4, and a hydroxy group and an epoxy group are up to 10 and preferably up to 8. An alkyl or alkenyl group, an alkyloxy group having an alkyl group having a carboxyl group attached through an ester bond, an alkyl group or an alkenyl group having a carboxyl group, a hydroxy group and one or more and one nitrogen An alkyl or alkenyl group having up to 10, preferably up to 8 carbon atoms containing a 5-membered heteroaromatic monocyclic ring containing 2 or 3 and an alkyl group containing a hydroxy group through an ether bond. Such as those in which a nitrogen-containing compound is bonded by a hydroxyalkyl group, and these alkyl or alkenyl groups have a substituent. It is also preferable that R 3 be bonded to a hydroxyalkyl group, an aldehyde group, a carboxyl group, or the like, and the above-mentioned hydroxy group, carboxyl group, etc. have a substituent or a protecting group. It may be.

Further, a carbonyl group at position 8 or a compound protected by a protecting group is represented by R 4 An alkyl or alkenyl group having a carbonyl group or a carbonyl group, which may have a protecting group or a substituent, an alkyl or alkenyl group having a hydroxy group, which may have a protecting group or a substituent, for example, hydroxy Preferred examples include combinations in which an amino acid is ester-bonded to a group and an alkyl group is bonded to the 4-position, and these substituents may form a non-toxic salt.

As the protecting group in the above description, for the hydroxy group, a methoxymethyl group (MOM), a methylthiomethyl (MTM), a tetrahydrodrobilanyl (THP), a t-butyl (t-Bu), a trityl (Trt), a benzyl ( Bzl or Bn), ether-type protecting groups such as p-methoxybenzyl (MP), acyl-type protecting groups such as acetyl, silyl-type protecting groups such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBDMS) In the case of carboxyl groups, ester-type protecting groups such as methyl and benzyl groups, and in the case of silyl ester-type protecting groups such as trimethylsilyl groups, and in the case of carbonyl groups, dimethyl ketones such as ethylene acetal. , Protecting group for amino acid, protecting group for amino acid, protecting group for amino acid, etc. Etc. can be used protecting groups used in the de-synthesis and the like, generally the protecting groups used in organic synthesis and the like can be used.

Substituents include alkyl or alkenyl bonded by a carbon bond, an epoxy or hydroxy group, a carboxylic acid having a hydroxy group, one having one or more carboxylic acids, and nitrogen as a complex. 5- or 6-membered heterocyclic monocyclic ring containing 1 or 3 nitrogens, 5- or 6-membered heterocyclic saturated monocyclic ring containing 1 nitrogen, 5- or 6-membered heterocyclic saturated monocyclic ring containing 2 nitrogens, oxygen or iodine and nitrogen An alkyl or alkenyl having a 6-membered heterocyclic saturated monocyclic ring containing 1 or a 6-membered heteroaromatic bicyclic ring containing 1 nitrogen atom, and may have a plurality of these functional groups bonded, such as ether, ester, and amide. , Of a substituent bonded by urethane, etc. Examples are alkyl or alkenyl or epoxy or hydroxy groups, carboxylic acids with hydroxy groups, those with one or more carboxylic acids, amines, alkyl groups with heterocycles and up to two nitrogens as heterocycles. 5- or 6-membered heteroaromatic monocyclic ring containing 1 or 3 nitrogens, 5- or 6-membered saturated monocyclic ring containing 1 nitrogen, 5- or 6-membered saturated monocyclic ring containing 2 nitrogens, 1 oxygen and 1 nitrogen Alkyl or alkenyl having a 6-membered heterocyclic saturated monocyclic ring, 6-membered heteroaromatic nitrogen containing one nitrogen atom, etc., which may have a plurality of these functional groups bonded, and further having an amino acid and a plurality of hydroxyl groups For example, glycerin, ethylene glycol, and the like, polyethylene glycol, terminal-blocked polyethylene glycol, sugar, and the like can also be used as a substituent.

As the compound in the present invention, for example, commercially available products such as sclareoyl, sclareolide, manol, and rapdanolic acid are applied, and furthermore, those obtained by employing conventional methods for these commercially available products. Derivatives apply. 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 therapeutic agent for mycosis involving fungi such as molds and yeasts included in humans. In the case of oral administration, tablets and capsules In the case of parenteral administration, it can be used as a solution, suspension, ointment and the like. The dosage 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 dosage once to several times a day. . In the case of an injection solution, it can be administered by drip.

For formulation, commonly used vehicles, carriers, swelling agents, excipients, binders, lubricants, buffers, antioxidants, preservatives, stabilizers, flavoring agents, etc. are required for formulation. Unit doses are mixed and formulated. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a ¹ H-NMR chart of AT-5.

FIG. 2 is an NMR chart of AT-24.

FIG. 3 is a ¹ H-NMR chart of AT-25.

FIG. 4 is a 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 HA L-2.

FIG. 8 is an NMR chart of HA L-3.

FIG. 9 is a ¹³ C-NMR chart of HA L-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 an NMR chart of labudanolic acid.

FIG. 14 is a tH-NMR chart of C〇P—e.

FIG. 15 is a ¹ H-NMR chart of C 0 P—a—0 H.

FIG. 16 is an NMR chart of COP—c.

FIG. 17 is an NMR chart of BC-2.

FIG. 18 is a ¹ H-NMR chart of BC-3.

Figure 19 shows a ^13C- MR chart of BC-3. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the present invention will be described below, but these examples do not limit the present invention.

In addition, the antifungal activity measurement method and infection treatment test method in each example are as follows. It is as follows.

Candida albicans) activity assay>

With respect to various compounds, Candida albicans (Candida albicans) was used as a test bacterium, and the susceptibility to the fungus was tested at in r 0 to confirm its activity. The antifungal susceptibility test was performed according to the method proposed in the Journal of the Japanese Society for Medical Mycology, Vol. 36 (1), 62-64 (1995).

The strains used in the experiments used were T IMM 1768 and T IMM33 18 which were provided by Teikyo University Medical Fungus Research Center Yuichi. Among these, the TIMM3318 strain has resistance to azolic antifungal agents.

The culture medium for sensitivity measurement was prepared by dissolving 10.4 RPMI1640 (Irvine Scientific Cat. # 9512) and 2.0 g of sodium bicarbonate in 900 ml of sterile distilled water, adding 34.53 g of MOPS as a buffer, and stirring well until dissolved. Next, the pH was adjusted to 7.0 with sodium hydroxide, the volume was adjusted to 1 liter by adding sterile distilled water, and the solution was sterilized by filtration and stored at 4 ° C.

The test strains were obtained by culturing at least twice at 35 ° C and 24 to 48 hours in YM agar medium (Difco), and then suspended in 5 ml of sterile physiological saline. The absorbance of this suspension was measured at 600 nm, the bacterial amount was determined from a calibration curve prepared in advance, and diluted with a culture medium for sensitivity measurement to a bacterial count of 2 × 10 ³ cells / ml to obtain a test bacterial solution.

The test sample was dissolved using a 20 mM SO-added methanol solution, and a test assay solution was prepared by 2-fold serial dilution.

To test for antifungal susceptibility, dispense 901 medium for sensitivity measurement into a 96-well flat-bottom microplate, add 10/1 test assay solution and 100/1 test bacterial solution to each well, and add Concentrations were made. Place the microplate in a container kept at humidity, incubate at 35 ° C for a maximum of 72 hours, observe every 24 hours, and when the turbidity of the growth control reaches 0.2,ゥ The turbidity of El It was measured.

Determination of 80% inhibitory concentration (IC _{8 Q)} after stirring the microplate mixer, growth controls in broth to 40〃1 up, this sensitivity measuring medium 160〃1 addition, IC _8. A substantial pail was made. The well that showed turbidity equal to or less than the turbidity of this well was defined as the end point.

Aspergillus / ^ aius) activity assay>

1. Chemical solution preparation method

The test drug was weighed and a drug dilution step was made with 20% DMSO-added methanol.

2. Sensitivity measurement medium and preparation method

RPMI1640 (Irvine Scientific Cat. # 9512 ) 10.4g, was dissolved in sterile distilled water 900ml and NaHCO ₃ 2.0, a MOPS 34.53G added and stirred as buffer capacity adjusted to 1 liter after correcting the pH 7.0 with NaOH And used after sterilization by filtration.

3. Preparation of inoculum

The test bacteria were cultured on a potato dextrose agar medium (Difco) at 30 ° C. for 1 week, and sterile physiological saline containing 0.05% Tween80 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

9 Dispense 90/1 medium into a 6-well flat-bottomed microplate, add 10〃1 of the drug solution prepared in 1 80, 801 of the inoculum, and 20〃1 of alamarblue solution to each well. Finally, the DMS0 is 1, the methanol is 4¾, the alamarblue is 10¾, and the growth control is the same medium without drug.) Cultured in a humidified container to prevent drying at 3 0 ° C, it was observed every 2 4 hours, developmental controls the OD _57. When the value reached 0.6, the end point was determined.

5. Judgment of results Using the 80% inhibitory concentration (IC ₈₀ ) for the growth control as the end point, this was defined as the minimum inhibitory concentration. Specifically, the drug concentration was defined as IC ₈₀ (MIC), which showed a measured value equivalent to or less than the measured value of 20 of the growth control.

Healthy growing mice (ICR, 4-week-old, female, 19-22g, Nippon Charles River) were tested against Aspergillus fumigatus (1.0%) suspended in saline containing 0.1% Tween80. (xl0 ^fi CFU / mouse) was inoculated through the tail vein (0.2 ml) to establish infection.

The treatment was performed by dissolving or suspending the sample in a gum arabic solution, and orally administering a 0.2 ml volume each time using a gastric probe (50 mg / kg and 10 mg / kg or 10 mg / kg and 2 mg / kg) o The first time One hour after inoculation, and once a day thereafter, 6 doses were given every 24 hours (once / day, for a total of 7 days). The control group received the vehicle alone in an amount of 0.2 ml.

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 survival rate of 60% or more

Moderately effective 40% survival

Ineffective survival rate of 20% or less

Example 1

Preparation of AT-1

Commercially available sclareolide (1.25 g, 5.00 mmoK Aldrich reagent) is dissolved in a mixture of tetrahydrofuran (hereinafter referred to as THF) (10 ml) and ether (10 ml), and lithium aluminum hydride (10 ml) is stirred under ice-cooling. 190 mg, 5.00 mmol) were added in small portions. After stirring at the same temperature for 1 hour, add ethyl acetate little by little and add excess Was decomposed. 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 sodium hydrogen carbonate solution and a saturated saline solution. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The precipitated crystals were collected by filtration, and two methyl groups were placed at the 4-position, a methyl group and a hydroxy group at the 8-position, and 2-hydroxy at the 9-position. 1.20 g of hydronaphthalene (hereinafter referred to as AT-1) having a droxyshetyl group and a methyl group at the 10th position were obtained as colorless needles (hereinafter, unless otherwise specified in the structural formula description, the 4th and 1st positions were obtained). The description of the methyl group at position 0 is omitted). The 'H-NMR spectrum (400 MHz) was as follows. _{(CDC1 3, ppm): 0.79} (3H, s, Me- CIO), 0.79 (3H, s, Me 5-C4), 0.88 (3H, s, Me monument - C4), 1.20 (3H, s, Me - C8), 1.90 (1H, ddd, J-12.2, 3.4, 2.9, H7), 3.46 (1H, ddd, J = 10.3, 8.3, 5.9, H12), 3.75 (1H, ddd, J-10.3, 4.4, 4.4 , H12,).

Preparation of A T-2

Acetic anhydride (1 ml) was added to a solution of AT-1 (1.20 g, 4.72 mol) in pyridine (1.5 ml) under ice cooling, and the mixture was allowed to stand at room temperature overnight. Ice water (40 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 ml). The extract was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue obtained was subjected to silica gel column chromatography [13 g, 1.5 cm IDxl6.5, eluting solvent: porcine form-ethyl acetate 100 / 0 7 0/3 0], and 1.35 g of hydronaphthylene (hereinafter referred to as AT-2) having a methyl group and a hydroxy group at the 8-position and a 2-acetoxityl group at the 9-position were obtained as a colorless candy. Obtained as a solid. The NMR spectrum (400 MHz) was as follows.

_{(CDC1 3, ppm): 0.79} (3H, s, Me-CIO), 0.79 (3H, s, Me ^ -C4), 0.87 (3H, s, Me monument - C4), 1.16 (3H, s, Me- C8), 1.89 (1H, ddd, J = 12.2, 2.9, 2.9, H7), 4.12 (2H, m, H12 and H12,). Preparation of AT-3

To a solution of the above AT-3 (1.35 g, 4.56 difficult ol) in pyridine (9 ml) was added phosphoryl chloride (860〃1, 9.2 ol) under ice cooling and stirring. The reaction solution was stirred overnight, added to ice water (30 ml), and the product was extracted twice with ethyl acetate (30 ml). 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. Next, a part (250 mg) of the residue was dissolved in ethanol (2.5 ml), and a 1N aqueous solution of sodium hydroxide (2.5 ml) was added, followed by stirring at room temperature overnight. The reaction solution was diluted with water (10 ml) and extracted with ethyl acetate (15 ml), and the extract was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was repeatedly subjected to silica gel column chromatography to obtain 114 mg of a compound represented by the following structural formula (hereinafter referred to as AT-3) as a white iron-like substance. Its ^ -NMR spectrum (400 MHz) was as follows.

_{(CDC1 3, ppm): 0.69} (3H, s, Me-C10) 5 0.80 (? 3H, s, Me / - C4), 0.87 (3H, s, Me monument -C4), 2.00 (1H, ddd , J = 12.7, 12.7, 4.9, H7), 2.39 (1H, ddd, J = 12.7, 4.4, 2.4, H7,), 3.49-3.58 (lH, m, H12), 3.60-3.76 (lH, m, H12,) , 4.54 (1H, d, J = 1.5, H17), 4.83 (1H, d, J = 1.5, H17,).

Preparation of AT-4

To a solution of sclareolide (1.50 g, 6.00 mmol) in THF (4 ml) -ethanol (8 ml) was added 1N aqueous sodium hydroxide solution (12 ml) with stirring. After stirring for 1 hour, 1N hydrochloric acid (15 ml) was added to the reaction solution, and the product was extracted twice with ethyl acetate (30 ml) did. The extract is thoroughly washed with water and saturated saline and dried over anhydrous magnesium sulfate.The solvent is distilled off, and the resulting crystal is recrystallized from ethyl acetate. 1.25 g of hydronaphthalene (hereinafter referred to as AT-4) having a 2-carboxymethyl group was obtained as colorless crystals. Its 1-NMR spectrum (400 MHz) and IR spectrum were as follows.

_{(CDC1 3, pm): 0.79} (3H, s, Me- CIO), 0.79 (? 3H, s, Me -C4) 5 0.88 (3H, s, Me monument _{- C4), 1.17 (3H 5} s, Me- C8), 1.83 (1H, dd, J = 5.9, 4.4, H9), 1.95 (1H, ddd, J = 12.2, 3.4, 2.9, H7), 2.34 (1H, dd, J-16.1, 4.4, H12), 2.50 (1H, dd, J2 16.1, 6.4, H12 ').

(KBr, cm " ¹ ): 3700-2200 (br), 3491, 3340, 3119, 2927, 1720, 1685, 1460, 1432, 1414, 1389, 1201, 938.

Preparation of A T-6

To a solution of AT-2 (1.86 g, 6.25 mmol) in dichloromethane (20 ml) was added chloromethyl methyl ether (715〃1, 9.38 mmol) and pilestilamine (1.74 ml, 9.99 marauders) under ice-cooling and stirring. ol) were added sequentially. After stirring the reaction solution at room temperature for 8 hours, the product was extracted by adding chloroform (30 ml) and water (30 ml), and the extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. did. After drying over anhydrous magnesium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography [30 g, 2.0 cm ID x 20.5, elution solvent: n-hexane ethyl acetate = 100/0 60/40] Thus, 621 mg of a compound represented by the following structural formula (hereinafter referred to as AT-6) was obtained as a colorless candy substance. The NMR spectrum (400 MHz) was as follows.

(CDC1 ₃ , ppm): 0.79 (3H, s, Me-CIO), 0.83 (3H, s, Me? -C4), 0.87 (3H, s, Me-C4), 1.23 (3H, s, Me- C8), 2.06 (1H, ddd , J = 12.2, 3.4, 2.9, H7), 3.37 (3H, s, 0CH 2 0CH 3), 3.45 (1H, ddd, J = 9.8, 9.8, 4.4, H12), 3.72 (1H, ddd, J = 9.8 , 5.4, 4.4, H12,), 4.75 (2H, s, 0CH 2 0CH 3) o

Preparation of A T-7

Sclareolide (1.50 g, 6.00 dishes ol) was dissolved in a mixture of ethanol (8 ml) and THF (4 ml), and a 1N aqueous solution of sodium hydroxide (12 ml) was added with stirring at room temperature. 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, and 1.51 g of a hydronaphthalene (hereinafter referred to as AT-7) having a methyl group and a hydroxy group at the 8th position and a sodium carboxymethyl group at the 9th position is obtained as a colorless product. Obtained as crystals. Its ¹ H-NMR spectrum (400 MHz) and IR spectrum were as follows.

_{_{(CDC1 3 -CD 3 0D = 9}} : 1, ppm): 0.78 (3H, s, Me-CIO), 0.79 (? 3H, s, Me / - C4), 0.87 (3H, s, Me monument one C4) , 1.15 (3H, s, Me-C8), 1.90 (1H, ddd, J = 12.7, 3.4, 2.9, H7), 2.24 (1H, dd, J = 16.1, 3.9, H12), 2.31 (1H, dd, J = 16.1, 6.8, H12,) o

(KBr, cm ¹ ): Preparation of 3700-2600 (br), 3484, 3321, 2925, 1637, 1546, 1406, 1384 _c AT-8

Dissolve AT-4 (1.20 g, 4.5011111101) in a mixture of ether (2.51111) and methanol (2.5 ml), and stir at room temperature to 10% n- of trimethylsilyldiazomethane. The hexane solution was added dropwise 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 are 1N hydrochloric acid, saturated carbonated water The organic layer was washed successively with a sodium phosphate aqueous solution and a saturated saline solution, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography [30 g (10% water-containing silica gel), 2.0 cm ID x 20.5 cm eluting solvent: n-hexane acetate = 100/097/3], 340 mg of the methyl ester of 8-methylene were obtained as a colorless candy substance together with the 7, 8- and 8,9-ene forms. Next, the methyl ester of 8-methylene (250 mg, 0.94 mmol) was dissolved in ethanol (2.5 ml), and a 1N sodium hydroxide solution (2.5 ml) was added, followed by stirring at 80 ° C for 6 hours. did. The mixture was acidified with 1N hydrochloric acid, further diluted with water (5 ml), and extracted twice with ethyl acetate (15 ml). The combined extracts were washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [7.5 g, 1.0 cm ID x 20.5, eluting solvent: ethyl form monoacetate = 100/90/100] and crystallized from n-hexane. As a result, 197 mg of a compound represented by the following structural formula (hereinafter referred to as AT-8) was obtained as colorless needles. Its ¹ H-NMR spectrum (400 MHz) and IR spectrum were as follows.

_{(CDC1 3, ppm): 0.70} (3H, s, Me- CIO), 0.81 (? 3H, s, Me -C4), 0.89 (3H, s, Me monument - C4), 2.09 (br, ddd, J = 12.7, 12.7, 4.9, H7), 2.39 (1H, ddd, J2 12.7, 3.4, 2.9, H7,), 2.39 (1H, dd, J2 15.6, 2.9, H12), 2.53 (1H, dd, J = 15.6, 3.4, H12 '), 4.53 (1H, s, H17), 4.78 (1H, s, H17,).

^{(KBr, cm '1):} 3600-2300 (br), 2937, 2843, 1702, 1649, 1457, 1423, 1385, 1329, 1264, 1192, 896.

Tables 1 and 2 show the results of the antifungal activity and infection treatment test of each prepared compound.

Table 1 Antifungal activity (IC 80

Example 2

Preparation of AT-5

Water (10 ml) is added to a solution of sclareoyl (1.5 g, 4.86 mmol, Aldrich reagent) in acetone (10 ml), and while stirring, an additional 50% N-methylmorpholine N-oxide (2.37 ml, lO .lmmol) and 2% osmic acid aqueous solution (250〃1) added. After stirring the reaction solution at room temperature for 6 hours, a 20% aqueous sodium thiosulfate solution (25 ml) was added, and the product was extracted twice with ethyl acetate (3 Oml). The extract was washed successively 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 IDx2, eluting solvent: quenched mouth form-medium = 100/0 → 80/20], and ethyl acetate was added. After crystallization, hydronaphthylene (hereinafter referred to as AT-5) having a methyl group and a hydroxy group at the 8-position and a 3,4,5-trimethyloxy-3-methylpentyl group at the 9-position 1.55 g was obtained as colorless needles. Its ^ -NMR spectrum _{_{(400MHz: CDC1 3 -CD 3 0D}} = 9: 1) Chiya shows an bets as FIG.

Preparation of AT-14, AT-15

Dissolve sclareol (2.0 g, 6.5 mmol) in dichloromethane (25 ml), and add 3,4-dihydro-2H-pyran (600-1, 6.5 mniol) and pyridinium p-toluenesulfonate under ice-cooling and stirring. 163 mg, 0.65 mmol) were added successively, and the mixture was stirred at room temperature for 24 hours. After the reaction solution was extracted with chloroform, it was washed with a saturated aqueous solution of sodium hydrogencarbonate 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 x 7 cm, proposed solvent: hexane / ethyl acetate = 95/5 to 70/30), and the three compounds represented by the following structural formulas (hereinafter referred to as the following) AT-14 (Chemical formula 7), AT-15 (Chemical formula 8) and AT-16-1 (Chemical formula 9) "are 1.04 g (yield 40.9%), 350 mg (yield 13.8) and 1.25, respectively. g (40.5% yield). In the structural formula, 0THP represents a tetrahydrovinyloxy group. Their properties were as follows:

(AT-14)

Rf value: Silica gel thin layer chromatography: 0.37 [silica gel 60F254 (merc), developing solvent: hexane / ethyl acetate = 4/1], 0.49 [RP-18F 254s (merc), developing solvent: methanol]. Coloring reagent: positive for anisaldehyde reagent (purple).

^ -NMR spectrum _{(400MHz, CDC1 3, ppm)} : 0.79 (6H, s, 20, 18-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, -CH 2), 4,59 (1H, m, l'-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, 18.07,

14-CH).

(AT-15)

Rf value: Silica gel thin layer chromatography: 0.25 [silica gel 60 F254 (Mel), developing solvent: hexane / ethyl acetate = 4/1], 0.51 [RP-18 F254s (Mel) , Developing solvent: methanol].

Coloring reagent: positive for anisaldehyde reagent (purple).

IR spectrum (KBr, Les cnf: 3447, 2940, 2868, 1637, 1459, 1388.

^ -NMR spectrum _{(400MHz, CDC1 3, ppm)} : 0.78 (6H, s, 20, 18 - 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), 3.95UH , m, 5, -CH ₂ ), 4.66 (1H, m,-CH ₂ ), 5.12 (1H, d, J = 1.0,

_{15- CH 2), 5.16 (1H} , d, J two _{3.4, 15-CH 2),} 5.79 (1H, dd, J = 10.7, 18.1, 14-CH) 0 C-NMR spectrum (100 negation z _{, CDC1 3, ppm): 15.5} , 18.5, 18.9, 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.

Preparation of AT-16

AT-16-1 (900 mg, 1.89 mmol) obtained in Example 2 was dissolved in dichloromethane (15 ml), and m-perbenzoic acid (hereinafter referred to as m-CPBA) (932 mg) was stirred with ice cooling. , 5.40 mmol), 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 x 26 cm, developing solvent: hexane / ethyl acetate = 95/5-80/20) to give a compound represented by the following structural formula (hereinafter AT-16) 408 mg (yield: 43.8¾) was obtained.

Then, sodium hydride (81 mg of NaH, 2.0 mmol) was added to 0.5 ml of dimethylformamide (hereinafter referred to as DMF) under a nitrogen atmosphere, and 1H-1,2,4-triazole (140 mg, 0.81 mmol) was added under ice-cooling and stirring. ) (0.5 ml) and stirred at room temperature for 1 hour, then add AT-16-2 (400 mg, 0.81 mmol) in DMF (10 ml) and stir at 60 ° C for 6 hours. The reaction solution was extracted with ethyl acetate, and then saturated brine was added. And 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 x 11 cm, developing solvent: hexane / ethyl acetate = 8/2, chloroform / methanol = 9/1), and a compound represented by the following structural formula (hereinafter referred to as AT) — 195 mg (yield: 42.8%) was obtained.

Next, AT-16-3 (195 mg, 0.35 mmol) was dissolved in methanol (15 ml), pyridinium p-toluenesulfonate (68 mg, 0.28 mmol) was added, and the mixture was allowed to stand 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, lcmID x 24 cm, developing solvent: chloroform / methanol = 10/0 to 9/1), and methyl at the 8th position Group with a hydroxy group, a hydroxy group and a 3,4-dihydroxy-3-methyl-5- (1-triazolyl) pentyl group at the 9-position 108 mg (Yield: AT-16) 79.4%). The characteristics were as follows.

Rf value: Silica gel thin layer chromatography 1: 0.30 [Silica gel 60F254 (Merck), developing solvent: Kuguchiguchi form / medium = 9/1], 0.64 [RP-18F 254s (Merck), developing solvent : Methanol].

Coloring reagent: positive for anisaldehyde reagent (purple).

NMR spectrum _{(400MHz, CDC1 3, ppm)} : 0.77 (6H, s, 18, 20-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 - CH 2), 4.22 (1H, OH), 4.37 (1H, d, J = 13.7, 15-CH ₂ ), 7.83 (1H, s, triazole), 8.22 (1H, s, triazole).

Preparation of AT-24

To a solution of sclareoyl (250 mg, 0.81 mmol) in dichloromethane (20 ml), m-CPBA (350 mg 2.00 mmol) 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-sodium sodium thiosulfate solution (20 ml), a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, 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 IDxl4, elution solvent: chloroform / methanol = 1100/0 → 97/3 (50 ml)] to obtain n-hexaneacetic acid. Crystallized from ethyl and has a methyl group and a hydroxy group at the 8-position and a hydroxy-3-methyl-4,5-epoxypentyl group at the 9-position. Was obtained as colorless crystals. Part ¹ H-NMR spectrum (400MHz: CDC1 ₃₎ Chiya shows an bets as FIG.

Preparation of AT-25

To a solution of sclareoyl (2.00 g, 6.49 mmol) in dimethicone solution was added, in succession, ice-cooled methyl methyl ether (1.08 ml, 15.6 mmol) and disoprovirethylamine (2.94 ml, 16.8 mmol) with stirring under ice-cooling. Was. The reaction solution was stirred at room temperature for 15 hours, added with chloroform (30 ml), washed with water, 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent, remove the residue by silica gel column chromatography [30 g, 2.0 cmIDx2U Elution solvent: n-hexaneethyl acetate = 100 / 0—70 / 30] Obtained. Next, an aqueous solution of osmic acid (200〃1) and 50% N-methylmorpholine N were added to a suspension of the obtained methoxymethyl ether (2.2 g, 5.56 mmol) in acetone (10 ml) -water (10 ml). -Oxide (3.14 ml) was added sequentially, and the mixture was stirred at 54 ° C for 17 hours. After adding an aqueous solution of 20% sodium thiosulfate to the reaction mixture to decompose excess reagent, the product was extracted twice with ethyl acetate (30 ml). The extract was thoroughly washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [22 g, 2.0 cm ID x 5.5 cm, elution solvent: chloroform-form monoethyl acetate = 95/5 50/50], and a methyl group and methoxymethylo at position 8 were obtained. 2.13 g of hydronaphthylene (hereinafter referred to as AT-25) having a xy group and a 4,5-dihydroxy-3- (methoxymethoxy) -3-methylpentyl group at the 9-position was obtained as a colorless candy substance. . Its NMR space-vector (400 MHz: CDC1 ₃₎ Chiya shows an bets as FIG.

Measurement of compound properties>

Tables 3 and 4 show the results of the antifungal activity and infection treatment test of each prepared compound. Table 3 Antifungal activity (IC 80

Table 4 Infection treatment test results

Example 3

Preparation of HAL-1

17.0 mL (5.1 g) of AT-2 obtained in Example 1 was placed in a 200 ml eggplant-shaped flask and dissolved in 50 ml of dichloromethane. With 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.) was added. 1.7 1.7 ol (425 mg) was added. After the temperature of the reaction solution was returned to room temperature, the mixture was stirred for 18 hours. After 18 hours, the reaction mixture was extracted with 20 ml of distilled water and 10 ml of chloroform, and the extract was washed with 20 ml of 1N hydrochloric acid, 20 ml of saturated aqueous sodium hydrogen carbonate and 20 ml of saturated saline, and then dried over anhydrous magnesium sulfate. And dried. This was removed by filtration under reduced pressure, and the residue was obtained by fractionating the residue by silica gel column chromatography (3.0 cm ID x 3.0 cm, eluent: hexane / ethyl acetate = 100/0 to 50/50). Hexane / ethyl acetate = 90 / 10-80 5.5 g of the eluted fraction was transferred to a 200 ml eggplant-shaped flask and dissolved in 50 ml of ethanol. After adding 50 ml of 1N sodium hydroxide water while stirring under ice cooling, the reaction solution was returned to room temperature and stirred for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure to remove the ethanol, and extracted twice with 50 ml of ethyl acetate. Went out. 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 removed by filtration under reduced pressure, and the residue was fractionated by silica gel column chromatography (3.0 cm ID x 4.0 cm, eluent: hexane / ethyl acetate = 100/0-50/50). Hexane / ethyl acetate = 70/30 to 50/50 As a fraction eluted, 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 characteristics are as follows, 'Η-ΝΜΙΙ spectrum (400MHz: CDC1 ₃₎ Chiya one preparative FIG 4, ¹³ C-NMR spectrum (400MHz: CDC1 ₃₎ Chiya 5 an bets As shown.

Rf value: Silica gel thin layer chromatography: 0.75 [silica gel 60 F254 (Merck), developing solvent: Cloth form / methanol = 20/1], 0.24 [RP-18 F254s (Merck), developing solvent: 90% methanol] .

Color reaction: Positive for Ehrlich's reagent (brown), positive for anialdaldehyde reagent (green-brown), positive for 50% sulfuric acid reagent (black).

Preparation of HAL-2

5.8 mmol (232 mg) of hydrogenated sodium (manufactured by Wako Pure Chemical Industries, Ltd.) was weighed into a dried 100 ml two-necked flask, and the inside of the flask was replaced with nitrogen. Then, 4 ml of dehydrated DMF was injected under ice cooling, and HAL-1 was further added. Of 2.9 l (1000 mg) was dissolved in 4 ml of dehydrated DMF and injected. After stirring the reaction solution 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 to 2 ml of DMF under ice-cooling again. And then stirred, followed by stirring at room temperature for 20 hours. After 20 hours, 10 ml of distilled water was added to the reaction solution, and the mixture was extracted twice with 20 ml of ethyl acetate. The extract was washed successively with distilled water and saturated saline, and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off under reduced pressure, and the residue is fractionated by silica gel column chromatography (3.0 cm ID x 20.0 cm, eluent: hexane / ethyl acetate = 90/10 to 50/50). As a result, 690 mg of a colorless oily product of a compound represented by the following structural formula (hereinafter referred to as HAL-2) was obtained as a fraction eluted with hexane / ethyl acetate = 50/50 to 40/60. Its characteristics are as follows, Έ- NMR spectrum (400MHz: CDC1 ₃₎ chart FIG 6, ¹³ C-NMR spectrum (400MHz: CDC1 ₃₎ Chiya shows an bets as FIG.

Rf value: silica gel thin layer chromatography: 0.73 [silica gel 60 F254 (Merck), developing solvent: chromatoform / methanol = 20/1], 0.20 [silica gel 60 F254 (Merck), developing solvent: hexane / Ethyl acetate = 2/1], 0.14 [RP-18 F254s (Merck), developing solvent: 90% methanol].

Color reaction: Positive for Ehrlich reagent (brown), positive for anisaldehyde reagent (yellow-green), positive for 50% sulfuric acid reagent (black).

Preparation of HAL-3

8.8 mmol (352 mg) of sodium hydride was weighed and placed in a dried 100 ml two-necked flask. After the inside of the flask was replaced with nitrogen, 6.0 ml of dehydrated DMF was injected under ice cooling, and 4.4 mmol of HAL-1 (4.4 mmol) was added. 1500 mg) was dissolved in 6.0 ml of dehydrated DMF and injected. After stirring the reaction solution at room temperature for 30 minutes, 8.8 mmol (750 l) of aryl bromide (manufactured by Wako Pure Chemical Industries, Ltd.) was injected under ice cooling. Thereafter, the mixture was stirred at room temperature for 20 hours. After 20 hours, 20 ml of distilled water was added to the reaction solution, and the mixture was extracted twice with 30 ml of ethyl acetate.The extract was washed sequentially with 5 ml of distilled water and 5 ml of saturated saline, and then dried over anhydrous magnesium sulfate. . After drying, the solvent is removed by filtration under reduced pressure and the residue is fractionated by silica gel column chromatography (2.0 cm ID x 8.0 cm, eluent: hexane / ethyl acetate = 100/0 to 20/80). As a result, 1300 mg of a colorless oil of a compound represented by the following structural formula (hereinafter referred to as HAL-3) was obtained as a fraction eluted with hexane / ethyl acetate = 90/10. Its characteristics are as follows, iH-NMR spectrum (400MHz: CDC1 ₃₎ chart FIG 8, ¹³ C-NMR spectrum (400MHz: CDC1 ₃₎ shows a chart as FIG.

Rf value: silica gel thin layer chromatography: 0.85 [silica gel 60 F254 (Merck), developing solvent: black-mouth form / methanol = 20/1].

Color reaction: Positive for Ehrlich's reagent (brown), positive for anisaldehyde reagent (purple), positive for 50% sulfuric acid reagent (black).

Preparation of HAL-4

1.8 mmol (700 mg) of HAL-3 is weighed into a 30 ml eggplant-shaped flask, 5 ml of acetone and 2 ml of distilled water are added, and then N-methylmorpholine-N-oxide (manufactured by Tokyo Chemical Industry Co., Ltd.) under ice-cooling. : 50 aqueous solution) 3.3 Marauder 01 (780 1) and Osumi II The humic acid solution 501 was added. Thereafter, the mixture was stirred at room temperature for 20 hours. After 20 hours, 5 ml of a 10% aqueous sodium hydrogen sulfite 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, and the extract was washed with distilled water and saturated saline in this order, and dried over anhydrous magnesium sulfate. After drying, the solvent is removed by filtration under reduced pressure, and the residue is separated by silica gel column chromatography (2.0 cm ID x 5.0 cm, eluent: chloroform / methanol = 100/1 to 100/100). As a result, 756 mg of a colorless oily product of the compound represented by the following structural formula (hereinafter referred to as HAL-4) was obtained as a fraction eluted with chloroform / methanol = 100/3 to 100/5. Its characteristics are as follows, -NMR spectrum (400MHz: CDC1 ₃₎ shows a chart as FIG zero.

Rf value: silica gel thin-layer chromatography: 0.60 [silica gel 60 F254 (Merck), developing solvent: chloroform / methanol = 10/1], 0.36 [silica gel 60 F254 (Merck), developing solvent: hexane / Ethyl acetate = 1/4], 0.23 [RP-18F 254s (Merck), developing solvent: 90 methanol].

Color reaction: Positive for Ehrlich reagent (purple), positive for anisaldehyde reagent (yellow-green), positive for 50% sulfuric acid reagent (purple).

Preparation of HAL-5

Sodium periodate 1.6 orchid 01 (3401½) was weighed into a 50 ml eggplant-shaped flask, and 3.5 ml of distilled water and 1.1 ol (435 mg) of HAL-4 were added at room temperature to a 3.5 ml jar. The mixture was dissolved in setone and added, followed by stirring 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 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 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 acetate and 1.7 mmol (636 ml) of a dione's reagent (2.67 fflmol / ml) were added under ice-cooling, followed by stirring for 1 hour. After 1 hour, add isopropyl alcohol until the reaction solution turns green, add an appropriate amount of celite, further add 30 ml of getyl ether, filter the cerate, and filter the filtrate in distilled water and saturated saline. And then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off under reduced pressure under filtration, and the residue is subjected to silica gel column chromatography (1.5 cm ID x 5.0 cm, eluent: chromatoform / medium 2-100 / 1 to 0/1100). By fractionation, the chromate form / methanol = 100/100 to 100/50 eluted as a fraction eluted with a methyl group and a hydroxy group at the 8-position and a 2-carboxymethyl group at the 9-position. As a result, 176 mg of a colorless oily substance of hydronaphthylene (hereinafter referred to as HAL-5) having a (toxic) ethyl group was obtained. Its characteristics are as follows, iH-NMR spectrum (400MHz: CDC1 ₃₎ shows a chart as FIG 1. Rf value: Silica gel thin layer chromatography: 0.20 [silica gel 60 F254 (Merck), developing solvent: Cloth form / methanol = 5/1], 0.36 [RP-18F 254s (Merck), developing solvent: 90% methanol ].

Color reaction: Positive for Ehrlich reagent (purple) / positive for anisaldehyde reagent (purple) / positive for 50% sulfuric acid reagent (purple).

0, CHO

"'^ ΟΤΗΡ Measurement of compound properties>

Tables 5 and 6 show the results of the antifungal activity and infection treatment test of each prepared compound.

Table 5 Antifungal activity (I C80: 〃g / ml)

Test bacteria type

A. fumigatus C. albicans C. albicans

Susceptible strains

H A L-1 0.25 8 1 6

H A L-2 0.5 8 1 6

H A L-3 0.5 8 32

H A L-4 1 1 6 1 6

H A L-5 32> 1 28 32 Table 6 Infection treatment test results

A. fumigatus A. fumigatus

Dose 50mg / kg Dose 10mg / kg

H A L-1 valid valid

H A L-2 valid valid

H A L-3 Valid Valid

H A L-4 Enable Disable

H A L-5 Invalid Invalid Example 4

Preparation of manol

2.5 g of methanol oil was subjected to silica gel column chromatography (50 g, 3 cm ID x 7 cm, developing solvent: hexane / ethyl acetate = 10/0 to 7/3), and the manol-containing fraction (1.28 g) was crystallized with hexane. To obtain 800 mg of manol crystals represented by the following structural formula. Its characteristics are as follows.

Rf value: silica gel thin layer chromatography: 0.66 [silica gel 60 F254 (Merck), developing solvent: hexane / ethyl acetate = 4/1], 0.53 [RP-18 F254s (Merck), developing solvent: methanol].

Color reaction: positive for anisaldehyde reagent (purple).

Melting point: 53 ° C (Measured value.

IR spectrum (max. Cm- ¹ ): 3391, 2923, 2846, 1714, 1643, 1458.

^ -NMR spectrum _{(400MHz, CDC1 3, pm)} : 0.67 (3H, s, 20- CH 3), 0.80 (3H, s, 18-CH 3), 0.87 (3H, s, 19-CH 3 ), 1.27 (3H, 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 (1H, dd, J = 17.1, 1.0, 15-CH ₂ ), 5.91 (1H, dd, J 2 17.1, 10.7, 14-CH).

¹³ C-NMR spectrum _{(100MHz, CDC1 3, ppm)} : 14.4, 17.7, 19.4, 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, 148.8.

Preparation of Manol E

2.0 g (6.9 mmol) of methanol was dissolved in 15 ml of dichloromethane, and 3.57 g (20.7 mmol) of m-CPBA was added under ice-cooling and stirring, followed by stirring at room temperature for 2 hours. The reaction solution was extracted with chloroform, washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (50 g, 3 cm IDxl6 cm, developing solvent: hexane / ethyl acetate = 95/5-60/40), and the following structure was obtained. 1.79 g (yield 80.6%) of hydronaphthylene (hereinafter referred to as manol E) represented by the formula was obtained. Its 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-18 F254s (Merck), developing solvent: methanol.

Coloring reagent: positive for anisaldehyde reagent (purple).

'H-NMR spectrum _{(400MHz) c5ppm (CDCl 3)} : 0.80 (3H, s, 20 - CH 3), 0.83 (3Η, 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 (1H, 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) ₀

Preparation of Manol F

2.0 g (6.9 mol) of manol was dissolved in 20 ml of dichloromethane, and 1.79 g (10.½mol) of m-CPBA was added under ice-cooled stirring, followed by stirring at room temperature for 2 hours. The reaction solution was extracted with chloroform, washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, 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 cms, developing solvent: hexane / ethyl acetate = 9/1 to 8/2), and hydronaphthylene (hereinafter referred to as “manol F”) represented by the following structural formula ) 1.49 g (70.6% yield). Its characteristics are as follows.

Rf value: Silica gel thin layer chromatography: 0.33 [silica gel 60 F254 (Merck), developing solvent: hexane / ethyl acetate = 4/1], 0.58 [RP-18 F254s (Merck), developing solvent: methanol].

Color reaction: positive for anisaldehyde reagent (purple).

IR spectrum (max, cm " ¹ ): 3447, 2932, 2866, 1640, 1460, 1389, 1367 _c- NMR spectrum (400 MHz) 6 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 = 4A , 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-CH ₂ ), 5.19 (1H, dd, J = 17.1, 1.5, 15-CH 2), 5.88 (1H, dd, J = 17.1, 10.5,14-CH).

Preparation of Manol G

400 mg (1.25 mmol) of methanol E was dissolved in 13/3 (16 ml) of THF / water, 100 l of 70 perchloric acid was added under ice-cooling stirring, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with ethyl acetate, washed with 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 (10 g, 1.5 cm IDxl4 cm, developing solvent: chloroform / methanol = 10/0 to 8/2), reversed-phase column mouth chromatography (Cosmosil 75C18-0PN 50 cc, 2 cm IDxl6 cm, developing solvent) : 20-100¾ methanol), silica gel column chromatography (9 g, 1.5 cm ID l2 cm, developing solvent: chloroform / methanol = 10 / 0-8 / 2), and a hydroxymethyl group and a hydroxy group at the 8th position Has a 3,4,5-trihydroxy-3-methylpentyl group at position 9 85.1 mg (yield: 19%) of hydronaphthylene (hereinafter referred to as manol G) was obtained. Its characteristics are as follows, 'H- NMR spectrum (400MHz: CDC1 ₃₎ Chiya - shows the door as Figure 1 2.

Rf value: Silica gel thin layer chromatography 0.24 [SiliKigel 60 F254 (Merck), developing solvent: chloroform / medium = 9/1], 0.70 [RP-18 F254s (Merck), developing solvent: methanol].

Color reaction: positive for anisaldehyde reagent (purple).

IR spectrum (max, cm " ¹ ): 3386, 2926, 2866, 1647, 1459, 1388. Preparation of Manol H

Dissolve 1.23 g (3.8 mmol) of methanol E in 15 ml of dichloromethane, and stir under ice-cooling with stirring for 3,4-dihydro-2H-pyran 690-1 (7.6 ban 01), pyridinium p-toluenesulfonate 95 mg (0.38 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with chloroform, washed with 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 (35 g, 2 cm ID x 25 cm, developing solvent: hexane / ethyl acetate = 100/0 to 75/25) to give a tetrahydroviranyl ether compound (manoyl ether) represented by the following structural formula. 517 mg (yield 33%) of 1 H-1) was obtained.

Subsequently, 154 mg (6.4 mmol) of sodium hydride was added to 1 ml of DMF under a nitrogen atmosphere, and 442 mg (6.4 mmol) of 1H-1,2,4-triazole in DMF (1.5 ml) was added under ice-cooling and stirring. Was added and stirred at room temperature for 1 hour. Thereafter, a DMF solution (2 ml) of 517 mg (1.28 mmol) of methanol H-1 was added, and the mixture was 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 x 21 cm, developing solvent: hexane / ethyl acetate = 8/2) to give a triazole (manol H-2) represented by the following structural formula. 250 mg (41.3% yield) was obtained.

Next, 250 mg (0.53 mmol) of methanol H-2 was dissolved in 2 ml of methanol, 58 mg (0.23 mmol) of pyridinium P-toluenesulfonate was added, and the mixture was stirred at room temperature for 24 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 3 cm _N developing solvent: kuguchi mouth form / methanol-100/0 to 94/6) and reversed-phase column chromatography (Cosmo Seal 75C18-OPN50cc) 2cmIDx 17cm, developing solvent: 60-85% methanol) to obtain 62.5 mg (yield 30.5%) of a compound represented by the following structural formula (hereinafter referred to as manol H). Its characteristics are as follows.

Rf value: silica gel thin layer chromatography: 0.58 [silica gel 60F254 (merck), eluent: chloroform / methanol = 9/1], 0.65 [RP-18 F254s (merck), eluent: methanol].

Color reaction: positive for anisaldehyde reagent (purple). Melting point: 53 ° C.

IR spectrum (max, cm " ¹ ): 3421, 2936, 2366, 1717, 1647, 1513, 1460, 1388, 1367, 1276, 1205, 1139, 1080.

- NMR spectrum _{(400MHz, CDC1 3, ppm)} : 0.80 (3H, s, 20-CH 3), 0.83 (3H, s, 18- CH 3), 0.90 (3H, s, 19-CH 3) , 1.16 (3H, 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-CHJ, 4.24 (1H, OH), 4.41, 4.46 (1H, d, J = 14.16, 15- CH 2), 7.86UH , Triazole), 8.14 (1H, Triazole).

Tables 7 and 8 show the results of the antifungal activity and infection treatment test of each prepared compound.

Table 7 Antifungal activity (IC 80 jug / ml)

Test bacteria type

A. fumigatus C. albicans C. albicans

Susceptible strains a,-anti-fungal drug-resistant strain Mal> 1 2 8> 1 2 8 1 2 8

Mano-le E 8 6 4 1 6

Mano-4 4 1

Mano-le G 3 2 6 4 4

Mar H 3 2 1 2 Table 8 Infection treatment test results

Example 5

Preparation of compound>

Preparation of AL B 00 3,07,08

According to the method of Maria Riavis et al. (J. Chem. Soc. Perkin Trans 1, 815-817 (1985)), three compounds represented by the following structural formula (hereinafter referred to as ALB003匕 23 2), AL B 707 (匕 2 4), ALB 008 (ィ匕 2 525). The structure was confirmed by the following ^{1 H-NMR (400MHz, CDC1} 3, ppm) spectrum Torude Isseki.

A L B 00 3

4.83 (1H, d, J = 1.5Hz, vinylic CH), 4.66 (1H, d, J: 1.5Hz, vinylic 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 (3H, s, Me), 0.88 (3H, s, Me), 0.81 (3H, s, Me).

A L B 00 7

7.96 (1H, d, J = 1.0Hz, -0-CO-H), 5.27 (1H, dt, J = 5.4, 11.2Hz, CH-0-C0),

3.66 (3H, s, -COOMe), 2.33 (1H, d, J = 11.2, CHC00), 2.29 (1H, m), 1.74 (1H, m), 1.56-1.15 (7H, m), 0.98 (2H, m), 1.03 (3H, s, Me), 0.89 (3H, s, Me), 0.83 (3H, s, Me) ₀

AL B 00 8 4.05 (1H, m, CH-O-CO), 3.69 (3H, s, -COOMe), 2.15 (1H, m, cyclic CH), 2.08 (1H, d, J = 10.8Hz, CHCOO), 1.84 (1H , m, cyclic CH), 1.74 (1H, m, cyclic CH), 1.56-1.15 (6H, m), 0.97 (3H, s, Me), 0.95 (2H,), 0.89 (3H, s, Me), 0.82 (3H, s, Me).

COOMe

COOMe

Preparation of ALB 004, 00 5, 0 15

According to the method of Maria Riavis et al. (J. Chem. Soc. Perkin Trans 1, 815-817 (1985)), three compounds represented by the following structural formula (hereinafter referred to as ALB004 Dani 2 6), ALB 00 5 (Dani 2 7), ALB 0 15 (28)). Its structure was confirmed from the following NMR (400 MHz) spectrum.

AL B 004

_{(DMSO- d 6, ppm):} 4.80 (1H, s, vinylic CH), 4.66 (1H, s, vinylic CH), 2.67 (1H, s, CH-COO), 2.35 (1H, m, cyclic CH), 2.02 (1H, m, cyclic CH), 1.7-1.05 (9H, m, cyclic CH), 0.97 (3H, s, Me), 0.86 (3H, s, Me), 0.80 (3H, s, Me) ₀

A L B 005

_{(CDC1 3, ppm): 4.94} (1H, d, J = 1.0Hz, vinyl), 4.64 (1H, d, J two 1.0Hz, vinyl), 3.82 (2H , m, CH 2 -0), 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), 0.8K3H , s, Me), 0.72 (3H, s, Me).

A L B 0 1 5

_{(CDCl 3, ppm): 4.90} (1H, brs, vinyl), 4.75 (1H, brs, vinyl), 3.93-3.50 (2H, m, CH 2 - 0), 2.37-1.20 (12H, m, cyclic CH) , 0.97 (3H, s, Me), 0.89 (3H, s, Me), 0.83 (3H, s, Me).

OH

Preparation of ALB 009, 0 10

A suspension obtained by adding 120 ml of anhydrous DMF to 15 g of ALB003 and 48.1 g of lithium iodide was heated and refluxed for 4 hours under a nitrogen stream. The reaction solution was transferred to a chloroform solution 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 is subjected to silica gel column chromatography (n-hexane: chloroform = 6: 4 to 0:10), which has a methyl group at position 8 and a carboxyl group at position 9 and has a double bond at positions 7 and 8. 3.4 g of hydronaphthylene (hereinafter referred to as ALB 909) linked by the bond, and its isomer, hydronaphthylene (hereinafter referred to as ALB 0 1), which is bonded by a double bond at the 8- and 9-positions 6.2 g). The spectrum of the 'H-NMR (400 band z) of ALB 909 and the ¹³ C-NMR (100 MHz) of ALB 009 and ALB 010 are as follows.

AL B 009

_{_{(CDC1 3, DMS0-d 6}} > ppm): 11.8 (1H, br, C00H), 5.49 (1H, brs, vinylic CH), 2.78 (1H, brs, CH-C00), 2.03-1.16 (9H, m, cyclic CH), 1.62 (3H, s, allylic Me), 0.94 (3H, s, Me), 0.91 (3H, s, Me), 0.87 (3H, s, Me). _{_{(CDC1 3, DMS0-d 6}} , ppm): 172.3, 127.9, 121.7, 60.1, 47.4, 40.2, 37.8, 33.9, 31.5, 31.1, 21.7, 20.2, 19.7, 16.8, 13.0.

AL B 0 1 0

_{(CDC1 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 A L B 0 1 1

Lg of AL B09 was dissolved in anhydrous THF, 5.2 ml of Red-Al (65 wt% in toluene) was added dropwise, and the mixture was 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 and concentration of the filtrate, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate 85:15 to 80:20:20) to give a methyl group at position 8 and a methyl group at position 9. There was obtained 590 mg (63) of a hydronaphthylene (hereinafter referred to as ALB011) having a hydroxymethyl group and having the 7-position and the 8-position bonded by a double bond. The ¹ H-NMR (400 MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 5.54} (1H, t, J two 1 · 95Ηζ, vinyl CH), 3.86 (1H, dd, J = 2.9, 11.2Hz, CH- 0), 3.74 (1H, dd, J = 4.9 , 11.2Hz, CH-0), 1.98-1.03 (10H, m, cyclic CH), 1.79 (3H, s, allylic Me), 0.89 (3H, s, Me), 0.87 (6H, s, 2Me) ₀ ALB Preparation of 0 1 3

2.3 g of AL B 005 and 1.69 g of anhydrous furanic acid 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 a saturated saline solution and dried over anhydrous sodium sulfate. After drying, filtration is performed, and the filtrate is distilled off under reduced pressure. The obtained white solid is washed with a small amount of ethyl acetate, and the solid is dried to obtain a compound represented by the following structural formula (hereinafter referred to as AL B 0 13) 3 lg (82% yield). The iH-NMl 400MHz) spectrum data is as follows.

(DMS0-d ₆ , ppm): 13.1 (1H, br, C00H), 7.76-7.54 (4H, m, aromatic CH), 4.84 (1H, s, vinylic CH), 4.60 (1H, s, vinylic CH), 4.50 (1H, dd, J = 3.9, 11.2Hz, CH-0), 4.3K1H, dd, J-8.3, 11.2Hz, CH-0), 2.4-1.1 (12H, m, cyclic CH), 0.87 (3H , S, Me), 0.80 (3H, s, Me), 0.75 (3H, s, Me).

Preparation of ALB 0 14

10 g of AL B07 (40 ml of THF solution) was added dropwise to a suspension of 1.75 g of lithium aluminum hydride and 20 ml of THF cooled in an ice bath. 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 a saturated saline solution, dried over anhydrous sodium sulfate. The aqueous layer was extracted twice more with ethyl acetate, and the combined organic layers were washed with saturated saline, and dried over anhydrous sodium sulfate. After drying, filtration was performed, the filtrates were combined, and the solvent was distilled off under reduced pressure to obtain 7.8 g of a reaction mixture. The residue was purified by recrystallization from ethyl acetate to obtain 6.4 g (80 kg) of hydroxynaphthalene 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 'Η-NMR (400 MHz) spectrum and the following data were obtained from the literature (Brian J. Lavey et al., J. Org. Chem. 59, 5492-5495 (1994) ) And confirmed.

_{(CDC1 3, ppm): 4.03} (1H, d, J = 3.91Hz, OH), 4.00 (1H, m, CH-0), 3.53 (2H, m, CH 2 -0), 1.83 (1H, m, cyclic CH), 1.69 (1H, 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) ₀

Preparation of AL B 0 18

600 mg of AL B 08, 590 mg of benzoic anhydride, and N, N-dimethylamino 29 mg of pyridine (hereinafter abbreviated as DMAP) 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), and hydronaphthylene having a benzoyloxy group at the 8-position and a methoxycarbonyl group at the 9-position (hereinafter ALB) 700 mg (83%) was obtained. The 'Η-NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 7.95} (2H, m, aromatic CH), 7.51 (1H, m, aromatic 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 ALB 0 19

Under a nitrogen atmosphere, 4.06 g of ALB008 was dissolved in 50 ml of dehydrated THF and stirred in an ice bath. Further, 712 mg of 60% NaH 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 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), and hydronaphth having a methoxy group at the 8-position and a methoxycarbyl group at the 9-position. Evening lent (hereinafter ALB 0 19) 4.07% was obtained. Its ^ -NMR ^ OOMHz) spectrum data is as follows.

(CDCl ₃ , ppm): 3.66 (3H, s), 3.51-3.58 (1H, td), 3 · 30 (3Η, s), 2.27-2.31 (1H, m), 2.09UH, d), 1.10-1.73 (10H, m), 1.02 (3H, s), 0.88 (3H, s), 0.82 (3H, s).

Preparation of AL B 0 20

When ALB008 was subjected to Swern oxidation, hydronaphthylene having a methylthiomethyloxy group at the 8-position and a methoxycarbonyl group at the 9-position (hereinafter referred to as ALB020) was also obtained. The NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 4} · 63 (1Η, d, J = 11.2Hz, 0-CH-S), 4.59 (1H, d, J = 11.2Hz, 0-CH-S), 3.99 (1H, dt , J = 5.4, 11.2Hz, CH-0), 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, cyclic CH), 1.69-1.13 (10H, m, cyclic CH), 1.03 (3H, s, Me), 0.93 (1H, m, cyclic CH), 0.88 (3H, s, Me), 0.82 (3H, s, Me). Preparation of ALB 0 21

700 mg of ALB 011 was dissolved in 15 ml of ethyl acetate, and 20 mg of 5% palladium carbon (Pd / C) was added. The inside of the reaction vessel was set to a hydrogen atmosphere, and vigorously stirred at room temperature for Ί days. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 85:15) to give hydronaphrene having a methyl group at the 8-position and a hydroxymethyl group at the 9-position ( (Hereinafter referred to as ALB021) 507 mg (72%) was obtained. Its ^ -NMR ^ OOMHz) spectrum data is as follows.

(DMS0-d ₆ , ppm): 4 · 08 (1Η, dd, J = 2.0, 3.9 Hz, OH), 3.59 (1H, m, CH-0), 3.32 (1H, m, CH-0), 2.1 K1H, m, cyclic CH), 1.66-1.12 (10H, m, cyclic CH), 0.92 (2H, m, cyclic CH), 0.89 (3H, d, J: 7.3Hz, Me), 0.83 (3H, s, Me), 0.80 (3H, s, Me), 0.79 (3H, s, Me).

Preparation of AL B 0 2 3

Under a nitrogen atmosphere, 260 mg of ALB019 was dissolved in 10 ml of THF, and the mixture was stirred in an ice bath. To it was added 45 mg of LiAlH ₄ and stirred for 15 minutes. At room temperature After stirring for 1 hour, the reaction solution was diluted by adding ethyl acetate, washed once with 2N hydrochloric acid, further twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration, the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 80:20), and hydronaphrene having a methoxy group at the 8-position and a hydroxymethyl group at the 9-position ( (Hereinafter referred to as AL B 0 2 3) lOlmg was obtained. The 'H-NMIU 400MHz) spectrum data is as follows.

_{(CDC1 3, pm): 3.78-3.8K2H} , d), 3.60- 3.63 (1H, m), 3.40 (3H, s), 2.26-23K1H, m), 0.95-1.79 (11H, m), 0.88 (3H , s), 0.79 (3H, s), 0.78 (3H, s) ₀

Preparation of ALB0224

Under a nitrogen atmosphere, 400 mg of ALB019 was dissolved in 20 ml of DMF and stirred, and 1200 mg of Lil and 200/1 of formic acid were added thereto and stirred 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). Hydronaphine having a methoxy group at the 8-position and a carboxyl group at the 9-position ( (Hereinafter referred to as ALB024) 150 mg (40%) was obtained. The 'H-NMR ^ OOMHz) spectrum is as follows.

(CDCl ₃ , ppm): 3.50-3.57 (1Η, td), 3.33 (3H, s), 2.28-233 (1Η, m), 2.11-1.14 (1H, d), 1.12- 1.74 (11H, m), 1.04 (3H, s), 0.89 (3H, s), 0.83 (3H, s).

Preparation of AL B 0 82

Dissolve 230 mg of ALB014 in 10 ml of DMF, add 150 l of pyridine, add 700 ^ 1 of fluoroisocyanate, and stir at room temperature for 1 hour did. After further stirring at 40 ° C. for 2 hours, the reaction solution was diluted with ethyl acetate, washed twice with a saturated saline solution, and dried over 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 (^ -hexane: ethyl acetate = 80: 20) to obtain the following structure. 280 mg (60%) of the compound represented by the formula (hereinafter referred to as ALB082) was obtained. The 'H-NMR ^ OOMHz) spectrum is as follows.

(DMS0, 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 (lH, m), 4.10-4.30 (2H, m), 2.22 (1H, m), 1.05-1.85 (11H, m), 0.96 (3H, s), 0.89 (3H, s), 0.83 (3H, s).

Tables 9 and 10 show the results of the antifungal activity and infection treatment tests of the prepared compounds. Table 9 Antifungal activity (IC 80

Table 10 Infection treatment test results

Example 6

Preparation of compound>

Preparation of AL B030

9 g of sclareolide was suspended in 300 ml of p-dioxane, 200 ml of a 28% aqueous ammonia solution was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure and dried to obtain 10.69 g of a hydronaphthylene having a methyl group and a hydroxy group at the -8-position and a rubamoylmethyl group at the ninth position (hereinafter referred to as ALB030). ^ -NMR ^ OOMHz) The spectrum data is as follows.

_{(DMS0 - 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 CH), 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), 0.75 (3H, s, Me) ₀

Preparation of ALB 031

5 g of ALB030 was dissolved in a mixed solvent of 80 ml of acetate and 20 ml of water, 8.8 g of bis (trifluoroacetoxoxy) chloride was added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform: methanol = 98: 2 to 90:10) to give a methyl group, a hydroxy group, and a ninth position at the 8th position. As a result, 1.72 g of hydronaphthylene (hereinafter referred to as ALB031) having an aminomethyl group was obtained. The ^ -NMiU 400MHz) spectrum was as follows, and ninhydrin coloring was positive.

_{(CDC1 3, ppm): 3.26} (2H, m, CH2-N), 2.03 (1H, m, cyclic CH), 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 AL B 0 73

254 mg of AT-1 and 1001 of pyridine were added to 10 ml of THF and stirred. To this was added 250ζ1 of phenylisocyanate, and the mixture was stirred at room temperature for 4 hours. Thereafter, the reaction solution was diluted by adding chloroform to the reaction solution, washed twice with a saturated saline solution, and dried by adding anhydrous sodium sulfate. After drying, filtration is performed, the filtrate is concentrated, dissolved in η-hexane, insolubles are removed, and the residue is purified by silica gel column chromatography (η-hexane: ethyl acetate 70:30). Then, 295 mg (80) of a compound represented by the following structural formula (hereinafter referred to as ALB073) was obtained. The 'H-NMIU 400MHz) spectrum is as follows.

(DMS0-, pm): 9.48 (1H, s, H), 7.43-7.46 (2H, d), 7.23- 7.29 (2H, t), 6.96-6.98 (lH, 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).

Preparation of AL B 0 7 4

254 mg of AT-1 and pyridine ΙΟΟ / Π were added to 10 ml of THF, and phenylisocyanate 800/1 was added thereto, followed by stirring at 50 ° C. for 14 hours. Thereafter, the reaction solution was diluted by adding chloroform to the reaction solution, washed twice with a saturated saline solution, and dried by adding anhydrous sodium sulfate. After drying, filtration, the filtrate is concentrated, and the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10) to obtain a compound represented by the following structural formula (hereinafter referred to as “the compound”). 400 mg (85) of ALB074). The 'H-NMR ^ OOMHz) spectrum is as follows.

_{(DMS0- 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).

Preparation of AL B 0 75

256 mg of AT-1 was dissolved in 5 ml of DMF, 100 ml of pyridine was added, 250 ml of cyclohexyl isocyanate was added, and the mixture was stirred at room temperature for 15 hours. Thereafter, the reaction solution was diluted by adding chloroform to the mixture, washed once with 2N 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 purified by silica gel column chromatography (n-hexane: ethyl acetate 90:10 to 70:30) to give a compound represented by the following structural formula ( 245 mg (65%) of ALB 075) was obtained. The ¹ H-NMR (400 MHz) spectrum is as follows.

_{(DMS0- d 6, ppm):} 6.83 (2H, d, NH), 3.80-4.10 (3H, m), 1.02-1.80 (20H, m), 1.0K3H, s), 0.84 (6H, s), 0.76 (3H, s), 0.72 (3H, s).

Preparation of AL B 0 76

256 mg of AT-1 and 100 ml of pyridine were added to 5 ml of DMF, and the mixture was stirred. To this was added 200,200,200,000-trifluorotrifluoroisocyanate, and the mixture was stirred at room temperature for 14 hours. Thereafter, the reaction solution was diluted by addition of chloroform, and the mixture was washed once with 2N hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying and filtration, the filtrate is concentrated, and the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10 to 70:30) to give a compound represented by the following structural formula ( ALB 0 7 6 ) 210 mg (48%) was obtained. The iH-NMR OOMHz spectrum is as follows.

(DMS0-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).

Preparation of ALB084

A suspension of 6.28 g of NaH (60% in oil) in 40 ml of THF was ice-cooled, a 100 ml solution of dehydrated THF containing 20 g of AT-1 was added dropwise, and the mixture was stirred at room temperature for 1 hour. Thereafter, 18.7 ml of benzyl bromide was added 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 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: 1-8: 2), and the reaction product (28.3 g, Rf = 0.5 (silicone force) Gel thin-layer chromatography, n-hexane: ethyl acetate = 8: 2) was obtained.

15 g of the reaction product was dissolved in 50 ml of pyridine, cooled with ice, and 6.74 ml of mesyl chloride was added. After removing the ice bath, the mixture was stirred at room temperature for 15 hours. After adding a small amount of water, pyridine was distilled off, the residue 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 saturated saline and then dried over anhydrous sodium sulfate. Dried. 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 6.12 g of a compound represented by the following structural formula (hereinafter referred to as ALB084) (43¾). ). Rf was 0.68 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 9: 1).

Preparation of AL B 085

4 g of ALB084 was suspended in a mixed solution of 40 ml of carbon tetrachloride, 40 ml of acetonitrile 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 re-extracted 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), and 1.38 g of a compound represented by the following structural formula (hereinafter referred to as ALB085) ( 39¾). The 'Η-NMR (400 MHz) spectrum was as follows, and Rf was 0.27 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 9: 1).

_{(CDC1 3) ppm): 7.3K5H} , m, Ph), 4.49 (1H, d, J = 12.21Hz, CH-Ph), 4.41 (1H 3 d, J = 12.21Hz, CH-Ph), 3.52 (1H , m, CH-0), 3.28 (1H, m, CH-0), 2.40 (1H, m, 7-CH), 2.26 (2H, m, 7-CH and 9-CH), 2.0 (2H, m , cyclic CH and CH-CH ₂ -0), 1.8-1.4 (7H, m, cyclic CH and CH-CH ₂ -0), 1.3-1.1 (2H, m, cyclic CH), 0.96 (3H, s, Me), 0.85 ( 3H, s, Me), 0.72 (3H, s, Me).

Preparation of ALB086

6 g of ALB084 was dissolved in 70 ml of dehydrated black-mouthed form, and 5.4 g of m-chlorofiltrated perbenzoic acid was added in three portions, followed by stirring 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 then dried over anhydrous sodium sulfate. After drying, the mixture is filtered, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5 to 90:10) to give a compound represented by the following structural formula. 3.37 g (70%) was obtained (hereinafter referred to as AL B086). Rf was 0.5 (silica gel thin layer chromatography, n-hexane: ethyl acetate 9: 1).

Preparation of AL B 06 7

2 g of ALB086 was dissolved in 10 ml of THF, 2 ml of an aqueous solution of 70% sodium perchlorate was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was partitioned between ethyl acetate and water. After the mixture was washed, the organic layer was washed with a saturated saline solution and dried over 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, the mixture is filtered, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9:;! To 7: 3) to give a hydroxymethyl group, a hydroxy group, 341 mg (22%) of hydronaphthalene (hereinafter referred to as ALB067) having a hydroxyxetyl group at its position and 227 mg (i) of its benzyl ether form were obtained. 'H-NMR (400 MHz) spectrum of ALB067 The following table shows the results of the Vectore, and the Rf was 0.15 (n-hexane: ethyl acetate = 8: 2).

_{(DMS0- d 6): 4.60 (} 1H, t, J: 5.9Hz, -OH), 4.44 (1H, s, -OH), 3.65 (1H, m, CH-0), 3.56 (1H, dd, J = 8.3, 16.1Hz, CH-0), 3.10 (1H, dd, J = 5.9, 10.7Hz, CH-0), 2.87 (1H, dd, J = 5.9, 10.7Hz, CH-0), 1.93 ( _{1H, m, CH-CH 2} - 0), 1.79-1.05 (11H, m, cyclic CH and _{CH-CH 2 -0), 0.89-0.75} (2H, m, cyclic CH), 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 0% 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 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 (1 ^ -hexane: ethyl acetate = 9: 1 to 8: 2) to obtain a methyl group and a hydroxy group at the 8th position, and a hydroxyxetil at the 9th position. Thus, 179 mg of hydronaphthylene (hereinafter referred to as ALB068) having a hydroxy group was obtained. Its NMR (400 MHz) spectrum data was as follows; Rf was 0.3 (silica gel thin-layer chromatography, n-hexane: ethyl acetate = 8: 2). (DMS0-d ₆ ): 4.47 (1H, s, -OH), 3.73 (1H, m, CH-0), 3.45 (1H,, CH-0), 2.01 (1H, m, CH- CH ₂ -0 ), 1.81-1.05 (12H, m, cyclic CH and _{CH- CH 2 -0), 1.02 (} 6H, s, Me * 2), 0.85 (3H, s, Me), 0.82 (3H, s, e) Q

Preparation of ALB 071 ''

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 solution of ammonium chloride, 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, the mixture is filtered, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3 to 5: 5, pore form: medium = 7: 3). Thus, 606 mg of a reaction product was obtained. Rf was 0.23 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 6: 4).

A solution of 600 mg of the above reaction product in 20 ml of dehydrated chloroform-form 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 separated with a liquid form and a sodium hydrogencarbonate aqueous solution, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer was re-extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After drying, the mixture is filtered, the filtrate is concentrated, and subjected to silica gel column chromatography (closure form: medium = 98: 2 to 9: 1) to give a 1-triazolylmethyl group at position 8 212 mg (45%) of hydronaphthylene having a hydroxy group and a hydroxyxetyl group at the 9-position (hereinafter referred to as ALB071) were obtained. That

) The spectrum was as follows, and Rf was 0.38 (thin gel thin layer chromatography, black form: methanol = 9: 1).

_{(DMS0-d 6): 8.32} (1H, s, bets Riazoru CH), 7.88 (1H, s , preparative Riazo Ichiru CH) of, 4.29 (1H, d, J = 14.2Hz, CH-N), 4.15 (1H, d, J = 14.2Hz, CH-N), 3.44 (2H, m, CH 2 -0), 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 AL B 0 8 7

29 mg of a 4,4-dimethyl-8-epoxy-9-hydroxyxethyl derivative of a decahydrodronaphthalene compound obtained by the method described in the literature (Helvetica Chimica Acta, Vol. 73, 1935-1947 (1990)) was added to 5 ml of morpholine. And 212 mg of lithium perchlorate was added, followed by stirring 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 give a compound represented by the following structural formula (hereinafter referred to as ALB087 and ぃぅ) 2501 Got ^ The -NMiU 400MHz) spectrum is as follows.

(DMS0-d ₆ , ppm): 3.58 (4H, t), 3.54 (2H, t), 2.40-2.60 (4H, 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).

Tables 11 and 12 show the antifungal activity and the results of infection treatment tests of the prepared compounds. Table 11 Antifungal activity (IC 80 g / \)

Table 12 Infection treatment test results

Example 7

Preparation of ALB 035

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, followed by stirring at room temperature for 15 hours. Separate the reaction solution with black form and 2N hydrochloric acid, The organic layer was washed with saturated saline 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 = 95: 5 to 90:10) to obtain a reaction product. Using the above reaction product as a raw material, Swern oxidation is performed, and the obtained reaction mixture is subjected to silica gel chromatography (n-hexane: ethyl acetate = 98: 2 to 95: 5) to obtain the following. 4.2 g (75%) of the compound represented by the structural formula (hereinafter referred to as ALB 035) was obtained. R f was 0.41 (silica gel thin-layer chromatography, n-hexane: ethyl acetate = 95: 5).

Preparation of ALB044

Under a nitrogen stream, 2 g of ALB 035 was dissolved in 25 ml of dehydrated ethyl acetate and cooled to 120 ° C. 5.6 ml of 1.6 M n-butyllithium was slowly added dropwise thereto, and the mixture was stirred at 0 ° C for 2 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 was performed, and the filtrate was concentrated and subjected to silica gel column chromatography (II-hexane: ethyl acetate 98: 2) to obtain 2.1 g of a reaction product. A solution of this 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 was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 80: 20-75: 25) to give an n-butyl group at the 8-position. 900 mg (54%) of hydronaphthylene having a hydroxy group and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB044) were obtained. The 'H-NMR ^ OOMHz) and ¹³ C-NMR (100MHz) spectrum data are as follows.

(DMS0-d ₆ , ppm): 4.99 (1H, t, J = 4.4Hz, OH), 3.98 (1H, s, OH), 3.74 (1H, m, CH-0), 3.60 (1H, m, CH -0), 1.80 (1H, m, cyclic CH), 1.6-1.05 (14H, m, cyclic CH), 1.02 (3H, s, Me), 0.90-0.72 (6H, m, Me and cyclic CH), 0.84 (3H, s, Me), 0.80 (3H, s, Me).

_{(DMS0-d 6, ppm)} : 79.15, 73.64, 57.66, 57.09, 55.17, 42.46, 41.64, 38.07, 37.73, 33.48, 32.95, 25.95, 23.08, 21.65, 18.01, 17.90, 16.34, 14.12.

Preparation of ALB045

In a nitrogen stream, 7 g of ALB035 was placed in a 40 ml solution of dehydrated THF, 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 to 7: 3) to give a hydronaphthalene having a carbonyl group at the 8-position and a hydroxymethyl group at the 9-position. (Hereinafter referred to as AL B 045) 3.45 g (74%). The NMR (400 MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 3.96} (1H, dd, J = 9.3, 11.2Hz, CH-0), 3.60 (1H, br, CH- 0), 2.46 (1H, ddd, J = 2.0, 4.9, 14.2Hz , CH-C0), 2.31 (2H, m, CH-CO and CH-CO), 2.03 (1H, m, cyclic CH), 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 AL B 0 42

Under a nitrogen atmosphere, 380 mg of ALB008 was dissolved in 20 ml of dehydrated THF, stirred in an ice bath, 66 mg of NaH was added thereto, and the mixture was stirred for 20 minutes. After further stirring at room temperature for 1 hour, 300 mg of benzylbutane was added and stirred. To the reaction solution Ethyl acetate was added for dilution, and the organic layer was washed once with 2N hydrochloric acid and twice with a saturated saline solution, and dried over anhydrous sodium sulfate. After drying, the mixture is filtered, the filtrate is concentrated, and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10) to give a benzyloxy group at the 8th position and a methoxycarbonyl group at the 9th position. As a result, 500 mg (97%) of hydronaphthene (hereinafter referred to as ALB042) was obtained.

Preparation of AL B 046

To a solution of 4.9 g of ALB 008 and 50 ml of dehydrated acetonitrile in DMAP 7.54, slowly add a 30 ml solution of 4 ml of phenylcrotinoformate in 30 ml of dehydrated acetate, and warm to 40 ° C. While stirring for 15 hours. The reaction solution was partitioned between ethyl acetate and an aqueous solution of ammonium chloride, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying and filtration, the filtrate was concentrated and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 85: 15) to obtain a compound represented by the following structural formula (hereinafter referred to as ALB046). . The ¹ H-NMR (400 MHz) spectrum is as follows, and Rf is 0.57 (silica gel thin layer chromatography, n-hexane: ethyl acetate == 8: 2).

_{(CDC1 3, ρρηι): 7.39} (2H, m, aromatic CH), 7.26 (1H, m, aromatic CH), 7.05 (2H, m, aromatic CH), 5.62 (1H, dt, J = 5A, 11.2Hz, CH-0), 3.70 (3H, s, COOMe), 2.58 (1H,, 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).

Preparation of ALB 049

Under a nitrogen atmosphere, 2 g of ALB008 was dissolved in 40 ml of dehydrated THF, cooled in an ice bath, 355 mg of NaH was added thereto, and the mixture was stirred for 15 minutes. After further stirring at room temperature for 30 minutes, aryl iodide l.lg was added and the mixture was stirred for 2 hours. The reaction solution was diluted by adding ethyl acetate, 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 subjected to silica gel column chromatography (n-hexane: ethyl acetate = 90: 10), which has an aryloxy group at the 8th position and a methoxycarbyl group at the 9th position. 2.0 g (97%) of hydronaphthylene (hereinafter referred to as ALB049) represented by the following structural formula was obtained. The NMR (400 MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 5.8-5.9} (1H, m), 5.08-5.22 (2H, dd), 3.88-4.08 (2H, m), 3.69-3.73 (lH, m) 3 3.66 (3H, s), 2.21-2.26 (1H, m), 2.15 (1H, d), 1.14-1.72 (10H, m), 1.02 (3H, s), 0.88 (3H, s), 0.82 (3H, s).

Preparation of AL B 0500

300 mg of ALB049 was dissolved in 10 ml of dehydrated black hole form 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. The reaction solution was diluted by addition of chloroform, and the organic layer was washed twice with a saturated saline solution, and dried by adding anhydrous sodium sulfate. After drying, the mixture is filtered, the filtrate is concentrated, and the mixture is subjected to silica gel column chromatography (n-hexane: Hydroethyl naphthylene (hereinafter referred to as ALB0500) having the following structural formula having a propyloxy group at the 8-position and a methoxycarbonyl group at the 9-position (ethyl acetate = 90: 10) 235 mg (78 %). Its ^ I-NMR ^ OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 3.65} (3H, s), 3.54- 3.63 (1H, m), 3.20-3.54 (2H, m), 2.1-2.26 (2H, m), 1.12-1.71 (12H, m), 1.02 (3H, s), 0.87 (3H, t), 0.85 (3H, s), 0.82 (3H, s).

Preparation of AL B 0 51

1.25 g of ALB008 and 73 mg of DMAP were added to 20 ml of pyridine and stirred at room temperature. After adding 780 mg of succinic anhydride, the mixture was stirred for 2 hours. After concentrating the reaction solution to about half the volume, ethyl acetate was added to dilute the solution, which was washed once with 2N hydrochloric acid, twice with saturated saline, and dried over anhydrous sodium sulfate. After drying and filtration, 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 ALB051) 1.05 g (60¾). The ^ -NMR ^ OOMHz) spectrum is as follows.

(DMS0-d ₆₃ ppm): 4.95-5.05 (1H, td), 3.57 (3H ₃ s), 239 (4Η, 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).

Preparation of ALB054

2.00 g (8.00 mmol) of ALB05 was dissolved in 200 ml of methylene chloride, 1.21 g (14.4 mmol) of sodium hydrogencarbonate was added, and the mixture was cooled to −78 ° C. under a nitrogen atmosphere. To the reaction solution was added 3.32 g (13.5 mmol) of 70-m-CPBA, and the mixture was stirred overnight while warming to room temperature. 200 ml of 0.5 M ferric sulfate was added to the reaction solution, and extracted twice with ether. The obtained organic layers were combined and washed once with a saturated aqueous sodium hydrogen carbonate solution and once 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), and represented by the following structural formula. 1.44 g (yield: 67%) of the resulting oily compound (hereinafter referred to as ALB 054) was obtained. Its -NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 3.64} (1H, ddd, J = 11.2, 10.8, 2.9Hz), 3.4K1H, dd, J = 11.2, 10.8Hz), 3.22 (1H, dd, J = 3.4, 2.0Hz), 3.12 (1H, d, J = 10.8Hz), 2.72 (1H, d, J = 3.4Hz), 2.01-1.82 (3H, m), 1.70-1.39 (6H, m), 1.2K2H, 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) o

Preparation of ALB 055

477 mg (12.6 mmol) of lithium aluminum hydride was suspended in 30 ml of THF under a nitrogen atmosphere, and 15 ml of a THF solution of 500 mg (2.10 bandol) of ALBO4 was added under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution 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 obtain 415 mg (yield: 84%) of a colorless needle compound represented by the following structural formula (hereinafter referred to as ALB055). Its -NMR ^ OOMHz) spectrum data is as follows.

_{(CDC1 3, ppm): 3.92} (2H, d, J two 6.8Hz), 3.33 (1H, brs ), 2.86 (1H, brs), 1.89 (1H, dt, J = 3.4, 12.2Hz), 1.76- 1.07 (10H, m), 1.35 (3H, s), 0.97 (1H, dd, J = 12.2, 2.0Hz), 0.88 (3H, s), 0.79 (6H, s).

Preparation of ALB 056

Add 500 mg of ALB 008 and 190 mg of isopropyl isopropaneate to 10 ml of dehydrated THF and stir.Add 5001 of triethylamine and stir at room temperature for 1 hour. For 4 hours. Chloroform was added to the reaction solution to dilute it, and the organic layer was washed once with 2N hydrochloric acid and 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 = 80: 20) to give a compound represented by the following structural formula (hereinafter referred to as ALB). 250 mg (38¾). The 'H-NMR ^ OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.98-} 5.07 (1H, m), 3.73-3.79 (1Η, m), 3.65 (3H, s), 3.49 (1H, d), 2.19-2.33 (2H, m), 1.13- 1.71 (13H, m), 1.12 (3H, s), 1.10 (3H, s), 0.88 (3H, s), 0.83 (3H, s).

Preparation of ALB 058

750 mg of AL B049 was dissolved in 50 ml of dehydrated black-mouthed form, and 1.2 g of 85% m-CPBA was added little by little with stirring, followed by stirring for 3 days. The reaction solution was concentrated and purified by silylation gel column chromatography (n-hexane: ethyl acetate: 80: 20) to give a 2,3-epoxypropyloxy group at the 8th position and a methoxycarboxy group at the 9th position. 386 mg (49%) of hydronaphthylene (hereinafter referred to as ALB 058) having a hydroxyl group was obtained.

Preparation of AL B 059

480 mg (2.01 mmol) of AL B 054 was dissolved in 10 ml of MF, 653 mg (10.0 mmol) of sodium azide 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 resulting residue was purified by silica gel column chromatography (16% ethyl acetate / hexane) to give an azidomethyl group at the 8-position. Hydronaphthalene having a hydroxy group and a hydroxymethyl group at the 9-position (hereinafter referred to as ALB059) is a yellow solid. 254 mg (yield: 45%) was obtained. The NMR (400 MHz) spectrum is as follows.

_{(CDC1 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, 2.9 Hz), 1.78-0.99 (11H, m), 0.89 (3H, s), 0.79 (6H, s).

Preparation of ALB 0600

Under a nitrogen atmosphere, 105 mg of N-1-Boc-phenylalanine was dissolved in toluene, and triethylamine 50/1 was added while stirring in an ice bath. To the reaction solution was added 50/1 of Viva-Irk®-Ride and stirred for 15 minutes. After returning to room temperature and stirring for further 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. The 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, 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 90:10) to give 98 mg of a compound represented by the following structural formula (hereinafter referred to as ALB600). (98%). The ^ -NMIU 400MHz) spectrum is as follows.

_{(CDC1 3, ppm): 7.12-7.3K5H} , m), 5.17-5.24 (IH, td), 4.43-4.46 (1Η, 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).

Preparation of ALB 061

To 98 mg of ALB600 was added 1 ml of trifluoroacetic acid, and the mixture was stirred in an ice bath. After 5 minutes, the trifluoroacetic acid was removed under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol: 70: 30) to give 78 mg (100%) of a compound represented by the following structural formula (hereinafter referred to as ALB061). The ^ -NMR ^ OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 7.15-7.30} (5H, m), 5.18-5.30 (1H, m), 3.65-4.00 (1H, m), 3.62 (3H, s), 2.82-3.20 (2H, m), 2.2-2.4 (2H, m) ₅ 1.12- 1.80 (10H, m), 0.98 (3H, s), 0.86 (3H, s), 0.81 (3H, s).

Preparation of ALB062

Under a nitrogen atmosphere, 215 mg of N-1-butoxycarbonyl-L-proline was dissolved in toluene, and while stirring in an ice bath, triethylamine 1401 was added and stirred. To the reaction solution was added 125-1 Viva-Irck-Ride, and the temperature was returned to room temperature. After stirring for 2 hours, insolubles were removed, and the solvent was removed under reduced pressure. 125 mg of ALB08 was added to 2 ml of pyridine and stirred, and the residue obtained above was dissolved in 3 ml of pyridine and added. Further, 10m of DMAP was added and the mixture was stirred at 40 ° C for 1 hour. Pyridine was reduced to half volume under reduced pressure, and ethyl acetate was added. This organic layer was washed once with 2N hydrochloric acid and twice with saturated saline, and dried by adding anhydrous sodium sulfate. After drying, the mixture is filtered and concentrated. The residue was subjected to chromatography (n-hexane: ethyl acetate = 90: 10) to obtain 220ing (97%) of a compound represented by the following structural formula (hereinafter referred to as ALB062). The ^ -NMIU 400MHz spectrum data is as follows.

_{(CDC1 3, ppm): 5.1-5.25} (1H, m), 4.1- 4.3 (1H, m), 3.62 (3H, 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).

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, the trifluoroacetic acid was removed under reduced pressure, and the residue was subjected to gel chromatography (silica gel gel: 90: 10) to obtain a compound represented by the following structural formula (hereinafter referred to as ALB0). 77 mg (100¾) was obtained. The 1-NMR (400 MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 5.21-5.28} (1H, m), 3.99-4.13 (1H, m), 3.65 (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).

Preparation of ALB 064

Under a stream of nitrogen, 800 mg of ALB 035 was dissolved in 10 ml of dehydrated THF and —20. Cooled to C. 3.6 ml of 2M hexylmagnesium chloride was slowly added dropwise thereto, followed by stirring 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 concentration by filtration, the residue was dissolved in 10 ml of dehydrated THF, 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 was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 to 8: 2), and cyclohexyl, hydroxy, and ninth positions were substituted at the 8th and 9th positions. 200 mg (27%) of hydronaphthylene having a hydroxymethyl group (hereinafter referred to as ALB064) was obtained. The 'H-NMR OOMHz) spectrum data is as follows, and Rf is 0.48 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2).

(DMS0-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 ALB08 and pyridine 100/1 were added to 10 ml of dehydrated THF, and the mixture was stirred. To this, 350 mg of phenylisocyanate was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, the reaction solution was diluted by adding chloroform to the mixture, and the organic layer was washed once with 2N hydrochloric acid and twice with saturated brine, and dried over anhydrous sodium sulfate. After drying and concentration by filtration, the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 90: 10-70: 30), and the compound represented by the following structural formula (hereinafter referred to as AL) 210 mg (57%). The ^ -NMIU 400MHz) spectrum is as follows.

(CDC1 "ppm): 7.06-7.37 (5H, m), 5.17-5.18 (1H ₃ td), 3.67 (3H, s), 2.32-2.45UH, m), 2.30 (1H, d), 1.07-1.80 (10H, m), 1.00 (3H, s 0.90 (3H, s), 0.86 (3H, s).

Preparation of ALB066

Under a nitrogen atmosphere, 290 mg of t-butoxy potassium was placed in 5 ml of dehydrated THF and stirred, 200 mg of 1,2,4-triazole dissolved in 2 ml of DMF was added, and the mixture was stirred for 15 minutes. Further, 100 mg of ALB058 was added, and the mixture was stirred at 80 ° C for 4 hours. The reaction solution was diluted by adding ethyl acetate, and the organic layer was washed twice with a saturated saline solution, dried over anhydrous sodium sulfate. After drying, the mixture is concentrated by filtration, and the residue is purified by silica gel column chromatography (form: methanol: 100: 0 to 95: 5). There was obtained 360 mg (73%) of hydronaphthylene (hereinafter referred to as ALB066) having a liazolyl) proviroxy group and a methoxycarbonyl group at the 9-position.

Tables 13 and 14 show the results of the antifungal activity and infection treatment test of each prepared compound. Table 13 Antifungal activity (IC 80

Table 14 Infection treatment test results

Example 8

Preparation of ALB203

Under a nitrogen stream, to a solution of 7.71 ml of DMS0 in 40 ml of methylene chloride cooled to 170 ° C, 8.52 ml of a solution of trifluoroacetic anhydride in 40 ml of methylene chloride was slowly added dropwise over 30 minutes. After further stirring for 30 minutes, a solution of 12 g of AT-6 in 40 ml of methylene chloride was slowly added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. Triethylamine 16.8π was slowly added dropwise over 30 minutes, and then the mixture was stirred for another 2 hours except for a 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 (η-hexane: ethyl acetate = 95: 5-9: 1) to give a methyl group, a methoxymethyloxy group at the 8-position, and a 9-position Formylmethyl group 7.06 g (59%) of hydronaphthylene (hereinafter referred to as ALB203) having the following formula: Its ^ -NMR ^ OOMHz) spectrum is as follows, and R f is 0.50 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 8: 2).

_{(CDC1 3, ppm): 9.6K1H} , br dd, J = 1.0, 1.5Hz, CHO), 4.63 (2H, s, 0- CH 2 -0-), 3.30 (3H, s, 0- Me), Z .45 (1H, m, CH-CHO), 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, cyclic CH), 0.89 (3H, s, Me), 0.84 (3H, s, Me), 0.80 (3H, s, Me). Preparation of ALB 204

1.68 g (60 wt% in oil) of sodium hydride was added to a solution of 20 g of (ethoxycarbonylmethyl) triphenylphosphonium bromide in 100 ml of DMSO, heated to 80 ° C. and stirred for 1 hour. 6.9 g of ALB203 was dissolved in MS030ml, added to the reaction solution, and stirred for 15 hours while heating to 80 ° C. The reaction solution was separated by adding ethyl acetate and water. The organic layer was washed sequentially with water and saturated saline, and dried over 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, the mixture is filtered, the filtrates are combined, 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 give a compound represented by the following structural formula (hereinafter ALB 2 7.22 g (85%) was obtained. The 'Η-NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 7.06} (1H, m, vinyl), 5.74 (1H, m, vinyl), 4.71 (1H, d, J = 7.3Hz, 0-CH-O), 4.63 (1H, d, J = 7.3Hz, 0-CH-O ), 4.15 (2H, m, CH 2), 3.33 (3H, s, 0-Me), 2.4K1H, m, allylic CH), 2.18 (1H, m, allylic CH) , 1.94 (1H, m, cyclic CH), 1.69-1.10 (15H, m, Me * 2 and cyclic CH), 0.92 (2H, m, cyclic CH), 0.86 (6H, s, Me * 2), 0.79 ( 3H, s, Me). COOEt

Preparation of ALB205

6.5 ALB204 was dissolved in 100 ml of ethyl acetate, and about 200 mg of 5% Pd / C was added. The reaction vessel was placed under a hydrogen gas atmosphere, and vigorously stirred at room temperature for 5 days. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to give 6.11 g (94¾) of a compound represented by the following structural formula (hereinafter referred to as ALB205). Obtained. That

The spectrum data is as follows.

_{(CDC1 3, ppm): 4.75} (1H, d, J = 7.3Hz, 0-CH-O), 4.63 (1H, d, J = 7.3Hz, 0-CH-O), 4.1K2H, m, C00CH 2 ), 3.34 (3H, s, 0-Me), 2.29 (2H, m, CH 2 - C00), 1.92 (1H, m, cyclic CH), 1.72-1.09 (16H, m, cyclic CH, CH 2 chain and C00CH ₂ -CH ₃ ), 0.95 (2H, m, cyclic CH), 0.86 (3H, s, Me), 0.80 (3H, s, Me), 0.78 (3H, s, Me) o

COOEt Preparation of ALB 206

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 succinic anhydride l.lg was added thereto, the mixture was stirred for 24 hours. After concentrating the reaction solution to about half the volume, ethyl acetate was added to dilute the solution, which was washed once with 2N hydrochloric acid, twice with saturated saline, and dried with anhydrous sodium sulfate. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography- (form: formanol = 80: 20) to obtain 3.3 g of a compound represented by the following structural formula (hereinafter referred to as ALB206) (95%). The NMR (400 MHz) spectrum is as follows.

_{(CDC1 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).

Preparation of ALB207

Under a nitrogen stream, a solution of ALB205 (1 lg) 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, a solution of 800 mg of getylmalonate in 5 ml of dehydrated THF was added dropwise, and the mixture was further stirred for 2 hours. The reaction solution was partitioned between ethyl acetate and an aqueous solution of ammonium chloride, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The aqueous layer is re-extracted with ethyl acetate, and the organic layer is saturated After washing with brine, it was 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 = 9: 1 to 7: 3), and the compound represented by the following structural formula (hereinafter referred to as ALB207) 860 mg (53%). That

The spectra are as follows, and Rf is 0.3 to 0.5 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 85:15).

_{(CDC1 3, ppm): 4.65} (2H, m, 0-CH 2 -0), 4.15 (6H, m, (CH 2) * 3), 3.32 (3H, s, 0-Me), 3.12 (1H, m, CH-COO), 2.75 (2H, m, CH-COO), 2.39 (1H, m, CH-COO), 1.93 (1H, m, cyclic CH), 1.8-1.1 (26H, m, Me * 4 And cyclic CH), 0.9-0.8 (2H, m, cyclic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me).

Preparation of ALB 208

351 mg of lithium aluminum hydride was suspended in 20 ml of dehydrated THF, cooled with ice, and a solution of 2.5 g of ALB207 in 20 ml of dehydrated THF was added dropwise thereto, followed by removing the ice bath and stirring for 2 hours. 2N hydrochloric acid and ethyl acetate were added to the reaction solution, and the mixture was vigorously stirred and then separated. The organic layer was washed twice with a saturated saline solution, and dried by adding anhydrous sodium sulfate. The aqueous layer was re-extracted twice with acetic Echiru, after the combined organic layers were washed with saturated sodium chloride aqueous solution and dried over anhydrous Natoriumu sulfate ₍ After drying, filtration, the filtrates were combined, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (form: methanol: methanol = 9: 1 to 8: 2) to give a methyl group at the 8-position. , A methoxymethyloxy group, and two types of compounds (Fr. A = 540mg) related to hydronaphthylene (hereinafter referred to as ALB208) having a 3,4-bishydroxymethyl-6-hydroxyhexyl group at the 9-position. Fr.B = 310 mg). The NMR (400 MHz) spectrum data is as follows, and Rf is Fr.A (hereinafter referred to as ALB108-A) 0.25 (silica gel thin-layer chromatography, pore form: methanol = 9: 1), and Fr.B (hereinafter referred to as ALB208-B) is 0.13 to 0.18 (same as above).

AL B 208 -A

(DMSO-d ₆ + D ₂ 0, ppm): 4.68 (1H, m, O-CH-0), 4.54 (1H, m, 0-CH-O), 3.5- 3.3 (6H, m, CH _2- 0), 3.23 (3H, s, 0-Me), 1.85 (1H, m, cyclic CH), 1.65-1.1 (17H, m, cyclic CH and CH chains), 1.11 (3H, s, Me), 0.84 ( 3H, s, me), 0.78 (3H, s, Me), 0.76 (3H, s, Me).

AL B 208 -B

_{_{(DMS0-d 6 + D 2}} 0, ppm): 4.68 (1H, m, O-CH-0), 4.54 (1H, m, O-CH-0), 3.5- 3.3 (6H, m, CH 2 - 0), 3.23 (3H, s , 0-Me), 1.85 (1H, m, cyclic CH), 1.65-1.1 (17H 5 m, cyclic CH and CH chain), 1.11 (3H, s, Me), 0.84 ( 3H, s, me), 0.78 (3H, s, Me), 0.76 (3H, s, Me).

Preparation of AL B 211

0.6 g of ALB204 was dissolved in 30 ml of a mixture of 2N aqueous sodium hydroxide / ethanol = 1/2 and stirred at room temperature for 15 hours. Chloroform was added to the reaction solution to dilute it, and the mixture was acidified by adding a 2N aqueous hydrochloric acid solution. 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 chromatography (n-hexane: ethyl acetate = 7: 3), and a methyl group and a methoxymethyloxy group at the 8-position, and 3- Carboxy 2-Pro Hydronaphthrene having a dinyl group and represented by the following structural formula Fr.A (Chemical formula 56, hereinafter referred to as ALB2111-A) and Fr.B (Chemical formula 57, hereinafter referred to as ALB2111-B) ) Got. The ^ -NMR ^ OOMHz spectrum is as follows, and Rf is 0.20 (Silicon gel thin layer chromatography, n-hexane: ethyl acetate = 8) for ALB211-A. 2), ALB 2 1 1—B is 0.19 (same as above). AL B 2 1 1-A

(DMS0-d6, ppm): 6.25 (1H, m, vinyl), 5.55 (1H, d, J = 11.7Hz, vinyl), 4.63 (IH, d, J = 7.3Hz, 0-CH-O), 4.58 (1H, d, J = 7.3Hz, 0-CH-O), 3.20 (3H, s, 0-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 (3H, s, Me) ₀ AL B 2 1 1-B

_{(DMSO - d 6, ppm)} : 6.85 (1H, m, vinyl), 5.68 (1H, d, J = 15.6Hz, vinyl), 4.65 (1H, d, J = 7.3Hz, 0-CH-O), 4.57 (1H, d, J2 7.3Hz, 0-CH-O), 3.22 (3H, s, 0-Me), 2.32 (IH, 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 (3H, s, Me).

Preparation of ALB212

ALB2111 (mixture of A and B) obtained by hydrolyzing ALB204 was dissolved in 5 ml of THF, 20 ml of an 80% aqueous acetic acid solution and 400〃1 of 2N hydrochloric acid were 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 2.8: 2-6: 4), and a methyl group, a hydroxyl group and a ninth position were placed at the 8th and 8th positions, respectively. 192 mg of naphthylene hydrazine having a 3-carboxy-2-propenyl group (hereinafter referred to as ALB212) were obtained as white crystals. Its ^ -NMR ^ OOMHz spectrum is as follows, and Rf is 0.50 (silica gel layer chromatography, n-hexane: ethyl acetate = 6: 4).

(DMS0-d ₆ ): 6.9K1H, m, vinyl), 5.68 (1H, d, J = 15.1Hz, vinyl), 4.08 (1H, br, OH), 2.38 (1H, m, allylic CH), 2.11 ( 1H, m, allylic CH), 1.72 (1H, m, cyclic CH), 1.6-1.05 (9H, m, cyclic CH), 1.0 (3H, s, Me), 0.85 (2H, m, cyclic CH), 0.84 Preparation of (3H, s, Me), 0.78 (3H, s, Me), 0.76 (3H, s, Me) ₀ AL B2 13

1.2 g of ALB205 was dissolved in 30 ml of a mixture of 2N aqueous sodium hydroxide solution / ethanol = 1/2, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted by adding chloroform and acidified by adding 2N hydrochloric acid, and then 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), and ranked 8th Thus, 970 mg (88%) of hydronaphthylene (hereinafter referred to as ALB213) having a methyl group, a methoxymethyloxy group, and a 3-carboxypropyl group at the 9-position were obtained. As a ^{1 Η-ΝΜίΙ (400ΜΗζ)} spectrum Torude Isseki is as follows, R f 0.21 (Shi Li force gel thin Sokuguchima Togurafi one, hexane n-: acetate Echiru = 8: 2 ).

(DMS0-d ₆ ): 4.68 (1H, d, J = 7.3Hz, 0-CH-O), 4.54 (1H, d, J = 7.3Hz, 0-CH-0), 3.22 (3H, s, 0 -Me), 2.15 (2H, m, CH ₂ C00), 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) _Q

Preparation of AL B 2 14

779 mg of ALB213 was dissolved in 5 ml of THF, 20 ml of 80 acetic acid aqueous solution and 4001 of 2N hydrochloric acid were 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 8th position and a 3rd position at the 9th position. -Hydronaphtherene having a carboxypropyl group (hereinafter referred to as ALB214) was obtained as white crystals. The NMH (400 MHz) spectrum is as follows, and Rf is 0.50 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 6: 4).

(DMSO, ppm): 2.24- 2.06 (2H, m, CH 2 -C00), 1.74-1.5Z (6H, m, CH), 1.39-1.07 (7H, in, 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 A L B 2 15

To a solution of 2 g of ALB2-07 in ethanol was added 10 ml of 6N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with water and neutralized by adding D0WEXlx8H-form. The filtrate was concentrated and subjected to silica gel column chromatography (cloth form: methanol = 95: 5 to 8: 2). Or The two compounds (Fr Fr) 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). .A = 318 mg, Fr.B = 462 mg). The Έ-NMR (400 MHz) spectrum is as follows, and the Rf is 0.4 for Fr.A (hereinafter referred to as ALB 215—A) (Silica gel thin-layer chromatography, Chloroform: The average is 8: 2), and Fr.B (hereinafter referred to as ALB2 15 -B) is 0.3 (same as above).

A L B 2 1 5-A

(DMS0-d ₆ , ppm): 4.65 (1H, m, 0-CH-O), 4.55 (1H, m, 0-CH-O), 3.32 (3H, m, 0-Me), 3.2 (1H, m, CH-COO), 2.75 (2H, m, CH-COO), 2.4-2.3 (lH, 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), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me) ₀

AL B 2 1 5-A

(DMS0-d ₆ , ppm): 4.65 (1H, m, 0-CH-O), 4.55 (1H, m, 0-CH-O), 3.32 (3H, m, 0-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 e), 0.9-0.8 (2H, m, cyclic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me) ₀

Preparation of A L B 2 16

To a solution of 3.6 g of ALB207 in 20 ml of THF were added an aqueous solution of acetic acid 80 and 4001 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 a 6N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with water and neutralized by adding D0WEXlx8H-form. The filtrate was concentrated, and subjected to silica gel column chromatography (cloth form: methanol = 9: 1 to 6: 4) to give the 8th position. Methyl group, Three types of compounds related to hydronaphthylene (hereinafter referred to as ALB216) having a hydroxy group and a 3,4,5-tricarboxypentyl group at the 9-position (Fr.A = 500 mg, Fr.B = 500 mg, Fr.C = 645 mg). The NMR (400 MHz) spectrum is as follows, and the Rf was 0.38 for Fr.A (hereinafter referred to as ALB216-A). 8: 2, 1% acetic acid added), Fr.B (hereinafter referred to as ALB2 16-B) 0.28 (as above), Fr.C (hereinafter as ALB2 16-C) as 0.25 (as above) ). ALB216-A and ALB216-B contain a small amount of a compound from which the 8-position hydroxyl group has been eliminated.

AL B 2 1 6-A

(DMS0-, pm): 3.2 (1H, m, CH-COO), 2.75 (2H, m, CH-COO), 2.4-2.3 (lH, 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), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 (3H, s, Me) ₀

A L B 2 1 6— B

_{(DMSO- d 6, ppm):} 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, cyclic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 ( 3H, s, Me).

AL B 2 1 6-C

_{(DMSO- d 6, ppm):} 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, cyclic CH), 0.85 (3H, s, Me), 0.78 (3H, s, Me), 0.77 ( 3H, s, Me) ₀

Preparation of AL B 222

Dissolve 7.71 ml of DMSO in 40 ml of methylene chloride cooled to 70 ° C under nitrogen flow A solution of 8.52 ml of trifluoroacetic anhydride in 40 ml of methylene chloride was slowly added dropwise to the solution over 30 minutes. After stirring for 30 minutes, a solution of 12 g of AT-6 in 40 ml of methylene chloride was slowly added dropwise over 30 minutes, and the mixture was further stirred for 3 °. After 16.8 ml of triethylamine was slowly added dropwise over 30 minutes, the mixture was stirred for another 2 hours, excluding the dry ice bath. Chloroform was added to the reaction solution to dilute it, and the organic layer was washed twice with a saturated saline solution, 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 9: 1), and apart from the above-mentioned ALB203, methyl was added to the 8-position. , A methoxymethyloxy group, a methylthiomethyloxethyl group at the 9-position, and a methyl group, a methoxymethyloxy group at the 8-position, and a trifluoroacetoxyl group at the 9-position. 1.17 g of Fr.B (hereinafter referred to as ALB2 23) 1.17 g was obtained. The NMR (400 MHz) spectrum is as follows, and Rf is 0.61 for ALB2222 (silica gel chromatography, n-hexane: ethyl acetate = 8: 2). And ALB 2 2 3 is 0.68 (same as above).

AL B 2 2 2

_{(CDC1 3, ppm): 4.75} (1H, d, J = 7.3Hz, 0-CH-O), 4.63 (1H, d, J = 7.3Hz, 0-CH-O), 4.62 (2H, s, 0 -CH ₂ -S), 3.61 (1H, m, CH-0), 3.48 (1H, m, CH-0), 3.35 (3H, s, 0-Me), 2.15 (3H, s, S-Me) , 1.95 (1H, m, cyclic CH), 1.8-1.1 (13H, m, cyclic CH), 1.21 (3H, s, Me), 0.86 (3H, s, Me), 0.83 (3H, s, Me), 0.79 (3H, s, Me).

A L B 2 2 3

(CDC1 ₃ , ppm): 4.69 (2H, m, 0-CH ₂ -0), 4.47 (1H, m, CH-0), 4.33 (1H, m, CH-0), 3.33 (3H, s, 0 -Me), 2.0-1.0 (12H, m, cyclic 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) ₀

Preparation of ALB232

A solution of 1.02 g of AT-1 and 2.02 g of N-1-Boc-a-benzyl-L-glucamic acid p-ditrophenyl ester and 980 mg of DMAP in 20 ml of dehydrated chloroform 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 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 then dried over anhydrous sodium sulfate. After drying, filtration, the filtrates were combined and concentrated. The residue obtained 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 carbonate (Pd / C) was 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 silica gel column chromatography (chloroform: methanol = 95: 5, 9: 1), and the compound represented by the following structural formula (hereinafter referred to as ALB232) 345 mg I got Its Rf is 0.35 (thin-layer gel thin-layer chromatography, black-hole form: methanol = 9: 1), and the iH-NMR OOMHz spectrum data is as follows.

(DMSO d ₆ , ppm): 7.42 (1H, br, NH), 4.03 (2H, m, CH ₂ -0-CO), 3.93 (1H, m, CO-CH-N), 2.2K2H, m, CH ₂ -C00), 1.91-1.05 (14H, m, cyclic CH), 1 · 38 (9Η, s, t-Bu), 0.9-0.7 (2H, m, cyclic CH), 1.00 (3H, s, Me) , 0.84 (3H, s, Me), 0.76 (3H, s, Me), 0.72 (3H, s, Me).

Preparation of AL B 234

N, N £ -Di-1-butoxycarbonyl-L-lysine 3.1 lg of dicyclohexylammonium salt and 1.57 g of pentachlorophenol were dissolved in 12 ml of dehydrated DMF and adjusted to 2M. 40 ml of a DMF solution of -dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) was added, and the mixture was stirred at room temperature for 4 hours. Lg of AT-1 and 40 mg of DMAP were added, and 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 solution of sodium hydrogen carbonate and a saturated saline solution in that 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 then 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 is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (cloth form: methanol = 8: 2 to 7: 3) to give a compound represented by the following structural formula (hereinafter referred to as ALB234). 1.58 g was obtained quantitatively. That

The spectrum data is as follows, and Rf is 0.29 (silica gel thin-layer chromatography, chloroform: methyl = 8: 2).

_{_{(DMS0-d 6 + D 2}} 0, ppm): 4.0 (2H, m, CH 2 -0), 3.58 (1H, m, CO-CH-N), 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, cyclic CH), 0.9 (3H, s, Me), 0.86 (3H, s, Me), 0.82 (3H, s, Me) ₀

Preparation of ALB083

ALB234 is hydrolyzed in a 2N aqueous solution of sodium hydroxide, and has a methyl group at the 8-position and a hydroxethyl group at the 9-position, and a double bond between the 8- and 9-positions. Len (hereinafter ALB 083) was obtained. The 'Η-NMR (400MHz) spectrum is as follows.

(DMS0-, ppm): 4.45 ( 1H, m, OH), 3.35 (2H, m, CH 2 -0), 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, cyclic CH), 0.90 (3H, s, Me), 0.86 (3H, s, Me), 0.80 (3H, s, Me).

Preparation of AL B 344

250 mg (0.739 minol) of AL B 211 was dissolved in 5 ml of THF under a nitrogen atmosphere, and −20. Cooled to C. To the reaction mixture was added 0.11 ml (0.789 mmol) of triethylamine and 0.1 ml (0.812 dragonol) of bivaloyl chloride, and the mixture was stirred at -20 ° C for 1 hour, and then 0.1 ml (0.838 mmol) of 1- (3-aminopropyl) imidazole was added. ) And stirred overnight while raising the temperature to room temperature. To the reaction mixture was added chloroform, and the organic layer was washed three times with a saturated aqueous sodium hydrogen carbonate solution 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 depressurized. The solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography.

(Methanol / chloroform 2/98 to 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 'H-NMR OOMHz) spectrum is as follows.

_{(CDC1 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 = 6.8Hz), 2.18-0.73 (19H, m), 1.56 (3H, s), 0.92 (3H, s), 0.88 (3H, s), 0.82 (3H, s).

Preparation of AL B 345

Using 250 mg (0.739 mmol) of ALB211 and 0.12 ml (0.821imnol) of 4- (3-aminobuguchi) morpholine, almost the same operation as that of ALB344 was performed. The resulting residue was purified by silica gel gel chromatography (methanol / gel mouth form = 2/98 to 4/96) to give a compound represented by the following structural formula (hereinafter ALB345). 164 mg (yield: 55%) was obtained as an oil. The Ή-NM (400MHz) spectrum is as follows. _{(CDC1 3, ppm):.} 6.77 (1H, brs), 3.72 (4H, t, J = 4.4Hz), 3.35 (2H, q 3 J = 6.4Hz), 2.47-2 4 (6H, m), 2.18 -0.73 (19H, m), 1.56 (3H, s), 0.93 (3H, s), 0.88 (3H, s), 0.82 (3H, s).

Preparation of A L B 2 3 7 and 2 3 8

A solution of 480 mg of AT-1, 0.99 g of N-benzyloxycarbonyl-L-aspartic acid P-nitrophenyl ester and 520 mg of DMAP in 20 ml of dehydrated liquid-mouthed form was stirred at 50 ° C. for 6 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed successively 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 then 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 give a condensation product (hereinafter referred to as ALB2). 1.07 g (92) was obtained. Its Rf is 0.55 (silica gel thin-layer chromatography, n-hexane: ethyl acetate = 6: 4). The NMR (400 MHz) spectrum data is as follows.

(DMS0-d ₆ , ppm): 7.79 (1H, d, J = 8.8 Hz, NH), 7.35 (10H, m, Ph * 2), 5.10 (2H, s, benzylic CH), 5.05 (2H, s, benzylic CH), 4.48 (1H, m, CO-CH-N), 4.10 (1H, m, CH-O-CO), 4.03 (1H, m, CH-O-CO), 2.90 (1H, dd, CH -COO), 2.76 (1H, dd, CH-COO), 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), 0.75 (3H, s, Me), 0.71 (3H, s, Me).

Lg of ALB237 was dissolved in 30 ml of methanol, and 50% of 5% Pd / C was 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-C180PN, 70¾ methanol) to obtain 0.4 g of a compound represented by the following structural formula (hereinafter, referred to as ALB238). That

The following is the Stokkulde evening.

(DMS0-, ppm): 4.15 ( 3H, m, CO-CH-N and _{CH 2 -0), 2.50 (2H} , m, CH 2 - C00), 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, Me), 0.73 (3H, s, Me).

Preparation of AL B240

2.97 g of Nt-butoxycarbonylalanine and 4.18 g of pentachlorophenol were dissolved in 30 ml of dehydrated DMF, 9.8 ml of a 2M DMF solution of DCC was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was filtered to remove insolubles The filtrate was concentrated, and 2 g of AT-1 and 30 ml of dehydrated DMF were added to the residue. 940 mg of DMAP was added, the mixture was heated to 80 ° C, and stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3 to 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: methyl alcohol = 8: 2 to 7: 3), and a methyl group, a hydroxy group, and a As a result, 1.63 g (50%) of 3-naaminopropanoyl) oxetyl group-containing hydronaphthalene (hereinafter referred to as ALB240) was obtained. The 'Η-NMR (400MHz) spectrum is as follows.

_{(DMS0- d 6, ppm):} 7.85 (2H, broad, NH 2), 3.9- 4 · 1 (2Η, m), 3.02-3.04 (2H, t), 2.64-2.68 (2H, t), 0.98- 2.10 (14H, m), 0.91 (3H, t), 0.86 (3H, t), 0.8K3H, s), 0.72 (3H, s).

Preparation of A L B 2 41

A solution of 480 mg of AT-1 and Nα, Ν £ -di-benzyloxycarbonyl-L-lysine P-nitrophenyl ester l.llg, 508 mg of DMAP in 20 ml of dehydrated clog form at 50 ° C for 15 hours Stirred. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with an aqueous sodium hydrogen carbonate solution and saturated brine in that 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 brine, dried over anhydrous sodium sulfate, and filtered. The filtrates were combined and concentrated, and the resulting residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3-6: 4) to obtain 1.15 g of a condensation product. 0.7 g of the obtained product was dissolved in 10 ml of methanol, and 50 mg of 5% 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 column chromatography (Cosmosil 140-C180PN, 80¾ methanol) to give a compound represented by the following structural formula (hereinafter referred to as “the compound”). 0.4 g was obtained. The -NMR ^ OOMHz) spectrum is as follows.

(DMS0-d ₆ + D ₂₀ , ppm): 4.0 (2H, m, CH ₂ -0-C0), 3.4-3,2 (3H, m, CO-CH- and CH ₂ -N), 1.75 -0.92 (17H, m, cyclic CH , CH 2 x3 of 9-CH ₂ and 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).

Preparation of ALB072

160 mg of ALB240 and 1001 of pyridine were added to 5 ml of dehydrated DMF, and 120 ml of cyclohexyl isocyanate was added, followed by stirring at room temperature for 6 hours. The reaction solution was diluted by addition of chloroform, 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 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 ALB072). ) 200 mg (88%) were obtained. That

The spectrum data is as follows.

_{(DMS0 - d 6, ppm)} : 3.9-4.2 (3H, m), 3.2 (2H, q), 2.40 (2H, t), 1.00-2.1 (22H, m), 0.9K3H, s), 0.85 (3H , S), 0.81 (3H, s), 0.71 (3H, s).

Preparation of ALB077

And攪拌the 170mg and Pyridine 100 zl of ALB 2 4 0 were added to the dehydrated DMF 5 ml, was added phenylene Ruisoshianeto, was diluted with acetic acid Echiru to 3 hours stirred _c This reaction solution at room temperature, the organic The 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), and the compound represented by the following structural formula (hereinafter referred to as ALB 205 mg (88%). The 'Η-ΝΜΙΚ 400MHz) spectrum is as follows.

(DMS0-d ₆ , ppm): 8.50 (1H, s, NH), 7.36-7.38 (2H, d), 7.18-7.20 (2H, t), 6.88 (1H, t), 6.25 (1H, t), 3.88-4.20 (4H, m), 2.47-2.50 ppm (2H, t), 0.95-2.05 (14H, m), 0.89 (3H, s), 0.86 (3H, t), 0.80 (3H, t), 0.69 (3H, s) ₀

O ^

Preparation of ALB 0 7 8

Under a nitrogen stream, 354 mg of ALB206 was dissolved in 10 ml of dehydrated DMF, and the mixture was stirred in an ice bath. Further, 200 g of aminopropyl morpholine, 101 mg of triethylamine and 270 mg of HOBt were added, and the mixture was 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. 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 (form: methanol: 80:20) to give 375 mg (78%) of a compound represented by the following structural formula (hereinafter referred to as ALB078). Obtained. Its ^ -NMRWOOMHz) spectrum is as follows.

_{(MSO- d 6, 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 (16H, m), 1.01 (3H, s), 0.84 (3H, s), 0.76 (3H, s), 0.73 (3H, s).

Preparation of AL B 079

Under a nitrogen stream, 354 mg of ALB206 was dissolved in 10 ml of dehydrated DMF, and the mixture was stirred in an ice bath. Further, 150 mg of aminoprovir imidazole, 101 mg of triethylamine, and 270 mg of HOBt were added, and the mixture was 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. afterwards, The reaction solution was diluted with ethyl acetate, 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 (chloroform: medium = 80:20), and the compound represented by the following structural formula (hereinafter referred to as ALB079) 360 mg (80% ). The NMR (400 MHz) spectrum is as follows.

_{(DMS0- d 6, ppm):} 7.9 (1H, t, H), 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),

Preparation of ALB080

Under a nitrogen atmosphere, 354 mg of ALB206 was dissolved in 10 ml of dehydrated DMF, and the mixture was stirred in an ice bath. Further, trishydroxymethylaminomethane 1501, triethylamine 101 mg, and HOBt 270 mg were added, and the mixture was 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. The reaction solution was diluted with ethyl acetate, 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 (chloroform: methanol = 80: 20) to give a compound represented by the following structural formula (hereinafter referred to as ALB0800). 420 mg (85%). The 'H-NMR ^ OOMHz) spectrum is as follows.

(DMS0-d ₆ , ppm): 7.19 (1H, s), 4.66 (t, OH), 3.90-4.10 (2H, m), 3.51 (6H, d), 2.43-2.5K4H, m), 0.95-1.80 (17H, m), 0.84 (3H, s), 0.76 (3H, s), 0.73 (3H, s).

Tables 15 and 16 show the results of the antifungal activity and infection treatment test of each prepared compound.

Table 15 Antifungal activity (IC 80 y ^ / ffll)

Table 16 Infection treatment test results

Example 9

Preparation of ALB104

330 mg of ALB 005 was dissolved in 10 ml of pyridine, 250〃1 of hexanoyl chloride was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated to about half the volume, diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with saturated brine, and dried over anhydrous sodium sulfate. After drying The mixture is filtered and the filtrate is concentrated. The residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5) to obtain a hydronaphate having a methylidene group at the 8-position and a hexanoyloxymethyl group at the 9-position. 450 mg (95 mg) of ren (hereinafter referred to as ALB104) was obtained. The 'H-NMR OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.74} (1H, d), 4.51 (1H, d), 4.1-4.4 (2H, m), 2.38-2.41 (lH, 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 suspended in 20 ml of dehydrated THF in an ice bath. 660 mg of ALB 005 was dissolved in 10 ml of dehydrated THF and added dropwise. After stirring for 10 minutes, 950 l of promohexane was added dropwise, and the mixture was stirred at 40 ° C for 3 days. Thereafter, the reaction mixture was diluted with ethyl acetate, and the mixture was washed once with 2N hydrochloric acid and twice with saturated brine, and dried by adding anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 95: 5), and a methylidene group was placed at the 8th position, and a hexyloxymethyl group was placed at the 9th position. 860 mg (94 mg) of hydronaphthylene (hereinafter referred to as ALB 105) having the following formula: Its ^ -NMR ^ OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.86} (1H, d), 4.60 (1H, d), 3.61 (2H, dd), 3.45 (2H, m), 2.37-2.4K1H, m), 1.10-1.75 (12H, m ), 0.90 (3H, t), 0.87 (3H, t), 0.8K3H, s), 0.73 (3H, s).

Preparation of ALB 106

700 mg of ALB 005 and 40 mg of DMAP were added to 30 ml of pyridine, and the mixture was stirred in an ice bath for 30 minutes. After adding acetic anhydride 5001, the mixture was returned to room temperature and stirred for 3 hours. After concentrating the reaction solution to about half volume, add ethyl acetate to dilute, This was washed once with 2N hydrochloric acid and twice with a saturated saline solution, 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 = 95: 5), and hydronaphthyl having a methylidene group at the 8th position and an acetylmethyl group at the 9th position. 790 ing (94%) of ren (hereinafter referred to as ALB 106) was obtained. The NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.85} (1H, d), 4.5K1H, 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. After stirring for 10 minutes, 1. 1 ml of bromine was added dropwise, and the mixture was heated at room temperature for 3 hours and at 40 ° C for 24 hours. Thereafter, 380 mg of NaH and 1.1 ml of promohexane were further added, and the mixture was stirred at 30 ° C for 2 days. Thereafter, the reaction mixture was diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with saturated saline, and dried over anhydrous sodium sulfate. After drying, filtration and concentration of the filtrate, the residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 95: 5), and a residue having a methylidene group at the 8-position and an ethoxymethyl group at the 9-position. 530 mg (67%) of Dronaf Yulen (hereinafter referred to as ALB 107) was obtained. Part ¹ H-R (400MHz) spectrum is as follows.

_{(CDC1 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), 0.8K3H, s), 0.73 (3H, s).

Preparation of AL B 108

350 mg of ALB 005 and 20 mg of MAP were added to 20 ml of pyridine, and the mixture was stirred for 30 minutes in an ice bath. After adding 730 mg of lauric anhydride, 3 Stirred for days. After concentrating the reaction solution to about half the volume, the reaction mixture was diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with saturated saline, and dried by adding sodium sulfate anhydride. 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 a methylidene group at position 8 and a lauroyloxymethyl group at position 9. As a result, 350 mg (54%) of hydronaphthylene (hereinafter referred to as ALB 108) was obtained. That ! The H-NMR (400 MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 4.84} (1H, d), 4.5K1H, 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 AL B109

Under a nitrogen atmosphere, 380 mg of NaH was suspended in 20 ml of dehydrated THF in an ice bath, 350 mg of ALBO5 was added, and the mixture was stirred. After 10 minutes, 2.4 ml of radiuryl iodide was dropped, and the mixture was stirred at 40 ° C for 7 days. Thereafter, the reaction mixture was diluted with ethyl acetate, washed once with 2N hydrochloric acid and twice with a saturated saline solution, 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 = 95: 5) to give a hydronaphthalene compound having a methylidene group at the 8-position and a lauryloxymethyl group at the 9-position. (Hereinafter referred to as ALB109) (280 mg, 45%). The 'H-NMR ^ OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.85} (1H, d), 4.59 (1H, d), 3.48-3.52 (2H, t), 3.33- 3.6K2H, d), 2.36-2.4K1H, m), 1.96-2.07 ( 2H, m), 1.09-1.74 (29H, m), 0.88 (6H, m), 0.81 (3H, s), 0.73 (3H, s).

Example 10

Preparation of AL B 301 and 302 According to the description of tetrahedron (Tetrahedron, 1995, 51, 8333-8338), methyl (±)-(1'hi, 4 '& hi, 8'&?)-Okunohydro-5,, 5, , 8, a-Trimethyl-spiro- [1,3-dioxolan-2,2,-(111)-]-1, -carboxylate (hereinafter referred to as ALB301) and (±)-( 1, hi, 4, ahi, 8, a?) -Ok Even Hydro--5,, 5,, 8, a-Trimethylspiro- [1,3-dioxolan-2,2 '-(1H) -Naphthalene] -Γ-methanol (hereinafter referred to as ALB302) was prepared. The respective 'H-NMR ^ OOMHz) spectrum data are as follows.

A L B 3 0 1

_{(CDC1 3, ppm): 4.11-4.06} (1H, m), 3.96-3.91 (1H, m), 3.87-3.82 (lH, m), 3.76-3.7K1H, in), 3.63 (3H, s), 2.51 (1H, 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, 2.4Hz), 0.89 (3H, s), 0.85 (3H, s).

A L B 302

(CDCI3, ppm): 4.09-4.02 (2H, m), 3.96-3.84 (2H, m), 3.84 (1H, dd, J = 7.8, 3.3Hz), 3.6K1H, d, J = 11.2Hz, 1.96 -1.11 (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 dissolved in 80 ml of THF under a nitrogen atmosphere, and 1.49 g (37.3 rol) of 60% sodium hydride / liquid paraffin was added under ice-cooling. Stirred for 0 minutes. Under ice cooling, 3.41 ml (37.3 mmol) of aryl iodide was added to the reaction solution, and the mixture was stirred at room temperature. 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 was purified by silica gel column chromatography (ethyl acetate / hexane = 2/98 to 4/96) to obtain a head having an ethylene acetal group at the 8-position and an aryloxymethyl group at the 9-position. Lonaf Yuren (hereinafter ALB 303) 2.28 g (yield: 50%) was obtained as an oil. The Έ-Έ 400MHz) spectrum is as follows.

_{(CDC1 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, 1.5 Hz), 4.00-3.80 (6H, m), 3.46 (1H, dd, J = 10.3, 2.9Hz), 3.40 (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 ALB304

8.88 g (28.8 mmol) of ALB303 was dissolved in 250 ml of porcine form, 10.7 g (43.4 mmol) of 70% 3-chloroperbenzoic acid was added, and the mixture was stirred for 20 hours. The reaction solution was washed three times with a saturated aqueous sodium hydrogen carbonate solution 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 by silica gel column chroma preparative chromatography (S i0 _2: 500 ml, acetate Echiru / to hexa down = 1 6/8 4) to give Echirenase evening Ichiru group at the 8-position, the 9-position (2, 77.22 g (yield: 77%) of hydronaphthylene having a 3-epoxypropyl) oxymethyl group (hereinafter referred to as ALB304) was obtained as an oily substance. The ^ -NMR (400 MHz) spectrum is as follows.

(CDCl ₃₃ ppm): 4.02-3.8K4H, m), 3.70-3.31 (4H, m), 3.15-3.11 (1H, m), 2.78-2.76 (lH, 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 (3H, s).

Preparation of AL B305

6.27 g (20.7 mmol) of ALB304 was dissolved in 160 ml of dioxane, 160 ml of 2N sodium hydroxide was added, and the mixture was heated under reflux for 8 hours. After cooling the reaction solution on ice, 160 ml of 2N hydrochloric acid was added, and the mixture was extracted three times with a black hole form. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue silica gel Rukaramukuroma preparative chromatography (Si0 _2: 500ml, acetate Echiru / hexane = 6 7/23 to 0/100), and hydronaphthalene having an ethylene acetate group at the 8-position and a (2,3-dihydroxypropyl) oxymethyl group at the 9-position (hereinafter ALB 3005). 5.60 g (yield: 79%) as an oil. The ¹ H-NMR (400 MHz) spectrum data is as follows.

_{(CDC1 3, pm): 4.03-} 3.78 (5H, m), 3.72-3.44 (6H, m), 1.93- 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 dissolved in 165 ml of methanol, and 6.61 g (30.9 dragonol) of sodium periodate was added, followed by stirring at room temperature for 12 hours. The solvent was distilled off from the reaction mixture under reduced pressure, ether was added to the residue, and the insoluble matter was removed by filtration. 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 and sodium chlorite 8.29 _§ (72.4 dragon ₀ 1 ) Was stirred at room temperature for 15 hours. Under ice-cooling, 200 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted three times with a black hole form. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (150 ml), dicyclohexylcarbodiimide (4.54 g, 22.0 mmol) 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, and the insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (S i0 _2: 400ml, acetate Echiru / hexane = 1 6/8 4) to obtain the compound represented by the following structural formula (hereinafter referred to as ALB 3 0 7) 1.25 g ( Yield: 35%) as a white solid. The -NMIU 400MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 4.16} (1H, d, J = 16.1Hz), 4.05 (1H, d, J = 16.1Hz), 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).

Preparation of ALB308

0.88 g (2.57 mmol) of ALB305 was dissolved in 35 ml of methanol, and 1.39 g (6.50 mmol) of sodium periodate was added, followed by stirring 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 insolubles were removed by filtration. The filtrate was evaporated under reduced pressure. The obtained residue was dissolved in methanol (30 ml), sodium borohydride (494 mg, 13.1 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. Under ice-cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted three times with a black hole form. After drying with anhydrous sulfate isocyanatomethyl Riumu combined organic layers were evaporated under reduced pressure solvent, the resulting residue was purified by silica gel column chromatography and purified by (Si0 ₂ 100 ml, acetate Echiru / hexane = 3 2/6 8) below 760 mg (yield: 95%) of the compound represented by the structural formula (hereinafter referred to as ALB 308) was obtained as an oily substance, and its ^ -NMIU 400 MHz spectrum was as follows.

_{(CDC1 3, ppm): 4.04-3.82} (4H, m), 3.72- 3.59 (2H, m), 3.56-3.46 (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).

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

Table 17 Antifungal activity (IC 80 μg / ml)

Example 1 1

Preparation of compound

Preparation of ALB320

10.0 g (33.5 mmol) of AT-6 was dissolved in 200 ml of THF, 2.68 g (67 mmol) of 60% sodium hydride / liquid paraffin was added under ice cooling and nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, 6.2 ml (68 mmol) of aryl iodide was added to the reaction solution, and the mixture was stirred at room temperature for 7 hours. Under ice cooling, add 60% sodium hydride / fluid 1.34 g (3½fflol) of raffin and 3.1 ml (34 mmol) of aryl iodide were further added, and the mixture was stirred at room temperature for 13 hours. After cooling the reaction solution on ice, a saturated aqueous solution of ammonium chloride (200 IQ1) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed three times 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 purified by silica gel column chromatography Ariruoki (Si0 ₂ 600 ml, to acetic acid E Chi le / hexane = 4/9 6) to give methyl group at the 8-position, main Tokishimechiruoki sheet group, the 9-position Thus, 11.0 g (yield: 97%) of hydronaphthylene (hereinafter referred to as ALB320) having a shetyl group and represented by the following structural formula was obtained as an oily substance. The ¹ H-NMR (400 MHz) spectrum data is as follows.

(CDCl ₃ , ppm): 5.9K1H, 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), 4.72 (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 (1H, ddd, J = 10.7, 8.8, 5.9Hz), 3.33 (3H, s), 1.94 (1H, dt, J = 12.2, 2.9Hz), 1.77-1.09U1H, m), 1.20 (3H, s), 0.92-0.88 (2H, m), 0.85 (3H, s), 0.82 (3H, s), 0.78 (3H, s).

Preparation of AL B 321

Using 5.56 g (16.½mol) of AL B320, the same operation as AL B304 Made a work. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 500 ml, ethyl acetate / hexane = 16/8 4), and 4.79 g of a compound represented by the following structural formula (hereinafter, referred to as ALB 3 21) was obtained. : 83%) as an oil. The ¹ H-NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.72UH} , d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.70- 3.66 (1H, m), 3.60- 3.53 (1H, m), 3.48- 3.38 (2H, m), 3.34 (3H, s), 3.16-3.13 (1H, m), 2.80 (1H, t, J-4.9Hz), 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).

AL B 3 2 2

Using 4.22 g (11.9 mmol) of ALB321, almost the same operation as for ALB305 was performed. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 500 ml, ethyl acetate / hexane = 67/2 3 to 0/100), and a methyl group, a methoxymethyloxy group, 3.84 g (yield: 87%) of hydronaphthylene (hereinafter referred to as ALB322) having a (2,3-dihydroxypropyl) oxhetyl group at the ninth position was obtained as an oily substance. The spectrum data (Έ-ΝΜΙΚ 400MHz) is as follows. _{(CDC1 3, ppm): 4.73} (1H, d, J = 7.3Hz), 4.65 (1H, d, J = 7.3Hz), 3.86-3.84 (lH, m), 3.74-3.64 (2H, m), 3.57 -3.45 (4H, m), 3.34 (3H, s), 1.97 (1H, dt, 3 = 12.2, 3.4Hz), 1.74-1.15 (11H, m), 1.21 (3H, s), 0.93-0.90 (2H _{3 m), 0.86 (3H,} s), 0.83 (3H, s), 0.79 (3H, s).

Preparation of A L B 3 25

Using 5.17 g (7.17 mmol) of ALB322, the same operation as that of ALB307 was performed. The obtained residue was purified by silica gel column chromatography (SiO 2: 400 ml, ethyl acetate / hexane 2 16/8 4), and 1.33 g of a compound represented by the following structural formula (hereinafter, referred to as ALB 325) was obtained (yield). : 50%) as a white solid. The ¹ H-NMR (400 MHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.72} (1H, d, J = 7.8Hz), 4.64 (1H, d, J = 7.8Hz), 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), 1.2K3H, s), 0.90 (2H, dd, J = 12.2, 2.0Hz), 0.86 (3H, s), 0.83 (3H, s), 0.78 (3H, s).

Preparation of AL B 327

1.00 g (2.70 mmol) of ALB325 was dissolved in 20 ml of THF under a nitrogen atmosphere and cooled to 178 ° C, and then 1.49 ml of a 2M lithium disoprovir amide heptane / THF / ethylbenzene solution was added. 2.98 mmol) over 5 minutes and stir at --78 ° C for 1 hour. Stirred. 0.53ffll (3.28 mmol) of getyl maleate was added to the reaction solution over 5 minutes, and the temperature was raised from 178 ° 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 at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed three times 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 purified by silica gel column chromatography (SiO ₂ : 100 ml, ethyl acetate / n-hexane = 16/8 4 to 32/68) to obtain 803 mg of a yellow oil (yield: 55%). ). 700 mg (1.29 minol) of the yellow oily substance 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 a black hole form. The obtained organic layer was dried燥後anhydrous sulfate Na preparative Riumu, the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chroma Togura Fi one (S I_〇 _2: 50 ml, main evening Nord / chloroform = 1 6 / 24 to 24/7 6), which has a methyl group, a methoxymethyloxy group at the 8-position, and a (1,2,3-tricarboxypropyl) oxhetyl group at the 9-position, with the following structural formula 253 mg (yield: 42%) of the indicated hydronaprene (hereinafter referred to as ALB 327) was obtained as a white powder. The ¹ H-NMR (400 MHz) spectrum is as follows. _{(CDC1 3, ppm): 4.74} (1H, d, J = 7.8Hz), 4.66 (1H, d, J = 7.8Hz), 3.67- 3.48 (3H, m), 3.34 (3H, s), 2.00 (1H , dt, J = 12.2, 3.4Hz ), 1.82-1.11 (14H 3 m), 1.22 (3H, s), 0.9K2H, dd, J = 12.Z, 2.0Hz), 0.87 (3H, s), 0.84 (3H, s), 0.79 (3H, s).

Preparation of ALB3228

Using 644 mg (1.73 mmol) of ALB322, the same operation as ALB308 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 8th position, and a (2-hydroxyethyl) group was placed at the 9th position. 426 mg (yield: 72%) of hydronaphthylene (hereinafter referred to as ALB328) having a (droxityl) oxhetyl group was obtained as an oily substance. The -NMiU 400MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 4.73UH} , d, J = 7.3Hz), 4.65 (1H, d, J = 7.3Hz), 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), 1.78-1.1K11H, 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 ALB 329

Dissolve 250 mg (0.705 mmol) of ALB321 and 73 mg (1.06 mmol) of 1,2,4-triazole in 5 ml of N, N-dimethylformamide, and add 95 mg (0.847 mmol) of potassium t-butoxide Was added 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. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 1/99 to 2/98) to give a compound represented by the following structural formula (hereinafter ALB32 9). 205 mg (yield: 69%) as a white powder. The iH-NMlU 400MHz) spectrum is as follows.

_{(CDC1 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, 3.9Hz), 4.25 (1H, dd, J2 13.7, 6.8Hz), 4.19- 4.09 (1H, m), 3.53-3.34 (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).

Preparation of ALB 330

250 mg (0.705 mmol) of ALB321, 0.1 ml (0.838 mmol) of l- (3-aminopropyl) imidazole and 150 mg (1.41 mmol) of lithium perchlorate are suspended in 5 ml of acetate. It became cloudy and was stirred at 50 ° C for 4 hours. After the reaction solution was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and the mixture was extracted with chloroform. Organic layer Was washed twice with a saturated aqueous sodium hydrogen carbonate solution 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 resulting residue by silica force gel column chromatography (S i0 _2: 50ml, methanol / black port Holm = 8/9 2-1 6/8 4) to obtain the compound represented by the following structural formula (hereinafter ALB 3 216 mg (yield: 64%) was obtained as an oil. Its ^ -NMW 400MHz) spectrum data is as follows.

_{(CDC1 3, ppm): 7.5K1H} , 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), 2.70-2.6K4H, m), 2.18 (3H, s), 2.00-1.94 (3H, m), 1.76-1.1K11H, m), 1.21 (3H, s), 0.91-0.89 (2H, m), 0.86 (3H, s), 0.83 (3H, s), 0.78 (3H, s).

Preparation of AL B 3 3 1

The same operation as that of ALB330 was carried out using 250 mg (0.705 mniol) of ALB321 and 0.12 ml (0.821 mmol) of 4- (3-aminopropyl) morpholine. The obtained residue was purified by silica gel column chromatography (SiO ₂ : 50 ml, methanol / chloroform = 4/96 to 16/84), and the compound represented by the following structural formula (hereinafter referred to as ALB 3 283 mg (yield: 80%) was obtained as a pale yellow powder. The ¹ H-NMR (400 MHz) spectrum is as follows. _{(CDC1 3, ppm): 4} · 72 (1Η, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 4.28- 4.18 (1H, m), 3.78-3.75 (4H 5 m) , 3.55-3.42 (4H, 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 ₃ s) , 0.92-0.89 (2H, m), 0.87 (3H, s), 0.83 (3H, s), 0.79 (3H, s).

Preparation of AL B 332

The same operation as that of ALB330 was carried out using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (l. Ulmmol) of morpholine. The resulting residue was purified by silica gel column chromatography (Si0 _2: 50 ml, main Yunoichiru / click every mouth Holm = 1/9 9 2/9 8) to obtain the compound represented by the following structural formula (hereinafter AL 278 mg (Yield: 89%) of B332 were obtained as an oil. (-NMR ^ OOMHz) The spectrum data is as follows.

_{(CDC1 3, ppm): 4.72} (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.92-3.87 (1H, m), 3.75-3.67 (4H, m), 3.56 -3.38 (4H, 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), 1.2K3H, s), 0.90 (2H, dd, J = 12.2, 2.4Hz), 0.86 (3H, s), 0.82 (3H, s), 0.78 (3H, s) ₀

Preparation of ALB 3 3 3

Using 250 mg (0.705 mmol) of ALB321 and 0.1 ml of biperidine (lOlmmol), the same operation as that of ALB330 was performed. The resulting residue was purified by silica gel column chromatography (Si0 _2: 50 ml, methanol / black port Holm = 2/9 8 4/9 6) to obtain the compound represented by the following structural formula (hereinafter referred to as ALB 3 3 3) 273 mg (Yield: 88%) was obtained as an oil. The NMR (400 MHz) spectrum data is as follows.

(CDCL, ppm): 4.72 (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.91-3.87 (1H, m), 3.56-3.52 (lH, m), 3.50-3.37 (3H, 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), 1.78-1.08U7H, m), 1.20 (3H ₃ s), 0.90 (2H, dd, J = 12.2, 2.4Hz), 0.86 (3H, s), 0.82 (3H, s), 0.78 (3H, s).

Preparation of AL B 3 3 4

The same operation as that of ALB330 was carried out using 250 mg (0.705 mmol) of ALB332 and 0.1 ml (0.90 mmol) of N-methylbiverazine. The resulting residue by silica gel column chromatography (Si0 _2: 60 ml, methanol / black port Holm = 4/9 6-1 6/8 4) to obtain the compound represented by the following structural formula (hereinafter ALB 3 3 248 mg (yield: 77%) was obtained as an oil. The ¹ H-NMR (400 MHz) spectrum is as follows. (CDCl ₃ , ppm): 4.72 (1H, d, J = 7.3 Hz), 4.64 (1H, d, J = 7.3 Hz), 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 = 12.2, 2.4Hz), 0.86 (3H, s), 0.82 (3H, s), 0.78 (3H, s),

Preparation of ALB3335

The same operation as that of ALB330 was performed using 250 mg (0.705 mmol) of ALB321 and 0.1 ml (0.82 orchidol) of l- (2-hydroxyxetyl) piperazine. The resulting residue was purified by silica gel column chromatography (Si0 _2: 60 ml, main evening Nord / black port Holm = 4/9 6-1 6/8 4) to give INDICATED compound of the following structural formula (hereinafter ALB 3 262 mg (yield: 77%) was obtained as an oil. The ^ -NMIU 400MHz) spectrum is as follows. (CDC1 _3J ppm): 4.72 (1H, d, J = 7.3Hz) ₃ 4.64 (1H, d, J = 7.3Hz), 3.90-3.85 (1H, m), 3.6K2H, 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 ).

Preparation of AL B 336

177 mg (0.418 mmol) of ALB329 was dissolved in a mixed solvent of 0.5 ml of THF and 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. The solution was washed three times with a saturated aqueous solution of sodium hydrogencarbonate and once with a saturated saline solution. The organic layer was dried over anhydrous sulfate isocyanatomethyl Riumu, The solvent was evaporated under reduced pressure, silica gel and the resulting residue was purified Rukaramukuroma Togurafi one (Si0 _2: 30 ml, main Yunoichiru / click every mouth Holm = 1/9 9 2/98), and 116 mg (yield: 73%) of a compound represented by the following structural formula (hereinafter referred to as ALB336) was obtained as an oily substance. The -NMIU 400MHz) spectrum is as follows.

_{(CDC1 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 (1H, m), 3.47- 3.34 (4H, m), 3.19 (1H, brs), 2.40-2.33 (lH, 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).

Preparation of ALB3337 and ALB338

Using 500 nig (1.41 iDmol) of ALB321 and 73 mg (0.847 mmol) of biazine, the same operation as in ALB330 was performed. The resulting residue was purified by silica gel column chromatography (Si0 _2: 100 ml, methanol / black port Holm = 2/9 8 4/9 6, 1 6/8 4-2 4/7 6) purified by the following structural formula in 330 mg (yield: 59¾) of the compound represented by the following formula (Chemical formula 83, hereinafter referred to as ALB 337), 330 mg (yield: compound represented by the following structural formula) : 29%) as oils. The 'Η-NMR (400 MHz) spectrum data is as follows.

AL B 3 3 7

_{(CDC1 3, ppm): 4.72} (2H, d, J = 7.3Hz), 4.64 (2H, d, J = 7.3Hz), 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).

A L B 338

_{(CDC1 3, ppm): 4.72} (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 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) o

Preparation of ALB339

Almost the same operation as ALB330 was performed using 250 mg (0.705 mmol) of ALB332 and 69 mg (1.06 mmol) of sodium azide. The resulting residue by silica gel column chromatography (Si0 _2: 50 ml, acetic acid Echiru / n - hexane; = 1 6/84) to give the methyl group at the 8-position, main Tokishimechiruoki sheet group, the 9-position 3- 209 mg (yield: 75) of hydronaphthylene (hereinafter referred to as ALB339) having an azide-2-hydroxyproviroxilethyl group was obtained as an oily substance. That

The following is the Stokkulde evening. _{(CDC1 3, ppm): 4.72} (1H, d, J = 7.3Hz), 4.65 (1H, d, J = 7.3Hz), 3.95- 3.9K1H, 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 = 11.7 Hz), 0.86 (3H, s), 0.83 (3H, s), 0.79 (3H, s).

Preparation of ALB340

250 mg (0.705 mmol) of ALB321 and tris (hydroxymethyl) amido Almost the same operation as that of ALB330 was performed using 128 mg (1.06 mmol) of methane. The resulting residue was purified by silica gel column chroma Bok photography one (Si0 _2: 50 ml, methanol / black port Holm = 1 6/8 4-2 8/7 2) to give the methylation group at the 8-position, main Tokishimechiruo 189 mg (yield: 56) of a hydroxy group having a 3- (tris (hydroxymethyl) methyl) amino-2-aminohydroxypropyloxyshetyl group at the 9-position. %) Was obtained as an oil. The 'H-NMIU 400MHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.72} (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.95- 3.9K1H, 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 (lH, m), 1.95 (1H, d, J = 12.7Hz), 1.78-1.12 (11H, m) , 1.20 (3H, s), 0.90 (2H, d, J = 12.2Hz), 0.86 (3H, s), 0.83 (3H, s), 0.79 (3H, s).

Preparation of A L B 3 4 1

The same operation as ALB330 was performed 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 (Si ₂ : 50 ml, methanol / chloroform: 4/96 to 24/76), and the compound represented by the following structural formula (hereinafter referred to as ALB) was obtained. 247 mg (yield: 76%) was obtained as an oil. Its ^ -NMR ^ OOMHz) spectrum is as follows.

_{(CDC1 3, ppm): 4.72} (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.93- 3.92 (1H, m), 3.79-3.37 (llH, m), 3.34 (3H, s), 2.82-2.47 (6H, m), 1.95 (1H, dt, J = 12.2, 2.9Hz), 1.78-1.1K11H, m), 1.2K3H, s), 0.90 (2H, dd, J = 12.2, 2.0Hz), 0.86 (3H, s), 0.83 (3H, s), 0.78 (3H, s).

Preparation of A L B 3 42

Almost the same operation as ALB330 was performed using 250 mg of ALB321 and 228 mg of D-glucosamine hydrochloride. The resulting residue was purified by silica gel column black Matogurafi one (S iO _2: 50ml, methanol / black port Holm = 4/9 6-1 6/8 4) to obtain the compound represented by the following structural formula (hereinafter AL B 3 4 284 mg (yield: 76%) as an oil. The -NMR OOMHz) spectrum data is as follows.

_{(CDC1 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), 4.53-4.4K1H, 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 = 12.2Hz), 0.86 (3H, s), 0.81 (3H, s), 0.78 (3H, s).

Preparation of A L B 3 4 3

The same operation as that for ALB330 was performed using 250 mg (0.705 mmol) of ALB321 and cis-2,6-dimethylmorpholine 0.11πι1 (0.89 dragonol). Resulting et the residue by silica gel column chromatography (Si0 _2: 50 ml, main evening Roh - le / chloroform = 1/9 9 2/9 8) to obtain the compound represented by the following structural formula (hereinafter ALB 34 3 274 mg (yield) of as an oil: 83%) of Compound _c its' Η-ΝΜΙΚ 400MHz) spectrum Torude Isseki is as follows.

_{(CDC1 3, ppm): 4.72} (1H, d, J = 7.3Hz), 4.64 (1H, d, J = 7.3Hz), 3.92-3.87 (1H, m), 3.72- 3.63 (2H, m), 3.57 -3.50 (I, 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 ₃ m) , 1.78-1.09 (12H, m), 1.20 (3H, s), 1.16 (3H, s), 1.15 (3H, s), 0.90 (2H, dd, J = 12.2, 2.0Hz) ₃ 0.86 (3H, s ), 0.82 (3H, s), 0.78 (3H, s).

Measurement of compound properties>

Table 19 and Table 20 show the antifungal activity and the results of infection treatment tests of the prepared compounds.

Table 19 Antifungal activity (IC 80

Table 20 Infection treatment test results

Example 1 2

Preparation of labdanolic acid

LABDUNUM 15.Og was added with 75 ml of ethyl acetate and 75 ml of 0.5N sodium hydroxide aqueous solution, and the mixture was made basic (pH = 8.6) and extracted. 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 x 2.5 cm) to remove adsorbed substances. The solvent was distilled off from the passing portion under reduced pressure to obtain 8.45 g of an extracted extract (oil). 8, 45 g of this extracted extract was applied to a gel column chromatography (4.0 cm ID x 2.0 cm, elution solvent: Sun / ethyl acetate = 9 / :! 2 /) to obtain 1.2 g of a fraction eluted with hexane / ethyl acetate 2/5/5 to 2/8. This was fractionated at 15 ml / tube using Sephadex LH-20 column chromatography (2.0 cm ID X 70.0 cm, elution solvent: methanol) to obtain Fr. (9-13): 0.96 g. This was dissolved in 10 ml of methanol, passed through an activated carbon column (1.5 cm ID x 20.0 cm), and the activated carbon column was further washed with 100 ml of methanol, and the passing part and the washing part were united. The solvent was distilled off from the combined fractions under reduced pressure to obtain 926nig. Next, this was fractionated by reverse phase column chromatography (2.0 cm ID x 5.0 cm, eluting solvent: 70 to 100 methanol) to obtain 445 mg of a fraction eluted with 80 to 85% methanol. This fraction was fractionated by silica gel column chromatography (2.0 cm ID x 7.0 cm, elution solvent: chloroform / methanol = 100/1 to 100/100) to obtain a chromatographic form. / Methanol = 1100 / 10-: L 0 00/20 As a fraction eluted, 128 mg of labudanolic acid was obtained as a colorless oil. The spectrum of ^ -NMR (400 MHz, CDCl ₃ ) is as shown in Fig. ¹³ , and the spectrum of ¹³ C-NMR (400 MHz, CDCl ₃ ) is as follows.

15.5, 18.5, 19.9, 20.4, 21.5, 23.0, 23.9, 31.2, 33.2, 33.4, 39.1, 39.6, 40.5, 41.5, 42.0, 43.9, 56.0, 62.0, 74.9, 178.0ppm _o

The Rf values were 0.47 (silica gel thin layer chromatography, silica gel 60 F254 (Merck) / cloth mouth / male = 10/1), and 0.51 (silica gel thin layer chromatography, silica gel 60 gel). F254 (Merck) / hexane / ethyl acetate 2 1/4) and 0.38 (Reverse-phase silica gel thin layer chromatography / RP-18 F254 (Merck) / 90% methanol) The reactions were positive for Ehrlich's reagent (purple), positive for anisaldehyde's reagent (purplish red), and positive for 50% sulfuric acid reagent (brown).

Table 21 and Table 2 show the results of the antifungal activity of ravudanolic acid and the results of treatment tests for infection. See Figure 2. Table 21 Antifungal activity (IC 80 g / ml)

Table 22 Infection treatment test results

Example 13

Preparation of C 0 P-a, C〇P-a-OH

After dissolving Copal resin (Copal C 2 · Hiratsuka Sangyo Co., Ltd.) in a mixture of black mouth form / medium mixture, insoluble matters were removed by cotton plug filtration. The solution was concentrated under reduced pressure to obtain 14. Og extract. Next, this extract was fractionated using silica gel column chromatography (6.0 cm ID x 30 cm, elution solvent: hexane / ethyl acetate = 10/1 to 1/1), and hexane / ethyl acetate = 5/1 to 3/1. Fraction 2.lg and hexane / ethyl acetate = 2/1 to 1/1 fraction 3.1 g was obtained _c hexane / ethyl acetate = 2/1 to 1/1 fraction 3.lg was reversed phase Fractionation was repeated several times by column chromatography, silica gel column chromatography, and 10% aqueous silica gel column chromatography to obtain 199 mg of a colorless oily compound (hereinafter referred to as C0Pa). C 0 P - scan Bae click Toruchiya one bets a of ^ -NMR ^ OOMHz CDC1 ₃₎ is as in Fig. ^{1 4, 13 C- NMR (100MHz} , CDC1 3) spectrum data 12.7, 17.9, 19.9, 26.0, 27.5, 29.0, 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 (form / methanol = 20/1) and 0.39 (hexane / ethyl acetate = 5/2), reversed phase. The Rf value of Silica gel thin layer chromatography (RP-18 F254 (Merck)) was 0.51 (90% methanol), and the color reaction was positive for Ehrlich's reagent (brown) and positive for anisaldehyde reagent (purple). , 50% sulfuric acid reagent positive (brown). From these data, C0P-a was identified as Cupressic acid.

100 mg (0.31 mmol) of the above-mentioned C-P-a was dissolved in 5 ml of diethyl ether, and diazomethone was added little by little to obtain a methyl ester form (102 mg). The methyl ester was dissolved in 5 ml of getyl ether, and 2 mg of lithium aluminum hydride was added little by little under ice-cooling and stirring, followed by stirring at room temperature for 6 hours. The reaction solution was extracted with ethyl acetate, washed with 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 gel chromatography (5.0 g, lcmIDxl6 cm, elution solvent: hexane / ethyl acetate = 9/1 to 1/1) to give a compound represented by the following structural formula (Irida 88, below) 67.4 mg (yield: 75%) was obtained. Scan Bae click Toruchiya one bets of the _{'Η- NMR (400MHz, CDC1 3} ) is as in Figure ^{1 5, 13 C- NMR (100MHz} , CDC1 3) spectrum Torude Isseki 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, 148.1. 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 the anisaldehyde reagent (purple).

Preparation of C 0 P—c

In addition, 3.1 g of the hexane / ethyl acetate = 2/1 to 1/1 fraction described above was fractionated by reversed-phase column chromatography, silica gel column chromatography, and 10% water-containing silica gel chromatography. As a result, 145 mg of a colorless oily compound different from C0P-a (hereinafter referred to as C0P-c) was obtained. C◦ P- c of ^{_{1 H- MR (400MHz, CDC1 3}} ) is as in FIG. ^{1 6, 13 C-NMR (} 100MHz, CDCl 3) spectral data 15.2, 18.9, 19.2, 21.0, 21.5 , 24.4, 27.5, 36.1, 37.3, 38.4, 38.8, 39.5, 39.9, 56.1, 56.1, 66.7, 106.9, 114.8, 147.4, 163.8, 171.1, 171.5. The R f values of silica gel thin-layer chromatography (silica gel 60 F254 (Merck)) were 0.56 (chloroform / methanol = 20/1) and 0.36 (hexane / ethyl acetate = 5/2), The Rf value of reversed-phase silica gel thin-layer chromatography (RP-18F254 (Merck)) was 0.33 (90% methanol), and the color reaction was positive for Ehrlich's reagent (brown) and positive for anisaldehyde's reagent. Red purple) and 50% sulfuric acid reagent positive (brown). From these data, C0P-c was identified as a acetyl group bonded to the hydroxyl group at position 19 of Agatholic acid. Preparation of COP-c '

The isolated C 0 P—c was hydrolyzed to remove the acetyl group, and C 0 P—c, (Agatholic acid) was obtained.

Table 23 and Table 2 show the results of the antifungal activity and infection treatment tests of the prepared compounds. See Figure 4. Table 2 3 antifungal activity (IC _8:. 〃G / ml)

Table 24 Infection treatment test results

Example 14

B C—Preparation of 1-3

Bacillus cereus IF03132 strain was inoculated into a medium having the composition shown in Table 25 below (aliquots of 100 ml each in 500 ml Erlenmeyer flasks, and sterilized by high-pressure steam at 121 ° C for 15 minutes). After heating 1.2 liters of the culture at 27 ° C for 4 days, heating at 65 ° C for 20 minutes, adding the mixture to 40 liters of medium of the same composition, and heating at 27 ° C for 24 hours Time shaking culture was performed. After 24 hours, it was confirmed that Bacillus cereus had grown sufficiently, and then 8 g of sclareol (10% ethanol solution) was added, followed by further culturing for 14 days. Table 25

Ezo,

Component a village

Glucose 2.0%

0.5% 0.5%

Peptone 0.5%

Sodium chloride 0.5%

Dipotassium hydrogen phosphate 0.5%

No pH adjustment The resulting culture was centrifuged at 3000 rpm for 20 minutes to separate the cells from the culture. The culture solution 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 extract.

This ethyl acetate extract is then fractionated on a silica gel column chromatography (200 g: 4 cm ID x 30 cm, elution solvent: ethyl acetate / hexane = 5.5 / 4.5 to 10/0), and the components of those fractions are used. , Ethyl acetate / hexane = 7/3 (fraction 1: 0.15 g), ethyl acetate / hexane = 8/2 (fraction 2: 0.46 g), ethyl acetate / hexane = 10/0 (fraction 3: 0.10 g).

Next, fraction 1 was fractionated by reverse phase chromatography (2 cm ID x 16 cm, elution solvent: 40 to 100% methanol), and 31.6 mg of a compound (hereinafter referred to as BC-1) was obtained from the 50 ° elution fraction. . The Rf value of the silica gel thin layer chromatography (silica gel 60 F254 (Merck)) is 0.38 (ethyl acetate / hexane = 9/1), and the color reaction is positive for the anisaldehyde reagent (blue to red).

Next, fraction 2 was recrystallized from hexane to obtain 69.5 mg of a compound represented by the following structural formula (yidani 92, hereinafter referred to as BC-2) as white powdery crystals ₍ the thin gel layer thereof). The Rf value of Kokuto-Matography I (Silikei Gel 60 F254 (Merck)) was 0.45 (ethyl acetate / hexane = 9/1), and the color reaction was positive for anisaldehyde reagent (blue to red).

CD ₃ 0D) of the scan Bae click Toruchiya —The figures are as shown in Figure 17.

Next, fraction 3 was fractionated by reverse-layer chromatography (2 cm ID x 6 cm, elution solvent: 50 to 100% methanol), and a compound represented by the following structural formula was obtained from the 70 to 80% elution fraction. 3, hereinafter referred to as BC-3). The Rf value of the thin layer gel chromatography (Silik Gel 60 F254 (Merck)) was 0.28 (ethyl acetate / hexane = 9/1), and the color reaction was positive for the anisaldehyde reagent (blue to blue). a red), NMR (400MHz, scan Bae click Toruchiya one bets CD ₃ 0D) is as in Figure ^{1 8, 13 C- NMR (100MHz} : CDCl 3 + CD 3 0D) spectrum Toruchiya one metropolitan Figure 19 shows the results.

Tables 26 and 27 show the results of the antifungal activity and infection treatment tests of the prepared compounds. Table 26 Antifungal activity (IC 80 g / ml)

Table 27 Results of Infection Treatment Test

Example 15

Preparation of compound>

Preparation of 15-hydroxy-albicanol

A 4N aqueous solution of sodium hydroxide was added to a solution of Roseolide A (200 mg: 0.28fflmol) separated from F. mushroom in tetrahydrofuran (5 ml), and the reaction solution was refluxed for 2 hours. The reaction solution was diluted with water (20 ml), and the product was extracted with ethyl acetate (25 ml × 2), and the extract was sufficiently washed with water and saturated saline. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography [column: 1.0 cm IDx l6.5 (5 g), eluent: CHCl ₃ -MeOH = 100/0, 95 / 5, 90/10] to give 15-hydroxyalbi ynol as a colorless candy. Yield: 28 mg.

_{400MHz Ή-NMR dppm (CDCl 3} ): 4.95 (1H, d, J = 1.5, H 12), 4.65 (1H, d, J = 1.5, H 12), 3.85 (1H, dd, J = 10.9, 3.9, _{H n), 3.77 (1H,} dd, J = 10.7, 9.8, H "), 3.4K1H, d, J = 10.7, H 15), 3.10 (1H, d, J = 10.7, H 15), 2.42 (1H , ddd, J = 13.2, 4.4 , 2.4, H 7), 2.08 (1H, dd, J = 13.2, 5.4, H 7), 2.03 (1H, br.d, J = 5.9, H 9), 0.76 (3H _{, s, H 14), 0.75} (3H, s, H 13). Preparation of MK-1

Sclareol (100 mg, 0.34 mmol) was dissolved in ethanol (5 ml), palladium-activated carbon (PdlO%, 10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. After filtering off the palladium-activated carbon, the solvent of the filtrate was distilled off to obtain MK-1 (89.4 mg, yield 89%).

R f value: Silica gel thin layer chromatography: 0.41 [Silikei gel 60 F254 (Merck), developing solvent: hexane / ethyl acetate = 3/2].

Coloring reagent: positive for anisaldehyde reagent (purple).

Ή-NMR (400MHz, double-mouthed form): S = 0.79 (3H, s), 0.79 (3H, s),

0 · 86 (3Η, s), 0.89 (3H, t, d = 7.3), 1.15 (3H, s), 1.17 (3H, s).

¹³ C-nuclear magnetic resonance spectrum (100 mm, double-mouthed form): 5 = 15.7, 18.7,

19.1, 20.8, 21.7, 24.5, 25.8, 33.5, 33.6, 35.8, 39.5, 39.9, 42.3, 44.4,

44.5, 56.3, 62.3, 73.6, 74.9.

Preparation of MK-2

C0P-a (cupressic acid) isolated from Copearl resin is converted into a methyl ester with diazomethane, and this methyl ester (300 mg, 0.9 mmol) is dissolved in dichloromethane (5 ml), and metachloroperbenzoic acid ( 234 mg, 1.4 mmol) under ice-cooling and stirring, and the mixture was stirred with water-cooling for 1 hour and at room temperature for 1.5 hours. The reaction solution was extracted with a chloroform solution, washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (7 g, lcmID × 20 cm, developing solvent: hexane / ethyl acetate = 9/1 to 3/2) to obtain an 8,17-epoxy compound (156 mg, yield 50%).

This 8,17-epoxy compound (60 mg, 0.17 mmol) was dissolved in ethyl ether (3 ml), lithium aluminum hydride (25 mg, 0.68 mmol) was added with stirring under ice-cooling, and the mixture was refluxed for 2 hours. Extract the reaction mixture with ethyl acetate, then add saturated sodium bicarbonate After washing sequentially with an aqueous solution of sodium chloride and saturated saline, the solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (3 g, lcmID xlOcm, developing solvent: chloroform / medium = 100/0 to 96/4) to give MK-2 (28 mg, 50% yield). ).

R f value: Silica gel thin layer chromatography: 0.53 [silica gel 60F254 (mercury), developing solvent: black-mouthed form / methanol = 9/1].

Coloring reagent: positive for anisaldehyde reagent (purple).

—NMR (400MHz, heavy metal): (5 = 0.79 (3H, s), 0.94 (3H, s), 1.10 (3H, s), 1.23 (3H, s), 3.32 (1H, m) , 3.64 (1H, d, J = 10.7), 5.01 (1H, dd, J = 10.7, 1.5), 5.19 (1H, dd, J = 17.1, 1.5), 5.88 (1H, dd, J2 17.1, 10.7) .

1 ³ C-nuclear magnetic resonance scan Bae-vector (100 MHz, Jumeyunoichiru) :( 5 = 16.6, 19.1, 20.7, 21.6, 23.9, 27.7, 28.2, 36.8, 39.6, 40.4, 41.2, 45.4, 46.4 , 58.2, 63.0, 65.1, 74.5, 75.1, 111.9, 146.4.

Preparation of MK-11

C0P-a-0H (19-hydroxymanooK 400mg, 1.32mmol) prepared by reducing C0P-a isolated from Copearl resin was dissolved in dichloromethane (5ml), and stirred under ice-cooling. 4,6-Tri-〇-acetylglucal (540 mg, 1.98 mmol) and triphenylphosphine hydrobromide (90 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 5 hours. After the reaction solution was extracted with chloroform, it was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (30 g, 2 cm ID × 21 cm, developing solvent: hexane ethyl acetate = 9 / :! to 7/3) to obtain acetyl-MK-11 (147 mgs, 20% yield). This was deacetylated with a 2% aqueous sodium hydroxide solution to obtain MK-11 (99 mg, yield 86%). R f value: Siri force gel thin layer chromatography: 0.37 [Shiri force gel 60 F254

(Merck), developing solvent: black form / methanol = 9/1]. Coloring reagent: positive for anisaldehyde reagent (purple).

Έ NMR (400ΜΗζ, double-mouthed form): ά = 0.64 (3Η, s), 0.96 (3H, s), 1.32 (3H, s), 3.0K2H, d, J29.3, 3.46 (3H, m) ), 3.73 (2H, m), 3.87 (2H, m), 4.52 (1H, s), 4.76 (lH, s), 4.81 (1H, s), 5.05 (1H, d, J = 10.7), 5.19 ( 1H, d, J = 17.1), 5.90 (1H, d, J = 17.1), 5.90 (1H, dd, J = 17.6, 10.7).

1 ³ C-NMR (100MHz, deuteriochloroform):. (5 = 15.2, 17.8, 19.0, 24.4, 27.3, 27.5, 36.5, 37.4, 37.7, 38.0 38.9, 39.7, 41.3, 56.2, 57.4, 61.6, 69.1, 70.0 , 71.4, 71.6, 73.6, 97.7, 106.8, 111.6, 145.2, 148.1.

Preparation of MK-12

C 0 Pa-0 H (100 mg, 0.33 ol) was dissolved in pyridine (2 ml), and 4-dimethylaminopyridine (5 mg, 0.04 mmol) and succinic anhydride (100 mg, l.Ommol) were added under ice cooling and stirring. The mixture was stirred at room temperature for 20 hours. The reaction solution was extracted with ethyl acetate, washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (5 g, lcmIDxl6 cm, developing solvent: porcine / ethyl acetate = 100/0 to 3/2) to give MK-12 (72 mg, yield 54%). Obtained.

R f value: Silica gel thin layer chromatography: 0.21 [silica gel 60 F254 (Merck), developing solvent: silica gel form / ethyl acetate = 9/1].

Coloring reagent: positive for anisaldehyde reagent (purple).

Ή-NMR (400MHz, double-mouthed form): 5 = 0.67 (3H, s), 0.95 (3H, s), 1.27 (3H, s), 2.63 (4H, m), 3.87 (1H, d, J = 10.7), 4,27 (1H, d, J = 10.7, 4.52 (1H, s), 4.82 (1H, s), 5.05 (1H, dd, J = 10.7, 1.0), 5.19 (1H, dd, J = 17.1, 1.0), 5.90 (1H, dd, J = 17.6, 10.7).

¹³ C-NMR (100 MHz, deuterated chloroform): 5 = 15.3, 17.9, 18.3, 24.5, 27.6, 29.1, 29.2, 36.1, 36.2, 37.4, 38.5, 38.9, 39.7, 41.3, 56.3, 57.4, 67.1, 73.8, 107.0, 111.8, 145.1, 147.9, 172.5, 176.4.

Preparation of MK-22

BC-3 (18-hydroxysclareoK 100mg, 0.31mmol) is dissolved in pyridine (2ml), and stirred under ice-cooling with 4-dimethylaminopyridine (llmg, 0.09 marl ol) and succinic anhydride (100mg, 1.0 ol). ) And stirred at room temperature for 24 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 (5 g (lcmlDx 16 cm, developing solvent: chloroform / methanol 100/0 to 9/1)) to give MK-22 (42 mg, yield 32%). Obtained.

R f value: Silica gel thin layer gel chromatography: 0.22 [silica gel 60 F254 (Merck), eluent: Cloth form / methanol = 9/1].

Coloring reagent: positive for anisaldehyde reagent (purple).

¹ H-NMR (400 MHz, double-mouthed form): δ = 0.76 (3H, s), 0.81 (3H, s), 1.16 (3H, s), 1.28 (3H, s), 2.59-Z.73 (4H , m), 3.30 (1H, d, J = 11.Z), 4.23 (1H, d, J = 11.2), 4.99 (1H, dd, J2 10.7, 1.0), 5.20 (1H, dd, J-17.1) , 1.0), 5.91 (1H, dd, J = 17.6, 10.7).

Preparation of Boc-MK-23

Boc-5-alanine (88 mg, 0.46 mmol) is dissolved in dichloromethane (1 ml), and Ν, Ν'-dicyclohexylcarpoimide (128 mg, 0.62 mmol) is added under ice-cooling with stirring. Stirred for minutes. Then, 4-dimethylaminopyridine (12 mg, 0.1 mmol) and BC-3 (100 mg, 0.31 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After filtering the reaction solution, the filtrate was washed sequentially with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (7.5 g, lcmID x 23 cm, developing solvent: hexane / ethyl acetate = 1/1 to: L / 4), and Boc-MK-23 (126 mg, 83% yield) ). R f value: Silikei gel thin layer mouth chromatography: 0.58 [Shiri gel 60 F254 (Merck), developing solvent: hexane / ethyl acetate = 1/4].

Coloring reagent: positive for anisaldehyde reagent (purple).

'H-NMRi 400 MHz, double-mouthed form): δ = 0.81 (3Η, s), 0.82 (3H, s), 1.15 (3Η, s), 1.27 (3H, s), 1.44 (9H, s), 2.54 -2.57 (2H, m), 3.39-3.40 (2H, m), 3.67 (1H, d, J = 10.7), 3.88 (1H, d, J = 10.7), 5.02 (1H, dd, J = 10.7, 1.0 ), 5.2K1H, dd, J = 17.6, 1.0), 5.93 (1H, dd, J = 17.1, 10.7).

1 ³ C-NMR (100MHz, heavy black port Holm): δ = 15.6, 17.3, 17.5, 19.0, 20.4, 24.1, 24.9, 25.6, 27.2, 28.4, 33.9, 34.6, 35.8, 36.2, 36.5, 39.1, 43.9, 44.9, 49.1, 61.6, 72.9, 43.5, 74.3, 111.2, 145.9.

Preparation of ΜΚ-26

BC-3 (100 mg, 0.31 mmol) was dissolved in pyridine (1 ml), and 4-dimethylaminopyridine (19 mg, 0.17 mmol) and diglycolic acid anhydride (116 mg, 1.0 mmol) were added under ice-cooling and stirring. The mixture was stirred at room temperature for 4 hours. After the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was extracted with a saturated aqueous solution of sodium hydrogen carbonate, the aqueous layer was acidified with IN hydrochloric acid, and then extracted again with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain MK-26 (79 mg, yield 585).

R f value: Silica gel thin layer mouth chromatography I: 0.04 [silica gel 60 F254 (Merck), eluent: black mouth form / methanol = 9/1].

Coloring reagent: positive for anisaldehyde reagent (purple).

'H-NMR (400 MHz, double-mouthed form): δ = 0.79 (3H, s), 0.82 (3H, s), 1.18 (3H, s), 1.3K3H, s), 3.78 (1H, d, J = 11.2), 3.95 (1H, d, J = 11.2), 4.21-4.33 (4H, m), 5.0K1H, dd, J = 10.7, 1.0), 5.20 (1H, dd, J = 17.6, 1.0), 5.91 ( 1H, dd, J = 17.1, 10.7).

¹³ C-NMR (100 MHz, double-mouthed form): δ = 15.3, 17.4, 17.5, 18.8, 20.1, 24.5, 26.0, 35.8, 36.7, 39.0, 39.1, 42.9, 43.1, 48.4, 60.1, 68.2, 68.6, 71.9, 74.7, 75.5, 111.2, 145.5, 170.3, 170.9.

Preparation of MK-27

BC-3 (100 mg, 0.31 mmol) was dissolved in pyridine (1 ml) and stirred under ice-cooling with 4-dimethylaminopyridine (19 mg, 0.17 mmol) and 3,3-dimethyl glucuric anhydride (142 mg, 1.0 t ) And stirred at room temperature for 48 hours. After the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was extracted with a saturated aqueous sodium hydrogen carbonate solution, the aqueous layer was made acidic with 1N hydrochloric acid, and then extracted again with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain MK-27 (63 mg, yield: 44%).

R f value: Shiri gel thin layer mouth chromatography: 0.45 [Sili gel 60 F254 (Merck), eluent: Cloth form / methanol = 9/1].

Coloring reagent: positive for anisaldehyde reagent (purple).

'H-NMR (400 MHz, double-mouthed form): δ = 0.78 (3Η, s), 0.81 (3H, s), 1.14 (6H, s), 1.17 (3H, s), 1.30 (3H, s) ), 2.42-2.46 (2H, m), 2.61 (1H, d, J-15.6), 2.76 (1H, d, J = 14.6), 3.54 (1H, d, J2 11.2), 3.93 (1H, d, J = 11.2), 5.01 (1H, dd, J = 10.7, 1.5), 5.2K1H, dd, J2 17.1, 1.5), 5.91 (1H, dd, J2 17.1, 10.7).

^13C -NMR (100MHz, double-mouthed form): δ = 15.4, 17.5, 17.6, 18.9, 20.2, 24.3, 26.3, 27.8, 28.5, 32.2, 36.1, 36.4, 39.0, 43.3, 43.6, 44.0, 44.9, 48.4 , 51.5, 60.4, 71.9, 74.2, 75.2, 111.1, 145.8, 172.5, 174.6.

Preparation of MK-2 8

After replacing the flask containing 2 ml of an anhydrous dichloromethane solution of oxalyl chloride (80〃1, 0.93 mmol) with nitrogen, the solution was cooled to −65 ° C, and an anhydrous dichloromethane solution of anhydrous dimethylsulfoxide (110〃1, 1.55 mmol) was added. 1 ml was added, and the mixture was stirred at 165 ° C for 30 minutes. Add BC-3 (200mg, 0.62 ol) to anhydrous diclo Methane: dimethyl sulfoxide = 3: 2 ml of 1 solution was added dropwise, and the mixture was stirred at 65 ° C for 30 minutes, then triethylamine (430〃1, 3.1 marl) was added, the cooling bath was removed, and the reaction solution was brought to room temperature. Back to.

After the reaction solution was extracted with chloroform, the solution was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (silica gel 7.5 g, lcmlD x 23 cm, developing solvent: hexane / ethyl acetate = 1/1 to 3/7), and the four positions of sclareoyl were aldehyde. Thus, MK-28 (42 mg, yield 215) was obtained.

R f value: Silikei gel thin layer gel chromatography: 0.52 [Silikki gel 60 F254 (Merck), developing solvent: hexane / ethyl acetate = 1/9].

Coloring reagent: positive for anisaldehyde reagent (purple).

¹ H-NMR (400 Hz, heavy black port Holm): δ = 0.85 (3H, s), 1.02 (3H, s), 1.17 (3H, s), 1.29 (3H, s), 5.04 (1H, dd, J = 10.7, 1.5), 5.22 (1H, dd, J: 17.6, 1.5), 5.92 (1H, dd, J = 17.6, 10.7), 9.22 (1H, s).

^13C -NMR (100MHz, double-mouthed form): δ = 13.9, 15.4, 16.6, 19.0, 22.9, 24.3, 27.3, 32.2, 38.0, 38.7, 43.6, 44.7, 48.2, 49.6, 61.4, 73.6, 74.5, 111.3 ,

The structural formulas of the obtained ΜΚ—11 (Formula 94) and Βοc—ΜΚ—23 (Formula 95) are shown below, and the substituents of other compounds are summarized in Table 28 below.

6 ^ 1

866lO / 66df / XDd II6eS / 66 OAV Table 28

Tables 29 and 30 show the antifungal activity and the results of infection treatment tests of the prepared MK-1, 2, and 12, respectively. Table 29 Antifungal activity (IC 80 fi g / ml)

Example 16

Synthesis of ALB089

ALB203 and Z-proline were condensed by DCC, and then the Z group was removed.

Synthesis of AL B 091 and AL B 092

AT-24 was dissolved in dehydrated acetonitrile, 2,6-dimethylmorpholine or tetrazol and anhydrous lithium perchlorate were added, and the mixture was stirred at room temperature for 1 day. Additional lithium oxide was added, and the mixture was stirred for 15 hours while heating to 60 ° C. The reaction solution was separated into chloroform and aqueous ammonium chloride solution, and the chloroform layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. The aqueous layer was extracted with black hole form and subjected to the same treatment as above. After filtration, the combined filtrates are concentrated, and the residue is subjected to silica gel column chromatography to give ALB091 in which 2,6-dimethylmorpholine is condensed and tetrahydrofuran. ALB 092 in which the zole was condensed was obtained.

Synthesis of ALB242

After DCC was added to a solution of 1.07 g of Z-aspartic acid in 20 ml of dehydrated THF, 925 mg of AT-1 and 977 mg of DMAP were added to the solution, and the mixture was stirred at room temperature for 3 days. The reaction solution was separated into a black hole form and an aqueous solution of ammonium chloride, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to silica gel gel column chromatography (black mouth: medium = 97: 3 to 8: 2) to give 690 mg of the title compound condensed with the carboxyl group of aspartic acid. (38%).

_{^ NMR (DMS0-d 6)} : 7.49 (1H, m, NH D 2 0 exchangeable), 7.35 (5H, m, Ph), 5.06 (1H, d, J two 12.2Hz, CH-Ph), 5.00 (1H _{3 d, J = 12.2Hz, CH} -Ph), 4.33 (1H, m, CO-CH-N), 4.07-3.98 (2H, m, CH 2 -0- C0), 2.49 (2H, m, CH2C00) , 1.72-0.72 (26H, m).

Synthesis of ALB2444

AT-1 (3 g) and 1-bromo-2,3,4,6-tetraacetylglucose (7.28 g) were dissolved in dehydrated chloroform (50 ml) and cooled in an ice bath. Silver re-flat

(4.6 g) and tetramethylperyl (2.8 ml) were added, and the mixture was stirred for 5 hours except for the ice bath. After diluting the reaction solution by addition of chloroform, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by vigorous stirring. The mixture was filtered through celite, the celite was washed with chloroform, the combined filtrates were separated, the chloroform layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. did. The concentrate was subjected to silica gel column chromatography, and the compound eluted with a mixed solvent of n-hexane: ethyl acetate = 9: 1 to 4: 6 was collected. The obtained compound was dissolved in methanol, sodium methoxide was added little by little, and the point at which spots with low Rf values became one on TLC was defined as the end point of the reaction. The solvent of the reaction solution is distilled off, and the residue is purified by silica gel column chromatography. Filtration yielded 800 mg of the title compound in 16.3% yield.

Rf value 0.48 (Silicone gel thin layer chromatography, chloroform: methano

—Le = 8: 2)

ALB 2 4 4 of ¹ H NMR de Isseki _{(DMSO- d 6): δ =} 4.94 (1H, d, OH, D 2 0 exchangeable), 4.88 (1H, d, OH, D 2 0 exchangeable), 4.85 ( _{1H, m, OH, D 2} 0 exchangeable), 4.44 (1H, t, OH, D 2 0 exchangeable), 4.12 (1H, d, CH), 3.92 (1H, s, OH, D 2 0 exchangeable), 3.80 (1H, m), 3.65 ( 1H, m), 3.40 (2H, m, - CH 2 - 0-), 3.12 (1H, m), 3.06 (2H, br s), 2.94 (1H, m), 1.75 -0.75 (26H, m).

Synthesis of ALB246

Sclareoyl l.Og was dissolved in 12 ml of dehydrated mouth-mouth form, 0.99 ml of dihydrovirane (DHP) and 120 mg of pyridinium p-toluenesulfonate (PPTS) were added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was separated into a liquid form and a sodium hydrogencarbonate aqueous solution, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 95: 5, 9: 1) to obtain a THP-protected product lg (yield: 65%). Was. This product was dissolved in 15 ml of dehydrated mouthpiece form, 900 mg of m-CPBA was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was separated into a mixture of chloroform and aqueous sodium hydrogen carbonate solution, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 85: 15, 8: 2) to obtain 730 mg of an epoxy product (yield: 71%). . 300 mg of this epoxy product was dissolved in 6 ml of dehydrated acetonitrile, 120 mg of N-methylpyrazine and 250 mg of lithium perchlorate were added, and the mixture was stirred at room temperature for 15 hours. After water was added to the reaction solution, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (form: methanol: 95: 5, 9: 1). To give 244 mg (68%) of the product. This product was dissolved in methanol (10 ml), 2N hydrochloric acid (0.5 ml) was added, and the mixture was stirred at room temperature for 15 hours. After evaporating the solvent, the residue was purified by recrystallization from acetone / ethanol, and 67 mg of ALB246 was added.

(40%) obtained.

Synthesis of ALB250

To a dehydrated 1,2-dimethoxetane solution of AT-1 (254 mg) and tetraethylene glycol di-to-tosylate (0.5 g) was added sodium hydride (80 mg, 60% inoil), and the mixture was heated to 40 ° C. The mixture was stirred for 2 hours while heating. After adding an aqueous solution of ammonium chloride to the reaction solution, ethyl acetate was added to separate the layers, and the aqueous layer was further extracted with ethyl acetate (twice). The combined ethyl acetate layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (cloth form: methanol = 95: 5, 9: 1) to quantitatively obtain 395 mg of the title compound.

Rf value 0.43 (black gel thin layer chromatography, black hole form: methanol = 9: 1).

AL B 2 5 1 of ¹ H NMR de Isseki _{(CDC1 3): δ = 3.65} (68H, br m, CH z -0-及beauty _{_{-0-CH 2 CH 2 -0- xl6}} ), 3.38 (3H, s, -0-Me), 2.1-1.1 (20H, m, cyclic CH and methylene and Me), 0.86-0.7K11H, m, cyclic CH and Mex3). Synthesis of ALB 2 5 1

Poly (ethylene glycol) monomethyl ether (molecular weight: about 750) (20 g) was dissolved in pyridine (100 ml) and cooled in an ice bath. After adding tosyl chloride (5.6 g), the ice bath was removed and the mixture was stirred at room temperature for 15 hours. After water was added to the reaction solution, pyridine was distilled off under reduced pressure, and the residue was partitioned between chloroform and a saturated saline / saturated aqueous solution of ammonium chloride. The chloroform layer was dehydrated by adding anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and further dried under high vacuum. To a solution of ALB 248 (500 mg) in dehydrated THF (30 ml) was added sodium hydride (160 mg, 60% in oil), and the mixture was stirred at room temperature for 30 minutes. 2.7 g) and stirred for 15 hours. After adding an aqueous solution of ammonium chloride to the reaction solution, ethyl acetate and a saturated saline solution were added thereto to carry out liquid separation, and the aqueous layer was further extracted twice with ethyl acetate. Anhydrous sodium sulfate was added to the combined ethyl acetate layers for dehydration. After filtration, the filtrate was concentrated and the residue was subjected to column chromatography (Cosmoseal ODS-C18, 75% methanol) to obtain 700 mg of the title compound in a yield of about 40%.

Synthesis of ALB2252

Poly (ethylene glycol) monomethyl ether (molecular weight: about 750) (20 g) was dissolved in pyridine (100 ml) and cooled in an ice bath. After adding tosyl chloride (5.6 g), the ice bath was removed and the mixture was stirred at room temperature for 15 hours. After water was added to the reaction solution, pyridine was distilled off under reduced pressure, and the residue was partitioned between chloroform and a saturated saline / saturated aqueous solution of ammonium chloride. Anhydrous sodium sulfate was added to the porcine layer for dehydration, and the solvent was distilled off under reduced pressure and further dried under high vacuum.

To a solution of AT-1 (500 mg) in dehydrated THF (30 ml) was added sodium hydride (160 mg, 60% in oil), the mixture was stirred at room temperature for 30 minutes, and the residue (2.7 g) obtained above was added. The mixture was stirred for 15 hours. After an aqueous solution of ammonium chloride was added to the reaction solution, ethyl acetate and saturated saline were added to separate the layers, and the aqueous layer was extracted twice more with ethyl acetate. The combined ethyl acetate layer was dehydrated by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to column chromatography (Cosmoseal ODS-C18, 75% methanol) to obtain 770 mg of the title compound at a yield of 40%.

AL B 2 5 2 of ¹ H NMR de Isseki _{(CDC1 3): 6 = 3.65} (66H, br m, CH 2 - 0-,及Beauty _{_{-0- CH 2 CH 2 - 0- xl6}} ), 3.38 (3H , S, -0-Me), 1.95-1.1 (15H, m, cyclic CH And Me), 0.96-0.8 (11Η, m, cyclic CH and Mex3).

Synthesis of 12-0- (2-cyanoethyl) —AT-1

To a solution of AT-1 (l.Og) and 3-bromopropionitrile (790 mg) in dehydrated DME (20 ml) was added sodium hydride (500 mg, 60% in oil), and the mixture was heated under reflux for 2 hours. Excess sodium hydride was deactivated by adding water little by little to the reaction solution, and the mixture was separated into ethyl acetate and an aqueous solution of ammonium chloride. The organic layer was washed with a saturated saline solution and dehydrated with anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 6: 4) to obtain 530 mg of the title compound in a yield of 44%.

Rf value: 0.25 (silica gel thin layer chromatography, n-hexane: ethyl acetate = 6: 4).

¹ H-NMR data of the title compound

δ = 3.7 (3H, m, CH-0- and _{0- CH 2) 3.45 (1H,} m, CH-0-) 2.6 (2H, t, CH 2 -CN) 1.9-0.75 (26H, m, cyclic CH And Mex4).

Synthesis of AL B 245

A solution of ALB030 (3.0 g) in dehydrated THF (40 ml) was added dropwise to a suspension of LAH (300 mg) in dehydrated THF (10 ml), and the mixture was stirred at 60 ° C for 15 hours. LAH (300 mg) and dehydrated THF (30 ml) were further added, and the mixture was refluxed for 8 hours. A small amount of water was added to the reaction solution to inactivate the excess reagent, and then chloroform and 2N hydrochloric acid were added to separate the solution. The aqueous layer was extracted with black-mouthed form, and the combined black-mouthed form layer was concentrated. The residue was subjected to silica gel column chromatography (chloroform: methanol = 9: 1, 7: 3) to give the title compound (1.25 g) in a yield of 44%.

Value: 0.22 (silica gel thin-layer chromatography, chloroform: methanol = 8: 2).

Ninhydrin color: positive. Synthesis of 2-butene-1,4-dioldi-0-AT-1 ether

To a solution of AT-1 (l.Og) and 1,4-dibromo-2-butene (0.84 g) in dehydrated THF (40 ml), add sodium hydride (320 mg, 60% in oil) and heat for 5 hours. Shed. After a small amount of water was added to the reaction solution to deactivate the excess reagent, the solution was separated into ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (570 mg) in a yield of 26%. Synthesis of A L B 247

AL B 3 21 (709 mg) was dissolved in dehydrated acetonitrile (10 ml), and 4-diimidazole (271 mg) and anhydrous lithium perchlorate (426 mg) were added. Stirred. Further, additional lithium perchlorate (410 mg) was added, and the mixture was stirred for 15 hours while heating at 60 ° C. The reaction solution was separated into chloroform and aqueous ammonium chloride solution, and the chloroform layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. The aqueous layer was extracted with black hole form and subjected to the same treatment as above. After filtration, the combined filtrate was concentrated, and the residue was subjected to silica gel column chromatography to give the title compound (250 mg) at a yield of 27%.

¹ H NMR data of AL B 247 (DMS0-d ₆ ): d = 8.26 (lH, s, -CH =), 7.76 (1H, s, -CH =), 4.68 (1H, d, J-7.33 Hz, -0-CH-0-), 4.56 (1H, d, J = 7.33Hz, - 0-CH-O-), 4.09 (2H, m, - CH 2 - DOO Riazo Ichiru), 3.45-3.16 (8H _{, m, -CH2- 0-CH 2} -, CH-OH and -O-Me), 1.91 (1H , m, cyclic CH), 1.7-0.76 (25H, m, cyclic CH and Mex4).

Synthesis of A L B 248

Manol (10.3 g) was dissolved in dehydrated THF (100 ml) and cooled in an ice bath. A 1M BH ₃ -THF complex solution (100 ml) was slowly added dropwise, and then The mixture was stirred for 2 hours except for the ice bath. The mixture was cooled again in an ice bath, and a 6N aqueous solution of sodium hydroxide (71 ml) was added dropwise while paying attention to foaming, followed by dropwise addition of 30% aqueous hydrogen peroxide (142 ml). The mixture was stirred for 15 hours without the ice bath, and the reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate (twice), and the combined ethyl acetate layers were treated as above. The combined filtrate was concentrated, and the residue was subjected to silica gel column chromatography (chloroform: methanol = ₉ : 1) to obtain a purified product of the title compound (9.2 g). This was dissolved in hot acetone and recrystallized to give a crystal of the title compound (4.9 g) in a yield of 42.3%.

Rf value: 0.32 (silica gel thin layer chromatography, chromate form: methanol = 9: 1).

The ¹ H-NMR data of the _{ALB 2 4 8 (CDC1 3 +} DMS0- + D 2 0): 5 = 4.30 (1H, br, OH, D 2 0 exchangeable), 4.05 (1H, br, 0H, D 2 0 exchangeable ), 3.77 (2H, m, -CH 2 - 0-), 3.62 (1H, d, J = 10.26Hz, CH-0-), 3.42 (1H, t, J = 10.26Hz, -CH-0-) , 2.06 (1H, m, cyclic CH), 1.86 (1H, m, 8-CH), 1.73-1.10 (19H, m, CH and Me), 0.9-0.8 (2H, m, CH), 0.85 (3H, s, Me), 0.80 (3H, s, Me), 0.70 (3H, s, Me).

Synthesis of 8 1 ^ 8 2 7 2 and 2 7 9

Manol (lOg) was dissolved in dehydrated THF (100 ml), and a 1 M BH ₃ · THF complex solution (100 ml) was slowly added dropwise at −20 ° C., followed by stirring for 6 hours. Thereafter, a 6N aqueous sodium hydroxide solution (71 ml) was added dropwise while paying attention to foaming, followed by a 30% aqueous hydrogen peroxide solution (142 ml). After stirring at room temperature for 1 hour, the reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was washed with saturated saline and dehydrated by adding anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate (twice) and the combined ethyl acetate layers were treated as above. Was. The combined filtrate is concentrated, and the residue is purified by silica gel column chromatography.

(Form: methanol = 9: 1) to give crude products of the title compound. This was dissolved in hot acetone and recrystallized to obtain the title compound. Synthesis of A L B 253

To a solution of ALB248 (500 mg) and 2-chloromethylquinoline (lg) in THF (30 ml) was added sodium hydride (184 mg, 60% in oil), and the mixture was stirred at room temperature for 15 hours. After an aqueous solution of ammonium chloride was added to the reaction solution, it was separated into ethyl acetate and saturated saline. The aqueous layer was extracted with ethyl acetate, combined with the previous ethyl acetate layer, and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (chloroform: methanol = 98: 2, 97: 3, 9: 1) to give the title compound (520 mg). A yield of 56 was obtained. In addition, a compound in which only the hydroxyl group at the 15-position reacted was obtained in a yield of 24%.

ALB 2 5 3 of ¹ H-NMR de Isseki _{(CDC1 3): 6 = 8.95-8.85} (4H, m, aromatic CH), 8.13- 7.98 (6H, m, aromatic CH), 7.85-7.82 (2H, i , aromatic CH), 5.48-5.27 (4H , m, - 0- CH2- Ar x2), 3.93 (2H, t, J two _{6.35Hz, - CH 2 - 0-)} , 3.73 (ZH, m, 8- CH _{2 - 0-), Z.16-1.10 (16H} , m, cyclic CH and methylene), 1.22 (3H, s, Me), 0.89-0.78 (3H, m, cyclic CH), 0.86 (3H, s, Me ), 0.80 (3H, s, Me), 0.7K3H, s, Me).

Synthesis of AL B 255 and AL B 255

Sclareol (660 mg) was dissolved in a solution of dehydrated black mouth form (20 ml), and diisopropylethylamine (4 ml) was added thereto. A reaction mixture of bis (benzoxymethyl) methyl bromomethyl ether synthesized according to the literature (J. Med. Chem., 31, 144-149 (1988)) was added in a large excess, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was separated into ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was washed with saturated saline, and anhydrous sodium sulfate was added. Pum was added and dehydrated. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The filtrates were combined and concentrated, and the residue was subjected to silica gel chromatography to obtain Fr.A (870 mg) and Fr.B (450 mg) in 65 and 34% yield, respectively.

Fr.A (870 mg) was dissolved in methanol, an excess amount of potassium carbonate was added, and the mixture was vigorously stirred at room temperature for 30 minutes. The reaction solution was separated into chloroform and aqueous ammonium chloride solution, and the aqueous layer was extracted with chloroform. The port-form layers were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was subjected to silica gel column chromatography (form: methanol = 97: 3, 95: 5) to give ALB255 (185 mg) in a yield of 32. %.

¹ H-NMR data of AL B 255 (CDCl ₃ ): d = 5.93 (lH, dd, J = 10.74, 17.58Hz, -CH =), 5.20 (1H, dd, J = 1.46, 17.58Hz) , 2CH), 5.00 (1H, dd, J = 1.46, 10.74Hz, 2CH), 4.97 (1H, d, J = 7.32Hz, -0-CH-0-), 4.83 (1H, d, J = 7.32Hz, -0-CH-0-) , 3.73- 3.54 (5H, m, - 0- CH (CH 2 -0-) 2), 1.96 (1H, m, cyclic CH), 1.86-0.78 (31H, m, cyclic CH and Mex5) _c

Fr.B (450 mg) was dissolved in methanol, an excess amount of potassium carbonate was added, and the mixture was vigorously stirred at room temperature for 30 minutes. The reaction solution was separated into chloroform and aqueous ammonium chloride solution, and the aqueous layer was extracted with chloroform. The port-form layers were combined, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was subjected to silica gel column chromatography (form: methanol = 97: 3, 9: 1) to give ALB254 (170 mg) in 56% yield. Obtained.

R f: 0.44 (silica gel thin-layer chromatography, black form: medium = 9: 1).

ALB 2 5 4 of ^l H-NMR data _{(CDC1 3): 6 = 5.82} (1H, dd, J = 10.75, 18.07Hz, -CH =), 5.18 (2H, m, = CH ₂ ), 4.84 (1H, d, J = 6.84Hz, -0-CH-0-), 4.79 (1H, d, J = 6.84Hz,-O- CH-0 -), 3.64-3.57 ( 5H, m, - 0 - CH (CH 2 -0-) 2), 1.98- 0.76 (32H, m, cyclic CH and Mex5).

Synthesis of ALB2256

A mixture of 1,3-dioxolane (10 ml) and acetyl chloride (9.2 ml) was heated at 70 ° C for 30 minutes to prepare a mixture of 2-acetoxityl chloromethyl ether.

To a solution of sclareoyl (616 mg) in dehydrated chloroform (20 ml) was added disopole pyrethylamine (5 ml), further the above mixture (0.8 ml) was added, and the mixture was stirred at room temperature for 15 hours. The mixture was separated into ethyl acetate and an aqueous solution of ammonium chloride, and the ethyl acetate layer was washed twice with an aqueous solution of ammonium chloride, washed with a saturated saline solution, and dried by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8: 2, 7: 3) to obtain the title compound (453 mg) in a yield of 53%. ALB 2 5 6 of '.eta. NMR de Isseki _{(CDC1 3): δ = 5.85} (1H, m, -CH =), 5.28- 4.99 (2H, m, = CH 2), 4.83-4.64 (2H, m , -0-CH _z -0-), 4.21 (2H, m, CH ₂ -0Ac), 3.75 (2H, m, -0- CH Factory), 2.06 (3H, s, -0-Ac), 1.97- 0.87 (31H, m, cyclic CH and Mex5).

Synthesis of ALB2257

A mixture of the above prepared 2-acetoxityl chloromethyl ether (3.8 ml) in a solution of AT-15 (2.46 g) and diisopropylethylamine (10 ml) in dehydrated mouth form (40 ml) Was added and stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and the residue was separated into ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was washed twice with an aqueous solution of ammonium chloride, washed with a saturated saline solution, and then dried over anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated. The residue was dissolved in methanol (100 ml), potassium carbonate (1.5 g) was added, and the mixture was vigorously stirred at room temperature for 1 hour. The reaction solution was separated into a black hole form and an aqueous solution of ammonium chloride. The aqueous layer was extracted with chloroform, and the combined chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 85: 15) to give the title compound (1.52 g) in a yield of 52%. At this time, sclareol (527 mg) as a starting material was recovered with a yield of 21%.

ALB 2 5 7 of 'H- NMR data (CDC1 _3): (5 two 5.77 (1H, dd, J = 11.23, 16.58Hz, - CH two), 5.10 (2H, m, = CH 2), 4.82 (1H , d, J = 7.82Hz, -0-CH-0-), 4.70 (1H, d, J = 7.82Hz, -0-CH-0-), 4.60 (1H, br s, 2-H of THP) , 3.92 (1H, in, 6 -H of THP), 3.72-3.64 (4H, m, - CH 2 CH 2 - 0-), 3.41 (1H, m, 6-H of THP), 1.91-1.10 (26H , M, cyclic CH and Mex2) ₅ 0.92-0.76 (11H, m, cyclic CH and Mex3).

Synthesis of AL B 2 5 8

To a solution of ALB 256 (350 mg) in methanol (10 ml) was added lithium carbonate (125 mg), and the mixture was vigorously stirred at room temperature for 1 hour. The reaction solution was separated between a form of ethyl acetate and an aqueous solution of ammonium chloride. The aqueous layer was extracted with chloroform, and the combined chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (form: methanol: 95: 5, 93: 7, 9: 1) to give the title compound (280 mg) in yield. 89%.

R f: 0.43 (silica gel thin-layer mouth chromatography, black mouth form: methanol = 9: 1).

Synthesis of ALB259

To a solution of ALB257 (470 mg) in dehydrated THF (5 ml) was added 2-chloromethylquinoline. (120 mg) and sodium hydride (40 mg, 60% in oil) were added, and the mixture was stirred at room temperature for 2 hours. Further, while checking the reaction by TLC, 2-chloromethylquinoline, sodium hydride and sodium bromide were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was separated into chloroform and aqueous ammonium chloride solution, and the chloroform layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 8: 2) to give the title compound.

(216 mg) was obtained in a yield of 35.

Rf: 0.63 (n-hexane: ethyl acetate = 6: 4).

AL B 2 5 9 of '.eta. NMR data (CDC1 _3): 5 two 8.17 (1H, d, J = 8.3Hz, aromatic CH), 8.05 (1H, d, J = 8.3Hz, aromatic CH), 7.8K1H , d, J = 8.3Hz, aromatic CH), 7.70 (1H, m, aromatic CH), 7.66 (1H, d, J 8.3Hz, aromatic CH) 7.52 (1H, m, aromatic CH), 5.78 (1H, dd, J = 11.23, 17.58Hz, - CH =) 5.12 (2H, m, = CH 2), 4.87 (2H, s, -O-quinoline), 4.86 (1H, d, J = 7.82Hz -0-CH -0-), 4.75 (1H, d, J = 7.82Hz, -0-CH-0-), 4.60 (1H, m, 2-H of THP) 3.92 (1H, m, 6-H of THP), 3.81 (2H, m, - 0- CH 2 -), 3.76 (2H, m, - CH 2 - 0-) 3.4K1H, m, 6-H of THP), 1.95-0.76 (32H, m, cyclic CH and (Mex5) _Q Synthesis of ALB260, ALB261 and ALB266

To a solution of sclareol (924 mg) in dehydrated form (30 ml) was added diisopropylpyrethylamine (4.2 ml), and the mixture was cooled in an ice bath. 2-Methoxyxylchloromethyl ether (1.37 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 5 days. The reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride, and the ethyl acetate layer was washed successively with an aqueous solution of ammonium chloride and a saturated saline solution, and dried by adding anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate, and anhydrous sodium sulfate was added to the ethyl acetate layer and dried. Combine these ethyl acetates After concentration, the residue was subjected to silylation gel column chromatography (n-hexane: ethyl acetate 75:25), ALB 260 (285 mg, 20%), ALB 261 (468 mg, 39%), AL B262 (324 mg, 27%) was obtained, respectively.

ALB 2 of 6 0 'H-NMR data _{(CDC1 3): 5 = 5.91} (1H, dd, J = 10.74, 17.58Hz, - CH =), 5.20 (1H, -dd, J = 1.46, 17.58Hz, = CH), 5.01 (1H, dd, J = 1.46, 10.74Hz, = CH), 4.84 (1H, d, J = 7.32Hz, -0-CH-0-), 4.75 (1H, d, J = 7.32Hz) , -0-CH-0-), 3.7K2H, m, - 0-CH 2 -), 3.54 (2H, m, - CH 2 - 0-), 3.38 (3H, s, -0-Me), 1.96 (1H, m, cyclic CH), 1.67-0.77 (30H, m, cyclic CH and Me x5).

ALB 2 6 1 of ^ -NMR data _{(CDC1 3): (5 =} 5.81 (1H, dd, J = 11.23, 17.58Hz, -CH =), 5.16 (2H, m, = CH2), 4.74 (2H, m , -0-CH2-0-), 3.73 ( 2H, m, -0- CH 2 -), 3.55 (2H, m, - CH 2 - 0-), 3.38 (3H, s, -0-Me), 1 · 86-0.78 (31H, m, cyclic CH and Mex5).

AL B 2 6 2 of ¹ H- NMR de Isseki _{(CDC1 3): 5 = 5.82} (1H, dd, J = 10.74, 17.58Hz, - CH two), 5.13 (2H, m, two CH2), 4.84 ( 1H, m-0-CH- 0- ), 4.76 (1H, m, - 0-CH- 0-), 4.7K2H, m, - 0- CH 2 - 0-), 3.74 (2H, m, -0 _{-CH 2 -), 3.65 (2H} , m, -0 - CH 2 -), 3.55 (4H, m, - CH 2 - 0- x2), 3.38 (6H, s, -0-Me), 1.94 (1H , M, cyclic CH), 1.82-1.1K22H, m, cyclic CH and Mex 2), 0.93-0.77 (11H, m, cyclic CH and Mex3).

Synthesis of AL B 2 63 and ALB 1 64

To a solution of sclareoyl (924 mg) in dehydrated form of mouth (30 ml) was added disopropylethylamine (4 ml), and the mixture was cooled in an ice bath. Octyl bromomethyl ether (1.32 ml) was added dropwise to this solution and stirred at room temperature for 4 days. The reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride, and the ethyl acetate layer was washed with an aqueous solution of ammonium chloride (twice) and a saturated saline solution in that order, and dried over anhydrous sodium sulfate. After drying, filtration, and filtration, the filtrate is concentrated. The residue was subjected to silylation gel column chromatography (n-hexane: ethyl acetate = 95: 5, 9: 1, 85:15, 6: 4) to give ALB263 (321 mg). , 23.7%) and ALB264 (344 mg, 25.4%), respectively. The raw material sclareol (425 mg) was recovered in 46 kg.

! ALB 2 6 3 of H- NMR de Isseki _{(CDC1 3): 5 = 5.91} (1H, dd, J = 10.74, 17.57Hz, - CH =), 5.20 (1H, dd, J = 1.46, 17.57Hz, = CH), 5.01 (1H, dd, J = 1.49, 10.74Hz, 2CH), 4.80 (1H, d, J = 7.32Hz, -0-CH-0-), 4.71 (1H, d, J-7.32 Hz, -0-CH-0-) , 3.52 (2H, m, - 0- CH 2 -), 1.96 (1H, m, CH), 1.71-0.77 (47H, m,

CH and Mex6).

ALB 2 of 6 4 'Η- NMR de Isseki _{(CDC1 3): (S =} 5.81UH, dd, J two 10.74, 17.58Hz, -CH =), 5.14 (1H, d, J two 17.58Hz, two CH ), 5.13 (1H, d, J = 10.74Hz, two CH), 4.68 (2H, d , J = 1.96Hz, - 0-CH 2 - 0 -), 3.56 (2H, t, J = 6.84Hz, - 0-CH _2- ), 1.86-0.77 (48H, m, CH and Mex6) _D

Synthesis of AL B 27 3, AL B 26 5, AL B 26 6 and ALB 2667

Disopropylethylamine (7 ml) was added to a solution of sclareoyl (3.08 g) in dehydrated chloroform (50 ml), and the mixture was cooled in an ice bath. An equimolar amount of a reaction mixture (5.5 ml) of 1,3-dioxane and acetyl chloride or separately synthesized 3-acetoxypropyl chloromethyl ether was added dropwise to the solution, and the mixture was stirred at room temperature for 24 hours. . The reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride, and the ethyl acetate layer was washed with an aqueous solution of ammonium chloride and a saturated saline solution in that order, and dried by adding anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate, and anhydrous sodium sulfate was added to the ethyl acetate layer and dried. After filtration, the filtrates were combined and concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1, 85:15, 8: 2), and Fr.A (1.7 g, 29.9%), Fr.B (ALB273: 1.77g, 40.4%) and 1 \ .0 (1.08 ^ 24.7%), respectively.

AL B 2 7 3 of ¹ H- NMR de Isseki _{(CDC1 3): (5 =} 5.91 (1H, dd, J = 10.74, 17.57Hz, -CH =), 5.20 (1H, dd, J = 1.46, 17.57Hz, = CH), 5.02 (1H, dd, J = 1.46, 10.74Hz, 2CH), 4.80 (1H, d, J = 7.33Hz, - 0- CH-0-), 4.70 (lH, d, J = 7.33Hz, -0-CH-0-), 4.16 (2H, m, - CH 2 - 0Ac), 3.60 (2H, m, -0 _{-CH 2), 2.05 (3H,} s, Ac), 1.96-1.87 (3H, m, CH 2 and cyclic CH), 1.72-1.16 (19H, m, cyclic CH and Mex2), 0.96-0.77 (llH, m , Cyclic CH and Mex3).

Fr. A (1.7 g) was dissolved in methanol (30 ml), potassium carbonate (1.3 g) was added, and the mixture was stirred at room temperature for 30 minutes. An aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted three times with black-mouthed form. Anhydrous sodium sulfate was added to the combined mouth layer and dried. After filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 6: 4, 4: 6) to give ALB 267 (900 mg) in 62% yield. I got it.

ALB 2 6 7 iH-NMR de Isseki of (CDC1 _3): 5 D 5.83 (1H, dd, J = 11.23, 17.09Hz, - CH :), 5.15 (2H, m, two CH), 4.81 (1H, d, J = 7.32Hz, - 0 - CH-0-), 4.69 (3H, m, -0-CH-O- and _{- 0 - CH 2 -0-),} 3.79-3.64 (8H, m, (- 0- CH ₂₎ x2 and _{(CH 2 -0H) X2),} 1.94-1.13 (Z4H, m, cyclic CH, CH 2 x2 and Mex2), 0.91-0.78 (11H, m , cyclic CH and Mex3).

Fr.B (ALB27.3) (1.77 g) was dissolved in methanol (30 ml), and potassium carbonate (740 mg) was added, followed by stirring at room temperature for 1 hour. An aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted three times with a black form. Anhydrous sodium sulfate was added to the combined foam layer and dried. After filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 7: 3, 6: 4, 4: 6) to give 11 ^ 265 (1.06 g). It was obtained in a yield of 66%.

AL B 2 6 5 of ¹ H-NMR de Isseki _{(CDC1 3): 5 = 5.91} (1H, dd, J = 10.74, 17.09Hz, - CH =), 5.20 (1H, dd, J = 1.47, 17.09Hz , 2CH), 5.01 (1H, dd, J = 1.47, 10.74Hz, = CH), 4.82 (1H, d, J = 6.84Hz, -0-CH-O-), 4.71 (lH, d, J = 6.84Hz, -0-CH-0-), 3.79- 3.65 (4H, m, -0-CH 2 and _{CH 2 - OH)), 1.97} (1H, m, cyclic CH), 1.82 (2H, m, CH Z), 1.67-1.14 (19H, m, cyclic CH and Mex2), 0.98-0.78U1H, m, cyclic CH and Mex3).

Fr.C (1.08 g) was dissolved in methanol (30 ml), potassium carbonate (530 mg) was added, and the mixture was stirred at room temperature for 1 hour. Aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted three times with black-mouthed form. Anhydrous sodium sulfate was added to the combined form mouth layer and dried. After filtration, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 6: 4) to give ALB266 (574 mg) in a yield of 58.8%. .

ALB 2 6 6 of H- NMR data (CDC1 _3):! 5 two 5.82 (1H, dd, J two 10.75, 17.58Hz, -CH =), 5.14 (2H, m, two CH _2), 4.69 (2H, _{s, -0- CH 2 - 0-)} , 3.75 (4H, m, - 0 - CH 2 and _{CH 2 - OH)), 1.86-} 1.78 (4H, m, cyclic CH and CH _2), 1.63-0.77 ( 29H, m, cyclic CH and Mex5) _Q

Synthesis of ALB2274

Diisopropylethylamine (2.2 ml) was added to a solution of ALB273 (1.4 g) in dehydrated cloper form (15 ml), and the mixture was cooled in an ice bath. 2-Methoxyxyl chloromethyl ether (1.46 ml) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was separated into ethyl acetate and an aqueous solution of ammonium chloride. The ethyl acetate layer was washed successively with an aqueous solution of ammonium chloride and a saturated saline solution, and then dried by adding anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate, and anhydrous sodium sulfate was added to the ethyl acetate layer and dried. After filtration, the filtrates are combined and concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 9: 1, 8: 2) to give the title compound (1.36 g) in a yield of 81%. %.

AL B 2 7 4 of ¹ H-NMR de Isseki _{(CDC1 3): 5 = 5.82} (1H, dd, J = 10.79, 17.58Hz, -CH =), 5.15 (2H, m, = CH 2), 4.79 -4.65 (4H, m, (-0- CH ₂ -0-) x2), 4.15 (2H, _{m, - CH 2 -0Ac),} 3.78- 3.54 (6H, m, -0- CH 2 - and _{_{-0- CH 2 CH 2 - 0-)}} , 3.38 (3H, s, -0-Me), 2.05 ( 3H, s, Ac), 1.95-1.85 (3H, m, CH 2 and cyclic CH), 1.75-1.10 (20H, m, cyclic CH and Mex2), 0.96-0.77 (10H, m , cyclic CH and Mex3) ₀

Synthesis of ALB2275

ALB274 (1.06 g) was dissolved in methanol (30 ml), and potassium carbonate (460 mg) was added, followed by stirring at room temperature for 1 hour. An aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. After washing the combined ethyl acetate layer with saturated saline, anhydrous sodium sulfate was added and dried. After filtration, the filtrate is concentrated, and the residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 75: 25, 7: 3, 6: 4) to give the title compound (755 mg). Obtained in 77% yield.

ALB 2 7 5 of 'H- NMR de Isseki _{(CDC1 3): δ = 5.82} (1H, m, - CH =), 5.15- 5.12 (2H, m, = CH 2), 4.81- 4.65 (4H, m , (- 0- CH-0-) x4), 3.79-3.53 (8H, m, - 0- CH 2 -, - CH 2 - 0- , and _{_{-0- CH 2 CH 2 - 0-)}} , 3.38 (3H , s, - 0- Me), 1.95- 1.12 (21H, m, CH 2, cyclic CH and Mex2), 0.96-0.78 (11H, m , cyclic CH and Mex3).

Synthesis of A L B 268

Copper iodide (1.14g) was suspended in dry THF (20ml) and cooled to-40 ° C. A 1M allyl-MgBr / getyl ether solution (12 ml) was added dropwise, and the mixture was stirred at −40 ° C. for 1 hour. A solution of MANO-F (613 mg) in dehydrated THF (5 ml) was added dropwise, and the mixture was stirred for 1 hour except for a cooling bath. Further, the mixture was heated to 40 ° C. and stirred for 15 hours. An aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution, and the mixture was filtered using celite. The celite was washed with ethyl acetate and combined with the filtrate. The solution was separated, the ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated. Chromatography (form: methanol: 95: 5, 9: 1) afforded the title compound in about 20% yield.

¹ H- NMR data of _{ALB 2 6 8 (CDC1 3)} : δ = 5.97-5.69 (2H, m, -CH = χ2), 5.24-4.95 (4H, m, two CH ₂ χ2), 2.29-2.03 (2H , m, allylic CH), 1.81-0.78 (30H, in, cyclic CH and Mex4).

Synthesis of ALB2276

Copper iodide (5.7g) was suspended in dehydrated THF (100ml) and cooled to-40 ° C. To this solution, a 2M cyclohexyl-MgCl / getyl ether solution (30 ml) was dropped, and the mixture was stirred at −40 ° C. for 20 minutes. Thereafter, MAN0-F (1.4 g) was added dropwise, the temperature was gradually raised, and the mixture was stirred in an ice bath for 1 hour. An aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the mixture was filtered using celite. The celite was washed with ethyl acetate and combined with the filtrate. The solution was separated, and the ethyl acetate layer was washed three times with an aqueous solution of ammonium chloride and once with a saturated saline solution, and dried by adding anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by crystallization from hot acetone to give the title compound (726 mg) in a yield of 42. The filtrate left considerable product as confirmed on TLC and the overall yield was expected to be over 70%.

ALB 2 7 6 of 'H- NMR de Isseki _{(CDC1 3): 5 = 5.93} (1H, dd, J = 10.74, 17.09Hz, -CH two) 5.2K1H, dd, J = 1.46 , 17.09Hz, = CH ) 5.03 (1H, dd, J two 1.46, 10.74Hz, two CH) 2.08 (1H, dd, J = 3.41, 9.27Hz, CH) 1.86-0.77 (41H, m, CH 2, c-hexane, cyclic CH, And Mex4) _c

Synthesis of AL B 26 9, A L B 27 0, A L B 27 1

MANO-F (1.8 g) was dissolved in a mixed solution of THF (45 ml) and water (5 ml), 3 drops of 70% aqueous perchloric acid was added, and the mixture was stirred at room temperature for 6 days. The reaction solution was partitioned between ethyl acetate and saturated saline, and anhydrous sodium sulfate was added to the ethyl acetate layer and dried. After filtration, the filtrate is concentrated and the residue is purified by silica gel column chromatography. Chromatography (cloth form: methanol = 95: 5, 92: 8) to give Fr.A (ALB269, 496 mg) in 28% yield, Fr.B (ALB270, 150 mg) in 8% yield, and Fr.C (ALB 271, 190 mg) in 10% yield. The raw material MANO-F (884 mg) was recovered by 49%. ALB269 was obtained as a mixture having double bonds at the 7 and 8 positions.

AL B 2 6 9 NMR data of Isseki _{(CDC1 3): (5 =} 5.92 (lH, m, - CH =), 5.73 (0.5H, m, 7- vinyl), 5.22 (1H, m, = CH) , 5.06 (1H, m, = CH), 4.12 (1H, m, -CH-0), 3.98 (1H, m, -CH-0), 2.45-0.75 (26-28H, m, CH and ex5) ₀

ALB 2 7 0 of ^ -NMR de Isseki _{(CDC1 3): (5 =} 5.93 (1H, dd, J = 10.74, 17.09Hz, -CH =), 5.2K1H, dd, J = 0.97, 17.09Hz, = CH), 5.03 (1H, dd, J2 0.97, 10.74Hz, = CH), 3.6K1H, d, J = 10.75Hz, -CH-0), 3.52 (1H, d, J = 10.75Hz, -CH- 0), 2.2K1H, m, CH ), 1.75-0.72 (27H, m, cyclic CH and Mex4) _D AL B 2 7 1 of ¹ H- NMR de Isseki _{(CDC1 3): 5 = 5.92} (1H, dd , J = 10.74, 17.57Hz,-CH =), 5.22 (1H, dd, J = 0.98, 17.57Hz, two CH), 5.05 (1H ₅ dd, J = 0.98, 10.74Hz, two CH), 3.50 (1H , D, J2 10.74Hz, -CH-0), 3.27 (1H, d, J = 10.74Hz, -CH-0), 1.84-0.82 (28H, m, cyclic CH and ex4) ₀

The resulting ALB 2 4 4 (I-Dani 96), ALB 250 (Chem. 97), 2-butene-1,4-diol di-0-AT- 1 ether (Chem. 98), ALB 2 The structural formulas of 59 (Chemical Formula 99) and ALB276 (Yidani 100) are shown below, and the substitution groups of other compounds are summarized in Tables 31 and 32 below.

O

i I6 one 66lo / 6i

o

Table 3 1

(Continued on next page) Table 3 1 (continued)

THP: Tetrohydrodrobilanil, MOM: methoxymethyl, Bzl (or Bn): benzyl, Bz: benzoyl Table 3 2

TUP: Tetrahidrobilanil, MOM: Methoxymethyl, Bzl (or Bn): Penzil, Bz: Benzoyl

Tables 33 and 34 show the results of the antifungal activity and infection treatment tests of the prepared compounds. Table 33 Antifungal activity (IC _8:. 〃G / ml)

Table 3-4 Results of infection treatment experiments

A. fimiga tus infection Dose Dose l Omg / kg 2mg / kg

ALB089 Invalid Somewhat valid

ALB091 Slightly effective Slightly effective

ALB092 Valid Valid

ALB242 Slightly valid Valid

ALB244 Slightly valid Valid

ALB245 Slightly valid Valid

ALB246 valid valid

ALB247 valid somewhat valid

ALB248 valid valid

ALB251 valid invalid

ALB252 Slightly valid Invalid

ALB253 Disabled Slightly enabled

ALB254 Somewhat valid Invalid

ALB255 valid somewhat valid

ALB258 valid somewhat valid

ALB259 valid somewhat valid

ALB260 valid valid

ALB261 Slightly valid Valid

ALB265 valid valid

ALB266 valid somewhat valid

ALB267 valid valid

ALB268 valid somewhat valid

ALB269 valid somewhat valid

ALB270 valid valid

ALB271 valid valid

ALB272 valid valid

ALB275 valid valid

ALB276 valid valid

ALB279 valid valid Industrial applicability

The above results indicate that the compounds of the present invention show excellent antifungal activity against Candida albicans and Aspergillus ある, which are pathogenic fungi that infect humans. It was found that these compounds are effective as chemotherapeutic agents against fungal infections such as candidiasis and aspergillosis.

Claims

The scope of the claims

1. It has a hydronaphthylene ring structure which may have an unsaturated bond represented by the following structural formula, and the structure derived from isosquenic acid is linked to the 9-position of the hydronaphthalene ring via an ether bond. An antifungal agent comprising, as an active ingredient, a compound not bound to a methyloxy group.

(Wherein R1, R2, and R3 are alkyl groups which may have the same or different substituents, and R4 is a carbon number of 1 to 4 which may have a substituent. A straight chain hydrocarbon having 0 to 3 carbon atoms which may have a hydroxy group and an organic group or a substituent having an ether, ester or urethane bond derived from the hydroxy group at the tip of the straight chain hydrocarbon. Is a carboxyl group and an organic group having an ester or amide bond attributable to the carboxyl group at the end.

2. An antifungal agent comprising as an active ingredient sclareol, sclareolide, manol, or rabdanolic acid or a compound derived therefrom.