JPH08259569A - Pyripropene derivative - Google Patents

Abstract

PURPOSE: To obtain a pyripropene derivative having inhibiting activities against acyl coenzyme A (acyl CoA) cholesterol transferases useful for treating diseases caused by accumulation of cholesterol in humans such as hyperlipemia or arteriosclerosis based thereon. CONSTITUTION: This derivative of the formula (R1 is OH or OCOR5 ; R2 is H, OH, O-alkyl, etc.; R5 is an alkyl, a heterocyclic group, etc.) is obtained by deacylating, e.g. pyripropene A (any one or two of R1 , R2 and R3 are OH and the rest are acylated). The deacylation is carried out in a solvent such as methanol at ambient temperature or under conditions of cooling with ice at 0 deg.C or heating under reflux by using sodium methoxide when the reaction is hydrolysis with an alkali. The hydrolysis with an acid is performed in a solvent such as methanol at ambient temperature by using hydrochloric or sulfuric acid.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pyripyropene derivatives.

[0002]

2. Description of the Related Art Conventionally, some drugs for treating hyperlipidemia are known. As a therapeutic drug for hyperlipidemia,
(1) Cholesterol biosynthesis inhibition, (2) Cholesterol absorption inhibition, (3) Cholesterol catabolism promotion,
(4) A drug having an action of suppressing the synthesis of lipoprotein is known.

[0003]

In recent years, with the improvement of eating habits, symptoms caused by cholesterol accumulation such as hyperlipidemia and arteriosclerosis in adults have been regarded as a modern disease. Hyperlipidemia is known as one of the factors that promote the progression of arteriosclerosis, and can reduce ischemic heart disease by lowering blood cholesterol. Further, it is desired to develop a more effective and safe therapeutic drug for hyperlipidemia, particularly hypercholesterolemia, such that the incidence of myocardial infarction increases with hyperlipidemia.

Cholesterol becomes cholesterol ester by acyl group transfer from acyl coenzyme A,
It is accumulated intracellularly and in blood lipoproteins. The enzyme that catalyzes this acyl group transfer reaction is acyl coenzyme A cholesterol acyl transferase, which is deeply involved in the absorption of cholesterol from the intestinal tract and the formation of foam cells in the coronary arteries. Therefore, a substance that inhibits acylcoenzyme A cholesterol acyltransferase is presumed to be effective for such diseases. Under such circumstances, it is useful for treating adult diseases such as hyperlipidemia and arteriosclerosis based on it, to provide a substance having an acylcoenzyme A cholesterol acyltransferase inhibitory activity.

[0005]

As a result of continuing research on metabolites produced by microorganisms, the present inventors have found that acylcoenzyme A cholesterol transferase in a culture of FO-1289 strain isolated from a new soil. It was found that a substance having inhibitory activity was produced. Then, an acylcoenzyme A cholesterol acyltransferase inhibitory active substance was separated from the culture and purified to obtain each substance having the physicochemical properties described below. Since these substances have not been known at all in the past, this substance was identified as pyripyropene (FO-1).
289 substance). (JP-A-6-184158
issue)

The present inventors have synthesized various derivatives of pyripyropene for the purpose of further increasing the acylcoenzyme A cholesterol acyltransferase inhibitory activity of pyripyropene (hereinafter referred to as ACAT inhibitory activity). The present invention has been completed based on such findings, and provides a pyripyropene derivative represented by the following formula.

[0007]

[Chemical 10] The pyripyropene derivatives of the present invention represented by the above formula can be broadly classified into the following groups of compounds.

[0008]

[Chemical 11] (Hereinafter, referred to as Group 1-1 compound)

[0009]

[Chemical 12] (Hereinafter, referred to as Group 1-2 compound)

[0010]

[Chemical 13] (Hereinafter, referred to as Group 1-3 compound)

[0011]

Embedded image (Hereinafter, referred to as Group 1-4 compound)

[0012]

[Chemical 15] (Hereinafter, referred to as Group 1-5 compound)

[0013]

Embedded image (Hereinafter, referred to as Group 1-6 compound)

[0014]

[Chemical 17] (Hereinafter, referred to as group 1-7 compound) Pyripyropene, which is a raw material of the pyripyropene derivative of the present invention, is a microbial Aspergillus sp. Bacterium as described in JP-A-6-184158. FO-1289
Can be obtained as a culture product of

The production methods of the compounds of each group will be described below. (1) Group 1-1 compound: 1) In the formula of Group 1-1 compound, R ₁ , R ₂ ,
A compound in which any one or two of R ₃ is OH and the other is acylated: pyripyropene A (in the formula 2, R ₁ =
R ₂ ═R ₃ ═OAc compound) is obtained by deacylation (deacetylation). It is carried out by a usual method in which hydrolysis is carried out in a deacylated hydrous solvent using an alkali or acid catalyst.

In the case of alkaline hydrolysis, for example, methanol, water-methanol mixed solvent (hydrous lower alcohol), water-tetrahydrofuran mixed solvent are used as the solvent, and the reaction temperature is room temperature, 0 ° C. ice-cooling or heating reflux. , Can be changed according to the reaction conditions. Examples of the reagent used include sodium methoxide, 1,8-diazabicyclo [5,4,0] undec-7-ene, sodium hydrogen carbonate, ammonia, potassium carbonate, lithium hydroxide, sodium hydroxide, 1,4- Examples thereof include diazabicyclo [2,2,2] octane.

In the case of acid hydrolysis, as the solvent, for example, methanol, ethanol, a water-methanol mixed solvent (hydrous lower alcohol) or the like is used. The reaction temperature is usually room temperature, but it may be cooling or heating depending on the reaction conditions. Examples of the reagent used include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like.

R₁, R₂, R₃One of the
In the case of an acyl group other than the cetyl group, an acyl group introduction part
Acylation at the desired position by protecting the hydroxyl groups other than
By removing the protective group of the hydroxyl group later,
The target product can be obtained. For example R₁, R₃Is OH,
R₂To obtain a compound in which is an acyl group, R₁, R₂,
R₃R of a compound in which the group of is OH₁, R₃The base of aceta
Protected, R ₂After acylation of R₁, R₃
The deacetalization of Deprotection of acetal is acid
Can be carried out by a usual method using

2) In the formula of the group 1-1 compound,
Compound in which R ₁ is an acyl group: It is obtained by acylating a hydroxyl group of a compound in which R ₁ ═R ₂ ═R ₃ ═OH in the formula of group 1-1 compound. Acylation is carried out by a usual method of acylation using an acid anhydride or an acid halide (acid chloride) and a base. Alternatively, it can also be carried out by a usual method of condensing a carboxylic acid with a condensing agent.

In the acylation reaction using an acid anhydride or an acid halide, for example, pyridine, dichloromethane, tetrahydrofuran or the like is used as a solvent, the reaction temperature is usually room temperature, and if necessary, the reaction is carried out under cooling or heating conditions. When an acid halide is used, a base such as pyridine or triethylamine is used as a deoxidizing agent, and dimethylaminopyridine is further added if necessary.
In the acylation reaction by the condensation reaction with a carboxylic acid, an anhydrous organic solvent such as dichloromethane or chloroform is used as a solvent, the reaction temperature is room temperature, and if necessary, the reaction is carried out under cooling or heating conditions.

Examples of the condensing agent include dicyclohexylcarbodiimide, N-hydroxybenzotriazole,
N, N'-bis (2-oxo-3-oxazolidinyl)
Phosphonic chloride or the like is used. As the base used in the reaction, dimethylaminopyridine,
Triethylamine and the like.

3) Compound in which either R ₁ or R ₂ is alkyl sulfonated: It can be obtained by subjecting a hydroxyl group of a compound in which R ₁ , R ₂ and R ₃ are OH to alkyl sulfonate. The alkyl sulfonation is carried out by a usual method using, for example, an alkyl sulfonic acid chloride or an alkyl sulfonic anhydride and a base. Examples of the solvent used include pyridine, dichloromethane, tetrahydrofuran and the like. The reaction temperature is
It may be carried out by cooling or heating at room temperature or depending on reaction conditions. As the base used, pyridine,
Triethylamine and the like. Each compound obtained as described above can be purified by a chromatographic method such as silica gel column chromatography.

(2) Group 1-2 compounds: compounds in which R ₃ is an acyl group, R ₁ and R ₂ are O-acetyl groups: In these compounds, R ₂ and R ₃ are OH, and R ₁ is R.
It is obtained by acylating a compound having a desired acyl group to be introduced into ₃ . The acylation can be carried out by a usual method of acylation using an acid anhydride or acid chloride and a base, or a usual method of condensation with a carboxylic acid.

Acylation using an acid anhydride or acid chloride can be carried out under the following conditions. Solvent: pyridine, dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible) Base: pyridine, triethylamine, etc. are used, and dimethylaminopyridine is further added if necessary.

Acylation by condensation reaction with a carboxylic acid can be carried out under the following conditions. Solvent: Dichloromethane (other anhydrous solvent may be used, for example, chloroform is used) Reaction temperature: Room temperature (cooling or heating conditions may be used) Condensing agent: Dicyclohexylcarbodiimide, N-hydroxybenzotriazole, N, N -Bis (2-oxo-3-oxazolidinyl) phosphinic chloride and the like can be used. Base: dimethylaminopyridine, triethylamine and the like. Each compound obtained as described above can be purified to obtain a pure product by column chromatography using silica gel or the like.

(3) Group 1-3 compound: R ₂ is O-
Compounds of this group that are acylated and R ₁ and R ₃ are O-acetylated include compounds in which R ₂ is OH and R ₁ and R ₃ are O.
It is obtained by O-acylating a compound that is an acetyl group. As a method of acylation, group 1-2
It can be carried out by the same reaction as for the compound of.

(4) Group 1-4 compound: R₁, R₃
Is O-acetylated and R₂Have various substituents on
Compounds of₁, R₃Is an O-acetyl group
Yes, R₂R of a compound in which is OH ₂Equivalent to the hydroxyl group of
It is obtained by introducing a substituent. How to install
Main methods of introduction differ depending on the substituents introduced.
The method is as follows.

Alkyl (or aryl) sulphonylation of hydroxyl groups: It is carried out by a conventional method using an alkyl (or aryl) sulfonic acid chloride or an alkyl (or aryl) sulfonic acid anhydride and a base. Solvent: pyridine, dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible) Base: pyridine, triethylamine, etc. are used.

Carbamate conversion of hydroxyl group: It is carried out by a usual method using an alkyl isocyanate. Base: triethylamine, pyridine, etc. Solvent: dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible)

Carbonation of hydroxyl group: carried out by a conventional method using carboalkyl chloride. Base: triethylamine Solvent: dichloromethane Reaction temperature: room temperature (cooling or heating conditions are possible)

Substitutional methyl etherification of hydroxyl groups: It is carried out by a usual method using a chloro-substituted ether. Reagent: methoxymethyl chloride, ethoxymethoxymethyl chloride, etc. Solvent: dichloromethane, tetrahydrofuran, etc. Base: triethylamine, pyridine, etc. Reaction temperature: room temperature (cooling or heating conditions are possible)

Methylthiomethylation of hydroxyl group: It is carried out by an ordinary method using a halide reagent or an ordinary method using dimethyl sulfoxide. Using a halide reagent Reagent: Methylthiomethyl chloride Solvent: Dichloromethane Reaction temperature: Room temperature (cooling or heating conditions are possible) Using dimethyl sulfoxide Reagent: Dimethyl sulfoxide and acetic anhydride or acetic acid Reaction temperature: Room temperature (cooling or There may be heating conditions)

Tetrahydropyranylation of the hydroxyl group: It can be carried out by a conventional method using dihydropyran and an acid. Reagent: dihydropyran acid Catalyst: pyridine hydrochloride, pyridinium p-toluenesulfonic acid, p-toluenesulfonic acid, etc. Solvent: dichloromethane Reaction temperature: room temperature (cooling or heating conditions are possible)

Glycosylation of hydroxyl groups: Suzuki et al., Tetrahedron Letter (30) 49, 1989, 687.
The method is described on page 9. Sugar: Tetra-O-benzyl-D-mannosylfluoride Reagent: Zirconocene chloride and silver triflate Drying agent: Molecular Sieves 4A Solvent: benzene Reaction temperature: room temperature, cooling

Thiocarbonylimidazolization of hydroxyl group:
It is carried out by a usual method using thiocarbonyldiimidazole. Reagent: Thiocarbonyldiimidazole Solvent: Toluene, benzene, tetrahydrofuran, etc. Reaction temperature: room temperature, heating under reflux

Deoxygenation reaction of hydroxyl group: It is carried out by a usual method of deoxygenating this after converting the hydroxyl group to thiocarbonylimidazole. Reagent: Tri-n-butyl hydrogen tin Radical reaction initiator: AIBN Solvent: Toluene Reaction temperature: Heating under reflux (room temperature or cooling conditions are possible)

Deprotection of pyridine N-oxide: It is carried out by a method using alkylphosphoric acid and light. Reagent: Triethyl phosphite Solvent: Chloroform, deuterated chloroform, etc. Light source: High-pressure mercury lamp Reaction temperature: room temperature (cooling or heating conditions are possible) The compound obtained as above is purified by column chromatography using silica gel, etc. It is possible to obtain a pure product.

(5) Group 1-5 compounds: R ₂ , R ₃
There is -O- acetyl group, R ₁ is an acyl group or an alkylsulfonyl group, the compounds of this group R ₁
Is a desired acyl group or alkylsulfonyl group,
It can be obtained by acetylating the hydroxyl group of a compound in which R ₂ and R ₃ are OH. As the acetylation method, the following acylation method can be used.

Acylation of hydroxyl group: It is carried out by an ordinary method of acylation using an acid anhydride or acid chloride and a base, or an ordinary method of condensation with a carboxylic acid. Acylation using acid anhydride or acid chloride: Solvent: pyridine, dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible) Base: pyridine, triethylamine, etc., and dimethylaminopyridine may also be added.

Acylation by condensation reaction with carboxylic acid: Solvent: Dichloromethane (other anhydrous solvent may be used, for example, chloroform) Reaction temperature: Room temperature (cooling or heating conditions may be used) Condensing agent: Dicyclohexylcarbodiimide, N -Hydroxybenzotriazole, N, N-bis (2-oxo-3-oxozolidinyl) phosphinic chloride, etc. Base: dimethylaminopyridine, triethylamine, etc.

(6) Group 1-6 compounds R ₁ , R ₂ and R ₃ are —O-acetyl groups, and R ₄ is O.
- an acyl or O- alkyl compounds of this group are obtained by introducing a substituent at R _1, R _2, pyripyropene A of R ₄ R ₃ is -O- acetyl group. Acylation of the hydroxyl group of R ₄ can be carried out by the following method.

Acylation of hydroxyl group: It is carried out by an ordinary method of acylation using an acid anhydride or acid chloride and a base, or an ordinary method of condensation with a carboxylic acid. Acylation using acid anhydride or acid chloride: Solvent: pyridine, dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible) Base: pyridine, triethylamine, etc., and dimethylaminopyridine may also be added.

Acylation by condensation reaction with carboxylic acid: Solvent: dichloromethane (other anhydrous solvent may be used, for example, chloroform) Reaction temperature: room temperature (cooling or heating conditions are possible) Condensing agent: dicyclohexylcarbodiimide, N-hydroxybenzotriazole, N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, etc. Base: dimethylaminopyridine, triethylamine, etc.

In the O-alkylation method of R ₄ , the pyridine ring of pyripyropene A is N-oxide protected and then the position of the R ₄ group is O-alkylated. After that, the desired compound can be obtained by deprotecting pyridine N-oxide. These reactions, N-oxidation of pyridine,
Deprotection of N-oxide of pyridine and O-alkylation are carried out as follows.

N-oxidation of pyridine: It is carried out by a conventional method using a peroxide. Reagent: m-chloroperbenzoic acid, hydrogen peroxide, etc. Solvent: Dichloromethane Reaction temperature: Room temperature (cooling or heating conditions are possible)

Deprotection of pyridine N-oxide: It is carried out by a method using alkylphosphoric acid and light. Reagent: Triethyl phosphite Solvent: Chloroform, deuterated chloroform, etc. Light source: High-pressure mercury lamp Reaction temperature: Room temperature (cooling or heating conditions are possible)

Alkylation: It is carried out by a conventional method using an alkyl halide and a base. Reagents: alkyl halides such as methyl iodide and benzyl bromide Bases: sodium hydride Solvents: tetrahydrofuran, dichloromethane, dimethyl sulfoxide, etc., or mixed solvents thereof Reaction temperature: room temperature, cooling (ice cooling, -40 ° C, etc.) or There may be heating conditions. The obtained compound can be isolated and purified by high performance liquid chromatography (HPLC) such as column chromatography using silica gel.

(7) Group 1-7 compound: R ₁ ,
Compounds of this group in which R ₂ and R ₃ are O-acyl groups and the like and R ₄ is OH or an O-acyl group are represented by R ₁ ,
It can be obtained by introducing a desired substituent into a compound in which R ₂ and R ₃ are OH, that is, a deacylated compound of Pyropyripene A. Further, a compound in which R ₁ , R ₂ , R ₃ and R ₄ are an O-acyl group and an OH group can be obtained by introducing a desired substituent into each predetermined position. Acylation of a hydroxyl group, alkylsulfone oxidation of a hydroxyl group, and tetrahydropyranylation of a hydroxyl group can be carried out by the following methods, for example.

Acylation of hydroxyl group: It is carried out by an ordinary method of acylation using an acid anhydride or acid chloride and a base, or an ordinary method of condensation with a carboxylic acid. Acylation using acid anhydride or acid chloride: Solvent: pyridine, dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible) Base: pyridine, triethylamine, etc., and dimethylaminopyridine may also be added.

Acylation by condensation reaction with carboxylic acid: Solvent: dichloromethane (other anhydrous solvent may be used, for example, chloroform) Reaction temperature: room temperature (cooling or heating conditions may be used) Condensing agent: dicyclohexylcarbodiimide, N -Hydroxybenzotriazole, N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, etc. Base: dimethylaminopyridine, triethylamine, etc.

Alkyl sulfonation of hydroxyl group The conventional method uses an alkyl (or aryl) sulfonic acid chloride or an alkyl sulfonic anhydride and a base. Solvent: pyridine, dichloromethane, tetrahydrofuran, etc. Reaction temperature: room temperature (cooling or heating conditions are possible) Base: pyridine, triethylamine, etc.

Tetrahydropyranylation of the hydroxyl group: carried out by the usual method using dihydropyran and an acid. Reagent: dihydropyran acid catalyst: pyridine hydrochloride, pyridinium p-toluenesulfonic acid, p-toluenesulfonic acid, etc. Solvent: dichloromethane Reaction temperature: room temperature (cooling or heating conditions are possible) The compound obtained as above is silica gel. A pure product can be obtained by purification by column chromatography using, for example.

The physicochemical properties and biological properties of the compounds obtained by the above methods are shown below. In addition, as a biological property, the inhibitory action against rat-derived acylcoenzyme A cholesterol acyltransferase by the in vitro activity measurement method described below is shown as a 50% inhibition value (IC ₅₀ ).

In vitro activity assay method: Inhibitory effect on rat-derived acylcoenzyme A cholesterol acyltransferase: The effect on acylcoenzyme A cholesterol acyltransferase activity is as described by Konda et al. (The Journal of Antibiotics, 45 Vol. 1626, 1992), using a crude enzyme prepared from rat liver microsome fraction, 1
00mM phosphate buffer (pH7.4) medium 300μM bovine serum albumin, 30μM [1- ¹⁴ C] oleoyl -Co
A (0.02 μCi), 30 μM cholesterol (30
1/10 weight of Triton WR-1339) was added to make a total volume of 200 μl, and the reaction was allowed to proceed at 37 ° C. for 30 minutes, and the reaction was stopped with a chloroform: methanol (1: 2) mixed solution to remove total lipids. Horsch et al. (Journal of Biological Chemistry, 226
Volume, page 497, 1957), and then each lipid was separated by TLC (Kieselgel GF ₂₅₄ , petroleum ether: diethyl ether: acetic acid = 90: 10: 1 as a developing solvent) and incorporated into a cholesterol ester fraction. Radioactivity was analyzed by RI scanner (manufactured by Ambis) to measure acylcoenzyme A cholesterol acyltransferase activity. The concentration at which this enzyme activity was inhibited by 50% was calculated. The results are shown below.

[0055]

Embedded image

Group 1-1 compound: Compound number R ₁ R ₂ R ₃ ACAT inhibitory activity (IC ₅₀ , μM) PR-3 OH OH OH> 220 PR-4 OCOCH ₃ OH OH> 200 PR-35 OCOCH ₂ CH ₃ OH OH NT PR-29 OCO (CH ₂ ) ₂ CH ₃ OH OH NT PR-52 OCO (CH ₂ ) ₃ CH ₃ OH OH NT PR-32 OCOCH (CH ₃ ) ₂ OH OH NT PR-119 OCO-p- Br-C ₆ H ₄ OH OH NT PR-85 OSO ₂ CH ₃ OH OH NT PR-96 OSO ₂ -p-CH ₃ -C ₆ H ₄ OH OH> 160 PR-5 OH OCOCH ₃ OH 100 PR-82 OH _{OCO (CH 2) 3 CH 3} OH 81 PR-6 OH OH OCOCH 3 38 PR-7 OCOCH 3 OH OCOCH 3 57 PR-42 OH OCOCH 3 OCOCH 3 3.3 PR-129 OSO 2 _{H 3 OSO 2 CH 3 OH NT} PR-154 OSO 2 CH 3 OCO (CH 2) 3 CH 3 OH 4.7

[0057]

[Chemical 19]

Group 1-2 compound: Compound number R ACAT inhibitory activity (IC ₅₀ , μM) PR-57 OCOCH ₂ CH ₃ (Pyripyropene D) 0.14 PR-55 OCO (CH ₂ ) ₂ CH ₃ 0.20 PR _{-75 OCO (CH 2) 3 CH} 3 0.62 PR-56 OCOCH (CH 3) 2 0.13

[0059]

Embedded image

Group 1-3 compound: Compound No. R ₂ ACTA inhibitory activity (IC ₅₀ , μM) PR-24 OCOCH ₂ CH ₃ (Pyripyropene C) 0.067 PR-25 OCO (CH ₂ ) ₂ CH ₃ 0.038 _{PR-45 OCO (CH 2)} 3 CH 3 0.013 PR-60 OCO (CH 2) 4 CH 3 0.019 PR-70 OCO (CH 2) 5 CH 3 0.17 PR-61 OCO (CH 2) _{6 CH 3 0.12 PR-15 OCO} (CH 2) 16 CH 3 7.7 PR-26 OCOCH (CH 3) 2 0.13 PR-58 OCOC (CH 3) 3 0.13 PR-59 OCOCH 2 CH _{(CH 3) 2 0.21 PR-} 71 OCO (CH 2) 2 CH (CH 3) 2 0.039 PR-118 OCO (CH 2) 2 CH = CH 2 0.080 PR-72 OCO-trans-CH = CHCH ₂ CH ₃ 0.030 PR-11 3 OCO (CH ₂ ) ₂ C≡CH 0.045 PR-106 OCOCH ₂ C≡CCH ₃ 0.37 PR-148 OCOCCCH ₂ CH ₃ 0.55 PR-69 OCOC ₆ H ₅ 0.14 PR-121 OCO ( CH ₂ ) C ₆ H ₅ 0.050

[0061]

[Chemical 21]

Group 1-4 compounds: Compound No. R ₂ ACTA inhibitory activity (IC _50, μM) PR-41 OCS-imidazole 0.14 PR-99 OSO ₂ CH ₃ 1.7 PR-107 OSO ₂ C ₆ H ₅ 3.1 PR-90 OCONHCH ₂ CH ₃ 1.2 PR-91 OCONH (CH ₂ ) ₂ CH ₃ 0.59 PR-92 OCONHCH ₂ C ₆ H ₅ 1.2 PR-100 OCOOCH ₂ C ₆ H ₅ 0. 41 PR-103 OCH ₂ C ₆ H ₅ 7.4 PR-27 OCH ₂ OCH ₃ 0.19 PR-20 OCH ₂ SCH ₃ 2.8 PR-87 OCH ₂ OCH ₂ CH ₂ OCH ₃ 7.0 PR-44 O-tetrahydropyran 1.0 PR-66 O-tetra-O-benzyl-mannose 48 PR-73 H 1.4

[0063]

[Chemical formula 22]

Group 1-5 Compounds: Compound No. R ₁ ACTA inhibitory activity (IC _50, μM) PR-49 OCOCH ₂ CH ₃ (Pyripyropene B) 0.27 PR-47 OCO (CH ₂ ) ₂ CH ₃ 4.2 PR-74 OCO (CH ₂ ) ₃ CH ₃ > 8.0 PR-48 OCOCH (CH ₃ ) ₂ 5.9 PR-86 OSO ₂ CH ₃ 0.019

[0065]

[Chemical formula 23]

Group 1-6 compound: Compound No. R ₄ ACTA inhibitory activity (IC _50, μM) PR-8 OCOCH ₃ 5.1 PR-21 OCOCH ₂ CH ₃ 23 PR-22 OCO (CH ₂ ) ₂ CH ₃ 2 _{.4 PR-46 OCO (CH 2} ) 3 CH 3 16 PR-97 OCH 3 38

[0067]

[Chemical formula 24]

Group 1-7 compounds: Compound No. R ₁ = R ₂ = R ₃ R ₄ ACTA inhibitory activity (IC _50, μM) PR-10 OCOCH ₂ CH ₃ OH 0.78 PR-31 OCO (CH ₂ ) _{2 CH 3 OH 0.62 PR-54 OCO} (CH 2) 3 CH 3 OH 0.84 PR-12 OCO (CH 2) 16 CH 3 OH> 80 PR-34 OCOCH (CH 3) 2 OH 0.34 PR- 14 OCOC (CH ₃ ) ₃ OH 9.6 PR-11 OCO-p-Br-C ₆ H ₄ OH> 99 PR-13 O-tetrahydropyran OH 43 PR-132 OSO ₂ CH ₃ OH 48 PR-9 OCOCH ₂ CH ₃ OCOCH ₂ CH ₃ 26 Compound number R ₁ R ₂ R ₃ R ₄ PR-80 OCOCH ₃ OCO (CH ₂ ) ₃ CH ₃ OCOCH ₃ OCO (CH ₂ ) ₃ CH ₃ 2.7 PR-130 OCO (CH ₂ ) ₂ CH ₃ OCOCH ₃ OCOCH ₃ OCOCH ₃ NT PR-155 OSO ₂ CH ₃ OCO (CH ₂ ) ₃ CH ₃ OCO (CH ₂ ) ₃ CH ₃ OH 0.47

Next, the mass spectrometry data of the pyripyropene derivative of the present invention will be described below. Group 1-1 compound: Compound number Composition formula Molecular weight measurement Theoretical value PR-3 C ₂₅ H ₃₁ O ₇ N ₁ 457.523 EI (+) 457.2090 457.2100 PR-4 C ₂₇ H ₃₃ O ₈ N ₁ 499.560 FAB (+) 500.2290 (M + 1) 500.2284 PR-35 C ₂₈ H ₃₅ O ₈ N ₁ 513.587 FAB (+) 514.2411 (M + 1) 514.2440 PR-29 C ₂₉ H ₃₇ O ₈ N ₁ 527.614 FAB (+) 528.2608 (M + 1 ) 528.2597 PR-52 C ₃₀ H ₃₉ O ₈ N ₁ 541.641 FAB (+) 542.2762 (M + 1) 542.2753 PR-32 C ₂₉ H ₃₇ O ₈ N ₁ 527.614 FAB (+) 528.2609 (M + 1) 528.2597 PR- 119 C ₃₂ H ₃₄ O ₈ N ₁ Br ₁ 639.909 FAB (+) 640.1555 (M + 1) 640.1546 PR-85 C ₂₆ H ₃₃ O ₉ N ₁ S ₁ 535.612 FAB (+) 536.1969 (M + 1) 536.1954 PR- 96 C ₃₂ H ₃₇ O ₉ N ₁ S ₁ 611.710 FAB (+) 612.2264 (M + 1) 612.2267 PR-5 C ₂₇ H ₃₃ O ₈ N ₁ 499.560 FAB (+) 500.2278 (M + 1) 500.2284 PR-82 C ₃₀ H ₃₉ O ₈ N ₁ 541.641 EI (+) 541.2675 541.2675 PR-6 C ₂₇ H ₃₃ O ₈ N ₁ 499.560 FAB (+) 500.2268 (M + 1) 500.2284 PR-7 C ₂₉ H ₃₅ O ₉ N ₁ 541.597 EI (+) 541.2288 541.2311 PR-42 C ₂₉ H ₃₅ O ₉ N ₁ 541.597 FAB (+) 542.2394 (M + 1) 542.2390 PR-129 C ₂₇ H ₃₅ O ₁₁ N ₁ S ₂ 613.701 FAB (+) 614 .1746 (M + 1) 614.1729 PR-154 C ₃₁ H ₄₁ O ₁₀ N ₁ S ₁ 619.730 FAB (+) 620.2528 (M + 1) 620.2529

Group 1-2 compound: compound number composition formula molecular weight measured value theoretical value PR-57 C ₃₂ H ₃₉ O ₁₀ N ₁ 597.661 FAB (+) 598.2681 (M + 1) 598.2652 PR-55 C ₃₃ H ₄₁ O ₁₀ N ₁ 611.688 FAB (+) 612.2814 (M + 1) 612.2808 PR-75 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2981 (M + 1) 626.2965 PR-56 C ₃₃ H ₄₁ O ₁₀ N ₁ 611.688 EI (+) 611.2702 611.2730

Group 1-3 compound: Compound number Composition formula Molecular weight Measurement value Theoretical value PR-24 C ₃₂ H ₃₉ O ₁₀ N ₁ 597.661 FAB (+) 598.2670 (M + 1) 598.2652 PR-25 C ₃₃ H ₄₁ O ₁₀ N ₁ 611.688 FAB (+) 612.2817 (M + 1) 612.2809 PR-45 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2945 (M + 1) 626.2965 PR-60 C ₃₅ H ₄₅ O ₁₀ N ₁ 639.742 FAB (+) 640.3123 (M + 1) 640.3121 PR-70 C ₃₆ H ₄₇ O ₁₀ N ₁ 653.769 FAB (+) 654.3262 (M + 1) 654.3278 PR-61 C ₃₇ H ₄₉ O ₁₀ N ₁ 667.796 PR-15 C ₄₇ H ₆₉ O ₁₀ N ₁ 808.066 FAB (+) 808.5010 (M + 1) 808.4999 PR-26 C ₃₃ H ₄₁ O ₁₀ N ₁ 611.688 FAB (+) 612.2806 (M + 1) 612.2809 PR-58 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2962 (M + 1) 626.2965 PR-59 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2957 (M + 1) 626.2965 PR-71 C ₃₅ H ₄₅ O ₁₀ N ₁ 639.742 FAB (+) 640.3115 (M + 1) 640.3121 PR-118 C ₃₄ H ₄₁ O ₁₀ N ₁ 623.699 FAB (+) 624.2787 (M + 1) 624.2808 PR-72 C ₃₄ H ₄₁ O ₁₀ N ₁ 623.699 FAB (+) 624.2791 (M + 1) 624.2808 PR-113 C ₃₄ H ₃₉ O ₁₀ N ₁ 621.683 FAB (+) 622.2628 (M + 1) 622.2652 PR-106 C ₃₄ H ₃₉ O ₁₀ N ₁ 621.683 FAB (+) 622.2673 (M + 1) 622.2652 PR-148 C ₃₄ H ₃₉ O ₁₀ N ₁ 621.683 FAB (+) 622.2653 (M + 1) 622.2652 PR-69 C ₃₆ H ₃₉ O ₁₀ N ₁ 645.705 FAB (+) 646.2662 (M + 1) 646.2652 PR-121 C ₃₈ H ₄₃ O ₁₀ N ₁ 673.759 FAB (+) 674.2976 (M + 1) 674.2965

Group 1-4 compounds: Compound number Composition formula Molecular weight measurement Theoretical value PR-41 C ₃₃ H ₃₇ O ₉ N ₃ S ₁ 651.735 FAB (+) 652.2349 (M + 1) 652.2328 PR-99 C ₃₀ H ₃₇ O ₁₁ N ₁ S ₁ 619.686 FAB (+) 620.2147 (M + 1) 620.2166 PR-107 C ₃₅ H ₃₉ O ₁₁ N ₁ S ₁ 681.757 FAB (+) 704.2134 (M + Na) 704.2142 PR-90 C ₃₃ H ₄₂ O ₁₀ N ₂ 626.703 FAB (+) 627.2911 (M + 1) 627.2918 PR-91 C ₃₄ H ₄₄ O ₁₀ N ₂ 640.730 FAB (+) 663.2908 (M + Na) 663.2967 PR-92 C ₃₇ H ₄₂ O ₁₀ N ₂ 674.747 FAB (+) 697.2721 (M + Na) 697.2737 PR-100 C ₃₇ H ₄₁ O ₁₁ N ₁ 675.731 FAB (+) 698.2573 (M + Na) 698.2577 PR-103 C ₃₆ H ₄₁ O ₉ N ₁ 631.722 FAB (+ ) 632.2864 (M + 1) 632.2860 PR-27 C ₃₁ H ₃₉ O ₁₀ N ₁ 585.650 FAB (+) 586.2656 (M + 1) 586.2652 PR-20 C ₃₁ H ₃₉ O ₉ N ₁ S ₁ 601.715 PR-87 C ₃₃ H ₄₃ O ₁₁ N ₁ 629.703 FAB (+) 630.2913 (M + 1) 630.2914 PR-44 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2972 (M + 1) 626.2965 PR-66 C ₆₃ H ₆₉ O ₁₄ N ₁ 1064.238 FAB (+) 1064.4840 (M + 1) 1064.4795 PR-73 C ₂₉ H ₃₅ O ₈ N ₁ 525.598 FAB (+) 526.2441 (M + 1) 526.2440 PR-163 C ₃₅ H ₃₈ O ₁₀ N ₂ 646.703 FAB (+) 647.2601 (M + 1) 647.2605

Group 1-5 compounds: Compound number Composition formula Molecular weight measurement Theoretical value PR-49 C ₃₂ H ₃₉ O ₁₀ N ₁ 597.661 FAB (+) 598.2642 (M + 1) 598.2652 PR-47 C ₃₃ H ₄₁ O ₁₀ N ₁ 611.688 FAB (+) 612.2799 (M + 1) 612.2808 PR-74 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2971 (M + 1) 626.2965 PR-48 C ₃₃ H ₄₁ O ₁₀ N ₁ 611.688 FAB (+) 612.2806 (M + 1) 612.2808 PR-86 C ₃₀ H ₃₇ O ₁₁ N ₁ S ₁ 619.686 FAB (+) 620.2173 (M + 1) 620.2166

Group 1-6 compound: Compound number Composition formula Molecular weight measurement Theoretical value PR-8 C ₃₃ H ₃₉ O ₁₁ N ₁ 625.671 FAB (+) 626.2609 (M + 1) 626.2601 PR-21 C ₃₄ H ₄₁ O ₁₁ N ₁ 639.698 FAB (+) 640.2744 (M + 1) 640.2758 PR-22 C ₃₅ H ₄₃ O ₁₁ N ₁ 653.725 FAB (+) 654.2892 (M + 1) 654.2914 PR-46 C ₃₆ H ₄₅ O ₁₁ N ₁ 667.752 FAB (+) 668.3065 (M + 1) 668.3071 PR-97 C ₃₂ H ₃₉ O ₁₀ N ₁ 597.661 FAB (+) 598.2652 (M + 1) 598.2652

Group 1-7 compound: Compound number Composition formula Molecular weight measured value Theoretical value PR-10 C ₃₄ H ₄₃ O ₁₀ N ₁ 625.715 FAB (+) 626.2946 (M + 1) 626.2965 PR-31 C ₃₇ H ₄₉ O ₁₀ N ₁ 667.796 FAB (+) 668.3422 (M + 1) 668.3434 PR-54 C ₄₀ H ₅₅ O ₁₀ N ₁ 709.877 FAB (+) 710.3888 (M + 1) 710.3904 PR-12 C ₇₉ H ₁₃₃ O ₁₀ N ₁ 1256.930 FAB (+) 1257.0062 (M + 1) 1257.0006 PR-34 C ₃₇ H ₄₉ O ₁₀ N ₁ 667.796 FAB (+) 668.3442 (M + 1) 668.3434 PR-14 C ₄₀ H ₅₅ O ₁₀ N ₁ 709.877 FAB (+) 710.3932 (M + 1) 710.3904 PR-11 C ₄₆ H ₄₀ O ₁₀ N ₁ Br ₃ 1006.550 PR-13 C ₄₀ H ₅₆ O ₁₀ N ₁ 710.885 PR-132 C ₂₈ H ₃₇ O ₁₃ N ₁ S ₃ 691.790 FAB (+) 692.1615 (M + 1) 692.1505 PR-9 C ₃₇ H ₄₇ O ₁₁ N ₁ 681.779 FAB (+) 682.3259 (M + 1) 682.3227 PR-80 C ₃₉ H ₅₁ O ₁₁ N ₁ 709.833 FAB (+) 710.3553 (M + 1) 710.3540 PR-130 C ₃₅ H ₄₃ O ₁₁ N ₁ 653.725 PR-155 C ₃₆ H ₄₉ O ₁₁ N ₁ S ₁ 703.848 FAB (+) 704.3095 (M + 1) 704.3104

Next, the nuclear magnetic resonance spectrum ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 1.

[0077]

[Table 1]

Next, the nuclear magnetic resonance spectrum ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 2.

[0079]

[Table 2]

Next, the nuclear magnetic resonance spectra ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 3.

[0081]

[Table 3]

Next, the nuclear magnetic resonance spectra ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 4.

[0083]

[Table 4]

Next, the nuclear magnetic resonance spectrum ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 5.

[0085]

[Table 5]

Next, the nuclear magnetic resonance spectrum ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 6.

[0087]

[Table 6]

Next, the nuclear magnetic resonance spectrum ( ¹ H-
NMR) and mass spectrometry (MS) are shown in Table 7.

[0089]

[Table 7]

[0090]

INDUSTRIAL APPLICABILITY As described above, since the pyripyropene derivative of the present invention exhibits a remarkable inhibitory activity on acylcoenzyme A cholesterol, it is useful for preventing and treating diseases caused by human cholesterol accumulation.

Next, the present invention will be specifically described with reference to Reference Examples and Examples, but it goes without saying that the present invention is not limited thereto. Example 1 (Group 1-1 compound): Compound PR-3: 583 mg of pyripyropene A was dissolved in 10 ml of 80% methanol aqueous solution, 166 mg of sodium mexide was added, and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off to obtain a crude product. The product was obtained. To this, 10 ml of 40% aqueous methanol solution was added, and the resulting precipitate was filtered using a Kiriyama funnel and washed with 40% aqueous methanol solution to obtain 350 mg of the target compound PR-3 colorless powder. Further, the filtrate and the washing solution are combined, the solvent is distilled off, and the solvent is distilled off and purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (9: 1) mixed solvent), and further, a colorless powder of compound PR-3. Was obtained in an amount of 110 mg. (Yield 100
%)

Example 2 Compounds PR-4, PR-5 and PR-6: 12 mg of the colorless powdery compound obtained in Example 1 was dried in pyridine (0.5 ml).
2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 3 days, and then 3 ml of ethyl acetate was added. The ethyl acetate solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a crude product.

This was subjected to silica gel column chromatography (developing solvent: dichloromethane-methanol (20: 1).
˜9: 1) mixed solvent) to give the desired compound PR-
4, a mixture of PR-5 and PR-6 was obtained, which was further subjected to high performance liquid chromatography (column: SenshuP).
ak ODS-4251-N, mobile phase: 30% aqueous acetonitrile solution) to give the target compound PR-4, P
0.2 mg each of R-5 and PR-6 colorless powder
(Yield 2%), 0.1 mg (Yield 1%) and 0.2 mg
(Yield 2%).

Example 3 Compound PR-35: Compound 1 as colorless powder obtained in Example 1
9 mg was dissolved in 1 ml of dry pyridine, 40 μl of propionic anhydride and 2 mg of dimethylaminopyridine were added and stirred, and then the solvent was distilled off together with methanol to obtain a crude product. This was subjected to silica gel column chromatography (developing solvent: dichloromethane-methanol (20: 1).
Purification with a mixed solvent) gave 7 mg of a colorless powder of the target compound PR-35. (Yield 32%)

Example 4 Compound PR-29: Compound 2 as colorless powder obtained in Example 1
Dissolve 0 mg in 1 ml of dry pyridine, butyric anhydride 70μ
1 and 2 mg of dimethylaminopyridine were added, and Example 3
The same treatment was carried out as in the above to obtain 14 mg of colorless powder of the target compound PR-29. (Yield 61%)

Example 5 Compound PR-52: Compound 2 as colorless powder obtained in Example 1
Dissolve 2 mg in 1 ml of dry pyridine and add valeric anhydride 54
μl and 2 mg of dimethylaminopyridine were added and treated in the same manner as in Example 3 to obtain 11.2 mg of a colorless powder of the target compound PR-52. (Yield 43%)

Example 6 Compound PR-32: Compound 2 as colorless powder obtained in Example 1
Dissolve 0 mg in 1 ml of dry pyridine and add 3 parts of isobutyric anhydride.
7 μl and 2 mg of dimethylaminopyridine were added and treated in the same manner as in Example 3 to obtain 4.5 mg of the target compound PR-32 as colorless powder. (Yield 20%)

Example 7 Compound PR-119: 5 mg of the colorless powder compound obtained in Example 1 was suspended in 1 ml of dry tetrahydrofuran, and p-
Brombenzoyl chloride (30 mg), triethylamine (10 μl) and dimethylaminopyridine (5 mg) were added and stirred. The solvent was distilled off and the residue was dissolved in dichloromethane and treated in the same manner as in Example 3 to give the target compound PR-1.
0.8 mg of 19 colorless powders were obtained. (Yield 11%)

Example 8 Compound PR-85: Compound 1 as colorless powder obtained in Example 1
Dissolve 58 mg in 2 ml of dry pyridine, add 6 μl of methanesulfonyl chloride, stir at 0 ° C. for 30 minutes, then OD
S column chromatography (developing solvent: 20-50%
(Methanol-water solution) to obtain a crude product, which is further purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (25: 1) mixed solvent) to give the target compound PR-85 colorless. 85.1 mg of powder was obtained. (Yield 49%)

Example 9 Compound PR-96: Compound 2 as colorless powder obtained in Example 1
0 mg was dissolved in 0.44 ml of dry pyridine, 93.2 mg of tosylic anhydride and 17 mg of dimethylaminopyridine.
Was added and stirred, then dichloromethane was added, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a crude product. This was subjected to silica gel column chromatography (developing solvent: dichloromethane-methanol (25:
1) Purification with a mixed solvent) to obtain 1 mg of colorless powder of the target compound PR-96. (Yield 4%)

Reference Example 1 24 mg of the colorless powdery compound obtained in Example 1 was dissolved in 0.5 ml of dry dimethylformamide, 50 μl of isopropenyl methyl ether and 4 mg of pyridine hydrochloride were added, and the mixture was stirred, dichloromethane was added, and water was added. After washing, it was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product. Preparative thin-layer silica gel chromatography (developing solvent: dichloromethane-methanol (20: 1)
(Mixed solvent) to obtain 16.8 of colorless powder of the compound.
mg was obtained.

Example 10 Compound PR-82: Compound 1 as colorless powder obtained in Reference Example 1
3 mg was dissolved in 60% acetic acid aqueous solution 2 ml, stirred at room temperature for 4 hours, extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain a crude product. Got This is purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (20: 1) mixed solvent) to give the target compound PR.
9.9 mg of -82 colorless powder was obtained. (Yield 82%)

Example 11 Compound PR-7: 291 mg of pyripyropene A was dissolved in 10 ml of 80% aqueous methanol solution, and 75 μl of 1,8-diazabicyclo [5,4,0] undeca7ene was added,
After stirring at room temperature for 10 minutes, 0.1 ml of acetic acid was added and the solvent was distilled off to obtain a crude product. This is purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (50: 1 to 7: 1) mixed solvent),
140.6 mg of colorless powder of the target compound PR-7 was obtained.
(52% yield)

Example 12 Compound PR-42: 80% of 240 mg of pyripyropene A
Dissolve in 6 ml of an aqueous methanol solution, add 60 μl of 1,8-diazabicyclo [5,4,0] undeca7ene,
After stirring at room temperature for 20 minutes, the same treatment as in Example 11 was carried out to obtain 3.3 mg of a colorless powder of the target compound PR-42. (Yield 1%)

Example 13 Compound PR-129: 45 mg of the colorless powdery compound obtained in Example 1 was dissolved in 2 ml of dry pyridine, 2 μl of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 26 hours, followed by the same procedure as in Example 8. By treatment, 1.1 mg of colorless powder of the target compound PR-129 was obtained. (Yield 2%)

Example 14 Compound PR-154: 12 mg of the colorless powdered compound obtained in Example 10 was dissolved in 2 ml of dry dichloromethane, 10 μl of triethylamine and 18 μm of methanesulfonyl chloride.
l was added, and the mixture was stirred, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a crude product. This was purified by preparative thin-layer silica gel chromatography (developing solvent: dichloromethane-methanol (20: 1) mixed solvent) to obtain 3.2 mg of a colorless powder of the target compound PR-154. (23% yield)

Reference Example 2 Compounds PR-57 and 49: The colorless powder compound 7 mg obtained in Example 3 was dissolved in dry dichloromethane 2 ml, acetic anhydride 3 μl, triethylamine 10 μl and dimethylaminopyridine 2 mg were added and stirred for 20 hours. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography to obtain a mixture of the target compounds PR-57 and 49, which was further subjected to high performance liquid chromatography (column: SenshuPak ODS-4251-).
N, mobile phase: 40% acetonitrile aqueous solution) to separate 1.2 mg (yield 15%) and 2.3 mg (yield 15) of colorless powders of compounds PR-57 and PR-49, respectively.
%)Obtained.

Example 15 (Groups 1-2 and 5 Compounds) Compounds PR-55 and 47: 14 mg of the colorless powder compound obtained in Example 4 was dissolved in 2 ml of dry tetrahydrofuran, and 5 μl of acetic anhydride, 10 μl of triethylamine and dimethylamino. Pyridine (2 mg) was added, the mixture was stirred, the solvent was evaporated, and dichloromethane was added. The mixture was treated in the same manner as in Reference Example 1 to obtain 1.2 mg each of colorless powders of the target compounds PR-55 and PR-47 (yield 7%. ) And 9.8 mg (60% yield) were obtained.

Example 16 Compounds PR-75 and 74: 11 mg of the colorless powder compound obtained in Example 5 was dissolved in 3 ml of dry dichloromethane,
Acetic anhydride (5 μl), triethylamine (20 μl) and dimethylaminopyridine (2 mg) were added and treated in the same manner as in Reference Example 1 to obtain colorless powders of the target compounds PR-75 and PR-74 (3 mg, yield 17%) and 5 mg (yield, respectively). Rate 28
%)Obtained.

Example 17 Compounds PR-56 and 48: 10 mg of the colorless powdery compound obtained in Example 6 was dissolved in 1 ml of dry dichloromethane,
Acetic anhydride (5 μl), triethylamine (20 μl) and dimethylaminopyridine (2 mg) were added and treated in the same manner as in Reference Example 1 to obtain colorless powders of the target compounds PR-56 and PR-48 (3.4 mg, yield 29%) and 5 respectively. .1 mg (yield 43%) was obtained.

Example 18 (Group 1-5 Compound) Compound PR-86: Compound 1 as colorless powder obtained in Example 8
13 mg was dissolved in 1 ml of dry pyridine, and acetic anhydride 0.1.
1 ml was added and treated in the same manner as in Example 23 to obtain 129.4 mg of a colorless powder of the target compound PR-86. (Yield 99%)

Reference Example 3 Compound PR-24: 9 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, 80 μl of propionic anhydride, 60 μl of triethylamine and 1 mg of dimethylaminopyridine were added and stirred, and washed with water. rear,
It was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product. This is subjected to silica gel column chromatography (developing solvent: dichloromethane-methanol (50: 1).
Purification with a mixed solvent) gave 4 mg of colorless powder of the target compound PR-24. (44% yield)

Example 19 (Group 1-3 compounds) Compound PR-25: 9 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 70 μl of butyric anhydride, 40 μl of triethylamine and 1 mg of dimethylaminopyridine were added. Then, the same treatment as in Reference Example 2 was carried out to obtain 10 mg of a colorless powder of the target compound PR-25. (Yield 98%)

Example 20 Compound PR-45: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 50 μl of valeric anhydride, 20 μl of triethylamine and 2 mg of dimethylaminopyridine were added, and the same as in Reference Example 2. Then, 10 mg of colorless powder of the target compound PR-45 was obtained.
(Yield 87%)

Example 21 Compound PR-60: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 25 μl of caproic anhydride, 30 μl of triethylamine and 4 mg of dimethylaminopyridine were added, and the same as in Reference Example 2. Then, 12 mg of a colorless powder of the target compound PR-60 was obtained. (100% yield)

Example 22 Compound PR-70: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 50 μl of enanthic anhydride, 50 μl of triethylamine and 4 mg of dimethylaminopyridine were added, and the same as in Reference Example 2. To a colorless powder of the target compound PR-70 (8.2 mg).
Obtained. (68% yield)

Example 23 Compound PR-61: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, 45 μl of capric anhydride, 30 μl of triethylamine and 4 mg of dimethylaminopyridine were added, and the same as in Reference Example 2. To a colorless powder of the target compound PR-61 for 12.4 m.
g was obtained. (100% yield)

Example 24 Compound PR-15: 5 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry pyridine, 15 mg of stearic anhydride and 5 mg of dimethylaminopyridine were added and stirred, and dichloromethane was added for reference. The same treatment as in Example 2 was carried out to obtain 2.7 mg of a colorless powder of the target compound PR-15.
Obtained. (36% yield)

Example 25 Compound PR-26: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 2 ml of dry tetrahydrofuran, and 50 μl of isobutyric anhydride, 20 μl of triethylamine and 2 mg of dimethylaminopyridine were added and stirred, and the solvent was distilled off. After the removal, dichloromethane was added and treated in the same manner as in Reference Example 3 to obtain 12 mg of the target compound PR-26 as colorless powder. (100% yield)

Example 26 Compound PR-58: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 0.4 ml of pivalic acid chloride and 20 μm of triethylamine were dissolved.
1 was added and treated in the same manner as in Reference Example 2 to obtain the target compound P.
5 mg of R-58 colorless powder was obtained. (Yield 43%)

Example 27 Compound PR-59: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, 50 μl of isovaleric anhydride and 20 μl of triethylamine were added, and the same treatment as in Reference Example 2 was carried out. Target compound PR-5
12 mg of 9 colorless powder was obtained. (100% yield)

Example 28 Compound PR-71: 16 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 4 μl of isocaproic acid and dicyclohexylcarbodiimide 1 were dissolved.
After adding 0 mg and dimethylaminopyridine 1.2 mg and reacting for 6 hours, the solvent was distilled off. Ethyl acetate was added to this, and the insoluble matter was filtered off and washed, and then the filtrate and the washing solution were combined, washed with water and concentrated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off. This was purified using silica gel column chromatography (developing solvent: dichloromethane-methanol (50: 1) mixed solvent) to obtain 19 mg of colorless powder of the target compound PR-71. (Yield 1
00%)

Example 29 Compound PR-118: 11 mg of the colorless powder compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane to give 4-
Pentenoic acid (5 μl), dicyclohexylcarbodiimide (6 mg) and dimethylaminopyridine (3 mg) were added,
The target compound PR-118 was treated in the same manner as in Example 28.
11.1 mg of colorless powder of was obtained. (Yield 87%)

Example 30 Compound PR-72: 11 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and trans-2-pentenoic acid 3 μl, dicyclohexylcarbodiimide 9.6 mg and dimethylaminopyridine 1 were dissolved.
mg was added and treated in the same manner as in Example 28 to obtain 7.8 mg of a colorless powder of the target compound PR-72. (Yield 62
%)

Example 31 Compound PR-113: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane to give 4-
Pentinoic acid 4 mg, dicyclohexylcarbodiimide 4 mg and dimethylaminopyridine 2 mg were added,
The target compound PR-113 was treated in the same manner as in Example 28.
10.6 mg of colorless powder of was obtained. (Yield 92%)

Example 32 Compound PR-106: 9 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, and 3 mg of 3-pentinoic acid, 6 mg of dicyclohexylcarbodiimide and 1 mg of dimethylaminopyridine were added, and Example 28 was used. The same treatment as in (1) was performed to obtain 0.9 mg of a colorless powder of the target compound PR-106. (Yield 8%)

Example 33 Compound PR-148: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane to give 2-
Pentinoic acid (3 mg), dicyclohexylcarbodiimide (16 mg) and dimethylaminopyridine (4 mg) were added and treated in the same manner as in Example 28 to give the target compound PR-1.
5.4 mg of 48 colorless powders were obtained. (Yield 47%)

Example 34 Compound PR-69: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 2 ml of dry tetrahydrofuran, 20 mg of benzoic anhydride, 20 μl of triethylamine and 2 mg of dimethylaminopyridine were added, and the same as in Example 25. To give 11m of colorless powder of the target compound PR-69.
g was obtained. (Yield 92%)

Example 35 Compound PR-121: 11 mg of the colorless powdery compound obtained in Example 11 was dissolved in 2 ml of dry dichloromethane, and 50 μl of hydrocinnamoyl chloride and 8 μl of triethylamine were added, and treated in the same manner as in Reference Example 2. Thus, 2.5 mg of colorless powder of the target compound PR-121 was obtained. (Yield 18%)

Example 36 (Group 1-4 compounds) Compound PR-41: 16 mg of the colorless powder compound obtained in Example 11 was dissolved in 2 ml of toluene, 16 ml of thiocarbonyldiimidazole was added, and the mixture was heated under reflux for 1 hour. The same treatment as in Reference Example 2 was carried out to obtain 13.3 mg of a colorless powder of the target compound PR-41. (Yield 69%)

Example 37 Compound PR-99: 32 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.59 ml of dry pyridine, 6.8 μl of mesyl chloride was added, and the same treatment as in Example 24 was carried out. 21.3 mg of colorless powder of target compound PR-99
Obtained. (Yield 58%)

Example 38 Compound PR-107: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.18 ml of dry pyridine, and 7.2 μl of benzenesulfonic acid chloride was added to give Example 3
The same treatment as in 7 was performed to obtain 5.3 mg of the target compound PR-107 colorless powder. (Yield 46%)

Example 39 Compound PR-90: 10.8 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.2 ml of dry dichloromethane, 2.5 μl of propyl isocyanate and 4 μl of triethylamine were added and stirred, and after 20 hours. The reaction was stopped by adding saturated aqueous ammonium chloride. After extraction with chloroform, washing with water, and drying with anhydrous sodium sulfate, the solvent was distilled off to obtain a crude product. This is purified by silica gel column chromatography (developing solvent: chloroform-methanol (50: 1) mixed solvent) and the target compound PR is obtained.
4.2 mg of -90 colorless powder was obtained. (Yield 33%)

Example 40 Compound PR-91: 10.8 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.2 ml of dry dichloromethane, and 3 μl of n-butylisocyanate and 4 μl of triethylamine were added. Then, 3.0 mg of the target compound PR-91 colorless powder was obtained. (23% yield)

Example 41 Compound PR-92: 12.3 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.23 ml of dry dichloromethane, and 7.67 mg of benzyl isocyanate, 8.4 μl of triethylamine and 4 mg of dimethylaminopyridine were dissolved. In addition, the same treatment as in Example 39 was carried out to obtain the target compound PR-
3.8 mg of 92 colorless powder was obtained. (Yield 25%)

Example 42 Compound PR-100: 10.8 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.2 ml of dry dichloromethane, and 44.4 mg of carbobenzyl chloride, 12 μl of triethylamine and 4 mg of dimethylaminopyridine were added. The target compound PR- was treated in the same manner as in Example 39.
8.5 mg of 100 colorless powder was obtained. (Yield 63%)

Reference Example 4 Compound PR-76: 80 mg of the colorless powdery compound obtained in Example 11 was dissolved in 5 ml of dry dichloromethane, 40 mg of m-chloroperbenzoic acid was added, washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain a crude product.
This was purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (20: 1) mixed solvent) to obtain 82 g of compound PR-76 colorless powder.
Obtained.

Reference Example 5 Compound PR-83: Compound 2 as colorless powder obtained in Reference Example 4
2 mg was dissolved in a mixed solvent of dry tetrahydrofuran and dry dimethyl sulfoxide (1: 1: 1 ml), 5 mg of sodium hydride was added at 0 ° C., then 5 μl of benzyl bromide was added and stirred, and then a saturated ammonium chloride aqueous solution was added. After the reaction was stopped, the reaction mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a crude product. This was purified by preparative thin layer silica gel chromatography (developing solvent: dichloromethane-methanol (10: 1) mixed solvent) to give compound PR-
2.6 mg of 83 colorless powder was obtained.

Example 43 Compound PR-103: 9 mg of the colorless powdery compound obtained in Reference Example 5 was dissolved in 0.5 ml of deuterated chloroform, 20 μl of triethyl phosphite was added, and 6 using a high pressure mercury lamp.
After irradiation for half an hour, the same treatment as in Reference Example 3 was carried out to obtain 0.2 mg of a colorless powder of the target compound PR-103. (Yield 2%)

Example 44 Compound PR-27: 10 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1.2 ml of dry tetrahydrofuran, 30 μl of methoxymethyl chloride was added, and the same treatment as in Example 25 was carried out. 2.4 mg of colorless powder of compound PR-27 was obtained. (Yield 22%)

Example 45 Compound PR-20: 7 mg of the colorless powdery compound obtained in Example 11 was dissolved in 250 μl of dimethyl sulfoxide, 10 μl of acetic anhydride was added, and the same treatment as in Example 24 was carried out. 1.8 mg of colorless powder of compound PR-20 was obtained. (23% yield)

Example 46 Compound PR-87: 7 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, 25 μl of methoxyethoxymethyl chloride and 20 μl of diisopropylethylamine were added, and treated in the same manner as in Reference Example 3. Thus, 7.3 mg of colorless powder of the target compound PR-87 was obtained. (Yield 63%)

Example 47 Compound PR-44: 9 mg of the colorless powdery compound obtained in Example 11 was dissolved in 1 ml of dry dichloromethane, 50 μl of dihydropyran and 5 mg of pyridine hydrochloride were added, and treated in the same manner as in Reference Example 3. Thus, 9.2 mg of colorless powder of the target compound PR-44 was obtained. (88% yield)

Example 48 Compound PR-66: 22 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.5 ml of benzene to give tetra-O-.
Benzyl-D-mannosyl fluoride 43.2 mg,
Zirconocene chloride (12 mg), silver triflate (18 mg) and molecular sieves 4A (100 mg) were added, the mixture was stirred at room temperature for 5 minutes, and then saturated sodium carbonate aqueous solution (1 ml) was added to stop the reaction. The resulting precipitate was filtered off using Celite, and the filtrate was washed with water and saturated saline,
It was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product. Preparative thin layer silica gel chromatography (developing solvent: dichloromethane-methanol = 25: 1).
At 9.3 m of colorless powder of the target compound PR-66.
g was obtained. (Yield 22%)

Example 49 Compound PR-73: The colorless powder compound of 7.5 mg obtained in Example 36 was dissolved in 1 ml of toluene, 5 μl of tri-n-butyltin hydride was added, and the mixture was heated under reflux at 120 ° C. for 3 hours. The target compound PR-73 was treated in the same manner as in Reference Example 3.
1 mg of colorless powder was obtained. (Yield 17%)

Example 50 Compound PR-163: 10 m of colorless powder obtained in Example 11
g was dissolved in 1 ml of dry dichloromethane to give 4 parts of nicotinic acid.
mg, dicyclohexylcarbodiimide 6 mg and dimethylaminopyridine 2 mg were added and reacted for 3 hours, then treated in the same manner as in Example 28 to obtain the target compound PR-1.
10.2 mg of 63 colorless powder was obtained. (Yield 85%)

Example 51 (Group 1-6 compound) Compound PR-8: 5 mg of pyripyropene A was dissolved in 0.1 ml of dry tetrahydrofuran, and 14 μl of acetic anhydride, 14 μl of triethylamine and dimethylaminopyridine 4 were dissolved.
After adding mg and treating in the same manner as in Example 25, further high performance liquid chromatography (column: SenshuPak) was used.
ODS-4251-N, mobile phase: 50% aqueous acetonitrile solution) to obtain 4 mg of colorless powder of the target compound PR-8. (75% yield)

Example 52 Compound PR-21: 5 mg of pyripyropene A was dissolved in 1 ml of dry tetrahydrofuran to give 40 μ of propionic anhydride.
1, triethylamine 10 μl and dimethylaminopyridine 3 mg were added and treated in the same manner as in Example 51 to obtain 3.1 mg of the target compound PR-21 as colorless powder. (Yield 57%)

Example 53 Compound PR-22: 5 mg of pyripyropene A was dissolved in 1 ml of dry tetrahydrofuran, and 40 μl of acetic anhydride, 10 μl of triethylamine and 3 m of dimethylaminopyridine.
g was added and treated in the same manner as in Example 51, to obtain 5.2 mg of a colorless powder of the target compound PR-22. (Yield 93
%)

Example 54 Compound PR-46: 5 mg of pyripyropene A was dissolved in 2 ml of dry dichloromethane, 40 μl of valeric anhydride and 4 mg of dimethylaminopyridine were added, and the same treatment as in Example 51 was carried out to give the desired compound PR-46 as colorless. 5.3m powder
g was obtained. (Yield 93%)

Reference Example 6 Compound PR-23: 20 mg of pyripyropene A was dissolved in 3 ml of dry dichloromethane, and m-chloroperbenzoic acid 40 was added.
After adding mg and washing with water, it was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (20: 1) mixed solvent) to obtain 20 g of compound PR-23 colorless powder.

Reference Example 7 Compound PR-78: Compound 9 as colorless powder obtained in Reference Example 7
mg was dissolved in 1 ml of dry dimethylformamide, 4 mg of sodium hydride and then 50 μl of methyl iodide were added and stirred, and then saturated ammonium chloride aqueous solution was added to stop the reaction, followed by extraction with dichloromethane, and washing with water,
It was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product. Preparative thin layer silica gel chromatography (developing solvent: dichloromethane-methanol (10: 1))
2.3) colorless powder of compound 78
mg was obtained.

Example 55 Compound PR-97: Compound 1 as colorless powder obtained in Reference Example 7
Dissolve 0 mg in 0.4 ml of deuterated chloroform, add 10 μl of triethyl phosphite, and use a high pressure mercury lamp to
After irradiation for an hour, the same treatment as in Reference Example 3 was carried out to obtain 3.5 mg of a colorless powder of the target compound PR-97. (Yield 36
%)

Example 56 (Group 1-7 Compound) Compound PR-10: 6.6 mg of the colorless powdery compound obtained in Example 1 was suspended in 0.6 ml of dry tetrahydrofuran, and 10 μl of propionic anhydride and triethylamine 1 were added.
4 ml was added and treated in the same manner as in Example 25 to obtain 3.5 mg of the target compound PR-10 as colorless powder. (Yield 3
4%)

Example 57 Compound PR-31: Compound 2 as colorless powder obtained in Example 1
0 mg was suspended in 2 ml of dry dichloromethane, 20 μl of butyric anhydride, 15 μl of triethylamine and 4 mg of dimethylaminopyridine were added, and treated in the same manner as in Reference Example 3 to obtain 3 mg of a colorless powder of the target compound PR-31. (Yield 10%)

Example 58 Compound PR-54: Compound 2 as colorless powder obtained in Example 1
2 mg was suspended in 1 ml of dry pyridine, and valeric anhydride 54
μl and 2 mg of dimethylaminopyridine were added and treated in the same manner as in Example 24 to obtain 2.6 mg of a colorless powder of the target compound PR-54. (Yield 8%)

Example 59 Compound PR-12: Compound 1 as colorless powder obtained in Example 1
8 mg was suspended in 1 ml of dry pyridine, 20 mg of stearic anhydride and 2 mg of dimethylaminopyridine were added,
The target compound PR-12 was treated in the same manner as in Example 24.
12 mg of colorless powder was obtained. (Yield 24%)

Example 60 Compound PR-34: Compound 2 as colorless powder obtained in Example 1
0 mg was suspended in 2 ml of dry dichloromethane, 37 μl of isobutyric anhydride, 20 μl of triethylamine and 2 mg of dimethylaminopyridine were added, and treated in the same manner as in Reference Example 3 to obtain 4.5 mg of a colorless powder of the target compound PR-34. (Yield 15%)

Example 61 Compound PR-14: Compound 4 as colorless powder obtained in Example 1
mg was dissolved in 1 ml of dry pyridine, 3.3 μl of pivalic acid chloride and 5 mg of dimethylaminopyridine were added, treated in the same manner as in Example 24, and the target compound PR-
4.9 mg of 14 colorless powder was obtained. (Yield 79%)

Example 62 Compound PR-11: Compound 5 as colorless powder obtained in Example 1
mg was dissolved in 1 ml of dry tetrahydrofuran, and 30 mg of p-bromobenzoyl chloride was added to give Example 2.
The same treatment as in 5 was carried out to obtain 0.9 mg of a colorless powder of the target compound PR-11. (Yield 8%)

Example 63 Compound PR-13: Compound 1 as colorless powder obtained in Example 1
1 mg was dissolved in 1 ml of dry dichloromethane, 150 μl of dihydropyran and 17 mg of pyridine hydrochloride were added, and then treated in the same manner as in Reference Example 3 to obtain the target compound PR-1.
6 mg of colorless powder of 3 was obtained. (35% yield)

Example 64 Compound PR-132: 54 mg of the colorless powdery compound obtained in Example 1 was dissolved in 2 ml of dry pyridine, 30 μl of methanesulfonyl chloride was added, and the mixture was stirred at 0 ° C. for 1 hour and 30 minutes, and then the above-mentioned mixture was added. The target compound P was treated in the same manner as in Example 8.
2.6 mg of R-132 colorless powder was obtained. (Yield 3%)

Example 65 Compound PR-9: Compound 5m as a colorless powder obtained in Example 1
4. g of the reaction product was suspended in 0.1 ml of dry tetrahydrofuran, 43 μl of propionic anhydride, 10 μl of triethylamine and 4 mg of dimethylaminopyridine were added, and treated in the same manner as in Example 25 to give 6.
5 mg was obtained. (Yield 87%)

Example 66 Compound PR-80: 5.5 mg of the colorless powdery compound obtained in Example 11 was dissolved in 0.3 ml of dry dichloromethane,
5 μl of valeric anhydride, 10 μl of triethylamine and 1 mg of dimethylaminopyridine were added and treated in the same manner as in Reference Example 3 to obtain 2.6 m of colorless powder of the target compound PR-80.
g was obtained. (Yield 43%)

Example 67 Compound PR-130: 7 mg of the colorless powdery compound obtained in Example 4 was dissolved in 1 ml of dry dichloromethane, and 190 μl of acetic anhydride, 14 μl of triethylamine and 2 mg of dimethylaminopyridine were added, and the same as in Example 25. Treated to give 1.4 mg of colorless powder of the target compound PR-130.
Obtained. (Yield 16%)

Example 68 Compound PR-155: 10 mg of the colorless powdery compound obtained in Example 8 was dissolved in 2 ml of dry dichloromethane, and 10 μl of valeric anhydride, 10 μl of triethylamine and 4 mg of dimethylaminopyridine were added, and the same as in Reference Example 3 To give 10.4 m of colorless powder of the target compound PR-155.
g was obtained. (Yield 79%)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area C07D 309: 38 311: 92)

Claims (15)

[Claims] 1. The following formula: [In the formula, R ₁ is OH, —OCOR ₅ (R ₅ is an alkyl group (the alkyl group may have a branch), or an aryl group which may have a substituent) Heterocyclic Group or -OSO ₂ R ₆ (R ₆ is an alkyl group or an aryl group which may have a substituent), R ₂ is H, OH,
Substituted or unsubstituted -O- alkyl group, a heterocyclic group, a sugar residue which may have a substituent, an alkyl group (the alkyl group -OCOR ₇ (R ₇ is a saturated or unsaturated substituent And / or optionally branched), or an optionally substituted aryl group, or a substituted amino group) or —OSO ₂ R ₈ (R ₈ may have a substituent) A good alkyl group or an aryl group which may have a substituent), R ₃ is OH, —OCOR ₉ (R ₉ is an alkyl group (the alkyl group may have a branch)), heterocyclic group, or -OSO ₂ R _10, (R ₁₀ is an alkyl group) a, R ₄ represents an OH, -O- alkyl or -O- acyl group. [However, ・ R ₁ , R ₂ , R ₃ are -O-acetyl groups, and R ₄ is OH (pyripyropene A (FO-1289A substance)) ・ R ₁ is -O-propionyl group, R ₂ , R ₃ Is an —O-acetyl group and R ₄ is OH (pyripyropene B (FO
-1289B substance)) A compound in which R ₁ and R ₃ are —O-acetyl groups, R ₂ is —O-propionyl group, and R ₄ is OH (pyripyropene C (FO
-1289C substance)) A compound in which R ₁ and R ₂ are —O-acetyl group, R ₃ is —O-propionyl group, and R ₄ is OH (pyripyropene D (FO
-1289D substance)) is excluded. ] The pyripyropene derivative represented by these. 2. The following formula:[In the formula, R₁Is OH, -OCOR_Five(R_FiveIs an alkyl group
(The alkyl group may have a branch), or
An aryl group which may have a substituent), -OSO ₂-R
₆(R₆May have an alkyl group or a substituent
Aryl group), R₂Is OH, -OCOR₇(R₇
Is an alkyl group), -OSO₂R₈(R₈Is an alkyl group)
Indicates R₃Is OH, -OCOR₉(R₉Is alkyl
Group)], wherein the pyripyropene derivative is represented by
conductor. 3. The pyripyropene derivative according to claim ₁ , wherein the groups R ₁ , R ₂ and R ₃ are compounds selected from the group consisting of compounds having the following combinations of substituents. Compound number R ₁ R ₂ R ₃ PR-3 OH OH OH PR-4 OCOCH ₃ OH OH PR-35 OCOCH ₂ CH ₃ OH OH PR-29 OCO (CH ₂ ) ₂ CH ₃ OH OH PR-52 OCO (CH _{2 ) 3 CH 3 OH OH PR-} 32 OCOCH (CH 3) 2 OH OH PR-119 OCO-p-Br-C 6 H 4 OH OH PR-85 OSO 2 CH 3 OH OH PR-96 OSO 2 -p-CH _3- C ₆ H ₄ OH OH PR-5 OH OCOCH ₃ OH PR-82 OH OCO (CH ₂ ) ₃ CH ₃ OH PR-6 OH OH OCOCH ₃ PR-7 OCOCH ₃ OH OCOCH ₃ PR-42 OH OCOCH ₃ OCOCH ₃ PR-129 OSO ₂ CH ₃ OH OSO ₂ CH ₃ PR-154 OSO ₂ CH ₃ OCO (CH ₂ ) ₃ CH ₃ OH 4. The following formula: The pyripyropene derivative according to claim 1, wherein R ₃ is —OCOR ₉ (R ₉ is an alkyl group, Ac is an acetyl group). 5. The pyripyropene derivative according to claim 1, wherein the group R ₃ is a compound selected from the group consisting of compounds having a combination of substituents shown below. Compound No. _{R 3 PR-55 OCO (CH} 2) 2 CH 3 PR-75 OCO (CH 2) 3 CH 3 PR-56 OCOCH (CH 3) 2 6. The following formula: [In the formula, R ₂ represents —O—CO—R ₇ (R ₇ represents a saturated or unsaturated alkyl group (the alkyl group may have a branch)), and Ac represents an acetyl group]. The pyripyropene derivative according to claim 1, which is represented. 7. The pyripyropene derivative according to claim 1, wherein the group R ₂ is a compound selected from the group consisting of compounds having a combination of substituents shown below. Compound No. _{R 2 PR-25 OCO (CH} 2) 2 CH 3 PR-45 OCO (CH 2) 3 CH 3 PR-60 OCO (CH 2) 4 CH 3 PR-70 OCO (CH 2) 5 CH 3 PR- _{61 OCO (CH 2) 6 CH} 3 PR-15 OCO (CH 2) 16 CH 3 PR-26 OCOCH (CH 3) 2 PR-58 OCOC (CH 3) 3 PR-59 OCOCH 2 CH (CH 3) 2 PR _{-71 OCO (CH 2) 2 CH} (CH 3) 2 PR-118 OCO (CH 2) 2 CH = CH 2 PR-72 OCO-trans-CH = CHCH 2 CH 3 PR-113 OCO (CH 2) 2 C ≡CH PR-106 OCOCH ₂ C≡CCH ₃ PR-148 OCOC≡CCH ₂ CH ₃ PR-69 OCOC ₆ H ₅ PR-121 OCO (CH ₂ ) ₂ C ₆ H ₅ 8. The following formula: [In the formula, R ₂ is H, —OCOR ₇ (R ₇ is an aryl group which may have a substituent or a substituted amino group), a heterocyclic group, and a sugar residue which may have a substituent. group, which may have a substituent group -O- alkyl group, -OSO ₂ R ₈ (R
₈ represents an alkyl group which may have a substituent or an aryl group which may have a substituent), and Ac represents an acetyl group.] The pyripyropene derivative according to claim 1. 9. The pyripyropene derivative according to claim 1, wherein the group R ₂ is a compound selected from the group consisting of compounds having a combination of substituents shown below. Compound number R ₂ PR-41 OCS-imidazole PR-99 OSO ₂ CH ₃ PR-107 OSO ₂ C ₆ H ₅ PR-90 OCONHCH ₂ CH ₃ PR-91 OCONH (CH ₂ ) ₂ CH ₃ PR-92 OCONHCH ₂ C ₆ H ₅ PR-100 OCOOCH ₂ C ₆ H ₅ PR-103 OCH ₂ C ₆ H ₅ PR-27 OCH ₂ OCH ₃ PR-20 OCH ₂ SCH ₃ PR-87 OCH ₂ OCH ₂ CH ₂ OCH ₃ PR-44 O -Tetrahydropran PR-66 O-tetra-O-benzyl-mannose PR-73 H [Chemical Formula 6] 10. The following formula: [In the formula, R ₁ represents —O—COR ₅ (R ₅ is an alkyl group which may have a branch) or —OSO ₂ R ₆ (R ₆ is an alkyl group), and Ac represents an acetyl group. ] The pyripyropene derivative according to claim 1, represented by 11. The pyripyropene derivative according to claim 1, wherein the group R ₁ is a compound selected from the group consisting of compounds having a combination of substituents shown below. Compound No. _{R 1 PR-47 OCO (CH} 2) 2 CH 3 PR-74 OCO (CH 2) 3 CH 3 PR-48 OCOCH (CH 3) 2 PR-86 OSO 2 CH 3 12. The following formula: [Wherein R ₄ represents an -O-acyl group or an -O-alkyl group, and Ac represents an acetyl group].
A described pyripyropene derivative. 13. The pyripyropene derivative according to claim 1, wherein the group R ₄ is a compound selected from the group consisting of compounds having a combination of substituents shown below. Compound No. _{R 4 PR-8 OCOCH 3 PR} -21 OCOCH 2 CH 3 PR-22 OCO (CH 2) 2 CH 3 PR-46 OCO (CH 2) 3 CH 3 PR-97 OCH 3 14. The following formula: _{Wherein, R 1, R 2, R} 3, R 4 is -OH, -O-CO
-R ₅ (R ₅ is a branched or optionally substituted alkyl _{group), - O-SO 2 R} 6 (R 6 is an alkyl group),
The arylpyrrole group which may have a substituent and the heterocyclic group are shown.] The pyripyropene derivative according to claim 1. 15. The pyripyropene derivative according to claim ₁ , wherein the groups R ₁ , R ₂ , R ₃ and R ₄ are compounds selected from the group consisting of compounds having a combination of substituents shown below. Compound No. _{R 1 = R 2 = R 3} R 4 PR-10 OCOCH 2 CH 3 OH PR-31 OCO (CH 2) 2 CH 3 OH PR-54 OCO (CH 2) 3 CH 3 OH PR-12 OCO (CH ₂ ) ₁₆ CH ₃ OH PR-34 OCOCH (CH ₃ ) ₂ OH PR-14 OCOC (CH ₃ ) ₃ OH PR-11 OCO-p-Br-C ₆ H ₄ OH PR-13 O-tetrahydropyran OH PR-132 OSO ₂ CH ₃ OH PR-9 OCOCH ₂ CH ₃ OCOCH ₂ CH ₃ R ₁ R ₂ R ₃ R ₄ PR-80 OCOCH ₃ OCO (CH ₂ ) ₃ CH ₃ OCOCH ₃ OCO (CH ₂ ) ₃ CH ₃ PR-130 _{OCO (CH 2) 2 CH 3} OCOCH 3 OCOCH 3 OCOCH 3 PR-155 OSO 2 CH 3 OCO (CH 2) 3 CH 3 OCO (CH 2) 3 CH 3 OH