JPH08269065A - Pyripyropnene derivative - Google Patents

Abstract

PURPOSE: To obtain a pyripyropene derivative useful for treating a hyperlipemia and geriatric diseases such as arteriosclerosis, etc. caused by it, having inhibitory activity against an acyl coenzyme A cholesterolacyltransferase. CONSTITUTION: This derivative is a compound of the formula R1 is a saturated or unsaturated alkyl, an O-acyl, an aryl which may contain a substituent group or forms an alkylene with R'1 ; R'1 is H, methyl or forms an alkylene with R1 or is O; R2 is OH, an O-acyl or a heterocyclic group} in which the 1-position and the 11-position of the skeleton of pyripyropene obtained by separation from a culture product of FO-1,289 strain and purification are acetalized or cyclic carbonylated and OH group at the 7-position is acylated. The introduction of the substituent group so as to obtain the objective derivative is carried out by dissolving pyripyropene in a solvent such as dimethyl sulfoxide, adding dimethyl acetal and an acid catalyst (e.g. pyridine hydrochloride), stirring, acetalizing a 1,3 diol and ketalizing.

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]

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As shown in the above formula, the pyripyropene derivative of the present invention is a compound in which the 1- and 11-positions of the pyripyropene skeleton are acetalized or cyclic carbonylated, or OH in the 7-position is acylated. . This acetalization, cyclic carbonylation, or acylation can be carried out by the following reaction, for example. In addition, pyripyropene A, which is a raw material of the pyripyropene derivative of the present invention, is disclosed in JP-A-6-1841.
It is manufactured according to the method described in No. 58.

The introduction of the substituent can be carried out, for example, by the following method. Acetalization and ketalization of 1,3-diol: It is carried out by a usual method using an alkyl aldehyde or an alkoxy aldehyde and an acid. Acid catalyst: pyridine hydrochloride, pyridinium-p-toluenesulfonic acid, p-toluenesulfonic acid, etc. Solvent: dimethylformamide, dichloromethane, etc. Reaction temperature: room temperature (cooling or heating conditions are possible)

Cyclic Carbonation of 1,3-diol: It is carried out by the usual method using carbonyldiimidazole. Reagent: Carbonyldiimidazole Solvent: Dichloromethane, Tetrahydrofuran, Benzene, Toluene, etc. Reaction temperature: Room temperature or heating under reflux

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. Further, dimethylaminopyridine may 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. The compound thus obtained is, for example, a column chromatograph using silica gel. The target compound can be obtained as a pure product after purification by e.

The physicochemical properties and biological properties of the compounds obtained by the above methods are shown below. In addition,
Biological properties include the following in vitro
50% inhibition of rat-derived acylcoenzyme A cholesterol acyltransferase by the activity measurement method
The inhibition value (IC ₅₀ ) is shown.

In vitro activity assay method: Inhibition of rat-derived acylcoenzyme A cholesterol acyltransferase activity: Effect of acylcoenzyme A cholesterol acyltransferase activity on the activity of Kyoda et al. (The Journal of Antibiotics, 44 Vol. 136, 1991), using a crude enzyme prepared from rat liver microsomal fraction, 300 μM bovine serum albumin, 30 μM in 100 mM phosphate buffer (pH 7.4).
M [1- ¹⁴ C] oleoyl -CoA (0.02μC
i), 30 μM cholesterol (dissolved in 1/30 weight Triton WR-1339) was added to make a total volume of 200 μl, reacted at 37 ° C. for 30 minutes, and reacted with a chloroform: methanol (1: 2) mixed solution To stop.

Next, total lipids were analyzed by the method of Holsch et al. (Journal of Biological Chemistry, Vol. 22,
Page 497, 1957), and after extraction of each lipid with TLC (Kieselgel GF ₂₅₄ , petroleum ether: diethyl ether: acetic acid = 90: 10: 1 as a developing solvent), the radioactivity incorporated in the cholesterol ester fraction was separated. Was analyzed by RI scanner (manufactured by Ambis) to measure the activity of acylcoenzyme A cholesterol acyltransferase. The concentration at which this enzyme activity was inhibited by 50% was calculated.
The results are shown below.

[0016]

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Compound number R ₁ R ₁ 'R ₂ ACAT inhibitory activity (IC ₅₀ , μM) PR-101 CH ₃ H OH> 10 PR-16 CH ₃ CH ₃ OH> 200 PR-127 CH ₂ CH ₃ H OH> _{200 PR-84 OCH 3 H OH} > 200 PR-134 CH (CH 3) 2 H OH> 200 PR-136 C (CH 3) 3 H OH> 190 PR-137 -CH = CH 2 H OH> 200 PR- _{126 - (CH 2) 5 OH} > 190 PR-93 C 6 H 5 H OH> 180 PR-124 p-OCH 3 -C 6 H 4 H OH> 170 PR-135 CH 2 C 6 H 5 H OH> 170 _{PR-140 C 6 H 5 CH} 3 OH> 180 PR-37 = O OH> 210

PR-110 CH ₃ H OCO (CH ₂ ) ₃ CH ₃ 0.025 PR-43 CH ₃ CH ₃ OCOCH ₃ 1.24 PR-79 CH ₃ CH ₃ OCO (CH ₂ ) ₃ CH ₃ 0.086 _{PR-146 CH 2 CH 3 H} OCO (CH 2) 3 CH 3 0.028 PR-104 OCH 3 H OCO (CH 2) 3 CH 3 0.091 PR-158 C (CH 3) 3 H OCO (CH 2 _{) 3 CH 3 0.48 PR-156} -CH = CH 2 H OCO (CH 2) 3 CH 3 0.29 PR-143 - (CH 2) 5 OCO (CH 2) 3 CH 3 0.039 PR-108 C ₆ H ₅ H OCOCH ₃ 0.12 PR-109 C ₆ H ₅ H OCO (CH ₂ ) ₃ CH ₃ 0.0064 PR-141 ρ-OCH ₃ -C ₆ H ₄ H OCO (CH ₂ ) ₃ CH _{3 0.35 PR-142 C 6 H 5} CH 3 OCO (CH 2) 3 CH 3 0.15 PR-111 = O OCO (CH 2) 3 CH 3 2.5 PR-38 = O OCO-imidazole> 170

Next, the mass spectrometric data of the pyripyropene derivative of the present invention will be described below. Compound number Compositional formula Molecular weight Measured value Theoretical value PR-101 C ₂₇ H ₃₃ O ₇ N ₁ 483.561 FAB (+) 484.2343 (M + 1) 484.2335 PR-16 C ₂₈ H ₃₅ O ₇ N ₁ 497.588 FAB (+) 498.2486 ( M + 1) 498.2491 PR-127 C ₂₈ H ₃₅ O ₇ N ₁ 497.588 FAB (+) 498.2488 (M + 1) 498.2491 PR-84 C ₂₇ H ₃₃ O ₈ N ₁ 499.560 FAB (+) 500.2310 (M + 1) 500.2284 PR-134 C ₂₉ H ₃₇ O ₇ N ₁ 511.615 FAB (+) 512.2650 (M + 1) 512.2648 PR-136 C ₃₀ H ₃₉ O ₇ N ₁ 525.642 FAB (+) 526.2808 (M + 1) 526.2804 PR-137 C ₂₈ H ₃₃ O ₇ N ₁ 495.572 FAB (+) 496.2346 (M + 1) 496.2335 PR-126 C ₃₁ H ₃₉ O ₇ N ₁ 537.653 FAB (+) 538.2805 (M + 1) 538.2804 PR-93 C ₃₂ H ₃₅ O ₇ N ₁ 545.632 FAB (+) 546.2500 (M + 1) 546.2491 PR-124 C ₃₃ H ₃₇ O ₈ N ₁ 575.658 FAB (+) 576.2591 (M + 1) 576.2597 PR-135 C ₃₃ H ₃₇ O ₇ N ₁ 559.659

PR-140 C ₃₃ H ₃₇ O ₇ N ₁ 559.659 FAB (+) 560.2636 (M + 1) 560.2648 PR-37 C ₂₆ H ₂₉ O ₈ N ₁ 483.517 FAB (+) 484.1972 (M + 1) 484.1917 PR -110 C ₃₂ H ₄₁ O ₈ N ₁ 567.679 FAB (+) 568.2905 (M + 1) 568.2910 PR-43 C ₃₀ H ₃₇ O ₈ N ₁ 539.625 FAB (+) 540.2616 (M + 1) 540.2597 PR-79 C ₃₃ H ₄₃ O ₈ N ₁ 581.706 FAB (+) 582.3062 (M + 1) 582.3066 PR-146 C ₃₃ H ₄₃ O ₈ N ₁ 581.706 FAB (+) 582.3071 (M + 1) 582.3067 PR-104 C ₃₂ H ₄₁ O ₉ N ₁ 583.678 FAB (+) 584.2847 (M + 1) 584.2860 PR-158 C ₃₅ H ₄₇ O ₈ N ₁ 609.760 FAB (+) 610.3370 (M + 1) 610.3380 PR-156 C ₃₃ H ₄₁ O ₈ N ₁ 579.657 FAB (+) 580.2913 (M + 1) 580.2910 PR-143 C ₃₆ H ₄₇ O ₈ N ₁ 621.771 FAB (+) 622.3370 (M + 1) 622.3379 PR-108 C ₃₄ H ₃₇ O ₈ N ₁ 587.669 FAB (+) 588.2615 (M + 1) 588.2597 PR-109 C ₃₇ H ₄₃ O ₈ N ₁ 629.750 FAB (+) 630.3089 (M + 1) 630.3066 PR-141 C ₃₈ H ₄₅ O ₉ N ₁ 659.776 FAB (+) 660.3180 (M + 1) ) 660.3172 PR-142 C ₃₈ H ₄₅ O ₈ N ₁ 643.777 FAB (+) 644.3218 (M + 1) 644.3223 PR-111 C ₃₁ H ₃₇ O ₉ N ₁ 567.635 FAB (+) 568.2560 (M + 1) 568.2546 PR- 38 C ₃₀ H ₃₁ O ₉ N ₃ 577.590

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

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

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 examples, but it goes without saying that the present invention is not limited to these. Reference Example 1 Pyripyropene A (583 mg) in 80% methanol aqueous solution 1
After dissolving in 0 ml and adding 166 mg of sodium methoxide and stirring at room temperature for 1 hour, the solvent was distilled off to obtain a crude product. To this, 10 ml of 40% aqueous methanol solution was added, and the resulting precipitate was filtered using a Kiriyama funnel to obtain 40%.
350m of colorless powder of compound after washing with aqueous methanol solution
g was obtained. In addition, the filtrate and the washing liquid were combined, the solvent was distilled off, and this was purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (9: 1) mixed solvent), and further 110 m of a colorless powder of the above compound was obtained.
g was obtained.

Example 1 Compound PR-101 21 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 1 ml of dry dimethylformamide, and dimethylacetal 3 was obtained.
After adding 10 μl and 4 mg of pyridine hydrochloride and stirring, dichloromethane was added, the mixture was washed with water and 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 column chromatography (developing solvent: dichloromethane-methanol (20: 1) mixed solvent) to obtain 6.0 mg of a colorless powder of the target compound PR-101. (Yield 27%)

Example 2 Compound PR-16 24 mg of the colorless powdery compound obtained in Reference 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 same as in Example 1. The target compound PR-1
16.8 mg of colorless powder 6 was obtained. (Yield 64%)

Example 3 Compound PR-127 30 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 1 ml of dry dimethylformamide, and 50 μl of propionaldehyde and 7 g of pyridinium-p-toluenesulfonic acid were dissolved.
mg, and the same treatment as in Example 1 was carried out to obtain the target compound P.
12.8 mg of R-127 colorless powder was obtained. (Yield 39
%)

Example 4 Compound PR-84 43 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 0.5 ml of dry dimethylformamide, 1 ml of trimethylorthoacetate and 4 mg of pyridine hydrochloride were added, and the same procedure as in Example 1 was conducted. This was treated to obtain 9.8 mg of colorless powder of the target compound PR-84. (Yield 21%)

Example 5 Compound PR-134 73 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 2 ml of dry dimethylformamide, 300 μl of isobutyraldehyde and 4 mg of pyridinium-p-toluenesulfonic acid were added, and the same as in Example 1 Then, 28.8 mg of colorless powder of the target compound PR-134 was obtained. (35% yield)

Example 6 Compound PR-136 The colorless powdery compound (8 mg) obtained in Reference Example 1 was dissolved in dry dimethylformamide (1 ml), and trimethylacetaldehyde (70 μl) and pyridinium-p-toluenesulfonic acid (4 mg) were added. Then, 6.0 mg of a colorless powder of the target compound PR-136 was obtained. (Yield 17%)

Example 7 Compound PR-137 50 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 1 ml of dry dimethylformamide, and 150 μl of acrolein diethyl acetal and 10 mg of pyridinium-p-toluenesulfonic acid were added to give Example 1 and The same treatment was performed to obtain 17.1 mg of a colorless powder of the target compound PR-137.
Obtained. (Yield 32%)

Example 8 Compound PR-126 30 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 1 ml of dry dimethylformamide, and 90 μl of 1,1-dimethoxycyclohexane and 10 mg of pyridinium-p-toluenesulfonic acid were added. The same treatment as in Example 1 was carried out to obtain 22.3 mg of a colorless powder of the target compound PR-126.
Obtained. (Yield 63%)

Example 9 Compound PR-93 140 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 5 ml of dry dimethylformamide, 240 μl of benzylidenedimethylacetal and 4 mg of pyridinium-p-toluenesulfonic acid were added, and the mixture was stirred and then dichloromethane was added. , Washed with water, dried over anhydrous sodium sulfate,
The solvent was distilled off to obtain a crude product. This was purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (25: 1) mixed solvent) to obtain 137.8 mg of colorless powder of the target compound PR-93. (83% yield)

Example 10 Compound PR-124 12 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 2.5 ml of dry dichloromethane to give m-chloroperbenzoic acid 2
0 mg was added and the same treatment as in Example 1 was carried out to obtain 6.1 mg of a yellow powder of the target compound PR-117. (Yield 4
9%)

Example 11 Compound PR-135 The colorless powdery compound (30 mg) obtained in Reference Example 1 was dissolved in dry dimethylformamide (1 ml), and phenylacetaldehyde (80 μl) and pyridinium-p-toluenesulfonic acid (4 mg) were added. To give 7.6 mg of colorless powder of the target compound PR-135. (Yield 2
1%)

Example 12 Compound PR-140 30 mg of the colorless powdery compound obtained in Reference Example 1 was dissolved in 1 ml of dry dimethylformamide, and 100 μl of (1,1-dimethoxyethyl) benzene and 4 mg of pyridinium-p-toluenesulfonic acid were dissolved. In addition, the same treatment as in Example 1 was carried out to obtain 31.3 m of colorless powder of the target compound PR-140.
g was obtained. (Yield 85%)

Example 13 Compound PR-37 40 mg of the colorless powder compound obtained in Reference Example 1 was suspended in 2 ml of tetrahydrofuran, 43 mg of N, N-carbonyldiimidazole was added, and the mixture was heated under reflux for 1 hour, and then Example 1
The same treatment as in (1) gave 11.5 mg of colorless powder of the target compound PR-37. (Yield 27%)

Example 14 Compound PR-110 4.2 mg of the compound obtained in Example 1 was dissolved in 1 ml of dry dichloromethane, 5 μl of valeric anhydride, 5 μl of triethylamine and 1 mg of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 15 hours. After washing with water, it was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain a crude product. This is purified by silica gel chromatography (developing solvent: dichloromethane-methanol (50: 1) mixed solvent),
3.2 mg of colorless powder of the target compound PR-110 was obtained.
(Yield 65%)

Example 15 Compound PR-43 15 mg of the compound obtained in Example 2 was mixed with dry dichloromethane 1
50 ml of acetic anhydride and 20 μl of triethylamine were added, and the mixture was treated in the same manner as in Example 14 to obtain 10 mg of colorless powder of the target compound PR-43. (Yield 61
%)

Example 16 Compound PR-79 20 mg of the compound obtained in Example 2 was dried on dichloromethane 2
20 ml of valeric anhydride, 20 ml of triethylamine and 2 mg of dimethylaminopyridine were added to the residue, and the mixture was treated in the same manner as in Example 14 to obtain 19.4 mg of colorless powder of the target compound PR-79. (83% yield)

Example 17 Compound PR-146 10 mg of the compound obtained in Example 3 was added to dry dichloromethane 1
After dissolving in ml, valeric anhydride (10 µl), triethylamine (10 µl) and dimethylaminopyridine (4 mg) were added and treated in the same manner as in Example 14 to obtain 7.7 mg of colorless powder of the target compound PR-146. (Yield 66%)

Example 18 Compound PR-104 6 mg of the compound obtained in Example 4 was dried with 1 m of dry dichloromethane.
l and dissolved in 1 ml of dry pyridine, 5 μl of valeric anhydride
And 10 μl of triethylamine were added and treated in the same manner as in Example 14 to obtain 4.1 mg of a colorless powder of the target compound PR-104. (Yield 58%)

Example 19 Compound PR-171 10 mg of the compound obtained in Example 5 was added to dry dichloromethane 1
Dissolve in 5 ml of valeric anhydride 5 μl, triethylamine 1
0 μl and 1 mg of dimethylaminopyridine were added and treated in the same manner as in Example 14 to obtain 6.6 mg of a colorless powder of the target compound PR-171. (Yield 57%)

Example 20 Compound PR-158 9.1 mg of the compound obtained in Example 6 was dissolved in 2 ml of dry dichloromethane, and 9 μl of valeric anhydride, 10 μl of triethylamine and 4 mg of dimethylaminopyridine were added and treated in the same manner as in Example 14. Thus, 6.3 mg of colorless powder of the target compound PR-158 was obtained. (60% yield)

Example 21 Compound PR-156 10 mg of the compound obtained in Example 7 was dried on dichloromethane 2
Dissolve in 5 ml of valeric anhydride 5 μl, triethylamine 5
μl and 2 mg of dimethylaminopyridine were added and treated in the same manner as in Example 14 to obtain 7.6 mg of a colorless powder of the target compound PR-156. (Yield 63%)

Example 22 Compound PR-143 10 mg of the compound obtained in Example 8 was dried with dichloromethane 1
After dissolving in ml, valeric anhydride (10 µl), triethylamine (10 µl) and dimethylaminopyridine (2 mg) were added and treated in the same manner as in Example 14 to obtain 8.9 mg of a colorless powder of the target compound PR-143. (Yield 77%)

Reference Example 2 20 mg of the colorless powdery compound obtained in Example 1 was dissolved in 1 ml of dry pyridine, 37 μl of isobutyric 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. I got a thing. This is purified by silica gel column chromatography (developing solvent: dichloromethane-methanol (20: 1) mixed solvent),
4.5 mg of a colorless powder compound was obtained.

Reference Example 3 10 mg of the colorless powdered compound obtained in Reference Example 2 was dissolved in 1 ml of dry dichloromethane, 5 μl of acetic anhydride, 20 μl of triethylamine and 2 mg of dimethylaminopyridine were added, and the mixture was stirred for 20 hours, washed with water and then dried. It was dried over sodium sulfate and the solvent was distilled off to obtain a crude product. This is subjected to silica gel column chromatography (column: Sensh
uPak ODS-4251-N, mobile phase: 40% aqueous acetonitrile solution) to give colorless compound 3.
4 mg was obtained.

Example 23 Compound PR-108 The colorless powdery compound (4.4 mg) obtained in Reference Example 3 was dissolved in dry dichloromethane (1 ml), and acetic anhydride (5 μl), triethylamine (5 μl) and dimethylaminopyridine (1 mg) were added. The target compound PR-
2.7 mg of 108 colorless powder was obtained. (Yield 57%)

Example 24 Compound PR-109 140 mg of the compound obtained in Example 9 was dissolved in 10 ml of dry dichloromethane, and 60 μl of valeric anhydride, 10 μl of triethylamine and 4 mg of dimethylaminopyrimidine were added and treated in the same manner as in Example 14. Target compound PR-
142.7 mg of 109 colorless powder was obtained. (Yield 88
%)

Example 25 Compound PR-141 7.8 mg of the compound obtained in Example 10 was dissolved in 1 ml of dry dichloromethane, and 10 μl of valeric anhydride, 10 μl of triethylamine and 4 mg of dimethylaminopyridine were added and treated in the same manner as in Example 14. Then, the target compound PR-
8.5 mg of 141 colorless powder was obtained. (Yield 95%)

Example 26 Compound PR-142 5.8 mg of the compound obtained in Example 12 was dissolved in 1 ml of dry dichloromethane, and 10 μl of valeric anhydride, 10 μl of triethylamine and 4 mg of dimethylaminopyridine were added and treated in the same manner as in Example 14. Then, the target compound PR-
6.4 mg of 142 colorless powder was obtained. (Yield 96%)

Example 27 Compound PR-111 4 mg of the compound obtained in Example 13 was added to dry dichloromethane 1
Dissolve in 5 ml of valeric anhydride 5 μl, triethylamine 5
μl and 1 mg of dimethylaminopyridine were added and treated in the same manner as in Example 14 to obtain 0.4 mg of the target compound PR-141 colorless powder. (Yield 9%)

Example 28 Compound PR-38 40 mg of the colorless powdery compound obtained in Reference Example 1 was suspended in 2 ml of tetrahydrofuran, 43 mg of N, N-carbonyldiimidazole was added, and the mixture was heated under reflux for 1 hr and the solvent was distilled off. Then, dichloromethane was added and treated in the same manner as in Example 14 to obtain 7 mg of a colorless powder of the target compound PR-38. (Yield 14%)

Claims (2)

[Claims] 1. The following formula: [In the formula, R ₁ represents a saturated or unsaturated alkyl group (the alkyl group may have a branch or may have a substituent), an —O-alkyl group, or a substituent. An aryl group which may have, or an alkylene group together with R ₁ ′ or O, R ₁ ′ is H, a methyl group, or an alkylene group together with R ₁ or O, R ₂ is OH, —O— An acyl group or a heterocyclic group is shown]. 2. The pyripyropene derivative according to claim ₁ , wherein the groups R ₁ , R ₁ 'and R ₂ are compounds selected from the group of compounds having a combination of substituents represented by the following formula. Compound No. _{R 1 R 1 'R 2 PR} -101 CH 3 H OH PR-16 CH 3 CH 3 OH PR-127 CH 2 CH 3 H OH PR-84 OCH 3 H OH PR-134 CH (CH 3) 2 H _{OH PR-136 C (CH 3} ) 3 H OH PR-137 -CH = CH 2 H OH PR-126 - (CH 2) 5 - OH PR-93 C 6 H 5 H OH PR-124 p-OCH 3 - _{C 6 H 4 H OH PR-} 135 CH 2 C 6 H 5 H OH PR-140 C 6 H 5 CH 3 OH PR-37 = O OH PR-110 CH 3 H OCO (CH 2) 3 CH 3 PR-43 _{CH 3 CH 3 OCOCH 3 PR-} 79 CH 3 CH 3 OCO (CH 2) 3 CH 3 PR-146 CH 2 CH 3 H OCO (CH 2) 3 CH 3 PR-104 OCH 3 H OCO (CH 2) 3 CH ₃ PR-171 CH (CH ₃ ) _{2 H OCO (CH 2) 3 CH} 3 PR-158 C (CH 3) 3 H OCO (CH 2) 3 CH 3 PR-156 -CH = CH 2 H OCO (CH 2) 3 CH 3 PR-143 - (CH ^{_{2) 5 - OCO (CH 2}} ) 3 CH 3 PR-108 C 6 H 5 H OCOCH 3 PR-109 C 6 H 5 H OCO (CH 2) 3 CH 3 PR-141 p-OCH 3 -C 6 H 4 _{H OCO (CH 2) 3 CH} 3 PR-142 C 6 H 5 CH 3 OCO (CH 2) 3 CH 3 PR-111 = O OCO (CH 2) 3 CH 3 PR-38 = O OCO-imidazole