JP2003286165A - 5alpha-REDUCTASE INHIBITOR COMPOSED OF ELLAGIC ACID DERIVATIVE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a nonsteroidal 5α-reductase inhibitor, especially a new-type 5α-reductase inhibitor originating from a natural resource and having high safety. <P>SOLUTION: The 5α-reductase inhibitor contains at least one kind of ellagic acid derivative of formula (1) or its salt. In formula (1), at least one of X<SB>1</SB>and X<SB>2</SB>is a gallic acid residue bonding through an ether bond or a lactone ring and the group X<SB>1</SB>or X<SB>2</SB>which is not gallic acid residue is hydroxy group. Especially preferable examples of the compound of formula (1) are valoneaic acid dilactone and gallagyldilactone and these compounds can be extracted from the heartwood of bangkirai belonging to the genus Shorea. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 5α-reductase inhibitor, and more specifically, a novel 5α-comprising a compound having an ellagic acid structure which is a compound related to plant tannins.
It relates to a reductase inhibitor.

[0002]

2. Description of the Prior Art 5α-reductase is an enzyme that converts testosterone, which is a major androgen (androgen) in blood, into dihydrotestosterone (hereinafter sometimes referred to as DHT) that exhibits a stronger androgen action. The resulting DHT binds to an androgen-specific receptor (androgen receptor), further binds to a response site (androgen responsive element) in the nucleus, and a coactivator protein, and the protein synthesis based on genetic information is initiated for the first time. Is understood.

DHT content is significantly higher in prostatic hypertrophic tissue than in normal prostatic tissue, and the expression level of 5α-reductase is high in the frontal region of male and female adolescents with male pattern baldness. Are involved in these diseases, and it is known that 5α-reductase inhibitory agents are useful for the treatment and prevention of benign prostatic hyperplasia and male pattern baldness.

In general, 5α-reductase inhibitors suppress the increase in sebum secretion and are effective in preventing dandruff in the scalp. Therefore, 5α-reductase inhibitors are used in prostatic hypertrophy and in men. In addition to alopecia areata, it is effective for the treatment of seborrheic alopecia, acne, and skin diseases such as seborrhea caused by enhancement of skin secretory function.

Furthermore, there is a report that the probability of developing prostate cancer in a prostatic hypertrophy patient is four times that of the control group (Armenian et al. Lancet 2: 115 (1974)), 5
The α-reductase inhibitor is also effective in preventing prostate cancer.

Steroids (4-azasteroids) as 5α-reductase inhibitors that have been developed so far
The compound finasteride (Rasmusson GH et al. J. Me
d. Chem. 29: 2298 (1986)). However, finasteride is known to have side effects such as sexual dysfunction, and it is desired to develop a nonsteroidal inhibitor in terms of safety.

ONO-3805 (EP 0 291 245 A2) and the like have been known so far as non-steroidal inhibitors. On the other hand, catechins (Liao S et a
l. Biochem. Biophys. Res. Commun. 214: 833 (199
5)), fatty acids (Liang T et al. Biochem. J. 285: 557.
(1992)), riboflavin (Nakayama O et al. J. Anti.
biot. 43: 1615 (1990)), menaquinones (Kim YU et a
Biol. Pharm. Bull 22: 1396 (1999)) and the like are known.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a non-steroidal 5α-reductase inhibitor, particularly a new type 5α-reductase inhibitor derived from a natural product and highly safe.

[0009]

Means for Solving the Problems As a result of repeated studies, the present inventor has found that a compound having an ellagic acid structure which is a tannin-related compound has a 5α-reductase inhibitory activity which has never been known. discovered. Furthermore, the present inventor has Shorea (Shorea) genus trees Bankirai (ba
It was also found that the heartwood part of ngkirai: Shorea laeviforia ) contains such a tannin-related compound having a 5α-reductase inhibitory activity.

Thus, according to the present invention, on the basis of this finding, there is provided a 5α-reductase inhibitor characterized by containing at least one ellagic acid derivative represented by the following general formula (1) or a salt thereof. Provided.

[0011]

[Chemical 4]

In the formula (1), at least one of X ₁ and X ₂ is a gallic acid residue bonded through an ether bond or a lactone ring, and X ₁ or X _{2 which} is not a gallic acid residue is a hydroxyl group. Is.

The ellagic acid derivative included in the above general formula (1) according to the present invention, which is particularly preferable as a 5α-reductase inhibitor, is a valon represented by the following formula (2). Acid dilactone (valoneic a
cid dilactone) or a gallagyldilactone represented by the following formula (3).

[0014]

[Chemical 5]

[0015]

[Chemical 6]

Valonate dilactone is known to inhibit xanthine oxidase (Hatano T. et al., Chem, Pharm. Bull. 38: 1224 (199).
(0)), and galazyl dilactone is known to inhibit carbonic anhydrase (Satomi H. et al., Biol. Pharm. Bull. 16: 7).
87 (1993)), it has not yet been reported that these compounds have 5α-reductase inhibitory activity.

Furthermore, according to the present invention, there is provided a method for producing an ellagic acid derivative of the above formula (1), in particular valonic acid dilactone and galazyl dilactone, which is extracted from the heartwood part of a tree of the genus Shorea. A method is provided which comprises:

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is based on the finding that a compound having a specific structure among compounds having an ellagic acid structure, which is one of plant tannin-related compounds, has 5α-reductase inhibitory activity. is there. That is, the ellagic acid derivative constituting the 5α-reductase inhibitor of the present invention is a gallic acid residue in which at least one of X ₁ and X ₂ in the formula (1) is bonded via an ether bond or a lactone ring. , X ₁ or X ₂ which is not a gallic acid residue
Has a molecular structure such that is a hydroxyl group. That is, X ₁ (or X ₂ ) of the formula (1) is represented by the chemical structure (2) of valonic acid dilactone, after the gallic acid is bonded to the ellagic acid site so as to form an ether bond. As shown in the chemical structure (3) of the residue or galazyldilactone, gallic acid is a lactone ring (γ
-Lactone) after being attached to the ellagic acid site to form a lactone).

The present inventor has found that compounds such as valonic acid dilactone and galazyl dilactone having the above specific ellagic acid structure are present in bankirai of the tree of the genus Shorea, and extracted from the heartwood part of this tree. Thus, the technology for obtaining these compounds was also established. Bankirai is a Southeastern tree of the genus Shorea of the Dipterocarpaceae family, and is known as the selangan-batu and yellow balau.
Ellow), also called by these names, specifically S. argentea, S. astylosa, S. atrineryosa, S.
balangeran, S. ciliata, S. gisok, S. glauca, S. l
aevis, S. materialis, S. maxwelliana, S. senimis,
Tree species such as S. scrobiculata, S. submontana, S. sumatrana can be used. According to the present invention, a method for producing a compound such as valonic acid dilactone or galazyl dilactone by extracting from a heartwood part of a shoreia tree bankirai generally comprises (1) crushing the heartwood part of the tree, It is extracted with a lower alcohol having a high affinity with wood (for example, methanol), and (2) diethyl ether is added to the alcohol extract to remove the ether-soluble component, and (3) Concentrating and purifying the residue, for example, adding ethyl acetate or n-butanol to the residue, concentrating the soluble component and purifying by various chromatographies, or concentrating the residue to dryness and then acetone and acetonitrile. Extraction with an aqueous solution containing a polar solvent such as alcohol, lower alcohol, etc., and purifying this with various chromatographies Including.

As described above, the present inventor has found that ellagic acid derivatives having a 5α-reductase inhibitory activity such as valonic acid dilactone and galazyl dilactone can be extracted from the heartwood of bankirai wood. The compound can also be obtained by hydrolyzing ellagitannins. That is, valonic acid dilactone can be obtained by hydrolysis of ellagitannins having a valoneoyl group, and galazyl dilactone can be obtained by hydrolysis of ellagitannins having a gallagyl group.

Hydrolysis can be efficiently carried out generally by boiling or treating with an acid such as dilute hydrochloric acid or dilute sulfuric acid, but hydrolytic enzyme treatment is also effective. Ellagitannins having a varone oil group include, for example, Dipterocarpaceae plants, Rhododendronaceae plants, Lythrumaceae plants, Euphorbiaceae plants, Camellia plants, Myrtaceae plants, Nobotanaceae plants, Gummyaceae plants, Hawthorne plants, Rosaceae plants, etc., Further, ellagitannins having a galazyl group include, for example, Dipterocarpaceae plants, pomegranates plants, birch plants,
It can be obtained from plants of the family Asteraceae, and it is possible to obtain valonic acid dilactone and galazyl dilactone as hydrolysates of these plant extracts. The hydrolysates of ellagitannins include gallic acid, ellagic acid, and flavogallonic acid dilactone.
Dilactone) and low molecular weight tannins are also known. Among them, the flavogalonic acid dilactone represented by the following formula (4) is different from the compound such as valonic acid dilactone used in the present invention by 5α. -Reductase promoting activity is observed and must be removed.

[0022]

[Chemical 7]

The 5α-reductase inhibitor of the present invention is composed of an ellagic acid derivative such as valonic acid dilactone or galazyl dilactone obtained as described above, or a salt thereof. Examples of salts include lithium, sodium, potassium and other alkali metal salts, calcium,
Examples thereof include alkaline earth metal salts such as barium, metal salts such as magnesium and aluminum, amines, amine salts such as ammonia, basic salts such as amino acid salts such as glutamine and asparagine, and they are preferably pharmacologically acceptable. It is the salt that is used. In addition, when a compound such as valonic acid dilactone or galazyl dilactone or a salt thereof forms a solvate (for example, a hydrate), and when left in the air or recrystallized to absorb water, the water is absorbed. And hydrates are formed, the present invention includes such solvates. Further, a compound that is converted into a compound such as valonic acid dilactone or galazyl dilactone or a salt thereof by metabolism in the living body, a so-called prodrug, is also included as a component of the 5α-reductase inhibitor according to the present invention. .

[0024]

EXAMPLES The features of the present invention will be more specifically described below.
However, the present invention is not limited to these examples.
Is not limited by.Example 1: Valonic acid dilactone from Bankirai wood
Extraction and purification of gallazyl dilactone Wood flour obtained by crushing the heartwood part of bankirai (~ 1.4
mm) was extracted with methanol. This methanol extract
Was concentrated and mixed with an equal volume of water, then diethyl ether was added.
It was added and the soluble component was removed. The residue obtained is concentrated to dryness.
After solidification, 100 times the amount of 10% acetonitrile based on the concentrated residue
Was added and suspended by ultrasonic treatment. Suspension as it is
The mixture was left at room temperature for a long time to precipitate the insoluble portion. The supernatant is thick
After contraction, reverse phase preparative high performance liquid chromatography (0.1%
Lifluoroacetic acid: acetonitrile = 90:10 to 50:50
Near gradient)
Lactone and galazyl dilactone were obtained. NMR data (400 MHz): Valonic acid dilactone¹
H-NMR analysis result: δ_H(DMSO-d6) 6.93 (s), 7.01
(s), 7.51 (s)¹³ Results of C-NMR analysis: δ_C(DMSO-d6) 106.9, 108.
0, 108.2, 108.4, 110.5, 111.9, 113.8, 114.6, 135.1,
 136.1, 136.5, 139.1, 139.4, 139.5, 140.4, 142.9,
148.4, 149.3, 159.0, 159.0, 165.6 Galazyl dilactone¹H-NMR analysis result: δ_H(DM
SO-d6) 7.50 (s)¹³ Results of C-NMR analysis: δ_C(DMSO-d6) 106.5, 107.
4, 110.1, 112.0, 112.4, 122.7, 135.7, 136.1, 138.7,
 139.1, 145.6, 147.7, 157.6, 158.8

[0025]Example 2: For hydrolysis of ellagitannins
Of Valonic Acid Dilactone and Galazyl Dilactone
Success Sonicate with the addition of acetonitrile in Example 1
IR analysis of the insoluble portion of the suspension obtained by
20-1740 cm^-1Carbonyl ester and lactone
Since the absorption derived from the group was observed, the high molecular weight
It was found to be a mixture of tannins. this
Hydrolysis of the precipitate by refluxing with 5% sulfuric acid for 6 hours
Then, after cooling, extraction with n-butanol was performed, and ethyl acetate was added.
After concentrating the chill-soluble portion, a reversed-phase preparative high-speed liquid was prepared as in Example 1.
Purification by body chromatography
Lactone and galazyl dilactone were obtained.

[0026]Example 3: 5α-reductase inhibitory activity
Measurement Valonic acid dilactone and gala obtained according to Example 1
Determine the 5α-reductase inhibitory activity of zirdilactone
It was The rate of 5α-reductase inhibitory activity was
Microsome (hereinafter referred to as microsome) suspension
It was used as a crude enzyme solution of 5α-reductase. Also, the basis
4.5mM as quality¹⁴C] Testosterone-ethanol
Solution (hereinafter referred to as testosterone), inhibitor sample
DMSO solution (hereinafter referred to as inhibitor), pH 6.5 phosphorus
Acid buffer (hereinafter referred to as buffer), 1 mM
NADPH (hereinafter referred to as NADPH), 3M Na
OH (hereinafter referred to as NaOH) was prepared. Enzymatic reaction
Is testosterone 0.01ml, inhibitor 0.01ml and 0.22m
0.01 ml of microsomes and NADPH in 1 buffer
After adding 0.05 ml and incubating at 37 ℃ for 10 minutes, NaO
It was performed by stopping the reaction with 0.01 ml of H 2.
After stopping the reaction, the enzyme reaction solution is extracted with diethyl ether.
Thin-layer chromatography of the soluble portion of diethyl ether.
(Kieselgel 60 F₂₅₄, Ethyl acetate: n-hexane = 7.
It was developed by 3). Obtained testosterone and DH
Radioactivity of T spot is measured by Imaging Analyzer
(Fuji Film Co., Ltd.). 5α-reductase inhibitory activity (%) = [(Xc-Xi)
/ Xc] x 100 Where Xi is the DHT production ratio when an inhibitor is used
(DHT production ratio = DHT radioactivity / DHT and test
Sum of radioactivity of sterone), Xc is an inhibitor
It is a DHT production ratio when there is no such. By the above method
Ri IC₅₀Value, that is, 5α-reductase inhibitory activity 50
When the concentration of% was examined, the results were as follows, and both were satisfied.
It is confirmed that it has a high 5α-reductase inhibitory activity.
It has been certified. Valonic acid dilactone IC₅₀Value: 129.1 μM Galazyl dilactone IC₅₀Value: 91.2 μM

[0027]

INDUSTRIAL APPLICABILITY According to the present invention, a novel non-steroidal 5α-reductase inhibitor comprising an ellagic acid derivative having a specific structure such as valonic acid dilactone and galazyl dilactone or a salt thereof can be obtained. Furthermore, the present invention has found that ellagic acid derivatives having 5α-reductase inhibitory activity such as valonic acid dilactone and galazyl dilactone are present in trees of the genus Shorea such as bangkirai wood, and these The new acquisition method of the compound was established. The 5α-reductase inhibitor of the present invention comprising an ellagic acid derivative such as valonic acid dilactone and galazyl dilactone or a salt thereof can be applied to pharmaceuticals, quasi-drugs, cosmetics and the like. It is considered to be expected to be effective in treating and preventing hair materials, acne, seborrheic skin disorders, benign prostatic hyperplasia, prostate cancer and the like.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 111 A61P 43/00 111 C07D 493/04 106 C07D 493/04 106A 493/22 493/22 C12N 9/99 C12N 9/99 (72) Inventor Ryuichiro Kondo 23-8, 8-1 Everif Kashii 1-8, Kashii, Higashi-ku, Fukuoka-shi, Fukuoka (72) Inventor Katsumi Sakai 33F term, 3693, Fukuma-cho, Munakata-gun, Fukuoka (reference) ) 4C071 AA01 AA07 AA08 BB01 BB03 CC12 CC14 EE07 FF07 HH09 JJ01 KK17 LL01 4C086 AA01 AA02 AA04 CA01 MA01 MA04 NA14 ZA81 ZA89 ZA92 ZB26 ZC20

Claims (4)

[Claims] 1. A 5α-reductase inhibitor, which comprises at least one ellagic acid derivative represented by the following general formula (1) or a salt thereof. [Chemical 1] [In the formula (1), at least one of X ₁ and X ₂ is a gallic acid residue bonded through an ether bond or a lactone ring, and X ₁ or X _{2 which} is not a gallic acid residue is a hydroxyl group. . ] 2. The 5α-reductase inhibitor according to claim 1, wherein the ellagic acid derivative is a valonic acid dilactone represented by the following formula (2). [Chemical 2] 3. The 5α-reductase inhibitor according to claim 1, wherein the ellagic acid derivative is galazyldilactone represented by the following formula (3). [Chemical 3] 4. A method for producing the ellagic acid derivative according to claim 1, wherein the ellagic acid derivative is extracted from a heartwood part of a shoreia genus bankirai.