JPH09124541A - New compound and nerve growth factor productive inducer with the same as active ingredient - Google Patents
New compound and nerve growth factor productive inducer with the same as active ingredientInfo
- Publication number
- JPH09124541A JPH09124541A JP7303772A JP30377295A JPH09124541A JP H09124541 A JPH09124541 A JP H09124541A JP 7303772 A JP7303772 A JP 7303772A JP 30377295 A JP30377295 A JP 30377295A JP H09124541 A JPH09124541 A JP H09124541A
- Authority
- JP
- Japan
- Prior art keywords
- derivative
- growth factor
- lactone
- nerve growth
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、エゾハリタケ科
（Climacodontaceae）ブナハリタケ属（Mycoleptodonoi
des ）のキノコであるブナハリタケ（Mycoleptodonoide
s aitchisonii ）の子実体や菌糸体から単離されるシク
ロペンテノン（cyclopentenone）誘導体及び該シクロペ
ンテノン（cyclopentenone）誘導体を有効成分とする神
経成長因子（ＮＧＦ）産生誘導剤並びにγ−ラクトン
（γ−lactone ）誘導体及び該γ−ラクトン（γ−lact
one ）誘導体を有効成分とする神経成長因子（ＮＧＦ）
産生誘導剤に関する。TECHNICAL FIELD The present invention relates to the genus Mycoleptodonoi (Climacodontaceae) of the genus Mycoleptodonoi.
beech mushroom (Mycoleptodonoide) which is a mushroom of des)
s aitchisonii), a cyclopentenone derivative isolated from the fruiting body or mycelium, and a nerve growth factor (NGF) production inducer containing the cyclopentenone derivative as an active ingredient and γ-lactone (γ- lactone) derivative and the γ-lactone (γ-lact)
nerve growth factor (NGF) containing one) derivative as an active ingredient
It relates to a production inducer.
【０００２】[0002]
【従来の技術】従来、キノコの子実体から単離される化
合物及びその薬剤効果については複数の報告がある。例
えば、サルノコシカケ科のキノコであるカワラタケ（Po
lyporus versicolor）の子実体から単離されるエルゴス
テロール誘導体には肝臓癌細胞に対する殺細胞効果のあ
ることがテトラヘドロン（tetrahedron ）３９、２７７
９〜２７８５（１９８３）に報告されている。またハラ
タケ科のキノコであるヒメマツタケ（Agaricus blazei
）の子実体から単離されるエルゴステロール誘導体に
は子宮頸癌細胞に対する殺細胞効果のあることがフィト
ケミストリ（Phytochemistry）２７、２７７７〜２７８
９（１９８８）に報告されている。同様のことは特公昭
４８−６７６６号公報、特公昭５５−７１７０２号公
報、特公昭５８−６２１１８号公報等にも報告されてい
る。2. Description of the Related Art Conventionally, there have been several reports on compounds isolated from mushroom fruiting bodies and their drug effects. For example, kawaratake (Po
The ergosterol derivative isolated from the fruiting body of lyporus versicolor) has a cell-killing effect on liver cancer cells tetrahedron 39, 277.
9-2785 (1983). In addition, the mushroom mushroom (Agaricus blazei), which is a mushroom in the agaric family.
The ergosterol derivative isolated from the fruiting body of) has a cytocidal effect on cervical cancer cells. Phytochemistry 27, 2777-278
9 (1988). The same is reported in JP-B-48-6766, JP-B-55-71702, JP-B-58-62118, and the like.
【０００３】エゾハリタケ科のキノコであるブナハリタ
ケについても、該ブナハリタケの子実体から香気物質が
抽出されることが特開平４−４５７９３に報告されてい
る。また、ブナハリタケ属キノコの培養瀘液中に含まれ
るムコ多糖を有効成分とした制癌剤の製造方法が特公昭
５２−４４６０６に報告されている。It has been reported in Japanese Patent Application Laid-Open No. 4-45793 that the aroma substance is extracted from the fruiting body of Bunaharitake mushroom, which is a mushroom belonging to the family Ezoharitake mushroom. Also, Japanese Patent Publication No. 52-44606 discloses a method for producing an anti-cancer agent containing mucopolysaccharide contained in the culture filtrate of mushrooms of the genus Bunaharitake as an active ingredient.
【０００４】[0004]
【発明が解決しようとする課題】しかし、ブナハリタケ
の子実体や菌糸体から単離される化合物及びその薬剤効
果については全く報告がない。However, there is no report on the compound isolated from the fruiting body or mycelium of Bunaharitake mushroom and its drug effect.
【０００５】[0005]
【発明が解決するための手段】しかして本発明者らは、
叙上の如き実情に鑑み、ブナハリタケの子実体や菌糸体
から単離される化合物及びその薬剤効果について鋭意研
究した結果、ブナハリタケの子実体や菌糸体に所定の抽
出処理及び分画処理を施すと、新規のシクロペンテノン
（cyclopentenone）誘導体及び新規のγ−ラクトン（γ
−lactone ）誘導体が単離され、該シクロペンテノン
（cyclopentenone）誘導体及び該γ−ラクトン（γ−la
ctone ）誘導体には神経成長因子（ＮＧＦ）産生誘導効
果のあることを見出した。DISCLOSURE OF THE INVENTION
In view of the above-mentioned circumstances, as a result of diligent research on compounds isolated from fruiting bodies and mycelia of Bunaharitake and mycelium, as a result of subjecting the fruiting bodies and mycelia of Bunaharitake to predetermined extraction and fractionation treatments, Novel cyclopentenone derivatives and new γ-lactone (γ
-Lactone) derivative is isolated, and the cyclopentenone derivative and the γ-lactone (γ-la) are isolated.
It was found that the ctone) derivative has a nerve growth factor (NGF) production-inducing effect.
【０００６】すなわち本発明は、下記の式１で示される
シクロペンテノン（cyclopentenone）誘導体及び該シク
ロペンテノン（cyclopentenone）誘導体を有効成分とす
る神経成長因子（ＮＧＦ）産生誘導剤並びに下記の式２
又は式３で示されるγ−ラクトン（γ−lactone ）誘導
体及び該γ−ラクトン（γ−lactone ）誘導体を有効成
分とする神経成長因子（ＮＧＦ）産生誘導剤に係る。That is, the present invention provides a cyclopentenone derivative represented by the following formula 1, a nerve growth factor (NGF) production inducer containing the cyclopentenone derivative as an active ingredient, and the following formula 2
Alternatively, the present invention relates to a γ-lactone derivative represented by Formula 3 and a nerve growth factor (NGF) production inducer containing the γ-lactone derivative as an active ingredient.
【０００７】[0007]
【式１】(Equation 1)
【０００８】[0008]
【式２】(Equation 2)
【０００９】[0009]
【式３】(Equation 3)
【００１０】[0010]
【発明の実施の形態】式１で示されるシクロペンテノン
（cyclopentenone）誘導体及び式２又は式３で示される
γ−ラクトン（γ−lactone ）誘導体はブナハリタケの
子実体及び／又は菌糸体を次のように処理することによ
って得られる。先ず、ブナハリタケの生あるいは乾燥子
実体及び／又は菌糸体を水および水溶性有機溶媒の均一
混合溶媒で抽出処理し、ろ過や遠心分離等で固液分離し
て抽出液を得、該抽出液から水溶性有機溶媒を蒸発する
ことにより水層を得る。均一混合溶媒としては、８０〜
８５％メタノール水溶液やエタノール水溶液、８５％ア
セトン水溶液等を使用できる。抽出は通常室温で行う
が、加熱還流しても良く、抽出時間は通常１〜７２時間
とする。例えば、８５％エタノール水溶液中にブナハリ
タケの乾燥子実体を加え、ホモジナイズ処理し、これを
室温で一昼夜放置した後、ろ過して抽出液を得、該抽出
液を減圧下に４０〜４５℃で加熱してエタノールを蒸発
することにより水層を得るのである。BEST MODE FOR CARRYING OUT THE INVENTION The cyclopentenone derivative represented by the formula 1 and the γ-lactone derivative represented by the formula 2 or the formula 3 represent the fruit body and / or mycelium of the beech mushroom as follows. It is obtained by processing as. First, raw or dried fruiting bodies and / or mycelium of Beech mushrooms are subjected to an extraction treatment with a homogeneous mixed solvent of water and a water-soluble organic solvent, and an extract is obtained by solid-liquid separation by filtration, centrifugation or the like. A water layer is obtained by evaporating the water-soluble organic solvent. As a homogeneous mixed solvent, 80 to
An 85% methanol aqueous solution, an ethanol aqueous solution, an 85% acetone aqueous solution, or the like can be used. The extraction is usually performed at room temperature, but it may be heated under reflux, and the extraction time is usually 1 to 72 hours. For example, a dried fruit body of Bunharitake is added to an 85% ethanol aqueous solution, homogenized, left to stand at room temperature for one day and then filtered to obtain an extract, and the extract is heated under reduced pressure at 40 to 45 ° C. Then, the water layer is obtained by evaporating the ethanol.
【００１１】次に、上記水層を水及び非水溶性有機溶媒
の混合溶媒を用いて液−液分配抽出処理し、非水溶性有
機溶媒層を分取して、該非水溶性有機溶媒層から非水溶
性有機溶媒を蒸発することにより乾固物を得る。この場
合、非水溶性有機溶媒としては、クロロホルム、酢酸エ
チル、ジエチルエーテル等を使用できる。例えば、上記
水層に酢酸エチルを加え、振盪して放置した後、分層し
た酢酸エチル層を分取し、該酢酸エチル層を減圧下に４
０〜４５℃で加熱して酢酸エチルを蒸発することにより
乾固物を得るのである。Next, the water layer is subjected to liquid-liquid partition extraction using a mixed solvent of water and a water-insoluble organic solvent, the water-insoluble organic solvent layer is separated, and the water-insoluble organic solvent layer is separated from the water-insoluble organic solvent layer. A dry solid is obtained by evaporating the water-insoluble organic solvent. In this case, chloroform, ethyl acetate, diethyl ether or the like can be used as the water-insoluble organic solvent. For example, ethyl acetate was added to the above aqueous layer, the mixture was shaken and allowed to stand, then the separated ethyl acetate layer was separated, and the ethyl acetate layer was concentrated under reduced pressure to 4
A dry solid is obtained by heating at 0 to 45 ° C and evaporating ethyl acetate.
【００１２】上記乾固物はそれ自体が神経成長因子（Ｎ
ＧＦ）産生誘導剤として有効なものであるが、該乾固物
から不純物を除去して神経成長因子（ＮＧＦ）産生誘導
効果を高めるために、該乾固物をクロマト分画処理し、
クロマト分画処理したものをさらに再分画処理して目的
とするシクロペンテノン（cyclopentenone）誘導体及び
γ−ラクトン（γ−lactone ）誘導体を単離する。この
場合、詳しくは実施例で後述するように、ベンゼン、ク
ロロホルム、ヘキサン、アセトン、酢酸エチル、クロロ
ホルム／アセトン、クロロホルム／メタノール、ヘキサ
ン／酢酸エチル、ベンゼン／アセトン、ヘキサン／ベン
ゼン、ヘキサン／アセトン、ベンゼン／酢酸エチル等を
移動相として用いたシリカゲルカラムクロマトグラフィ
ー、薄層クロマトグラフィー等でクロマト分画処理する
ことができ、またＯＤＳカラムを用いた高速液体クロマ
トグラフィーで再分画処理することができる。The dry matter itself has a nerve growth factor (N
GF) is effective as a production inducer, but in order to remove impurities from the dried solid matter and enhance the effect of inducing nerve growth factor (NGF) production, the dried solid matter is subjected to chromatographic fractionation treatment,
The chromatographically-fractionated product is further re-fractionated to isolate the target cyclopentenone derivative and γ-lactone derivative. In this case, as will be described later in detail in Examples, benzene, chloroform, hexane, acetone, ethyl acetate, chloroform / acetone, chloroform / methanol, hexane / ethyl acetate, benzene / acetone, hexane / benzene, hexane / acetone, benzene. / Chromatographic fractionation can be performed by silica gel column chromatography using ethyl acetate as a mobile phase, thin layer chromatography and the like, and re-fractionation can be performed by high performance liquid chromatography using an ODS column.
【００１３】詳しくは実施例で後述するように、かくし
て再分画処理することにより３種の化合物が単離され
る。単離される３種の化合物のうちで、第１の化合物の
物理化学的性質及び構造解析結果は下記の通りである。 （１）分子量：１４２（Ｃ7 Ｈ10Ｏ3 ） （２）赤外吸収スペクトル（cm-1) ：１０１６，１６５
１，１６９７，２８８１，２９２５，３３７１ （３）核磁気共鳴スペクトル（ 1Ｈ−ＮＭＲ，δ）：
２．１５（３Ｈ，Ｓ），２．３１（１Ｈ，ｄｄ，Ｊ＝１
８．４７，１．９８），２．８０（１Ｈ，ｄｄ，Ｊ＝１
８．４７，６．２７），４．３１（２Ｈ，Ｓ），４．７
２（１Ｈ，ｄｄ，Ｊ＝６．２７，１．９８） （４）核磁気共鳴スペクトル（13Ｃ−ＮＭＲ，δ）：１
３．６，４４．４，５４．９，７１．７，１３９．３，
１７１．５，２０６．４ （５）溶媒に対する溶解性：クロロホルム、アセトン、
酢酸エチル、メタノールに可溶、水に不溶 （６）塩基性、酸性、中性の区別：中性 （７）色および性状：無色油状As will be described in detail in Examples, three kinds of compounds are isolated by the re-fractionation treatment as described above. The physicochemical properties and structural analysis results of the first compound among the three kinds of isolated compounds are as follows. (1) Molecular weight: 142 (C 7 H 10 O 3 ) (2) Infrared absorption spectrum (cm −1 ): 1016, 165
1,1697,2881,925,3371 (3) Nuclear magnetic resonance spectrum ( 1 H-NMR, δ):
2.15 (3H, S), 2.31 (1H, dd, J = 1
8.47, 1.98), 2.80 (1H, dd, J = 1)
8.47, 6.27), 4.31 (2H, S), 4.7
2 (1H, dd, J = 6.27, 1.98) (4) Nuclear magnetic resonance spectrum ( 13 C-NMR, δ): 1
3.6, 44.4, 54.9, 71.7, 139.3
171.5, 206.4 (5) Solubility in solvent: chloroform, acetone,
Soluble in ethyl acetate and methanol, insoluble in water (6) Basic, acidic, neutral: neutral (7) Color and properties: colorless oil
【００１４】上記の物理化学的性質及び構造解析結果か
ら、単離される第１の化合物は式１で示されるシクロペ
ンテノン（cyclopentenone）誘導体であることが決定さ
れた。From the above physicochemical properties and structural analysis results, it was determined that the first compound to be isolated was the cyclopentenone derivative represented by the formula 1.
【００１５】また単離される３種の化合物のうちで、第
２の化合物の物理化学的性質及び構造解析結果は下記の
通りである。 （１）分子量：１４４（Ｃ7 Ｈ12Ｏ3 ） （２）赤外吸収スペクトル（cm-1）：１０１８，１１７
６，１７６１，２９３５，２９７４，３４６６ （３）核磁気共鳴スペクトル（ 1Ｈ−ＮＭＲ，δ）：
１．２１（３Ｈ，ｄ，Ｊ＝６．５９），１．３５（３
Ｈ，ｄ，Ｊ＝６．６０），２．１４（１Ｈ，ｄｄ，Ｊ＝
７．１０，１０．０５），２．４４（１Ｈ，ｄｄｄｑ，
Ｊ＝６．５９，８．５７，９．２４，１０．０５），
３．７６（１Ｈ，ｄｄ，Ｊ＝８．７４，９．２４），
３．９６（１Ｈ，ｄｑ，Ｊ＝６．６０，７．１０），
４．４２（１Ｈ，ｄｄ，Ｊ＝８．５７，８．７４） （４）核磁気共鳴スペクトル（13Ｃ−ＮＭＲ，δ）：１
７．２，２０．８，３３．１，５３．０，６７．５，７
３．０，１７９．１ （５）溶媒に対する溶解性：クロロホルム、アセトン、
酢酸エチル、メタノールに可溶、水に不溶 （６）塩基性、酸性、中性の区別：中性 （７）色および性状：無色油状The physicochemical properties and structural analysis results of the second compound among the three kinds of isolated compounds are as follows. (1) Molecular weight: 144 (C 7 H 12 O 3 ) (2) Infrared absorption spectrum (cm −1 ): 1018, 117
6,1761,2935, 2974,3466 (3) Nuclear magnetic resonance spectrum ( 1 H-NMR, δ):
1.21 (3H, d, J = 6.59), 1.35 (3
H, d, J = 6.60), 2.14 (1H, dd, J =
7.10, 10.05), 2.44 (1H, dddq,
J = 6.59, 8.57, 9.24, 10.05),
3.76 (1H, dd, J = 8.74, 9.24),
3.96 (1H, dq, J = 6.60, 7.10),
4.42 (1H, dd, J = 8.57, 8.74) (4) Nuclear magnetic resonance spectrum ( 13 C-NMR, δ): 1
7.2, 20.8, 33.1, 53.0, 67.5, 7
3.0, 179.1 (5) Solubility in solvent: chloroform, acetone,
Soluble in ethyl acetate and methanol, insoluble in water (6) Basic, acidic, neutral: neutral (7) Color and properties: colorless oil
【００１６】上記の物理化学的性質及び構造解析結果か
ら、単離される第２の化合物は式２で示されるγ−ラク
トン（γ−lactone ）誘導体であることが決定された。From the above physicochemical properties and structural analysis results, it was determined that the second compound isolated was the γ-lactone derivative represented by the formula 2.
【００１７】また単離される３種の化合物のうちで、第
３の化合物の物理化学的性質及び構造解析結果は下記の
通りである。 （１）分子量：１４４（Ｃ7 Ｈ12Ｏ3 ） （２）赤外吸収スペクトル（cm-1）：１０１６，１１８
６，１６７６，１７３６，２９２９，３４３５ （３）核磁気共鳴スペクトル（ 1Ｈ−ＮＭＲ，δ）：
１．２２（３Ｈ，ｄ，Ｊ＝７．２５），１．４０（３
Ｈ，ｄ，Ｊ＝６．６０），２．２９（１Ｈ，ｍ），２．
８４（１Ｈ，ｍ），３．６５（１Ｈ，ｄｄ，Ｊ＝６．９
３，１０．５５），４．５４（１Ｈ，ｍ），５．４４
（１Ｈ，ｄｄ，Ｊ＝５．４４，１０．５５） （４）核磁気共鳴スペクトル（13Ｃ−ＮＭＲ，δ）：１
０．０，２０．４，３５．６，４６．８，６０．７，７
７．５，１７９．４ （５）溶媒に対する溶解性：クロロホルム、アセトン、
酢酸エチル、メタノールに可溶、水に不溶 （６）塩基性、酸性、中性の区別：中性 （７）色および性状：無色油状The physicochemical properties and structural analysis results of the third compound among the three kinds of isolated compounds are as follows. (1) Molecular weight: 144 (C 7 H 12 O 3 ) (2) Infrared absorption spectrum (cm −1 ): 1016, 118
6,1676,1736,2929,3435 (3) Nuclear magnetic resonance spectrum ( 1 H-NMR, δ):
1.22 (3H, d, J = 7.25), 1.40 (3
H, d, J = 6.60), 2.29 (1H, m), 2.
84 (1H, m), 3.65 (1H, dd, J = 6.9
3, 10.55), 4.54 (1H, m), 5.44
(1H, dd, J = 5.44, 10.55) (4) Nuclear magnetic resonance spectrum ( 13 C-NMR, δ): 1
0.0, 20.4, 35.6, 46.8, 60.7, 7
7.5, 179.4 (5) Solubility in solvent: chloroform, acetone,
Soluble in ethyl acetate and methanol, insoluble in water (6) Basic, acidic, neutral: neutral (7) Color and properties: colorless oil
【００１８】上記の物理化学的性質及び構造解析結果か
ら、単離される第３の化合物は式３で示されるγ−ラク
トン（γ−lactone ）誘導体であることが決定された。From the above physicochemical properties and structural analysis results, it was determined that the third compound isolated was the γ-lactone derivative represented by the formula 3.
【００１９】詳しくは実施例で後述するように、本発明
のシクロペンテノン（cyclopentenone）誘導体及びγ−
ラクトン（γ−lactone ）誘導体は神経成長因子（ＮＧ
Ｆ）産生誘導効果があり、神経成長因子（ＮＧＦ）産生
誘導効果を有する化合物は痴呆症治療剤としての利用が
注目されている。As will be described later in detail in Examples, the cyclopentenone derivative of the present invention and γ-
Lactone (γ-lactone) derivatives are nerve growth factors (NG
F) Compounds having a production-inducing effect and a nerve growth factor (NGF) production-inducing effect have been attracting attention as therapeutic agents for dementia.
【００２０】[0020]
試験区分１ シクロペンテノン（cyclopentenone）誘導体及びγ−ラ
クトン（γ−lactone）誘導体の抽出および単離：ブナ
ハリタケの乾燥子実体４ｋｇをミキサーにて破砕後、８
５％エタノール水溶液２０リットルを加え、ホモジナイ
ズ処理し、これを室温で一夜放置した後、ろ過して抽出
液を得た。残渣に８５％エタノール水溶液２０リットル
を加え、同様に抽出処理を行なった。同様の抽出処理を
合計５回繰り返し、それぞれの抽出液と合わせた。そし
て合わせた抽出液を減圧下に４０〜４５℃で加熱してエ
タノールを蒸発することにより水層を得た。Test Category 1 Extraction and isolation of cyclopentenone derivative and γ-lactone derivative: 4 kg of dried fruit body of Bunaharitake mushroom was crushed with a mixer, then 8
After adding 20 liters of a 5% aqueous ethanol solution and homogenizing it, the mixture was allowed to stand overnight at room temperature and then filtered to obtain an extract. To the residue was added 20 liters of 85% ethanol aqueous solution, and the extraction treatment was performed in the same manner. The same extraction treatment was repeated a total of 5 times, and the extracts were combined. Then, the combined extracts were heated under reduced pressure at 40 to 45 ° C. to evaporate ethanol to obtain an aqueous layer.
【００２１】上記水層に酢酸エチル２リットルを加え、
振盪して放置した後、分層した酢酸エチル層を分取し
た。残渣に酢酸エチル２リットルを加え、同様に液−液
分配抽出処理を行なって酢酸エチル層を分取した。同様
の液−液分配抽出処理を合計３回繰り返し、それぞれの
酢酸エチル層を合わせた。合わせた酢酸エチル層を減圧
下に４０〜４５℃で加熱して酢酸エチルを蒸発し、更に
デシケータで乾燥して乾固物６．０１ｇを得た。2 l of ethyl acetate was added to the above aqueous layer,
After shaking and allowing to stand, the separated ethyl acetate layer was separated. Ethyl acetate (2 liters) was added to the residue, and liquid-liquid partition extraction treatment was performed in the same manner to separate the ethyl acetate layer. The same liquid-liquid partition extraction process was repeated three times in total, and the respective ethyl acetate layers were combined. The combined ethyl acetate layers were heated under reduced pressure at 40 to 45 ° C. to evaporate ethyl acetate, and further dried with a desiccator to obtain 6.01 g of a dry solid.
【００２２】上記乾固物をクロロホルムで溶解し、シリ
カゲルカラムクロマトグラフィーに供した（担体はワコ
ーゲルＣ−２００、商品名、和光純薬社製）。この際、
移動相として、順次極性が高くなるように、クロロホル
ムを１００ml、クロロホルム／アセトン＝９／１（容量
比）を２００ml，クロロホルム／アセトン＝７／３（容
量比）を３００ml、クロロホルム／メタノール＝９／１
（容量比）を３００mlの計４区分、合計９００ml用い、
各１００mlの画分を合計９画分（以下、ＢＭ９画分と言
う。）を得た。The above dried product was dissolved in chloroform and subjected to silica gel column chromatography (carrier is Wakogel C-200, trade name, manufactured by Wako Pure Chemical Industries, Ltd.). On this occasion,
As a mobile phase, 100 ml of chloroform, 200 ml of chloroform / acetone = 9/1 (volume ratio), 300 ml of chloroform / acetone = 7/3 (volume ratio), and chloroform / methanol = 9 / so that the polarities gradually increase. 1
(Volume ratio) 300ml total 4 divisions, total 900ml,
A total of 9 fractions (hereinafter referred to as BM9 fractions) were obtained from 100 ml fractions.
【００２３】上記ＢＭ９画分のうちの第７画分を更にシ
リカゲルカラムクロマトグラフィーに供した（担体はＫ
ｉｅｓｅｌｇｅｌ ６０、商品名、メルク社製）。この
際、移動相として、クロロホルム／メタノール＝９／１
（容量比）を１０００ml用い、各１００mlの画分を合計
１０画分を得た。このうちの第８画分を更に薄層クロマ
トクロマトグラフィーに供した（担体はＫｉｅｓｅｌｇ
ｅｌ ６０、商品名、メルク社製）。この際、展開溶媒
として、クロロホルム／メタノール＝８５／１５（容量
比）を用いて展開を行なった。このうちのＲｆ＝０．５
〜０．７より、式１に示されるシクロペンテノン（cycl
opentenone）誘導体を３４．９mg単離した。The seventh fraction of the BM9 fraction was further subjected to silica gel column chromatography (K was used as a carrier).
ieselgel 60, trade name, manufactured by Merck). At this time, as a mobile phase, chloroform / methanol = 9/1
(Volume ratio) of 1000 ml was used to obtain a total of 10 fractions of 100 ml fractions. The eighth fraction of these was further subjected to thin layer chromatography (the carrier was Kieselg).
el 60, trade name, manufactured by Merck). At this time, the development was performed using chloroform / methanol = 85/15 (volume ratio) as the developing solvent. Rf = 0.5 of these
From ~ 0.7, cyclopentenone (cycl
34.9 mg of the opentenone derivative was isolated.
【００２４】前記ＢＭ９画分のうちの第３画分を更にシ
リカゲルカラムクロマトグラフィーに供した（担体はＫ
ｉｅｓｅｌｇｅｌ ６０、商品名、メルク社製）。この
際、移動相として、クロロホルム／メタノール＝９／１
（容量比）を１４００ml用い、各２００mlの画分を合計
７画分を得た。このうちの第３画分を更に高速液体クロ
マトグラフィーに供した（担体はＹＭＣ Ｒ＆Ｄ Ｄ−
ＯＤＳ−５−Ａ、商品名、ワイエムシィ社製）。この
際、移動相として、アセトニトリルを１０００ml用い、
各２００mlの画分を合計５画分を得た。このうちの第２
画分より、式２に示されるγ−ラクトン（γ−lactone
）誘導体を５９．４mg単離した。The third fraction of the BM9 fraction was further subjected to silica gel column chromatography (the carrier was K.
ieselgel 60, trade name, manufactured by Merck). At this time, as a mobile phase, chloroform / methanol = 9/1
Using (volume ratio) of 1400 ml, 200 ml of each fraction was obtained in total of 7 fractions. The third fraction of these was further subjected to high performance liquid chromatography (the carrier was YMC R & D D-
ODS-5-A, trade name, manufactured by YMC Corporation). At this time, 1000 ml of acetonitrile was used as a mobile phase,
Fractions of 200 ml each gave a total of 5 fractions. The second of these
From the fractions, γ-lactone represented by Formula 2 (γ-lactone)
59.4 mg of the derivative was isolated.
【００２５】前記ＢＭ９画分のうちの第４画分を更にシ
リカゲルカラムクロマトグラフィーに供した（担体はＫ
ｉｅｓｅｌｇｅｌ ６０、商品名、メルク社製）。この
際、移動相として、クロロホルムを７００ml用い、各１
００mlの画分を合計７画分を得た。このうちの第６画分
及び第７画分を合わせて、シリカゲルカラムクロマトグ
ラフィーに供した（担体はワコーゲルＣ２００、商品
名、和光純薬社製）。この際、移動相として、順次極性
が高くなるように、ヘキサン／ベンゼン＝１／１，クロ
ロホルム、クロロホルム／アセトン＝９５／５（容量
比）の合計３区分を各３００ml用い、各１００mlの画分
を合計９画分を得た。このうちの第８画分より、式３に
示されるγ−ラクトン（γ−lactone ）誘導体を２０．
０mg単離した。The fourth fraction of the BM9 fraction was further subjected to silica gel column chromatography (the carrier was K.
ieselgel 60, trade name, manufactured by Merck). At this time, 700 ml of chloroform was used as the mobile phase, and 1
A total of 7 fractions were obtained from 00 ml fractions. The sixth and seventh fractions were combined and subjected to silica gel column chromatography (carrier is Wakogel C200, trade name, manufactured by Wako Pure Chemical Industries, Ltd.). At this time, as the mobile phase, 300 ml each of a total of three categories of hexane / benzene = 1/1, chloroform, and chloroform / acetone = 95/5 (volume ratio) were used so that the polarities of the fractions were 100 ml each. A total of 9 fractions were obtained. From the eighth fraction among these, 20-fold γ-lactone derivative represented by Formula 3 was obtained.
0 mg was isolated.
【００２６】試験区分２ シクロペンテノン（cyclopentenone）誘導体及びγ−ラ
クトン（γ−lactone）誘導体の神経成長因子（ＮＧ
Ｆ）産生誘導効果：古川らの方法｛バイオケミカル ア
ンド バイオフィジカル リサーチ コミュニケーショ
ンズ（Biochemical and Biophysical Research Communi
cations ），１３６，５７−６３（１９８６）｝にした
がい、胎生後期（１９日令）ラットの大脳皮質から調製
した初代アストログリア細胞を、１０％牛胎仔血清を含
むダルベッコ変法イーグル培地（ＤＭＥＭ）で無菌的に
培養した。培養は３日毎に培地を交換して、１〜２週間
行なった。コンフルエントに達したところで、培地を
０．５％牛血清アルブミンを含むＤＭＥＭに変え、更に
数日間培養し、培養ベースを得た。別に、試験区分１で
単離したシクロペンテノン（cyclopentenone）誘導体及
びγ−ラクトン（γ−lactone ）誘導体を各々、ジメチ
ルスルホキシドに溶解し、その溶液を０．５％牛血清ア
ルブミンを含むＤＭＥＭに変えたものを調整しておい
た。そしてこれらを上記培養ベースに投与して、合計３
区分の投与群を調製した。各投与群はシクロペンテノン
（cyclopentenone）誘導体及びγ−ラクトン（γ−lact
one ）誘導体の濃度が各々１ｍＭとなるようにした。比
較のためシクロペンテノン（cyclopentenone）誘導体又
はγ−ラクトン（γ−lactone）誘導体を溶解すること
なく、ジメチルスルホキシドだけを０．５％牛血清アル
ブミンを含むＤＭＥＭに加えたものを調製しておき、こ
れを上記培養ベースに投与して、対照群を調製した。合
計３区分の投与群と１区分の対照群とを２４時間培養し
た後、培養液を集め、古川らの方法｛ジャーナル オブ
ニューロケミストリー（Journal of Neurochemistry
），４０，７３４−７４４（１９８３）｝によるエン
ザイムアッセイ法で神経成長因子（ＮＧＦ）濃度を測定
した。シクロペンテノン（cyclopentenone）誘導体又は
γ−ラクトン（γ−lactone ）誘導体を投与しないで培
養した対照群とシクロペンテノン（cyclopentenone）誘
導体及びγ−ラクトン（γ−lactone ）誘導体を各々１
ｍＭ投与して培養した各投与群との間でｔ検定を行なっ
た。その結果、各投与群は１％の危険率で有効と有意に
検定された。Test Category 2 Cyclopentenone derivative and γ-lactone derivative nerve growth factor (NG)
F) Production-inducing effect: Furukawa's method {Biochemical and Biophysical Research Communi
cations), 136, 57-63 (1986)}, primary astroglial cells prepared from the cerebral cortex of late embryonic (19-day-old) rats were treated with Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum. It was cultivated aseptically. The culture was carried out for 1 to 2 weeks by changing the medium every 3 days. Upon reaching confluence, the medium was changed to DMEM containing 0.5% bovine serum albumin, and the cells were further cultured for several days to obtain a culture base. Separately, the cyclopentenone derivative and the γ-lactone derivative isolated in Test Category 1 were each dissolved in dimethyl sulfoxide, and the solution was changed to DMEM containing 0.5% bovine serum albumin. I adjusted things. And these were administered to the above-mentioned culture base, and a total of 3
Divided administration groups were prepared. Each administration group had a cyclopentenone derivative and γ-lactone (γ-lact).
The concentration of each one) derivative was adjusted to 1 mM. For comparison, a solution prepared by adding dimethyl sulfoxide alone to DMEM containing 0.5% bovine serum albumin without dissolving a cyclopentenone derivative or a γ-lactone derivative was prepared, This was administered to the above culture base to prepare a control group. After culturing a total of three groups of administration groups and one group of control groups for 24 hours, the culture solutions were collected and the method of Furukawa et al. {Journal of Neurochemistry was used.
), 40, 734-744 (1983)}, and the nerve growth factor (NGF) concentration was measured by the enzyme assay method. A control group, which was cultured without administration of a cyclopentenone derivative or a γ-lactone derivative, and a cyclopentenone derivative and a γ-lactone derivative each
A t-test was performed between each of the administration groups that were cultured by administration of mM. As a result, each administration group was significantly tested as effective at a risk rate of 1%.
【００２７】[0027]
【発明の効果】既に明らかなように、以上説明した本発
明のシクロペンテノン（cyclopentenone）誘導体及びγ
−ラクトン（γ−lactone ）誘導体には神経成長因子
（ＮＧＦ）産生誘導剤として有効という効果がある。As is apparent from the above, the cyclopentenone derivative of the present invention and the γ
-Lactone (γ-lactone) derivative is effective as a nerve growth factor (NGF) production inducer.
【化１】 Embedded image
【化２】 Embedded image
【化３】 Embedded image
───────────────────────────────────────────────────── フロントページの続き (72)発明者 石黒 幸雄 栃木県那須郡西那須野町東三島５丁目96番 地16 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yukio Ishiguro 5-96 16 Higashimishima, Nishinasuno-cho, Nasu-gun, Tochigi Prefecture
Claims (6)
（cyclopentenone）誘導体。 【式１】1. A cyclopentenone derivative represented by the following formula 1. (Equation 1)
−lactone ）誘導体。 【式２】2. A γ-lactone (γ represented by the following formula 2
-Lactone) derivative. (Equation 2)
−lactone ）誘導体。 【式３】3. A γ-lactone (γ represented by the following formula 3
-Lactone) derivative. (Equation 3)
opentenone）誘導体を有効成分とする神経成長因子（Ｎ
ＧＦ）産生誘導剤。4. The cyclopentenone according to claim 1.
Nerve growth factor (N) containing an opentenone derivative as an active ingredient
GF) production inducer.
one ）誘導体を有効成分とする神経成長因子（ＮＧＦ）
産生誘導剤。5. The γ-lactone (γ-lact according to claim 2)
nerve growth factor (NGF) containing one) derivative as an active ingredient
Production inducer.
one ）誘導体を有効成分とする神経成長因子（ＮＧＦ）
産生誘導剤。6. The γ-lactone (γ-lact according to claim 3)
nerve growth factor (NGF) containing one) derivative as an active ingredient
Production inducer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30377295A JP3741163B2 (en) | 1995-10-27 | 1995-10-27 | Nerve growth factor production inducer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30377295A JP3741163B2 (en) | 1995-10-27 | 1995-10-27 | Nerve growth factor production inducer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH09124541A true JPH09124541A (en) | 1997-05-13 |
| JP3741163B2 JP3741163B2 (en) | 2006-02-01 |
Family
ID=17925105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30377295A Expired - Fee Related JP3741163B2 (en) | 1995-10-27 | 1995-10-27 | Nerve growth factor production inducer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3741163B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002049661A1 (en) * | 2000-12-19 | 2002-06-27 | Kirin Beer Kabushiki Kaisha | Preventievs/remedies for diabetes and functional foods containing the same |
| JP2014073987A (en) * | 2012-10-04 | 2014-04-24 | Fromseeds Corp | Process of producing cyclopentenone derivative |
-
1995
- 1995-10-27 JP JP30377295A patent/JP3741163B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002049661A1 (en) * | 2000-12-19 | 2002-06-27 | Kirin Beer Kabushiki Kaisha | Preventievs/remedies for diabetes and functional foods containing the same |
| JP2014073987A (en) * | 2012-10-04 | 2014-04-24 | Fromseeds Corp | Process of producing cyclopentenone derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3741163B2 (en) | 2006-02-01 |
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