JPH0567157B2 - - Google Patents
Info
- Publication number
- JPH0567157B2 JPH0567157B2 JP62147017A JP14701787A JPH0567157B2 JP H0567157 B2 JPH0567157 B2 JP H0567157B2 JP 62147017 A JP62147017 A JP 62147017A JP 14701787 A JP14701787 A JP 14701787A JP H0567157 B2 JPH0567157 B2 JP H0567157B2
- Authority
- JP
- Japan
- Prior art keywords
- hydroxy
- trione
- pregnene
- progesterone
- prognene
- 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.)
- Expired - Lifetime
Links
Landscapes
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明は、排卵阻止作用等を有するプロゲステ
ロン誘導体を製造するための中間体として利用さ
れる新規物質、7β−ヒドロキシ−４−プレグネ
ン−３，15，20−トリオン及びその製造法に関す
る。
技術的背景
４−プレグネン−３，20−ジオンはプロゲステ
ロンと称せられる黄体ホルモンとして知られてお
り、その誘導体は、排卵阻止作用等を有すること
が知られている。
本発明者は、上記プロゲステロンを基質とし、
これに糸状菌であるアクレモニウム・ストリクタ
ム（Acremonium Strictum）を作用させること
により、上記生物学的活性を有する種々のプロゲ
ステロン誘導体を製造するための中間体として有
用な新規物質、7β−ヒドロキシ−４−プレグネ
ン−３，15，20−トリオンが得られることを見出
し、本発明をなすに至つた。
発明が解決しようとする課題
本発明は、排卵阻止作用等の生物学的活性を有
するプロゲステロン誘導体を製造するための中間
体として利用される7β−ヒドロキシ−４−プレ
グネン−３，15，20−トリオン及びその製造法を
提供することにある。
以下本発明を詳しく説明する。
発明の構成
本発明の特徴は、下記式()で示される新規物
質、7β−ヒドロキシ−４−プレグネン−３，15，
20−トリオンにある。
Industrial Application Field The present invention relates to a new substance, 7β-hydroxy-4-pregnene-3,15,20-trione, which is used as an intermediate for producing progesterone derivatives having ovulation-blocking effects, etc., and a method for producing the same. Regarding. Technical Background 4-Pregnene-3,20-dione is known as a progesterone called progesterone, and its derivatives are known to have ovulation inhibiting effects. The present inventor uses the above progesterone as a substrate,
By reacting this with the filamentous fungus Acremonium Strictum, a new substance, 7β-hydroxy-4- It was discovered that pregnene-3,15,20-trione can be obtained, and the present invention was completed. Problems to be Solved by the Invention The present invention relates to 7β-hydroxy-4-pregnene-3,15,20-trione, which is used as an intermediate for producing progesterone derivatives having biological activities such as ovulation-blocking activity. and its manufacturing method. The present invention will be explained in detail below. Structure of the Invention The present invention is characterized by a novel substance represented by the following formula (), 7β-hydroxy-4-pregnene-3,15,
20- Located in Trion.
【式】
上記式()で示される7β−ヒドロキシ−４−プ
レグネン−３，15，20−トリオンは、下記の理化
学的性状を有することにより特定される。
外 観 白色粉末
分子量 344
分子式 C21H28O4
融 点 254〜259℃
EIマススペクトル 第１図に示すとおり。
ｍ／ｚ＝344
プロトン核磁気共鳴吸収 第２図に示すとお
り。
13C−核磁気共鳴吸収スペクトル
第３図に示すとおり。
さらに、本発明は、プロゲステロン（４−プレ
グネン−３，20−ジオン）にアクレモニウム・ス
トリクタム（Acremonium Strictum）に属し、
プロゲステロンを7β−ヒドロキシ−４−プログ
ネン−３，15，20−トリオンに変換する能力を有
する菌株を作用させてプロゲステロンを7β−ヒ
ドロキシ−４−プログネン−３，15，20−トリオ
ンに変換させ、これを採取することを特徴とする
7β−ヒドロキシ−４−プログネン−３，15，20
−トリオンの製造法に関する。
課題を解決するための手段
上記式()で示される7β−ヒドロキシ−４−プ
レグネン−３，15，20−トリオンは下記方法によ
り得ることができる。
7β−ヒドロキシ−４−プレグネン−３，15，20
−トリオンの調製
アクレモニウム・ストリクタム
（Acremonium Strictum）NN106株（ハンガリ
ー国立衛生研究所保存株）微工研条寄等2716号
（微工研菌寄第9143号を国際寄託に変更）を、例
えば下記組成の培地に接種して振とう培養を行
う。
培地組成：
麦芽エキス 30(ｇ)
ペプトン 20
大豆粉 10
リン酸二水素カリウム ５
硫酸マグネシウム ５
精製水 1000ml
培養終了後、基質としてのプロゲステロンを一
定濃度になるようにジメチルホルムアミドに溶解
した液を、上記培養により得られた培養液に添加
して振とう培養させながら反応を行う。
反応終了後、得られた反応混合液から遠心分離
又は濾過により固形分及び菌体成分を除去し、得
られた上澄より酢酸エチルで抽出を行い、抽出液
から酢酸エチルを除去して粗製画分を得る。次い
で、この画分を少量のクロロホルム又はエタノー
ルに溶解し、シリカゲルカラムに通液してクロロ
ホルム：メタノール（98：２）で溶出、分取して
7β−ヒドロキシ−４−プレグネン−３，15，20
−トリオンを得る。
発明の効果
本発明に係る7β−ヒドロキシ−４−プレグネ
ン−３，15，20−トリオンは、マウス由来のMI
細胞に対して若干の分化誘導活性を示し、ホルモ
ン剤として有用である。
M1細胞に対する分化誘導活性
プロゲステロン −
7β−ヒドロキシ−４−プレグネン
−３，15，20−トリオン 50％
さらに、本発明の製造法によると、プロゲステ
ロン（４−プレグネン−３，20−ジオン）を２％
前後の高い収率で7β−ヒドロキシ−４−プログ
ネン−３，15，20−トリオンに変換することがで
きる。そして得られた化合物は、前記のように
M1細胞に対して分化誘導活性を持つのでホルモ
ン剤、化学試薬等として有用である。
さらに、この化合物は、排卵阻止作用等の種々
の生物学的活性を有するプロゲステロン誘導体製
造のための中間体となる。例えば、前記化合物
（）からジドロゲステロン、酢酸クロロマジン、
ベタメタゾンなどを製造することができ、この化
合物はホルモン剤として有用である。本発明の方
法によると前記化合物()を醗酵法により高い収
率で得ることができるので、この化合物を工業的
有利に製造することができる。
以下実施例により本物質の具体的な製造法を示
す。
実施例
7β−ヒドロキシ−４−プレグネン−３，15，
20−トリオンの製造
アクレモニウム・ストリクタムNN106株（寄
託番号微工研条寄第2716号）を、下記組成の培地
100mlを500ml容の三角フラスコに収容したものに
接種し、ロータリー式振とう培養機を用い、24℃
の温度で200rpmにて48時間培養を行つた。
麦芽エキス 30ｇ
ペプトン 20ｇ
大豆粉 10ｇ
リン酸二水素カリウム ５ｇ
硫酸マグネシウム ５ｇ
精製水 1000ml
得られた培養液に、基質としての４−プレグネ
ン−３，20−ジオンを0.1ｇ／mlの濃度になるよ
うにジメチルホルムアミドに溶解した液２mlを添
加し、上記同様の培養条件下に24〜48時間反応を
行つた。
反応終了後、培養液を遠心分離に付して固形分
及び菌体成分を除去し、得られた上澄からその1/
３容量の酢酸エチルを用いて３回抽出を行い、ロ
ータリーエバポレーターにて酢酸エチルを除去し
て粗製画分を得た。
次いで、この画分を少量のクロロホルム（又は
メタノール）で溶解し、シリカゲルカラム（20φ
×300mm）に通液し、クロロホルム：メタノール
（98：２）を用いて溶出、分取した。
分取した画分を結晶化させ、この化合物の理化
学的性質を測定したところ、前記〜の性質を
示し、7β−ヒドロキシ−４−プログネン−３，
15，20−トリオンであることが固定された。収率
は出発物質の４−プログネン−３，２−ジオンに
対して２％であつた。[Formula] 7β-hydroxy-4-pregnene-3,15,20-trione represented by the above formula () is specified by having the following physical and chemical properties. Appearance White powder Molecular weight 344 Molecular formula C 21 H 28 O 4 Melting point 254-259°C EI mass spectrum As shown in Figure 1. m/z=344 Proton nuclear magnetic resonance absorption As shown in Figure 2. 13 C-Nuclear Magnetic Resonance Absorption Spectrum As shown in Figure 3. Furthermore, the present invention relates to progesterone (4-pregnene-3,20-dione) belonging to Acremonium Strictum,
A bacterial strain capable of converting progesterone to 7β-hydroxy-4-prognene-3,15,20-trione is used to convert progesterone to 7β-hydroxy-4-prognene-3,15,20-trione, and this characterized by collecting
7β-hydroxy-4-prognene-3,15,20
-Relating to a method for producing trion. Means for Solving the Problems 7β-hydroxy-4-pregnene-3,15,20-trione represented by the above formula () can be obtained by the following method. 7β-hydroxy-4-pregnene-3,15,20
- Preparation of trione Acremonium Strictum strain NN106 (Hungarian National Institute of Health archived stock) FIKEN Co., Ltd. No. 2716 (FER. Co., Ltd. No. 9143 has been changed to international deposit) is prepared as follows, for example: Inoculate into a medium of the same composition and culture with shaking. Medium composition: Malt extract 30 (g) Peptone 20 Soybean flour 10 Potassium dihydrogen phosphate 5 Magnesium sulfate 5 Purified water 1000 ml After culturing, progesterone as a substrate was dissolved in dimethylformamide to a constant concentration and added to the above solution. It is added to the culture solution obtained by culturing and the reaction is carried out while culturing with shaking. After the reaction is complete, solids and bacterial components are removed from the resulting reaction mixture by centrifugation or filtration, and the resulting supernatant is extracted with ethyl acetate.Ethyl acetate is removed from the extract to obtain a crude fraction. get a minute Next, this fraction was dissolved in a small amount of chloroform or ethanol, passed through a silica gel column, eluted with chloroform:methanol (98:2), and fractionated.
7β-hydroxy-4-pregnene-3,15,20
- Obtain Trion. Effects of the Invention The 7β-hydroxy-4-pregnene-3,15,20-trione according to the present invention is derived from mouse-derived MI
It shows some differentiation-inducing activity in cells and is useful as a hormonal agent. Differentiation-inducing activity for M1 cells Progesterone - 50% 7β-hydroxy-4-pregnene-3,15,20-trione Furthermore, according to the production method of the present invention, progesterone (4-pregnene-3,20-dione) is added to 2%
It can be converted to 7β-hydroxy-4-prognene-3,15,20-trione with high yield. The resulting compound was then prepared as described above.
Since it has differentiation-inducing activity against M1 cells, it is useful as a hormone agent, chemical reagent, etc. Furthermore, this compound serves as an intermediate for the production of progesterone derivatives having various biological activities such as ovulation-blocking activity. For example, from the above compound (), dydrogesterone, chloromazine acetate,
Betamethasone and the like can be produced, and this compound is useful as a hormonal agent. According to the method of the present invention, the compound () can be obtained in a high yield by fermentation, and thus this compound can be industrially advantageously produced. A specific method for producing this substance will be shown below in Examples. Example 7 β-hydroxy-4-pregnene-3,15,
20-Production of trione Acremonium strictum NN106 strain (deposit number FEIKENJOKI No. 2716) was grown in a medium with the following composition.
Inoculate 100ml into a 500ml Erlenmeyer flask and incubate at 24℃ using a rotary shaking culture machine.
Culture was carried out for 48 hours at a temperature of 200 rpm. Malt extract 30g Peptone 20g Soy flour 10g Potassium dihydrogen phosphate 5g Magnesium sulfate 5g Purified water 1000ml Add 4-pregnene-3,20-dione as a substrate to the resulting culture solution to a concentration of 0.1g/ml. 2 ml of a solution dissolved in dimethylformamide was added, and the reaction was carried out for 24 to 48 hours under the same culture conditions as above. After the reaction is complete, the culture solution is centrifuged to remove solids and bacterial components, and 1/1/2 of the resulting supernatant is
Extraction was performed three times using 3 volumes of ethyl acetate, and the ethyl acetate was removed using a rotary evaporator to obtain a crude fraction. Next, this fraction was dissolved in a small amount of chloroform (or methanol) and applied to a silica gel column (20φ
x 300 mm), eluted using chloroform:methanol (98:2), and fractionated. When the separated fractions were crystallized and the physicochemical properties of this compound were measured, it showed the above-mentioned properties, 7β-hydroxy-4-prognene-3,
It was fixed to be 15,20-trion. The yield was 2% based on the starting material 4-prognene-3,2-dione.
第１図は、本物質のEIマススペクトルを、第
２図は、本物質のプロトン核磁気共鳴スペクトル
を第３図は本物質の13C−核磁気共鳴スペクトル
をそれぞれ示す。
FIG. 1 shows the EI mass spectrum of this substance, FIG. 2 shows the proton nuclear magnetic resonance spectrum of this substance, and FIG. 3 shows the 13 C-nuclear magnetic resonance spectrum of this substance.
Claims (1)
−プレグネン−３，15，20−トリオン 【式】 ２ プロゲステロンにアクレモニウム・ストリク
タム（Acremonium Strictum）に属し、プロゲ
ステロンを7β−ヒドロキシ−４−プログネン−
３，15，20−トリオンに変換する能力を有する菌
株を作用させてプロゲステロンを7β−ヒドロキ
シ−４−プログネン−３，15，20−トリオンに変
換させ、これを採取することを特徴とする7β−
ヒドロキシ−４−プログネン−３，15，20−トリ
オンの製造法[Claims] 1 7β-hydroxy-4 represented by the following formula
-Pregnene-3,15,20-trione [Formula] 2 Progesterone belongs to Acremonium Strictum, and progesterone is 7β-hydroxy-4-prognene-
7β-trione, which is characterized by converting progesterone into 7β-hydroxy-4-prognene-3,15,20-trione by using a bacterial strain capable of converting it into 3,15,20-trione, and collecting this.
Process for producing hydroxy-4-prognene-3,15,20-trione
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62147017A JPS63313798A (en) | 1987-06-15 | 1987-06-15 | Novel 7beta-hydroxy-4-pregnene-3,15,20-trione |
| US07/294,567 US5028722A (en) | 1987-02-06 | 1988-02-05 | Novel 7 β-hydroxy-4-pregnene-3,20-dione derivatives and method for preparing same |
| EP88901463A EP0301102B1 (en) | 1987-02-06 | 1988-02-05 | NOVEL 7$g(b)-HYDROXY-4-PREGNENE-3,20-DIONE DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
| PCT/JP1988/000115 WO1988005782A1 (en) | 1987-02-06 | 1988-02-05 | NOVEL 7beta-HYDROXY-4-PREGNENE-3,20-DIONE DERIVATIVES AND PROCESS FOR THEIR PREPARATION |
| AT88901463T ATE69236T1 (en) | 1987-02-06 | 1988-02-05 | NEW 7-G(B)-HYDROXY-4-PREGNEN-3,20-DIONE DERIVATIVES AND METHODS OF MANUFACTURE. |
| EP90201279A EP0391503B1 (en) | 1987-02-06 | 1988-02-05 | Preparation of 7 beta-hydroxy-4-pregnene-3,20-dione derivatives |
| DE3850260T DE3850260T2 (en) | 1987-02-06 | 1988-02-05 | Preparation of 7-beta-hydroxy-4-pregnen-3,20-dione derivatives. |
| DE8888901463T DE3866047D1 (en) | 1987-02-06 | 1988-02-05 | NEW 7-G (B) -HYDROXY-4-PREGNEN-3,20-DION DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. |
| AT90201279T ATE107363T1 (en) | 1987-02-06 | 1988-02-05 | PREPARATION OF 7-BETA-HYDROXY-4-PREGNEN-3,20-DIONE DERIVATIVES. |
| US07/397,376 US5098630A (en) | 1985-03-08 | 1989-08-21 | Method of molding a solid state image pickup device |
| US07/436,582 US5164302A (en) | 1987-02-06 | 1989-11-15 | Method for preparing 7β-hydroxy-4-pregnene-3,20-dione derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62147017A JPS63313798A (en) | 1987-06-15 | 1987-06-15 | Novel 7beta-hydroxy-4-pregnene-3,15,20-trione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63313798A JPS63313798A (en) | 1988-12-21 |
| JPH0567157B2 true JPH0567157B2 (en) | 1993-09-24 |
Family
ID=15420660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62147017A Granted JPS63313798A (en) | 1985-03-08 | 1987-06-15 | Novel 7beta-hydroxy-4-pregnene-3,15,20-trione |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63313798A (en) |
-
1987
- 1987-06-15 JP JP62147017A patent/JPS63313798A/en active Granted
Non-Patent Citations (1)
| Title |
|---|
| JOURNAL OF CHEMICAL ECOLOGY=1987 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63313798A (en) | 1988-12-21 |
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