JPH10287617A - New diterpenes and antivirus agent containing diterpenes as active ingredient - Google Patents
New diterpenes and antivirus agent containing diterpenes as active ingredientInfo
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- JPH10287617A JPH10287617A JP9098654A JP9865497A JPH10287617A JP H10287617 A JPH10287617 A JP H10287617A JP 9098654 A JP9098654 A JP 9098654A JP 9865497 A JP9865497 A JP 9865497A JP H10287617 A JPH10287617 A JP H10287617A
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は生薬の一種として使
用されている瑞香狼毒（Stellera chamaejasme)、フジ
モドキ(Daphne genkwa)又は芫花(フジモドキの花穂)よ
り得られた抗ウイルス作用（抗ＨＩＶ作用）を有する新
規ジテルペン類及びジテルペン類を有効成分とする抗ウ
イルス剤（抗ＨＩＶ剤）に関するものである。TECHNICAL FIELD The present invention relates to an antiviral effect (anti-HIV activity) obtained from Suzuka luma venom (Stellera chamaejasme), Fujimodoki (Daphne genkwa) or Cinnaflora (Fujimodoki spike) used as a kind of crude drug. ) And an antiviral agent (anti-HIV agent) containing the diterpene as an active ingredient.
【０００２】更に、本発明のジテルペン類は抗ウイルス
活性（抗ＨＩＶ活性）を有するのみならず、細胞毒性が
低く更に発癌プロモーター作用が低いことを特徴とする
化合物である。Furthermore, the diterpenes of the present invention are compounds having not only an antiviral activity (anti-HIV activity), but also a low cytotoxicity and a low carcinogenic promoter action.
【０００３】[0003]
【従来の技術】レトロウイルスの一種であるヒト後天性
免疫不全症ウイルス（ＨＩＶ）への感染を原因として発
症するエイズは、現在その治療薬の開発を目的とした研
究が世界中で進められている。抗エイズウイルス作用を
有する薬剤として現在臨床の場で医薬品として使用され
ている化合物には、ＡＺＴを代表とする核酸誘導体等が
存在するが、それらの化合物は非常に細胞毒性が強く且
つ効果も充分とは言えなかった。そこで、より強い抗エ
イズウイルス作用を有し且つ細胞毒性が低い薬剤の開発
が望まれている中、ホルボール誘導体が強い抗ＨＩＶ活
性と低い細胞毒性を有することが報告（特許公開平成７
年第６９８８１号）されている。2. Description of the Related Art AIDS, which is caused by infection with human acquired immunodeficiency virus (HIV), a kind of retrovirus, is currently being studied around the world for the development of a therapeutic drug therefor. I have. Among the compounds currently used as drugs having an anti-AIDS virus action in clinical practice, there are nucleic acid derivatives such as AZT, but these compounds are very cytotoxic and sufficiently effective. I couldn't say. Therefore, while the development of a drug having a stronger anti-AIDS virus action and lower cytotoxicity is desired, it has been reported that a phorbol derivative has strong anti-HIV activity and low cytotoxicity (Patent Publication 1995).
No. 69881).
【０００４】その他に、抗エイズウイルス作用を有する
化合物の探索において比較的安全性の高い天然物由来成
分の探索において瑞香狼毒より得られた抽出画分に強い
抗ＨＩＶ活性があること（特許公開平成８年第９２１１
８号）及び瑞香狼毒成分であるジテルペン類等が抗エイ
ズウイルス作用を有しており且つ細胞毒性が低い化合物
が存在すること（特許公開平成８年第３１０９９３号，
特許公開平成８年第３１１０５６号）も開示されてい
る。In addition, in the search for compounds having an anti-AIDS virus activity, in the search for relatively safe components derived from natural products, the extract fraction obtained from Mizuoka venom has a strong anti-HIV activity (Patent Publication) 1996 No. 9211
No. 8) and the presence of a compound having low cytotoxicity, such as diterpenes, which are the components of the mizuoka wolf venom, have an anti-AIDS virus effect (Patent Publication No. 1996309993,
(Patent Publication No. 1996-311056) is also disclosed.
【０００５】しかし、前述の特許公報中ではふれられて
いないが、該特許公報記載化合物も含めて、ホルボール
類が非常に強い発癌プロモーター作用を有している事が
多数文献報告されている。 なかでも特にテトラデカノ
イルホルボールアセテート（ＴＰＡ）は非常に強い発癌
プロモーター作用を有しており、発癌に関連する研究に
おいて、実際に発癌プロモーターとして使用されている
化合物である（特許公開平成６年第７２８８７号等）。
ここで問題となる発癌プロモーター作用とは、以下のよ
うなものである。[0005] However, although not mentioned in the above-mentioned patent publications, many literatures have reported that phorbols, including the compounds described in the patent publications, have a very strong tumor-promoting action. In particular, tetradecanoylphorbol acetate (TPA) has a very strong tumor-promoting activity, and is a compound that is actually used as a tumor-promoting promoter in studies related to carcinogenesis (Patent Publication 1994 No. 72887).
Here, the oncogenic promoter action that poses a problem is as follows.
【０００６】現在、発癌のメカニズムとして一般化しつ
つあるものに『発癌二段階説』がある。『発癌二段階
説』とは、正常細胞の癌化のステップの一端に「イニシ
エーター」と呼ばれる物質と「プロモーター」と呼ばれ
る物質が関係しており、発癌の機構としては［正常細胞
の癌化は{正常細胞の染色体がイニシエーターにより
ＤＮＡレベルでの障害を受け、潜在的腫瘍細胞に変化す
る。潜在的腫瘍細胞にプロモーターが作用して腫瘍細
胞に変化させる。}の２段階を経て起こるとされるもの
である。即ち、発癌プロモーター作用とは潜在的腫瘍細
胞を腫瘍細胞に変化させる作用をいうものである。前述
のイニシエーター作用を有する化合物として代表的なも
のは、ジメチルベンズアントラセン（ＤＭＢＡ）が挙げ
られ、プロモーター作用を有する化合物として代表的な
ものがＴＰＡである。At present, a "carcinogenesis two-stage theory" is being generalized as a mechanism of carcinogenesis. The two-stage theory of carcinogenesis involves a substance called an "initiator" and a substance called a "promoter" at one end of the step of normal cell carcinogenesis. {The chromosomes of normal cells are damaged at the DNA level by the initiator, turning them into potential tumor cells. The promoter acts on potential tumor cells to turn them into tumor cells. } Occurs in two stages. That is, the oncogenic promoter action refers to the action of converting a potential tumor cell into a tumor cell. A typical compound having the above-described initiator action is dimethylbenzanthracene (DMBA), and a typical compound having a promoter action is TPA.
【０００７】従って、発癌プロモーター作用を有してる
化合物であれば、その投与による発癌誘発の可能性が憂
慮され、医薬品として開発する上で非常な障害となるも
のである。[0007] Therefore, if a compound has a carcinogenesis promoter effect, there is concern about the possibility of inducing carcinogenesis by its administration, which is a serious obstacle to the development of a drug.
【０００８】[0008]
【発明が解決使用とする課題】即ち、本発明の目的は、
抗ＨＩＶ活性（抗ウイルス活性）を有し、しかも細胞毒
性が低く更に発癌プロモーター作用が低い、医薬品とし
て有用な抗ＨＩＶ剤（抗ウイルス剤）を創成することに
あった。That is, the object of the present invention is to
An object of the present invention is to create an anti-HIV agent (anti-viral agent) having anti-HIV activity (anti-viral activity), having low cytotoxicity and further having a low carcinogenesis promoter effect, which is useful as a pharmaceutical.
【０００９】[0009]
【課題を解決するための手段】本発明者らは、瑞香狼毒
だけでなくジンチョウゲ科ダフネ(DAPHNE)属植物中にも
強い抗ＨＩＶ作用を有する物質が存在する事を発見し、
化合物の単離精製を行ったところ、これらがホルボール
と類似骨格を有するジテルペンであることが判明し、該
化合物中に細胞毒性が低く且つ発癌プロモーター作用が
非常に低い化合物を見いだした。Means for Solving the Problems The present inventors have found that a substance having a strong anti-HIV activity exists not only in Mizuoka venom but also in plants of the genus Daphne (DAPHNE).
When the compounds were isolated and purified, they were found to be diterpenes having a skeleton similar to phorbol, and among these compounds, compounds having low cytotoxicity and extremely low carcinogenesis promoter activity were found.
【００１０】更に、ダフネ属植物より得られた既知であ
り抗ＨＩＶ作用を有しているが非常に強い発癌プロモー
ター作用を有している化合物の誘導体化を検討した結
果、該誘導体中にも優れた抗ＨＩＶ活性を有しており、
しかも細胞毒性も低く更に発癌プロモーター作用が低い
新規化合物が存在することが判明し、本発明に到達した
ものである。Furthermore, as a result of examining the derivatization of a compound obtained from a plant of the genus Daphne, which has a known anti-HIV activity but has a very strong tumor-promoting activity, it has been found that the derivative is superior among the derivatives. Has an anti-HIV activity,
In addition, it has been found that there is a novel compound having low cytotoxicity and further low oncogenic promoter action, and the present invention has been achieved.
【００１１】抗ＨＩＶ作用が抗ウイルス作用に基づくも
のであれば、該化合物は当然抗ウイルス剤としての使用
が可能であり、細胞毒性が低く且つ発癌プロモーター作
用が弱い化合物で有れば抗ウイルス剤としての医薬品と
しての使用が可能である。すなわち本発明は以下の通り
である。If the anti-HIV activity is based on the anti-viral effect, the compound can naturally be used as an anti-viral agent. If the compound has low cytotoxicity and a weak oncogenic promoter effect, the compound can be used as an anti-viral agent. It can be used as a pharmaceutical. That is, the present invention is as follows.
【００１２】(1)下記式１(1) Formula 1
【００１３】[0013]
【化９】 式１ ｛式中Ｒ1は-OCO(CH2)nCH3（n=1〜7)であり、Ｂｚはベ
ンゾイル基を示す。｝により示される新規ジテルペン
類。Embedded image Formula 1 wherein R 1 is —OCO (CH 2 ) n CH 3 (n = 1 to 7), and Bz represents a benzoyl group. New diterpenes represented by｝.
【００１４】(２)下記式２(2) Formula 2 below
【００１５】[0015]
【化１０】 式２ ｛式中Ｒ2は-CO(CH=CH)2(CH2)nCH3(n=1〜9)であり、Ｒ3
は水素原子又はアセトキシル基とする。但し、Ｒ2が-CO
(CH=CH)2(CH2)8CH3でありＲ3が水素原子である場合を除
く。｝により示される新規ジテルペン類。Embedded image Formula 2 {wherein R 2 is -CO (CH = CH) 2 ( CH 2) n CH 3 (n = 1~9), R 3
Represents a hydrogen atom or an acetoxyl group. Where R 2 is -CO
(CH = CH) 2 (CH 2 ) 8 Except when it is CH 3 and R 3 is a hydrogen atom. New diterpenes represented by｝.
【００１６】(３)下記式３(3) Formula 3 below
【００１７】[0017]
【化１１】 式３ ｛式中Ｒ4はアセチル基又はベンゾイル基を示し、Ｒ5は
-(CH2)6CH(OH)-又は-(CH2)7-を示し、Ｒ6はカルボニル
基又はベンゾイルオキシメチン基を示す。但し、Ｒ4が
ベンゾイル基であり、Ｒ5が-(CH2)6CH(OH)-であり、Ｒ6
がベンゾイルオキシメチン基である場合を除く。｝によ
り示される新規ジテルペン類。Embedded image Formula 3 wherein R 4 represents an acetyl group or a benzoyl group, and R 5 represents
— (CH 2 ) 6 CH (OH) — or — (CH 2 ) 7 —, and R 6 represents a carbonyl group or a benzoyloxymethine group. Provided that R 4 is a benzoyl group, R 5 is — (CH 2 ) 6 CH (OH) —, and R 6 is
Is a benzoyloxymethine group. New diterpenes represented by｝.
【００１８】(４)下記式４(4) Formula 4 below
【００１９】[0019]
【化１２】 式４ ｛式中Ｒ7は-CO(CH=CH)m1(CH2)n1CH3{m1=0〜2,n1=1〜4}
を示す。但し、Ｒ7が-CO(CH=CH)2(CH2)4CH3である場合
を除く。｝により示される新規ジテルペン類。Embedded image Formula 4 wherein R 7 is —CO (CH = CH) m 1 (CH 2 ) n 1 CH 3 {m 1 = 0 to 2, n 1 = 1 to 4}
Is shown. However, this excludes the case where R 7 is —CO (CH = CH) 2 (CH 2 ) 4 CH 3 . New diterpenes represented by｝.
【００２０】(５)下記式５(5) Formula 5
【００２１】[0021]
【化１３】 式５ ｛式中Ｒ8は、水素原子，水酸基，置換もしくは無置換
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ9は、置換もしくは無置換のフェニル
基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(CH=
CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示す。｝により
示される新規ジテルペン類。Embedded image Formula 5 wherein R 8 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 9 is a substituted or unsubstituted phenyl group, — (CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0 to 3, n 4 = 0 to 8} or-(CH =
CH) m 5 (CH 2) n 5 C 6 H 5 {m 5 = 0~3, n 5 = 0~8} indicating the. New diterpenes represented by｝.
【００２２】(６)下記式６(6) Formula 6
【００２３】[0023]
【化１４】 式６ ｛式中Ｒ10は、水素原子，水酸基，置換もしくは無置換
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ11は、置換もしくは無置換のフェニ
ル基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(C
H=CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示す。｝によ
り示される新規ジテルペン類。Embedded image Formula 6 wherein R 10 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 11 is a substituted or unsubstituted phenyl group,-(CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0-3, n 4 = 0- 8} or-(C
H = CH) m 5 (CH 2) n 5 C 6 H 5 {m 5 = 0~3, n 5 = 0~8} indicating the. New diterpenes represented by｝.
【００２４】(７)式１〜６に記載された新規ジテルペン
類及びその医薬的に可能な塩を有効成分とする抗ウイル
ス剤。 (８)式１〜６に記載された新規ジテルペン類及びその医
薬的に可能な塩を有効成分とする抗ＨＩＶ剤。 (９)発癌プロモーター活性がテトラデカノイルホルボー
ルアセテート（以下ＴＰＡと略す）の１０分の１以下で
あるジテルペン類及びその医薬的に可能な塩を有効成分
とする抗ＨＩＶ剤。(7) An antiviral agent comprising the novel diterpenes represented by the formulas (1) to (6) and a pharmaceutically acceptable salt thereof as an active ingredient. (8) An anti-HIV agent comprising the novel diterpenes represented by formulas 1 to 6 and a pharmaceutically acceptable salt thereof as an active ingredient. (9) An anti-HIV agent comprising a diterpene having a carcinogenesis promoter activity of 1/10 or less of tetradecanoylphorbol acetate (hereinafter abbreviated as TPA) and a pharmaceutically acceptable salt thereof as an active ingredient.
【００２５】(１０)下記式７(10) The following equation (7)
【００２６】[0026]
【化１５】 式７ ｛式中Ｒ12は、水素原子，水酸基，置換もしくは無置換
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ13は、置換もしくは無置換のフェニ
ル基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(C
H=CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示し、Ｒ14〜
Ｒ16は、水酸基，置換もしくは無置換のベンゾイルオキ
シ基，-OCO(CH=CH)m6(CH2)n6CH3{m6=0〜3,n6=0〜8}又は
-OCO(CH=CH)m7(CH2)n7C6H5{m7=0〜3,n7=0〜8}を示
す。｝により示されるジテルペン類及びその医薬的に可
能な塩を有効成分とする抗ウイルス剤。Embedded image Formula 7 wherein R 12 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 13 represents a substituted or unsubstituted phenyl group, — (CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0 to 3, n 4 = 0 to 8} or-(C
H = CH) m 5 (CH 2 ) n 5 C 6 H 5 {m 5 = 0 to 3, n 5 = 0 to 8}, and R 14 to
R 16 is a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 6 (CH 2 ) n 6 CH 3 {m 6 = 0-3, n 6 = 0-8} or
-OCO (CH = CH) m 7 (CH 2 ) n 7 C 6 H 5 {m 7 = 0 to 3, n 7 = 0 to 8}. An antiviral agent comprising, as an active ingredient, a diterpene represented by｝ and a pharmaceutically acceptable salt thereof.
【００２７】(１１)下記式８(11) Equation 8 below
【００２８】[0028]
【化１６】 式８ ｛式中Ｒ17は、水素原子，水酸基，置換もしくは無置換
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ18は、置換もしくは無置換のフェニ
ル基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(C
H=CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示し、Ｒ19〜
Ｒ22は、水酸基，置換もしくは無置換のベンゾイルオキ
シ基，-OCO(CH=CH)m6(CH2)n6CH3{m6=0〜3,n6=0〜8}又は
-OCO(CH=CH)m7(CH2)n7C6H5{m7=0〜3,n7=0〜8}を示
す。｝により示されるジテルペン類及びその医薬的に可
能な塩を有効成分とする抗ウイルス剤。Embedded image Formula 8 wherein R 17 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 18 represents a substituted or unsubstituted phenyl group, — (CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0 to 3, n 4 = 0 to 8} or-(C
H = CH) m 5 (CH 2 ) n 5 C 6 H 5 {m 5 = 0 to 3, n 5 = 0 to 8}, and R 19 to
R 22 represents a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 6 (CH 2 ) n 6 CH 3 {m 6 = 0-3, n 6 = 0-8} or
-OCO (CH = CH) m 7 (CH 2 ) n 7 C 6 H 5 {m 7 = 0 to 3, n 7 = 0 to 8}. An antiviral agent comprising, as an active ingredient, a diterpene represented by｝ and a pharmaceutically acceptable salt thereof.
【００２９】(１２)式７及び８記載のジテルペン類及び
その医薬的に可能な塩を有効成分とする抗ＨＩＶ剤。(12) An anti-HIV agent comprising, as an active ingredient, the diterpenes of the formulas 7 and 8 and pharmaceutically acceptable salts thereof.
【００３０】[0030]
【発明の実施の形態】本発明の化合物は、以下に示す製
法により製造されるが，その詳細な製造方法については
実施例に示す。瑞香狼毒又はジンチョウゲ科ダフネ属植
物の適量を常法により適当な大きさに切断又は粉砕等を
行った後、水，メタノール，エタノールその他の水性溶
媒若しくはエーテル，クロロホルム，酢酸エチルその他
の有機溶媒又はそれらの混合溶媒を用いて、震盪，超音
波，加熱等を行いながら抽出し、植物の細片又は粉末等
を濾過し抽出液を得る。BEST MODE FOR CARRYING OUT THE INVENTION The compounds of the present invention are produced by the following production methods, and the detailed production methods will be described in Examples. After cutting or pulverizing an appropriate amount of Mizuko venom or Daphne plant of the family Rhododendron to an appropriate size by a conventional method, water, methanol, ethanol or other aqueous solvent or ether, chloroform, ethyl acetate or other organic solvent or Using these mixed solvents, extraction is performed while shaking, sonication, heating, and the like, and plant fragments or powders are filtered to obtain an extract.
【００３１】得られた抽出液を減圧下乾固して得られた
エキス粉末を，溶出溶媒として水，メタノール，エタノ
ールその他の水性溶媒若しくはエーテル，クロロホル
ム，酢酸エチルその他の有機溶媒並びにそれらの適当な
割合の混合溶媒を用いて、シリカゲルカラムクロマトグ
ラフィー，高速液体クロマトグラフィー等に付して化合
物を精製し製造されるものである。又、前述の製法にお
いて製造された化合物を、常法にしたがって加水分解，
還元，アセトナイド化その他を行って製造されるもので
ある。The extract obtained is dried under reduced pressure, and the extract powder obtained is dried. Water, methanol, ethanol or other aqueous solvent or ether, chloroform, ethyl acetate or other organic solvent or an appropriate organic solvent thereof is used as an eluting solvent. The compound is produced by purifying the compound by silica gel column chromatography, high performance liquid chromatography or the like using a mixed solvent in a proportion. Further, the compound produced in the above-mentioned production method is hydrolyzed according to a conventional method,
It is produced by reduction, acetonidation, etc.
【００３２】本発明化合物を医薬として投与する場合、
本発明化合物はそのまま又は医薬的に許容される無毒性
かつ不活性の担体中に、例えば０．１％〜９９．５％、
好ましくは、０．５％〜９０％含有する医薬組成物とし
て、人を含む動物に投与される。担体としては、固形、
半固形、又は液状の希釈剤、充填剤、及びその他の処方
用の助剤一種以上が用いられる。When the compound of the present invention is administered as a medicament,
The compound of the present invention may be used as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.1% to 99.5%,
Preferably, it is administered to animals including humans as a pharmaceutical composition containing 0.5% to 90%. As a carrier, solid,
One or more semi-solid or liquid diluents, fillers and other formulation aids are used.
【００３３】抗ＨＩＶ剤又は抗ウイルス剤は、投与単位
形態で投与することが望ましい。本発明の抗ＨＩＶ剤又
は抗ウイルス剤は、静脈内投与、経口投与、組織内投
与、局所投与（点鼻、点眼投与等）又は経直腸的に投与
することができる。これらの投与方法に適した剤型で投
与されるのはもちろんである。なかでも経口投与が特に
好ましい。経口剤として初期の効果を発揮するために
は、患者の年齢，体重，疾患の程度等によっても異なる
が、通常成人で１日あたり、５ｎｇ〜５０００ｍｇの範
囲内、好ましくは１０ｎｇ〜１００ｍｇの範囲内の量を
数回に別けて服用することが適当であろうと考えられ
る。場合によっては、これ以下で充分であるし、また逆
にこれ以上の用量を必要とすることもある。The anti-HIV or anti-viral agent is desirably administered in a unit dosage form. The anti-HIV agent or anti-viral agent of the present invention can be administered intravenously, orally, intra-tissuely, locally (eg, by nasal or ophthalmic administration) or rectally. It is needless to say that the composition is administered in a dosage form suitable for these administration methods. Of these, oral administration is particularly preferred. In order to exert an initial effect as an oral preparation, it varies depending on the age, weight, degree of disease, etc. of the patient, but it is usually in the range of 5 ng to 5000 mg, preferably 10 ng to 100 mg per day for an adult. It may be appropriate to take several doses of the drug. In some cases, less is sufficient, and conversely, higher doses may be required.
【００３４】経口投与は固形又は液状の用量単位、例え
ば、散剤、錠剤、糖衣剤、カプセル剤、顆粒剤、懸濁
剤、液剤、シロップ剤、ドロップ剤、舌下錠その他の剤
型によって行うことができる。経口剤は、賦形剤として
例えばデンプン、乳糖、白糖、マンニット、カルボキシ
メチルセルロース、コーンスターチ、無機塩類等を用い
て常法に従って製造されるものである。この種の製剤に
は適宜前述の賦形剤の他に、結合剤，崩壊剤，界面活性
剤，滑沢剤，流動性促進剤，溶解遅延化剤，再吸収剤，
吸着剤，矯味剤，着色剤，香料等を使用する事が出来
る。それぞれの具体例は以下に示す如くである。For oral administration, solid or liquid dosage units, for example, powders, tablets, sugar coatings, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets and other dosage forms Can be. Oral preparations are those produced by conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like as excipients. In addition to the above-mentioned excipients, binders, disintegrants, surfactants, lubricants, fluidity enhancers, dissolution retardants, reabsorbents,
Adsorbents, flavoring agents, coloring agents, fragrances and the like can be used. Specific examples are as follows.
【００３５】［結合剤］デンプン，デキストリン，アラ
ビアゴム末，ゼラチン，ヒドロキシプロピルスターチ，
メチルセルロース，カルボキシメチルセルロース，ヒド
ロキシプロピルセルロース，結晶セルロース，エチルセ
ルロース，ポリビニルピロリドン，マクロゴール，ポリ
ビニルアルコール等。[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, polyvinyl alcohol and the like.
【００３６】［崩壊剤］デンプン，ヒドロキシプロピル
スターチ，カルボキシメチルセルロースナトリウム，カ
ルボキシメチルセルロースカルシウム，カルボキシメチ
ルセルロース，低置換ヒドロキシプロピルセルロース，
クロスカルメロースナトリウム、カルボキシスターチナ
トリウム、炭酸カルシウム、炭酸ナトリウム等。[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose,
Croscarmellose sodium, sodium carboxystarch, calcium carbonate, sodium carbonate and the like.
【００３７】［界面活性剤］ラウリル硫酸ナトリウム，
大豆レシチン，ショ糖脂肪酸エステル，ポリソルベート
８０等。[Surfactant] Sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80 and the like.
【００３８】［滑沢剤］タルク，ロウ類，水素添加植物
油，ショ糖脂肪酸エステル，ステアリン酸マグネシウ
ム，ステアリン酸カルシウム，ステアリン酸アルムニウ
ム，ポリエチレングリコール等。[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol and the like.
【００３９】［流動性促進剤］軽質無水ケイ酸，乾燥水
酸化アルミニウムゲル，合成ケイ酸アルミニウム，ケイ
酸マグネシウム等。[Fluidity accelerator] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like.
【００４０】［溶解遅延化剤］パラフィン，ワックス，
硬化ヒマシ油等。[Dissolution retarder] Paraffin, wax,
Hydrogenated castor oil and the like.
【００４１】［再吸収剤］四級塩等。[Reabsorbent] quaternary salts and the like.
【００４２】［吸着剤］ベントナイト、カオリン、リン
酸ジカルシウム等。[Adsorbent] Bentonite, kaolin, dicalcium phosphate and the like.
【００４３】また、本化合物は、懸濁剤，エマルジョン
剤，シロップ剤，エリキシル剤としても投与することが
でき、これらの各種剤形には、矯味矯臭剤，着色剤を含
有してもよい。The present compounds can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring and coloring agents.
【００４４】非経口剤として初期の効果を発揮するため
には、患者の年齢，体重，疾患の程度等によっても異な
るが、通常成人で１日あたり、０．５ｎｇ〜１００ｍｇ
までの静注、点滴静注、皮下注射、筋肉注射等が適当で
あると考えられる。In order to exhibit an initial effect as a parenteral preparation, it depends on the patient's age, weight, degree of disease and the like, but usually 0.5 ng to 100 mg per day for an adult.
Intravenous injection, intravenous drip injection, subcutaneous injection, intramuscular injection, etc. are considered appropriate.
【００４５】この非経口剤は常法に従って製造され、希
釈剤として一般に注射用蒸留水、生理食塩水、ブドウ糖
水溶液、注射用植物油、ゴマ油、ラッカセイ油、ダイズ
油、トウモロコシ油、プロピレングリコール、ポリエチ
レングリコール糖を用いることができる。更に必要に応
じて、殺菌剤、防腐剤、安定剤を加えてもよい。また、
この経口剤は安定性の点から、バイアル等に充填後冷凍
し、通常の凍結乾燥技術により水分を除去し、使用直前
に凍結乾燥物から液剤を再調製することもできる。さら
に、必要に応じて適宜、等張化剤、安定剤、防腐剤、無
痛化剤等を加えてもよい。This parenteral preparation is produced according to a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Sugar can be used. Further, if necessary, a bactericide, a preservative and a stabilizer may be added. Also,
From the viewpoint of stability, this oral preparation can be frozen after filling into a vial or the like, water can be removed by a usual freeze-drying technique, and a liquid preparation can be prepared again from the freeze-dried product immediately before use. Further, if necessary, an isotonic agent, a stabilizer, a preservative, a soothing agent and the like may be added as appropriate.
【００４６】その他の非経口剤としては、外用液剤軟膏
剤等の塗布剤直腸投与のための坐剤等が挙げられ、常法
に従って製造される。Other parenteral preparations include suppositories for rectal administration, such as topical solutions and ointments, which are manufactured according to a conventional method.
【００４７】[0047]
【実施例】以下に本発明に係る化合物の製造方法，試験
例及び製剤例を掲げて本発明をさらに詳しく説明する。The present invention will be described in more detail with reference to the production methods, test examples and preparation examples of the compounds according to the present invention.
【００４８】[製造方法] （１）瑞香狼毒からの新規ジテルペン類の製造 瑞香狼毒のメタノール抽出物をソックスレー抽出器を用
い石油エーテルを溶媒として抽出した。抽出物をシリカ
ゲルカラムクロマトグラフィーに付し、n-ヘキサン:酢
酸エチル＝1:1溶出分画（以降本分画を画分Ａと称
す。）2 gを得た。該分画をベンゼン:アセトン＝5:1を
溶出溶媒としたシリカゲルカラムクロマトグラフィーに
付し、2 つの画分（A-1；0.5 g，A-2；0.3g）を得た。[Production Method] (1) Production of New Diterpenes from Mizuoka Toxin A methanol extract of Mizuka washi was extracted with a Soxhlet extractor using petroleum ether as a solvent. The extract was subjected to silica gel column chromatography to obtain 2 g of a fraction eluted with n-hexane: ethyl acetate = 1: 1 (hereinafter, this fraction is referred to as fraction A). The fraction was subjected to silica gel column chromatography using benzene: acetone = 5: 1 as an elution solvent to obtain two fractions (A-1; 0.5 g, A-2; 0.3 g).
【００４９】A-1（0.5 g）を、C.I.G.カラム(草野科学
社製,2.2cmφ×30cm) を用いたクロマトグラフィー（溶
出溶媒；ベンゼン:アセトン＝7:1）に付した後、Sephad
ex LH-20 (ファルマシアバイオテク社製)を用いたカラ
ムクロマトグラフィー（溶出溶媒：クロロホルム:エタ
ノール=7:3）に付し，さらにＯＤＳカラム（株式会社ワ
イエムシー社製,YMCS-343,2.0cmφ×25cm）を用いた分
取高速液体クロマトグラフィー（溶媒：メタノール:水=
90:10，流量：5.0ml/min）に付し、下記式９で表される
化合物 17 mgを得た。A-1 (0.5 g) was subjected to chromatography (eluent: benzene: acetone = 7: 1) using a CIG column (Kusano Scientific Co., Ltd., 2.2 cmφ × 30 cm), followed by Sephad.
Ex LH-20 (manufactured by Pharmacia Biotech) was subjected to column chromatography (elution solvent: chloroform: ethanol = 7: 3), and an ODS column (YMCS-343, 2.0 cmφ × Preparative high-performance liquid chromatography (solvent: methanol: water =
90:10, flow rate: 5.0 ml / min) to obtain 17 mg of a compound represented by the following formula 9.
【００５０】A-2（266mg）を、C.I.G.カラムを用いたカ
ラムクロマトグラフィー（溶出溶媒;ベンゼン:アセトン
=7:3)に付した後、ＯＤＳカラムを用いた分取高速液体
クロマトグラフィー（溶媒;メタノール:水=90:10，流
量;5.0ml/min）に付し、下記式１０で示される化合物 7
mgを得た。A-2 (266 mg) was subjected to column chromatography using a CIG column (elution solvent: benzene: acetone)
= 7: 3), followed by preparative high-performance liquid chromatography using an ODS column (solvent; methanol: water = 90: 10, flow rate: 5.0 ml / min) to give a compound represented by the following formula 10: 7
mg was obtained.
【００５１】[0051]
【化１７】 式９Embedded image Equation 9
【００５２】以下に式９の化合物の物性データを示す。 性状:無色油状物. 旋光度[α]D 28 +12.9°(c=1.02,クロロホルム). 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε) :230(4.12),201
(4.22). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 :3370 br,1708.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：8.03 (2H,dt, J=7.4 and 1.3 Hz),7.61 (1H,dd,J=
2.4 and 1.4 Hz),7.57(2H,tt,J= 7.4 and 1.3 Hz),7.45
(2H,tt,J= 7.4 and 1.3 Hz),5.77(1H,br s),5.73 (1H,
br d,J= 5.6 Hz),5.67 (1H,d,J= 10.3 Hz),4.07 (1H,d,
J= 12.8 Hz),4.01 (1H,d,J= 12.8 Hz),3.34 (1H,dd,J=
5.6 and 5.3 Hz),3.29(1H,dd,J= 2.9 and 2.4 Hz),2.60
(1H,br d,J= 19.2 Hz),2.51 (1H,d,J= 19.2Hz),2.37
(2H,m),2.34 (1H,m),1.77 (3H,dd,J= 2.9 and 2.4 Hz),
1.65 (2H,m),1.39 (3H,s),1.35-1.25 (8H,m),1.21 (3H,
s),1.13 (1H,d,J= 5.3 Hz),0.95(3H,d,J= 6.5 Hz),0.88
(3H,t,J= 7.2 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：208.9 (s),176.5 (s),166.2 (s),160.8 (d),140.5
(s),133.0 (d),132.9(s),130.2 (s),129.7 (d),129.7
(d),129.2 (d),128.4 (d),128.4 (d),78.3(s),77.7
(d),73.7 (s),68.1 (t),65.5 (s),56.2 (d),43.4 (d),3
9.2 (d),38.7 (t),36.7 (d),34.4 (t),31.6 (t),29.0
(t),28.9 (t),26.0 (s),24.6(t),23.8 (q),22.6 (t),1
7.0 (q),14.5 (q),14.0 (q),10.1 (q). EI-MS m/z: 594(M+),473,328,310,127,105. HR-EI-MS m/z : 594.3176(M+). Calcd for C35H46O8:59
4.3193.The physical data of the compound of the formula 9 is shown below. Properties: colorless oil. Optical rotation [α] D 28 + 12.9 ° (c = 1.02, chloroform). Ultraviolet absorption spectrum UV λ max (methanol) nm (log ε): 230 (4.12), 201
(4.22). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3370 br, 1708. 1 H-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 500 MH
z) δ: 8.03 (2H, dt, J = 7.4 and 1.3 Hz), 7.61 (1H, dd, J =
2.4 and 1.4 Hz), 7.57 (2H, tt, J = 7.4 and 1.3 Hz), 7.45
(2H, tt, J = 7.4 and 1.3 Hz), 5.77 (1H, br s), 5.73 (1H,
br d, J = 5.6 Hz), 5.67 (1H, d, J = 10.3 Hz), 4.07 (1H, d,
J = 12.8 Hz), 4.01 (1H, d, J = 12.8 Hz), 3.34 (1H, dd, J =
5.6 and 5.3 Hz), 3.29 (1H, dd, J = 2.9 and 2.4 Hz), 2.60
(1H, br d, J = 19.2 Hz), 2.51 (1H, d, J = 19.2Hz), 2.37
(2H, m), 2.34 (1H, m), 1.77 (3H, dd, J = 2.9 and 2.4 Hz),
1.65 (2H, m), 1.39 (3H, s), 1.35-1.25 (8H, m), 1.21 (3H,
s), 1.13 (1H, d, J = 5.3 Hz), 0.95 (3H, d, J = 6.5 Hz), 0.88
(3H, t, J = 7.2 Hz). 13 C-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 208.9 (s), 176.5 (s), 166.2 (s), 160.8 (d), 140.5
(s), 133.0 (d), 132.9 (s), 130.2 (s), 129.7 (d), 129.7
(d), 129.2 (d), 128.4 (d), 128.4 (d), 78.3 (s), 77.7
(d), 73.7 (s), 68.1 (t), 65.5 (s), 56.2 (d), 43.4 (d), 3
9.2 (d), 38.7 (t), 36.7 (d), 34.4 (t), 31.6 (t), 29.0
(t), 28.9 (t), 26.0 (s), 24.6 (t), 23.8 (q), 22.6 (t), 1
7.0 (q), 14.5 (q), 14.0 (q), 10.1 (q) .EI-MS m / z: 594 (M + ), 473,328, 310, 127, 105.HR-EI-MS m / z: 594.3176 (M + ). Calcd for C 35 H 46 O 8 : 59
4.3193.
【００５３】[0053]
【化１８】 式１０Embedded image Equation 10
【００５４】以下に式１０の化合物の物性データを示
す。 性状:無色油状物. 旋光度[α]D 28 +10.6°(c=0.47, クロロホルム). 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε):262(4.58). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1: 3530 br,1725,1698,1
234.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：7.66 (1H,dd,J= 2.4 and 1.4 Hz),7.33 (1H,dd,J=
15.2 and 10.2 Hz),6.15 (2H,m),5.92 (1H,d,J= 5.4 H
z),5.88 (1H,d,J= 15.2 Hz),5.24 (1H,t,J= 0.6 Hz),5.
04 (1H,dd,J= 1.5 and 0.6 Hz),4.88 (1H,d,J= 2.8 H
z),4.28(1H, s),4.10 (1H,d,J= 5.4 Hz),3.99 (1H,br
s),3.90 (1H,d,J= 12.4 Hz),3.67 (1H,d,J= 12.4 Hz),
3.58 (1H,dd,J= 2.8 and 2.5 Hz),3.52 (1H,br s),3.25
(1H,s), 2.30 (1H,qd,J= 7.3 and 2.8 Hz),2.17 (2H,
m),1.99 (3H,s),1.86 (3H,dd,J= 1.5 and 0.6 Hz),1.80
(3H,dd,J= 2.8 and 1.4 Hz),1.42(2H, m),1.30-1.25
(12H,m),1.29 (3H,d,J= 7.3 Hz),0.88 (3H,t,J= 7.0 H
z).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：209.3 (s),170.1 (s),166.9 (s),160.0 (d),147.2
(d),146.4 (d),144.7(s),137.2 (s),128.2 (d),117.9
(d),114.8 (t),79.3 (d),75.6 (s),75.1 (s),72.7 (d),
72.4 (s),65.6 (t),62.5 (d),62.0 (s),50.8 (d),42.7
(d),39.9(d),33.1 (t),31.9 (t),29.53 (t),29.45 (t),
29.3 (t),29.2 (t),28.7 (t),22.7 (t),21.2 (q),19.6
(q),16.1 (q),14.1 (q),10.0 (q). Positive FAB-MS m/z : 661,643,207,81. HR-positive FAB-MS m/z : 661.3569.Calcd for C36H53
O11:661.3588.The physical data of the compound of the formula 10 is shown below. Properties: colorless oil. Optical rotation [α] D 28 + 10.6 ° (c = 0.47, chloroform). Ultraviolet absorption spectrum UV λ max (methanol) nm (log ε): 262 (4.58). Infrared absorption spectrum IR ν max (Chloroform) cm -1 : 3530 br, 1725,1698,1
234. 1 H- nuclear magnetic resonance spectrum (δ ppm in CDCl 3, 500 MH
z) δ: 7.66 (1H, dd, J = 2.4 and 1.4 Hz), 7.33 (1H, dd, J =
15.2 and 10.2 Hz), 6.15 (2H, m), 5.92 (1H, d, J = 5.4 H
z), 5.88 (1H, d, J = 15.2 Hz), 5.24 (1H, t, J = 0.6 Hz), 5.
04 (1H, dd, J = 1.5 and 0.6 Hz), 4.88 (1H, d, J = 2.8 H
z), 4.28 (1H, s), 4.10 (1H, d, J = 5.4 Hz), 3.99 (1H, br
s), 3.90 (1H, d, J = 12.4 Hz), 3.67 (1H, d, J = 12.4 Hz),
3.58 (1H, dd, J = 2.8 and 2.5 Hz), 3.52 (1H, br s), 3.25
(1H, s), 2.30 (1H, qd, J = 7.3 and 2.8 Hz), 2.17 (2H,
m), 1.99 (3H, s), 1.86 (3H, dd, J = 1.5 and 0.6 Hz), 1.80
(3H, dd, J = 2.8 and 1.4 Hz), 1.42 (2H, m), 1.30-1.25
(12H, m), 1.29 (3H, d, J = 7.3 Hz), 0.88 (3H, t, J = 7.0 H
z). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 209.3 (s), 170.1 (s), 166.9 (s), 160.0 (d), 147.2
(d), 146.4 (d), 144.7 (s), 137.2 (s), 128.2 (d), 117.9
(d), 114.8 (t), 79.3 (d), 75.6 (s), 75.1 (s), 72.7 (d),
72.4 (s), 65.6 (t), 62.5 (d), 62.0 (s), 50.8 (d), 42.7
(d), 39.9 (d), 33.1 (t), 31.9 (t), 29.53 (t), 29.45 (t),
29.3 (t), 29.2 (t), 28.7 (t), 22.7 (t), 21.2 (q), 19.6
(q), 16.1 (q), 14.1 (q), 10.0 (q) .Positive FAB-MS m / z: 661,643,207,81.HR-positive FAB-MS m / z: 661.3569.Calcd for C 36 H 53
O 11 : 661.3588.
【００５５】瑞香狼毒のエタノール抽出物を、n-ヘキサ
ン、酢酸エチル（4.0lx3）で抽出した。酢酸エチル抽出
物（200 g）をシリカゲルカラムクロマトグラフィーに
付し、n-ヘキサン:酢酸エチル=1:4溶出画分（38.2g）を
得た．これをシリカゲルカラムクロマトグラフィーに付
し、n-ヘキサン:アセトン=2:1溶出画分（以降本分画を
画分Ｂと称す；1.6g），n-ヘキサン:アセトン=1:1溶出
画分（以降本分画を画分Ｃと称す；2.1g）を得た。The ethanol extract of Mizuoka wolf venom was extracted with n-hexane and ethyl acetate (4.0 l × 3). The ethyl acetate extract (200 g) was subjected to silica gel column chromatography to obtain a fraction (38.2 g) eluted with n-hexane: ethyl acetate = 1: 4. This was subjected to silica gel column chromatography, and fractions eluted with n-hexane: acetone = 2: 1 (hereinafter, this fraction is referred to as fraction B; 1.6 g), fractions eluted with n-hexane: acetone = 1: 1 (Hereinafter, this fraction is referred to as fraction C; 2.1 g).
【００５６】画分Ｃ（1.9g）をn-ヘキサン:アセトンを
溶出溶媒としたシリカゲルカラムクロマトグラフィーに
繰り返し付した後、C.I.G.カラム(1.5 cmφ×30 cm)を
用いたカラムクロマトグラフィー（溶出溶媒；n-ヘキサ
ン:アセトン）に繰り返し付し、ジテルペン含有画分（1
50mg）を得た。これをＯＤＳカラムを用いた分取高速液
体クロマトグラフィー（溶媒;メタノール:水=90:10，ア
セトニトリル:水:テトラヒドロフラン=70:30:2，流量 :
3.0ml/min）に繰り返し付し、下記式１１で示される化
合物 12 mgを得た。The fraction C (1.9 g) was repeatedly subjected to silica gel column chromatography using n-hexane: acetone as an eluting solvent, and then column chromatography using a CIG column (1.5 cmφ × 30 cm) (eluting solvent; n-Hexane: acetone) repeatedly to obtain the diterpene-containing fraction (1
50 mg). This was subjected to preparative high performance liquid chromatography using an ODS column (solvent; methanol: water = 90: 10, acetonitrile: water: tetrahydrofuran = 70: 30: 2, flow rate:
3.0 ml / min) to obtain 12 mg of a compound represented by the following formula 11.
【００５７】画分Ｂ（1.6g）を、C.I.G.カラムを用いた
カラムクロマトグラフィー（溶出溶媒；n-ヘキサン:ア
セトン）に繰り返し付し、ジテルペン含有画分（570m
g）を得た。これをＯＤＳカラムを用いた分取高速液体
クロマトグラフィー（溶媒;メタノール:水=90:10，アセ
トニトリル:水=80:20，アセトニトリル:水=70:30，流量
:3.0ml/min）に繰り返し付し、下記式１２で示される
化合物 81 mg及び下記式１３で示される化合物 22 mgを
得た。The fraction B (1.6 g) was repeatedly subjected to column chromatography using a CIG column (elution solvent: n-hexane: acetone) to obtain a diterpene-containing fraction (570 m 2).
g) was obtained. This was subjected to preparative high performance liquid chromatography using an ODS column (solvent; methanol: water = 90: 10, acetonitrile: water = 80: 20, acetonitrile: water = 70: 30, flow rate
: 3.0 ml / min) to obtain 81 mg of a compound represented by the following formula 12 and 22 mg of a compound represented by the following formula 13.
【００５８】[0058]
【化１９】 式１１Embedded image Equation 11
【００５９】以下に式１１の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 28 + 4.8°(c=1.24,クロロホルム). 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε) :230(4.13),201
(4.25). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 :3540 br,1726,1692,1
286.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：8.18 (2H,dt,J= 7.5 and 1.3 Hz),7.61 (1H,tt,J=
7.5 and 1.3 Hz),7.47 (1H,tt,J= 7.5 and 1.3 Hz),5.1
4 (1H,dd,J= 1.5 and 0.8 Hz),4.94(1H,d,J= 4.8 Hz),
4.92 (1H,t,J= 1.5 Hz),4.88 (1H,dd,J= 10.6 and 2.5
Hz),4.35 (1H,d,J= 2.8 Hz),4.11 (1H,d,J= 10.6 Hz),
4.05 (1H,d,J= 2.6 Hz),3.93 (1H,br d,J= 2.6 Hz),3.8
4 (3H,m),3.34 (1H,d,J= 0.9 Hz),3.01 (1H,d,J= 2.8 H
z),2.96 (1H,d,J= 12.7 Hz),2.79 (1H,dd,J= 12.7 and
12.2 Hz),2.64 (1H,ddd,J= 10.6, 7.6, and 2.5 Hz),2.
29 (1H,m),2.20 (1H,d,J= 14.7Hz),2.10 (3H,q),1.90
(1H,dd,J= 14.7 and 7.5 Hz),1.82 (1H,m),1.79 (3H,d
d,J= 1.5 and 0.8 Hz),1.70-1.10 (12H,m),1.14 (3H,d,
J= 6.8 Hz),1.07 (3H,d,J= 7.5 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：170.9 (s),168.2 (s),145.6 (s),133.6 (d),130.2
(d),130.2 (d),129.5(s),128.6 (d),128.6 (d),118.5
(s),111.8 (t),84.3 (s),82.7 (d),81.4 (d),81.2 (s),
79.7 (s),73.6 (d),70.7 (d),67.1 (t),65.9 (t),63.6
(d),60.8(s),49.3 (d),48.0 (d),41.1 (d),37.4 (d),3
6.7 (d),29.4 (t),28.5 (t),27.3 (d),25.2 (t),24.0
(t),23.7 (t),23.0 (t),22.6 (t),21.2 (q),19.0(q),1
8.0 (q),14.6 (q). EI-MS m/z :712(M+), 105. HR-EI-MS m/z :712.3468(M+). Calcd for C39H52O12:71
2.3459.The physical properties data of the compound of the formula 11 are shown below. Properties: colorless oil. Optical rotation [α] D 28 + 4.8 ° (c = 1.24, chloroform). Ultraviolet absorption spectrum UV λ max (methanol) nm (log ε): 230 (4.13), 201
(4.25). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3540 br, 1726,1692,1
286. 1 H- nuclear magnetic resonance spectrum (δ ppm in CDCl 3, 500 MH
z) δ: 8.18 (2H, dt, J = 7.5 and 1.3 Hz), 7.61 (1H, tt, J =
7.5 and 1.3 Hz), 7.47 (1H, tt, J = 7.5 and 1.3 Hz), 5.1
4 (1H, dd, J = 1.5 and 0.8 Hz), 4.94 (1H, d, J = 4.8 Hz),
4.92 (1H, t, J = 1.5 Hz), 4.88 (1H, dd, J = 10.6 and 2.5
Hz), 4.35 (1H, d, J = 2.8 Hz), 4.11 (1H, d, J = 10.6 Hz),
4.05 (1H, d, J = 2.6 Hz), 3.93 (1H, br d, J = 2.6 Hz), 3.8
4 (3H, m), 3.34 (1H, d, J = 0.9 Hz), 3.01 (1H, d, J = 2.8 H
z), 2.96 (1H, d, J = 12.7 Hz), 2.79 (1H, dd, J = 12.7 and
12.2 Hz), 2.64 (1H, ddd, J = 10.6, 7.6, and 2.5 Hz), 2.
29 (1H, m), 2.20 (1H, d, J = 14.7Hz), 2.10 (3H, q), 1.90
(1H, dd, J = 14.7 and 7.5 Hz), 1.82 (1H, m), 1.79 (3H, d
d, J = 1.5 and 0.8 Hz), 1.70-1.10 (12H, m), 1.14 (3H, d,
J = 6.8 Hz), 1.07 (3H, d, J = 7.5 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 170.9 (s), 168.2 (s), 145.6 (s), 133.6 (d), 130.2
(d), 130.2 (d), 129.5 (s), 128.6 (d), 128.6 (d), 118.5
(s), 111.8 (t), 84.3 (s), 82.7 (d), 81.4 (d), 81.2 (s),
79.7 (s), 73.6 (d), 70.7 (d), 67.1 (t), 65.9 (t), 63.6
(d), 60.8 (s), 49.3 (d), 48.0 (d), 41.1 (d), 37.4 (d), 3
6.7 (d), 29.4 (t), 28.5 (t), 27.3 (d), 25.2 (t), 24.0
(t), 23.7 (t), 23.0 (t), 22.6 (t), 21.2 (q), 19.0 (q), 1
8.0 (q), 14.6 (q) .EI-MS m / z: 712 (M + ), 105.HR-EI-MS m / z: 712.3468 (M + ) .Calcd for C 39 H 52 O 12 : 71
2.3459.
【００６０】[0060]
【化２０】 式１２Embedded image Equation 12
【００６１】以下に式１２の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 28 +76.3°(c=0.97,クロロホルム) 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε) :229(4.05),201
(4.25). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 :3540 br,1740,1712.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：8.04 (2H,dt,J= 7.5 and 1.4 Hz),7.55 (1H,dt,J=
7.5 and 1.4 Hz),7.42(2H,dt,J= 7.5 and 1.4 Hz),5.04
(1H,dd,J= 1.5 and 0.9 Hz),4.92 (1H,t,J= 1.5 Hz),
4.88 (1H,d,J= 11.4 Hz),4.68 (1H,dd,J= 11.4 and 8.5
Hz),4.39(1H,d,J= 2.5 Hz),4.09 (1H,s),3.90 (1H,d,J
= 12.4 Hz),3.74 (1H,d,J= 12.4Hz),3.60 (1H,s),3.44
(1H,d,J= 0.6 Hz),3.39 (1H,d,J= 11.0 Hz),2.93 (1H,
d,J= 2.5 Hz),2.83 (1H,dd,J= 8.5 and 7.4 Hz),2.78
(1H,m),2.38 (1H,m),2.35 (1H,m),2.26 (1H,d,J= 14.5
Hz),2.15 (1H,dd,J= 14.5 and 7.4 Hz),2.05 (1H,dt,J=
14.0 and 8.5 Hz),1.81 (1H,dt,J= 14.0 and 5.0 Hz),
1.79(3H,br s),1.70-1.10 (12H,m),1.19 (3H,d,J= 6.1
Hz),0.90 (3H,d,J= 6.5Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：219.2 (s),166.6 (s),146.0 (s),132.9 (s),130.4
(d),129.6 (d),129.6(d),128.4 (d),128.4 (d),119.9
(s),111.3 (t),83.5 (s),82.6 (d),79.9 (s),75.9 (s),
71.2 (d),69.2 (t),65.4 (t),63.9 (d),61.3 (s),48.2
(d),43.0(d),42.5 (d),41.6 (d),38.1 (t),36.0 (d),3
3.5 (t),31.8 (t),29.9 (d),28.34 (t),28.27 (t),26.8
(t),24.6 (t),20.5 (t),18.8 (q),13.5 (q),12.4(q). EI-MS m/z :652(M+),621,105. HR-EI-MS m/z :652.3238(M+). Calcd for C37H48O10:65
2.3248.The physical data of the compound of the formula 12 is shown below. Properties: colorless oil. Optical rotation [α] D 28 + 76.3 ° (c = 0.97, chloroform) UV absorption spectrum UV λ max (methanol) nm (log ε): 229 (4.05), 201
. (4.25) Infrared absorption spectrum IR [nu max (chloroform) cm -1:. 3540 br, 1740,1712 1 H- nuclear magnetic resonance spectrum (δ ppm in CDCl 3, 500 MH
z) δ: 8.04 (2H, dt, J = 7.5 and 1.4 Hz), 7.55 (1H, dt, J =
7.5 and 1.4 Hz), 7.42 (2H, dt, J = 7.5 and 1.4 Hz), 5.04
(1H, dd, J = 1.5 and 0.9 Hz), 4.92 (1H, t, J = 1.5 Hz),
4.88 (1H, d, J = 11.4 Hz), 4.68 (1H, dd, J = 11.4 and 8.5
Hz), 4.39 (1H, d, J = 2.5 Hz), 4.09 (1H, s), 3.90 (1H, d, J
= 12.4 Hz), 3.74 (1H, d, J = 12.4Hz), 3.60 (1H, s), 3.44
(1H, d, J = 0.6 Hz), 3.39 (1H, d, J = 11.0 Hz), 2.93 (1H,
d, J = 2.5 Hz), 2.83 (1H, dd, J = 8.5 and 7.4 Hz), 2.78
(1H, m), 2.38 (1H, m), 2.35 (1H, m), 2.26 (1H, d, J = 14.5
Hz), 2.15 (1H, dd, J = 14.5 and 7.4 Hz), 2.05 (1H, dt, J =
14.0 and 8.5 Hz), 1.81 (1H, dt, J = 14.0 and 5.0 Hz),
1.79 (3H, br s), 1.70-1.10 (12H, m), 1.19 (3H, d, J = 6.1
Hz), 0.90 (3H, d, J = 6.5Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 219.2 (s), 166.6 (s), 146.0 (s), 132.9 (s), 130.4
(d), 129.6 (d), 129.6 (d), 128.4 (d), 128.4 (d), 119.9
(s), 111.3 (t), 83.5 (s), 82.6 (d), 79.9 (s), 75.9 (s),
71.2 (d), 69.2 (t), 65.4 (t), 63.9 (d), 61.3 (s), 48.2
(d), 43.0 (d), 42.5 (d), 41.6 (d), 38.1 (t), 36.0 (d), 3
3.5 (t), 31.8 (t), 29.9 (d), 28.34 (t), 28.27 (t), 26.8
(t), 24.6 (t), 20.5 (t), 18.8 (q), 13.5 (q), 12.4 (q) .EI-MS m / z: 652 (M + ), 621,105.HR-EI-MS m / z: 652.3238 (M + ) .Calcd for C 37 H 48 O 10 : 65
2.3248.
【００６２】[0062]
【化２１】 式１３Embedded image Equation 13
【００６３】以下に式１３の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 28 +9.5°(c=1.69, クロロホルム). 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε) : 253(4.14), 20
1(4.05). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 : 3460 br,1692 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：7.65 (1H,dd,J= 2.5 and 1.4 Hz),7.33 (1H,dd,J=
15.3 and 10.1 Hz),6.20 (2H,m),5.90 (1H,d,J= 15.3 H
z),5.67 (1H,dd,J= 2.6 and 1.4 Hz),5.13(1H,s),5.07
(1H,d,J= 1.4 Hz),4.25 (1H,d,J= 2.6 Hz),4.02 (1H,br
s),3.87(1H,d,J= 12.3 Hz),3.87 (1H,dd,J= 2.9 and
2.5 Hz),3.68 (1H,d,J= 12.3Hz),3.65 (1H,d,J= 2.3 H
z),3.16 (1H,s),2.18 (2H,m),2.12 (1H,m),1.92(1H,d,J
= 14.4 Hz),1.88 (3H,s),1.79 (1H,m),1.78 (3H,dd,J=
2.9 and 1.4Hz),1.43 (2H,m),1.33-1.25 (14H,m),1.05
(3H,d,J= 6.7 Hz),0.88 (3H,t,J= 7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：209.4 (s),167.4 (s),162.3 (d),147.3 (d),146.6
(d),145.9 (s),134.8(s),128.2 (d),117.8 (d),114.0
(t),77.8 (d),76.7 (s),74.1 (s),72.4 (s),70.8 (d),6
5.3 (t),63.6 (d),62.0 (s),50.0 (d),39.2 (d),37.8
(t),37.5(d),33.1 (t),31.9 (t),29.61 (t),29.57 (t),
29.4 (t),29.3 (t),29.2 (t),28.7 (t),22.7 (t),19.0
(q),18.2 (q),14.1 (q),9.8 (q). Positive FAB-MS m/z : 617,599,221. HR-positive FAB-MS m/z : 617.3686. Calcd for C35H
53O9 : 617.3690.The physical data of the compound of the formula 13 is shown below. Properties: colorless oil. Optical rotation [α] D 28 + 9.5 ° (c = 1.69, chloroform). Ultraviolet absorption spectrum UV λ max (methanol) nm (log ε): 253 (4.14), 20
1 (4.05). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3460 br, 1692 br. 1 H-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 500 MH
z) δ: 7.65 (1H, dd, J = 2.5 and 1.4 Hz), 7.33 (1H, dd, J =
15.3 and 10.1 Hz), 6.20 (2H, m), 5.90 (1H, d, J = 15.3 H
z), 5.67 (1H, dd, J = 2.6 and 1.4 Hz), 5.13 (1H, s), 5.07
(1H, d, J = 1.4 Hz), 4.25 (1H, d, J = 2.6 Hz), 4.02 (1H, br
s), 3.87 (1H, d, J = 12.3 Hz), 3.87 (1H, dd, J = 2.9 and
2.5 Hz), 3.68 (1H, d, J = 12.3Hz), 3.65 (1H, d, J = 2.3H
z), 3.16 (1H, s), 2.18 (2H, m), 2.12 (1H, m), 1.92 (1H, d, J
= 14.4 Hz), 1.88 (3H, s), 1.79 (1H, m), 1.78 (3H, dd, J =
2.9 and 1.4Hz), 1.43 (2H, m), 1.33-1.25 (14H, m), 1.05
(3H, d, J = 6.7 Hz), 0.88 (3H, t, J = 7.0 Hz). 13 C-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 209.4 (s), 167.4 (s), 162.3 (d), 147.3 (d), 146.6
(d), 145.9 (s), 134.8 (s), 128.2 (d), 117.8 (d), 114.0
(t), 77.8 (d), 76.7 (s), 74.1 (s), 72.4 (s), 70.8 (d), 6
5.3 (t), 63.6 (d), 62.0 (s), 50.0 (d), 39.2 (d), 37.8
(t), 37.5 (d), 33.1 (t), 31.9 (t), 29.61 (t), 29.57 (t),
29.4 (t), 29.3 (t), 29.2 (t), 28.7 (t), 22.7 (t), 19.0
(q), 18.2 (q), 14.1 (q), 9.8 (q) .Positive FAB-MS m / z: 617,599,221.HR-positive FAB-MS m / z: 617.3686.Calcd for C 35 H
53 O 9 : 617.3690.
【００６４】（２）フジモドキ根部からの新規ジテルペ
ンの製造 フジモドキ根部のメタノール抽出物を、酢酸エチルで抽
出した。酢酸エチル抽出物（15.0g）を、シリカゲルカ
ラムクロマトグラフィーに付し、ｎ‐ヘキサン:アセト
ン=2:1〜1:1溶出画分（0.7 g）を得、これをＯＤＳカラ
ム（ジーエルサイエンス社製，Inertsil ODS,2.0 cmφ
×25 cm）を用いた分取高速液体クロマトグラフィー
（溶媒;アセトニトリル:水=75:25，流量：4.0 ml/min）
に付し、下記式１４で表される化合物 23 mgを得た。(2) Production of New Diterpene from Roots of Mulberry The methanol extract of the roots of Mulberry was extracted with ethyl acetate. The ethyl acetate extract (15.0 g) was subjected to silica gel column chromatography to obtain a fraction (0.7 g) eluted with n-hexane: acetone = 2: 1 to 1: 1. This was separated into an ODS column (GL Science Co., Ltd.). , Inertsil ODS, 2.0 cmφ
Preparative high-performance liquid chromatography using x25 cm) (solvent; acetonitrile: water = 75: 25, flow rate: 4.0 ml / min)
Then, 23 mg of a compound represented by the following formula 14 was obtained.
【００６５】[0065]
【化２２】 式１４Embedded image Equation 14
【００６６】以下に下記式１４の化合物の物性データを
示す。 性状:無色油状物. 旋光度[α]D 25 +60.4°(c=1.06,クロロホルム). 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε) :232 (5.13). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 :3550 br, 1700 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：7.74 (2H,m),7.36 (1H,dd,J= 15.2 and 11.3 Hz),
7.35 (4H,m),6.59 (1H,dd,J= 15.0 and 10.7 Hz),6.24
(1H, dd,J= 15.3 and 11.3 Hz),6.16 (1H,dd,J= 15.3 a
nd 10.7 Hz),5.98 (1H,dd,J= 15.0 and 7.3 Hz),5.93
(1H,d,J= 15.2 Hz),5.04 (1H, dd,J= 1.5 and 0.8 Hz),
4.90 (1H,t, J= 1.5 Hz),4.69 (1H,d,J= 4.9 Hz),4.50
(1H,d,J= 2.8 Hz),4.05 (1H,s),3.86(1H,d,J= 12.4 H
z),3.78 (1H,d,J= 12.2 Hz),3.43 (1H,d,J= 1.0 Hz),2.
95 (1H,d,J= 2.8 Hz),2.81 (1H,dd,J= 13.0 and 5.5 H
z),2.47 (1H,dd,J= 8.0 and 6.9Hz),2.19 (1H,dd,J= 1
4.1 and 8.0 Hz),2.14 (2H,dt,J= 7.3 Hz),1.91 (1H,d
t,J= 10.5 and 5.5 Hz),1.80 (1H,m),1.82 (3H,dd,J=
1.5 and 0.8 Hz),1.77(1H,d,J= 14.1 Hz),1.70 (1H,dt,
J= 13.0 and 10.5 Hz),1.46 (2H,dt,J= 7.3Hz),1.32 (3
H,d,J= 6.4 Hz),1.04 (3H,d,J= 6.4 Hz),0.92 (3H,t,J=
7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：169.3 (s),146.9 (s),148.5 (d),142.7 (d),141.8
(d),136.2 (s),129.9(d),129.2 (d),128.0 (d),128.0
(d),127.4 (d),126.1 (d),126.1 (d),118.5(d),117.4
(s),111.2 (t), 84.3 (s),82.6 (d),82.0 (d),81.6
(s),80.3 (s),74.7 (d),66.1 (t),64.0 (d),60.4 (s),4
8.7 (d),36.4 (d),36.2 (t),36.1(d),35.8 (t),35.3
(d),35.1 (t),22.1 (t),20.9 (q),19.1 (q),13.7 (q),1
3.1 (q). EI-MS m/z (%) :648(M+),151,105,81. HR-EI-MS m/z :648.2935(M+). Calcd for C37H44O10:64
8.2935.The physical data of the compound of the following formula 14 is shown below. Properties: colorless oil. Optical rotation [α] D 25 + 60.4 ° (c = 1.06, chloroform). UV absorption spectrum UV λ max (methanol) nm (log ε): 232 (5.13). Infrared absorption spectrum IR ν max (Chloroform) cm -1 : 3550 br, 1700 br. 1 H-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 500 MH
z) δ: 7.74 (2H, m), 7.36 (1H, dd, J = 15.2 and 11.3 Hz),
7.35 (4H, m), 6.59 (1H, dd, J = 15.0 and 10.7 Hz), 6.24
(1H, dd, J = 15.3 and 11.3 Hz), 6.16 (1H, dd, J = 15.3 a
nd 10.7 Hz), 5.98 (1H, dd, J = 15.0 and 7.3 Hz), 5.93
(1H, d, J = 15.2 Hz), 5.04 (1H, dd, J = 1.5 and 0.8 Hz),
4.90 (1H, t, J = 1.5 Hz), 4.69 (1H, d, J = 4.9 Hz), 4.50
(1H, d, J = 2.8 Hz), 4.05 (1H, s), 3.86 (1H, d, J = 12.4 H
z), 3.78 (1H, d, J = 12.2 Hz), 3.43 (1H, d, J = 1.0 Hz), 2.
95 (1H, d, J = 2.8 Hz), 2.81 (1H, dd, J = 13.0 and 5.5 H
z), 2.47 (1H, dd, J = 8.0 and 6.9Hz), 2.19 (1H, dd, J = 1
4.1 and 8.0 Hz), 2.14 (2H, dt, J = 7.3 Hz), 1.91 (1H, d
t, J = 10.5 and 5.5 Hz), 1.80 (1H, m), 1.82 (3H, dd, J =
1.5 and 0.8 Hz), 1.77 (1H, d, J = 14.1 Hz), 1.70 (1H, dt,
J = 13.0 and 10.5 Hz), 1.46 (2H, dt, J = 7.3Hz), 1.32 (3
H, d, J = 6.4 Hz), 1.04 (3H, d, J = 6.4 Hz), 0.92 (3H, t, J =
7.0 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 169.3 (s), 146.9 (s), 148.5 (d), 142.7 (d), 141.8
(d), 136.2 (s), 129.9 (d), 129.2 (d), 128.0 (d), 128.0
(d), 127.4 (d), 126.1 (d), 126.1 (d), 118.5 (d), 117.4
(s), 111.2 (t), 84.3 (s), 82.6 (d), 82.0 (d), 81.6
(s), 80.3 (s), 74.7 (d), 66.1 (t), 64.0 (d), 60.4 (s), 4
8.7 (d), 36.4 (d), 36.2 (t), 36.1 (d), 35.8 (t), 35.3
(d), 35.1 (t), 22.1 (t), 20.9 (q), 19.1 (q), 13.7 (q), 1
. 3.1 (q) EI-MS m / z (%): 648 (M +), 151,105,81 HR-EI-MS m / z:. 648.2935 (M +) Calcd for C 37 H 44 O 10:. 64
8.2935.
【００６７】（３）ジテルペン化合物の新規誘導体の製
造 Ｈｕｒａｔｏｘｉｎの還元 [Huratoxin]15.4mgのエタノール(1.0ml)溶液に、アルゴ
ン気流下、水素化ホウ素ナトリウム(NaBH4) 1.4mgを加
え、0.5時間室温にて撹拌した。反応液を減圧下溶媒を
留去し、水を加えジエチルエーテルにて抽出した。抽出
液を硫酸ナトリウムにて乾燥後、減圧下溶媒を留去し、
残渣を得、これをシリカゲルカラムクロマトグラフィー
に付し、ｎ‐ヘキサン:アセトン=2:1溶出画分より下記
式１５で表される化合物 6.8 mgを得た。(3) Production of New Derivative of Diterpene Compound Reduction of Huratoxin To a solution of 15.4 mg of [Huratoxin] in 1.0 ml of ethanol was added 1.4 mg of sodium borohydride (NaBH 4 ) under a stream of argon, and the mixture was stirred at room temperature for 0.5 hour. And stirred. The solvent was distilled off from the reaction solution under reduced pressure, water was added, and the mixture was extracted with diethyl ether. After drying the extract over sodium sulfate, the solvent was distilled off under reduced pressure.
A residue was obtained and subjected to silica gel column chromatography to obtain 6.8 mg of a compound represented by the following formula 15 from a fraction eluted with n-hexane: acetone = 2: 1.
【００６８】[0068]
【化２３】 式１５Embedded image Equation 15
【００６９】以下に式１５の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 27 ＋7.3°(c=0.30,クロロホルム). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1: 3500 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ:6.67 (1H,dd,J= 15.5 and 10.5 Hz),6.03 (1H,dd,J=
15.5 and 10.5 Hz),5.82 (1H,dt,J= 15.5 and 7.0 H
z),5.68 (1H,d,J= 15.5 Hz),5.64 (1H,m),5.01 (1H,s),
4.88 (1H,s),4.42 (1H,s),4.38 (1H,d,J= 2.6 Hz),4.08
(1H,br s),4.01 (1H,d,J= 12.5 Hz),3.88 (1H,s),3.69
(1H,d,J= 12.5 Hz),3.46 (1H,br s),3.38 (1H,s),2.87
(1H,d,J= 2.6 Hz),2.43 (1H,m),2.21(1H,dd,J= 14.4 an
d 7.9 Hz),2.08 (2H,q,J= 7.0 Hz),1.79 (3H,s),1.73(3
H,s),1.65 (1H,d,J= 14.4 Hz),1.37 (2H,m),1.30-1.20
(12H,m),1.21(3H,d,J= 7.0 Hz),0.88 (3H,t,J= 7.0 H
z). Positive FAB-MS m/z :587,207,81. HR-EI-MS m/z :586.3511(M+). Calcd for C34H50O8:58
6.3506.The physical data of the compound of the formula 15 is shown below. Properties: colorless oil. Optical rotation [α] D 27 + 7.3 ° (c = 0.30, chloroform). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3500 br. 1 H-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 500 MH
z) δ: 6.67 (1H, dd, J = 15.5 and 10.5 Hz), 6.03 (1H, dd, J =
15.5 and 10.5 Hz), 5.82 (1H, dt, J = 15.5 and 7.0 H
z), 5.68 (1H, d, J = 15.5 Hz), 5.64 (1H, m), 5.01 (1H, s),
4.88 (1H, s), 4.42 (1H, s), 4.38 (1H, d, J = 2.6 Hz), 4.08
(1H, br s), 4.01 (1H, d, J = 12.5 Hz), 3.88 (1H, s), 3.69
(1H, d, J = 12.5 Hz), 3.46 (1H, br s), 3.38 (1H, s), 2.87
(1H, d, J = 2.6 Hz), 2.43 (1H, m), 2.21 (1H, dd, J = 14.4 an
d 7.9 Hz), 2.08 (2H, q, J = 7.0 Hz), 1.79 (3H, s), 1.73 (3
H, s), 1.65 (1H, d, J = 14.4 Hz), 1.37 (2H, m), 1.30-1.20
(12H, m), 1.21 (3H, d, J = 7.0 Hz), 0.88 (3H, t, J = 7.0 H
z) Positive FAB-MS m / z:.. 587,207,81 HR-EI-MS m / z: 586.3511 (M +) Calcd for C 34 H 50 O 8:. 58
6.3506.
【００７０】Ｓｕｂｔｏｘｉｎの還元 [Subtoxin] 9.0 mgのエタノール（1.0ml）溶液に、アル
ゴン気流下水素化ホウ素ナトリウム 0.7mgを加え、0.5
時間室温にて撹拌した。反応液を減圧下溶媒を留去し、
水を加えジエチルエーテルにて抽出した。抽出液を硫酸
ナトリウムにて乾燥後、減圧下溶媒を留去し、残渣を
得、これをシリカゲルカラムクロマトグラフィーに付
し，ｎ‐ヘキサン:アセトン=2:1溶出画分より下記式１
６で表される化合物 7.1 mgを得た。Reduction of Subtoxin [Subtoxin] To a solution of 9.0 mg of ethanol (1.0 ml) was added 0.7 mg of sodium borohydride under a stream of argon to give 0.5 mg of Subtoxin.
Stir at room temperature for hours. The solvent was distilled off from the reaction solution under reduced pressure,
Water was added and extracted with diethyl ether. After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography. From the eluted fraction of n-hexane: acetone = 2: 1, the following formula 1 was obtained.
7.1 mg of the compound represented by 6 was obtained.
【００７１】[0071]
【化２４】 式１６Embedded image Equation 16
【００７２】以下に式１６の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 27 -4.1°(c=0.39,クロロホルム). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1:3500 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ:6.64 (1H,dd,J= 15.5 and 10.7 Hz),6.02 (1H,dd,J=
15.2 and 10.7 Hz),5.82 (1H,dt,J= 15.2 and 7.0 H
z),5.62 (1H,d,J= 15.5 Hz),5.60 (1H,J= 3.5 and 1.5
Hz),4.99 (1H,dd,J= 1.5 and 0.8 Hz),4.98 (1H,s),4.9
4(1H,t,J= 0.8 Hz),4.70 (1H,d,J= 2.7 Hz),4.40 (1H,
s),4.09 (1H,br s),4.03(1H,d,J= 12.5 Hz),3.73 (1H,
d,J= 12.5 Hz),3.49 (1H,m),3.48 (1H,d,J= 0.9 Hz),3.
43 (1H,d,J= 2.7 Hz),2.33 (1H,q,J= 7.0 Hz),2.08 (2
H,q,J= 7.0 Hz),2.01 (3H,s),1.83 (3H,dd,J= 1.5 and
0.8 Hz),1.72 (3H,dt,J= 2.6 and 1.3 Hz),1.37 (2H,
m),1.35-1.25 (12H,m),1.32 (3H,d,J= 7.3 Hz),0.88 (3
H,t,J= 7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ:169.8 (s),143.5 (s),139.0 (d),136.1 (s),134.9
(d),128.8 (d), 127.5(d),122.7 (d),117.0 (s),113.0
(t),83.6 (d),83.3 (s),80.9 (d),79.3 (s),79.2 (s),7
8.4 (s),75.7 (d),65.4 (t),64.0 (d),61.2 (s),51.6
(d),44.1(d),35.7 (d),32.7 (t),31.9 (t),29.6 (t),2
9.5 (t),29.3 (t),29.14 (t),29.10 (t),22.7 (t),21,3
(q),19.0 (q),18.7 (q),14.1 (q),13.4 (q). EI-MS m/z : 644(M+),626,608,207,81,43. HR-EI-MS m/z : 644.3574(M+). Calcd for C36H52O10:6
44.3560.The physical data of the compound of the formula 16 is shown below. Properties: colorless oil. Optical rotation [α] D 27 -4.1 ° (c = 0.39, chloroform). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3500 br. 1 H-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 500 MH
z) δ: 6.64 (1H, dd, J = 15.5 and 10.7 Hz), 6.02 (1H, dd, J =
15.2 and 10.7 Hz), 5.82 (1H, dt, J = 15.2 and 7.0 H
z), 5.62 (1H, d, J = 15.5 Hz), 5.60 (1H, J = 3.5 and 1.5
Hz), 4.99 (1H, dd, J = 1.5 and 0.8 Hz), 4.98 (1H, s), 4.9
4 (1H, t, J = 0.8 Hz), 4.70 (1H, d, J = 2.7 Hz), 4.40 (1H,
s), 4.09 (1H, br s), 4.03 (1H, d, J = 12.5 Hz), 3.73 (1H, br
d, J = 12.5 Hz), 3.49 (1H, m), 3.48 (1H, d, J = 0.9 Hz), 3.
43 (1H, d, J = 2.7 Hz), 2.33 (1H, q, J = 7.0 Hz), 2.08 (2
H, q, J = 7.0 Hz), 2.01 (3H, s), 1.83 (3H, dd, J = 1.5 and
0.8 Hz), 1.72 (3H, dt, J = 2.6 and 1.3 Hz), 1.37 (2H,
m), 1.35-1.25 (12H, m), 1.32 (3H, d, J = 7.3 Hz), 0.88 (3
H, t, J = 7.0 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 169.8 (s), 143.5 (s), 139.0 (d), 136.1 (s), 134.9
(d), 128.8 (d), 127.5 (d), 122.7 (d), 117.0 (s), 113.0
(t), 83.6 (d), 83.3 (s), 80.9 (d), 79.3 (s), 79.2 (s), 7
8.4 (s), 75.7 (d), 65.4 (t), 64.0 (d), 61.2 (s), 51.6
(d), 44.1 (d), 35.7 (d), 32.7 (t), 31.9 (t), 29.6 (t), 2
9.5 (t), 29.3 (t), 29.14 (t), 29.10 (t), 22.7 (t), 21,3
(q), 19.0 (q), 18.7 (q), 14.1 (q), 13.4 (q) .EI-MS m / z: 644 (M + ), 626,608,207,81,43.HR-EI-MS m / z: 644.3574 (M + ) .Calcd for C 36 H 52 O 10 : 6
44.3560.
【００７３】Ｙｕａｎｈｕａｃｉｎｅの還元 「Yuanhuacine」 30.9mgのエタノール（2.0ml）溶液
に、アルゴン気流下水素化ホウ素ナトリウム 4.9 mgを
加え、1.5時間室温にて撹拌した。反応液を減圧下溶媒
を留去し、 水を加え酢酸エチルにて抽出した。抽出液
を硫酸ナトリウムにて乾燥後、減圧下溶媒を留去し、残
渣を得、これをC.I.G.カラムを用いたカラムクロマトグ
ラフィー（溶出溶媒；ｎ‐ヘキサン:アセトン=2:1）に
付し、下記式１７で表される化合物 22.9 mgを得た。Reduction of Yuanhuacine To a solution of 30.9 mg of “Yuanhuacine” in ethanol (2.0 ml) was added 4.9 mg of sodium borohydride under a stream of argon, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off from the reaction solution under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was subjected to column chromatography using a CIG column (elution solvent: n-hexane: acetone = 2: 1), 22.9 mg of a compound represented by the following formula 17 was obtained.
【００７４】[0074]
【化２５】 式１７Embedded image Equation 17
【００７５】以下に式１７の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 27 +26.3°(c=1.21,クロロホルム). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 : 3400 br,1710 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ :7.92 (2H,dt,J= 7.0 and 1.3Hz),7.56 (1H,tt,J=
7.0 and 1.3 Hz),7.43(2H,tt,J= 7.0 and 1.3 Hz),6.67
(1H,dd,J= 15.5 and 10.7 Hz),6.04 (1H,dd,J= 15.2 a
nd 10.7 Hz),5.84 (1H,dt,J= 15.2 and 7.0 Hz),5.65
(1H,d,J= 15.5 Hz),5.59 (1H,dd,J= 3.5 and 1.5 Hz),
5.22 (1H,s),4.99 (1H,t,J= 0.8 Hz),4.97 (1H,dd,J=
1.5 and 0.8 Hz),4.83 (1H,d,J= 2.6Hz),4.31(1H,s),4.
00 (1H,br s),3.98 (1H,d,J= 12.5 Hz),3.68 (1H,d,J=
12.5 Hz),3.54 (1H,d,J= 2.6 Hz),3.53 (1H,s),3.48 (1
H,m),2.50 (1H,q,J= 7.2 Hz),2.09 (2H,q,J= 7.0 Hz),
1.86 (3H,s),1.68 (3H,td,J= 2.6 and 1.3 Hz),1.40(3
H,d,J= 7.0 Hz),1.38 (2H,m),1.35〜1.25 (4H,m),0.88
(3H,t,J= 7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ:165.5 (s),143.3 (s),139.1 (d),136.3 (s),135.0
(d),133.2 (d),130.0(s),129.6 (d),128.7 (d),128.6
(d),127.3 (d),122.7 (d),117.1 (s),113.3(t),83.5
(s),83.3 (d),80.9 (d),79.8 (d),79.4 (s),78.3 (s),7
5.4 (d),65.2 (t),64.0 (d),61.4 (s),51.5 (d),44.2
(d),36.1 (d),32.7 (t),31.3(t),28.7 (t),22.5 (t),1
9.0 (q),18.8 (q),14.0 (q),13.4 (q). EI-MS m/z :650(M+),632,614,151,105,81. HR-EI-MS m/z :650.3092(M+).Calcd for C37H46O10 :65
0.3091.The physical data of the compound of the formula 17 are shown below. Properties: colorless oil. Optical rotation [α] D 27 + 26.3 ° (c = 1.21, chloroform). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3400 br, 1710 br. 1 H-nuclear magnetic resonance spectrum (Δ ppm in CDCl 3 , 500 MH
z) δ: 7.92 (2H, dt, J = 7.0 and 1.3Hz), 7.56 (1H, tt, J =
7.0 and 1.3 Hz), 7.43 (2H, tt, J = 7.0 and 1.3 Hz), 6.67
(1H, dd, J = 15.5 and 10.7 Hz), 6.04 (1H, dd, J = 15.2 a
nd 10.7 Hz), 5.84 (1H, dt, J = 15.2 and 7.0 Hz), 5.65
(1H, d, J = 15.5 Hz), 5.59 (1H, dd, J = 3.5 and 1.5 Hz),
5.22 (1H, s), 4.99 (1H, t, J = 0.8 Hz), 4.97 (1H, dd, J =
1.5 and 0.8 Hz), 4.83 (1H, d, J = 2.6Hz), 4.31 (1H, s), 4.
00 (1H, br s), 3.98 (1H, d, J = 12.5 Hz), 3.68 (1H, d, J =
12.5 Hz), 3.54 (1H, d, J = 2.6 Hz), 3.53 (1H, s), 3.48 (1
H, m), 2.50 (1H, q, J = 7.2 Hz), 2.09 (2H, q, J = 7.0 Hz),
1.86 (3H, s), 1.68 (3H, td, J = 2.6 and 1.3 Hz), 1.40 (3
(H, d, J = 7.0 Hz), 1.38 (2H, m), 1.35-1.25 (4H, m), 0.88
(3H, t, J = 7.0 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 165.5 (s), 143.3 (s), 139.1 (d), 136.3 (s), 135.0
(d), 133.2 (d), 130.0 (s), 129.6 (d), 128.7 (d), 128.6
(d), 127.3 (d), 122.7 (d), 117.1 (s), 113.3 (t), 83.5
(s), 83.3 (d), 80.9 (d), 79.8 (d), 79.4 (s), 78.3 (s), 7
5.4 (d), 65.2 (t), 64.0 (d), 61.4 (s), 51.5 (d), 44.2
(d), 36.1 (d), 32.7 (t), 31.3 (t), 28.7 (t), 22.5 (t), 1
9.0 (q), 18.8 (q), 14.0 (q), 13.4 (q) .EI-MS m / z: 650 (M + ), 632, 614, 151, 105, 81.HR-EI-MS m / z: 650.3092 (M + ) .Calcd for C 37 H 46 O 10 : 65
0.3091.
【００７６】Ｈｕｒａｔｏｘｉｎのアセトナイド化「 Huratoxin」 15.2 mgのアセトン（2.0ml）溶液にアルゴ
ン気流下、p-トルエンスルホン酸 5.1 mgを加え、一昼
夜室温にて撹拌した。反応液に水を加え酢酸エチルにて
抽出した。抽出液を硫酸ナトリウムにて乾燥後、減圧下
溶媒を留去し、残渣を得、これをシリカゲルカラムクロ
マトグラフィーに付し、ｎ‐ヘキサン:アセトン=8:1溶
出画分より下記式１８で表される化合物 8.5 mgを得
た。To a solution of 15.2 mg of Huratoxin in acetonide of "Huratoxin" (2.0 ml) was added 5.1 mg of p-toluenesulfonic acid under a stream of argon, followed by stirring at room temperature for 24 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography. 8.5 mg of the compound to be obtained were obtained.
【００７７】[0077]
【化２６】 Embedded image
【００７８】以下に式１８の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 27+59.0°(c=0.21,クロロホルム). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 : 3550 br,1710 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ:7.48 (1H,dd,J= 2.6 and 1.4Hz),6.69 (1H,dd,J= 1
5.5 and 10.6 Hz),6.06(1H,dd,J= 15.2 and 10.6Hz),5.
84 (1H,dt,J= 15.2 and 7.0Hz),5.70 (1H,d,J= 15.5H
z),5.01 (1H,dd,J =1.5 and 0.9Hz),4.90 (1H,t,J= 1.5
Hz),4.40(1H,d,J= 2.6 Hz),4.12 (1H,d,J= 0.8 Hz),3.
98 (1H,d,J= 12.5 Hz),3.82(1H,t,J= 2.6 Hz),3.68 (1
H,d,J= 12.5 Hz),3.39 (1H,d,J= 1.0 Hz),2.92(1H,d,J=
2.6 Hz),2.49 (1H,dd,J= 8.8 and 7.1 Hz),2.23 (1H,d
d,J= 14.4and 8.8 Hz),2.09 (2H,q,J= 7.0 Hz),1.79 (3
H,dd,J= 2.6 and 1.4Hz),1.78(3H,dd,J= 1.5 and 0.9 H
z),1.67 (1H,d,J= 14.4 Hz),1.46 (3H,s),1.45(3H,s),
1.38 (2H,m),1.35-1.25 (12H,m,),1.15 (3H,d,J= 7.1H
z),0.88 (3H,t,J= 7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ:205.7 (s),157.9 (d),146.3 (s),138.8 (d),136.9
(s),134.7 (d),128.8(d),122.9 (d),116.6 (s),111.2
(t),101.2 (s),84.4 (s),81.8 (d),79.5 (s),72.7 (s),
68.8 (d),65.6 (t),63.7 (d,),59.1 (s),48.1 (d),36.8
(d),36.4(t),34.8 (d),32.7 (t),31.9 (t),29.6 (t),2
9.5 (t),29.3 (t),29.2 (t),29.1 (t),24.6 (q),22.7
(t),22.5 (q),20.3 (q),19.0 (q),14.1 (q),10.1(q). EI-MS m/z (%) :624(M+),207,81. HR-EI-MS m/z :624.3659(M+). Calcd for C37H52O8:62
4.3662.The physical data of the compound of the formula 18 are shown below. Properties: colorless oil. Optical rotation [α] D 27 + 59.0 ° (c = 0.21, chloroform). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3550 br, 1710 br. 1 H-nuclear magnetic resonance spectrum (Δ ppm in CDCl 3 , 500 MH
z) δ: 7.48 (1H, dd, J = 2.6 and 1.4Hz), 6.69 (1H, dd, J = 1
5.5 and 10.6 Hz), 6.06 (1H, dd, J = 15.2 and 10.6Hz), 5.
84 (1H, dt, J = 15.2 and 7.0Hz), 5.70 (1H, d, J = 15.5H
z), 5.01 (1H, dd, J = 1.5 and 0.9Hz), 4.90 (1H, t, J = 1.5
Hz), 4.40 (1H, d, J = 2.6 Hz), 4.12 (1H, d, J = 0.8 Hz), 3.
98 (1H, d, J = 12.5 Hz), 3.82 (1H, t, J = 2.6 Hz), 3.68 (1
H, d, J = 12.5 Hz), 3.39 (1H, d, J = 1.0 Hz), 2.92 (1H, d, J =
2.6 Hz), 2.49 (1H, dd, J = 8.8 and 7.1 Hz), 2.23 (1H, d
d, J = 14.4and 8.8 Hz), 2.09 (2H, q, J = 7.0 Hz), 1.79 (3
H, dd, J = 2.6 and 1.4Hz), 1.78 (3H, dd, J = 1.5 and 0.9H
z), 1.67 (1H, d, J = 14.4 Hz), 1.46 (3H, s), 1.45 (3H, s),
1.38 (2H, m), 1.35-1.25 (12H, m,), 1.15 (3H, d, J = 7.1H
z), 0.88 (3H, t, J = 7.0 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 205.7 (s), 157.9 (d), 146.3 (s), 138.8 (d), 136.9
(s), 134.7 (d), 128.8 (d), 122.9 (d), 116.6 (s), 111.2
(t), 101.2 (s), 84.4 (s), 81.8 (d), 79.5 (s), 72.7 (s),
68.8 (d), 65.6 (t), 63.7 (d,), 59.1 (s), 48.1 (d), 36.8
(d), 36.4 (t), 34.8 (d), 32.7 (t), 31.9 (t), 29.6 (t), 2
9.5 (t), 29.3 (t), 29.2 (t), 29.1 (t), 24.6 (q), 22.7
(t), 22.5 (q), 20.3 (q), 19.0 (q), 14.1 (q), 10.1 (q) .EI-MS m / z (%): 624 (M + ), 207,81.HR -EI-MS m / z: 624.3659 (M + ) .Calcd for C 37 H 52 O 8 : 62
4.3662.
【００７９】Ｓｉｍｐｌｅｘｉｎのアセトナイド化「 Simplexin」 10.1 mgのアセトン（2.0ml）溶液にアルゴ
ン気流下p-トルエンスルホン酸 3.6 mgを加え、一昼夜
室温にて撹拌した。反応液に水を加え酢酸エチルにて抽
出した。抽出液を硫酸ナトリウムにて乾燥後、減圧下溶
媒を留去し、残渣を得、これをシリカゲルカラムクロマ
トグラフィーに付し、ｎ‐ヘキサン:アセトン=8:1溶出
画分より、下記式１９で表される化合物 8.5 mgを得
た。3.6 mg of p-toluenesulfonic acid was added to a solution of 10.1 mg of Simplexin in acetone (2.0 ml) under a stream of argon, followed by stirring at room temperature for 24 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography. From the elution fraction of n-hexane: acetone = 8: 1, the following formula 19 was obtained. 8.5 mg of the compound represented were obtained.
【００８０】[0080]
【化２７】 Embedded image
【００８１】以下に式１９の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 27 +60.6°(c=0.34,クロロホルム). 赤外線吸収スペクトル IR ν max (クロロホルム) cm-1 :3550 br,1710 br.1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ:7.45 (1H,dd,J= 2.6 and 1.4 Hz),5.01 (1H,dd,J=
1.5 and 0.8 Hz),4.88(1H,t,J= 1.5 Hz),4.33 (1H,d,J=
2.6 Hz),4.12 (1H,d,J= 0.8 Hz),3.99 (1H,d,J= 12.9
Hz),3.76 (1H,dd,J= 2.7 and 2.6 Hz),3.58 (1H,d,J= 1
2.9Hz),3.36 (1H,s),2.87 (1H,d,J=2.6Hz),2.45 (1H,d
d,J= 8.6 and 7.1 Hz),2.20(1H,dd,J= 14.3 and 8.8 H
z),1.93 (2H,m),1.78 (3H,dd,J =2.7 and 1.4 Hz),1.77
(3H,dd,J= 1.5 and 0.8 Hz),1.63 (1H,d,J=14.3 Hz),
1.60 (2H,m),1.46 and 1.45 (each 3H,s),1.35-1.25 (1
0H,m),1.12 (3H,d,J= 7.1Hz),0.88(3H,t,J= 7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ:205.8 (s),158.0 (d),146.5 (s),136.8 (s),119.5
(s),111.1 (t),101.0(s),84.1 (s),81.6 (d),78.6 (s),
72.7 (s),68.8 (d),65.6 (t),63.8 (d),59.2 (s),48.2
(d),36.8 (d),36.4 (t),34.9 (t),34.8 (d),31.9 (t),2
9.7(t),29.6 (t),29.5 (t),29.3 (t),24.5 (q),23.5
(t),22.7 (t),22.5(q),20.2 (q),19.0 (q),14.1 (q),1
0.1 (q). EI-MS m/z :572(M+),43. HR-EI-MS m/z :572.3327(M+).Calcd for C32H48O8:572.
3349.The physical data of the compound of the formula 19 are shown below. Properties: colorless oil. Optical rotation [α] D 27 + 60.6 ° (c = 0.34, chloroform). Infrared absorption spectrum IR ν max (chloroform) cm -1 : 3550 br, 1710 br. 1 H-nuclear magnetic resonance spectrum (Δ ppm in CDCl 3 , 500 MH
z) δ: 7.45 (1H, dd, J = 2.6 and 1.4 Hz), 5.01 (1H, dd, J =
1.5 and 0.8 Hz), 4.88 (1H, t, J = 1.5 Hz), 4.33 (1H, d, J =
2.6 Hz), 4.12 (1H, d, J = 0.8 Hz), 3.99 (1H, d, J = 12.9
Hz), 3.76 (1H, dd, J = 2.7 and 2.6 Hz), 3.58 (1H, d, J = 1
2.9Hz), 3.36 (1H, s), 2.87 (1H, d, J = 2.6Hz), 2.45 (1H, d
d, J = 8.6 and 7.1 Hz), 2.20 (1H, dd, J = 14.3 and 8.8 H
z), 1.93 (2H, m), 1.78 (3H, dd, J = 2.7 and 1.4 Hz), 1.77
(3H, dd, J = 1.5 and 0.8 Hz), 1.63 (1H, d, J = 14.3 Hz),
1.60 (2H, m), 1.46 and 1.45 (each 3H, s), 1.35-1.25 (1
0H, m), 1.12 (3H, d, J = 7.1 Hz), 0.88 (3H, t, J = 7.0 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 205.8 (s), 158.0 (d), 146.5 (s), 136.8 (s), 119.5
(s), 111.1 (t), 101.0 (s), 84.1 (s), 81.6 (d), 78.6 (s),
72.7 (s), 68.8 (d), 65.6 (t), 63.8 (d), 59.2 (s), 48.2
(d), 36.8 (d), 36.4 (t), 34.9 (t), 34.8 (d), 31.9 (t), 2
9.7 (t), 29.6 (t), 29.5 (t), 29.3 (t), 24.5 (q), 23.5
(t), 22.7 (t), 22.5 (q), 20.2 (q), 19.0 (q), 14.1 (q), 1
0.1 (q) EI-MS m / z:. 572 (M +), 43 HR-EI-MS m / z:. 572.3327 (M +) .Calcd for C 32 H 48 O 8: 572.
3349.
【００８２】Ｙｕａｎｈｕａｃｉｎｅの加水分解 「Yuanhuacine」（13.2mg，0.020mmol）のメタノール
（1.0ml）溶液に、0.1M ナトリウムメトキシド(NaOMe)
のメタノール溶液（2.0ml）を加え、室温下一昼夜撹拌
した。氷冷下、水， 5%塩酸を加え、酢酸エチルにて抽
出した。抽出液を硫酸ナトリウムにて乾燥後、減圧下溶
媒を留去し、残渣を得、これをC.I.G.カラムを用いたカ
ラムクロマトグラフィー（溶出溶媒；ｎ‐ヘキサン:ア
セトン=4:1）に付し、下記式２０で表される化合物 7.1
mgを得た。Hydrolysis of Yuanhuacine 0.1 M sodium methoxide (NaOMe) was added to a solution of “Yuanhuacine” (13.2 mg, 0.020 mmol) in methanol (1.0 ml).
Methanol solution (2.0 ml) was added, and the mixture was stirred at room temperature for 24 hours. Under ice cooling, water and 5% hydrochloric acid were added, and the mixture was extracted with ethyl acetate. After the extract was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue, which was subjected to column chromatography using a CIG column (elution solvent: n-hexane: acetone = 4: 1), Compound represented by the following formula 20 7.1
mg was obtained.
【００８３】[0083]
【化２８】 式２０Embedded image Equation 20
【００８４】以下に式２０の化合物の物性データを示
す。 性状：無色油状物. 旋光度[α]D 27 +16.7°(c=1.15,メタノール). 赤外線吸収スペクトル IR ν max (KBr) cm-1 : 3450 br,1692,1658. 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε) : 231(4.47),200
(4.41).1 H-核磁気共鳴スペクトル（δ ppm in CDCl3, 500 MH
z） δ：7.59 (1H,dd,J= 2.6 and 1.4 Hz),6.64 (1H,dd,J=
15.5 and 10.6 Hz),6.04 (1H,dd,J= 15.5 and 10.8 H
z),5.84 (1H,dd,J= 14.2 and 7.0 Hz),5.64(1H, d,J=1
5.5 Hz),5.10(2H,m),4.72 (1H,d,J= 2.6 Hz),4.24 (1H,
d,J= 2.7Hz),4.07 (1H,d,J=2.7 Hz),3.98 (1H,br s),
3.90 (1H,d,J= 12.4 Hz),3.83(1H,dd,J= 2.8 and 2.6 H
z),3.77 (1H,d,J= 12.4 Hz),3.74 (1H,d,J= 2.6 Hz),3.
53 (1H,d,J= 0.9 Hz),2.49 (1H,q,J= 7.3 Hz),2.09 (2
H,dt,J= 7.0 Hz),1.87 (3H,dd,J= 2.8 and 1.4 Hz),1.8
0 (3H,dd,J= 2.8 and 1.4 Hz),1.38(2H,dt,J= 7.0 Hz),
1.33-1.25 (4H,m),1.22 (3H,d,J= 7.3 Hz),0.88 (3H,t,
J= 7.0 Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：209.8 (s),160.8(d),144.9 (s),139.1 (d),136.7
(d),134.9 (d),128.7(d),122.8 (d),116.8 (s),112.6
(d),85.1 (s),80.7 (d),78.5 (s),77.3 (d),72.4 (s),7
2.1 (d),65.0 (t),64.4 (d),60.5 (s),47.7 (d),44.9
(d),34.9(d),32.7 (t),31.3 (t),28.8 (t),22.5 (t),1
8.9 (q),18.7 (q),14.0 (q),9.9(q). EI-MS m/z : 544(M+),151,81. HR-EI-MS m/z : 544.2671(M+). Calcd for C30H40O9 :5
44.2672.The physical properties data of the compound of the formula 20 are shown below. Properties: colorless oil. Optical rotation [α] D 27 + 16.7 ° (c = 1.15, methanol). Infrared absorption spectrum IR ν max (KBr) cm -1 : 3450 br, 1692,1658. Ultraviolet absorption spectrum UV λ max (Methanol) nm (log ε): 231 (4.47), 200
(4.41). 1 H-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 500 MH
z) δ: 7.59 (1H, dd, J = 2.6 and 1.4 Hz), 6.64 (1H, dd, J =
15.5 and 10.6 Hz), 6.04 (1H, dd, J = 15.5 and 10.8 H
z), 5.84 (1H, dd, J = 14.2 and 7.0 Hz), 5.64 (1H, d, J = 1
5.5 Hz), 5.10 (2H, m), 4.72 (1H, d, J = 2.6 Hz), 4.24 (1H,
d, J = 2.7Hz), 4.07 (1H, d, J = 2.7 Hz), 3.98 (1H, br s),
3.90 (1H, d, J = 12.4 Hz), 3.83 (1H, dd, J = 2.8 and 2.6 H
z), 3.77 (1H, d, J = 12.4 Hz), 3.74 (1H, d, J = 2.6 Hz), 3.
53 (1H, d, J = 0.9 Hz), 2.49 (1H, q, J = 7.3 Hz), 2.09 (2
H, dt, J = 7.0 Hz), 1.87 (3H, dd, J = 2.8 and 1.4 Hz), 1.8
0 (3H, dd, J = 2.8 and 1.4 Hz), 1.38 (2H, dt, J = 7.0 Hz),
1.33-1.25 (4H, m), 1.22 (3H, d, J = 7.3 Hz), 0.88 (3H, t,
J = 7.0 Hz). 13 C-NMR spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 209.8 (s), 160.8 (d), 144.9 (s), 139.1 (d), 136.7
(d), 134.9 (d), 128.7 (d), 122.8 (d), 116.8 (s), 112.6
(d), 85.1 (s), 80.7 (d), 78.5 (s), 77.3 (d), 72.4 (s), 7
2.1 (d), 65.0 (t), 64.4 (d), 60.5 (s), 47.7 (d), 44.9
(d), 34.9 (d), 32.7 (t), 31.3 (t), 28.8 (t), 22.5 (t), 1
8.9 (q), 18.7 (q), 14.0 (q), 9.9 (q) .EI-MS m / z: 544 (M + ), 151, 81.HR-EI-MS m / z: 544.2671 (M + ). Calcd for C 30 H 40 O 9 : 5
44.2672.
【００８５】「Wisktroemia factor M1」の加水分解 「Wisktroemia factor M1」（23.2mg）に、0.1M ナトリ
ウムメトキシドのメタノール溶液（1.0ml）を加え、室
温下 0.5 時間撹拌した。氷冷下、水（5ml）を加え、
酢酸エチルにて抽出した．酢酸エチル可溶部を硫酸ナト
リウムにて乾燥後、減圧下溶媒留去し、残渣を得、これ
をシリカゲルカラムクロマトグラフィーに付し、ｎ‐ヘ
キサン:アセトン=1:1溶出画分より、下記式２１で表さ
れる化合物 16.2 mgを得た。[0085] the hydrolysis of the "Wisktroemia factor M 1", "Wisktroemia factor M 1" (23.2 mg), 0.1 M sodium methoxide in methanol solution (1.0 ml) was added, the mixture was stirred at room temperature for 0.5 hours. Under ice cooling, add water (5 ml)
Extracted with ethyl acetate. After the ethyl acetate-soluble portion was dried over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue.The residue was subjected to silica gel column chromatography.From the elution fraction of n-hexane: acetone = 1: 1, the following formula was obtained. 16.2 mg of the compound represented by 21 were obtained.
【００８６】[0086]
【化２９】 Embedded image
【００８７】以下に下記式２１の化合物の物性データを
示す。 性状:無色油状物. 旋光度[α]D 27 +0.6°(c=1.32,メタノール). 赤外線吸収スペクトル IR ν max (KBr) cm-1 : 3400 br. 紫外線吸収スペクトル UV λ max (メタノール) nm (log ε): 263(3.38),228
sh(3.67),203(4.18)1H-核磁気共鳴スペクトル（δ ppm
in CDCl3, 500 MHz） δ：7.74 (2H, m),7.35 (3H, m),5.06 (1H,dd,J= 1.4 a
nd 0.8 Hz),4.92 (1H,t,J= 1.4 Hz),4.50 (1H,d,J= 2.8
Hz),4.06 (1H,s),3.94 (1H,d,J= 12.3 Hz),3.81 (1H,b
r d,J= 3.2 Hz),3.74 (1H,d,J= 12.3 Hz),3.43 (1H,d,J
= 0.6 Hz),3.21 (1H,br s),2.96 (1H,d,J= 2.8 Hz),2.7
6 (1H, br s),2.70 (1H,dd,J= 13.1 and 5.7 Hz),2.34
(1H,dd,J= 7.8 and 6.8 Hz),2.21 (1H,dd,J= 14.0and
8.1 Hz),1.83 (3H,dd,J= 1.4 and 0.8 Hz),1.78 (1H,d,
J= 14.0 Hz),1.77(1H,m),1.61 (1H,m),1.55 (1H,m),1.2
9 (3H,d,J= 6.8 Hz),1.03 (3H,d,J= 6.4Hz).13 C-核磁気共鳴スペクトル（δ ppm in CDCl3, 125 MH
z） δ：146.5 (s),136.2 (s),129.2 (d),128.0 (d),128.0
(d),126.1 (d),126.1(d),117.4 (s),111.2 (t),84.4
(s),82.7 (d),80.3 (s),79.9 (s),78.1 (d),72.8 (d),6
5.5 (t),63.9 (d),61.2 (s),48.8 (d),36.8 (d),36.5
(d),36.0(t),35.2 (d),34.4 (t),20.8 (q),19.2 (q),1
3.0 (q). Positive FAB-MS m/z : 487,105 . HR-positive FAB-MS m/z : 487.2331. Calcd for C27H
35O8 : 487.2332.The physical data of the compound represented by the following formula 21 is shown below. Properties: colorless oil. Optical rotation [α] D 27 + 0.6 ° (c = 1.32, methanol). Infrared absorption spectrum IR ν max (KBr) cm -1 : 3400 br. UV absorption spectrum UV λ max (methanol) nm (log ε): 263 (3.38), 228
sh (3.67), 203 (4.18) 1 H-nuclear magnetic resonance spectrum (δ ppm
in CDCl 3 , 500 MHz) δ: 7.74 (2H, m), 7.35 (3H, m), 5.06 (1H, dd, J = 1.4 a
nd 0.8 Hz), 4.92 (1H, t, J = 1.4 Hz), 4.50 (1H, d, J = 2.8
Hz), 4.06 (1H, s), 3.94 (1H, d, J = 12.3 Hz), 3.81 (1H, b
rd, J = 3.2 Hz), 3.74 (1H, d, J = 12.3 Hz), 3.43 (1H, d, J
= 0.6 Hz), 3.21 (1H, br s), 2.96 (1H, d, J = 2.8 Hz), 2.7
6 (1H, br s), 2.70 (1H, dd, J = 13.1 and 5.7 Hz), 2.34
(1H, dd, J = 7.8 and 6.8 Hz), 2.21 (1H, dd, J = 14.0and
8.1 Hz), 1.83 (3H, dd, J = 1.4 and 0.8 Hz), 1.78 (1H, d,
J = 14.0 Hz), 1.77 (1H, m), 1.61 (1H, m), 1.55 (1H, m), 1.2
9 (3H, d, J = 6.8 Hz), 1.03 (3H, d, J = 6.4 Hz). 13 C-nuclear magnetic resonance spectrum (δ ppm in CDCl 3 , 125 MH
z) δ: 146.5 (s), 136.2 (s), 129.2 (d), 128.0 (d), 128.0
(d), 126.1 (d), 126.1 (d), 117.4 (s), 111.2 (t), 84.4
(s), 82.7 (d), 80.3 (s), 79.9 (s), 78.1 (d), 72.8 (d), 6
5.5 (t), 63.9 (d), 61.2 (s), 48.8 (d), 36.8 (d), 36.5
(d), 36.0 (t), 35.2 (d), 34.4 (t), 20.8 (q), 19.2 (q), 1
3.0 (q). Positive FAB-MS m / z: 487,105 .HR-positive FAB-MS m / z: 487.2331. Calcd for C 27 H
35 O 8 : 487.2332.
【００８８】その他既知化合物である［Ｓｉｍｐｌｅｘ
ｉｎ］，［Ｈｕｒａｔｏｘｉｎ］，［Ｓｕｂｔｏｘｉｎ
Ａ］，［Ｙｕａｎｈｕａｃｉｎｅ］等については、
｛Ａｕｓｔ．Ｊｏｕｒｎａｌ ｏｆ Ｃｈｅｍｉｓｔｒｙ
１９７９，３２，２４９５−｝、｛Ｊ．Ｎａｔ．Ｐｒ
ｏｄ．１９８３，４６，５６３−｝、｛Ｊ．Ｎａｔ．Ｐ
ｒｏｄ．１９８４，４７，２９０−｝、｛Ａｇｒｉｃ．
Ｂｉｏｌ．Ｃｈｅｍ．１９７１，３５，１０８４−｝、
｛Ｘｕａｘｕｅ Ｘｕｅｂａｏ（化学学報）．１９７
７，３５，１０３−｝等に記載されている方法により製
造が可能である。Other known compounds [Simplex
in], [Huratoxin], [Subtoxin
A], [Yuanhuacine], etc.
{Aust. Journal of Chemistry
1979, 32, 2495-｝, {J. Nat. Pr
od. 1983, 46, 563-｝, {J. Nat. P
rod. 1984, 47, 290-｝, Agric.
Biol. Chem. 1971, 35, 1084-｝,
｛Xaxue Xuebao (Chemical Science Report). 197
7, 35, 103-｝ and the like.
【００８９】以下に本発明の化合物の試験例について記
載する。 試験例 (1)HIV-1 に対する抗ウイルス試験 10%の牛胎仔血清，100IU/mlのペニシリンG，20mg/ml の
ゲンタマイシンを含むRPMI1640培地中で、MT-4細胞 1.0
x105個に、細胞1個あたり0.02個のHIV-1を感染させ、特
許請求の範囲記載の化合物を含む検体を所定量添加し、
37℃で培養した。The test examples of the compound of the present invention are described below. Test example (1) Antiviral test against HIV-1 MT-4 cells were cultured in RPMI1640 medium containing 10% fetal calf serum, 100 IU / ml penicillin G, and 20 mg / ml gentamicin in a medium containing 1.0%.
x10 5 cells were infected with 0.02 HIV-1 per cell, and a predetermined amount of a specimen containing the compound described in the claims was added,
The cells were cultured at 37 ° C.
【００９０】培養4日後に生細胞数をMTT法により測定
し、MT-4細胞の細胞死を50%防ぐのに要する化合物濃度
（EC50: 50% effective concentration）を求めた。After 4 days of culture, the number of viable cells was measured by the MTT method, and the compound concentration (EC 50 : 50% effective concentration) required to prevent cell death of MT-4 cells by 50% was determined.
【００９１】またHIV-1を感染させずに上記と同様に培
養し、MT-4細胞の50%が死滅する化合物濃度（CC50:50%
cytotoxic concentration）を求めた。その結果は表１
に示す通りである。Further, the cells were cultured in the same manner as described above without infection with HIV-1, and the compound concentration at which 50% of MT-4 cells were killed (CC 50 : 50%
cytotoxic concentration) was determined. Table 1 shows the results.
As shown in FIG.
【００９２】[0092]
【表１】 [Table 1]
【００９３】(2)発癌プロモーター活性試験（Raji細胞
でのエプステイン−バーウイルス早期抗原検出法） Raji細胞を1.1×106個/mlの濃度で96穴プレートの10%の
牛胎仔血清、100IU/mlのペニシリン及び100mg/mlのスト
レプトマイシンを含む RPMI1640培地中に各100μlずつ
播種し、誘導物質として1mMのn-ブチル酸を添加し、適
当な濃度に希釈した本発明の化合物を加えて37℃、5%二
酸化炭素下で40-48時間培養した。 培養細胞をあらか
じめ0.006%コラーゲンでコートしたスライドグラスにス
ポットし、4%パラホルムアルデヒドで固定した。(2) Tumor Promoter Activity Test (Epstein-Barr Virus Early Antigen Detection Method in Raji Cells) Raji cells were cultured at a concentration of 1.1 × 10 6 cells / ml in a 96-well plate at 10% fetal calf serum, 100 IU / ml. 100 μl each was inoculated in RPMI1640 medium containing 100 ml / ml of penicillin and 100 mg / ml of streptomycin, 1 mM of n-butyric acid was added as an inducer, and the compound of the present invention diluted to an appropriate concentration was added at 37 ° C. The cells were cultured under 5% carbon dioxide for 40-48 hours. The cultured cells were spotted on a slide glass previously coated with 0.006% collagen, and fixed with 4% paraformaldehyde.
【００９４】次に10%ヤギ血清(in PBS buffer)で処理し
たのち一次抗体として250倍希釈した患者血清を反応さ
せ、その後二次抗体であるFITC-ラベル抗ヒトIgG(H+L)
{Ｚｙｍｅｄ社製｝で蛍光ラベルして蛍光顕微鏡下観察
した。Next, the cells were treated with 10% goat serum (in PBS buffer) and reacted with a patient antibody diluted 250-fold as a primary antibody, and then a secondary antibody, FITC-labeled anti-human IgG (H + L)
It was fluorescently labeled with {Zymed} and observed under a fluorescent microscope.
【００９５】抗原の存在が確認された最低濃度の１０分
の１の濃度を発癌プロモーター作用存在レベルとした。
発癌プロモーター作用の比較対照としてＴＰＡについて
も同様に試験を行った結果、表２に示す通りである。The concentration which was one-tenth of the lowest concentration at which the presence of the antigen was confirmed was defined as the level at which the oncogene promoter was present.
Table 2 shows the results of the same test performed on TPA as a control for comparison of the oncogenesis promoter activity.
【００９６】[0096]
【表２】 [Table 2]
【００９７】以下に本化合物の製剤例を示す。 製剤例１(錠剤) 式１７の化合物 ５０ ｍｇ 乳糖 ４６ ｍｇ トウモロコシ澱粉 ２０ ｍｇ 低置換度ヒドロキシプロピルセルロース ８ ｍｇ ヒドロキシプロピルメチルセルロース ５ ｍｇ ステアリン酸マグネシウム １ ｍｇ 計１３０ ｍｇThe preparation examples of the present compound are shown below. Formulation Example 1 (tablet) Compound of Formula 17 50 mg Lactose 46 mg Corn starch 20 mg Low-substituted hydroxypropylcellulose 8 mg Hydroxypropylmethylcellulose 5 mg Magnesium stearate 1 mg Total 130 mg
【００９８】ヒドロキシプロピルメチルセルロース及び
ステアリン酸マグネシウムを除く上記処方成分を均一に
混合した後、ヒドロキシプロピルメチルセルロース８％
（ｗ／ｗ）水溶液を結合剤として湿式造粒法にて打錠用
顆粒を製造した。これにステアリン酸マグネシウムを混
合した後、打錠機を用いて直径７ｍｍ、１錠重量１３０
ｍｇに成形し、内服錠とした。After uniformly mixing the above-mentioned ingredients except for hydroxypropylmethylcellulose and magnesium stearate, hydroxypropylmethylcellulose 8%
(W / w) Tablet granules were produced by a wet granulation method using an aqueous solution as a binder. After mixing this with magnesium stearate, the diameter was 7 mm and the weight of one tablet was 130 using a tableting machine.
mg.
【００９９】 製剤例２(細粒剤) 式１８の化合物 １００ ｍｇ 乳糖 ５３０ ｍｇ マンニトール ３２０ ｍｇ ヒドロキシプロピルセルロース ４０ ｍｇ 含水二酸化ケイ素 １０ ｍｇ 計１０００ ｍｇFormulation Example 2 (fine granules) Compound of Formula 18 100 mg Lactose 530 mg Mannitol 320 mg Hydroxypropylcellulose 40 mg Hydrous silicon dioxide 10 mg Total 1000 mg
【０１００】ヒドロキシプロピルメチルセルロースを除
く上記処方成分を均一に混合する。これにヒドロキシプ
ロピルセルロース８％（ｗ／ｗ）水溶液を結合剤として
湿式造粒を行い、細粒剤とした。The above ingredients except for hydroxypropylmethylcellulose are mixed uniformly. This was subjected to wet granulation using 8% (w / w) aqueous solution of hydroxypropylcellulose as a binder to obtain fine granules.
【０１０１】[0101]
【発明の効果】本発明に係るホルボールエステル誘導体
は極めて強い抗ＨＩＶ作用を有し、しかも毒性が弱く発
癌プロモーター作用が弱いので、医薬品として有用であ
る。Industrial Applicability The phorbol ester derivative according to the present invention has an extremely strong anti-HIV activity, and has a low toxicity and a weak carcinogenic promoter effect, and is therefore useful as a pharmaceutical.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ // Ａ６１Ｋ 35/78 Ａ６１Ｋ 35/78 Ｃ (72)発明者 馬場 昌範 鹿児島県鹿児島市皇徳寺台３−54−17 (72)発明者 池川 哲郎 千葉県千葉市美浜区幕張西１−13−２────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 6 Identification code FI // A61K 35/78 A61K 35/78 C (72) Inventor Masanori Baba 3-54-17 (72) Inventor Tetsuro Ikegawa 1-13-2 Makuhari Nishi, Mihama-ku, Chiba-shi, Chiba
Claims (12)
ンゾイル基を示す。｝により示される新規ジテルペン
類。(1) The following formula (1): Formula 1 wherein R 1 is —OCO (CH 2 ) n CH 3 (n = 1 to 7), and Bz represents a benzoyl group. New diterpenes represented by｝.
は水素原子又はアセトキシル基とする。但し、Ｒ2が-CO
(CH=CH)2(CH2)8CH3でありＲ3が水素原子である場合を除
く。｝により示される新規ジテルペン類。2. A compound represented by the following formula 2: Formula 2 {wherein R 2 is -CO (CH = CH) 2 ( CH 2) n CH 3 (n = 1~9), R 3
Represents a hydrogen atom or an acetoxyl group. Where R 2 is -CO
(CH = CH) 2 (CH 2 ) 8 Except when it is CH 3 and R 3 is a hydrogen atom. New diterpenes represented by｝.
-(CH2)6CH(OH)-又は-(CH2)7-を示し、Ｒ6はカルボニル
基又はベンゾイルオキシメチン基を示す。但し、Ｒ4が
ベンゾイル基であり、Ｒ5が-(CH2)6CH(OH)-であり、Ｒ6
がベンゾイルオキシメチン基である場合を除く。｝によ
り示される新規ジテルペン類。(3) The following formula (3): Formula 3 wherein R 4 represents an acetyl group or a benzoyl group, and R 5 represents
— (CH 2 ) 6 CH (OH) — or — (CH 2 ) 7 —, and R 6 represents a carbonyl group or a benzoyloxymethine group. Provided that R 4 is a benzoyl group, R 5 is — (CH 2 ) 6 CH (OH) —, and R 6 is
Is a benzoyloxymethine group. New diterpenes represented by｝.
を示す。但し、Ｒ7が-CO(CH=CH)2(CH2)4CH3である場合
を除く。｝により示される新規ジテルペン類。4. A compound represented by the following formula 4: Formula 4 wherein R 7 is —CO (CH = CH) m 1 (CH 2 ) n 1 CH 3 {m 1 = 0 to 2, n 1 = 1 to 4}
Is shown. However, this excludes the case where R 7 is —CO (CH = CH) 2 (CH 2 ) 4 CH 3 . New diterpenes represented by｝.
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ9は、置換もしくは無置換のフェニル
基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(CH=
CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示す。｝により
示される新規ジテルペン類。5. The following formula 5 Formula 5 wherein R 8 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 9 is a substituted or unsubstituted phenyl group, — (CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0 to 3, n 4 = 0 to 8} or-(CH =
CH) m 5 (CH 2) n 5 C 6 H 5 {m 5 = 0~3, n 5 = 0~8} indicating the. New diterpenes represented by｝.
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ11は、置換もしくは無置換のフェニ
ル基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(C
H=CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示す。｝によ
り示される新規ジテルペン類。6. The following formula 6: Formula 6 wherein R 10 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 11 is a substituted or unsubstituted phenyl group,-(CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0-3, n 4 = 0- 8} or-(C
H = CH) m 5 (CH 2) n 5 C 6 H 5 {m 5 = 0~3, n 5 = 0~8} indicating the. New diterpenes represented by｝.
類及びその医薬的に可能な塩を有効成分とする抗ウイル
ス剤。7. An antiviral agent comprising the novel diterpenes according to claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient.
類及びその医薬的に可能な塩を有効成分とする抗ＨＩＶ
剤。8. An anti-HIV comprising the novel diterpenes according to claim 1 and a pharmaceutically acceptable salt thereof as an active ingredient.
Agent.
ホルボールアセテート（以下ＴＰＡと略す）の１０分の
１以下であるジテルペン類及びその医薬的に可能な塩を
有効成分とする抗ＨＩＶ剤。9. An anti-HIV agent comprising, as an active ingredient, a diterpene having a carcinogenesis promoter activity of 1/10 or less of tetradecanoylphorbol acetate (hereinafter abbreviated as TPA) and a pharmaceutically acceptable salt thereof.
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ13は、置換もしくは無置換のフェニ
ル基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(C
H=CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示し、Ｒ14〜
Ｒ16は、水酸基，置換もしくは無置換のベンゾイルオキ
シ基，-OCO(CH=CH)m6(CH2)n6CH3{m6=0〜3,n6=0〜8}又は
-OCO(CH=CH)m7(CH2)n7C6H5{m7=0〜3,n7=0〜8}を示
す。｝により示されるジテルペン類及びその医薬的に可
能な塩を有効成分とする抗ウイルス剤。10. The following formula 7 Formula 7 wherein R 12 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 13 represents a substituted or unsubstituted phenyl group, — (CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0 to 3, n 4 = 0 to 8} or-(C
H = CH) m 5 (CH 2 ) n 5 C 6 H 5 {m 5 = 0 to 3, n 5 = 0 to 8}, and R 14 to
R 16 is a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 6 (CH 2 ) n 6 CH 3 {m 6 = 0-3, n 6 = 0-8} or
-OCO (CH = CH) m 7 (CH 2 ) n 7 C 6 H 5 {m 7 = 0 to 3, n 7 = 0 to 8}. An antiviral agent comprising, as an active ingredient, a diterpene represented by｝ and a pharmaceutically acceptable salt thereof.
のベンゾイルオキシ基，-OCO(CH=CH)m2(CH2)n2CH3{m2=0
〜3,n2=0〜8}又は-OCO(CH=CH)m3(CH2)n3C6H5{m3=0〜3,n
3=0〜8}を示し、Ｒ18は、置換もしくは無置換のフェニ
ル基，-(CH=CH)m4(CH2)n4CH3{m4=0〜3,n4=0〜8}又は-(C
H=CH)m5(CH2)n5C6H5{m5=0〜3,n5=0〜8}を示し、Ｒ19〜
Ｒ22は、水酸基，置換もしくは無置換のベンゾイルオキ
シ基，-OCO(CH=CH)m6(CH2)n6CH3{m6=0〜3,n6=0〜8}又は
-OCO(CH=CH)m7(CH2)n7C6H5{m7=0〜3,n7=0〜8}を示
す。｝により示されるジテルペン類及びその医薬的に可
能な塩を有効成分とする抗ウイルス剤。11. The following formula 8: Formula 8 wherein R 17 is a hydrogen atom, a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 2 (CH 2 ) n 2 CH 3 {m 2 = 0
~ 3, n 2 = 0 ~ 8} or -OCO (CH = CH) m 3 (CH 2 ) n 3 C 6 H 5 (m 3 = 0 ~ 3, n
3 = 0 to 8}, and R 18 represents a substituted or unsubstituted phenyl group, — (CH = CH) m 4 (CH 2 ) n 4 CH 3 {m 4 = 0 to 3, n 4 = 0 to 8} or-(C
H = CH) m 5 (CH 2 ) n 5 C 6 H 5 {m 5 = 0 to 3, n 5 = 0 to 8}, and R 19 to
R 22 represents a hydroxyl group, a substituted or unsubstituted benzoyloxy group, —OCO (CH = CH) m 6 (CH 2 ) n 6 CH 3 {m 6 = 0-3, n 6 = 0-8} or
-OCO (CH = CH) m 7 (CH 2 ) n 7 C 6 H 5 {m 7 = 0 to 3, n 7 = 0 to 8}. An antiviral agent comprising, as an active ingredient, a diterpene represented by｝ and a pharmaceutically acceptable salt thereof.
及びその医薬的に可能な塩を有効成分とする抗ＨＩＶ
剤。12. An anti-HIV comprising the diterpene according to claim 10 or 11 and a pharmaceutically acceptable salt thereof as an active ingredient.
Agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9098654A JPH10287617A (en) | 1997-04-16 | 1997-04-16 | New diterpenes and antivirus agent containing diterpenes as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9098654A JPH10287617A (en) | 1997-04-16 | 1997-04-16 | New diterpenes and antivirus agent containing diterpenes as active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH10287617A true JPH10287617A (en) | 1998-10-27 |
Family
ID=14225505
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP9098654A Pending JPH10287617A (en) | 1997-04-16 | 1997-04-16 | New diterpenes and antivirus agent containing diterpenes as active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH10287617A (en) |
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| WO2001082927A1 (en) * | 2000-05-02 | 2001-11-08 | Lead Chemical Co., Ltd | Antibiral compositions containing phorbol derivatives as the main active ingredient |
| KR20030069232A (en) * | 2002-02-04 | 2003-08-27 | 주식회사 팜트리 | Diterpene derivatives and anti-inflammatory analgestic agents comprising the same |
| WO2011055979A3 (en) * | 2009-11-03 | 2011-09-29 | 한국생명공학연구원 | Antiviral composition containing an aleurites fordii or daphne kiusiana extract or a fraction thereof as an active ingredient |
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| WO2022186391A1 (en) * | 2021-03-04 | 2022-09-09 | 国立大学法人 熊本大学 | Therapeutic agent for hiv infection |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001082927A1 (en) * | 2000-05-02 | 2001-11-08 | Lead Chemical Co., Ltd | Antibiral compositions containing phorbol derivatives as the main active ingredient |
| KR20030069232A (en) * | 2002-02-04 | 2003-08-27 | 주식회사 팜트리 | Diterpene derivatives and anti-inflammatory analgestic agents comprising the same |
| KR101425048B1 (en) * | 2009-11-03 | 2014-08-04 | 한국생명공학연구원 | A composition for anti-virus comprising the extract or fraction of Daphne kiusiana as an effective ingredient |
| WO2011055979A3 (en) * | 2009-11-03 | 2011-09-29 | 한국생명공학연구원 | Antiviral composition containing an aleurites fordii or daphne kiusiana extract or a fraction thereof as an active ingredient |
| AU2010316120B2 (en) * | 2009-11-03 | 2013-11-21 | Korea Research Institute Of Bioscience And Biotechnology | Antiviral composition containing an Aleurites fordii or Daphne kiusiana extract or a fraction thereof as an active ingredient |
| US9375456B2 (en) | 2009-11-03 | 2016-06-28 | Korea Research Institute Of Bioscience And Biotechnology | Antiviral composition containing an Aleurites fordii or Daphne kiusiana extract or a fraction thereof as an active ingredient |
| WO2013062247A3 (en) * | 2011-10-26 | 2013-06-20 | 한국생명공학연구원 | Phorbol type diterpene compound, pharmaceutical composition for treatment or prevention of viral infectious diseases including same |
| CN104011009A (en) * | 2011-10-26 | 2014-08-27 | 韩国生命工学研究院 | Diterpene compound, pharmaceutical composition for treatment or prevention of viral infectious diseases including same |
| US9174925B2 (en) | 2011-10-26 | 2015-11-03 | Korea Research Institute Of Bioscience And Biotechnology | Phorbol type diterpene compound, pharmaceutical composition for treatment or prevention of viral infectious diseases including same |
| KR101374760B1 (en) * | 2011-10-26 | 2014-03-17 | 한국생명공학연구원 | Phorbol type diterpene compound and a pharmaceutical composition for treatment and prevention of virus infection comprising the same |
| CN105287497A (en) * | 2014-06-30 | 2016-02-03 | 复旦大学 | Application of daphnetoxin diterpene in preparing anti-HIV drug |
| CN110540506A (en) * | 2018-05-29 | 2019-12-06 | 复旦大学 | Preparation method of stellera chamaejasme total diterpene and application thereof in pharmacy |
| CN110317209A (en) * | 2019-07-31 | 2019-10-11 | 山西大学 | Diterpene-kind compound wikstroelide E and the application in the drug that latent HIV virus is removed in preparation |
| WO2022186391A1 (en) * | 2021-03-04 | 2022-09-09 | 国立大学法人 熊本大学 | Therapeutic agent for hiv infection |
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